ISSN:0003-2654    

DOI:10.1039/AN99520BP038

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

’” Ana I y s tThe Analytical Journal of The Royal Society of ChemistryAnalytical Editorial BoardChairman: J. N. Miller (Loughborough, UK)M. Cooke (Sheffield, UK)C. S. Creaser (Nottingham, UK)A. G. Davies (London, UK)A. G. Fogg (Loughborough, UK)J. M. Gordon (Cambridge, UK)G. M. Greenway (Hull, UK)S. J. Hill (Plymouth, UK)D. L. Miles (Keyworth, UK)R. M. Miller (Gouda, The Netherlands)B. L. Sharp (Loughborough, UK)M. R. Smyth (Dublin, Ireland)Y. Thomassen (Oslo, Norway)P. Vadgama (Manchester, UK)Advisory BoardJ. F. Alder (Manchester, UK)A. M. Bond (Victoria, Australia)J. G. Dorsey (Cincinnati, OH, USA)L. E bdm (Plymouth, UK)A. F. Fell (Bradford, UK)J. P. Foley (Villanova, PA, USA)M. F. Gine (Sao Paulo, Brazil)T. P. Hadjiioannou (Athens, Greece)W.R. Heineman (Cincinnati, OH, USA)A. Hulanicki (Warsaw, Poland)I. Karube (Yokohama, Japan)E. J. Newman (Poole, UK)J. Pawliszyn (Waterloo, Canada)T. B. Pierce (Harwell, UK)E. Pungor (Budapest, Hungary)J. RSiiEka (Seattle, WA, USA)R. M. Smith (Loughborough, UK)K. Stulik (Prague, Czechoslovakia)J. D. R. Thomas (Cardiff, UK)J. M. Thompson (Birmingham, UK)K. C. Thompson (Sheffield, UK)P. C. Uden (Amherst, MA, USA)A. M. Ure (Aberdeen, UK)C. M. G. van den Berg (Liverpool, UK)A. Walsh, KB (Melbourne, Australia)J. Wang (Las Cruces, NM, USA)T. S. West (Aberdeen, UK)Regional Advisory EditorsFor advice and help to authors outside the UKProfessor Dr. U. A. Th. Brinkman, Free University of Amsterdam, 1083 de Boelelaan, 1081 HVAmsterdam, THE NETHERLANDS.Professor P.R. Coulet, Laboratoire de Genie Enzymatique, EP 19 CNRS-Universite ClaudeBernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex,FRANCE.Professor 0. Osibanjo, Department of Chemistry, University of Ibadan, Ibadan, NIGERIA.Professor F. Palmisano, Universita Degli Studi-Bari, Departimento di Chimica Campus,Professor K. Saito, Coordination Chemistry Laboratories, Institute for Molecular Science,Professor M. Thompson, Department of Chemistry, University of Toronto, 80 St. GeorgeProfessor Dr. M. Valchrcel, Departamento de Quimica Analitica, Facultad de Ciencias,Professor J. F. van Staden, Department of Chemistry, University of Pretoria, Pretoria 0002,Professor Yu Ru-Qin, Department of Chemistry and Chemical Engineering, Hunan University,Professor Yu.A. Zolotov, Kurnakov Institute of General and Inorganic Chemistry, 31 LeninUniversitario, 4 Trav. 200 Re David-70126 Bari, ITALY.Myodaiji, Okazaki 444, JAPAN.Street, Toronto, Ontario, CANADA M5S 1Al.Universidad de Cordoba, 14005 C6rdoba, SPAIN.SOUTH AFRICA.Changsha, PEOPLES REPUBLIC OF CHINA.Avenue, 117907, Moscow V-71, RUSSIA.Editorial Manager, Analytical Journals: Janice M. GordonEditor, The AnalystHarpal S. MinhasThe Royal Society of Chemistry,Thomas Graham House, Science Park,Milton Road, Cambridge, UK CB4 4WFFax +44(0)1223 420247.E-Mail :Analyst@RSC.ORG(lnternet)Senior Assistant Editor Assistant EditorsCaroline SeeleyUS Associate Editor, The AnalystDr Julian F.TysonDepartment of Chemistry,University of Massachusetts,Box 3451 0 Amherst MATelephone +1 413 545 0195Fax +1 413 545 4846Sarah Williams, Yasmin KhanTelephone +44(0)1223 420066. 01 003-451 0, USAEditorial Secretaries: CI a i re Harris, Frances Tho mso nAdvertisements: Advertisement Department, The Royal Society of Chemistry, BurlingtonHouse, Piccadilly, London, UK WIV OBN. Telephone +44(0)171-287 3091.Fax +44(0)171-494 1134.Information for AuthorsFull details of how to submit material forpublication in The Analyst are given in theInstructions to Authors in the January issue.Separate copies are available on request.The Analyst publishes original researchpapers, critical reviews, tutorial reviews,perspectives, news articles, book reviewsand a conference diary.Original research papers.The Analyst pub-lishes full papers on all aspects of the theoryand practice of analytical chemistry, funda-mental and applied, inorganic and organic,including chemical, physical, biochemical,clinical, pharmaceutical, biological, environ-mental, automatic and computer-basedmethods. Papers on new approaches toexisting methods, new techniques andinstrumentation, detectors and sensors, andnew areas of application with due attentionto overcoming limitations and to underlyingprinciples are all equally welcome.Full critical reviews. These must be acritical evaluation of the existing state ofknowledge on a particular facet of analyticalchemistry.Tutorial reviews.These should be infor-mally written although they should still be acritical evaluation of a specific topic area.Some history and possible future develop-ments should be given. Potential authorsshould contact the Editor before writingreviews.Perspectives. These articles shouldprovide either a personal view or a philoso-phical look at a topic relevant to analyticalscience. Alternatively, they may be relevanthistorical articles. Perspectives are includedat the discretion of the Editor.Particular attention should be paid to theuse of standard methods of literaturecitation, i ncl ud i ng the jou rna I abbreviationsdefined in Chemical Abstracts ServiceSource Index. Wherever possible, thenomenclature employed should followIUPAC recommendations, and units andsymbols should be those associated with SI.Every paper will be submitted to at leasttwo referees, by whose advice the EditorialBoard of The Analyst will be guided as to itsacceptance or rejection.Papers that areaccepted must not be published elsewhereexcept by permission. Submission of amanuscript will be regarded as an under-taking that the same material is not beingconsidered for publication by anotherjournal.Regional Advisory Editors. For the benefitof potential contributors outside the UK andN. America, a Group of Regional AdvisoryEditors exists. Requests for help or advice onmatters related to the preparation of papersand their submission for publication in TheAnalystcan be sent to the nearest member ofthe Group.Currently serving RegionalAdvisory Editors are listed in each issue ofThe Analyst.Manuscripts (four copies typed in doublespacing) should be addressed to:H. S. Minhas, Editor, orJ. F. Tyson, US Associate EditorAll queries relating to the presentation andsubmission of papers, and any correspon-dence regarding accepted papers andproofs, should be directed either to theEditor, or Associate Editor, The Analyst.Members of the Analytical Editorial Board(who may be contacted directly or via theEditorial Office) would welcome comments,suggestions and advice on general policymatters concerning The Analyst.There is no page charge.Fifty reprints are supplied free of charge.The Analyst (ISSN 0003-2654) is published monthly by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road,Cambridge, UK CB4 4WF.All orders, accompanied with payment by cheque in sterling, payable on a UK clearing bank or in US dollars payableon a US clearing bank, should be sent directly to The Royal Society of Chemistry, Turpin Distribution Services Ltd., Blackhorse Road,Letchworth, Herts, UK SG6 1 HN. Turpin Distribution Services Ltd., is wholly owned by the Royal Society of Chemistry. 1995 Annual subscriptionrate EC f408.00, USA $749.00, Canada f428.00 (excl. GST), Rest of World f428.00. Purchased with Analytical Abstracts EC f807.00, USA$1472.00, Canada f841 .OO (excl. GST), Rest of World f841 .OO. Purchased with Analytical Abstracts plus Analytical Proceedings EC f925.00, USA$1699.00, Canada f971 .OO (excl. GST), Rest of World f971 .OO. Purchased with Analytical Proceedings EC f492.00, USA $905.00, Canada f517.00(excl. GST), Rest of World f517.00. Airfreight and mailing in the USA by Publications Expediting Inc., 200 Meacham Avenue, Elmont, NY 11003.USA Postmaster: Send address changes to: The Analyst, Publications Expediting Inc., 200 Meacham Avenue, Elmont, NY 11003. Second classpostage paid at Jamaica, NY 11431. All other despatches outside the UK by Bulk Airmail within Europe, Accelerated Surface Post outsideEurope. PRINTED IN THE UK.@ The Royal Society of Chemistry, 1995. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, ortransmitted in any form, or by any means, electronic, mechanical, photographic, recording, or otherwise, without the prior permission of thepublishers

ISSN:0003-2654    

DOI:10.1039/AN99520FX046

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

ANALAO 120( 10) 2435-2654, 131 N-l38N (1 995) OCTOBER 1995I IllREV I EW 2435SEPARATION SC I EN C E2461246924752479248324892493ATOMIC SPECTROSCOPY249725052509251 3252 1MOLECULAR/SPECTROSCOPY2529253725432549CHEMOMETRlCSlSTAT I ST I CS25532561'""An al y stThe analytical journal of The Royal Society of ChemistryCONTENTSAnalysis of Organic Polymorphs-Terence L. ThrelfallUnified Chromatograph for Gas Chromatography, Supercritical Fluid Chromatography and Micro-liquidChromatography-Daixin Tong, Keith D. Bartle, Anthony A. Clifford, Robert E. RobinsonFast Determination of Sulfate by Ion Chromatography Based on a Permanently Coated Column-Xiao Jun,Jose L. F. C. Lima, M. Conceiqao B. S. M. MontenegroSimple and Rapid Method for Simultaneous Gas Chromatographic Determination of Bitertanol, Metalaxyl,Oxadixyl, Propiconazole, and Triadimefon Residues in Cucumbers-Wai-on Lee, Siu-kay WongDetermination of Carbosulfan in Oranges by High-performance Liquid Chromatography With Post-columnFluorescence-M.W. Brooks, A. BarrosDetermination of Benzoic and Sorbic Acids in Packaged Vegetable Products. Comparative Evaluation ofMethods-Alfred0 Montatio, Antonio H. Sanchez, Luis RejanoDetermination of Vitamins A, E and K, in Milk by High-performance Liquid Chromatography With DualAmperometric Detection-M. M. Delgado Zamarretio, A. Sanchez Perez, M. C. Gomez Perez, M. A.Fernandez Moro, J. Hernandez MendezSimultaneous Determination of Rufloxacin and Theophylline by High-performance Liquid Chromatographyin Human Plasma-Giuseppe Carlucci, Pietro Mazzeo, Giancarlo PalumboRational Design of Linear Calibration Experiments for the Quantitative Estimation of Chlorophyll a UsingHigh-performance Liquid Chromatography, Atomic Absorption Spectrometry and Electronic AbsorptionSpectrometry-Pedro W.Araujo, Richard G. BreretonAtomic Absorption Spectrometry and Polarographic Determination of the Copper(i)/Copper(ii) Ratio inBorate Glass-Nagwa Nawar, Abdel Monem El-Askalany, Mohamed M. El-DefrawySynthesis, Characterization and Metal Sorption Studies of a Chelating Resin Functionalized WithN-Hydroxyethylethylenediamine Ligands-Kapil Dev, G. N. RaoMechanized Method for Measuring Metal Partition in n-Octanol-Aqueous Systems. Partition of AluminiumComplexes-Lars-Goran Danielsson, Yu-Hui Zhang, Anders SparenAnalytical Procedures on Multi-element Determinations of Airborne Particles for Receptor Model Use-C.F.Wang, E. E. Chang, P. C. Chiang, N. K. ArasCarbon Dioxide Recognition by Rhodium(!) Complexes Studied by Infrared and Nuclear MagneticResonance Spectroscopies and Acoustic Wave Sensor-P. C. H. Li, M. ThompsonUrban Air Pollution Monitoring: Laser-based Procedure for the Detection of N0,Gases-W. X. Peng, K. W.D. Ledingham, A. Marshall, R. P. SinghalElectrogenerated Chemiluminescent Determination of Pyruvate UsingTris(2,2'-bipyridine)rutheniurn(ii)-Andrew W. Knight, Gillian M. GreenwayElectrogenerated Chemiluminescent Determination of Codeine and Related Alkaloids and PharmaceuticalsWith Tris(2,2'-bipyridine)ruthenium(11)-Gillian M.Greenway, Andrew W. Knight, Paul J. KnightSelf-modelling Curve Resolution Analysis of Synchronous Fluorescence Spectroscopy Data forCharacterization of Acid Mixtures and Study of Acid-Base Equilibria-Joaquim C. G. Esteves da Silva,Adelio A. S. C. MachadoQuantitative Determination of Aroma Components in Wine by Sorbent Extraction: Improvement andChemometric Evaluation-lvo MoretContinued on inside back cover-Typeset and printed by Black Bear Press Limited,Cambridge, Englan25672573SENSORS/ELECTRODES257925852589FLOW METHODS259326012605261 3OTHER TECHNIQUES261 72623262726352639264326492651Simultaneous Kinetic Spectrophotometric Determination of 2-Furfuraldehyde and5-Hydroxymethyl-2-furfuraldehyde by Application of a Modified Winkler’s Method and Partial Least SquaresCalibration-Isabel Duran Meras, Anunciacidn Espinosa Mansilla, Francisco Salinas LopezStudy on a Modified Algorithm-Iterative Kalman Filter and Its Application in Enzymic Kinetics-DezhongLiu, Huwei Tan, Lili Bao, Lihua Nie, Shouzhuo YaoIndium-Tin Oxide Film Electrode as Catalytic Amperometric Sensor for Hydrogen Peroxide-Xiaohua Cai,Bofidar Ogorevc, Gabrijela TavCar, Joseph WangDetermination of Europium With Solid-surface Room-temperature PhosphorescenceOptosensing-Jianzhong Lu, Zhujun ZhangDevelopment of a Flow Fluoroimmunosensor for Determination of Theophylline-Carlos M.Rico, M. delPilar Fernandez, Ana M. Gutierrez, M.Concepcion Perez Conde, Carmen CamaraAutomatic Determination of Optimum Dilution Levels for Laser-enhanced Ionization Detection ofMatrix-interfered Sample by Flow Injection-Shau-Chun Wang, King-Chuen LinFlow Injection Spectrophotometric Determination of Silicate Based on the Formation of the Ion AssociateBetween Molybdosilicate and Malachite Green-J. Saurina, S. Hernandez-CassouAdsorption-Concentration of Ion Associate Formed Between Molybdosilicate and Malachite Green on aMiniature Filter: Its Application to Trace and Ultratrace Determination of Silicate-Joko P. Susanto, MitsukoOshima, Shoji MotomizuDetermination of Inorganic Phosphate by Flow Injection With Fluorescence Quenching-Elena Diacu,Pinelopi C. loannou, Christoforos K. Polydorou, Constantinos E.EfstathiouSupercritical Fluid Extraction Coupled With Enzyme lmmunoassay Analysis of Soil Herbicides-G. KimStearman, Martha J. M. Wells, Scott M. Adkisson, Tadd E. RidgillDetermination of Sulfadoxine Concentrations in Whole Blood Using CI8 Solid-phase Extraction, SodiumDodecyl Sulfate and Dimethylaminocinnamaldehyde-Michael D. Green, Dwight L. Mount, G. Daniel ToddKinetic Study on the Degradation of lndomethacin in Alkaline Aqueous Solutions by Derivative UltravioletSpectrophotometry-Helen A. ArchontakiProcess Monitor for an Ammoniacal Nickel Solution Employing an Infrared Light-emitting Diode and aLog-ratio Amplifier-Peter C. Hauser, Thusitha W. T. Rupasinghe, Cheryl C. Lucas, Alex McClureNew Tautomerism Suggested by pK, Determinations-Hugues-Olivier Bertrand, Marie-Odile Christen,Jean-Louis BurgotCadmium, Copper and Zinc Complexes of Poly-L-cysteine-Holly A. Autry, James A. HolcombeERRATUMCUMULATIVE AUTHOR INDEXNEWS AND VIEWS 131N Conference Diary136N Courses137N Papers in Future Issues138N List of Abbreviations and AcronymsCover picture: Photomicrograph showing the liquid- and solid-state conversion of two polymorphs (seep. 2435) of potassium nitrate. Kindly supplied by G. Nichols, Pfizer Central Research, Sandwich, Kent

ISSN:0003-2654    

DOI:10.1039/AN99520BX048

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Analyst, October 1995, Vol. 120 13 IN Conference Diary Date Conference 1995 November 1-3 5-10 5-10 8-9 12-17 14-15 14-16 14-16 20-24 22 22-25 27-1/12 27-1/12 29-2/12 12th LC-MS Montreux Symposium 1st Mediterranean Basin Conference on Analytical Chemistry OPTCON '95 Biological Applications of Inorganic Mass Spectrometry 1995 Eastern Analytical Symposium International Conference for Chemical Information Users Nordic Polymer Meeting KEMIA 95 International Conference on Ultrafast Processes in Spectroscopy Analytical Challenges in Mass Spectrometry International Conference on Electron Spin Resonance in Electron Transfer and Organic Solids 7th Italian-Hungarian Symposium on Spectrochemistry Materials Research Society 3rd International Conference on Scientific Optical Imaging December 4-5 Quality Assurance for Analytical 4-5 ChemiChromics '95 Laboratories: How to Prepare Testimony Location Hilton Head Island, USA Cordoba, Spain San Jose, USA Nonvich, UK Somerset, USA Manchester, UK Helsinki, Finland Helsinki, Finland Trieste, Italy Coventry, UK Dresden, Germany Rome, Italy Boston, USA Georgetown, Grand Cayman Islands B a1 timore, USA Manchester, UK Contact Shirley E.Schlessinger, LC-MS '95, Suite 1015, 400 E. Randolph Dr., Chicago, IL 60601 Tel: +1312 527 2011. Professor Alfredo Sanz-Medel, Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, C/Julian Claveria, no. 8 33006 Oviedo, Spain Tel: +34 85 10 34 74. Fax: +34 85 10 31 25 Meetings Department, Optical Society of America, 2010 Massachusetts Avenue, NW, Washington, DC Tel: +1 202 223 9034.Fax: +1 202 416 6100 Ms. Helen Phipps, Institute of Food Research, Norwich Laboratory, Nonvich Research Park, Colney, Norwich, UK NR4 7UA Tel: +44 (0) 1603 255219. Fax: +44 (0) 1603 255168 EAS, P.O. Box 633, Montchanin, DE 19710-0633 Tel: +1302 738 6218. Fax: +1302 738 5275 Dr. M. P. Coward, Chemistry Department, UMIST, P.O. Box 88, Manchester, UK M60 1QD Tel: +44 (0)161 200 4491. Fax: +44 (0)161 228 1250 Dr. Matti Elomaa, Laboratory of Polymer Chemistry, P.O. Box 55, FIN-00014 University of Helsinki Tel: +358 0 191 40338. Fax: +358 0 191 40330 Ms. Ritva Becker, Exhibition Manager, P.O. Box 21, FIN-00521 Helsinki, Finland Tel: +358 0 150 9211. Fax: +358 0 142 358 G. Denardo, International Centre for Theoretical Physics, Strada Costiera 11, P.O.Box 586,I-34100 Trieste, Italy R. N. Ibbett, Courtaulds Research and Technology, P.O. Box 11 1, Lockhurst Lane, Coventry, UK CV6 5RS Dr. L. Dunsch, Institut fur Festkorperforschung im IFW Dresden eV., Helmholtzstrasse 20, D-01069 Dresden, Germany S. Caroli, Laboratorio di Tossicologia Applicata, Istituto Superiore de Sanita, Viale Regina Elena, 229, 1-00161 Rome, Italy Tel: +39 6 4990 2366. Materials Research Society, 9800 McKnight Road, Pittsburgh, PA 15237-6006 Tel: +1412 367 3003. Fax: +1412 367 4373 M. Bonner Denton, Department of Chemistry, University of Arizona, Tucson, AZ 85721 Tel: +1520 621 8246. Fax: +1520 621 8272. E-mail: mbdention@ ccit. arizona.edu 20036-1023, USA E-mail: infor@ aoac.org Spring Innovations, 216 Moss Lane, Bramhall, Stockport, Cheshire, UK, SK7 IBD Tel: +44 (0)161 440 0082.Fax: +44 (0)161 440 9127132N Analyst, October, 199.5, Vol. 120 Date Conference Location Contact 13-14 BMSS 2nd LC-MS Symposium Cambridge, UK Dr. J. Oxford, Glaxo Research and Development Ltd., Park Road, Ware, Hertfordshire, UK SG12 ODJ 17-22 International Symposium on Environmental Hawaii, K. S. Subramanian, Environmental Health Biomonitoring and Specimen Banking USA Directorate, Health Canada, Tunney 's Pasture, Ottawa, Ontario, Canada KIA OL2 Tel: +1 613 957 1874. Fax: +I 613 941 4545 1996 January 8-13 1996 Winter Conference on Plasma Spectrometry 10-13 Environmental Science Florida, USA Trivandrum, India 20-23 8th Sanibel Conference on Mass Spectrometry Sanibel Island, 21-25 VIth Latin American Congress on Caracas, 21-25 HPCE '96 Orlando, USA Chromatography Venezuela USA February 4-7 5-8 7-9 20-2 I The Fifth International Congress on Trace Elements in Medicine and Biololgy: Therapeutic Uses of Trace Elements Second International Symposium on Modern Principles of Air Monitoring Fourth International Symposium on Hyphenated Techniques in Chromatography (HTC 4); Hyphenated Chromatographic Anal y sers Inbio '96: Industrial Biocatalysis March 3-8 47th Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy 19-23 International Solvent Extraction Conference 1996 (ISEC '96) 24-28 29th International Meeting of the ESRDG of the RSC: ESR Spectroscopy of Inorganic Radicals and Metal Ions in Inorganic and Biological Systems ESEAC '96,6th European Conference on ElectroAnal ysis 25-29 Meribel, France Salen, Sweden Bruges, Belgium Manchester, UK Chicago, USA Melbourne, Australia Edinburgh, UK Durham, UK R.Barnes, Department of Chemistry, Lederle GRC Tower, University of Massachusettes, P.O. Box 34510, Amherst, MA 01003-4510, USA Tel: +1 413 545 2294. Fax: +1 413 545 4490 Dr. C. S. P. Iyer, Convener, ICES-96, Regional Research Laboratory (CSIR), Trivandrum-695 019, India Tel: +91 471 77459. Fax: +91 471 75186. E-mail: nit@ sirnetm.emet .in ASMS, 1201 Don Diego Ave., Santa Fe, NM 87505 Tel: +1505 989 4517. Fax: +1505 989 1073 Irene Romero, Interep SA, P.O. Box 76343, Caracas 1070-A, Venezuela Shirley E. Schlessinger, Symposium Manager, HPCE '96, Suite 1015, 400 East Randolph Drive, Chicago, IL 60601, USA Tel: +1 312 527 2011.Arlette Alcaraz, Chrug H8pital A. Michallon, Biochimie C, BP 217, F-38043 Grenoble Cedex 9, France Tel: +33 767 65484. Fax: +33 767 65664 Pirjo Turtiainen, NIVA, Topeliuksenkatu 41 aA, FIN-00250 Helsinki, Finland Tel: +358 0 4747349. Fax: +358 0 4747497. E-mail: pirjo. turtianen@ occupheath.fi Dr. R. Smits, Royal Flemish Chemical Society (KVCV), Working Party on Chromatography, BASF Antwerpen N.V., Central Laboratory, Haven 725, Scheldelaan 600, B-2040 Antwerp, Belgium Tel: +32 3 561 2831. Fax: +32 3 561 3250 Spring Innovations, 216 Moss Lane, Bramhall, Stockport, Cheshire, UK, SK7 1BD Tel: +44 (0)161 440 0082. Fax: +44 (0)161 440 9127 The Pittsburgh Conference, 300 Penn Center Boulevard, Suite 332, Pittsburgh, PA 15235-5503, USA Dr.R. W. Cattrall, Secretary Organising Committee, ISEC '96, School of Chemistry, La Trobe University, Bundoora 3083, Victoria, Australia Tel: +61 3 9479 2539. Fax: +61 3 9479 1399. E-mail: r.w.c.@latrobe.edu.au Dr. C. C. Rowlands, Department of Chemistry, University of Wales Cardiff, P.O. Box 912, Cardiff, UK CF1 3TB Dr. A. G. Fogg, Loughborough University of Technology, Loughborough, Leicestershire, UK LE 11 3TU Tel: +44 (0) 1509 263171. Fax: +44 (0) 1509 233163Analyst, October 1995, Vol. 120 133N Date 3 1 4 4 April 9-10 9-12 9-12 17-19 23-26 28-1/5 May 5-8 6-8 6-10 13-14 19-22 19-24 20-22 Conference Location 7th International Symposium on Supercritical Indianapolis, Fluid Chromatography and Extraction USA 1996 Northeastern Environmental Symposium East Rutherford, 26th International Symposium on Environmental Analytical Chemistry Scanning '96 VIIth International Symposium on Luminescence Spectrometry in Biomedical Analysis-Detection Techniques and Applications in Chromatography and Capillary Electrophoresis Analytica Conference '96 87th AOCS Annual Meeting and Expo International Colloquium on Process Related Analytical Chemistry in Environmental Investigations EuroResidue 111, Third International Conference on Residues of Veterinary Drugs in Food 2nd European Symposium and Exhibition on Photonics in Manufacturing I1 Chiral USA '96 4th International Symposium on Metal Ions in Biology and Medicine 9th International Symposium on Trace Elements in Man and Animals Symposium on Dairy Quality Assurance USA Vienna, Austria Monterey, USA Nice, France Munich, Germany Indianapolis, USA Gramado, Brazil Veldhoven, The Netherlands Paris, France Boston, USA Barcelona, Spain Banff, Canada Sonthofen, Germany Contact Mrs.Janet Cunningham, Barr Enterprises, 10120 Kelly Road, P.O. Box 279, Walkersville, MD 21793 USA Tel: +1 301 898 3772. Fax: +1 301 898 5596 Sandy Galla, ISC Exhibit Management Co., P.O. Box 313, Shelton, CT 06484-0313 Tel: +1203 926 9300. Fax: +1203 926 9722 Professor Dr. M. Grasserbauer, Institute for Analytical Chemistry, Vienna University of Technology, Getreidemarkt 9/15 1, A- 1060 Wien, Austria Fax: +43 1 5867813 Mary K. Sullivan, Foundation for Advances in Medicine and Science, P.O. Box 832, Mahwah, NJ Tel: +1 201 818 1010. Fax: +1 201 818 0086. E-mail: fams@holonet.net Professor Willy R.G. Baeyens, University of Ghent, Pharmaceutical Institute, Department of Pharmaceutical Analysis, Harelbekestraat 72, B-9000 Ghent, Belgium Tel: +32 9 221 8951. Fax: +32 9 221 4175 Congress Center, Messegelande, D-80325 Munchen, Germany Tel: +49 89 5107 159. Fax: +49 89 5107 180 AOCS Education/Meetings Department, P.O. Box 3489, Champaign, IL, USA 61 826-3489 Tel: +1 217 359 2344. Fax: +I 217 351 8091 07430-0832, USA Centro de Ecologia, Universidade Federal do Rio Grande do Sul, C.P. 15007, 91501-970 Port0 Alegre, Brazil Tel: +55 51 2281 633. Fax: +55 51 3361 568. E-mail: Ceneco@ifl .ufrgs.Br Dr. N. Haagsma, Utrecht University, Faculty of Veterinary Medicine, P.O. Box 80.175, NL-3508 TD Utrecht, The Netherlands Tel: +31 30 535365. Fax: +31 30 532365 Francoise Chavel, Executive, Secretary, European Optical Society, B.P. 147-91403 Orsay Cedex, France Tel: +33 1 69 85 35 92.Fax: +33 1 69 85 35 65. E-Mail: francoise.chavel@iota.u-psud.fr Spring Innovations, 216 Moss Lane, Bramhall, Stockport, Cheshire, UK, SK7 1BD Tel: +44 (0)161 440 0082. Fax: +44 (0)161 440 9127 Mercedes Gomez, Laboratory of Toxicology and Biochemistry, School of Medicine, c/o San Lorenzo 21, E-43201 Reus, Spain Tel: +34 77 759376. Fax: +34 77 759322 Mary L' Abbe, Nutrition Research, Health Canada, Ottawa, ON K1A OL2, Canada Tel: +1613 957 0924. Fax: +1613 941 6182. E-mail:mlabbe@ hpb.hwc.ca Michael Carl, Milschwirtschaffliche Untersuchungs und Versuchsanstalt Mempten, Postfach 2025, D87410, Kempten, Germany Tel: +49 8315 2900. Fax: +49 8 315 290100134N Analyst, October, 1995, Vol.120 Date 20-24 23-25 June 9-13 10-14 16-21 17-2 1 July 8-12 17-19 Conference Location 18th International Symposium on Capillary Riva del Garda, Chromatography Italy XIIIth National Conference on Analytical Craiova, Chemistry Romania 8th International Conference on Metalorganic Cardiff, Vapour Epitaxy UK 11th International Converence on High-Power Prague, Particle Beams (BEAMS '96) Czech Republic HPLC '96: 20th International Symposium on High Performance Liquid Phase Separations and Related Techniques California, USA 2nd European Symposium and Exhibition on Optical Instrument and Systems Design Glasgow, UK XVI International Congress of Clinical Chemistry UK London, 8th Biennial National Atomic Spectroscopy Symposium (BNASS) UK Norwich, August 11-16 ICORS '96: XV International Conference on Pittsburgh, 20-23 7th International Symposium on Osaka, Raman Spectroscopy USA Pharmaceutical and Biomedical Analysis Japan (PBAT '96) 25-30 XXIII EUCMOS September 1-7 Euroanalysis IX Balatonhred, Hungary Bologna, Italy 8-13 CLEO '96: European Conferences on Lasers Hamburg, and Electro-Optics Germany 9-1 1 Sixth International Symposium on Field Flow Ferrara, Fractionation Italy Contact Professor D.P. Sandra, IOPMS, Kennedypark 20, B-8500 Kortrijk, Belgium Tel: +32 56 204960. Fax: +32 56 204859 Romanian Society of Analytical Chemistry, 13 Boulevard Republicii, Sector 3, 70346 Bucharest, Romania Tel: +40 1 631 00 60. Fax: +40 1 631 2279 Glenda Bland, Global Meeting Planning Tel: +44 01222 700053.Fax: +44 01222 700665. E-mail: 10046.1402@ compuserve.com Dr. Jiri Ullschmied, Conference Co-Chairman, Institute of Plasma Physics, AS CR, Za Slovankou 3, Prague 182 00, Czech Republic Fax: +422 858 6389. E-Mail: BEAMS96@ IPP. CAS .CZ Mrs. Janet Cunningham, Barr Enterprises, 10120 Kelly Road, P.O. Box 279, Walkersville, MD 21793, USA Tel: +I 301 898 3772. Fax: +1 301 898 5596 Francoise Chavel, Executive Secretary, European Optical Society, B.P. 147-91403 Orsay Cedex, France Tel: +33 1 69 85 35 92. Fax: +33 1 69 85 35 65. E-Mail: francoise.chavel@iota.u-psud.fr Mrs. Pat Nielsen, XVIth International Congress of Clinical Chemistry, P.O. Box 227, Buckingham, UK MK18 5PN Fax: +44 (0) 1280 6487 Ms. Brenda Holliday, BNASS Secretariat, Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge, UK CB4 4WF Tel: +44 (0)1223 420066.Fax: +44 (0)1223 423623 Professor S. Asher, Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA Professor Susumu Honda, Faculty of Pharmaceutical Sciences, Kinki University, Kowakae 3-4-1, Higashi Osaka 577, Japan Fax: +81 6 721 2353 Professor Dr. J. Mink, Department of Analytical Chemistry, University of Veszprkm, P.O. Box 158, H-8201 Veszprkm, Hungary Professor Luigia Sabbatini, Euroanalysis IX, Dipartimento di Chimica, Universiti di Bari, Via Orabona, 4,70126 Bari, Italy Tel: +39 80 242020. Fax: +39 80 242026 CLEO/Europe '96, Institute of Physics, Meetings and Conferences Department, 47 Belgrave Square, London, UK SWlX 8QX F. Dondi, Department of Chemistry, University of Ferrara, Via L.Borsari, 46,I-44100 Ferrara, Italy Tel: +39 532 291154. Fax: +39 532 240709135N Analyst, October 1995, Vol. 120 Date Conference Location 9-13 14th International Conference on High Prague, Resolution Molecular Spectroscopy Czech Republic 10-14 International Symposium and Exhibition on Graz, Biomedical Optics IV Austria 15-20 21st International Symposium on Stuttgart, Chromatography Germany November 4-8 International Symposium on the Industrial Johannesburg, Application of the Mossbauer Effect South Africa 1997 April 14-19 Genes and Gene Families in Medical, Texas, Agricultural and Biological Research: 9th International Congress on Isozymcs USA May 12-16 European Symposium on Photonics in Paris, Manufacturing I11 France June 16-20 European Symposium on Environmental and Munich, Public Safety I1 Germany September 8-12 Biomedical Optics V Poland Contact Dr.V. Spirko, Academy of Sciences of the Czech Republic, J. Heyrovsk, Institute of Physical Chemistry, Dolejskova 3, C2-18223 Praha 8, Czech Republic Francoise Chavel, Executive Secretary, European Optical Society, B.P. 147-91403 Orsay Cedex, France Tel: +33 1 69 85 35 92. Fax: +33 1 69 85 35 65. E-Mail: francoise.chavel@iota.u-psud.fr GDCh-Geschaftsstelle, Abt. Tagungen, Varrentrappestr. 40-42, Postfach 90 04 40, D-6000 Frankfurt am Main 90, Germany Tel: +49 69 791 7358. Fax: +49 69 791 7475 Herman Pollak, Mossbauer Laboratory, University of the Witwatersrand, Private Bag 3, WITS 2050, Johannesburg, South Africa Tel: +27 11 716 4053/2526. Fax: +27 11 339 8262. E-Mail: ISIAME@PHYSNET.PHY S .WITS. AC.ZA Mrs. Janet Cunningham, Ban Enterprises, 10120 Kelly Road, P.O. Box 279, Walkersville, MD 21793, USA Tel: +1 301 898 3772. Fax: +1 301 898 5596 Francoise Chavel, Executive Secretary, European Optical Society, B.P. 147-91403 Orsay Cedex, France Tel: +33 1 69 85 35 92. Fax: +33 1 69 85 35 65. E-Mail: francoise.chavel@iota.u-psud.fr Francoise Chavel, Executive, Secretary, European Optical Society, B.P. 147-91403 Orsay Cedex, France Tel: +33 1 69 85 35 92. Fax: +33 1 69 85 35 65. E-Mail: francoise.chavel@iota.u-psud.fr Francoise Chavel, Executive Secretary, European Optical Society, B.P. 147-91403 Orsay Cedex, France Tel: +33 1 69 85 35 92. Fax: +33 1 69 85 35 65. E-Mail: francoise.chavel@iota.u-psud.fr

ISSN:0003-2654    

DOI:10.1039/AN995200131N

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

136N Analyst, October, 1995, Vol. 120 Courses Date Conference 1995 November 7-8 14-16 27-111 2 29-21] 2 29-211 2 Foreign Bodies in Food Basic Chemical Analysis of Foods Quality Management (including TQM, IS0 9000, GLP, NAMAS) Tandem Mass Spectrometry Workshop 8th Annual Tandem Mass Spectrometry Workshop December 6 Meat Authenticity. Introduction to Immunoassay Test Kits 11-12 BMSS LClMS Course 1996 January 8-9 5-6 5-6 5-6 5-6 Present Status of Analysis of Trace Metals and Nutrients in the Environment Pre- and Postcolumn Techniques in HPLC for Improved Analyte Isolation, Derivatization, Clean-up, Separation and Detection Isotopically Labelled Compounds in Hyphenated GC-techniques Analytical Tools for GC-MS (Advanced Modes of Ion-trap Mass Spectrometry) Biomedical Applications of GC-MS Location Chipping Campden, UK Chipping Campden, UK Loughborough, UK Alberta, Canada Lake Louise, USA Chipping Campden, UK Cambridge, UK Trivandrum, India Bruges, Belgium Bruges, Belgium Bruges, Belgium Bruges, Belgium Contact Training Manager, Campden and Chorleywood Food Research Association, Chipping Campden, Gloucestershire, UK GL55 6LD Tel: +44 (0) 1386 840319.Fax: +44 (0) 1386 841306 Training Manager, Campden and Chorleywood Food Research Association, Chipping Campden, Gloucestershire, UK GL55 6LD Tel: +44 (0) 1386 840319. Fax: +44 (0) 1386 841306 Dr. Barry Sharp, Department of Chemistry, Loughborough University of Technology, Loughborough, Leicestershire, UK LEI 1 3TU Tel: +44 (0) 01509 222 572. Fax: +44 (0) 01509 233 163. E-mail: B.L.Sharp@LUT.ac.uk Ms.Margaret Northcott, Geological Survey of Canada, 3303 - 33rd Street NW, Calgary, Alberta, Canada T2L 2A7 Margaret Northcott, Geological Survey of Canada, 3303-33rd St., NW, Calgary, AB T2L 2A7, Canada Tel: +I403 292 7041. Fax: +1403 292 5377. E-mail: mnorthcott@gsc.emr.ca Training Manager, Campden and Chorleywood Food Research Association, Chipping Campden, Gloucestershire, UK GL55 6LD Tel: +44 (0) 1386 840319. Fax: +44 (0) 1386 841306 Dr. J. Oxford, Glaxo Research and Development Ltd., Park Road, Ware, Hertfordshire, UK SG12 ODJ Dr. C. S. P. Iyer, Convener, ICES-96, Regional Research Laboratory (CSIR), Trivandrum 695 019, India Tel: +91 471 77459. Fax: +91 471 75186. E-mail: rrlt@ sirnetm.ernet.in Congress Secretariat, Ordibo bvba, L. Hennickstraat 18, B-26 10 Wilrijk, Antwerpen, Belgium Tel: +32 38 28 89 61. Congress Secretariat, Ordibo bvba, L. Henninckstraat 18, B-2610 Wilrijk, Antwerpen, Belgium Tel: + 32 38 28 89 61. Congress Secretariat, Ordibo bvba, L. Henninckstraat 18, B-2610 Wilrijk, Antwerpen, Belgium Tel: +32 38 28 89 61. Congress Secretariat, Ordibo bvba, L. Henninckstraat 18, B-2610 Wilrijk, Antwerpen, Belgium Tel: + 32 38 28 89 61. Entries in the above listing are included at the discretion of the Editor and are free of charge. If you wish to publicize a forthcoming meeting please send full details to: The Analyst Editorial Office, Thomas Graham House, Science Park, Milton Road, Cambridge, UK CB4 4WF. Tel: +44 (0)1223 420066. Fax: +44 (0) 1223 420247. E-mail:Analyst@RSC.ORG.

ISSN:0003-2654    

DOI:10.1039/AN995200136N

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Analyst, October 1995, Vol. 120 137N Future Issues Will lnclude- Solvent Extraction Separation of Lanthanum(II1) with Dibenzo- [24]-crown-8 From Picrate Solution-Muhammad Idiris Saleh, Abdussalam Salhin and Bahruddin Saad Characterization of Odour in Pioglitazone-Tore Ramstad, Ashley H. Bates, Thomas J. Yellig, Steven J. Borchert and Kent A. Mills Extraction-Spectrophotometric Determination of Silver in Ores, Electronics, Flow-solder and White Metals With 2-Carboxybenzaldehyde Thiosemicarbazone-P. L. Lopez- De-Alba, F. Salinas and A. Espinosa-Mansilla Analysis of Rocks, Soils and Sediments for the Chalocophilic Elements by Laser Ablation-Inductively Coupled Plasma Mass Spectrometry-Frederick E. Lichte and Xun Guo Chemical Equilibrium Calculation for Evaluating the Buffering Capacity of Acidic Natural Waters-Shuping Bi and Wei Yin Electrochemical Trace Analysis of Gold in Ore Samples (Mixture of Chalcopyrite, Galen and Sphere1ite)-K. S.Pitre and Hyotsna Shukla The Influence of Concentration and Sample Volume on the Recovery of Compounds from Water Following Direct Sorp- tion-Thermal Desorption-Jacek Namiesnik, Lidia Wolska and Waclaw Janicki Spectrophotometric Determination of Sodium Chondroitin Sulfate in Eye Drops after Derivatization With 4-Amino- 3-hydrazino-5-mercapto- 1,2,4-triazoIe-Kunihiro Kamata, Misako Takahashi, Kiyosi Terasima and Motohiro Nishijima New Detection Cell for Piezoelectric Quartz Crystals: Fre- quency Changes Strictly Follow Brukenstein and Shay 's Equation in Very Dilute Non-electrolyte Aqueous Solutions- Naoki Kamo and Hedayat 0.Ghourchian New Observations on the Behaviour of Some Trifluoroaceto- phenone Derivatives as Neutral Carrier for Carbonate Ion- selective Electrode-Adam Hulanicki, Tomasz Sokalski, Dariusz Paradowski, Joanna Ostaszewska, Magdalena Maj- Zurawska, Jozef B. Mieczkowski and Andrzej Lewenstam Lead Carbonate-Phosphate System: Solid-Dilute Solution Equilibria in Aqueous Systems-S. M. Grimes, Simon R. Johnston and D. N. Batchelder Automated Gravimetric Management of Solutions. Part 2. Automated Gravimetric Approach to Direct Potentiometry and Kappa Number Determination-Celio Pasquini and Ildenize B. S. Cunha Evaluation of Ractopamine Cross-reactivity in Several Com- mercially Available Beta-agonist Enzyme Immunoassay Kits- Alan L. Wicker, Michael P.Turberg and Mark R. Coleman Catalytic Spectrofluorimetric Determination of Vanadium Using Oxidation of 0-Phenylenediamine with Bromate in the Presence of Gallic Acid-Susumu Kawakubo, Kiyoshi Ogihara and Masaaki Iwatsuki Flow Injection Amperometric Determination of Trace Amounts of Ammonium Using a Gas-diffusion Cell as the Sample Loop-Renmin Liu, Bianting Sun and Ian Johns Ion-selective Electrodes in Organic Analysis: Determination of Carboxylic Acids via in-situ Conversion into Amines-Albert W. M. Lee, Wing Hong Chan and Yiu Sing Lam Piezoelectric Immunosensor for the Detection of Immunoglo- bulin M-Xia Chu, Zhao-Hui Ling, Guo-Li Shen and Ru- Qin Yu Modelling the relation between CieLab Parameters and Sensory Scores for Quality Control of Red Wine Colour- M.C. Ortiz, Ana Herrero, M. Sagrario Sanchez, Luis A. Sarabia and Montserrat Iniguez Piezoelectric Crystal Sensor With a Plasticized PVC Coating for Determination of Trace Ethanol Vapour-Ke-Min Wang, Zhong Cao, Hui-Gai Lin, Shi-Hua Wang, Bin-Feng Wang and Ru-Qin Yu Use of the Median in the Direct Determination of Metals in Solid Samples by Graphite Furnace Atomic Absorption Spec- trometry-M. A. Belarra, I. Lavilla and Juan R. Castillo Proficiency Testing in Sampling: Pilot Study on Contaminated Land-Ariadni Argyraki, M. H. Ramsey and Michael Thompson Spectrophotometric Determination of Cadmium by New Chro- mogenic Reagent 2-Pyridinediazoaminozobenzene in the Pres- ence of Triton X-100-Yu-Rui Zhu, Chao-Cun Wang, Jun Chen, Wan-Quan Jiang and Gu Jin Surface Acoustic Wave Enzyme Sensor Applied to Kinetic Assay of Acid Phosphatase-Shouzhuo Yao, Qingyun Cai, Ronghui Qang, Liyin Wu and Lihua Nie Comparison of Chemical Modifiers for the Determination of Vanadium in Water and Oil Samples by Electrothermal Atomization Atomic Absorption Spectrometry-Efrosini Piperaki and Nikolaos S. Thomaidis COPIES OF CITED ARTICLES The Royal Society of Chemistry Library can usually supply copies of cited articles. For further details contact: The Library, Royal Society of Chemistry, Burlington House, Piccadilly, London W1V OBN, UK. Tel: +44 (0)171-437 8656. Fax: +44 (0)171-287 9798. Telecom Gold 84: BUR210. Electronic Mailbox (Internet) LIBRARY@RSC.ORG. If the material is not available from the Society's Library, the staff will be pleased to advise on its availability from other sources. Please note that copies are not available from the RSC at Thomas Graham House, Cambridge.

ISSN:0003-2654    

DOI:10.1039/AN995200137N

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

138N Analyst, October 1995, Vol. 120 Technical Abbreviations and Acronyms The presence of an abbreviation or acronym in this list should NOT be read as a recommendation for its use. However, those defined here need not be defined in the text of your manuscript. AAS ac m ADC ANOVA AOAC ASTM bP BSA BSI CEN cpm CMOS c.m.c. CRM CVAAS C.W. CZE dc DRIFT dPm DELFIA DNA EDTA ELISA emf ETAAS EXAFS EPA FAAS FAB FAO-WHO FIR FT FPLC FPD GC GLC HGAAS HPLC ICP id INAA IR ISFET iv im IGFET ISE LC LED LOD atomic absorption spectrometry alternating current analogue-to-digital analogue-to-digital converter analysis of variance Association of Official Analytical Chemists American Society for Testing and Materials boiling point bovine serum albumin British Standards Institution European Committee for Standardization counts per minute complementary metal oxide silicon critical micellization concentration certified reference material cold vapour atomic absorption spectrometry continuous wave capillary zone electrophoresis direct current disintegrations per minute diffuse reflectance infrared Fourier transform spectroscopy dissociation enhanced lanthanide fluorescence immunoassay deoxyribonucleic acid ethylenediaminetetraacetic acid enzyme linked immunosorbent electromotive force electrothermal atomic absorption spectrometry extended X-ray absorption fine structure spectroscopy Environmental Protection Agency flame atomic absorption fast atom bombardment Food and Agriculture Organization, far-infrared Fourier transform fast protein liquid chromatography flame photometric detector gas chromatography gas-liquid chromatography hydride generation atomic absorption spectroscopy high-performance liquid chromatography inductively coupled plasma internal diameter instrumental neutron activation infrared ion-selective field effect transistor intravenous intramuscular insulated gate field effect transistor ion-selective electrode liquid chromatography light emitting diode limit of determination assay spectrometry World Health Organization analysis LOQ mP MRL mRNA MS NIR NMR NIST od OES PBS PCB PAH PGE PIXE PPt PPb PPm PTFE PVC PDVB QC QA REE rf RIMS rms rpm RNA SCE SE SEM SIMS SIMCA SRM STM STP TIMS TLC TOF TGA TMS tris TRIS uv UVNIS VDU XRD XRF YAG Commonly Used Symbols M Mr r S U limit of quantification melting point maximum residue limit messenger ribonucleic acid mass spectrometry near-infrared nuclear magnetic resonance National Institute of Standards and Technology outer diameter optical emission spectrometry phosphate buffered saline polychlorinated biphenyl polycyclic aromatic hydrocarbon platinum group element particle/proton-induced X-ray parts per trillion (1012; pg g-l) parts per billion (109; ng g-') parts per million (106; yg g- ) poly( tetrafluoroethylene) poly(viny1 chloride) poly( divinyl benzene) quality control quality assurance rare earth element radiofrequency resonance-ionization mass spectrometry root mean square revolutions per minute ribonucleic acid saturated calomel (reference) electrode standard error scanninghrface (reflection) secondary-ion mass spectrometry soft independent modelling of class Standard Reference Material scanning tunnelling (electron) standard temperature and pressure thermal ionization mass thin-layer chromatography time-of-flight thermogravimetric analysis trimethylsilane 2-amino-2-( hydroxymethy1)- propane-l,3-diol (ligand) 2-amino-2-( hydroxymethy1)- propane-173-diol (reagent) ultraviolet ultraviolet-visible visual display unit X-ray diffraction X-ray fluorescence yttrium aluminium garnet emission electron microscopy analogy microscopy spectrometry molecular mass relative molecular mass correlation coefficient standard deviation atomic mass

ISSN:0003-2654    

DOI:10.1039/AN995200138N

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Analyst, October 1995, Vol. 120 2435 Analysis of Organic Polymorphs A Review Terence L. Threlfall, Chemistry Department, University of York, Heslington, York, UK YO1 5DD Summary of Contents Introduction and Definition of Polymorphism Significance of Polymorphism Distinction From Related Phenomena Stability of Polymorphs Methods for the Examination of Polymorphs Microscopy Infrared Spectroscopy Raman Spectroscopy Ultraviolet and Fluorescence Spectroscopy Solid-state Nuclear Magnetic Resonance and Nuclear Quadrupole Resonance Spectroscopy X-ray Crystallography Thermal Analysis Solubility and Density Measurement Solvates Quantitative Aspects Amorphous and Crystalline Solids References Keywords: Polymorphism; phase transitions; amorphous materials; solvates; microscopy; thermal analysis; infrared spectroscopy; Raman spectroscopy; solid-state nuclear magnetic resonance spectroscopy; X-ray diflraction Introduction and Definition of Polymorphism Polymorphism1-7 in the chemical sense of the word* is a phenomenon of the solid state, associated with the structure of the solid.It has proved difficult to define precisely although the basic concept is readily understood. The definitions which have been offered vary in breadth but the implication of all of them is that polymorphs involve different packings of the same molecules in the solid.4 The question of how similar the same molecules must be and of how dissimilar the different packing arrangements must be in order to qualify as polymorphs is more than a matter of semantics but goes to the root of our understanding of the organic molecular solid state.McCrone has defined a polymorph as ‘a solid crystalline phase of a given compound resulting from the possibility of at least two crystalline arrangements of the molecules of that compound in the solid state’ and has listed those types of solid phenomena which are excluded from this definition. Later writers who have accepted this definition have tended to substitute their own list of exclusions,5 if they have addressed the matter at all. Buerger ’s tentative definition3 ‘ideally, two polymorphs are different forms of the same chemical compound which have distinctive properties’ is broader and appears not to * An on-line search of Chemical Abstracts will reveal more than 47000 entries under ‘polymorphism’.Over 90% of these relate to genetic polymorphism, which at least in its origins can claim the true etymology of the word. Some selectivity between biological and chemical uses can be achieved, but there is no certain searching strategy. Searching under ‘phase transition’ and related concepts will generate a further 44000 entries, most of which refer to inorganic systems, and cannot be easily disentangled. Nevertheless, these represent only a proportion of the papers containing information on polymorphs and polymorphism. Hence it is not possible to state how many publications relate to those aspects of polymorphism described here. accept. the need for separate phases and to include amorphous forms. The nature of the amorphous state899 will be discussed later.Polytypismlo is one-dimensional polymorphism, referring to different stacking of the same layers. It is most familiar in inorganic systems, particularly silicon carbide, but has been recognized in organic crystals, both as orderedll-13 and as disordered stacking.14 There is no special term for two- dimensional polymorphism, although some liquid crystal systems display it. Liquid crystals are notorious for their ability to exist in different phases both in the mesomorphic and in the solid state15-17 and this has led to the suggestion that the term polymorphism should apply to liquids as well as solids,’* but it is only the solid dimensions of liquid crystals which can adopt distinct packing arrangements. Liquid-crystal polymorphism will not be dealt with specifically in this review except where it is related to the polymorphism of solids.The long standing questionlg of whether allotropy and polymorphism are dis- tinct20 is not an issue in the case of organic compounds. Inorganic polymorphs have been excluded because the ex- tended structures of which most inorganic crystals are com- posed raise concepts not discussed here.21.22 Protein polymor- phism usually refers to minor molecular sequence changes23924 rather than to packing, but different crystal packing of protein molecules is also known? Polymorphism of thin films26327 and polymers, both of biologica128,29 and of synthetic30 origin, although of the same nature as the concept of polymorphism considered here, will not be discussed. There is a profusion of words in the English language for the phenomena discussed in this review, yet not enough because of the overlapping usage. ‘Polymorph’ (dimorph, trimorph) ‘form’ and ‘modification’ are all used to describe polymorphic phases, but ‘form’ and ‘modification’ are also used in reference to crystal habit.‘Polymorph’ and ‘form’ have been used to describe solvates, whilst ‘pseudopolymorph’ doubles for both solvates and for those solids which are otherwise not considered true polymorphic forms. The term ‘pseudopolymorphic solvate’ applied to crystals losing solvent molecules without change of crystalline form offers yet another source of confusion in terminology. Genetic polymorphism which is now the major use of the term is often described as ‘polymorphisms’ but this is occasionally seen also in chemical senses.In view of the almost universal use of ‘polymorphic’ as the appropriate adjective, the word ‘polymorphous ’ seems superfluous despite dictionary support. There is an urgent need for consistent usages so as to be able to delineate the phenomena under consideration. There is no clear choice as to the best method of designating polymorphs. Arbitrary systems are to be discouraged, but numbering based either on order of melting point or of room temperature stability have been recommended. Both are susceptible to change as a result of later identification of new polymorphic forms. Numbering based on order of discovery is unchangeable, but requires a knowledge of the history of the compound. The addition of the crystal class, as has been suggested for minerals31 is not very practicable, since crystal- lographic classes are rarely determined from optical micro- scopic or X-ray powder diffraction studies for organic com- pounds.The assignment of a space group is even less realistic.2436 Analyst, October 1995, Vol. 120 In any case the distribution of organic molecules amongst crystal classes and space groups is extremely limited, as is discussed later.32.33 The addition of a melting or upper transition point to a Roman numeral is probably the best compromise,l although care must be taken to distinguish the melting point of the polymorph and that of the transformed product. Significance of Polymorphism The continuing investigation of polymorphism by the Innsbruck school (Kofler, Kuhnert-Brandstatter, Burger) over more than half a century has shown that around one-third of organic substances show crystalline polymorphism under normal pres- sure c0nditions.3~,35 A further third are capable of forming hydrates and other solvates.Much of the literature on the polymorphism of organic compounds relates to pharmaceutical products.l,3~0 The incentive for this interest in polymorphism began with the need to satisfy regulatory authorities in various countries as to the bioavailability of formulations of new chemical entities.36.37 Of the several contributory factors to the bioavailability of finished products, the inherent solubility and rate of dissolution of the drug substance itself are of major importance. The solubility is dependent on the polymorphic state, as different polymorphs have different energies and therefore different solubilities.40 It has been pointed out, particularly by Burger,36 that the difference in solubility between polymorphs is likely to result in significant bioavailability differences, in practice, only in exceptional cases.Although some may think that this represents an extreme view, the consequences of polymorphism on bioavailability are commonly overstated. Chloramphenicol palmitate, over which the original concerns were is unique in that the solubility is related to the rate of enzymic attack on the s0lid.4~ This and novobiocin,43 which involves consideration of the amorphous state, are among the handful of examples of marketed products showing major bioavailability differences as a result of polymorphism.As formulations have become more sophisticated and as the tolerances on products have become tighter, the need to identify polymorphic behaviour at an early stage of development has become important in the pharmaceutical industry as a means of ensuring reliable and robust processes44 and conformity with good manufacturing practice. The aim is to avoid, inter alia, tabletting problems and subsequent tablet f a i l ~ r e , ~ ~ , ~ ~ crystal growth in suspension^^^^^^ and resultant caking, precipitation from solutions and problems with ~uppositories,~9 as well as chemical production problems such as filtrability and to ensure analytical reproducibility. By extension such considerations relate to the control of quality in manufacture and product reliability in any industry by ensuring that the processes are well understood and under control so that unpleasant surprises do not occur.^^ This point is most dramatically illustrated in the explosives industry, where the wrong polymorph can have greatly increased sensitivity to detonation.51.52 Pigment colour and solubility are polymorph dependent,53-5’ as are photo- graphic and photolithographic sensitizers.6O The performance of industrial products, particularly those based on natural fats and waxes61Jj2 and derived soaps,63 and on petroleum produ~ts6~365 is in many cases related to polymorphic composition and degree of crystallinity.The same is true of the processing, acceptability and deterioration of foods and confectionery containing fats,66,67 sugars,68-7* polysaccharides73 and other constitu- ents.74-75 A comprehensive summary of the solid-state proper- ties of lipids has recently appeared.76 It is also worth establishing the polymorphic behaviour of a compound for the sake of good order in documentation so that reference works, for example, pharmacopoeias, do not contain conflicting data34.77 such as a spectrum of one polymorph, but the melting point of another.A major incentive to the study of polymorphism in the pharmaceutical industry during development has become strikingly apparent recently in the use of subsidiary patents on desirable polymorphic to prolong the patent life of major products. Much recent pharmaceutical patent litigation has concerned polymorphs and particular interest has been taken in Glaxo’s patent on the polymorph of ranitidine79 (Zantac) which if held valid will extend the patent protection from 1995 to 2002 in many countries.80 For a compound with annual sales of over 2 400 million pounds sterling,gl the financial incentives to investigate polymorphs are obvious.Finally, the very existence of polymorphism tells us some- thing about the solid-state. Investigation of polymorphic systems, especially those with a large number of forms can help in understanding solid-state and molecular behaviour and intermolecular interactions82 and the relationship between crystal structure, crystal growth and crystal habits3 and their influence on bulk properties. Apart from knowledge for its own sake, this is of clear application in the development of organic electronicS4,85 and other specialty productsgcg8 and in under- standing the function of biological membranes.89 Distinction From Related Phenomena At one time polymorphism was regarded only as different arrangements of rigid molecules in the solid ~tate.gO,~l* A clear dichotomy existed between this and arrangements of molecules in different forms, such as could be imagined would occur with isomeric, tautomeric, zwitterionic and chiral structures and later with different conformers.92 The early crystallographic studies on rigid aromatic molecules tended to reinforce the distinction.This simple division could only be maintained whilst details of the rich variety of solid-state structures were inaccessible. The early examples of dynamic isomerism and tautomerism were f e ~ 9 3 - 9 ~ and the proposition that they could not be part of polymorphism was copied by reviewers until even the examples were f0rgotten.9~ A quoted example of a tautomeric solid-state structure, that of 3,5-dichloro-2,6-dihydroxy dimethyl tere- phthalic acid was shown in 1972 not to be tautomeric, but to involve conformational change with hydrogen bonding differ- ences.96 One would have expected examples of tautomerically related solid structures to be exceedingly numerous, since the molecular energetic requirements can easily be fulfilled as is shown by the widespread occurrence of tautomerism in solution.97 Tautomeric polymorphism is surprisingly rare, but a well investigated example is now known, that of 2-amino- 3 -hydroxy-6-phenylazopyridine .98 There are a few papers in the literature either where tautomeric polymorphism is invoked99-105 or where examina- tion of the IR spectra is suggestive of forms whose difference resides in transfer of hydrogen between one part of the molecule and another.106 The instances of 1,3-~yclohexadienone and squaric acid (3,4-dihydroxy-3-cyclobutene- 1,2-dione are more difficult to place unambiguously in the category of tautomeric polymorphism. Proton transfer between donor and acceptor oxygen sites results in little change in over-all structure. lo7 Both tautomeric equilibrium and the neutral ++ zwitterionic equilibrium formally involve such an intramolecular hydrogen transfer. The nominal difference is that a charge separation is produced in zwitterions which cannot be extinguished intra- molecularly by a double-bond rearrangement cascade.The difference may be even smaller in practice because charge stabilization of zwitterions can occur intermolecularly, for example, in solution through solvation, whilst tautomeric structures can retain a substantial part of their charge as shown by dipole moment and IR spectroscopic studies.108JO9 Anthra- * Earlier literature can be accessed Ilia references I , 2 and 10.Analyst, October 1995, Vol. 120 2437 nilic acid exists as two metastable forms containing only uncharged molecules and a form stable at room temperature, half the molecules of which have been shown from crystallo- graphic studies to be zwitterionic and half uncharged.110 A related phenomenon is the changing of allegiance of hydrogen- bonded hydrogens between electron donor atoms, which is a prolific source of polymorphism.I 11 The role of hydrogen- bonding networks in determining crystal structure has been discussed extensively. 1 12 Conformational differences between molecules of different structures have been admitted, perhaps reluctantly, and distinguished by the title conformational polymorphism.113 The original examples form one extremity where molecules in distinctive conformations pack similarly,9* but it is now obvious from the plethora of crystal structures, as could always have been deduced from elementary considera- tions of energy minimization, that any change of packing will cause geometrical change in molecules and conversely that any change in geometry will invite different packing of the molecules.82 The extent will depend on the rigidity of the molecules.Although some floppy ring systems maintain their shape in different forms] 14,115 even nominally rigid structures such as the ring systems of steroids116 can show substantially different conformations in different polymorphs. Heteroaro- matic117-121* and benzoquinone122 planes are frequently bent and even benzene rings123 may be. Thus it seems pragmatic to accept conformational polymorphism as a normal sub-set of polymorphism and the term will only be used here when it is necessary to distinguish cases of substantial conformational change. The distinction between polymorphism and chirality is made in most accounts of polymorphism; yet it has recently been pointed out that if conformational polymorphism is accepted, then racemates and conglomerates of rapidly interconverting chiral systems are in fact polymorphs.5 Such systems are generally ones with an easy conformational change where the trivial distinguishing feature from other conformational poly- morphism is that the result of such a change is a reflection of an asymmetrical structure across a mirror plane.Although this seems difficult to accept, the dextrorotatory and laevorotatory forms of such systems are then equally p01ymorphs.l~~ The narrow line of demarkation between polymorphism, conforma- tional polymorphism and chirality first seems to have been recognized by Eistert et al..l*5 Examples of rapidly inter- changing enantiomers in solution capable of independent existence in the solid state are known126-127 but uncommon. A further extension of the concept of conformational polymorphism is to be found where there is rapid interconver- sion between isomers.l28 As in the chiral examples, one molecular species or the other becomes exclusively incorpor- ated in the crystal because the mechanism of crystal growth acts as such an exquisitely discriminatory process.Since a hydrate and an anhydrous form are constitutionally distinct, they cannot bear a strictly polymorphic relationship on the basis of any definition. However, the observation of material of different melting point or other properties during re- crystallization may be due (apart from chemical reaction with solvent or decomposition) to solvation or polymorphism and the methods of examination are similar in either case.Hence the term 'pseudopolymorphism' has become common 3o particu- larly in the pharmaceutical industry. The term seems un- necessary and could lead to confusion131 with its use to describe all other phenomena related to polymorphism] and so will not be used here. It must be emphasized, however, that the distinction between solvates and polymorphs is not as clear-cut as might be imagined, either conceptually or practically. * In the case of phenothiazines'zl the point of interest is not that the ring system is bent, but that the heteroatoms are out of the plane of the aromatic rings and in the opposite sense to expectation. The traditional narrow view of polymorphism, rigidly excluding chirality and isomerism, has caused considerable difficulty128 to the investigators of the systems described above and it is suggested that the way to avoid these problems is to adopt the gloss originally proposed by McCrone and co- workers1.37 on his definition of polymorphism, namely that the criterion is that the component molecules must have the same structure in solution irrespective of the polymorph from which they were derived; but, as has been suggested by D ~ n i t z , ~ without excluding tautomerism, isomerism or conformers per se.Thus, rapidly interconverting species would be accepted, whilst slowly interconverting species would be excluded, as was surely within the original contemplation. Despite appear- ances, this proposal is likely to multiply examples of poly- morphism very little and it avoids what otherwise must be artificial situations of accepting phases as polymorphs based on impeccable polymorph behaviour until their crystal structure reveals excluded molecular forms.98.l 10~132 If, as asserted, the transition between polymorph I and polymorph I1 of 1,3-cyclo- hexadiene occurs by transfer of hydrogen from one oxygen to another, then this is nominally an example of tautomeric polymorphism.107 If, on the other hand, the same change occurs or can be made to occur by a movement of the whole molecule then it is an example of regular polymorphism.The boundaries between the various alternative solid structural concepts are too subtle and too vague to be used to define polymorphism. Although the requirement of the same structure in solution has been canvassed above, one-component phase diagrams are constructed on the basis of equilibrium with vapour, rather than liquid.It is just in the instance of conformational, configura- tional or hydrogen mobility that molecular differences between vapour,133,134 melt, solutionl26,135 and solid are found. The mobilities are inevitably of different magnitudes in different states. We shall be increasingly obliged to decide where to draw the boundaries of polymorphism as more comparative studies involving polymorphs and molecular structure in different states are undertaken. One negative consequence of accepting the wider view of polymorphism should be noted, namely that the thermodynamic relationships discussed later are likely to be less certain for the wider polymorphic farnily.9O Stability of Polymorphs Polymorphs, or strictly dimorphs where only two forms are under consideration, may be in an enantiotropic or monotropic relationship.19.136 An enantiotropic relationship implies that each form has a range of temperature over which it is stable with respect to the other and a transition point at which the forms are equistable and in principle interconvertible. 137 Above that temperature the thermodynamic tendency is to the formation exclusively of the form stable at the higher temperature.Below the transition temperature the low- temperature form is the only stable one with respect to the other, although there is usually a greater tendency for the high temperature form to become frozen-in than for a low- temperature form to persist beyond its stability range.8 Forms outside their range of stability are described here as metastablel38.In the case of a monotropic relationship one form is metastable with respect to another at all temperatures. There is no observable transition point, although the thermodynamic description implies a theoretical transition point above the melting point which is therefore unattainable. 139 The use of the terms enantiotropic or monotropic in reference to a phase, as opposed to a transition, is ambiguous and likely to lead to confusion, since a polymorph can have a monotropic relationship to a second polymorph, but be enantiotropic in relation to a third polymorph. Flufenamic acid provides such an example. 140 The distinction between thermodynamic and kinetic transition points also needs to be drawn.1412438 Analyst, October 1995, Vol. 120 Polymorphs only exist in the solid state: melting or dissolution destroys any distinctions.It is therefore important in examining polymorphs analytically not to submit them to conditions under which they melt, dissolve or are rendered more likely to interconvert. Heating and gri11ding142-1~4 are obviously potentially hazardous operations in this context, but often cannot be avoided. The presence of solvent, even one in which the substance appears insoluble, will speed up the inter- conversion.145 Trace moisture, acid or alkali on vessels can be similarly effective in interconverting polymorphs or in catalys- ing competing and confusing phenomena such as ring-opening reactions, for example, in 3,5-dihydroxy-3-methylvaleric acid derivatives,l46, or group transfer reactions. 147 It might be supposed that a transition during grinding would always be from less stable polymorph to the polymorph more stable at that temperature, but in our experience, as well as from the literature,145 this is not always true, presumably because the transformation takes place at a local temperature generated by the grinding and the unstable form becomes frozen-in by rapid cooling outside the immediate area of grinding.148 This can only occur in cases in which the transition temperature does not lie too far above ambient.There may be alternative explanations, namely interconversion via amorphization or that a less stable polymorph may become the more stable one when in the form of small crystallites, as a result of surface effects.The latter phenomenon has been observed and investigated theoretically in the case of phthalocyanine pigments.149 The possibility of growing unstable forms in microdrop conditions has been known for some time,34 but recently the value of emulsions for this purpose has been suggested.150 Although it would be desirable to have more compelling evidence than that obtained by differential scanning calorimetry (DSC) alone to establish the relationship between forms grown in this way, it does appear that new forms can be produced as well as metastable ones which are otherwise only accessible via the melt. The product of a polymorphic transition can also depend on particle Mnyukh and Petropavlov, in extensive studies of the transformation of individual crystals, observed that strict orientation of axes between mother and daughter phases was not preserved upon transformation.153 They have concluded that only reconstructive transitions, i.e., those involving the growth of new crystals in place of the old, take place for organic compounds. Even rapid transitions, described as atypical, were observed to follow the same patterns.No displacive (marten- sitic, co-operative) mechanism involving concerted structural change is therefore possible for organic compounds in Mnyukh’s scheme. Whilst it would now appear that the reconstructive mechanism is the usual one, there are many examples involving preservation of axial orientation at phase transitions4 some of which appear to be topotactic rather than only epitaxial.154-157. Irrespective of the mechanism and the rate of conversion at the point of transition, the stability in practice of a metastable polymorph at room temperature varies enormously, 158 from examples where the transformation is so rapid that the only evidence of the transient existence of a polymorph is its pseudomorphic outline, 1 to those which can be kept indefinitely and indeed refuse to transform in the absence of heat, high humidity or solvents.152 The majority of systems are in fact quite robust to handling. It may therefore be thought that some of the present work presents over-concern with the possibility of transforming polymorphs during analytical examination. How- ever, the modifications of some compounds show extraordinary sensitivity to handling in so many different ways.For example, with octakisphenylthionaphthalene, pressure on a cover-slip causes the yellow form to change to red;lsY with ethylenedia- mine hydrochloride, mere contact with KBr is stated to cause transformation;160 with D,l-pantolactone 2,4-dihydroxy-3,3-di- size. 15 1,152 methylbutyric acid y-lactone, absorption of IR radiation in the spectrometer is sufficient for transformation; 161 and with meprobamate, high humidity may rapidly transform an other- wise indefinitely stable polymorph.162 The problem is that this sensitivity may not be apparent until after the measurements have been made and then only if the analyst is alert, so that it is not possible to be too careful at the outset.Three of the commonest methods, IR spectroscopy, X-ray powder diffrac- tion and differential scanning microscopy are unreliable for comparison of identity unless the sample is examined as a fine powder, but grinding can mislead into belief of identity if it induces transformation. This is why optical microscopy is so valuable for the initial examination. On the other hand, where transformation is sluggish, solubility determinations will be of more value than instrumental measurements for establishing the stability relation~hips.3~ The existence of enantiotropically related polymorphs is indicative of the fact that the relative stabilities and therefore the Gibbs energies of the forms are very similar.163Jw For this reason the empirical forecasting of polymorphism of a given compound is unlikely to be reliable.88J65 Despite this, groups of compounds such as sulfonamides, barbiturates and steroids are known to be extraordinarily susceptible to polymorph forma- tion.39 Around 70% of these are now known to be polymorphic.Other examples include theophylline derivative^,^^ coumar- ins,87 alkanes,64,65 fatty acids and their derivatives61362 mol- ecules which form liquid crystals, l~~~ and molecules which pack badly.166 With the advent of molecular modelling techniques for crystal growth prediction, interest has been generated in the computer prediction of polymorphism.87 The task is difficult because of the lacunae in our understanding of polymorph structure. Methods for the Examination of Polymorphs Polymorphs can be sought deliberately by cooling or quenching of melts, by condensation of vapour, or by crystallization under different conditions, although they are often encountered by chance.In the process of crystallization from solution, the expected effect of crystallization temperature may be overshad- owed by other factors, particularly deliberate or adventitious seeds.167 The importance of crystallization control during process development and the attitudes when unexpected polymorphic forms are encountered has been described by Bavin? ‘the process of crystallization is taken for granted by most chemists and it takes a reaction vessel clogged with an unstirrable mass to provoke serious thought’. All the solid-state properties of the different polymorphic modifications of a compound will be different, but often only marginally so, to the point of instrumental indistinguishability.For this reason, it is important to look at potentially poly- morphic systems by a variety of techniques to avoid erroneous conclusions. Failure to recognize a polymorph is the more obvious situation but it is also possible to identify polymorphs where none exist, if reliance is placed on too few techniques.168 Substances with multiple forms can require substantial effort for their complete elucidation, especially when previous studies have characterized the forms inadequately. 142~48,15191697170 The techniques which have been available for a long time for the examination of polymorphs include those listed in Table 1. Which are the commonest methods depends to some extent on the area of interest, but in industrial practice, microscopy, IR spectroscopy, DSC, X-ray powder diffraction, solubility and density measurements have been the most widely used techniques.Within the past decade several new techniques and instrumental accessories have become widely available. These ease the manipulation of polymorphs and so lessen the danger of interconversion, or enable new properties to be investigated and allow measurements to be made which would have formerlyAnalyst, October 1995, Vol. 120 2439 been impossible on the specimen under examination because of its size or microcrystallinity, for example. These developments are listed in Table 2. In general, the application of these newer techniques to polymorphism has not been adequately reviewed.Much of this article will therefore be devoted to a description of these methods in relation to examples taken from the literature on polymorphism. Some attention will also be devoted to aspects of the traditional techniques which have been given surprisingly little coverage in the reviews. Apart fom the techniques discussed below, there have of course been many other methods applied to particular aspects of polymorphism and solid-solid phase transitions. Examples include scanning tunnelling micr0scopy,6~ electron diffra~tion,~~ atomic force microscopy,l71 crystal etching,17* electron microscopy64J73 and thermobarometric measurements. 174 The analytical strategy in approaching a polymorphism study will be dictated by the availability of instrumentation, time and material.At the beginning of a study, the fact that minimal quantities of a compound are required by IR spectroscopy, DSC and, particularly microscopy can be a significant consideration. Since thousands of compounds are put into pre-development in the pharmaceutical industry for each successful marketed product175* the cost of extensive investigation of polymorphism also needs to be borne in mind. Microscopy Although a theme of this review is that no one technique should be used in isolation, hot-stage microscopy has been often so used and remains the outstanding method for the examination and generation of polymorphs.’ In the hands of experts, Table 1 Techniques which have been available for many years for the examination of polymorphs Hot-stage microscopy Thermal methods- DTA DSC Thermogravimetric analysis Solution calorimetry Infrared spectroscopy Solubility measurements Density measurements- Flotation Pyknometry Dilatometry X-ray powder diffraction X-ray single-crystal diffraction Table 2 Techniques of particular value for the examination of polymorphs which have become readily or more widely available within the past decade Solid-state NMR Diffuse-reflectance IR spectroscopy Near-IR spectroscopy Raman spectroscopy Area detectors on diffractometers Combined techniques including- Hot-stage IR spectroscopy IR microscopy Video recording on the microscope * According to Lumley and Walker”* ‘5000-1OOO0 candidate substances have to be synthesized and screened for every one new medicine that reaches the market’.surprisingly comprehensive accounts of polymeric behaviour have been generated from microscopy alone,37,39J40J76 but it is a technique which requires experience for rapid study and the drawing of confident conclusions. A preliminary examination under a binocular microscope will enable the overall character- istics of the sample to be ascertained. Temperature cycling and melt and solvent recrystallization experiments with a polarizing microscope equipped with a hot-stagel77-179 will allow the identification of transition points, the distinguishing of mono- tropic and enantiotropic relationships, estimation of the ten- dency of melts and individual phases to supercool, the generation of stable and unstable polymorphs and the recording of their optical properties.140,180,1gl The identification of solvates and the observation of sublimates and of any tendency to decompose are added information.175 This can be carried out with minute amounts of material.The field has been excellently and comprehensively reviewed in the past,1,37-39,178,179 and for that reason only the developments since then will be considered in detail here. The basic hot-stage methods have changed little in the intervening years, although there have been considerable improvements in the design of microscopes in terms of greater stability, versatility, ease of use and optical excellence. The availability of phasels2? 83 and differential interference contrast (Nomarski) methods l84 and of interference microscopy has enabled precise refractive indices to be more readily deter- mined. Several designs of hot-stage have been developed and are commercially available. Unfortunately, convenience is often sacrificed to temperature precision and many are unsatisfactory in maintaining temperature control whilst allowing for the manipulation of the specimen since the housings restrict access to the specimen.In fact in some designs, access cannot be gained at all whilst the stage is in position on the microscope. Recourse to a more open design, such as the Kofler stage, a graduated hot-stage186-1s8 or a purpose-built heated microscope slide189 will be necessary for such a requirement. The simplest rotating needle stages177Jgs are similarly more useful in practice than four-axis or five-axis Federov stages, because of the open access.Although the determination of refractive indices and optic axis angles on birefringent specimens is time-~onsuming,~9~ these optical measurements are critically distinctive of phases140 especially when variation methods can be justi- fied,177,191,192 and such measurements ought to be more widely considered when doubt remains as to whether different specimens represent different phases. Such doubt is of more frequent occurrence than is ever suggested in the literature. This is owing, at least partly, to our inadequate understanding of the molecular solid state, and the relationship of that state to its properties. X-ray crystallographic studies have shown that hot- stage microscopic investigations have tended to overestimate the number of polymorphs, l93 presumably because crystal habits have been judged as modifications and because samples of different melting or transition points have been assumed necessarily to represent distinct forms.In fairness to the early investigators it is by no means clear how samples of the same polymorph, for example, can have the same unit cell yet melt 19 “C apart where purity considerations can be excluded.146 Crystal strain which has been invoked in other,179 less extreme cases, seems to be a rationalization rather than an explana- tion. A major advance in microscopy for the analyst confronted with potential polymorphism has been the availability of video recording.5 A change in a specimen or perhaps only in a few crystals of the specimen under examination is often only noticed after it has occurred.The ability to replay the video and re- observe the changes, perhaps in slow motion and to compare the timing of the changes in different crystals of the specimen can be exceedingly useful in making judgements of whether sample2440 Analyst, October 1995, Vol. 120 homogeneity is in question, in determining transition tem- peratures or temperature ranges, in recording events in systems displaying irreproducible, erratic behaviour and in sorting out sequential but nearly concurrent events that sometimes occur. For example, a melting followed by resolidification of the low- temperature form will often accompany the transition without melting,194, individual crystals or crystal domains within the field of view behaving independently.110,122 A particularly valuable use is in distinguishing the movement of boundaries between domains or phases178,195 and so distinguishing poly- morphic changes from related behaviour such as crystal strain effects. 179 A more elaborate arrangement has been described196 in which a differential scanning calorimeter and a hot-stage microscope are linked through video recording. Commercial hot-stages with associated thermal sensors are also available which enable the optical changes and the associated changes in thermal properties to be examined simultaneously. There is a compromise197 between optical and thermal excellence, ver- satility and convenience so that it is best regarded as a supplement for a microscope plus a calorimeter rather than a substitute. Close transitions or meltings are better resolved by microscopy than by DSC.198 There are transitions which are seen by microscopy and not by DSC'06,199 and vice versa.The different behaviour of ethyl morpholine HC1.2H20 under the microscope and in DSC is particularly striking.200 Thermo- microphotometry has been recommended and shown to be effective in detecting phase transitions that were not detected either by microscopy or DSC.201 A triple system of DSC-microscopy-microphotometry has also been described.202 The combination of microscopes with other instruments is discussed in the following sections. Infrared Spectroscopy The first intimation of polymorphism not previously noticed as a melting point discrepancy or sought deliberately by hot-stage microscopy is often from inconsistencies in solid-state IR spectra.Infrared spectroscopy has had, of course, enormous exposure in the literature through reviews204 and papers but there are surprisingly few descriptions of the precautions to be taken when recording or interpreting the IR spectra of polymorphs. For example, in the case of non- matching spectra, a wide variety of causes might be suspected, including mis-labelling of a homologue,205* sample purity, crystal ~ize,206,~07 crystal habit and orientation,208,209 instability to comminution,210 formation or partial decomposition of a salt,2' solubility in the mulling medium, hydration,2 l 2 dehy- dration213 or other solvent loss under vacuum, level of impurities in the mulling or disk medium and instrumental variables214 including the inadequate elimination of back- ground peaks.The latter can be more of a problem with the Fourier transform instruments now in almost universal use, because of the high (often unnecessarily high) resolution which can be achieved in routine use. Experience of the expected levels of instrument and sample reproducibility is the best prophylactic against the discovery of non-existent polymorphs or the disregard of actual polymorphs. The choice of routine sample presentation methods now includes rnulls215-217, disks215-219, diffuse reflection2203221 and attenuated total reflection (ATR).222,223 All present hazards particularly for amorphous forms and for crystals of limited stability. The running of solution spectra is, of course, excluded for distinguishing between polymorphs, but can be used to check the molecular identity and purity of the specimens and so distinguish polymorphism from solvation, isomerism and other * The fact that a homologue and a polymorph can produce similar degrees of difference was first noted by Jones as quoted by Rosenkrantz and Z a b l o ~ .~ ~ ~ phenomena. The key factor in determining the sample proce- dure is simply the stability of the polymorph to the chosen conditions. Disks or mulls are usually most appropriate for routine use, but diffuse reflectance spectra are particularly suited for preliminary examination because the preparation technique will minimize polymorphic interconversion in most cases. For particularly sensitive compounds, the choice between ATR, photoacoustic spectroscopy or microspectroscopy will probably be determined by the availability of the appropriate accessories.Interconversion depends on the nature of the compound as well as the vigour of the preparatory stages of the examination. It is desirable to establish the sensitivity of the forms to grinding at an early stage of the investigation, but it is rarely indicated in the literature that this is ever considered. In general the preparation of a mull is less likely to produce polymorphic changes than that of a disk,224%225 presumably because the heat of grinding is carried away more efficiently by a liquid than by a solid. However, Nujol itself can cause polymorphic change.128.143 There is also the belief that the pressure itself during disk formation can bring about poly- morphic transitions.226.227 KCI and KI have been recommended in place of KBr for various reasons,206,211 but KBr is now most commonly used.It is softer than KC1228 and so safer for this reason. On the other hand, it is less neutral and so can cause salt formation. Ethylenediamine dihydrochloride is so sensitive to KBr that merely placing a Nujol mull in contact with a KBr disk causes transformation, as previously noted, although a KCl disk is inert in the same circurnstances.l60 Different alkali halides have different refractive indice~.20~>228 Although not often a problem with organic materials, mismatch of refractive index of medium and sample can cause distorted spectra due to the Christiansen filter e f f e ~ t , ~ ~ 9 which in extreme cases also produces an apparent band shift to lower frequencies.Some- times, with strong bands, substantial shifts in the opposite direction result204 a phenomenon which has never been satisfactorily explained. This reinforces the importance of always comparing spectra run under the same conditions. The use of a grinding or dispersion promoter such as acetone for disk making is excluded, as polymorphic changes are catalysed by solvents.145 This raises the caveat that non-polar polymorphic systems should not be examined as paraffin rnulls.l28,143 In an extreme case, there is the possibility of observing the solution spectrum of the compound being mulled. The further problem with mulls is that they are less quantita- tively reproducible and parts of the spectra are obscured owing to the bands of the mulling agent which makes comparison of spectral identity or differences more difficult.230 For this reason, the use of alternative mulling agents such as hexachloro- butadiene or Fluorolube98 may be attractive if only the high- frequency region of the spectrum is of interest.This is only likely to be the case for hydrogen-bonded molecules. The most pronounced band shifts are, however, often to be found below 800 cm-1 and into the far IR (FIR) region.231.232 In the diffuse reflectance (DRIFTS)233J34 technique the substance to be examined is dispersed in a matrix of a powdered alkali halide and placed in a sample cup in the diffuse reflectance accessory. The sample is illuminated by a wide cone of radiation and the reflected radiation collected over a wide angle.The effects of multiple scatter and multiple reflection within the sample over a wide range of permutations of angles of incidence and reflection tend to reduce orientation effects accompanying insufficient grinding of needle or platey crystals. The observed spectrum results primarily from the transmission of radiation through crystals rather than from reflection from individual faces. Acceptable spectra of polymorphs can gen- erally be obtained by this technique, with much gentler grinding than either for disks or for mulls. For this reason it is to be regarded as the presentation method of for the initial examination of the IR spectra of polymorphs. KC1 hasAnalyst, October 1995, Vol. 120 244 1 I l l been recommended as the best diluent.226 For quantitative work, it may be necessary to grind the sample thoroughly, but this may be avoidable for an initial examination.Care must be taken to ensure reproducible dispersion and packing of the sample in the sample cup.235-237 The use of diffuse reflection is now becoming more commonly reported for the examination of polymorphic systems and the reader is referred to the lit- erature226,234 for details of the preparation of samples. In ATR spectroscopy, also called frustrated total reflection or internal reflection spectroscopy, the evanescant wave that penetrates the low refractive index medium under total internal reflectance conditions at a high refractive indexflow refractive index boundary is minutely absorbed.This is because the depth of penetration is only of the order of magnitude of the wavelength of the radiation or less. In practice IR radiation is directed through a thallium bromide iodide crystal which represents the high refractive index medium against which the sample is pressed. ATR spectroscopy is widely used for the examination of materials which present problems when exam- ined by other methods. It is particularly valuable for samples which are strongly absorbing or which must be examined in situ or at least neat. ATR would thus appear at first sight to be the ideal way of obtaining the IR spectra of polymorphs238-240 which is possibly why it has been preferred by some of the pharmacopoeias and authorities, for example, in Australia. In principle neither grinding nor any preparation other than possibly sprinkling the sample on to transparent sticky tape is required.However, ATR spectra are particularly susceptible to packing and crystal orientation problems. This, combined with the difficulty in obtaining sufficiently strong and acceptably reproducible spectra, without finely grinding the sample and pressing it to the face of the ATR crystal, makes the technique less attractive and it is rarely used in polymorphism studies. The potential presence of a dispersion component superimposed on the absorption component can also make the comparison of subtle differences less certain.241 Nevertheless, if a sample proves susceptible to grinding, as in the case of phenyl- butazone239 or sulfathiazole,242 ATR spectroscopy may be a valuable resort. Sulfathiazole is one of the few substances in the literature for which spectra run as KBr disks,243 Nujol mulls169 and ATR242 are displayed.The differences in scale make comparisons difficult. Therefore, in Fig. 1 a set of spectra of sulfathiazole polymorph 111 is displayed, to highlight typical differences. These are mostly in the background and in intensity variation; the position of bands, except those associated with hydrogen bonding, remain at the same wavelengths. Diffuse reflectance spectra of sulfathiazole forms are illustrated in Fig. 2 to give an idea of typical spectral differences between polymorphs. Comparison with spectra in the literaturel69.242.243 reveal differences due, apart from the variation in sample presentation technique, to the possibility of interconversion during prepara- tion for spectral examination and to the difficulty in producing pure polymorphs or even reproducible specimens.The spectra of 111 and IV show only minute differences. This is a consequence of the inherent similarity of the crystal structures and is reflected in the ease of conversion of IV to 111. The largest spectral differences between polymorphs I and 111 are in the NH stretching region, reflecting the substantially different hydrogen bonding networks. Despite the curious appearance of the spectrum of polymorph IT above 1700 cm-1, all the features are genuine, but have become exaggerated because of the crystal- linity of the sample. This illustrates the dilemma in examining polymorphs. Grinding would improve the appearance of the spectrum but at the risk of promoting a transition.The IR spectra of polymorph 111 shown243 or implied169 in the two most carefully conducted studies in the literature are those of an approximately (1 + 1) mixture of polymorphs I11 and IV, as are some samples of the commercial material. By near IR difference l l l l l I I measurements (see below) the specimen of polymorph 111 used here was estimated to contain 8% of IV and the specimen of IV to contain 9% of 111. The polymorphs of sulfathiazole must be ”% I 3500 3000 2500 I 1800 1600 1400 12001000 800 6001 2000.0 500.0 Waven um ber/cm-’ Fig. 2 Diffuse IR spectra of forms of sulfathiazole, admixed into a KBr matrix using minimal grinding. A, polymorph IV prepared inadvertantly; B, polymorph 111, commercial sample; C, polymorph I1 by boiling an aqueous saturated solution to dryness; D, polymorph I by heating polymorph I11 above 175 “C; E, melt; and F, amorphous form produced by quenching the melt in liquid nitrogen.The spectrum of the melt (in a KBr matrix) is shown for comparison with the amorphous form.2442 Analyst, October 1995, Vol. 120 regarded as amongst the most difficult to make and keep as pure specimens, as the number of papers on this topic reflect.243 Photoacoustic spectroscopy (PAS) relies on the detection of the acoustic signals generated by the absorption of modulated radiation2449245 and is therefore not subject to the blacking out effect that occurs when IR spectra of too strongly absorbing samples are recorded by any other technique.Hence spectra can be obtained from neat samples and as such it might be expected to have been more widely explored for polymorphic sy~tems.2~6 Control of particle size is, however, important in ensuring reproducibility.247 PAS has been used to obtain IR spectra of 2R ,4S-6-fluoro-2-methylspiro(chroman-4,4’-imidazoline)-2’,5 - dione because the forms were too sensitive to grind.248 Comparisons of DRIFTS and PAS have been made.249-251. There is a difference in the over-all intensity relationship with wavelength between these techniques and transmission meth- ods related to the variation of depth of penetration with wavelength and this needs to be taken into account in comparing spectra obtained by the different methods. Spectra at low temperatures are more highly resolved and so more characteristic than those at room temperature, owing to suppression of the thermal motion. Low temperature spectra have been recommended for the examination of antibi0tics.25~ The relative ease of obtaining spectra at - 196 “C has been stressed and the technique has been applied to polymorphic steroids to achieve greater resolution and distinguishability.116 The absorption of polarized radiation is dependent on molecular orientation and therefore potentially of value in examining packing modes of molecules,253 but appears to have been little explored for enhancing the distinguishability of polymorphs. The transformation of polymorphs of fatty acids has, however, been recently investigated. Monoclinic phases of fatty acids pack in layers with oblique orientation of the hydrocarbon chains within a layer.An orthorhombic polytypic phase of both the B and the E forms is known, in which alternate layers have the contrary 0rientation.~54 Polarized IR spectro- scopic studies have been used in establishing the relationship between the orientation of crystal axes in crystals undergoing tran~formation.~55 Recording the IR spectra on thin films made by rapid cooling of melts between salt plates or pressed KBr disks is a valuable way of investigating polymorphic propen~ities.25632~7 Ostwald’s principle257 predicts that the form involving the least loss of Gibbs energy, that is, the modification least stable at low temperatures will be first formed on cooling and if it can be trapped by rapid cooling, it may be possible to follow a whole series of polymorphic changes with time and temperature by IR spectroscopic examination of the film. This can be achieved by warming the centre of the disk with a hot r0d,~5~ although it is more elegantly carried out on a hot-stage.This technique of making thin films can only be used for substances stable at moderate melting temperatures because of the possibility of fracture of the salt plates from thermal shock.230 Commercial heated stages for IR spectrometers have been available for some time, but have not always had sufficient temperature control or insulation to enable differential scanning calorimetric or hot-stage microscopic observations, for exam- ple, to be matched with the spectral changes. An alternative is to adapt a hot-stage to fit the IR cell compartment.The expectation of sharp changes in the spectrum at the transition points is not always borne out in practice,259 because the degradation of the resolution and signal-to-noise ratio at high temperatures may obscure the small changes being sought. Thermal emissivity, convection currents and change in focus may be the main causes of the problem. Detailed studies have established generally the decrease in intensity of IR bands of condensed phases with temperature260 and a sudden decrease at transition points for alkanes.261 It is important to make allowances for these variations when comparing spectra taken at different tem- peratures, as may be necessary when the polymorphs inter- convert readily and so cannot be examined outside their range of stability.To overcome these problems and render small changes more visible, it was advantageous to record difference spec- tra,262 but now chemometric methods have been brought to bear.263 Gu2a has used Malinowski’s criteria of number of components to determine the number of transitions and temperature of transition points for glycerides. Two-dimen- sional correlation plots applied to variable temperature DRIFTS have also been used to pair-up bands in the spectra and so identify the spectroscopic components of the different phases.265 Partial least squares computation has also been used in conjunction with variable temperature DRIFTS .234 The most exciting development in the application of IR spectroscopy to the study of polymorphism has been that of the IR microscope.208,253,26~269 Normally a single crystal or crystalline powder of sufficient area to fill the sample aperture of an IR spectrometer cannot be examined by transmission because of excessive absorption and can be examined only with difficulty by reflectance because of the mixture of diffuse and specula reflectance components.Although there are techniques and computer programs for the transformation based on the Kronig-Kramers relati~nship~~l (Hilbert t r a n ~ f o r m a t i o n ~ ~ o ~ ~ ~ ~ the residual uncertainties make the technique unsatisfactory for comparing subtly differing spectra. With an IR microscope, however, individual small crystals can be examined directly in transmission. The pigment naphthazarin (5,s-dihydroxy 1,4-naphthoquinone) has been examined in this ~ a y .2 ~ 5 Thicker crystals can be examined by seeking thinner areas of acceptable absorptivity near the edges.272 Apart from the virtue of minimizing polymorphic transformation and of allowing meas- urements to be made on minimum sample quantities, the difference in the spectra of individual crystals can be ascer- tained, since it is not unknown for a crystallization to produce a mixture of polymorphs.85J99J73 Microphases can also be examined.274 Naturally a great deal more time and manipulation is required for IR microscopy, so in the usual instance, in which sufficient sample is available, an IR macro spectrum would normally be taken first under standard conditions. Despite all the potential problems, many of which have been discussed above, in most cases IR spectroscopy provides a simple and reliable tool for the investigation of polymorphism.The distinction between spectra of different phases is rarely large, although there are exceptions. 160,275-277 Small changes in peak positions, peak shapes, and absence or presence of a few bands may be all that can be distinguished. This may be enough to characterize a whole series of polymorphs, for example all nine polymorphs and solvates of phenobarbitone prepared by Mesley et al. were clearly distinguishable by IR spectros- copy.151 On the other hand, IR spectra of polymorphs have been frequently reported as virtually identical. 116~60,277-28l In some instances such indistinguishability may be an artefact2g2 of interconversion.Reports of identity or difference in IR spectra and in X-ray diffraction patterns in many publications are not borne out upon examination of the accompanying spectra or diffractograms where these have been reproduced at sufficient size to make an informed comparison. A valuable application of IR spectra (and X-ray diffracto- grams) of polymorphs is as the basis of a patent The use of the NH and OH stretching band positions in establishing stability relationships in hydrogen bonded polymorphic systems is discussed in the section on solubility and density measure- ment. Near IR (NIR) spectra due to overtone and combination bands283 are less resolved than spectra in the fundamental region in the mid-IR. The multivariate methods which are routinely used in this region2847285 minimize this disadvantage and enable small differences between spectra to be distin- guished. The spectra are also much less intense, but providedAnalyst, October 1995, Vol.120 2443 that sufficient sample is available, this is an advantage, because saturation of the absorption will not occur and so neat samples can be used. NIR microscopy has also been tried286 and should show the same advantages for polymorph investigation as IR microscopy. For the normal macro technique, the same problems of reproducible packing and effects of crystal size and orientation as discussed under diffuse reflection apply, but are reduced because of the larger illuminated area. The absence of diluent also removes three variables: the distribution of the analyte, the particle size of the carrier; and the bands due to the carrier or its impurities,287 particularly moisture.The question of the particle size and reproducible packing discussed above for the mid-IR region are equally important here, although chemometric methods have been applied to try to minimize their effe~ts.~88,~89 Since the bands in the NIR region are due to OH, NH and CH stretching vibrations, it would be expected that the spectral changes would be most noticeable in hydrogen- bonded s y ~ t e m s ~ 9 ~ and in conformational polymorphism. The published reports291 are too few to confirm this, although the NIR spectra of many pharmaceutical polymorphs have been recorded. Therefore Fig. 3 shows the NIR spectra of a typical set of polymorphs of a substance, sulfathiazole, in which hydrogen- bonding networks play a significant role.Note that the differences in the spectra of polymorph I11 and polymorph IV, for example, are greater in the NIR region than in the mid-IR region, in line with the expectations expressed above. The technique is non-invasive, these spectra being obtained by placing a fibre optics probe on the outside of the glass tubes containing the samples. A further advantage of NIR spectra is the ease with which data manipulation, such as spectral differences, can be performed without generating unrealistic results. Raman Spectroscopy The Raman effect depends on the inelastic scattering, with loss of vibrational energy, of radiation in the near-UV, visible or NIR region of the spectrum.292-294 It is inherently very weak and needs an intense, monochromatic excitation source and good filters to remove the excitation line from the collected radiation.295 Although commercial Raman spectrometers have been available -for a long time, visible excitation sources tend to i l l I I I I I I I 7 I I l l I l l I I I I I I I 1000 9500 900085008000 7500 7OO0650060OO 550050004500 4000 Wavenum ber/cm-’ Fig.3 Near IR spectra of sulfathiazole forms. A, Polymorph IV; B, polymorph 111; C, polymorph 11; D, polymorph I; and F, amorphous. The spectral differences appear larger than in the mid-IR region because MR spectroscopy is insensitive to ring and chain modes and records only the XH modes, in this case particularly the NH stretchings. produce swamping fluorescence from many compounds .296,297 Where this is due to impurities it may be possible to bum them 0~t798 but otherwise the Raman spectrum is difficult or impossible to record against the background.In this case also there is a tendency to char the sample.299. There have been numerous mechanical293 and electronic devices299 proposed to minimize these effects, but they all have disadvantages. It is only since the advent of NIR Fourier transformation Raman (NIR-FT Raman) spectrometers using the Nd. YAG laser source at 1064 nm with efficient cut-off filters to remove Rayleigh scattering from the laser line,300 that routine Raman spectra have become reliably available from most organic solids.296 Although the spectra obtained are broadly similar to IR spectra, the difference in selection rules makes the information complementary.294,301 Polar groups such as car- bony1 and hydrogen-bonded hydroxy groups which are strongly apparent in the IR, are weak in Raman, whereas non-polar symmetrical or nearly symmetrical bonds such as carbon- carbon single and double bonds are strong in Raman.292 Furthermore, the Raman effect, being a polarizability, falls off as the sixth power of the distance, whereas IR coupling, being a polarization, falls off only as the cube of the distance.302 Therefore Raman spectra of molecular organic solids in the bond stretching and bending region would be expected to show little influence from neighbouring molecules.The effect is enhanced because the typical organic molecule consists of a non-polar backbone with polar groups on the periphery, so minimizing further the coupling of Raman active bands. The effect of this is firstly that Raman spectra of solids tend to have narrower bands than IR spectra.In one polymorphic set that we examined, the typical bands in the IR in the 700-1500 cm-1 region had bandwidths at half height of about 15 cm-1, whereas the equivalent Raman bandwidth was about 1 1 cm- l. Secondly, IR spectra are influenced by neighbouring molecules both directly by hydrogen b0nding303.~~ and indirectly by the above spatial distance effect. One would therefore expect that conformational polymorphism would show up more distinctly in Raman spectroscopy and that packing effects especially of hydrogen-bonded molecules would show up most clearly in the IR spectra.There is little in the literature to test this, but we have encountered examples which support this contention. For rigid, non-hydrogen bonded molecules, the largest differences would be expected to occur in the region of the low-frequency lattice modes.231.232 Comparison of coincidences in IR and Raman bands of symmetrical molecules can lead directly to a decision between alternative structures. The possible centrosymmetric structures for polymorphs B and C of naphthazarin were eliminated in this wa~.~05 This study shows that the Raman spectra of even deeply coloured solids can be obtained with NIR-FT Raman spectroscopy.306 The chief advantage of Raman spectroscopy is that no sample manipulation is required294 and therefore in the case of polymorphs which are, or are suspected to be, susceptible to transformation, the spectra can be obtained with complete certainty of the identity of the sample under examination.The multiple scattering taking place in powder samples307 tends to eliminate orientation effects in the same way as occurs in DRIFTS. Because glass is transparent to the excitation and emitted radiation and gives no interfering bands, spectra can even be obtained without removal of the specimen from the sample tube. Consequently, Raman spectra of polymorphs are now actually easier to obtain than IR spectra and deserve to be more widely recorded than the handful of papers 169,233,308~309 in the literature would indicate. A disadvantage of the NIR-FT Raman system is that commercial instruments do not allow vectra to be recorded to very low frequencies, so that the reLion where the greatest difference between polymorphs might be expected to be seen,231J32,310>311 is inaccessible.As this region is also outside2444 Analyst, Octohei. 1995, Vol. 120 the range of most IR instruments, recourse must be made to conventional Raman spectrometers. As a result, there are few examples in the literature of the examination of organic polymorphs in this low-frequency region,312-3’4 reflecting the difficulty of measurement. Raman microscopy offers in principle even greater advan- tages than IR microscopy because the theoretical limit of resolution, related to the wavelength of the incident radiation, allows samples of an area less than 1 pm2 to be exam- ined.296J97.315 The limit for IR is in the region of 50 pm2 dependent on the wavelength range of interest.316 However, in practice, the optical throughput due to the instrumental aperture characteristics, render it difficult to reach the theoretical limit of resolution with FT-NIR ~ystems.296-29~ Conventional instru- mentation with argon-ion laser sources at 488 nm, which can be used to examine smaller areas, produce the problems for organic compounds mentioned earlier of fluorescence and charring.The latter is particularly troublesome because of the high intensity at the focus of the beam. Even when charring is not observed, the possiblity of phase transition due to local heating needs to be taken into account. Ultraviolet and Fluorescence Spectroscopy Although electronic reflection spectroscopy has been rarely invoked for the examination of polymorphs, it has long been known that different polymorphs of coloured compounds317-3 19 including certain dyes and pigments,58,59 in particular, phthalo- cyanines,149,320-323 display different hues.Bandshifts of up to 170 nm in the solid state as a result of packing differences of the molecules have been reported.3224-326 Furthermore, it is remark- able how many organic crystals deepen in colour on transforma- tion to a higher melting polymorph,”8.~2’,~55~159 so it must be presumed that many, probably most, uninvestigated colourless polymorphs would also show a spectral change in the UV region on transformation. The information that can be extracted from UV reflection is less than from the techniques whose spectral characteristics are more readily related to structure, and the measurements are more difficult.The electronic spectrum may, however, be recording more subtle solid-state changes. It has been recently ascertained that the yellow to red transformation of pyridinium picrate which has been known since 1929 does not occur at the temperature of the only transition point recorded by variable temperature X-ray diffraction st~dies.~*7 The use of polarized near-normal UV spectral reflectance from different faces of single crystals has been applied to the conformational polymorphism of dichlorobenzylidene anilines to relate solu- tion and crystal properties and to elucidate the relationship between molecular conformation and electronic proper tie^.^ The origin of these colour differences has been discussed only briefly, but must be presumed to be due to intermolecular charge- transfer effects.Ultraviolet spectra of solids can also be obtained by transmission from the mull or KC1 disk technique328 (KC1 is transparent to shorter wavelengths than KBr), provided that a thinner matrix is used and account is taken of the vast difference in molar absorption coefficients in the IR and UV regions. The UV spectra of polymorphs of 2(2-methyl-3-chloroanilino)nico- tinic acid have been investigated by diffuse reflectance from Nujol mulls.’32. A detailed comparison of the relative merits of photoacoustic spectroscopy and diffuse reflectance in the UV, visible and NIR regions has been made.Q9 The colour of cyanine dyes is related to the aggregated state in solution, concentrated solutions yielding the more deeply coloured solid-state forms containing the more extensive molecular aggregates.33t) The absorption spectra, the fluores- cence spectra and the electronic properties of solid cyanines3lI display marked differences between the polymorphs.The fluorescence spectral differences in this and other cases332 have been ascribed to a type of excimer formation. Fluorescence spectra have otherwise been little reported although they have been investigated for possible quantitative analysis of poly- morph content.333 Polymorphs may also differ in their thermo- luminescent characteristics.334-335 Solid-state Nuclear Magnetic Resonance and Nuclear Quadrupole Resonance Spectroscopy An NMR spectrum on a solid run under similar conditions to those used for solutions will result only in a broad hump of extremely low signal intensity.For the investigation of melting phenomena or of order-disorder transitions representing the onset of molecular rotation or libration this is advantageous: the phase yielding signals of moderate width as a result of orientational, positional or configurational freedom can be measured with little interference from the signals generated from the rigid solid pha~e.~36,337 For detailed observation and interpretation of the molecular structure, however, it is neces- sary to narrow the s i g n a l ~ . ~ ~ ~ , ~ ~ 9 The breadth and low sensitivity of the solid state signals in NMR spectroscopy is due to three separate effects, each of which must be minimized.34s342 The lines are broadened firstly by anisotropic dipole-dipole coupling and the quadrupole field gradient.Secondly, the chemical field anisotropy which is normally averaged to zero in liquids cannot be averaged out by molecular tumbling in solids. Finally, the extremely long spin- lattice relaxation times require long pulse repetition times to build up the signal. The chemical field anisotropy can be averaged by magic-angle spinning (MAS) in which the sample is rotated at speeds of 4-15 kHz.340--342 The dipolar and quadrupolar field effects can be removed by high-power heteronuclear decoupling. Finally, the spin-lattice relaxation time is reduced by cross-polarization involving pulse sequences which transfer energy between nuclei, thus involving the 1H nucleus in the mechanism of relaxation.The net result is that NMR spectra of solids are now routinely available of acceptable signal-to-noise ratio which show adequate resolution for structural interpretati0n,343-3~5 although longer acquisition times than for solution spectra are necessary. The detail and information content of NMR spectra should be particularly valuable in distinguishing polymorphs and in understanding the sources of their differences.64.3 13,342-345 The use of NMR spectra for examination of dosage forms has been can- vassed.345.346 In practice, relatively few descriptions of the NMR spectra of polymorphs are available in the literature and in several cases where phases which have proved to be very similar by other techniques have been examined, they have also proved to show few differences by NMR spectros- copy.5.169,281,347 This illustrates that very small packing differ- ences are sometimes characteristic of phases or polymorphs.The interpretation of the spectra in terms of molecular structure is normally by comparison with the solution spectrum, but the assignment of carbon type can be made in the solid state with the use of appropriate pulse-sequence techniques.348 A promis- ing use of solid-state NMR spectra is in investigating amor- phous forms.28,349,350 The amorphous form of testosterone was assumed to have ordered packing but disordered molecular orientation from examination of the features in the NMR spectrum associated with the different portions of the mole- cules.116 Conclusions could therefore be drawn as to the probable mechanism of solidification.It is not clear why a solid with positional order but rotational freedom behaves as an amorphous phase rather than a disordered one. Solid-state NMR signals can sometimes be observed to be doubled as a result of non-equivalent crystallographic molecules in the unit cell. 116,340.35 1Analyst, October 1995, Vol. 120 2445 Nuclear quadrupole resonance spectroscopy352 (NQR) is not troubled by the broadening effects encountered by NMR spectroscopy and has been widely used particularly for the examination of inorganic systems. It relies on the detection of the electric quadrupolar effects and is confined to those nuclei with suitable spins. For organic compounds these are princi- pally 2H, 14N, l7O, l9F, 35Cl, 3Tl, 79Br and 81Br.It is relatively insensitive so large quantities of material are required. Chlorine and bromine can be detected by conventional radiofrequency spectroscopy but 14N, which is probably the most generally useful nucleus for organic compounds,353 requires sensitivity enhancement. Cross-relaxation experiments, similar to the cross-polarization experiments discussed above, are appro- priate. 2H and 1 7 0 studies require isotopic enrichment. All these nuclei have been used to study phase transitions, particularly in relation to mechanism and molecular dynamics.354.355 The use of 1 7 0 to study order-disorder phenomena is discussed later. Phase transitions are detected by changes in relaxation times, couplings or multiplicity with temperature.Malononitrile356,357 is particularly interesting, because the change in multiplicity of the 14N NQR signals at - 132 and 22 “C heralds a new phase in between those temperatures, although the phase below the lower temperature appears to be the same as that above the higher one. It can be seen from Fig. 4 that the Gibbs energy values for the two polymorphs are constrained to follow very similar paths. As might be expected from this, the intermediate phase has a structure which is only marginally different from the surrounding phase. X-ray Crystallography X-rays are reflected from crystals only when the angle between the ray and the planes in the crystal fulfil the Bragg condition nh = 2asin0, where 8 is the angle between the ray and the plane, h is the wavelength of the radiation, a is the interplanar spacing and n is an integer.There is an infinite number of possible planes through the crystal, but only a limited number which give reflections within the accessible range 2 < €)/degrees < 180. With a single-crystal brought into all orientations with respect to the beam, a series of spots is generated on the surface of a sphere centred on the crystal. In the case of a powder sample a set of concentric cones is generated which can be recorded as a series of arcs on a photographic strip or as a diffraction trace via a Polymorph: I I I I I Poiyrnorph I I , I I I T, T2 Temperature -+ Fig. 4 Interpretation of the phase transitions of malononitrile in terms of Gibbs energy. The upper part of the diagram is a schematic representation of the variation of the 14N NQR spectrum of malononitrile with temperature.T I and T2 are the transition points at -132 and 22 “C, respectively. The lower part of the diagram represents the Gibbs energy situation. Instead of crossing once as in the enantiotropic system in Fig. 7, the Gibbs energy curves GA and Ge (for polymorphs I and 11, respectively) must cut twice (see text). detect0r.35~ Every molecular repetition will give a unique set of reflections and so generate a unique pattern. Any change in crystal packing will lead to changes in the form of the molecular repetition. In principle, then, any polymorph will give a distinctive X-ray powder pattern. X-ray powder crystallography is therefore of great value for distinguishing and identifying polymorphs.3~9 X-ray single-crystal diffraction is, of course, even more descriptive and in principle can lead to unique definition of the packing of the molecule, the molecular interconnectivity and the three-dimensional conformation of the molecule in the crystal. However, it often proves difficult in practice to grow crystals of sufficient size and perfection for an X-ray structural analysis to be carried out whereas a powder pattern can nearly always be obtained.73 The difficulties which may be encoun- tered in growing crystals of the polymorph stable at room temperature are much magnified when unstable polymorphs and enantiomeric polymorphs are required and particularly when crystals of unstable polymorphs of enantiomers are involved.z48,36@-”63 The evidence for this packing prejudice against optically active molecules has been undermined by a detailed comparison of the density measurements recorded in the literature for racemates and enantiomers and a consideration of the statistical bias,l24 but it remains a matter of common observation during crystallization experiments that optical isomers are difficult to produce as good crystals.364 The problems with metastable forms are easy to understand as owing to the presence of crystal strain and defects.Some crystals show such a large change in volume on transition that they generate enough strain to shatter or move violently and are therefore sometimes characterized27533 13.3473-367 as ‘jumping crystals’. Variable-temperature X-ray diffractometers368.369 are helpful and, of course, essential for the examination of polymorphs which have no existence at room temperature but the required apparatus is infrequently available in laboratories where polymorphs are encountered. It is good practice to look at a sample under the polarizing microscope for homogeneity and for appearance of individual crystals as single and perfect, free from twinning or unusual features, before submission for single crystal X-ray examination.Occasionally, even the most beauti- ful and transparent crystals may be twisted, too thin to produce an adequate signal, multiply twinned, polycrystalline or other- wise defective and hence fail to give an interpretable diffraction ~attern.3~0 Even if the diffraction pattern is too poor for a complete structural analysis, the unit cell dimensions are a criterion for the existence of distinctive phases and the derived density a further critical reference value for the polymorph.Regrettably, crystallographers often fail to record minimum physical characteristics of specimens of polymorphs such as melting point, range of stability or relative stability37I.37’ or even 0rigin373,”~ thus limiting the usefulness of their results. For this reason it proved impossible, by examination of the Cambridge Structural Database (Cambridge Crystallographic Data Centre), to check the reliability of the rule that the polymorph stable at higher temperature has the more symmet- rical structure. The structure of over a thousand pairs of organic polymorphs has been recorded, but only a small portion have adequate accompanying physical information.The theoretical basis of the rule has been described by Kitaigorod~ki’~5 and Desiraju.376 The total energy of a crystal is the sum of the lattice energy and the vibrational energy. Close packing minimizes the lattice energy but interferes with vibrational motion increas- ingly at higher temperatures. The loss of lattice energy stabilization in a more open lattice can be compensated by the entropy gain resulting from the more symmetrical structure. The close packing requirement means that the majority of organic crystal structures reside in very few space groups (P2,/c, P i , C2/c, P21, P212121).322.33 The combined effect of the vibrational and close packing requirements on organic polymorphs is that2446 Analyst, October 1995, Vol.120 one of the commonest patterns for a dimorphic system on transition is monoclinic at low temperature to orthorhombic (P212121) at higher temperatures. Higher symmetry space groups are adopted by disordered states.275. Plastic crystals generally adopt cubic space groups in the disordered pha~e,~,37~ reflecting the requirements for the molecular motions. The development of area detectors for diffractometers for small molecule work means that crystals previously too small to examine can be successfully tackled, or areas of otherwise unsatisfactory crystals can be ch0sen.3~~ This can be very effective in conjunction with the use of synchroton radia- tion.312,379-382 Although there are occasional reports of incor- rect conclusions being drawn from X-ray data5*327,383,384 the most likely source of error in studying polymorphs is picking the wrong crystals.385 As mentioned above, metastable forms often crystallize badly and in a sample of such a product it is not uncommon for the only satisfactory crystals to be interlopers of the stable polymorph. Computation of the correlation of X-ray single-crystal diffraction patterns with powder patterns is now possible and should capture such error at an early stage.142,169,386 The contrary process, converting powder pat- terns of complex molecular crystals to structural information,387 although an exciting prospect, is not yet applicable to sufficiently large molecules to be of general interest for studying polymorphs of commercially interesting compounds.However, for the ordinary laboratory environment an X-ray powder diffractometer is of more general value. It will sometimes identify differences between samples which are too subtle to be detected up by thermal analysis53313 microscopy or IR spectroscopy,388, although a few contrary examples are known.312 One such general instance is where water or other sma11389.390 molecules fill voids in a structure in a random fashion without altering the crystal packing itself as in the examples of antibiotics such as cefaloglycin and cefalexin.391 A mixture of crystalline and amorphous material will be indis- tinguishable from a pure sample of the crystalline material except in absolute intensity which is rarely measured in normal use. There are other cases which are not so easy to explain.2s2 For example, the X-ray patterns of the forms of D,1-norleucine are virtually identical, although the IR spectra are easily distinguishable.160~392 Examination of the IR spectra excludes the possibility that a neutral w zwitterionic transformation is involved.A more common problem with X-ray powder diffraction is in the examination of samples consisting of larger crystals. These may produce a spotty pattern which is difficult to reduce to a series of line intensity measurements and is impossible to compare satisfactorily with diffractograms from other sam- ples.358 If the crystals are not roughly isometric, particularly if they are needles or platey, the pattern may show distinctive features from crystal orientation effects169 as is shown in Fig.5. Grinding is appropriate providing that the polymorph is stable. For soft crystals an inert powder may be mixed in,393 in order to facilitate grinding. An alternative approach is the use of the Gandolfi camera which can be made to generate a simulated powder pattern from a single crystal. The orientational bias for platey crystals of polymorphs I11 and IV of sulfathiazole was eliminated in this way. 169 The calculation of powder patterns from single-crystal data mentioned above has been recom- mended by several groups as a means of obtaining the best reference X-ray powder pattern. 142,169,387,394 Neutron diffraction, although of less general value than X-ray diffraction, has the advantage that the scattering factors for atoms vary little with atomic number.395.396 Light atoms can therefore be detected and located accurately in the presence of heavy atoms, in contrast to X-ray studies.As such, it is of potential value in examining polymorphic systems for their hydrogen bonded networks82,84,111,122,397 and in investigating tautomeric or zwitterionic polymorphism. The naphthazarin C polymorphs have been examined by neutron diffraction to establish their hydrogen-bonding characteristics and the order- disorder transition.398 The deduced centrosymmetric structure, in contrast to the Raman results mentioned earlier, is the result of the averaging of the structure over a substantial time-scale. This factor also applies to X-ray structures399 and needs to be borne in mind when comparing these with NMR and vibrational data.The comparative rarity of sources and the need for relatively large crystals means that neutron diffraction is likely to be infrequently used for investigation of polymorphs. X-ray crystallography is well supported by texts at all levels, both for single-crystal work4-04 and powder meth- ods .358,395,405,406 Thermal Analysis Although the term thermal analysis is sometimes considered to include hot-stage microscopy, it is convenient to deal with these methods separately. Microscopy is concerned with qualitative visual observations whilst instrumental thermal analysis is capable of giving quantitative measurements, but without necessarily identifying the nature of the processes responsible. Thus the techniques are complementary and best used in conjunction.407 The main thermal techniques considered will be thermogravimetric analysis (TGA) and differential thermal analysis (DTA)/ DSC.408 TGA measures the change in mass of a sample with temperature and is therefore particularly valuable in examining solvent loss from crystals and in identifying sublimation and decomposition processes.As it is recording dynamic processes, not only the temperature at which changes occur will vary with procedure but the very occurrence of those processes may depend on sample environment and heating conditions. The subtleties of thermal analysis are often overlooked. In the vivid words of Garn,409 'The apparent simplicity of the technique leads the uninformed to assume that satisfactory data may be obtained, for example, by stickmg a pair of thermocouples into a sample and reference and lighting a fire under them.' DSC and DTA are alternative ways of measuring heat capacity changes in a sample.196,410 Although they may occasionally give significantly different thermal traces,41 the term DSC will be used here without implying the method of acquisition of the data.Any compound will absorb heat in acquiring a higher temperature. During a transition, heat will be absorbed or emitted in effecting a change of phase. The remarks 5.0 8.5 12.0 15.5 19.0 22.5 26.0 29.5 33.0 36.5 40.0 20ldegree.s Fig. 5 Crystal orientation effects in X-ray powder diffraction. Traces due to A, the platey and B, acicular habits of the same polymorph of RF' 54275 are shown. At high values of 28, the traces are similar, but at low values they are different.Reproduced with permission of Rh6ne-Poulenc Rorer Ltd.Analyst, October 1995, Vol. 120 2447 made above regarding the dynamic nature of TGA apply equally to DSC. In most cases where the forms are stable to grinding and the transitions are rapid the resulting curves will be sensibly reproducible. In other cases, the thermograms obtained may depend on the heating rate,412,413 sample packing,414 crystal si~e,415?~16 the ambient atmosphere417 and encapsula- tion239*367,407,41* and interpretation needs appropriate care. In particular, it is often overlooked that the history of a polymorphic crystal may be critical, for example, a later run may differ because of tempering on standing with loss or gain of seed nuclei of other Many instruments now run TGA and DSC simultaneously.This is valuable in that it enables a clear distinction to be made between processes involving solvent loss, sublimation and decomposition on one hand and pure phase changes on the other. The principles of thermal analysis have been set out recently in a book422 and in an introductory video.423 The features to be seen in a DSC trace (Fig. 6) are endotherms, representing absorption of heat, exotherms repre- senting the emission of heat and the so-called second-order transitions representing a change in the heat capacity without either absorption or emission of heat. A sloping baseline could represent a continually changing heat capacity, but is often due to imbalance between sample and reference, or slow loss of mass from the sample during heating.During a heating cycle endothermic processes are the most common ones. Melting and sublimation are always endothermic as are transitions involving enantiomorphs at or above transition points. Desolvation is usually endothermic and chemical reactions can be, especially at lower temperatures. Monotropic transitions, crystallization and most decomposition reactions are exothermic. On cooling, crystallization and enantiotropic transitions are exothermic, so cooling cycles normally contain only exotherms. Despite this there is often value in running the sample under both heating and cooling modes.414 Although this has long been recom- mended, it is rarely indicated in the thermal analysis literature on small molecules that this has been considered.208 By contrast it is common in lipid and polymer work to run both heating and cooling curves.89 If it is intended to identify the material at room temperature after a phase transition, it is imperative to check on the cooling cycle that no reverse change has occurred.Heats of transformation and melting can be evaluated from the area under a DSC curve,424,425 although not, of course, as satisfacto- rily as from a precision adiabatic calorimeter.426 Conditions need to be chosen carefully in order to obtain reliable results. The greatest difficulty is in determining the most suitable base line.427 It is common for a polymorph to show a transition to a higher melting polymorph at the appropriate transition temperature when heated slowly, but to overshoot and melt at its own melting point under more rapid heating c0nditions.l9~ This is often followed immediately by re-solidification to the higher melting polymorph giving a characteristic curve shape (Fig.6, c). The polymorph thus produced may or may not be the same as that resulting from the transition at the proper transition point and in other instances the re-solidification may be delayed.224 Dependent on the complexity of the polymorphic set, a whole series of such events may take place. Finally, the form with the highest melting point will melt if it has not previously decomposed. Several meltings may take place in the case of a Recrystal I izatio n Pure Polymorph Ill Melting of Melting of polymorph I t Exothermic 4 Endothermic Spontaneous crystallization f Polymorph 111 Polymorph I Glass transition Supercooled liquid Quenched Sample Ill - I Commercial Sample Melting of Polymorph I Temperature - Fig.6 Typical features in the DSC of a polymorphic system. A, Quenching the melt of sulfathiazole gives an amorphous solid, which on heating undergoes a second-order transition (glass transition) to a supercooled liquid (see refs. 422,542-544). In a second order transition no heat is evolved or absorbed and only the heat capacity alters. This is seen as a drop in the base line. A supercooled liquid always represents an unstable phase and on heating spontaneous crystallization of this can occur. In this case it happens suddenly, causing the rapid movement away from this new base line. Irreversible processes are exothermic, but the complex exotherm which follows is unusual and probably represents several overlapping transitions. As described by Ostwald's Principle (see refs.258 and 436) this is a cascade of transitions to successively more stable forms at that temperature. The resulting phase must be polymorph I, since it melts at 201 "C without further thermal events occurring, B, a specimen of polymorph 111 shows an endotherm due to the transition from polymorph I11 to polymorph I, followed by melting. The fact that it is endothermic indicates that polymorph I and polymorph I11 are enantiotropic. This endotherm always occurs around 150-175 "C although it is known that the true transition point lies many degrees below this; and C , a specimen of polymorph I11 which is free from seeds of polymorph I (see refs. 194 and 242), may overshoot the transition point and melt at its own melting point.This is often followed immediately by recrystallization, which is an exothermic process, of the higher melting polymorph I giving the characteristic trace shown.2448 Arinlyst, October 1995, Kol. 120 compound with liquid crystal phases, but finally a clear melt will form. The literature on the investigation of the behaviour of phenylbutazone239.428432 provides an instructive example of the role of thermal analysis in polymorphism. Early work produced the not untypical situation of conflicting data on the number and properties of polymorphs.239,428 Subsequent appli- cation of thermogravimetric analysis showed that two of the reported polymorphs were in fact solvates.429 In a substantial re- investigation, five polymorphs were identified and charac- terized.430 The IR spectra were not very useful for differ- entiating between the crystal forms because of their ~imilarity.~30 The X-ray diffractograms were also reported as somewhat similar, although the earlier work429 had relied on these to distinguish forms.The published patterns look distinguishably different239-429.431 but it is reported that phenyl- butazone shows orientation effects and is sensitive to grind- ing,*39 which is undoubtedly the reason for the reported similarity of the IR spectra. Dissolution rate data were also acquired, but in the absence of surface area information (see later) they cannot be regarded as definitive evidence for polymorphism.Distinction between the polymorphs relies then in this study430 on thermal analysis. The temperatures of peak maxima are quoted for all polymorphs as well as onset temperatures of melting, the latter agreeing closely with the melting point as determined on a hot-stage microscope. The two highest melting polymorphs, A and B, show only a single peak due to melting at all heating rates, with onset temperatures of 105 and 103 "C, respectively. The remaining three polymorphs, C, D and E, each show a single melting endotherm at 96,94 and 92.5 "C under rapid heating rate conditions of 32 "C min-1. At lower heating rates they all display a melting endotherm adjacent to a recrystallization exotherm (similar to that shown in Fig. 6, c) followed by a melting endotherm at 105 "C.This was interpreted as the formation of polymorph A from the melt. Grinding or compressing the polymorphs C, D and E caused an increase in the area under this higher melting peak and a small reduction in the observed temperature of all the endotherms. In view of this and the closeness of the melting points it is difficult to be sure that A and B do not represent only one polymorph and C, D and E another, although there is some evidence of a third endotherm in some of the thermograms and evidence from the other papers of at least four forms. Subsequent studies have identified other fo1-t-11~43 1 and confirmed the sensitivity of the results to the thermal history of the sample.432 By contrast, the melting points of the three polymorphs of gepirone hydrochloride433 are substantially different and the conclusions from thermal analysis about the relationship between them unambiguous. Under siow heating conditions, samples of the low melting polymorph (mp 180 "C) showed an endotherm due to the transformation to the higher melting polymorph. At faster heating rates, a melting endotherm followed immediately by an exotherm representing re-solidifi- cation of the higher melting polymorph was observed. The higher melting polymorph then melted at 220 "C.This interpretation of the DSC measurements was confirmed by hot- stage microscopy. By prolonged heating of the lower melting polymorph it could be converted entirely to the higher melting form. The sample then showed a single endotherm at 220 "C. The endotherms of mixtures showed the disproportionate effect of small quantities of the higher melting form.The third polymorph could only be produced by crystallization as a minor component of a mixture. From DSC supported by thermomicro- scopy the melting endotherm could be identified at 212 "C. Consideration of the relative thermal stabilities allowed small samples of the pure polymorph to be produced by heat treating mixtures in the calorimeter; the pure polymorph so produced showed only a single endotherm at 212 "C whereas the mixture had shown endotherms at all three melting points. From these experiments it was possible to decide on the relative thermal stabilities of the polymorphs and to calculate their heats of fusion. The most important advance in understanding of the thermodynamic relationships between polymorphs and in interpretation of DSC curves has been through the formulation of Burger's rules.1369434 Two of these will be discussed here and the other two in Solubility and Density Measurement. Burger's heat of transition rule implies that ( i ) if an endothermic transition is observed at a certain temperature on heating, then there must be an enantiotropic transition point at or below that temperature; but (ii) if an exothermic transition is observed, then the transition point must lie above that temperature, or the two forms are related monotropically.Burger's heat of fusion rule is of value when the heat of transition cannot be observed, owing to the failure of the polymorphs to transform readily. This states that the higher melting polymorph will have the lower heat of fusion if the polymorphs are in an enantiomorphic relationship, otherwise they are monotropically related. Because of the misunder- standing of these rules which is apparent from the literature, and because of the insight into the stability relationships between polymorphs which they yield, a simplified derivation will be given here. Fig.7(a) and (b) are representations of the Gibbs-Helmholtz equation for enantiotropic and monotropic cases, respectively. The shape of the H (enthalpy) curves is determined by H = H, + jc,dT. Since the specific heat C, is always positive, they must slope upwards at an increasing rate with temperature, as shown. G, the Gibbs energy, is related to the negative summation of all the entropies, S.The value of S is again dependent on C,. The value of S must be positive, therefore the G curves must slope increasingly downwards, again as shown. At absolute zero, H = G and the curves meet. The lowest energy crystalline structure at absolute zero will have the strongest intermolecular bonds. Strong bonds imply high lattice vibration frequencies (phonon modes396943s) which make the smaller contribution to C,. Therefore, the angle of divergence of the G and H curves of the polymorph most stable at low temperatures will be less than that of the less stable polymorph. Hence the G curves will tend to cross, but the H curves will not. The heat of transformation rule can be ascertained by concentrating on the H curves and noting the enthalpy consequences on going from Ha to Hb or vice versa, remembering that this is only possible by lowering the Gibbs energy, i.e., AG must be positive.Hence processes which are exothermic on raising the temperature are spontaneous ones and are irreversible at or below that temperature, and vice versa for endothermic processes. The heat of fusion rule depends on the enthalpy curves for the polymorphs and the liquid phase being approximately parallel over the relevant region, so that the differences in C, do not obscure differences in the heats of transition. These rules are extra-thermodynamic, in that they involve structural considerations, so they are not 100% certain. It is not clear whether there are any exceptions in practice as re- evaluation of the literature data has eliminated many of the apparent exceptions.42 These rules, as already implied, can be helpful in sorting out DSC results.The concept of enantiotropism as reversibility needs to be approached with caution. Mirror image curves cannot be expected on heating and cooling. Apart from Ostwald's r~le~57,~36 and hysteresis due to high energy bar- riers,194,434 leading to offset of heating and cooling events, consider the energy-temperature diagram for a trimorphic enantiotropic system, Fig. 8(a). The heating cycle might produce transformations at A, B and C whilst the cooling cycle might proceed via any of the many paths on the diagram. A form such as polymorph I1 in Fig. 8(b) which is metastable at any temperature would be most unlikely to form on heating, but could well be the product of cooling the melt.Analyst, October 1995, Vol.I20 2449 For investigation of melting by DSC, small samples are usually appropriate and the temperature of melting is taken as either the peak maximum, or more precisely as a peak maximum corrected for heat f l 0 ~ 3 ~ 5 or as the extrapolation of the leading edge back to the base li11e.~37 Because solid-solid transforma- tions are often s l ~ g g i s h l ~ 7 , ~ 3 ~ and may reflect very small enthalpy changes, the use of larger quantities of compacted sample has been recommended, together with low heating rates and the assignment of the first discernible movement away from the base-line as the transition temperature. 197 The appropriate- ness of this may depend on the thermal stablity of the material under examination.Similar treatment of cooling curves then yields a transition range dependent on the hysteresis of the system. Organic compounds may be more appropriate cali- brants than the almost universally used indium, as they are likely to have conductivity characteristics similar to the sample. 197,439 It is often implied in accounts of the determination of purity by DSC that the true melting endotherm of a pure substance will be infinitely sharp,MO but of course this cannot be so for organic powders. Apart from practical considerations of thermal conductivity, edges and surfaces are less stable than bulk and will melt first and so small crystals will melt before larger ones.441 Melting normally starts at crystal defect sites. The observed melting will also be affected by a polymorphic transition very near to the melting temperature or decomposi- tion at the melting point and, of course, impurities.Although it was generally thought that the melting temperature could not be exceeded without melting occurring, there are scattered reports of slow melting4427443 and superheating444 and increasing acceptance of the existence of this phenomenon.445 In addition there are instrumental factors. Different instruments (DSC, DTA, melting point apparatus, hot stages, thermal photometers) measure different manifestations of the melting process and so will not necessarily give the same value. 196,199 All these factors apply also to solid-solid transformations. Even after the elimination of the possible effects, there still remain un- explained examples of anomalous melting behaviour.For obvious reasons most of these never appear in the literature but there are a few44w49 and further examples are known to the author. Note that whilst examples of curious melting and transition behaviour ought to be carefully checked, they are not necessarily the result of inaccurate observation. A large endotherm followed by a small melting endotherm is characteristic of the formation of a disordered phase in which the positional order of the crystal is retained, but the orientational order is 1ost.8,275,426,438 This may be due to random orientation of molecules, but is most often associated in organic systems with the onset of 'free' rotation. Molecules of roughly spherical shape are particularly likely to show an order-disorder transition to a plastic crystal state.8,224,426,450.451.At lower temperatures, crystals of such molecules sometimes show a glass transition in the crystalline ~tate.~52,453 Order-disorder transitions have been regarded as second-order transi- tions, 154~18*,454 but organic examples are not characterized by 'second-order ' DSC traces. Although second-order transitions are widely discussed in the literature, the concept presents certain difficulties as has been well addressed by West.154 On the whole the term is better avoided, except in reference to glass transitions, in considering the inter-relationships of organic polymorphs. From a study involving a selection of appropriate techniques it should be possible in most cases to acquire a reliable listing of the polymorphs, their relative stabilities and their transition points, which is as far as present day economics of industry may allow.However, a study is incomplete without the drawing of a semi-schematic energy-temperature or the equivalent pressure- temperature diag1-am.~33 If all the relevant data have been assembled such a figure takes, except in complicated cases, only a few minutes to prepare. The discipline of setting out the results in this form leads to a great confidence that the system is understood and avoids the erroneous descriptions of poly- morphic systems sometimes presented in the literature.35 Whilst the unwelcome appearance of a further polymorph at a late stage of investigation cannot thereby be excluded, it is rendered less likely.A development which offers greater sensitivity as well as enabling overlapping spontaneous and reversible processes to be separated is oscillating, alternating or modulated DSC.455 The superposition on the temperature ramp of a periodic temperature function allows a computational separation via a Fourier transform. Although the rate of modulation in commer- cial instrumentation is too slow for many polymorphic transi- tions, it is already being found useful in pharmaceutical investigations. Thermosonimetry456 is a relatively unexplored technique owing to the lack of convenient instrumentation and the dearth of applicable theory. It is mentioned here because it would appear to have considerable potential for the identification of phase changes and possibly for the understanding of the crystal structure changes accompanying these.The frequency spectra of the sonic emission of solids on heating are very rich, although it is only possible to use these at present as a signature.4",458 Phase changes are accompanied by increased activity and a change in the spectrum. Solubility and Density Measurement These are two of the measurements traditionally used to identify polymorphic behaviour. They remain important today: solu- bility because that is often the target property which is required of the polymorph in practice: and density because of its reliability and theoretical linkage with crystal structure and with stability. A pigment which bleeds, a solution of an agrochem- ical* which is liable to precipitate and block spray nozzles or a suspension of any product which cakes47-493461 during storage is probably unmarketable.The solubility also has an important thermodynamic feature: it is inversely related to the stability of the polymorph such that the most stable polymorph is always the least soluble at a given temperature.19.34 At a transition point, the interconverting polymorphs are equally soluble. There is an implicit assumption behind these assertions that the solutions prepared from either of the polymorphs are identical. There is limited evidence against this in some cases. For example, in the case of sulfonamides the polymorph crystalliz- ing from solution is dependent on that dissolved.462 In principle then, the determination of the solubility over a temperature range for two or more forms of a substance will readily establish the transition points and thermodynamic stabilities.463 It is the author's experience, however, that the measurement of solu- bility gives rise to more difficulty and more erroneous data than any other connected with polymorphism.The problem is three- fold. (i) The attainment of equilibrium is often slow, particularly with poorly soluble or poorly wettable sub~tances,~64 for which several days' agitation may be required to establish a consistent value. Either through system instability, lack of awareness or time constraints this is often not done and the measured solubility is then effectively a dissolution rate measurement. This latter, whilst related to solubility via the Noyes-Whitley equation465 and so roughly parallelling it in many cases, is also a direct function of surface area and therefore of particle size.36,466 If particle size is checked only instrumentally * Examples of polymorphs of agrochemicals in the open literature are few, E .R . , B~rka.~sY Instability of formulations is more often related to supersaturation than to polymorphism and problems are often solved pragmatically. However, the more sophisticated formulations now being introduced demand attention to polymor- ~hism.~Go2450 Analyst, October 1995, Vol. 120 (Coulter counter, Malvern analyser) over-all aggregate size rather than individual grain size may well be measured.467 Any differences in grain and aggregate size can then result in erroneous solubility comparisons.A preliminary microscopic examination will give forewarning of such a situation, but may not indicate how to solve it. Intrinsic dissolution measure- ments464.468 may provide a surrogate solution to the problem. ‘Surrogate’ because there are both practical and theoretical reasons why the intrinsic dissolution rate ratio of polymorphs will only approximate the relative solubilities. (For an example see Table 1 in the study by Buxton, et ~1.~69). Wettability differences can totally destroy any correlation.470.471 Nor can slow equilibrium be overcome by working at higher tem- peratures followed by cooling, because the temperature- solubility hysteresis usually determines an even longer equili- bration time. The second factor is the susceptibility of the polymorphs to transformation when examined outside their stability ranges.472 As indicated earlier, the presence of a solvent can be particularly efficacious at promoting a polymorphic transition. It is often possible to measure the solubility of a polymorph below its lower transition point, but rarely many degrees above its upper one.(ii) The possibility of a transformation to a s0lvate,~73 or hydrolysis146 or other chemical reaction. Sometimes the shape of a solubility-time curve will indicate whether a trans- formation is occurring, but whether or not this is so depends on the relative kinetics of the dissolution and transformation processes. One solution is to measure the solubility of the polymorphs in an inert solvent and then measure the partition coefficient rapidly.474 (iii) There are the consequences of pH variation in the measurement of the solubility of ionizable spe~ies.~63,~~5 The self-buffering capacity of organic acids and bases can often make a dramatic difference to the observed solubility.The need to match buffer capacity to the expected solubility is rarely considered.476 Trace ionic477 or other (oxygen, carbon dioxide) contamination can occasionally present a source of error. If the solubilities are being measured spectrophotometrically the effect of pH or complexation on the absorption spectrum also needs to be taken into acco~nt.36,~78 When the solubilities cannot be determined in the region of the supposed transition point, it is possible to extrapolate from other temperatures using the van’t Hoff isochore.This proce- dure needs to be applied with caution as the experimental inaccuracies and theoretical assumptions are often not appre- For molecular solids in which hydrogen bonding is not a structural feature, the stability of a form is nearly always closely related to the density. Although this relationship, as a con- sequence of the rapid reduction of intermolecular attractive forces with distance, has been understood for a long time, the structural implications were first explored in detail by Kitaigor- odski.480 Dipole4ipole interactions can contribute to the structural stability (surprisingly, however, they do not appear to contribute to the preferential formation of polymorphs481), but the only common and significant attractive force other than van der Waal’s forces is hydrogen bonding.This can produce more open structures in which the loss of polarizability energy is matched by favourable disposition of the strong hydrogen bonds. This is the basis of the other two of Burger’s rules,l36 namely the density rule ‘the more stable polymorph at absolute zero will possess the highest density’ and the IR rule ‘the highest frequency OH or NH stretching band will be associated with the form least stable at absolute zero’. The highest frequency OH or NH stretching will be associated with the weakest hydrogen bond. Juxtaposition with the heat of transformation and heat of fusion rules will usually allow the deductions to be generalized to working temperatures. Con- sideration of the circumstances pertinent to these rules could ciated.77,162,463,479 lead to the expectation of exceptions. It is found in practice that whilst there is a small proportion of exceptions to each rule, their complementarity makes the concurrent failure of both rules less likely.42 Density can be measured by flotation,482,483 by volume- nometry, or by pykn0met1-y.~~~ All are time consuming.Alternatively the true density* can be calculated from the unit cell dimensions.485 The latter must always be marginally greater than the measured density, as the crystal voids and other defects always lower the overall density of the crystals. Any discrep- ancy is a warning of solvates or other incorrectly assumed molecular structure. Generally, the measured density will increase marginally on grinding as a result of cracking occurring preferentially at crystal pores and defects, but on prolonged grinding it may begin to decrease owing to increased surface area and amorphization.42.486 An attempt to check Burger’s density rule against the true densities by using the Cambridge Crystallographic Data Centre data base for X-ray structures failed for the reasons mentioned earlier.The air comparison pyknometer represents an instrumental method of measuring densities with enhanced sensitivity. Flotation is best carried out with centrifugation and it may detect the presence of interloper crystals of a different polymorph in a specimen. The main problems with flotation are in finding a liquid mixture of suitable density that does not dissolve the sample and in maintaining that density through adequate temperture control.The first requirement is particu- larly critical for organic polymorphs. Solvates Hydrates or other solvates often produce a further level of complexity in a polymorphic system.487,488 There is the expectation of a monohydrate or monosolvate but, in fact, the accommodation in a unit cell for a small molecule can produce multiple,489~490 fractional,282 irrational412 or ~ariable469.~91 molar ratios. Amongst the polymorphs of a molecule some can be hygroscopic and others stable to water or water vap0ur.~89 Different hydrates can be produced from different poly- m0rphs.~5 This is probably related to the ‘stuffing’ effect of impurities described by Buerger.3 Where there are two or more hydrates of the same composition, these are in a polymorphic relationship with each other.l38 In practice it may be difficult to interconvert polymorphic solvates, because of the likelihood of preceding d e s o l ~ a t i o n .~ ~ ~ . ~ ~ ~ The desolvation of a solvate can sometimes produce a polymorph not obtainable in any other way.138,389 A detailed study of celiprolol hydrochloride has shown that the hydrate is not a true one in the usual sense but appears to be a solid solution of the drug in water.492 This leads to speculation about the exact nature of the crystal structure involved. Thermomicroscopy in silicone oil will reveal desolvation on heating by bubble formation.178 DSC will show features corresponding to solvent loss, but such features are notoriously sensitive to heating rate, crystal size, mass of sample, sample packing, and to the use of open as against closed or sealed pans or even pan shape.427 When the transitions are accompanied by inhomogeneous melting (dissolution) or a mixture of in- homogeneous and homogeneous melting282 or when the desolvation overlaps the normal melting or a phase transition, the DSC can become difficult on interpret.Another phenom- enon which leads to confusion when the DSC trace is viewed in isolation is stepwise loss of solvent, especially when this occurs in irrational proportions.492 A simultaneous TGA is of unique * The term ‘true density’ is used by other authors in contrast with bulk density to describe what is here called the ‘measured density’. For a discussion of different measures of density, see Lowell and Shields.484Analyst, October 1995, Vol.120 245 1 value in these cases in pinpointing the temperature or tem- peratures of solvent loss in the particular run. It cannot be necessarily assumed that the form resulting from recrystalliza- tion from an ‘anhydrous’ solvent will be the anh~drate.~9~ In contrast, the anhydrous form I11 of cortisone acetate is reported as only obtainable in the presence of water, whilst the hemihydrate is produced from wet solvents and the mono- hydrate from dry solvents.488 Erythromycin dihydrate is said to dehydrate when heated in water at lower temperatures than in Whilst X-ray powder diffraction patterns will distinguish a solvate except for the rare examples discussed earlier, they do not display any characteristic features of the solvent as such.By contrast, all of the common solvents have strong and distinct bands in the IR spectrum which generally reappear at the same or similar wavelengths in the ~olvate.~95 Those bands sensitive to hydrogen bonding will shift, but these shifts are again very characteristic. It could be supposed that except for very low molar ratios of solvent or high molecular mass compounds, IR spectra would be a totally reliable reflection of the presence of a solvate. The bands due to water are often difficult to distinguish from those due to hydrogen-bonded hydroxy groups in the host molecules and there are occasional reports of the indistinguishability of IR spectra of hydrates and other sol~ates.365.~30,496,~97 There is the danger of pumping off the solvent if the sample is prepared as a KBr disk, or of rehydration.365 Some of the literature reports may well reflect this.Hydrates have occasionally been mistaken for enolic tautomers498 and frequently for simple polymorphs. A mic- roanalysis, Karl-Fischer or mass loss determination will avoid such misinterpretation. Quantitative DSC has also been used to determine the degree of hydration, based on assumptions of the energy of binding of the water molecules.499 Solid-state 13C NMR spectra will show bands due to solvate guest molecules but not, of course, to water. The presence of the latter will affect the positions of other signal~,3~9?500 except presumably in those cases where X-ray diffraction shows no change in packing. In one such case of spectral indistinguishability, resort was made to differences in spin-lattice relaxation times.346 The solubility of a hydrate in water or a solvate in its own solvent is always less than that of the unsolvated form, for thermodynamic reasons.On the other hand, the solubility of the hydrate in ethanol or of an ethanolate in water will be always greater than that of the unsolvated f0rm.~63 The vacuum microbalance which measures the mass of a sample under different pressure and humidity conditions is a valuable way of quantifying the stepwise loss and gain of solvent.501 ak.417.487 Quantitative Aspects The requirement of analytical control implies reliable methods of detecting, distinguishing and quantifying polymorphs. All the caveats in the examination of polymorphs referred to previously apply with greater force when quantification is required.A method needs to be selected in which the differences between the polymorphs is maximal, yet unlikely to be interfered with by the presence, in particular, of other potential polymorphs or solvates. X-ray powder crystallograpy,359~393~502 IR,2347469 NIR291 and Raman308 spectroscopy, DSC234 and DTA503 have all been investigated for the determination. They have a common feature, namely that the transfer of energy to and through the powdered sample is one of the critical factors with respect to the precision of the measurement. Whilst solution transmission properties are capable of being dealt with theoretically, powder absorption can only be tackled when simplifying assumptions are made.251>504 The critical features are the particle size and shape of the sample and of the diluent, if one is present, and the homogeneity.505 It is therefore necessary to grind, and to grind reproducibly.The sample then needs as a minimum requirement to be stable under the grinding conditions. Again microscopy comes into play to check whether the sample is dispersed. Care must be taken to ensure that the sample is quantitatively transferred with the matrix powder, rather than left coating the vesse1.505 This applies particularly to greasy, low melting or plastic crystals. Each compound will present its own problems. It is unlikely that any one technique will prove universally suitable. Because of the small differences that are commonly encountered, realistic limits of quantifica- tion even with the use of chemometric methods will probably be 1-lo%, dependent on the individual problem.The few examples in the literature on the determination of polymorphic mixtures support most of these contentions. The precautions needed to obtain reliable results in DRIFT spectra have been explored in detail in the case of sulfametho~azole~3~ and of a new anti-inflammatory drug.226 The potential of X-ray methods have been explored on a model system.394 Although it has a long history,359 quantitative X-ray analysis has often been used without attention to possible sources of error. The a-inosine content of mixtures of a- and P-inosine has been investigated by both X-ray powder diffraction and IR spectroscopy.393 The limit of detection by the X-ray method was decidedly superior to that by IR spectroscopy, but the IR spectra display some curious features.X-ray diffraction has also been used for the detection of a-prasosin in y-prasosin. Using a profile fitting analysis, a detection limit of 0.5% was achieved.506 Possible interference from other polymorphs was not considered. The polymorphic composition of cortisone-acetate mixtures and of a candidate hypolipidaemic drug have been determined by Raman spectros- copy,309 as has chlorpropamide.507 DTA was found to be superior to X-ray powder diffraction for the determination of fatty acid polymorph~.~~3 If the enthalpy of solution of two polymorphs is sufficiently different, then solution calorimetry can be used for their determination in a mixt~re.~O~>509 The solution obtained by dissolution of one polymorph must be the same by definition, as that obtained from another polymorph of the same sub- ~tance.199~62 The difference in heat (enthalpy) of solution therefore determines the relative enthalpies of the poly- morphs.463 the polymorph stable at lower temperatures will have the lower enthalpy (see Fig.7). The determination can be made indirectly from solubility measurements over a tem- perature range with the application of the van’t Hoff isochore or preferably, directly by measuring the heat of solution in an adiabatic ~alorimeter.~63 The enthalpy difference will be the same whatever solvent is chosen: therefore it is possible to select one in which adequate solubility is shown. The occurrence of polymorphic change during dissolution will not affect the calorimetric result, as the heat of transition will be summed in the measured heat of diss0lution.~~3 X-ray powder studies are most commonly used to determine the degree of crystallinity.510 Solution calorimetry has also been applied to the determination of degree of crystallinity of partly amorphous antibiotics, proving more reliable than X-ray powder meth- 0ds.512 The values of crystallinity determined by the two methods were substantially different.The polymorphic compo- sition of phenobarbitone411 and phenylbutazone512 by X-ray powder diffraction and by DSC have also been reported to be different, but no explanation of either of these observations has been offered. Amorphous and Crystalline Solids There are different schools of thought as to whether amorphous states ought or ought not to be included in the definition of polymorphism.513 Crystalline solids are distinguished by the presence of periodic pattern repetition in three dimensions2452 Analyst, October 1995, Vol.120 leading to long-range order*: this can be defined as the expectation of finding an identical pattern repeated at regular intervals in any direction throughout the solid.514 Isotropic liquids and amorphous solids, on the other hand, have no long- range order so the most that can be said about the structure is that the probability of finding a particle distant from any point is given by the particle density. The neatness of this distinction has been obscured firstly by the existence of liquid crystals515 with one- or two-dimensional long-range order and incommensurate phases516 and more recently by the discovery of quasicrystals517~518 with long-range non-periodic order,519 often characterized by pseudo five-fold crystallographic axes,520?521 some of which enjoy greater stability than the equivalent crystalline ~ t a t e .5 ~ ~ The term non- crystaliine therefore does not imply total randomness an( / :here 0 TI Tf.Brf,A Temperature/K Fig. 7 Energy-temperature diagrams of dimorphic systems. Reproduced from Burger, A., and Ramberger, R., Mikrochim. Actu, 1979, 11, 261 by permission of Springer-Verlag, Vienna (a) Enantiotropic systems and (b) monotropic systems. (Tp, transition point; Tf, fusion point; H , molar enthalpy; G, molar free energy; S, molar entropy; A, B: crystalline modifications; 1, liquid phase).* More precisely, the definition of a crystalline array is given by: lim I x - x’ I -+ m < p (x) p (x:) > = F(x - x’) Where < p (x) p (x’) > is the density-density correlation between two points x and x’ related by a basis factor. Isotropic liquids and amorphous solids, on the other hand, have no long-range order, so the probability of finding a particle distant from x is given lim 1 x - y’ 1 + m < p (x) p (x’) > = p2, by where p is the average particle density. is an increasing awareness of the possibility of different amorphous structures.523-524 For example, the amorphous and liquid state are generally considered to represent the same phase, yet there are substances which exist in two amorphous forms separated by what appears to be a phase t r a n s i t i ~ n .l ~ ~ ? ~ * ~ . Different amorphous structures may arise from different processes of production.5257526 In practice many of the organic materials usually described as amorphous are the ‘meringues’ produced by evaporation of solvent from solutions of sub- stances which do not crystallize readily, or the powders produced by precipitation, transition,487 freeze drying,527 spray drying259,528 or grinding,49 although the terms microcrystalline or colloidal might be more appropriate, dependent on the size of the crystalline volume. The concept of an amorphous solid as microcrystallite clusters rather than as a continuous random network or dense random packing has fallen into disfavour, but most of the work has been done with semiconductor materials, and the conclusion may not apply to organic molecular solids.Quasicrystal clusters or ‘amorphons’ may need to be considered for organic states.8.9~529 However, there is limited possibility with the analytical tools presently at our disposal of deciding the nature of the detailed structure of amorphous materials. X-ray crystallography has been the most used technique for establish- ing structure both in terms of long- and short-range order,9,358,530, although calorimetric methods, vibrational spec- troscopy, and increasingly NMR spectro~copy~~ 1,532 provide structural information. Solid-state 13C NMR spectroscopy can show, for example, conformational preferences of molecules even when there is no discernable X-ray Despite this, there has been an almost total neglect of the study of organic amorphous materials.When they are reported they are usually characterized inadequately, if at all. It is not always possible even to ascertain if the reported lack of crystallinity is derived from visual examination, polarized light microscopy or X-ray examination. The significant advances in our under- standing of the amorphous solid-state have come recently not in the area of structure but in recognizing the entropic relation- ships between liquids, crystals and the amorphous state.533-537 The most investigated amorphous materials are p0lymers36~ and inorganic glasses formed by cooling silicate melts3 although amorphous metals and semiconductors have become the subject of intense research activity in recent years.320,539 The solids most typically and traditionally regarded as amor- phous are those produced by cooling a liquid in the absence of crystallization.During this process the material passes by continual change from a liquid state though the glass transition to a solid state, via a more viscous, possibly rubbery or malleable ~tate.5~095~~ The term ‘supercooled liquid’ gives rise to some confusion.542 A solid is usually arbitrarily defined as a material whose shear viscosity exceeds 10’4.6 poise (10’3-6 N s m-2).515 Amorphous materials have therefore been described as having the rheological properties of a solid but the structure of a liq~id.5~3 Given the limited knowledge of the structure of either liquids or amorphous materials, it may be felt that the latter half of that statement is ambitious. The glass transition temperature is the point at which the melt sets, accompanied by changes in many other properties.There are several methods of investigating the glass transition, including DSC.5449545 In the idealized case, the DSC trace shows no peak, but only a step representing a change in the heat capacity. This occurs only when the heating rate is the same as the cooling rate which has produced the glass. If the heating rate is faster than the cooling rate, an exotherm is superimposed and if the cooling rate is faster, the usual case, an endotherm is superimposed.546 These effects are due to strain as a result of the structure failing to reach equilibrium within the experimental t i m e - s ~ a l e .~ ~ ~ ~ In either case the underlying heat capacity change can beAnalyst, October 1995, Vol. I20 2453 obscured. The temperature of the glass transition is not fixed, but is lower the slower the cooling and heating rate~.~~29546 Amorphous solids are always less stable than crystalline forms and so on heating will normally show an exothermic transition to a crystalline phase, although this may be preceded by a glass tran~ition.2~2>~22 There are a few compounds which, as solids, are only known in the amorphous state and these display only a step corresponding to the glass tran~ition.5~7 Many organic materials can be prepared as glasses by rapid cooling. 162 Molecules with myriad conformational possibilities, particularly polysaccharides and synthetic polymers, tend to occur as amorphous forms.Molecules whose shape precludes a packing density, that is, the ratio of the volume occupied by the molecules as such to the volume of the space in which they reside, of at least 0.60 also solidify most easily as glas~es.~~,548 Directed bonds favour the more open structure implied by these low densities, so that multiply hydrogen-bonded molecules, for example, carbohydrates, are notoriously difficult to crystal- The industrial significance of amorphous organic materials has increased enormously. Polymers are, of course, ubiquitous. In the pharmaceutical industry there are compounds, partic- ularly antibiotics, which have long been used in that form because of the difficulty of crystallization and solubility lize.73,549,540 I , I I ./ I ' -QO\J"'- jmp TI Temperature + Fig. 8 Vapour pressure-temperature diagrams for trimorphic systems showing that heating and cooling curves can follow different paths via different polymorphs. Dashed lines represent metastable equilibria and full lines stable equilibria. The heating cycle in the system shown in (a) will probably proceed via A, B and C (but see ref. 194 and the caption to Fig. 6 whilst any propensity to undercool might give routes to polymorph I11 via CBF, CDB or CEA. In addition the paths may well end at the amorphous form or polymorphs I or 11. Similarly in (b) heating will probably proceed via A and B, but cooling could follow several paths. In either case spontaneous transitions (vertical drops) are also possible. problems of the crystalline forrns.439512,55 More recently attention has been paid to the deliberate use of amorphous forms with a crystallization inhibitor as a means of more rapid drug delivery.521 Interest in amorphous forms relates not only to active ingredients but to excipients including sugars550,552 and polymers.In the food industry, carbohydrates often need to be used in amorphous forms and many food constituents exist naturally in an amorphous state.66-73,553,554 Amorphous material may result from grindingM93555, deliber- ately or inadvertently. The effect of comminution of a crystal is to reduce the long-range periodicity and broaden the signals in X-ray diffraction patterns until in the limit the pattern is so diffuse as to be indistinguishable from that of an amorphous form produced from the melt.524 On this argument there is no break between a crystalline and an amorphous form.If by contrast, one cools a melt so as to produce a glass, then by this process there is no break between the liquid state and the amorphous form. There may be distinction between the products of the two processes. It may be possible in principle, or in practice in favourable cases, to distinguish between limit- ingly small crystalline domains and large non-crystalline domains, for example by analysis of the shapes of X-ray powder diffraction line~,~~~,405,556 but it would be very artificial to draw the boundaries of the coverage of this review between the two, especially as their properties for all practical purposes are likely to be identical.On balance then, the wider definition is adopted here, intended to allow the reader to decide on the inclusion of amorphous states or otherwise in the term polymorphism. On this wider definition, McCrones' view' that every system will be discovered to be polymorphic if studied enough, comes much nearer to verification. The author thanks numerous colleagues for their help in locating references. The IR spectra in Figs. 1 and 2 and DSC measurement in Fig. 6 were provided by P. Elliott and S. Taramer, University of York. I am grateful to G. Nichols of Pfizer, Sandwich, and Dr. B. Slater of Rh8ne-Poulenc Rorer, Dagenham, for suggestions about the manuscript and I am particularly indebted to Professor M. Hursthouse, University of Wales, Cardiff, for his comments on crystallographic aspects of the manuscript and for help in so many ways over many years.References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 McCrone, W. C. in Physics and Chemistry of the Organic Solid State, ed. Fox, D., Labes, M. M., and Weissberger, A., Interscience, New York, 1965, vol. 11, p. 725. Deffet, L., Re'pertoire des Compose's Organiques Polymorphes, Desoer, Liege, 1942. Buerger, M. J., Trans. Am. Crystallogr. Assoc., 1971, 7, 1. Bemstein, J. in Organic Crystal Chemistry, ed. Garbarczyk, J. B. and Jones, D. W., International Union of Crystallography, Oxford University Press, 1991. Dunitz, J. D., Pure Appl. Chem., 1991, 63, 177. Bayard, F., Decoret, C., and Royer, J., Stud. Phys. Theort. Chem., 1990, 69, 211. Rao, C. N. R., and Rao, K. J., Phase Transitions in Solids, McGraw- Hill, New York, 2nd edn., 1978.Ubbelhohde, A. R., The Molten State of Matter, Wiley, Chichester, 1978. Elliott, S. R., The Physics of Amorphous Materials, Longmans, Harlow, 2nd edn., 1990. Verma, A. R., and Krishna, P., Polytypism and Polymorphism in Crystals, Wiley, New York, 1966. Amelinkx, S., Acta Cryst., 1955, 8, 53. Amelinkx, S., Acta Cryst., 1955, 9, 16. Amelinkx, S., Acta Cryst., 1955, 9, 217. Dunitz, J. D., Pure Appl. Chem., 1991, 63, 177. Maliniak, A., Greenbaum, S., Poupko, R., Zimmermann, H., and Lutz, Z., J. Chem. Phys., 1993,97,4832.2454 Analyst, October 1995, Vol. 120 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 Bhide, V.G., Agrihotri, S. A., and Chaudra, S., Indian J . Pure Appl. Phys., 1981, 19, 821. Gruger, A., Romain, F., and Le CalvC, N., Thermochim. Acta, 1984, 116, 57. Reinke, H., Heinz, D., and Hans, M., J . Chem. Ed., 1993, 70, 101. Campbell, A. N. and Smith, N. O., Alexander Findlay’s The Phase Rule, Dover, New York, 9th edn., 1951. Sharma, B. D., J . Chem. Ed., 1987,64,404. Sirota, N. N., Cryst. Res. Technol., 1987, 22, 1343. Sirota, N. N., Cryst. Res. Technol., 1982, 17, 661. Doyle, B. B., Hukins, D. W. L., Hulnes, J. S., Miller, A. and Woodhead-Galloway, J., J. Mol. Biol., 1975, 91, 79. Oxford, G. S., and Rollinson, D., Protein Polymorphism: Adaptive and Taxonomic Significance, Academic Press, London, 1983. Jackson, A. P., Maxwell, A., and Wigley, D. B., J.Mol. Biol., 1991, 217, 15. Knobler, C. M., and Desai, R. C., Annu. Rep. Phys. Chem., 1992,43, 207. Chapman, D., Urbino, J. and Keough, K. M., J . Biol. Chem., 1974, 249,2512. Saito, H., Yuki Gosei Kagaku Kyokaishi, 1992, 50,488. Burden, C. H., PhD Thesis, University of Leeds, 1987. Corradini, P. and Guerra, G., Adv. Polymer Sci., 1992, 100, 182. CRC Handbook of Chemistry and Physics, ed. Weast, R. C., CRC Press, Cleveland, 61st edn., 1981, p. B-69. Wilson, A. J. C., Acta Cryst., Sect. A, 1988, 44, 715. Wilson, A. J. C., Acta Cryst., Sect. A, 1990, A46, 742. Kuhnert-Brandstatter, M. and Riedmann, M., Mikrochim. Acta, 1987, 11, 107. Burger, A., Acta Pharm. Tech., 1979, Suppl. 7, 107. Burger, A., in Topics in Pharmaceutical Sciences, ed. Bremer, D. D., and Speiser, P., Elsevier, Amsterdam, 1983, p.347. Halebian, J. K., and McCrone, W. C., J. Pharm. Sci., 1969, 58, 911. Halebian, J. K., J . Pharm. Sci., 1975, 64, 1269. Kuhnert-Brandstatter, M., Thermomicroscopy in the Analysis of Pharmaceuticals, Pergamon Press, Oxford, 1974. Bym, S. R., Solid State Chemistry of Drugs, Academic Press, New York, 1982. Aguiar, A. J., Krc, J., Kinkel, A. W., and Samyn, J. C., J . Pharm. Sci., 1967,56, 847. Burger, A., Phurm. Int., 1982,3(5), 158. Mullins, J. D. and Macek, T. J., J. Pharm. Sci., 1960, 49, 245. Bavin, M., Chem. Ind., 1989, 527. Nakamachi, H., Yamaoka, T., Wada, Y. and Miyaka, F., Chem. Pharm. Bull., 1982, 30, 3685. Chan, H. K., and Doelker, E., Drug Dev. Ind. Pharm., 1985, 11, 315. Macle, C. H. G., and Grant, D. J. W., Pharm.Int., 1986, September, 233. Thoma, K., and Serno, P., Deut. Apotek. Z., 1984, 124(43), 2162. Liversidge, G. G., Grant, D. J. W., and Padfield, J. M., Anal. Proc., 1982,549. Woodard, G. D., and McCrone, W. C., J. Appl. Crystallog., 1975, 8, 342. Kohlbeck, J. A., Microscope, 1982,30, 249. Teetsov, A., and McCrone, W. C., Microscope, 1965, 15, 13. Kendall, D. N., Anal. Chem., 1952,24, 382. Susich, G., Anal. Chem., 1950, 22, 425. Ebert A. A., and Gottlieb, H. B., J. Am. Chem. SOC., 1952, 74, 2806. Whitaker, A., J. SOC. Dyers Colour, 1992, 108, 282. Thomas, A., and Ghode, P. M., Paintindia, 1989, 39, 25. Kuhnert-Brandsttter, M. and Riedmann, M., Mikrochim. Acta, 1989, I, 373. Warwicker, J. O., J. Text. Inst., 1959, 50, T443. Etter, M. C., Kress, R. B., Bemstein, J., and Cash, D.J., J . Am. Chem. SOC., 1984, 106, 6921. The Physical Chemistry of Lipids, ed. Small, D., Plenum, New York, 1986. Crystallization and Polymorphism of Fats and Fatty Acids, ed. Garti, N. and Sato, K., Marcel Dekker, New York, 1988. Gupta, S., J. Am. Oil Chem. SOC., 1991, 94, 450. Srivastara, S. P., Handoo, J., Agrawal, K. M., and Joshi, G. C., J . Phys. Chem. Solids, 1993. 54, 639. 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 1 04 105 106 107 108 109 110 111 Ungar, G., J . Phys. Chem., 1983,87,689. Cebula, D. J., and Ziegleder, G., Fett Wiss. Technol., 1993, 95, 340. deMan, L., Shen, C. F., and deMan, J. F.,J. Am. Oil Chem. SOC., 1991, 68, 70. Saltmarsh, M., and Labuza, T. P., J .Food Sci., 1980, 45, 1231. Roos,Y., and Karel, M., Znt. J . Food Sci. Technol., 1991, 26, 55. Herrington, T. M. and Branfield, A. C., J. Food Technol., 1984, 19, 427. Cammenga, H. K., and Steppuhn, I. D., Thermochim. Acta, 1993,229, 253. Siniti, M., Carr6, J., Bastide, J. P., EtoffC, J. M., and Claudy, P., Thermochim. Acta, 1993,224, 105. Imberty, A., Buleon, A., Vihn, T., and Perez, S., StarchlStaerke, 1991, 43, 375. Bothe, H., and Cammenga, H. K., J . Therm. Anal., 1979,16,267. Pirttimiiki, J., Laine, E., Ketolainen, J., and Parrien, P., Znt. J. Pharm., 1993, 95, 93. Gunstone, F. D., Harwood, J. L., and Padley, F. B., The Lipid Handbook, Chapman and Hall, London, 2nd edn., 1994. Burger, A,, and Ramberger, R., Mikrochim. Acta, 1980, I, 17. Bavin, P. M. G., Sly, J.C. P., Tovey, G. D., and Ward, R. J., Ger. Offenlegung 1978,742,2,531. Cholerton, T. J., Hunt, J. H., Klinkert, G., and Martin-Smith, M., J . Chem. SOC., Perkin Trans. 2, 1984, 1761. Crookes, D. L., UK Pat. 2084580B, 1982. Guardian, September 9, 1994. Reutzel, S. M., and Etter, M. C., J. Phys. Org. Chem., 1992, 5, 44. Hammond, R. B., Roberts, K. J., Singh, D., and York, P., in preparation. Bemstein, J., J . Phys. D; Appl. Phys., 1993, 26, 1366. Bernstein, J., and Chosen, E., Mol. Cryst. Liquid Cryst., 1988, 164, 213. Sato, K., J. Phys. D; Appl. Phys., 1993, 26, B77. Desiraju, G. R., Crystal Engineering, Elsevier, Amsterdam, 1989. Gavezzotti, A., Acc. Chem. Rex, 1994, 27, 309. Mannock, D. A., Lewis, R. N. A. H., Sen, A. and McElhaney, R. N., Biochemistry, 1988,27,6852.Hartshorne, N. H., and Stuart, A., Crystals and the Polarising Microscope, Edward Amold, London, 4th edn., 1970, p. 20. Stobbe, H., Ber. Deut. Chem. Ges., 1905, 44, 2732. Bemstein, J., and Hagler, A. J., J. Am. Chem. SOC., 1978, 100, 673. Bancroft, J. Phys. Chem., 1898, 2, 143. Bancroft, J. Phys. Chem., 1899,3,44. Rao, B. R., Rao, G. R., and Avadhmlu, A. B., J. Sci. Ind. Res., 1987, 46, 450. Bym, S. R., Curtin, D. Y., and Paul, I. C., J . Am. Chem. SOC., 1972,94, 890. Elguero, J., Marzin, C., Katritzki, A. R., and Linda, P., The Tautomerism of Heterocycles, Academic Press, London, 1966. Desiraju, G. R., J . Chem. SOC., Perkin Trans. 2, 1983, 1025. Gassim, A. E. H., Takla, P. G., and James K. C., Int. J. Pharm., 1986, 34, 23. Costakis, E., Canone, P., and Tsala, G., Can.J . Chem., 1969, 47, 4483. Annese, M., Corradi, A. B., Forlani, L., Rizzoli, C., and Sgarabotto, P., J . Chem. SOC., Perkin Trans. 2, 1994, 614. Terol, A., Pauvert, B., Bouasseb, A., Chevallet, P., and Cassaneus, G., J. Therm. Anal., 1992, 38, 1545. Kehrmann, F., and Matusinsky, Z., Ber. Deut. Chem. Ges., 1912,45, 3498. Elguero, J., Marzin, C., Katritzki, A. R., and Linda, P., The Tautomerism of Heterocycles, Academic Press, London, 1966, Cleverly, B., and Williams, P. P., Tetrahedron, 1959, 7, 277. Kuhnert-Brandstiitter, M., and Sollinger, H. W., Mikrochim. Acta, 1990, III, 247. Katrusiak, A., J. Mol. Struct., 1992, 269, 329. Elguero, J., Marzin, C., Katritzki, A. R., and Linda, P., The Tautomerism of Heterocycles, Academic Press, London, 1966, p.5. Threlfall, T. L., PhD Thesis, University of London, 1972. Ojala, W. H., and Etter, M. C., J. Am. Chem. SOC., 1992, 114, 10288. Bernstein, J., Acta Cryst Sect. B , 1991, 47, 1004. p. 57.Analyst, October 1995, Vol. 120 2455 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 Bemstein, J., Acta Cryst Sect. C, 1988, 44, 900; Etter, M. C., Acc. Chem. Res., 1990,23,120; Aakeroy, C. B. and Seddon, K. R., Chem. SOC. Rev., 1993, 22, 397. Bernstein, J., in Organic Solid State Chemistry, Studies in Organic Chemistry, Vol. 32, ed. Desiraju, G. R., Elsevier, Amsterdam, 1987. Duax, W. L., J. Chem. Ed., 1988,65, 502. Blake, A. J., Gould, R. O., Halerow, M.A., and Schroeder, M., Acta Cryst., Sect. B, 1993, 49, 773. Fletton, R. A., Harris, R. K., Kenwright, A. M., Lancaster, R. W., Packer, K. J., and Sheppard, N., Spectrochim. Acta, Part A, 1987,43, 1111. Phillips, D. C., Acta Cryst., 1956, 9, 237. Senge, M. O., Hope, H., and Smith, K. M., J. Chem. SOC., Perkin Trans. 2, 1993, 11. Barikigia, K. M., Renner, M. W., Furentio, L. R., Medforth, C. J., Smith, K. M., and Fajer, J., J. Am. Chem. SOC., 1993, 115, 3627. Williams, P. P,, Acta Cryst., Sect. B, 1974, 30, 12. McDowell, J. J. H., Acta Cryst., Sect. B, 1977, 33, 5. Desiraju, G. R., Paul, I. C., and Curtin, D. Y., J. Am. Chem. SOC., 1977, 99, 1594. Penin, R., Lamartine, M., Pemn, R., and Thozet, A., in Organic Solid State Chemistry, Studies in Organic Chemistry, Vol.32 ed. Desiraju, G. R., Elsevier, Amsterdam, 1987. Brock, C. P., Schweizer, W, B., and Dunitz, J. D., J. Am. Chem. SOC., 1991, 113,9811. Eistert, B., Weygand, F., and Csenides, E., Chem. Ber., 1952,85,164. Okada, Y., Takebayashi, T., Mashimoto, M., Kasiga, S., Sato, S., and Tamura, C., J. Chem. SOC., Chem. Commun., 1983, 784. Wilson, K. R., and Pincock, R. E., Can. J. Chem., 1977,55, 889. Matthews, T. H., Paul, I. C., and Curtin, D. Y., J. Chem. SOC., Perkin Trans. 2, 1991, 113. McBride, J. M., Angew. Chem., Int. Ed. Eng., 1989, 28, 377. David, R., and Giron, D., Handbook ofpowder Technology, 1994,9, 193. Stezowski, J. J., Biedermann, P. U., Hildenbrand, T., Dorsch, J. A., Eckhardt, C. J., and Agranat, I., J. Chem. SOC. Chem. Commun., 1993, 213. Takasuka, M., Nakei, H.and Shiro, M., J. Chem. SOC., Perkin Trans. 2, 1982, 106. Zhang, Z., Rettig, S. J. and Orvig, C., Can. J. Chem., 1992, 70, 763. Nelson, W. O., Karpishin, T. B., Rettig, S. J., and Orvig, C.. Can. J. Chem., 1988,66, 123. Kessler, H., Zimmermann, G., Foerster, H., Engel, J., Oepen, G., and Sheldrick, W. S., Angew. Chem., Znt. Ed. Eng., 1981,20, 1053. Burger, A., and Ramberger, R., Mikrochim. Acta, 1979,11, 259. Mnyukh, Y. U., and Panfilova, N. A., J. Phys. Chem. Solids., 1973,34, 159. McCauley, J. A., Varsolona, R. J., and Levorse, D. A,, J. Phys. D; Appl. Phys., 1993, 26, B85. Westrum, E. R. and McCullough, J. P., in Physics and Chemistry of the Organic Solid State, ed. Fox, D., Labes, M. M., and Weissberger, A., Interscience, New York, 1963, vol. 1, p.76. Krc, J., Microscope, 1977, 28, 25. Gunning, S. R., Freeman, M., and Stead, J. A., J. Pharm. Pharmacol., 1976, 28, 758. Bar, I., and Bemstein, J., J. Pharm. Sci., 1985, 74, 255. Cleverley, B., and Williams, P. P., Chem. Ind., 1959, 49. Smakula, E., Gori, A., and Wotiz, H. H., Spectrochim. Acta, 1957,9, 346. Burger, A., and Ramberger, R., Mikrochim. Acta, 1979,II, 271. Threlfall, T. L.. and Slater, B. J., in preparation. Sukenik, C. N., Bonapace, J. A., Mandel, N. J., Land, P. Y., Wood, G., and Bergin, R. J., J. Am. Chem. SOC., 1977, 99, 851. Katritsky, A. R., and Lagowski, J. M.,Adv. Heterocyclic Chem., 1963, 1, 382. Iwatsu, F., J. Phys. Chem., 1988, 92, 1678. Dumas, J. P., Tounsi, F., and Babin, L., J. Dispersion Sci. Technol., 1987, 8, 29. Mesley, R. J., Clements, R.L., Flaherty, B., and Goodhead, K., J. Pharm. Pharmacol., 1968,20,239. Kuhnert-Brandstatter, M., and Moser, I., Mikrochim. Acta, 1979, I, 125. 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 Mnyukh, Y. V., and Petropavlov, N. N., J. Phys. Chem. Solids, 1972, 33, 2079. West, A. R., Solid State Chemistry and its Applications, Wiley, Chichester, 1984. Theocharis, C. R., and Jones, W., J. Chem. SOC. Chem. Commun., 1984,369. Theocharis, C. R., Jones, W., and Rao, C. N. R., J. Chem. SOC. Chem. Commun., 1984, 1291. Jones, W., Thomas, J. M., and Williams, J. O., Philos. Mag., 1975,32, 1. Kuhnert-Brandstatter, M., and Sollinger, H.W., Mikrochim. Acta, 1990, 111, 233. Barbour, R. H., Freer, A. A., and MacNichol, D. D., J . Chem. SOC., Chem. Commun., 1983,362. Kuhnert-Brandstiitter, M., and Moser, I., Mikrochim. Acta, 1981, I, 421. Kuhnert-Brandstatter, M., and Friedl, L., Mikrochim. Acta, 1979,II, 97. Burger, A., and Schulte, K., Arch. Pharm., 1981, 314, 398. Carter, P. W., and Ward, M. D., J. Am. Chem. SOC., 1994,116,769. Royer, J., Decoret, C., Tinland, B., Pemn, M., and Pemn, R., J. Phys. Chem., 1989,93, 3393. Etter, M., Britton, D., and Reutzel, S. M., Acta Cryst., Sect. C, 1991, 47, 556. Di, L., and Small, D. L., J. Lipid Res., 1993,34, 1611. Dunitz, J. D., and Bemstein, J., Acc. Chem. Res., 1995, 28, 193. Pfeiffer, R. R., J. Pharm. Pharmacol., 1971,23,75. Anwar, J., Tarling, S. E., and Barnes, P., J.Pharm. Sci., 1989, 78, 337. Harris, R. K., Kenwright, A. M., Say, B. J., Yeung, R. R., Fletton, R. A., Lancaster, R. W. and Mangrove, G. L., Spectrochim. Acta, Part A, 1990,46A, 927. Sntvity, D., Vancso, J., and Rutledge, G. C., Macromolecules, 1992, 25, 7037. Kaneko, F., Sakashita, H., Kobayashi, M., and Suzuki, M., J. Phys. Chem., 1994, 98,3801. Jones, W., and Thomas, J. M., Prog. Solid State Chem., 1980, 12, 101. Lourdin, D., Roux, A. H., Grolier, J. P. E., and Butsin, J. M., Thermochim. Acta, 1992, 204, 99. Lumley, C. E. and Walker, S. R., in Medicines: Regulation, Research and Risk, ed. Griffin, J. P., Greystone, Antrim, 1989, p. 157. Kofler, L., and Kofler, A., Thermomikromethoden, Wagner, Innsbruck, 1952. Hartshorne, N. H., and Stuart, A., Crystals and the Polarising Microscope, Edward Arnold, London, 4th edn., 1970.Kuhnert-Brandstatter, M., in Comprehensive Analytical Chemistry, ed. Svehla, G., Elsevier, Amsterdam, 1982, vol. XVI. McCrone, W. C., Fusion Methods in Chemical Microscopy, Inter- science, New York, 1957. Bloss, F. D., Crystallography and Crystal Chemistry, Holt, Reinhart and Winston, New York, 1971. Jordan, D. D., J. Pharm. Sci., 1993,82, 1269. Ojena, S. M., and DeForest, P. R., J. Forensic Sci. SOC., 1972, 12, 315. Ojena, S. M., and DeForest, P. R., J. Forensic Sci., 1972, 17, 409. Holik, A. S. and Taylor, D. F., Microscope, 1977,28,265. Bloss, F. D., The Spindle Stage, Cambridge University Press, 1981. Hartshome, N. H., Microscope, 1975,23, 177. Hartshome, N. H., Microscope, 1976, 24, 102.Hartshome, N. H., Microscope, 1976,24,215. McCrone, W. C., Microscope, 1991, 39, 43. Watanabe, A., Tanaku, Y. and Tanaku, Y., Chem. Phurm. Bull., 1977, 25, 2239. Saylor, C. P., Anal. Chem., 1975, 47, 1114. Chao, E. C. T., Am. Mineral., 1976,61, 212. Craven, B. M., and Vizzici, E. A., Acta Cryst., Sect. B, 1971, 27, 1917. Kuhnert-Brandstatter, M., Thermomicroscopy in the Analysis of Pharmaceuticals, Pergamon Press, Oxford, 1974, p. 19. McCrone, W. C., Discuss. Faraday SOC., 1949, 5, 158. Wiedemann, H. G., and Bayer, G., J. Therm. Anal., 1985, 30, 1273. Burger, A., Pharm. uns. Zeit, 1982, 11, 177.2456 Analyst, October 1995, Vol. 120 198 199 200 20 1 202 203 204 205 206 207 208 209 210 21 1 212 213 214 215 216 217 218 219 220 22 1 222 223 224 225 226 227 228 229 230 23 1 232 233 234 235 236 237 238 239 240 24 1 242 243 244 Kuhnert-Brandstatter, M., and Sollinger, H.W., Mikrochim. Acta, 1990,111, 137. Richardson, M. F., Yang, Q. C., Novotny-Bregger, E., and Dunitz, J. D., Acta Cryst., Sect. B, 1990, 46, 653. Kuhnert-Brandstatter, M., and Proell, F., Mikrochim. Acta, 1983,111, 287. Reffner, J. A., and Ferrillo, R. G., J . Therm. Anal., 1988, 34, 19. Cammenga, H. K., and Hemminger, W. F., Labo, 1990,21,7. Willis, H. A., van der Maas, J. H., and Miller, R. G. J., Laboratory Methods in Vibrational Spectroscopy, Wiley, Chichester, 3rd edn., 1987. Duyckaerts, G., Analyst, 1959, 84, 201. Rosenkrantz, H., and Zablow, L., Anal. Chem., 1953, 25, 1025. Baker, A. W., J. Phys. Chem., 1957, 61,450. Sharpless, N. E. and Gregory, D.A., Appl. Spectrosc., 1963, 17, 47. Griesser, U. J., and Burger, A., Sci. Pharm., 1993, 61, 113. Kobayashi, M., Matsumoto, Y., Ishida, A., Ute, K., and Hatada, K., Spectrochim. Acta, Sect. A, 1994, 50, 1605. Farmer, V. C., Spectrochim. Acta, 1957, 8, 374. Stewart, J. E., J . Chem. Phys., 1957, 26, 248. Kuhnert-Brandstatter, M., and Riedmann, M., Mikrochim. Acta, 1989, I, 81. Burger, A., and Ramberger, R., Mikrochim. Acta, 1979, 11, 271. Free, M. L., and Miller, J. D., Appl. Spectrosc., 1994, 48, 891. De Faubert Maunder, M. J., Practical Hints on Infrared Spectroscopy, Adam Hilger, London, 1971. Potts, W. F., Chemical Infrared Spectroscopy, Wiley, New York, 1963, vol. 1. Bradley, K. B., and Potts, W. J., Appl. Spectrosc., 1958, 12(3), 77. Roberts, G., Anal.Chem., 1957,29,911. White, R. G., Handbook of Industrial InfraredAnalysis, Plenum, New York, 1964. Fuller, M. P., and Griffiths, P. R., Anal. Chem., 1978, 50, 1906. Krishnan, K., and Ferraro, J. R. in Fourier Transform Infrared Spectroscopy, ed. Ferraro, J. R. and Basile, L. J., Academic Press, New York, 1982, vol. 3, p. 149. Harrick, N. J., Internal Reflection Spectroscopy, Wiley, New York, 1967. Mirabella, F. M., Internal Reflectance Spectroscopy, Marcel Dekker, New York, 1992. Kuhnert-Brandstatter, M., and Riedmann, M., Mikrochim. Acta, 1989, 11, 173. Schutte, C. J. H., and Paul, S. O., S . A f . Tydskr. Chem., 1986, 39, 252. Roston, D. A., Walters, M. C., Rhinebarger, R. R., and Ferro, L. J., J . Pharm. Biomed. Anal., 1993, 11, 293. Barker, S. A., Bourne, E.J., Weigl, M., and Whiffen, D. H., Chem. Ind., 1956, 318. Ford, M. A., and Wilkinson, G. R., J . Sci. instr., 1954, 31, 338. Price, W. C., and Tetlow, K. S., J. Chem. Phys., 1948, 16, 1157. Kuhnert-Brandstatter, M., and Bachleitner-Hoffman, F., Spectrochim. Acta, Part A, 1971, 27, 191. Kirov, N., Fontana, M. P., and Cavatorte, F., J . Mol. Struct., 1980,59, 147. Gruger, A., Romain, F., and le CalvC, N., Thermochim. Acta, 1984, 116, 85. Neville, G. A., Beckstead, H. D., and Shurvell, H. F., J. Pharm. Sci., 1992,81, 1141. Hartauer, K. J., Miller, E. S., and Guillory, J. K., Int. J . Pharm., 1992, 85, 163. Yeboah, S. A., Wong, S-H., and Griffiths, P. R., Appl. Spectrosc., 1984, 38, 259. Brimmer, P. J., and Griffiths, P. R., Appl. Spectrosc., 1988, 42, 242. TeVrucht, M.L. E., and Griffiths, P. R., Appl. Spectrosc., 1989, 43, 1492. Marabella, L. J., Appl. Spectrosc. Revs., 1985, 21, 45. Ibrahim, G., Pisano, F., and Bruno, A., J. Pharm. Sci., 1977, 66, 669. Hartauer, K. J., and Guillory, J. K., Pharm. Res., 1989, 6, 608. Katon, J. E., and Sommers, A. J., Anal. Chem., 1992, 64, 931A. Lagas, M., and Lerk, C. F., Int. J . Pharm., 1981, 8, 11. Burger, A., and Dialer, R. D., Pharm. Acta Helv., 1983, 58, 72. Vidine, D. W., in Fourier Transform Infrared Spectroscopy ed. Ferraro, J. R., and Basile, L. J., Academic Press, New York, 1982, vol. 3. 245 246 247 248 249 250 25 1 252 253 254 255 25 6 257 25 8 259 260 26 1 262 263 264 265 266 267 268 269 270 27 1 272 27 3 274 275 276 277 27 8 279 280 28 1 282 283 284 285 286 287 Graham, J.A., Grim, N. M., and Fateley, W. G., in Fourier Transform Infrared Spectroscopy, ed. Ferraro, J. R. and Basile, L. J., Academic Press, New York, 1985, vol. 4, p. 346. Belton, P. S., Saffron, A. M., and Wilson, R. H., in Analytical Applications of Spectroscopy, ed. Creaser, C. S. and Davies, A. M. C., The Royal Society of Chemistry, London, 1988. Rockley, N. L., Woodard, M. K., and Rockley, M. G., Appl. Spectrosc., 1984, 38, 329. Ashizawa, K., J. Pharm. Sci., 1989,78, 256. Griffiths, P. R., and Fuller, M. P. in Advances in Spectroscopy, ed. Clark, R. J. H., and Hester, R. E., 1982, 9, 63. Huvenne, R., Depecker, C., and Legrand, P., S.T.P. Pharma, 1989,5, 350. Chalmers, J. M., and Mackenzie, M. W. in Advances in Applied Fourier Transform Infrared Spectroscopy, ed.Mackenzie, M. W., Wiley, New York, 1988. Brickell, W. S., Proc. Anal, Div. Chem. SOC., 1978, 343. Yano, J., Ueno, S., Arishima, T., Sagi, N., Kaneko, K., and Kobayashi, M., J . Phys. Chem., 1993,97, 12967. Kaneko, F., Sakashita, H., and Kobayashi, M., Acta Cryst., Sect. C, 1994, 50, 245, 247. Kaneko, K., Shirai, O., Miyamoto, H., Kobayashi, M., Kitagawa, Y., Matsuura, Y., and Sasaki, M., J. Phys. Chem., 1994, 98, 2185. Kuhnert-Brandstatter, M., and Junger, E., Spectrochim. Acta, Part A, 1976,23, 1453. Ostwald, W., 2. Phys. Chem., 1897, 22, 306. Cocks, G. G., and Jelley, E. E., in Physical Methods of Chemistry, ed. Weissberger, A., and Rossiter, B. W., Wiley, New York, 1972, Matsuda, Y., and Tatsumi, E., Int. J. Pharm., 1990, 60, 11. George, W. O., Hassid, D. V., and Maddams, W.F., J . Chem. SOC., Perkin Trans. 2, 1973, 957. Snyder, S. G., Maroncelli, S., and Hallmark, V. M., J . Phys. Chem., 1986,90,5623. Chapman, D., J. Chem. Soc., 1958,3186. Rao, G. R., and Zerbi, G., Appl. Spectrosc., 1984, 38, 795. Gu, W., Anal. Chem., 1993, 65, 827. White, R. L., Appl. Spectrosc., 1993, 47, 1492. Bergin, F. J., Appl. Spectrosc., 1989, 43, 511. Humecki, H. J., Practical Guide to Infrared Microspectrometry, Marcel Dekker, New York, 1988. Nguyen, N. A. T., Ghosh, S., Gatlin, L. A., and Grant, D. J. W., J. Pharm. Sci., 1993, 83, 1116. The Design, Sampling, Handling and Application of Infrared Microscopes, ASTM Special Technical Publication 9494 , ed. Roush, P. B., American Society for Testing and Materials, Philadelphia, 1987. Marshall, A.G., Fourier, Hadamurd and Hilbert Transformations in Chemistry, Plenum, New York, 1982. Marshall, A. G., Chemom. Intell. Lab. Syst., 1988, 3, 261. Turner, P. M., Anal. Proc., 1986, 23, 268. Okada, Y., Takebayashi, T., and Sato, S., Chem. Pharm. Bull., 1989, 37, 5. Kellner, R., Kuhnert-Brandstatter, M., and Malissa, H., Mikrochim. Acta, 1988, 111, 153. Kuhnert-Brandstatter, M., and Moser, I., Mikrochim. Acta, 1980, 11, 333. Todori, K., Sano, K., and Mori, Y., Spectrochim. Acta, Part B , 1994, 50, 1201. Geiger, W., Spectrochim. Acta, 1963, 10, 655. Kuhnert-Brandstatter, M., Wurian, I., and Geiler, M., Sci. Pharm., 1982, 50, 91. Kuhnert-Brandstatter, M., and Wurian, I., Sci. Pharm., 1982, 50, 3. Borka, L., Acta Pharm. Suec., 1977, 14, 205. Bettinetti, G., Giordiano, F., Fronza, G., Italia, A., Pellegrata, R., Villa, M., and Ventura, P., J .Pharm. Sci., 1990, 79, 470. Burger, A., and Lettenbichler, A., Pharmazie, 1993, 48, 262. Kaye, W., Spectrochim. Acta, 1954, 6, 257. Osborne, B. G., Fearn, T., and Hindle, P. H., Practical NIR Spectroscopy, Longmans, Harlow, 2nd edn., 1993. Mark, H., Principles and Practice of Spectroscopic Calibration, Wiley, Chichester, 199 1. Smith, H. J., and Carl, R. T., Appl. Spectrosc., 1989, 43, 865. Ollinger, J. M., and Griffiths, P. R., Anal. Chem., 1988, 60, 2427. p. I11Analyst, October 1995, Vol. 120 2457 288 289 290 29 1 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 3 10 311 312 313 3 14 315 3 16 317 318 319 3 20 321 322 323 324 325 326 Barnes, R. J., Dhanoa, M.S. and Lister, S. J., Appl. Spectrosc., 1989, 43, 772. Aucott, L. S., Garthwaite, P. H., and Buckland, S. T., Analyst, 1988, 113, 1849. Miller, C. E., and Honigs, D. E., Spectroscopy, 1989, 4, 44. Gimet, R., and Luong, A. T., J. Pharm. Biomed. Anal., 1987, 5, 205. Colthup, N. B., Daly, L. H., and Wiberley, S. E., Introduction to Infrared and Raman Spectroscopy, Academic, New York, 2nd edn., 1975. Grasselli, J. G., and Bulkin, B. J., Analytical Raman Spectroscopy, Wiley, New York, 1991. Hendra, P. J., Jones, C., and Wames, J., Fourier Transform Raman Spectroscopy, Ellis Horwood, 1991. Hirschfeld, T., and Chase, B., Appl. Spectrosc., 1986, 40, 133. Bergin, F, J., and Shurvell, H. F., Appl. Spectrosc., 1989, 43, 516. Messerschmidt, R. G., and Chase, B., Appl.Spectrosc., 1989, 43, 11. Schrader, B., Hoffman, A., and Keller, S., Spectrochim. Acta, Part A , 1991,47, 1135. Loewenschuss, A., and Moss, A., Appl. Spectrosc., 1982,36, 183. Chase, B., Appl. Spectrosc., 1994, 48, 14A. Cutmore, E. A., and Skett, P. W., Spectrochim. Acta, Part A, 1993,49, 809. Wright, J. D., Molecular Crystals, Cambridge University Press, Cambridge, 1987. Cannon, C. F., Spectrochim. Acta, 1958, 10, 341. Schuster, P., Zundel, G., and Sandorfy, C., The Hydrogen Bond, North Holland, Amsterdam, 1976. Paul, S . O., Schutte, C. J. H., and Hendra, P. J., Spectrochim. Acta, Part A,, 1990, 46, 323. Zimba, C. G., Hallmark, V. M., Swalen, J. D. and Rabolt, J. F., Appl. Spectrosc., 1987, 41, 721. Waters, D. N., Spectrochim. Acta, Part A , 1994, 50, 1833. Deeley, C.M., Spragg, R. A., and Threlfall, T. L., Spectrochim. Acta, Part A , 1991, 47, 1217. Tudor, A. H., Davies, M. C., Melia, C. D., Lee, D. G., Mitchell, R. C., Hendra, P. J., and Church, S. J., Spectrochim. Acta, Part A , 199 1 ,,47, 1389. Kobayashi, M., Kobayashi, T., Itoh, Y., and Sato, K., J. Chem. Phys., 1984,80, 2897. Ishii, K., Kawahara, M., Yakasaki, Y., Hibino, Y., and Nakayana, H., J. Phys. D: Appl. Phys., 1993, 26, B193. Davey, R. J., Maginen, S. J., Andrews, E. J., Black, S. N., Buckley, A. M., Cotties, D., Dempsey, P., Plowman, R., Rout, J. E., Stanley, D. R., and Taylor, A., J. Chem. SOC., Faraday Trans., 1994, 90, 1003. Ip, D. P., Brenner, G. S., Stevenson, J. M., Lindenbaum, S., Douglas, A. W., Klein, S. D., and McCauley, J. A., Int. J. Pharm., 1986, 28, 183.Kaneko, F., Yamazaki, K., Kobayashi, M., and Sato, K., Spectrochim. Acta, Part A, 1995, 50, 1589. Sawatzki, J., Bruker Applications Note, Fourier Transform Raman Microspectroscopy, 1990. Messerschmidt, R. G., in The Design, Sampling, Handling and Application of Infrared Microscopes, ASTM Special Technical Publication 9494, ed. Roush, P.B., American Society for Testing and Materials, Philadelphia, 1987, p. 12. Cohen, M. D., Schmidt, G. M. J., and Flavian, S., J. Chem. SOC., 1964, 204 1. Pfeiffer, P., Braude, S., Kleber, J., Marcon, G., and Wittkop, P., Ber. Deut. chem. Ges., 1915, 48, 1777. Desiraju, G. R., Paul, I. C., and Curtin, D. Y., J. Am. Chem. SOC., 1977, 99, 1594. Qian, R., Mol. Cryst. Liq. Cryst., 1988, 171, 117. Enokida, T., and Enashi, S., Chem.Lett., 1988, 179. Takano, S., Enokida, T., Kakuta, A., and Mori, Y., Chem. Lett., 1984, 2073. Cook, M. J., in Advances in Spectroscopy, ed. Clark, J. H., and Hester, R. E., 1993, 22, 87. Klebe, G., Graser, F., Haedicke, E., and Bemdt, J., Acta Cryst., Secr. B , 1989,45,69. McKerrow, A. J., Buncel, E., and Kazmeier, P. M., Can. J. Chem., 1993, 71, 390. Loutfy, R. O., Hor, A. M., Kazmaier, P., and Tam, M., J. Imaging Sci., 1989, 33, 151. 327 328 329 330 33 1 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 35 1 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 Botoschanski, M., Herbstein, F. H., and Kapon, M., Acta Cryst., Sect. B, 1994,50, 191. Everett, A. J., personal communication. Childers, J. W., Rohl, R., and Palmer, R.A., Anal. Chem., 1986, 58, 2629. Daehnen, S., Bomowski, B., Grimm, B., Kulpe, S., Leopold D., and Naether, M., J. Signalaufzeichnungsmater., 1977, 5 , 277. Morel, D. L., Strogryn, E. L., Ghosh, E. K., Feng, T., Punvin, P. E., Shaw, R. F., Fushman, C., Bird, G. R., and Piechowski, A. P., J. Phys. Chem., 1984,88,923. Becker, H.-D., Hall, S. R., Skelton, B. W., and White, A. H., Aust. J. Chem., 1984,37, 1313. Sanchez-Felix, M., personal communication. Chandra, B. P., and Zink, J. I., Phys. Rev. B, Condens. Matter, 1980, 21, 816. Hardy, G. E., Kaska, W. C., Chandra, B. P., and Zink, J. I., J. Am. Chem. SOC., 1981, 103, 1074. Lynch, L. J., Webster, D. S., and Barton, W. A., Adv. Mag. Res., 1988, 12, 285. Dosseh, G., Fressigne, C., and Fuchs, A. H., J. Phys.Chem. Solids, 1992, 53, 203. Gavezzoti, A., and Simonetta, M., in Organic Solid State Chemistry, ed. Desiraju, G. R., Elsevier, Amsterdam, 1987. Chirlian, L. E., and Opella, S. J., Adv. Magn. Res., 1990, 14, 183. Harris, R. K., Chem. Br., 1993,601. Bruker CXP Applications Note, High Resolution NMR in Solids, 1983. Bugay, D. E., Pharm. Res., 1993,10, 317. Fletton, R. A., Lancaster, R. W., Harris, R. H., Kenwright, A. M., Parker, K. J., Waters, D. N., and Yeadon, A., J. Chem. SOC., Perkin Trans. 2, 1986, 1705. Bym, S. R., Pfeiffer, R. R., Stevenson, G., Grant, D. J. W., and Gleason, W. B., Chem. Muter., 1994, 6, 1148. Saindon, P. J., Cauchon, N. S., Sutton, P. A., Chang, C. J., Peck, G. E., and Byron, S. R., Pharm. Res., 1993, 10, 197. Suryanaryanan, R., and Wiedman, T.S., Pharm.Res., 1990,7, 184. Steiner, T., Hinrichs, W., Saenger, W., and Gigg, R., Acta Cryst., Sect. B, 1993, 49,708. Opella, S. J., and Frey, H. M., J. Am. Chem. Soc., 1979, 101, 5854. Byrn, S. R., Gray, G., Pfeiffer, R. R., and Frye, J., J. Pharm. Sci., 1985, 74, 565. Fyfe, C. A., Solid Stare NMR for Chemists, CFC, Guelph, Ontario, 1984. Etter, M., Jahn, D. A., and Urbanczyk-Lipkowska, Z., Acra Cryst., Sect. C, 1987,43, 260. Smith, J. A. S., Chem. SOC. Rev., 1986, 25, 225. Gourdji, M., GuibC, L., Kaplan, A., and PCneau, A., J. Mol. Struct., 1983, 111, 371. Rao, C. N. R., in Organic Solid State Reactions, ed. Desiraju, G. R., Elsevier, Amsterdam, 1987. van Driel, H. M., Wiszniewska, M., Moores, B. M., and Armstrong, R. L., Phys. Rev., 1972, 6B, 1596.Dove, M. T., and Rae, A. I. M., Faraday Discuss. Chem. SOC., 1980, 69, 98. Rae, A. I. M., and Dove, M. T., J. Phys. C., 1983, 16, 3233. Klug, M. P., and Alexander, L. E., X-ray DifSraction Procedures for Polycrystalline and Amorphous Materials, Wiley, New York, 2nd edn., 1974. Takahashi, H., Takenishi, T., and Nagashijna, N., Bull. Chem. SOC. Japan, 1962,35,925. Azibi, M., Draguet-Brughmans, M., Bouche, R., Tinant, B., Germain, G., Declercq, J.-P., and van Meersche, M., J. Pharm. Sci., 1983,72, 322. Forni, A., Moretti, I., Torre, G., Brueckner, S., Malpezzi, L., and DiSilvestro, G., J . Chem. SOC., Perkin Trans. 2, 1984,791. Fuhrup, J. H., Krull, M., and Bueldt, G., Angew. Chem., Znt. Ed. Eng., 1987, 26, 698. Goldberg, I., and Becker, Y., J. Pharm. Sci., 1987, 76, 255.Tiers, G. V. D., Thermochim. Acta, 1993, 226, 317. Kuhnert-Brandstatter, M., and Lehner, G., Sci. Pharm., 1984, 52, 267. Kuhnert-Brandstatter, M., and Sollinger, H. W., Mikrochim. Acta, 1990, 111, 137. Kuhnert-Brandstatter, M., and Vollenklee, R., Sci. Pharm., 1987,55, 13.2458 Analyst, October 1995, Vol. 120 368 369 370 37 1 372 373 374 375 376 377 378 379 380 38 1 382 383 3 84 385 386 387 388 389 390 39 1 392 393 394 395 396 397 398 399 400 40 1 402 403 404 405 406 407 408 409 410 Epple, M., and Cammenga, H. K., Ber. Bunsenges. Phys. Chem., 1992,96, 1774. Epple, M., and Cammenga, H. K., J. Therm. Anal., 1992,38,619. Lloyd, L. F., Bruk, P., Mei-Ehe, L., Chagen, N. E., and Blow, D. G., J. Mol. Biol., 1991, 217, 19. Manor, P. C., and Saenger, W., J. Am. Chem.SOC., 1974, 86, 3630. Lindler, K., and Saenger, W., Acta Cryst., Sect. B, 1982, 38, 1982. Polishchuk, A. P., Kulishov, V. I., Antipin, M. Y., Gerr, R. G., and Struchov, Y. T., Cryst. Struct. Commun., 1981, 10, 895. Polishchuk, A. P., Kulishov, V. I., Antipin, M. Y., and Struchov., Y. T., Cryst. Struct. Commun., 1289. Kitaigorodski, A. I., Molecular Crystals and Molecules, Academic Press, New York 1973, p. 36. Desiraju, G. R., Crystal Engineering, Elsevier, Amsterdam, 1989, p. 42ff. Petrouslas, V., Lemmon, R. M., and Christensen, A., J. Chem. Phys., 1978,68,2243. Hursthouse, M., in Encyclopaedia of Advanced Materials, ed. Bloor, D., Brook, R. J., Hemming, M. C. and Majahu, S., Pergamon, Oxford, 1995. Harding, M. M., Chem. Br., 1990, 956. Rizkullah, P. J., Harding, M.M., Lindsey, P. F., Aiger, A., and Bauer, A., Acta Cryst., Sect. B, 1990, 46, 262. King, H. E., Sirota, E. B., Shao, H., and Singer, D. M., J. Phys. D: Appl. Phys., 1993,26, B137. Sato, K., J. Phys. D: Appl. Phys., 1993, 26, B77. Harmon, K. M., and Avci, G. F., J. Mol. Struct., 1986, 140, 261. Marsh, R. E., Appl. Cryst., Sect. C , 1993,49, 193. Aakeroy, C. B., and Seddon, K. R., Chem. SOC. Rev., 1993, 22, 397. Harris, K. D. M., and Patterson, L. J., J. Chem. SOC., Perkin Trans. 2, 1994, 1201. Lightfoot, P., Tremayne, M., Harris, K. D. M., and Bruce, P. G., J. Chem. SOC., Chem. Commun., 1992, 1012. Yang, S. S., and Guillory, J. K., J. Pharm. Sci., 1972, 61, 26. Kitamura, S., Chang, L.-C., and Guillory, K. J., Int. J. Pharm., 1984, 101, 127. Brenner, G., Roberts, F. E., Hoinowski, A., Budvari, J., Powell, B., Hinkley, D., and Schoenewaldt, E., Angew.Chem., Int. Ed, Eng., 1969, 8, 975. Pfeiffer, R. R., Yang, K., and Tucker, M. A., J. Pharm. Sci., 1989,78, 337. Mynukh, Y. V., Panfiiova, N. A., Petropavlov, N. N., and Uchvatova, N. S., J. Phys. Chem. Solids, 1975,36, 127. Doff, D. H., Brownen, F. L., and Corrigan, 0. I., Analyst, 1986,111, 179. Kidd, W. C., Varlashin, P., and Li, C., Powder Difi., 1993, 8, 180. Dent Glasser, L. S., Crystallography and its Applications, Van Nostrand Reinhold, 1977. Hall, H. E., Solid State Physics, Wiley, London, 1974. Grindley, T. B., McKinnon, M. S., and Wasylishen, R. E., Carbohy- drate Res., 1990, 197, 41. Herbstein, F. H., Capon, M., Reisner, G. M., Lehmann, M. S., Kress, R. B., Shiau, W.I., Duesler, E. N., Paul, I. C., and Curtin, D. Y., Proc. R. SOC. A, 1985,399,295. Ermer, O., Angew. Chem., Int. Ed. Eng., 1987, 26, 782. BUM, C. W., Chemical Crystallography, Oxford University Press, 2nd edn., 1961. Nyburg, S. C., X-Ray Analysis of Organic Structures, Academic Press, New York, 1961. Giaccovazzo, G., Fundamentals of Crystallography, International Union of Crystallography, Oxford, 1992. Dunitz, J. D., X-ray Analysis and the Structure of Organic Molecules, Cornell University Press, Ithica, 1979. Rossi, M., and Berman, H. M., J. Chem. Ed., 1988, 6, 472. Modern Powder Difiaction, ed. Bish, D. L., and Post, J. E., Reviews in Mineralogy, vol. 2, Mineralogical Society of America, 1989. AzAroff, L. V., and Buerger, M. J., The Powder Method in X-ray Crystallography, McGraw-Hill, New York, 1958.Shafizadeh, F., and Susott, R. A., J. Org. Chem., 1973,38, 3710. Perrenot, B., and Widman, G., Thermochim. Acta, 1994,234,31. Garn, P. D., Thermoanalytical Methods of Investigation, Academic Press, New York, 1965, p. 21. Voress, L., Anal. Chem., 1994,66, 1035A. 41 1 412 413 414 415 416 417 418 419 420 42 1 422 423 424 425 426 427 428 429 430 43 1 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 45 1 ~~ Kopp, S., Beyer, C., Graf, E., Kubel, F., and Doelker, E.,Acta Pharm. Technol., 1988, 34, 213. Burger, A., and Lettenbichler, A., Eur. J . Pharm. Biopharm., 1993,39, 64. Chataing, G., and Vergnaud, J. M., Thermochim. Acta, 1985, 94, 379. Kuhnert-Brandstatter, M., and Seidel, D., Mikrochim.Acta, 1982, I, 243. Van Dooren, A. H., and Muller, B. W., Thermochim. Acta, 1983,66, 161. Kuhnert-Brandstiitter, M., and Heindle, W., Sci. Pharm., 1976, 44, 18. Allen, P. V., Rahn, P. D., Sarapu, A. C., and Vanderwielen, A. J., J. Pharm. Sci., 1978, 67, 1087. Kuhnert-Brandstiitter, M., and Proell, F., Mikrochim. Acta, 1983,II, 463. Kuhnert-Brandstatter, M., Geiler, M., and Wurian, I., Mikrochim. Acta, 1983, I, 221. Giron-Forest, D., Goldbrunn, C., and Piechon, P., J. Pharm. Biomed. Anal., 1989,7, 144. Kuhnert-Brandstatter, M., and Vollenklee, R., Sci. Pharm., 1987,55, 27. Haines, P., Thermal Analysis, Blackie, London, 1995. Thermal Analysis: an Introduction to Principles and Practice, ed. Hodgson, A., University of York, York. Takahashi, Y., Thermochim. Acta, 1985, 88, 199.McNaughton J. L., and Mortimer, C. T., Differential Scanning Calorimetry, Perkin-Elmer, Norwalk, Connecticut. Westrum, E. R., and McCullough, J. P., in Physics and Chemistry of the Organic Solid State, ed. Fox, D., Labes, M. M., and Weissberger, A., Interscience, New York, 1963, vol. 1. Daniels, T., Thermal Analysis, Halsted Press, New York, 1973. Matsunaga, J., Nambu, N., and Nagai, T., Chem. Pharm. Bull., 1976, 24, 1169. Muller, B. W, W., Pharm. Acta Helv., 1978, 53, 333. Taludar, M. D., Carless, J. E., and Summers, M. P., J. Pharm. Phamacol., 1983,35, 208. Matsumoto, T., Ichikawa, J., Kaneniwa, N., and Otsuka, M., Chem. Pharm. Bull., 1988, 36, 1074. Forni, F., Coppi, G., Iannuccelli, V., and Cameroni, R., J. Therm. Anal., 1990, 36, 35. Behme, R.J., Brooke, D., Farney, R. F., and Kensler, T. T., J. Pharm. Sci., 1985, 74, 1041. Burger, A., and Ramberger, R., Mikrochim. Acta, 1979, II, 273. Prasad, P. N., in Organic Solid State Chemistry, ed. Desiraju, G. R., Elsevier, Amsterdam, 1989. Ostwald, W., Z. Physik. Chem., 1897, 22, 306. Wentlandt, W. W., Thermal Methods of Analysis, Interscience, New York, 1964. Kuhnert-Brandstiitter, M., and Sollinger, H. W., Mikrochim. Acta, 1989,111, 125. Sarge, S., and Cammenga, H. K., Thermochim. Acta, 1985,94, 17. Barell, E. M., Thermochim. Acta, 1973,5, 377 quoted by Ford, J. L., and Timmins, P., Pharmaceutical Thermal Analysis, Ellis Horwood, Chichester, 1989, p. 27. Harbury, L., J. Phys. Chem., 1946,50, 190. Kuhnert-Brandstatter, M., and Heindl, W., Sci. Pharm., 1975, 43, 112.Kuhnert-Brandstatter, M., and Lindler, R.,Wikrochim. Acta, 1976, I, 513. Ubbelhohde, A. R., The Molten State of Matter, Wiley, Chichester, 1978, p. 317. Cahn, R. W., Nature (London), 1992,356, 108. Docherty, C., and York, P., Znt. J. Pharm., 1988,47, 141. Serpinet, J., Nature (London) Phys. Sci., 1971, 232, 42. Serpinet, J., and Robin, J., C.r. Acad. Sci. Paris., 1971, 272C, 1765. Florence, A. T., and Salole, E. G., J. Pharm. Pharmacol., 1976, 28, 637. Sherwood, J. N., The Plastically Crystalline State, Wiley, New York, 1979. Aston, J. G., in Physics and Chemistry of the Organic Solid State, ed. Fox, D., Labes, M. M., and Weissberger, A., Interscience, New York, 1963, vol. 1.Analyst, October 1995, Vol. 120 2459 452 45 3 454 455 456 457 458 459 460 46 1 462 463 464 465 466 467 468 469 470 47 1 472 473 474 475 476 477 478 479 480 48 1 482 483 484 485 486 487 488 489 490 Adachi, K., Suga, H., and Seki, S., Bull.Chem. SOC. Japn., 1970,43, 1916. Westmm, E. R., and McCullough, J. P., in Physics and Chemistry of the Organic Solid State, ed. Fox, D., Labes, M. M., and Weissberger, A., Interscience, New York, 1963, vol. 1, p. 83. Staveley, L. A. K., Quart. Rev., 1949,3, 65. Reading, M., Trends in Polym. Sci., 1993, 1, 248. Ford, J. L., and Timmins, P., Pharmaceutical Thermal Analysis, Ellis Horwood, Chichester, 1989. Clark, G. M., Anal. Proc., 1986, 23, 393. Wenzell, P. D., and Wade, A. P., Anal. Chem., 1989, 61, 2638. Borka, L., Acta Pharm. Suec., 1974, 11,413. Bergman, E., Hoff, E. E., Lefiles, J. H., McKinney, L.J., and Misselbrook, J., Eur. Pat. 380325. Pearson, J. T., and Varney, G., J. Pharm. Pharmacol., 1969, 21, 60s. Mesley, R. J., and Houghton, E. E., J. Pharm. Pharmacol., 1967,19, 295. Grant, D. J. W., and Higuchi, T., Solubility Behaviour of Organic Compounds, Techniques in Chemistry, Vol. XXI, Wiley, New York, 1990. Mader, W.J., and Grady, L. T., in Physical Methods of Organic Chemistry, ed. Weissberger, A., and Rossiter, B. W., Wiley, New York, 1971, vol. 1, pt. V. Florence, A. T., and Attwood, D, Physicochemical Principles of Pharmacy, Macmillan, London, 1981. Doughty, D. G., Drug Dev. Ind. Pharm., 1989, 15,2455. Windram, V. A., and Threlfall, T. L., Anal. Proc., 1992, 29, 108. Abdou, H. M., Dissolution, Bioavailablity and Bioequivalence, Mack, Easton, 1989, p.126. Buxton, P. C., Lynch, I. R., and Roe, J. M., Int. J. Pharm., 1988,42, 135. Murthy, K. S., Turner, N. A., Nesbitt, R. U., and Fawzi, M. B., Drug Dev. Ind. Pharm., 1986, 12, 665. Martinez-Oh6rriz, M. C., Martin, C., Goiii, M. M., Rodriguez- Espinosa, C., Tros de Ilarduya-Apadaza, M. C., and Shchez, M., J. Pharm. Sci., 1994, 83, 174. Higuchi, T., J. Pharm. Sci., 1969, 56, 200. Kuhnert-Brandstatter, M., and Linsmeyer, L., Sci. Pharm., 1986,54, 1. Beall, H. D., Getz, J. J., and Sloane, K. B., Int. J. Pharm., 1993, 93, 37. Albert, A., and Sargeant, E. P., The Determination of Zonisation Constants, Chapman and Hall, London, 3rd edn., 1984. Perrin, D. D., and Dempsey, B., Buffers forpH and Metal Ion Control, Science Paperbacks, London, 1979. Steams, E. I., The Practice of Absorption Spectroscopy, Wiley, New York, 1969, p. 75. Perkampus, H. H., UV-VIS Spectroscopy and its Applications, Springer, Berlin, 1992. Burger, A., Acta Pharm. Technol., 1982, 28, 1. Kitaigorodski, A. I., Organic Chemical Crystallography, Consultants Bureau, New York, 1961. Whitesell, J. K., Davis, R. E., Saunders, L. L., Wilson, R. J., and Feagin, J. P., J. Phys. D: Appl. Phys., 1993, 26, B56. Andreev, G. A., and HartmanovB, M., Phys. Status Solidi. A, 1989, 116, 457. Bauer, N., and Lewin, S. Z., in Physical Methods of Organic Chemistry, ed. Weissberger, A., and Rossiter, B. W., Wiley, New York, 1972, vol. 1, pt. IV. Lowell, S., and Shields, J. E., Powder Sulface Area and Porosity, Chapman and Hall, London, 3rd edn., 1991. Dent Glasser, L. S., Crystallography and its Applications, Van Nostrand Reinhold, 1977, p. 11 1-1 14. Orr, C., and Dallevalle, J. M., Fine Particle Measurement, Macmil- lan, New York, 1959. Fukumori, Y., Fukuda, T., Yamamoto, Y., Shigitami, Y., Hanyu, Y., Takeuchi, Y., and Sato, N., Chem. Pharm. Bull., 1983, 31, 4029. Carless, J. E., Moustafa, M. A., and Rapson, H. D. C., J. Pharm. Pharmacol., 1966, 18, 190s. Botha, S. A., Caira, M. R., Guillory, J. K., and Lotter, A. P., J. Pharm. Sci., 1988, 77, 444. Otsuka, M., and Kanemiwa, N., Chem. Pharm. Bull., 1983, 31, 1021. 49 1 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 5 10 511 512 513 5 14 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 53 1 532 533 534 535 536 537 Chapman, J. H., Page, J. E., Parker, A. C., Rogers, D., Sharp, C. J., and Staniforth, S. E., J. Pharm. Pharmacol., 1968,20,418. Burger, A,, Ratz, A. W., and Zolss, G., Acta Pharm. Technol., 1988, 34, 147. Michel, G., in Analytical Profiles, vol. 6., ed. Florey, K., Academic Press, New York, 1977, vol. 6. Kuhnert-Brandstiitter, M., Pharm. Ind., 1977,39,377. Pouchert, C. J., Aldrich Library of Infrared Spectra, Aldrich, Milwaukee, 3rd edn., 1981. Bjaen, A. K. B., Nord, K., Furuseth, S., Agren, T., Tonneson, H. H., and Karlsen, J., Znt. J. Pharm., 1993, 92, 193. Chauvet, A., Masse, J., Ribet., J. P., Bigg, D., Autin, J. M., Maurel, J. L., Patoneau, J. F., and Jans, J., J. Pharm. Sci., 1992, 81, 836. Williams, P. P., Acta Cryst., Sect. B, 1973, 29, 1572. Khankhari, R. J., Law, D., and Grant, D. J. W., Znt. J. Pharm., 1992, 82, 117. Harris, R. K., Say, B. J., Yeung, R. R., Fletton, R. A., and Lancaster, R. W., Spectrochim. Acta, Part A, 1989,45,465. Hendricksen, B. A., Preston, M. S., and York, P., in the press. Chrzanowski, F. A., Fegley, B. J., Sisco, W. R., and Newton, M. P., J. Pharm. Sci., 1984, 73, 10. Garti, N., Sarig, S., and Wellner, E., Thermochim. Acta, 1980, 37, 131. Hirshfeld, T., in Fourier Transform Infrared Spectroscopy, ed. Ferraro, J. R., and Basile, L. J., Academic Press, 1979, vol. 2. Hamadah, L. M., Yeboah, S. A., Tumbull, K. A., and Griffiths, P. R., Appl. Spectrosc., 1984,38,486. Tanninen, V. P., and Yliruusi, J., Znt. J. Pharm., 1992, 81, 169. Tudor, A. M., Church, S. J., Hendra, P. J., Davies, M. C., and Melia, C. D., Pharm. Res., 1993, 10, 1771. Guillory, J. K., and Erb, D. M., Pharm. Manuf, 1985, 2(9), 28. Lindenbaum, S., and McGraw, S. E., Pharm. Manuf., 1985, 2(1), 273. Crocker, L. S., and McCauley, J. A., J. Pharm. Sci., 1995, 84, 226. Pikal, M. J., Lukes, A. L., Lang, J. E., and Gaines, K., J . Pharm. Sci., 1978, 67, 676. Matsuda, Y., Tatsumi, E., Chiba, E., and Miwa, Y., J. Pharm. Sci., 1984,73, 1453. Jenkins, E. W., The Polymorphism of Elements and Compounds, Methuen Educational, London, 1973. Rosenberg, H. M., The Solid State, Oxford University Press, 3rd edn., 1988. De Gennes, P. G., and Prost, J., The Physics of Liquid Crystals, Clarendon, Oxford, 1993. Janner, A., and Janssen, T., Phys. Rev. B: Condens Matter, 1977,13, 643. Stevens, P. W., and Goldman, A. T., Sci. Am., 1991, 261(April), 24. Janot, C., Dubois, J.M., and de Boisseau, M., Amer. J. Phys., 1989,57, 972. Nelson, D. R., Sci. Am., 1986, 255(August), 32. Ronchetti, M., Philos. Mag., 1987, 56, 237. Goldman, A. I., and Kelton, R. F., Rev. Mod. Phys., 1993, 65, 213. Holzer, J. C., and Kelton, R. F., in Crystal-Quasicrystal Transitions, ed. Yacaman, M. J., and Torres, M., Elsevier, Amsterdam, 1993. Finney, J. L., Stud. Phys. Theor. Chem., 1981, 13, 439. Mayer, E., and Pletzer, R., NATO AS1 Ser., Ser. 3, 1985,156, 81. Samwer, K., Phys. Rep., 1988, 161, 1. Sandman, D. J., Elman, B. S., Hamill, G. P., Velazquez, C. S., and Samuelson, L. A., Mol. Cryst. Liq. Cryst., 1986, 134, 89. Halebian, J. K., Koda, R. T., and Biles, J. A., J.Pharm. Sci., 197 1,60, 1485. Corrigan, 0. I., and Holohan, E. M., J . Pharm. Pharmacol., 1984,36, 217. Parthasathy, R., Rao, K. J., and Rao, C. N. R., Chem. Soc. Rev., 1984, 361. Hukins, D. W. L., X-Ray DifSraction by Ordered and Disordered Systems, Pergamon Press, Oxford, 198 1. Elliott, S. R., Nature (London), 1991,354,445. Atalla, R. H., Gast, J. C., Sindorf, D. W., Bartuska, V. G., and Maciel, G. E., J. Am. Chem. SOC., 1980, 102,3249. Fecht, H. J., Nature (London), 1992, 365, 133. Fecht, H. J., and Johnson, W. L., Nature (London), 1988,334, 50. Cahn, R. W., Nature (London), 1988,334, 17. Cahn, R. W., Nature (London), 1992, 356, 108. Tallon, J. L., Nature (London), 1989,342, 658.2460 Analyst, October 1995, Vol. 120 538 539 540 54 1 542 543 544 545 546 547 548 Zarzicki, J., Glasses and the Vitreous State, Cambridge University Press, 1982. Chauhadri, P., Giessen, B. C., and Tumbull, D., Sci. Am., 1980, 242(April), 84. Kauzmann, W., Chem. Rev., 1948,43,219. Jaeckle, J., Rep. Prog. Phys., 1986, 49, 17. Randall, J. T., The Diffraction of X-rays and Electrons by Amorphous Solids, Liquids and Gases, Chapman and Hall, London, 1934. Jaeckle, J., Philos. Mag. B , 1987, 56, 113. Wunderlich, B., Thermal Analysis, Academic, New York, 1990. Sichina, W. J., Int. Laboratory, 1994, March, 20. van der Plaats, G., The Practice of Thermal Analysis, Mettler, Greifensee, Switzerland. Westrum, E. R., and McCullough, J. P., in Physics and Chemistry of the Organic Solid State, ed. Fox, D., Labes, M. M., and Weissberger, A., Interscience, New York, 1963, vol. 1, p, 43. Kitaigorodski, A. I., Molecular Crystals and Molecules, Academic Press, New York, 1973, p. 18. 549 550 55 1 552 553 554 555 556 Paxtington, J. R., The Properties of Solids, Advanced Treatise on Physical Chemistry, vol. 111, Oxford University Press, 1952, p. 519. Saleki-Gerhardt, A., Stowell, J. G., Bym, S. R., and Zografi, G., J. Pharm. Sci., 1995, 84, 318. Burger, A., and Ratz, A. W., Sci. Pharm., 1990, 58, 69. van Skoik, K. G., and Carstensen, J. T., Znt. J. Pharm., 1990, 58, 185. White, G. W., and Cakebread, S. H., J. Food Technol., 1966, 1, 73. Talbot, G., in Industrial Chocolate Manufacture and Use, ed. Beckett, S.T., Blackie, London, 2nd edn., 1993. Suryanarayanan, R., and Mitchell, A. G., Znt. J . Pharm., 1986,32, 213. James, R. W., The Optical Principles of the Difiaction of X-Rays, Bell, London, 2nd edn., 1962. Paper 5/01 094B Received February 23,1995 Accepted July 6, 1995

ISSN:0003-2654    

DOI:10.1039/AN9952002435

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Analyst, October 1995, Vol. 120 246 1 Unified Chromatograph for Gas Chromatography, Supercritical Fluid Chromatography and Micro-liquid Chromatography Daixin Tong, Keith D. Bartle, Anthony A. Clifford and Robert E. Robinson School of Chemistry, University of Leeds, Leeds, UK LS2 9JT A unified chromatograph with a single-valve switching system, which allows single separation mode and sequential analyses, is described. High-resolution GC, supercritical fluid chromatography (SFC), and micro-LC analyses for a variety of samples, on either open tubular or packed capillary columns, are demonstrated. Sequential GC-SFC analyses for samples of a pesticide-contaminated vegetable oil and a household wax show the separation power of the unified chromatograph for samples with a wide range of volatilities.This paper illustrates the potential usefulness of unified chromatography in practical analysis and the possibility of the unification and minimization of chromatographic instruments. Keywords: Gas chromatography; supercritical fluid chromatography; high-performance liquid chromatography; microcolumn chromatography; unified chromatography; sequential analysis; open microtubular column; packed capillary column Introduction Chromatographic separation modes, GC, supercritical fluid chromatography (SFC), and LC, are classified according to the physical state of the mobile phase (gas, supercritical fluid or liquid) in the column. However, these distinctions are artificial, owing to the absence of theoretical boundaries between them.'" In practice, the distinction between GC and SFC is obscured when the SFC pressure program starts from a pressure below the critical pressure.The use of binary or ternary mobile phases (C02 + liquid) in packed-column SFC analyses, sometimes near or even below the critical temperature (en- hanced fluidity liquids), has also obscured the distinction between SFC and HPLC, particularly when high-temperature HPLC is considered. Commonly, conventional GC and HPLC have different types of column, and different means of injection and detection to meet their own requirements, and SFC is an intermediate technique. However, open tubular columns with internal diameters of less than 150 ym and packed capillary columns with internal diameters of less than 500 ym and packed with 3-10 ym particles can be used in either GC, SFC, or HPLC (micro-LC), and may be located in the same type of oven.Because of the thin wall and small heat capacity of these columns, micro-LC can also be carried out in an oven similar to that used in GC and SFC with temperature programming. In addition, the small volume of the mobile phase in the column means that the mobile phase can be easily changed. The small mass flow rate makes capillary columns easier to interface with mass spectrometers and flame-based detectors under HPLC or modified SFC conditions. As Yang pointed out, many years ago, the practice of GC, SFC, and HPLC becomes more similar as the column diameter becomes ~maller.~ Different modes of separation can be carried out with a single chromatographic system using the same column, injector and detector and can be performed in series (for example, sequential GC and SFC) in a single chromatographic run, leading to the concept of unified chromatography.In recent years, several research groups have demonstrated that unified chromato- graphy is achievable,6-28 and much effort has been made to develop detection methods which are appropriate to all separation m0des.~9-3~ One of the major difficulties in unified chromatography is that the optimum flow rates in GC, SFC and HPLC modes are very different from each other. Yang and co-workers demon- strated a unified chromatographic system using high-pressure GC with a single-frit restrictor post-column21722 to allow both GC with helium and SFC with C02 mobile phase. We have recently described several unified chromatographic systems; their operating parameters, including the flow rates, can be optimized independently in each separation mode by means of an extra rotary valve following the colum,23-26 and band broadening during the transformation from GC to the SFC mode can be restricted by optimizing the operating condition~.~5 However, these previously described unified chromatographic systems required two or more valves, so that the operation was inconvenient, and it proved difficult25 in practice to restrict band broadening during mobile-phase transformation because of the large replaceable volume in the valves and connection tubing.In this paper, we describe a novel, unified chromatographic system with a simplified switching technique.High-resolution sequen- tial GC-SFC, SFC and micro-LC analyses can be carried out all in the same system. Highly efficient packed capillary columns prepared by our recently developed packing te~hnique273~8 were employed under either SFC or HPLC conditions. Experimental Unified Chromatograph A diagram of the novel unified chromatograph is shown in Fig. 1. The system is based on a Lee Scientific Series 600 SFC/GC chromatograph (Dionex, Surrey, UK). The apparatus comprises a helium cylinder with a two-stage pressure regulator, a C02 cylinder, which supplies chromatographic-grade carbon diox- ide, a Lee Scientific 600 syringe pump and an oven with a flame ionization detector (FID), a Lee Scientific 501 UV/VIS detector with a home-made low-volume cell, a Merck-Hitachi (Hitachi, Tokyo, Japan) reciprocating pump which can supply microlitre liquid flows, an injection valve (Model A-4-C14W, Valco Instruments) with a pneumatic actuator and a Valco digital valve sequence programmer, an analytical column (either an open microtubular column or a packed capillary column), a six-port two-position low dead-volume high-temperature valve (Valco Instruments, Model DN6WT; specially machined; calculated2462 Analyst, October 1995, Vol.120 dead-volume of rotor slot, 0.19 p1; maximum operating temperature, 250 "C), which is used as a mode-selector valve. Fig. 2 shows the novel switching system for separation mode selection. Different arrangements allow the chromatograph to be used for GC, SFC, HPLC, and sequential GC-SFC analyses. By positioning the single rotary valve in the oven, either helium, carbon dioxide or liquid can be introduced into the analytical column and the column eluent can be directed to either an FID or a UV detector. Fig.3 is the arrangement of the novel unified chromatograph for GC, SFC, and sequential GC-SFC analyses. Either helium or C02 can be introduced into the analytical column by using the mode-selector valve in the oven. A retention gap (RG) was inserted between the injection valve and the analytical column to allow valve injection for GC at ambient temperature. In GC ection val e uv detector etention ap [LM Integrator / Frit restrictor \\, C~llection vi> Reciprocating Mode selector Column Butt connector Pump valve Fig. 1 Schematic diagram of the unified GC, SFC, and HPLC chromato- graph.Injector Q Frit restrictor Linear restrictor Carbon dioxide Column I uv Fig. 2 phase selection and post-column operation. Schematic diagram of the six-ports, two-way valve for both mobile Transforming Pressure regulator restrictor \w Syringe pump t Mode selector valve Frit restrictor \, \ Column Butt connector Fig. 3 Schematic diagram of the unified GC-SFC arrangement. mode, as shown in Fig. 2, the mode selector valve is in the position to introduce helium to the column; meanwhile, the flow of column eluent is directed to the FID through a linear restrictor (50 cm X 50 ym id fused-silica capillary); during this process, carbon dioxide from the syringe pump is directed towards the FID through a frit restrictor (30 cm X 50 pm id, Dionex) without passing through the column (i.e., the column is 'shorted' through the mode-selector valve).In SFC mode, the mode-selector valve is switched into position to introduce C02 to the column, and the flow of column eluent is directed towards the FID through the frit restrictor, and the helium from the cylinder flows directly to the FID through the linear restrictor. The end of the linear restrictor and the frit restrictor are passed through a common connection at the base of the FID and positioned together approximately 1 mm below the flame tip. Both the helium effluent flow from the linear restrictor and the carbon dioxide effluent flow from the frit restrictor are continuous when the mode-selector valve is switched to either GC mode or SFC mode; in this way, the effect on the flame of the FID in different modes is minimized. A 10 m X 50 pm id fused-silica open tubular column coated with a 0.25 pm film of SB-Methyl or a 10 m X 50 pm id column coated with a 0.25 pm film of SB Biphenyl-30 (Dionex) is installed in the oven.The pressure of the helium carrier gas is adjusted by means of the two-stage pressure regulator at 15 atm (1.52 X 106 Pa). The oven temperature can be operated up to 250°C which met most of our requirements in GC, SFC and sequential GC-SFC analyses. Figs. 4 and 5 show the arrangements of the unified chromatograph for SFC and HPLC analyses. Both FID and the UV/VIS detectors are employed. Either C02, supplied by the syringe pump, or liquid mobile phase, supplied by the reciprocating pump, can be introduced to the column via the injection valve by appropriate positioning of the mode-selector valve, as shown in Fig.2. The arrangement shown in Fig. 4 allows the flow eluent from the column to be directed either to the FID through the frit restrictor in SFC mode or to the UV/VIS detector through fused-silica tubing to waste, in the HPLC mode. The arrangement for HPLC with UV detection, or SFC with UV followed by FID detection, is shown in Fig. 5 . The outlet connecting tubing (50 cm X 50 pm id, 196 pm od) of the column is inserted directly into the cell of the UV detector and the outlet of the UV detector is connected to the mode-selector valve, so that the eluent flow from the UV detector can be either directed to the FID during SFC analysis or through fused-silica tubing to waste during HPLC.For SFC using an organic supercritical fluid or modified carbon dioxide as mobile phase, the FID is used as a heater to protect the frit restrictor from blockage. In this novel unified chromatograph, only one valve is employed to select mobile phases and to choose the detection method. This design makes the system simple and the operations convenient. In addition, the replaceable volume for mobile-phase transformation is reduced25 due to the reduction of the number of valves and connecting tubing. Except for the injection valve, all elements which affect the transforming processes are installed in the oven to accelerate the various processes during change from one mode to another, especially after HPLC analysis. Band broadening25 due to mobile-phase transformation can be greatly limited and the time for the transformation can be reduced.Highly efficient packed capillary columns were obtained using a recently developed packing technique using super- critical carbon dioxide as packing carrier with sonication.27.28 The excellent stability of these columns allowed them to be used with frequent pressurization and de-pressurization without losing column efficiency, and the reproducibility in chromato- graphic behaviour of these columns used in multi-mode separations are very good. The high permeability permittedAnalyst, October 1995, Vol. 120 2463 longer column lengths. Two 50 pm id X 30 cm fused-silica capillaries are connected to the two ends of the column using two Valco unions as the inlet and outlet of the column.The column was packed with one of the following packing materials: 5 pm Spherisorb ODs-1, ODs-2, C18 (Phase Separation, Deeside, UK) or 10 pm LiChrosorb Diol (Merck, Darmstadt, Germany); The column tubing material was 250 pm id fused silica (Composite Metal Services, Worcester, UK). The cell of the UV/VIS detector has volume of 38 ml and is fabricated from a piece of 200 pm id fused-silica tubing. The polyimide coating was removed over a 10 mm length, which is positioned in the slot of the UV/VIS detector. A fused-silica capillary with 50 pm id and 196 pm od is used as connection tubing between the mode-selector valve and the inlet of the UV/ VIS detector. The end of this connection tubing is inserted into the inlet of the cell up to the cell window to reduce the dead- volume at the connection.The outlet of the cell is led to waste. The f i t restrictor is connected to the FID in the same way as described above. Separation Modes and Operation Procedures Sample introduction, either in GC, SFC, or HPLC mode, is effected by means of the pneumatically actuated injection valve with a 60 nl sample-slot rotor. Gas chromatographic injection is normally operated without a split. In order to meet the requirement of low mobile-phase flow rate in the column under HPLC conditions and small injection dead-volume for HPLC and SFC, split-injection was used in the arrangements shown in Figs. 4 and 5. The injection sample size can be changed using moving injection (time split) with different injection times.The mode-selector valve is switched to the correct position before use. Depending on the sample to be analysed, the chromato- graph can be operated for either GC, SFC, HPLC, or sequential GC-SFC by positioning the mode selector valve to introduce appropriate mobile phase and detector selection. Syringe pump In GC mode, the mode-selector valve is positioned so as to introduce helium as carrier gas and to direct column effluent flow to the FID through the linear restrictor. Separation in GC mode is usually carried out at constant pressure with temperat- ure programming. In SFC mode, the mode-selector valve is positioned to introduce carbon dioxide mobile phase, mean- while directing column effluent through the frit restrictor towards the FID. Operation in SFC mode is normally performed with pressure programming.Sequential GC-SFC is achieved as follows: with the mode- selector valve in the position to select helium as mobile phase and to allow column effluent directly into the FID as described previously, the sample is injected, and the temperature program is started. After the elution of components for which GC was appropriate (maximum temperature, 250 "C), the column tem- perature is kept constant (typically below 120 "C) or rapidly adjusted to a low value (about 60°C), and the mode-selector valve is switched to shut off helium flow while simultaneously introducing supercritical carbon dioxide into the column at a low pressure, for example 6.08 X 106 Pa; meanwhile, column effluent is directed through the frit restrictor towards the FID.The pressure and oven temperature are rapidly increased to appropriate initial values, and then the SFC pressure program is started. Components not eluted during GC are then separated by SFC. This operation can restrict band broadening during mobile-phase transformation.25 Results and Discussion Fig. 6 is a GC chromatogram of a dichloromethane solution of a diesel fuel obtained using the unified chromatograph with the arrangement shown in Fig. 3. This shows that, for GC analysis, valve injection onto a 50 pm id open microtubular column is appropriate and that high resolution and fast separation can be achieved. This procedure avoids the problems of quantitative reproducibility for samples with a wide range of volatility Reciprocating pump \ 1 Fri;restrictor \ \ \ Splitter Collection vial Mode selector valve Fig.4 Schematic diagram of the unified SFC-HPLC arrangement with FID and UV detection in parallel. Syringe pump I 7 Transforming restrictor !ID Injection valve / Collection vial UV detector / / Mode selector valve Frit ' \ Column Splitter -. Reciprocating pump Fig. 5 Schematic diagram of the unified SFC-HPLC arrangement with FID and UV detection in series.2464 Analyst, October 1995, Vol. 120 inherent with the split-injection technique, and the operating inconveniences with normal splitless-injection techniques. When a less volatile sample containing many volatile components is to be analysed, sequential GC-SFC is a good choice. Fig. 7(a) is a SFC chromatogram of a household wax preparation based on beeswax.The terpenes could not be separated and were eluted together with the solvent peak. Using sequential GC-SFC, the chromatogram shown in Fig. 7(b) was obtained. The terpenes were firstly analysed by GC with temperature programming from 40 to 130°C and then the beeswax alkanes (C23-C35), esters (CI5 H31 COOR, R = C24H49 to C34H69, even carbon numbers), and diesters (palmi- tate esters of 15-hydroxypalmitate esterified with primary n- alcohols, C24-C34 even carbon numbers) were eluted by SFC at 120 "C, with pressure programming (1 atm = 101.325 P a ) from 60 to 120 atm in less than 1 min, and then from 120 to 360 atm at 5 atm min-1. Both separations in either GC or SFC mode were thus performed under optimum conditions and there is no loss of resolution in the SFC separation following the GC separation.Low initial pressure of carbon dioxide is advant- ageous to restrict band broadening during transformation from GC to SFC mode.25 These results show higher chromatographic I r I I I I I I I I I 1 0 5 10 15 20 25 30 35 40 45 50 Ti me/m i n Fig. 6 Analysis of a dichloromethane solution of a diesel fuel by GC on the unified chromatograph. Conditions: valve injection with 60 nl injection volume; 10 m x 50 pm id coated with a 0.25 pm film of SB-Methyl fused-silica open tubular column. helium mobile phase at 12 atm; FID detection; and temperature programming from 60 to 240 "C at 4 "C min-l. z : ;o ;o 3b 40 sb Qo ;o t, Ib io ;o 40 t o Qo ;o 8'0 do d o Time/min Fig. 7 Separation of a dichloromethane solution of a household wax by (a), SFC alone and (b), sequential GC-SFC on the unified chromatograph.Conditions: 10 m X 50 pm id coated with a 0.25 pm film of SB-Methyl fused-silica open tubular column; valve injection and FID detection. (a), Carbon dioxide mobile phase, at 120 "C, from 70 to 360 atm at 5 atm min-l. (b) Helium mobile phase at 15 atm from 40 to 150 "C at 5 "C min-l and then to 120 min-' within 1 min; carbon dioxide mobile phase at 120 "C from 120 to 360 atm at 5 atm min-1. Peak identifications: 1, terpenes; 2, C23-C35 alkanes; 3, C15H31 COOR esters, R = C24H49 to C34H69; 4, diesters C15H31 COOC15H30 COOR, R = C24H49 to C34H69; 5 , triesters.Analyst, October 1995, Vol. 120 2465 resolution than that obtained using an earlier unified system24 without optimization during the mobile-phase change.Fig. 8 shows another example of a sequential GC-SFC analysis. A pesticide-contaminated vegetable oil was separated under appropriate GC and SFC conditions. The GC separation was carried out with temperature programming up to 250 "C and the temperature then rapidly reduced to 70 "C. SFC analysis was performed at 100 "C with pressure programming from 60 to 200 atrn in about 1 min, and then from 200 to 300 atm at 5 atm min- l. During the mobile-phase transformation period, a low oven temperature is necessary to restrict band broadening.25 Since there is no requirement of high resolution in SFC separation of vegetable oil, a larger column diameter and a thick stationary phase (a commonly used GC column) could be used to achieve higher detection limits in GC-mode analysis.Although high temperature GC can also be applied to separate samples with wide volatility range, a thin film must be used for the elution of less volatile components resulting in poor resolution in the analysis for volatile components. All the analyses described above were carried out using the arrange- ment shown in Fig. 3. SFC analyses can be carried out on both open microtubular columns and packed capillary columns. Fig. 9 illustrates an analysis of a dichloromethane solution of an ethoxylate by using a 10 m X 50 pm id fused-silica open-tubular column coated with a 0.25 pm SB-Biphenyl-30 film (Dionex). The main constituent oligomer series, C12H25(OCH2CH2)nOH, C14H29(OCH2CH2)nOH, ~ S O - C ~ ~ H ~ ~ ( O C H ~ C H ~ ) ~ O H , and re- sidual C 12H250CH2CH20H and C 14H290CH2CH20H were separated.In order to increase the resolution of the early eluted components, a low initial pressure (50 atm) was used. Initially, the carbon dioxide in the column was gaseous, and gradually became supercritical with pressure programming. This kind of operation is widely used in SFC analyses, especially when packed columns are employed. Such operations with single mobile phase from sub-critical to supercritical fluid conditions can also be classed as sequential GC-SFC or 'borderless' chromatographic analy~es.9-12J8-~0 Temperature programming from 80 to 240 "C was used along with the pressure program- ming from 50 to 4 15 atm. During the GC-type of separation, the retention times of the later-eluting components were reduced and peaks for the components were better focused owing to simultaneous temperature and pressure programming.A reduc- tion in peak width results from more rapid diffusion of the solute in the mobile phase (reduction of C, in the van Deemter equation) and desorption of components from the stationary phase at higher temperature. This analysis was carried out using the arrangement shown in Fig. 4. Fig. 10 shows an SFC analysis of a net crude oil on a 50 cm X 0.25 mm id fused-silica column packed with 5 pm ODs-1 particles. The column inlet was split connected to the T-piece, J I I I I 1 I I 0 10 20 30 40 50 60 Tim elm i n Fig. 9 Analysis of a dichloromethane solution of an ethoxylate by SFC on the unified chromatograph. Conditions: a 10 m X 50 pm id fused-silica open tubular column coated with a 0.25 pm film of SB-Biphenyl-30; FID detection; carbon dioxide mobile phase from 50 to 415 atm at 7 atm min-I; column temperature from 40 to 240 "C at 3 "C min-1.I I I I I I I I 1 0 5 10 15 20 25 30 35 40 Time/min Fig. 8 Analysis of pesticides spiked into vegetable oil by GC-SFC on the unified chromatograph. Conditions: 10 m X 50 pm id coated with a 0.25 pm film of SB-Methyl fused-silica open tubular column; FID detection; helium mobile phase at 12 atm, temperature programming from 150 to 248 "C at 5 "C min-1 and then to 100 "C within 1.5 min; carbon dioxide phase: at 100 "C, 200 to 300 atm at 5.5 atm min-1. Peak identifications: 1, hexachlorocyclopentadiene; 2, atrazine; 3, hexachlorobenzene; 4, alachlor; 5, heptachlor; 6, Aldrin; 7, Heptachlor epoxide; 8, y-chlordane; 9, trans-nonachlor; 10, dieldrin; 11, endrin; 12, Methoxychlor; 13, vegetable oil.2466 Analyst, October 1995, Vol.I20 and the outlet of the column was connected to the mode-selector valve as shown in Fig. 4. Sample introduction was performed using both split and time split injection. Separation was carried out with high resolution similar to that of GC but at much lower temperature and with a shorter analysis time. Packed capillary columns can achieve higher resolution and faster analyses than those obtained with open tubular columns for SFC analyses for non-polar samples (such as alkanes and PAHs). If the arrange- ment shown in Fig. 5 is used, the components can be monitored simultaneously by both UV and FID detection, and peaks for PAHs from UV detection are clearly shown without interference from alkanes.26 The chromatogram shown in Fig.11 was obtained by using the arrangement given in Fig. 5 . A 40 cm X 0.25 mm id capillary column packed with 5 pm ODs-1 particles was employed. Nitrated PAHs (nitro-PAHs) were analysed by isocratic reversed-phase HPLC (67% acetonitrile in water) with , ~ . . 9 * I . I t l 0 10 2 0 30 40 50 60 7 0 80 90 100 Time/min Fig. 10 Analysis of a crude oil by SFC on the unified chromatograph. Conditions: 50 cm X 0.25 mm id fused-silica column packed with 5 pm ODs-1 particles; FID detection; carbon dioxide mobile phase at 100 "C, from 100 a m (hold 5 min) to 415 atm at 2.5 atm min-1. t 'd UV detection at 254 nm. 1-Nitronaphthalene and 2-nitro- naphthalene (peaks 2 and 3 in Fig.11) were completely separated in only 8 min, in contrast to a standard nitro-PAH analysis with a 25 cm conventional column packed with the same stationary phase, with which the separation of these two compounds with the same resolution required 18 min with a linear gradient from 24% acetonitrile in water to 80% acetonitrile in water. The resolution in micro-LC analysis can be improved by using long columns, and the analysis speed can be increased by using 'stronger' solvents (greater percentages of acetonitrile or methanol), resulting in high resolution and fast analysis. The good permeability of packed capillary columns aids this improvement. The pressure drop across the 40 cm long column was only 1.70 X 107 Pa when a mixture of acetonitrile and water (2 + 1 v/v) was used for the above separations.0 5 10 15 Time/min Fig. 12 A purity analysis of 2-chloro-4-methylaniline by HPLC on the unified chromatograph. Conditions: a 40 cm X 0.25 mm id fused-silica column packed with 5 pm ODs-1 particles; UV detection at 254 nm; acetonitrile-water (2 + 1, v/v) mobile phase at 3 pl min-1 and room temperature. t 7 I I I 1 I l l i 0 5 10 15 20 25 30 35 Time/min Fig. 11 Separation of an acetonitrile solution of nitrated polycyclic atomatic hydrocarbons by isocratic HPLC on the unified chromatograph. Conditions: a 40 cm X 0.25 mm id fused-silica column packed with 5 pm ODs-1 particles; UV detection at 254 nm; acetonitrile-water (2 + 1 v/v) mobile phase at room temperature. Peak identifications: 1,4-nitroaniline; 2, 1 -nitronaphthalene; 3, 2-nitronaphthalene; 4, 2-nitrofluorene; 5 , 3-nitro- biphenyl; 6,9-nitroanthracene; 7, 1 -nitropyrene.4b L r l I I I r l I r i 0 5 10 15 20 25 30 35 40 45 Ti me/m i n Fig. 13 Analysis of an acetonitrile solution of bergamot oil by HPLC on the unified chromatograph. Conditions: a 40 cm X 0.25 mm id fused-silica column packed with 5 pm ODS-1 particles; UV detection at 214 nm; acetonitrile-water (2 + 1, v/v) mobile phase at 3 pl min-1 and room temperature.Analyst, October 199.5, Vol. 120 2467 Because of their high over-all column efficiency (longer column length) and high detectability (concentrated solutes for detection due to the small column id) packed capillary columns are very suitable for purity analysis.Fig. 12is a chromatogram for purity analysis of an acetonitrile solution of 2-chloro- 4-methylaniline. If a Z-configuration capillary UV detector were used, greater sensitivity could be obtained.26 Packed capillary columns are also suitable for the analyses of complex samples owing to their high over-all column effi- ciency. Fig. 13 is a HPLC chromatogram of an analysis of an acetonitrile solution of a bergamot oil under isocratic condi- tions. A small loss of peak height due to the absorption of the rotary valve in SFC analyses (and probably also in GC) was observed and reported earlier,*4 but considerable differences in peak height in HPLC analysis with the valve and without the valve were not observed. A new valve for mode selection, which has smaller dead volume and is more chemically inert is desirable.The development of a new detection method which is applicable in all separation modes is very important for new applications of unified chromatography and the achievement of a commercial unified chromatograph. Conclusions Different separation modes (GC, SFC, and HPLC) can be selected and performed by positioning a single valve in the novel unified chromatograph without loss of resolution. Band broadening was greatly restricted with the improved system. High-resolution HPLC analysis was achieved by using highly efficient packed capillary columns. The advantages of unified chromatography are: (1) the possibility of analysis of a variety samples with a single chromatographic instrument in which all separation modes can be selected; (2) the use of a single separation run for samples with a wide range of volatility; (3) injection without any limitations from the physical state of the mobile phase; (4) utilization of the selectivity of different mobile phases in different physical states in a single run; (5) unification and miniaturization of chromatographic instruments.The authors thank the European Coal and Steel Community for support of this work (Grant number 7220-EC866) and Dr. P. Myers for his encouragement and gifts of column materials. References 1 Giddings, J. C., Unified Separation Science, Wiley, New York, 1991. 2 Martire, D. E., J . Chromatogr., 1988, 452, 17. 3 Martire, D. E., J . Chromatogr., 1988, 461, 165. 4 Martire, D. E., J . Liq. Chromatogr., 1988, 11, 1779.5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Yang, F. J., Microbore Column Chromatography: a Unified Approach to Chromatography, Marcel Dekker, New York, 1989. Ishii, D., and Takeuchi, T., J. Chromatogr. Sci., 1989, 27, 71. Pentoney, S. L., Jr., Giorgetti, A., and Griffiths, P. R., J. Chromatogr. Sci., 1987, 25, 93. Bartle, K. D., Davies, I. L., Raynor, M. W., Clifford, A. A., and Kithinji, J. P., J . Microcolumn Sep., 1989, 1, 63. Ishii, D., Takeuchi, T., Saito, M., Toshinobu, H. H., Jpn. Pat., IP 88265164 A2, 1988. Takeuchi, T., Niwa, T., and Ishii, D., Chromatographia, 1987, 23, 929. Takeuchi, T., Ohta, K., and Ishii, D., Chromatographia, 1988, 25, 125. Ishii, D., Niwa, T., Ohta, K., and Takeuchi, T., HRC CC, J . High. Resolut. Chromatogr. Chromatogr. Commun., 1988, 11, 800. Lu, P., Zhou, L., Wang, C., Wang, G., Xia, A., and Xu, F., J. Chromatogr., 1979, 186, 25. Tong, D., Xu, F., and Lu, P., Chromatographia, 1987, 23, 499. Takeuchi, T., Ohta, K., and Ishii, D., Chromatographia, 1989, 27, 182. Takeuchi, T., Hamanaka, T., and Ishii, D., Chromatographia, 1988, 25, 993. Takeuchi, T., Hashimoto, Y., and Ishii, D., J . Chromatogr., 1987,402, 328. Gemmel, B., Schmitz, F., and Klesper, E., J . Chromatogr., 1988,455, 17. Gemmel, B., Schmitz, F. P., and Klesper, E., HRC CC, J. High. Resolut. Chromatogr. Chromatogr. Commun., 1988, 11, 901. Steenackers, D., and Sandra, P., J. High Resolut. Chromatogr., 1991, 14, 842. Davies, I. L., and Yang, F. J., Anal. Chem., 1991, 63, 1242. Liu, Y., and Yang, F. J., Anal. Chem., 1991, 63, 926. Robinson, R. E., Tong, D., Moulder R., Bartle, K. D., and Clifford, A. A., J. Microcol. Sep., 1991, 3, 403. Tong, D., Bartle, K. D., and Clifford, A. A., J. High Resolur. Chromatogr., 1992, 15, 505. Tong, D., and Bartle, K. D., J . Microcol. Sep., 1993, 5, 237. Tong, D., Bartle, K. D., and Robinson, R. E., J . Chromatogr. Sci., 1993, 31, 77. Tong, D., Bartle, K. D.. and Clifford, A. A., J. Microcol. Sep., 1994, 6, 249. Tong, D., Bartle, K. D., and Clifford, A. A., J. Microcol. Sep., in the press. McGuffin, V. L., and Novotny, M., Anal. Chem., 1983, 55, 2296. Hill, H. H., and McMinn, D.G., Detectors for Capillary Chromato- graphy, Wiley, New York, 1992. Hill, H. H., Jr., St. Louis, R. H., Morrissey, M. A., Shumate, C. B., Siems, W. F., and McMinn, D. C., J . High Resolut. Chromatogr., 1992, 15, 417. Paper 51007840 Received February 9, 1995 Accepted June 24, 199.5

ISSN:0003-2654    

DOI:10.1039/AN9952002461

出版商:RSC    

年代:1995

数据来源: RSC

摘要:

Analyst, October 1995, Vol. 120 2469 Fast Determination of Sulfate by Ion Chromatography Based on a Permanently Coated Column Xiao Jun, Jose L. F. C. Lima and M. Conceit$io B. S. M. Montenegro* CEQUP, Departamento de Quimica Fiscia, Faculdade de Farmcicia, R. Anibal Cunha, 164, 4050 Porto, Portugal A method based on a permanently coated C18 column for the fast determination ( c 2 min) of sulfate at the picogram level using indirect UV (205 nm) detection is described. Potassium hexacyanoferrate(rn) and 1,12-diaminododecane were used as eluent and coating reagent, respectively. Over a period of 6 d the day-to-day reproducibility, expressed as the relative standard deviation for a 1.0 mg 1-1 sulfate standard, is +_3.2% for the peak area and +1.7% for the retention time. Determinations of synthetic samples incorporating some inorganic ions and some organic anions showed that sufficient resolution in the presence of excess amounts of common ions was achieved.The proposed method was applied to water analysis. The analytical results of 27 different water samples including tap, well, surface, waste and mineral water were in good agreement with those obtained by the turbidimetric method. The paired Student's t-test showed that there was no statistical difference in the results. Keywords: Ion chromatography; sulfate, permanently coated column; water analysis Introduction Sulfate has been determined frequently in a wide variety of sample matrices1y2 and detection of low concentration levels has become of particular importance in the last decade.2 The application of classical analytical methods (such as gravimetry, turbidimetry and titrimetry), various spectrophotometric3~4 and flow injection methodss-7 is usually limited by insufficient sensitivity, limiting working range or labour-intensive proced- ures.1.3-4 Indirect methods in AAS278 have also been proposed for determination of trace levels of sulfate.These methods involve complex chemical reactions and time-consuming pre- preparation of samples. Moreover, they may suffer from interference of co-existing metal ions. These drawbacks are, however, overcome by using ion chromatography.9-12 Sulfate tends to be strongly adsorbed by the ion-exchange column. A retention time of greater than 10 min is required in standard ion chromatography, which slows down the analytical process.Although a high eluent concentration can be used to reduce the retention time, it raises the response baseline and consequently causes a loss in detection sensitivity.13-15 A more appropriate method to reduce the retention time would be the use of a low-capacity ion column combined with strong displacers as the eluent. l1~l27'5 However, these conventional ion chromatographic methods, using both dual- and single-col- umns, are rather expensive if the determination of sulfate alone is desired.' Recently, short guard columns to promote sulfate separation have been used to provide an inexpensive and rapid * To whom correspondence should be addressed. analysis.1.16 Although sulfate was determined rapidly (about 60 s), the detection limit (0.5 mg 1-l) was not improved and the method could not be applied to the precise analysis of drinking water containing a high calcium Concentration.' As an alternative to expensive fixed-site ion columns used in conventional ion chromatography, permanently coated re- versed-phase columns17-20 have shown the ability to solve some specific analytical drawbacks21-25 related to the sensitivity of individual determinations and the retention times of inorganic constituents of the samples. Advantages of the coated column over the fixed-site column are: greater chromatographic efficiency, low price of the columns and greater flexibility concerning the choice of column capacity and eluent composi- tion.20 They are also useful when the need for an ion-exchange separation is immediate but infrequent.26 In this paper an ion chromatographic method using a permanently coated C 18 reversed-phase column was examined for the fast determination of sulfate, at trace level, and the method was applied to the analysis of 27 water samples. The results were comparable with those obtained by turbidimetric method.In order to evaluate the possibility of extending this method to determine sulfate in other sample matrices, experi- ments were also carried out with some organic acids as the co- existing species. Experimental Reagents and Solutions Except for 1,lZdiaminododecane (purity > 98%; Merck, Darmstadt, Germany), the reagent for synthesis, all remaining chemicals used were of analytical-reagent grade. All the solutions used were made up with de-ionized water (1 8 MS2 cm) purified in an Anatron water-purification system (Anatron, Matosinhos, Portugal). Working solutions were prepared weekly and stored in a refrigerator.The eluent, a 30 pmol 1-1 potassium hexacyano- ferrate(II1) aqueous solution, was prepared by dilution of a concentrated mother solution (0.01 mol 1-1) in de-ionized water. Prior to its use it was filtered through a 0.22 ym membrane filter (Millipore, Milford, MA, USA) and de-gassed, for 30 min, by means of an ultrasonic wave. Apparatus A Gilson chromatographic system equipped with two Model 302 piston pumps, an 802 manometric module, an 8 1 1 dynamic mixer and a variable-wavelength UV detector and a Rheodyne (Cotati, CA, USA) Model 7125 injection valve with a 20 pl sample loop and a prime purge valve was used.An on-line filter was incorporated into the system between the column and the injector. A computer with a 506 Gilson interface module (Gilson, Worthington, WI, USA) was coupled with the chroma- tographic system for control of operating conditions. Data2470 Analyst, October 1995, Vol. 120 acquisition and measurement of chromatographic parameters were carried out using the 712 HPLC Gilson system software controller. A Waters Nova-Pak C18 (4 pm) column (3.9 X 150 mm id; Milford, MA, USA) was used to prepare the coated column. Coating Column The column was coated with 250 ml of 5 mmol 1-1 1,12-diaminododecane in water containing approximately 10% (v/v) methanol at a 0.45 ml min-l flow rate and conditioned in eluent before use. The coating solution was pre-adjusted to pH 4.20 with sulfuric acid, filtered and de-gassed.The coating volume was shown to be adequate to reach equilibrium on the coating column and thereby to obtain a constant retention time. A decrease in methanol concentration in the coating solution from 10 to 6% (v/v) produced an increase of only 3% in the retention time. The mean retention time for four replicate coatings was 1.75 k 0.02 min. An average of 55 samples (about 220 injections) could be determined with the coated column, during the lifetime of which variations in retention time of more than 12% were not observed. When necessary, regeneration of the column was carried out by washing in 100 ml of water and 200 ml of methanol at a flow rate of 1.0 ml min-1. Analytical Procedures Water samples tested were prepared by filtering them through a 0.22 pm syringe filter (Millex-GV 13, Millipore) and, when necessary, diluting them with de-ionized water.The external standard method was used for sulfate determination. The chromatographic conditions are shown in Table 1. Results and Discussion A coating reagent with weak ion-exchange group and a mobile phase with high eluting strength could be useful in reducing the retention time for sulfate. 1,12-Diaminododecane was used as a coating reagent which could provide a weak ion-exchange site on the CI8 stationary phase. The selection of hexacyanofer- rate(w) as an eluent was based on its UV active absorption and its strong elution at low concentration, which is necessary to obtain a low limit of detection for indirect UV detection.23 Eluting Conditions and Chromatographic Separation When optimizing the chromatographic parameters, i.e., the concentration of the eluent, pH, ionic strength, as well as the flow rate of the mobile phase, the relative retention charac- teristics of sulfate and co-existing ions were also considered.In order to evaluate the possibility of using the proposed method in the analysis of other matrices in addition to waters, both inorganic ions and some organic acids were examined as the co- existing species. Although the change in pH of the mobile phase does not produce great variation in the capacity factors for sulfate and thiocyanate, as shown by Fig. 1, it influences the retention of Table 1 Operating conditions Column Nova-Pak C column, permanently Detection wavelength Column temperature Ambient temperature Mobile phase Flow rate of mobile phase coated with l112-diaminododecane 205 nm (with 0.01 or 0.02 aufs sensitivity) 30 pmol I-' K3[Fe(CN)6] aqueous solution 0.8 ml min-1 Sample loop volume 20 p1 organic anions. The pH mainly influences the ionization and anionic forms of the diprotic organic acids other than those of inorganic anions and the ion-exchange capacity of the coated column, because the coated reagent, eluent, sulfate and thiocyanate were completely ionized over the pH range examined.At a pH of 5.72 (the corresponding value of the natural pH of the mobile phase) there was good separation of sulfate from the referred ionic species, while other weakly retained inorganic anions (fluoride, chloride, bromide, nitrite, nitrate, phosphate and hydrogencarbonate) and organic acids examined (formic, acetic, lactic, malic and oxalic) were eluted in void volume.The influence of eluent concentration, ionic strength and flow rate on the retention of sulfate were also studied. A linear relationship between log of the capacity factor for sulfate and log of eluent concentration in the range 5.G100.0 pmol l-l at pH 5.72 was obtained. The slope (-0.62) of the linear regression equation ( r = 0.997) is consistent with the theoretical value (-0.67) calculated by the proposed equation for ion-exchange chromatography.llJ1 This suggests that sulfate was mainly retained on the coated column by an ion- exchange mechanism. The ionic strength, adjusted by adding potassium chloride to the mobile phase over a range of 0-1.0 mmol 1-1, had no significant influence on the retention time.Experiments carried out with different flow rates over a 0.25-1.5 ml min-1 range showed that a rate of 0.8 ml min-1 is the most appropriate. In addition, there was no system peak14727 in the present experiments while the injection peak, in both shape and height, was dependent on eluent concentration, pH and ionic strength of the mobile phase and sample composition. Attention was given to the influence of sample composition on the injection peak. The addition of other ions to the standard produced an injection peak, which consisted of an initial negative portion closely followed by a positive portion. However, the latter decreased with increasing concentration of sulfate or other ions added, which suggests that the resolution between injection peak and that for sulfate was not influenced by sample composition.In all, a set of optimum eluting conditions (Table 1) was selected for the rapid separation of sulfate from most inorganic and organic anions. Under these conditions, common inorganic anions (fluoride, chloride, bromide, nitrite, nitrate, phosphate and hydrogencarbonate) and some organic acids (formic, acetic, lactic, malic and oxalic) were eluted in void volume. The capacity factors of those ions which eluted out around sulfate, and their detection sensitivities relative to that of sulfate, are listed in Table 2. There was a maximum of detection sensitivity corresponding to maximum eluent absorption23 at 205 nm, 0.5 0.4 + Sulfate + Thiocyanat ---t Malonic Succinic + Maleic 0.3 j j , 0.2 4 4.5 5 5.5 6 6.5 7 PH Fig.1 Effect of pH of the mobile phase on capacity factors of anions. Mobile phase: 60 pmol l-1 K3[Fe(CN),] at different pH levels, which were adjusted with hydrochloric acid and potassium hydroxide. Flow rate: 0.8 ml min-1. Detection: 254 nm at 0.01 aufs.Anulyst, October 1995, Vol. 120 247 1 which was selected based on the graph of height of chromato- graphic peak versus wavelength. As expected, variations in wavelength produce changes in relative sensitivity of the detection for other anions (see Table 2). Analytical Performance Evaluation of the analytical features of the method was carried out by checking reproducibility, working range, sensitivity and precision.A average retention time for sulfate is 1.75 k 0.02 (n = 6), which was obtained by six repeated injections of a sample containing 2 mg 1-1 sulfate, malonate and maleate, respectively, and 1 mg 1-1 of thiocyanate. The relative standard deviation for the retention time at six different concentrations in the range 0.08-10.0 mg 1-1 sulfate is +4.6% (n = 6). Over a period of 6 d the day-to-day reproducibility expressed as the relative standard deviation for a 1 .O mg 1-1 sulfate standard is +3.2% for chromatographic peak area and +1.7% for retention time. The working range was determined by injecting sulfate standard solutions at different concentrations (0.0 1-10.0 mg 1-1). The calibration graph was constructed every day for 6 d.Good linearity ( r = 0.9996 f 0.0006; n = 6) from 0.08 to 10.0 mg 1-l was obtained for sulfate. For concentrations higher than 10.0 mg 1-1, asymmetrically shaped peaks were obtained and the retention time was significantly increased. The detection limit of sulfate, defined as 4.65 times the standard deviation of six replicated analyses of a standard containing 0.08 mg 1-1 of sulfate,28 is 0.034 mg 1-1. The precision of this method was evaluated through recov- eries calculated by spiking known concentrations with well water over the whole linear concentration range. The recoveries determined for three replicate analysis in six samples are between 96 and 108%. Influence of Co-existing Ions The influence of co-existing ions was evaluated by the determinations of synthetic samples which contain inorganic anions or some organic acids.For the anions the results obtained showed that common inorganic anions, such as fluoride, chloride, bromide, nitrite, nitrate, phosphate, hydrogencarbo- nate and iodide, and some organic anions such as formate, acetate, tartarate, citrate, malate and oxalate, did not interfere significantly with determination of sulfate when their concen- tration ratio to sulfate was up to 64 : 1 and 48 : 1, respectively. Recoveries of sulfate for samples containing these two groups of anions are between 92 and 98.1%. However, the anions which eluted around sulfate, such as thiocyanic, succinic, malonic and maleic ions, showed a significant interference if the concentration of each one was higher than 3.0 mg 1- where the recovery at 0.5 mg 1-1 sulfate is 110%.Table 2 Capacity factors for different anions and their detection sensitivities relative to sulfate" Peak characteristics Relative peak height Anion k 205 nin 254 nm 205 nm 254 nm Sulfate 0.64 positive positive 1.00 1.00 Thiocyanate 0.53 negative positive -0.03 0.69 Succinate 0.45 positive positive 0.01 0.56 Malonate 0.55 positive positive 0.01 0.04 Maleate 0.80 negative negative -0.22 -0.31 * Chromatographic conditions used: aqueous solution containing 30 pmol 1- I of potassium hexacyanoferrate(II1) as mobile phase without adjusting pH and ionic strength, with a flow rate of 0.8 ml min-l. Detection sensitivity expressed as relative peak height (PH), i.e., PHanionJHsulfate. Other chromatographic conditions are given in Table 1.In the ion chromatographic determination of anions, the presence of high level of divalent ions, such as calcium, may cause disturbance of the chromatogram baseline due to interaction of metal ions with the active silanol sites of the stationary phase.29 However, interferences of calcium were not found in the present work, which is probably due to the use of an end-capping Nova-Pak CIS column. A 10 mg 1-1 calcium concentration did not cause any changes to the sulfate chromatogram except for the injection peak which was somewhat enlarged. For the sample containing 1.97 mg 1-l sulfate, 0.5 mg 1-1 magnesium, 10 mg 1-1 calcium and 17.8 mg 1-l chloride the recovery is 92.3%. Effect of Sample Dilution on Analytical Results With the present method a dilution pre-treatment for samples with high concentrations of sulfate is required before injection.Hence, the influence of diluting samples on the determination of sulfate was evaluated with both a standard sample and a real sample. The results obtained are presented in Table 3. No significant influence from the high dilution of samples was observed. Table 3 Effect of dilution of samples on the results Results/ Recovery Sample/mg 1-1 Dilution* mg 1-l (%) Standard- 5000 (1 :5000) 1011.3 f 13.1 101.1 1000 1000 (1 : 1000) 976.5 f 5.4 97.7 Waste water- 100 (1 : 100) 376.9 f 9.2 93.0 405.2 f 18.9+ 1000 (1 : 1000) 413.4 f 23.5 102.0 * Dilutions were performed with de-ionized water. t The result was obtained by the standard method.30 Table 4 Analytical results of water samples compared with the standard method Sample Proposed Standard No.method/mg 1-1 method3O/rng I-' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 2.74 f 0.11 0.65 f 0.01 8.71 f 0.38 7.52 f 0.05 1.45 f 0.05 13.87 k 0.28 4.29 f 0.49 19.9 f 0.11 395.2 f 2.52 1.70 f 0.21 3.05 f 0.10 6.25 f 0.27 15.4 f 0.4 24.9 f 0.2 6.25 f 0.21 11.8 f 0.2 22.5 f 2.2 23.3 f 1.4 120.4 f 2.1 140.0 f 4.5 20.5 f 0.14 10.3 f 1.4 76.5 f 1.6 1.24 f 0.32 0.50 f 0.04 55.8 f 1.26 4.71 f 0.08 2.1 f 0.16 8.14 f 0.08 7.49 f 0.14 1.35 f 0.04 9.08 f 0.01 2.44 f 0.16 19.6 f 0.14 405.2 f 1.56 0.729 f 0.012 2.96 k 0.18 5.28 f 0.20 17.2 f 1.6 23.6 f 2.7 6.38 f 0.06 12.4 f 0.4 20.5 f 1.9 22.0 f 0.2 118.3 f 2.3 146.7 f 4.5 27.9 f 0.9 9.26 f 0.35 77.8 k 0.11 1.33 f 0.05 45.9 f 1.41 3.09 f 0.08 Not found Not found2472 Analyst, October 1995, Vol.120 Determination of Sulfate in Water Samples The composition of water varies greatly, and could include either inorganic anions and metal cations or organic compounds depending on the type of water.ll Hence, the proposed method was evaluated for analysis of various water samples, e.g., waste, well, surface, tap and some Portuguese mineral waters. The results obtained are given in Table4. All the samples were analysed at least twice and the relative standard deviation generally was less than 5% (for 22 out of 27 samples). To assess the results obtained with the proposed method, a standard procedure, namely turbidimetry30 for sulfate determination was used. The results of regression analysis and statistical treatment are summarized in Table 5.As can be seen, there is no statistical difference between the results obtained by the proposed method and the standard procedure. Two typical chromatograms obtained are illustrated in Fig. 2. Table 5 Results of the statistical treatment performed on the pairs of data obtained by using the proposed chromatographic method and the standard procedure. Tabulated values were obtained at the 95% confidence level Linear regression* Student’s t-test Slope Intercept r2 tcalc. ttab. Sulfate 0.973 f 0.006 1.556 f 0.587 0.999 0.708 2.06 n = 25 * Proposed method versus standard procedure. 1 0.00 0.50 1-00 1.50 2.00 2.50 Timdmin Fig. 2 Chromatograms of (a) a waste water and (b) a surface water sample. Operating conditions are given in Table 1.1, Water dip; 2, the peak for sulfate. [E is in per cent., 100% = 20.89 mV (A) or 26.18 mV (B).] Conclusion The proposed method is less expensive (Le., lower price of the reversed-phase column), more rapid and more sensitive than the conventional ion chromatographic procedure for samples in which a single sulfate determination only is desired. The ease of use encourages its implementation in laboratories for routine analytical control. The coated column can also be conveniently regenerated for subsequent analytical work. The use of 1,12-diaminododecane as the coating reagent results in a weak exchange group whereas the strong eluting power of the multi-charged hexacyanoferrate(II1) complexed anion reduces the retention time of sulfate greatly so as to achieve a rapid determination (in 2 min).This system also uses a low eluent concentration so that trace amounts of sulfate at the picogram level can be detected. On the other hand, the low eluent concentration limits the maximum concentration of sulfate that can be injected. Therefore, an appropriate elution pre-treatment for those samples containing high sulfate is suggested. Large dilution of samples can also significantly reduce the influence of complex matrices and does not pose detection problems with the proposed method. The method was successfully applied to water analysis. No significant interference was found from co-existing anions and cations. The results provided by the proposed method were in good agreement with those obtained by turbidimetry (see Table 5). The results obtained with the synthetic samples, which incorporated inorganic anions and some organic acids, showed that the method could also be applied to other sample matrices in addition to water.This work was supported by IDARN (Project PRI No. 24). One of us (X.J.) would like to thank the Orient Foundation (Lisbon, Portugal) for financial support. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Frenzel, W., and Rauterberg, A., Mikrochim. Acta, 1992,106, 175. Chattaraj, S., and Das, A. K., Analyst, 1992, 117, 413. American Society of Testing and Materials, Standard Test Methods for Sulfate Ion in Water, ASTM, Philadelphia, 1982, pp. D516-82. Kojlo, A., Michalowski, J., and Trojanowicz, M., Anal. Chim. Acta, 1990,228,287.Koch, B., Fresenius’ Z. Anal. Chem., 1988, 329,707. Fernandez-Band, B., Linares, P., Luque de Castro, M. D., and ValcArcel, M., Analyst, 1991, 116, 305. Ueno, K., Sagara, F., Higashi, K., Yakata, K., Yoshida, I., and Ishii, D., Anal. Chim. Acta, 1992, 261, 241. Campbell, A. D., and Tioh, N. H., Anal. Chim. Acta, 1978, 100, 451. Wetzel, R. A., Pohl, C. A., Riviello, J. M., and MacDonald, J. C., in Inorganic Chromatographic Analysis, ed. MacDonald, J . C., Wiley, London, 1985, ch. 9, p. 355. Johnson, E. L., and Haak, K. K., in Liquid Chromatography in Environmental Analysis, ed. Lawrence, J. F., Humana Press, New Jersey, 1983, ch. 6, p. 263. Shpigun, 0. A., and Zolotov, Y. A., Zon Chromatography in Water Analysis, translated by Cox, P. J., Ellis Horwood, Chichester, 1988. Gjerde, D. T., and Fritz, J . S., Zon Chromatography, Huthig, Heidelberg, 2nd edn., 1987. Yeung, E. S., Acc. Chem. Res., 1989,22, 125. Rocklin, R. D., J . Chromatogr., 1991,564, 175. Small, H., and Miller, T. E., Jr, Anal. Chem., 1982, 54,462. Jupille, T., Burge, D., and Togami, D., Chromatographia, 1982, 16, 312. Cassidy, R. M., and Elchuk, S., J. Chromatogr. Sci., 1983,21,454. Duval, D. L., and Fritz, J. S., J. Chromatogr., 1984, 295, 89. Mullins, F. G. P., Analyst, 1987, 112, 665. Ito, K., Ariyoshi, Y., Tanabiki, F., and Sunahara, H., Anal. Chem., 1991, 63, 273. Michigami, Y., Fujii, K., Ueda, K., and Yamamoto, Y., Analyst, 1992, 117, 1855.Analyst, October 1995, Vol. I20 2473 22 23 24 25 26 27 28 Michigami, Y., Yamamoto, Y., and Ueda, K., Analyst, 1989, 114, 1201. Groh, T., and Bachmann, K., J . Liq. Chromatogr., 1992, 15, 2611. Barkley, D. J., Charbonneau, J. R., Chenier, M. J., Glasgow, C. C., and Graham, J. A., J . Chromatogr., 1993, 642, 371. Ito, K., and Ariyoshi, Y., J . Chromatogr., 1992, 598, 237. Dorsey, J. G., Foley, J. P., Cooper, W. T., Barford, R. A., and Barth, H. G., Anal. Chem., 1992,64, 353R, sect. H. Michigami, Y., and Yamamoto, Y., J . Chromatogr., 1992, 623, 148. Cheam, V., Analyst, 1992, 117, 1137. 29 Jenke, D. R., and Pagenkopf, G. K., Anal. Chem., 1983,55, 1168. 30 American Public Health Association, American Water Works Asso- ciation and Water Pollution Control Federation, Standard Methods for the Examiantion of Water and Wastewater, APHA, New York, 18th edn., 1992, pp. 4-134. Paper 5102091 C Received April 3, I995 Accepted June 13, I995

ISSN:0003-2654    

DOI:10.1039/AN9952002469

出版商:RSC    

年代:1995

数据来源: RSC