ISSN:0003-2654    

DOI:10.1039/AN97499FX045

出版商:RSC    

年代:1974

数据来源: RSC

ISSN:0003-2654    

DOI:10.1039/AN97499BX047

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

i V THE ANALYST [December, 1974THE ANALYSTEDITORIAL ADVISORY BOARDChairman: H. J. Cluley (Wembley)*L. S. Bark (Solford)R. Belcher (Birmingham)L. J. Bellamy, C.B.E. (Waltham Abbey)L. S. Birks (U.S.A.)E. Bishop (Exeter)'R. M. Dagnall (Hunfingdon)E. A. M. F. Dahmen (The Netherlands)*J. B. Dawson (Leeds)A. C. Docherty (Billingham)D. Dyrssen (Sweden)*W. T. Elwell (Birmingham)*D. C. Garratt (London)J. Hoste (Belgium)D. N. Hume (U.S.A.)H. M. N. H. Irving (Leeds)M. T. Kelley (U.S.A.)*J. A. Hunter (Edinburgh)W. Kemula (Poland)*G. F. Kirkbright (London)G. W. C. Milner (Harwell)G. H. Morrison (U.S.A.)*J. M. Ottaway (Glasgow)*G. E. Penketh (Billingham)S. A. Price (Tadworth)D. 1. Rees (London)E. B. Sandell (U.S.A.)*R. Sawyer (London)A.A. Smales, O.B.E. (Harwell)H. E. Stagg (Manchester)E. Stahl (Germany)A. Walsh (Australia)T. S. West (London)P. Zuman (U.S.A.)*A. Townshend (Birmingham)* Members of the Board serving on the Executive Committee.NOTICE TO SUBSCRIBERS(other than Members of the Society)Subscriptions for The Analyst, Analytical Abstracts and Proceedings should beThe Chemical Society, Publications Sales Ofnce,Blackhorse Road, Letchworth, Herts.Rates for 1974sent to:(a) The Analyst, Analytical Abstracts, and Proceedings, with indexes . . . . €37.00(b) The Analyst, Analytical Abstracts printed on one side of the paper (withoutindex), and Proceedings . . . . . . . . . . . . . . f38.00(c) The Analyst, Analytical Abstracts printed on one side of the paper (withindex), and Proceedings .. . . . . . . . . . . . . 1245.00The Analyst and Analytical Abstracts without Proceedings-(e) The Analyst, and Analytical Abstracts printed on one side of the paper (without(f) The Analyst, and Analytical Abstracts printed on one side of the paper (with(d) The Analyst and Analytical Abstracts, with indexes . . . . . . . . €34.00index) . . . . . . . . . . . . . . . . . . €3500index) . . . . . . . . . . . . . . . . . . f42-00(Subscriptions are NOT accepted for The Analyst and/or for Proceedings aloneVi SUMMARIES OF PAPERS I N THIS ISSUE [December, 1974Summaries of Papers in this IssueOne Hundred Years of Development in Analytical ChemistryCentenary LectureH. M. N. H. IRVINGDepartment of Inorganic and Structural Chemistry, Leeds University, Leeds,LS2 9JT.Analyst, 1974, 99, 787-801.Analytical Chemistry and EducationPlenary LectureR.BELCHERDepartment of Chemistry, University of Birmingham, P.O. Box 363, Birmingham,B15 2TT.Aqaalyst, 1974, 99, 802-809.Analytical Chemistry in Public ServicePlenary LectureJ. MARKLANDThe County Laboratory, County Offices, Matlock, Derbyshire, DE4 3AG.Analyst, 1974, 99, 810-816.Analytical Chemistry in IndustryPlenary LectureC. WHALLEYLaporte Industries Limited, General Chemicals Division, Moorfield Road, Widnes,Lancashire,Analyst, 1974, 99. 817-823December, 19741 SUMMARIES OF PAPERS I N THIS ISSUEBioavailability from Pharmaceutical Dosage FormsThe last few years have witnessed a concentration of interest in theeffectiveness of pharmaceutical dosage forms.This interest has arisen froma growing awareness that the efficacy of an otherwise acceptable drug canbe severely affected by insufficient attention to the manner of its presentationfor administration by different manufacturers. This has found expressionin the concept of bioavailability.Strictly, bioavailability is only assessable in terms of availability of thedrug substance at the actual site of action. For various reasons, however,direct measurement of bioavailability is frequently not possible in humansubjects. Its assessment, therefore, usually rests on the measurement ofsecondary parameters of which blood levels and urinary excretion data arethe most common.The route of administration adopted for any drug depends on a com-bination of the clinical requirement, the physicochemical properties of thedrug substance, and the extent to which these can be modified by formulation.Within the limitations imposed by such considerations, bioavailability de-pends principally on the skill of the formulator and his assessment of thephysiological parameters that affect the absorption, transport, metabolismand excretion of the drug from the body.Once the product is formulated,standardisation of its production depends on the ability of the productionpharmacist and his quality controller to specify and keep check on theparameters necessary to achieve uniformity from one batch to the next.Physiological factors, which affect blood levels and tissue availabilityof drug substances, are considered.These include plasma and tissue proteinbinding, cell binding, lipid deposition and metabolism, and assessment ofthe interplay between them. The physicochemical properties that affecttheir availability from oral dosage forms, aerosols and topical preparationsare examined with particular reference to factors affecting rates of solutionof substances with low water solubility. Crystallinity, polymorphism, particlesize, wettability and ease of dissolution are examined from this point of view.J. B. STENLAKEDepartment of Pharmaceutical Chemistry, University of Strathclyde, 204 GeorgeStreet, Glasgow, G1 IXW.Analyst, 1974, 99, 824-837.viiAn Instrumentation-orientated Micro-computer : An ExtremelyInexpensive Data Acquisition Computer Optimised for theAutomated LaboratoryThe design and realisation of a maximally versatile multi-access on-linedigital computer system for support of instrumentation design, experimentcontrol and data interpretation in chemical research are discussed.Featuresincluded are (i) development of low-cost modular experiment control pro-cessors for installation in, and dedication to, laboratory-captive instru-mentation systems, (ii) configuration and installation of a central multi-programmed computer system which serves as a common experiment-design,data analysis and mass-storage resource, (iii) current and proposed researchof new varieties of computer-assisted experiment design techniques for therapid implementation of instrumentation by research chemists and (iv)application of the complete system to a variety of chemical research environ-ments representative of a broad range of instrumentation requirements. Themodular experiment control processors (micro-computers) serve as remote,“intelligent” data acquisition terminals of the central system. Their designutilises recent developments in micro-circuit technology and the results ofdetailed analysis of the requirements of the research environment to achievea unique level of cost-effectiveness.W. STEPHEN WOODWARD, THOMAS H. RIDGWAY and CHARLES N.REILLEYKenan Laboratories of Chemistry, University of North Carolina, Chapel Hill, NorthCarolina 27514, U.S.A.Analyst, 1974, 99, 838-862

ISSN:0003-2654    

DOI:10.1039/AN97499FP135

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

x SUMMARIES OF PAPERS I N THIS ISSUEIndustrial Sampling and Analysis[December, 1974Quality control by sampling and analysis is essential in the chemicalindustry. Raw materials, process intermediates and finished products mustall be analysed for conformity with the relevant specifications. With in-creasing concern for the environment this control has been extended toeffluents. Illustrative examples are given of the methods used for thequality control of compound fertilisers and for the analysis of gaseous andliquid effluents.A. C. DOCHERTYImperial Chemical Industries Limited, Agricultural Division, Billingham, Cleveland,TS23 1LE.Analyst, 1974, 99, 853-858.Preferred Experimental Conditions for Trace Analysis by ModernLiquid ChromatographyModern (high-pressure) liquid chromatography (LC) is uniquely suitedto the trace analysis of a wide variety of non-volatile or labile materials, bothorganic and inorganic in composition.In addition to the gentle conditionsof separation in LC, accurate analyses can be made as a result of the highresolution afforded by the unique interactions in liquid systems with thefour LC methods liquid - solid, liquid - liquid, ion exchange and exclusion.Sensitive LC detectors are now available which also permit highly selectivemeasurements, some of them not obtainable by other chromatographic tech-niques. The sensitivity and accuracy of trace LC analyses are affected bythe chromatographic sampling technique, calibration procedure, sample pre-treatment and column resolution. For instance, experiments show that thesensitivity of methods based on both peak height and peak area measure-ments is influenced by the efficiency of the column, the velocity of the mobilephase, and the value of the capacity factor (k’) for the solute.Detectionsensitivity can also be influenced by the type of pumping system used in theLC apparatus. Based on these considerations, preferred conditions for theanalysis of trace components by LC can now be established.J. J. KIRKLANDCentral Research Department, E. I. du Pont de Nemours & Company, Wilmington,Del. 19898, U.S.A.Analyst, 1974, 99, 859-885.Atomic-Fluorescence and Atomic- Absorption Spectrometryfor Chemical AnalysisAtomic-absorption spectroscopy, which was first described in the litera-ture in 1955, has now become widely accepted as a trace technique for theanalysis of most metals.However, atomic fluorescence, which was firstdescribed in 1964, has not yet found widespread use. This situation isanalysed and some aspects of the relative performance and properties of thetwo techniques are discussed. Particular attention is paid to the type ofexcitation source and atomising device. The effects that recent developmentsmay have on the relative importance and use of these techniques are assessed.Attention is focused on a new analytical possibility in which hydratedatomic species are generated by electro-reduction in the solution phase above acathode and in which the optical ultraviolet absorption and fluorescencespectra of these hydrated atom species are measured.T.S . WESTChemistry Department, Imperial College of Science and Technology, Universityof London, London, SW7 2AY.Analyst, 1974. 99, 886-899xii SUMMARIES OF PAPERS I N THIS ISSUEHighways and Byways in Thermal AnalysisTwo thermoanalytical techniques, differential thermal analysis (DTA)and thermogravimetry (TG) , have always held the limelight. However,there has been an increasing trend to introduce variants of these for specificpurposes, to develop methods dependent on properties other than energyand mass, to employ several techniques simultaneously and to combinethermoanalytical and non-thermoanalytical methods. The main aim of thesedevelopments is to produce in the minimum time the maximum amountof relevant and accurate information on the systems studied.Variants of DTA, obtained by altering specimen holder design, bychanging furnace atmosphere, by modifying sample size or by dispensingwith the reference material, can improve the accuracy of energy-changedetermination, permit measurement of various thermal constants and allowexamination of materials that would not give interpretable results in conven-tional equipment.Variants of TG can be used to derive more accurate kineticinformation. Differential scanning calorimetry (DSC) has a somewhat differentbasis from DTA and is fundamentally quantitative for energy changes;recent developments allow it to be used to about 750 "C, opening the possi-bility of its application to a much wider range of materials.Changes observed in dimensions and in mechanical, optical, electrical,magnetic and acoustic properties on heating all assist in interpreting thesignificance of results obtained by DTA, DSC and TG.Evolved gas detection and evolved gas analysis are gaining increasingrecognition.Although usually coupled with DTA or TG measurements, theyare sometimes used independently, as in thermal volatilisation analysis,which is of value in the study of polymers, and in rapid pyrolysis coupledwith gas chromatography or mass spectrometry, which has yielded interestinginformation on the nature of organic materials.The use of two or more methods t o examine one sample simultaneouslyhas several advantages, particularly in facilitating comparison and inter-pretation of results.Although the optimum conditions for one determinationare not necessarily those for another and care must therefore be taken inassessing results, multiple techniques can serve a useful function in manyinvestigations.Future trends seem to be towards the increasing development of somecurrently less well established methods ; more extensive application of com-puters in experimental control and in interpretation of results can also beexpected. In certain applications, the links with calorimetry may wellbecome closer.[December, 1974R. C. MACKENZIEThe Macaulay Institute for Soil Research, Craigiebuckler, Aberdeen.Analyst, 1974, 99, 900-912December, 19741 THE ANALYST xiiiI NE w fromAnalytical Sciences Monograph No.2The Chemical Analysis of WaterGeneral Principles and Techniques(Water Research Centre,Medmenham Laboratory)I by A. L. WilsonPp. viii + 188 f 7.50ClothboundISBN 0 85990 502 0CS Members' price f5.75The Societyfor Analytical ChemistrySelected Annual Reviewsof the Analytical SciencesVolume 3CONTENTS'Solvent Extraction in Inorganic AnalyticalChemistry,' by S. J. Lyle'Selective Ion-sensitive Electrodes,' byG. J. Moody and J. D. R. Thomas'The Application of Separated Flames inAnalytical Atomic Spectrometry,' by M. S.Cresser, P. N. Keliher and G. F. KirkbrightPp. vi + 162 f 6.00ISBN 0 85990 203 XCS Members' price f3.00To be published on December 30th, 7974After January lst, 1975, orders for a// SACpublications, including these two new books,should be sent direct or through your usualbookseller to-The Publications Sales OfficerTHE CHEMICAL SOCIETYBlackhorse Road, Letchworth,Herts. SG6 1 HN, EnglandCS Members must write direct to the above addressenclosing the appropriate remittance.SPECIALIST ABSTRACTJOURNALSpublished byP.R.M.SCIENCE &TECHNOLOGY AGENCYLTD.Atomic Absorption and EmissionSpectrometry AbstractsVol. 6, 1974, bimonthly f30X- Ray Fluorescence SpectrometryAbstractsVol. 5, 1974, quarterly f28Gas Chromatography-MassSpectrometry AbstractsVol. 5, 1974, quarterly f37Thin-Layer Chromatography AbstractsVol. 4, 1974, bimonthly f28Nuclear Magnetic ResonanceSpectrometry AbstractsVol.4, 1974, bimonthly f30Laser-Raman Spectroscopy AbstractsVol. 3,1974, quarterly f30Activation Analysis Abstracts'Vol. 3, 1974, quarterly f30X-Ray Diffraction Abstracts'Vol. 2, 1974, quarterly f30Electron Microscopy Abstracts'Vol. 2, 1974, quarterly f30Liquid Chromatography Abstracts"Vol. 1 , 1974, quarterly f30Electron Spin Resonance SpectroscopyAbstracts'Vol. 1, 1974, quarterly f30Infrared Spectroscopy AbstractsVol. 1, 1974, quarterly f30'These volumes began publication in July1973.Sample copies on request from:P.R.M. SCIENCE &TECHNOLOGY AGENCYLTD.,3 HARRINGTON ROAD,SOUTH KENSINGTON,LONDON, SW7 3ES01-584 808XiV SUMMARIES OF PAPERS IN THIS ISSUE [December, 1974Historical Review of the Analytical Control of InsulinFollowing the discovery of insulin in 1922, the lack of knowledge of itschemical structure caused biological methods of assay based on the measure-ment of the hypoglycaemic response in rabbits and the convulsive responsein mice to be developed in order to assess the potency of the hormone.These classical methods, the evolution of which contributed largely to theestablishment of biometrics, are still the only acceptable pharmacopoeialmethods for the determination of insulin potency.By using these methodsfour International Standards for insulin were established during the period1926 to 1959. Other in vivo methods were developed so as to increase thesensitivity of the assay.Attempts to replace the in vivo assays by in vitvo assays have been made,based mainly on the observation in 1940 that insulin increased glucose uptakeand glycogen deposition in the isolated rat diaphragm and on the laterobservation in 1958 that insulin enhanced glucose uptake and oxidation inisolated rat epididymal fat.While methods utilising these parameters aresensitive they lack precision and also lack specificity when used as in-processassays for monitoring the isolation of insulin from the pancreas.Following the establishment of radioimmunoassays for the measurementof the amount of insulin in blood, attempts during the last decade havebeen made to replace the pharmacopoeial assays by radioimmunoassay. Thismethod of assay is, however, not always correlated with biological potency.Assays based on the physico-chemical properties of insulin have beendeveloped in the last 20 years, involving the use notably of chromatographicand electrophoretic techniques. In general they are less sensitive and giveless reproducible quantitative results from one laboratory to another thanbiological assays but have been invaluable in assessing the purity of insulinby revealing the presence of any associated polypeptides that could giverise to unwanted immunological responses in man.Insulin preparations with prolonged action have been developed from1936 onwards, in which insulin is rendered insoluble at neutral pH by com-plexing it with a protein such as protamine or globin (PZI or GZI) or bycrystallising it in the presence of excess of zinc (Lente Insulins).Pharma-copoeial tests to ensure uniformity of the preparations may include a test todemonstrate prolongation of action in rabbits or guinea pigs.In further defining the purity of insulin, other analytical controls areapplied including the determination of nitrogen, zinc, ash, moisture andglucagon.No comprehensive pharmacopoeial monograph yet exists forcrystalline insulin but all pharmacopoeias contain monographs to controlthe quality and concentration of insulin in formulated preparations.Insulin in clinical use is largely bovine or porcine in origin but other speciesinsulins have been used. The biological activity of various species insulinis discussed.Insulin has also been modified chemically, usually by acylation, in anattempt to increase potency, prolong activity or reduce immunogenicity.The chemical and biological control of these insulins is also discussed.Since the discovery of the linear and tertiary structures of insulin,attempts have been made to determine active regions of the molecule witha view to their synthesis and preservation of the tertiary structure.Thesynthesis of insulin itself has also been achieved, although not yet commer-cially. The analytical controls that will have to be exercised on syntheticinsulin and insulin-like molecules are discussed.G. A. STEWARTThe Wellcome Foundation Ltd., Dartford, Kent.Analyst, 1974, 99, 913-928xvi SUMMARIES OF PAPERS IN THIS ISSUEManagement Studies and Techniques for Application in AnalyticalResearch, Development and ServiceOver the past two decades or so, management studies and techniqueshave been applied to an increasing extent in both governmental and industrialresearch and development establishments, and some of this knowledge is ofdirect relevance to the management of the analytical sciences function.The topic can be considered under three closely interrelated headings,namely the work, the organisation and the people.In the work-orientatedsector, attention is focused on some of the techniques that are being usedfor project selection, evaluation and control. On selection, apart from generalplanning, use may be made of various forecasting techniques, and in thesearch for innovation there may be scope for both lateral thinking andsynectics or group brainstorming.On evaluation, there may be uses fordecision trees and for credibility diagrams in addition to the techniquesof operational research and cost - benefit analysis. On control, there canbe value in aids such as check lists, bar charts, network analysis and researchplanning diagrams.In the organisation-orientated sector, it has been suggested that themajor types of organisational systems can be reduced to two theoreticalmodels, namely the hierarchical or mechanistic type and the flexible ororganic type. In reality, many research and development establishmentsoperate some form of combined system, of which the matrix type is receivingconsiderable attention. Such systems have their advantages in terms ofgeneral effectiveness but can present difficulties in human relation terms,e.g., in r6le identification, extent of responsibility and dual authority relation-ships.An important aspect of any organisational system is that of thepatterns of communication that it dictates from both the structural (hier-archical) and the physical (proximity) standpoints.In the most important sector, relating to people, attention must bepaid to the optimal selection of staff, their further training from both thetechnical standpoint and that of personal development and, ideally, to anappropriate method of job evaluation that will ensure that analytical staffwill be treated equitably in relation to their professional colleagues in otherdisciplines. Help in this people-orientated sector may be obtained fromthe behavioural scientists, whose studies can assist in understanding man’sneeds, motivations and behaviour when working in groups, as well as theconsequences resulting from the employment of different managerial styles.Modification of some of these behavioural characteristics forms an essential partof the process of organisation development from which, hopefully, greaterachievements may be realised than were previously possible.R.GOULDENShell Research Ltd., Woodstock Laboratory, Sittingbourne Research Centre,Sittingbourne, Kent.Analyst, 1974, 99, 929-947.[December, 1974Turning Surface Chemical Phenomenona to Advantage inQuantitative Trace AnalysisAdsorption processes are usually regarded as anathemas in inorganicchemical analysis since they often account for significant losses in separationsor in electrochemical measurements.Apart from chromatographic separationsand adsorption indicators, little attention seems to have been paid to surfacephenomena in a constructive manner for carrying out analyses. Threeexamples, namely an account of the mechanism of the adsorption of organo-metallic chelates on aluminium and silicon oxides, the deliberate superimposi-tion of an adsorbed film of protein on platinum micro-electrodes used indeterminations of oxygen in body tissue and novel measurements of chargeson gas bubbles passing through electrolyte solutions, are discussed in termsof their physical chemistry and their possible application to specific problemsin inorganic analysis in order to demonstrate that adsorption can be turnedto good account.D.A. PANTONYMaterials Analysis Group, Royal School of Mines, Imperial College of Science andTechnology, London, SW7 2BP.Analyst, 1974, 99, 948-958xviii [December, 1974 SUMMARIES OF PAPERS IN THIS ISSUEParticle Size Analysis : Past, Present and FutureAlthough the Particle Size Analysis Group of the Society for AnalyticalChemistry has been in existence for only 8 per cent. of its parent’s life, themethods used for the analysis of particle size can be traced back into antiquity.For example, the Egyptians were mining precious metals in the Sinai penin-sula at about 4000 B.C. and there is documentary evidence that sievingwas utilised by these early technologists.The behaviour of particulate solids is influenced by size and shape; theanalysis of particle size is therefore of vital concern to many different moderntechnologies ranging from the manufacture of paint to the formulation ofdrugs and phytochemicals.A feature of particle size analysis today is thatit is not strictly a discipline in its own right but cuts across many scientificareas. The techniques of analysis are applied by many different types ofscientist from chemists and physicists to pharmacists and chemical engineers.Indeed, this cross-fertilisation of disciplines has been one of the mostattractive features of the Particle Size Analysis Group, and this is illustratedby reference to some of the personalities associated with the Group since itsformation.Methods of analysis vary from the direct microscope analysis to theindirect methods that depend on inertial or optical properties of the particlesthemselves.In addition there are other indirect methods that depend onmeasuring properties of packed powder beds, such as gas permeability oradsorption. Many of these methods have been developed and improvedin recent years, but each method yields a unique estimate of size for materialsthat are other than spheres. Interpretation of the results obtained bymethods of size analysis may therefore present a different type of problemfrom, say, the interpretation of a relatively simple chemical analysis. Atpresent there is an urgent need to reconsider established methods of analysisby using modern ideas of mathematics, statistics and, in some situations,hydrodynamics. The criticism has been made that the instrument manu-facturer has outstripped the theoretician, and it seems that now is the timein this field to sit down and think.The techniques of size analysis do not exist in their own right and haveno use in isolation without their applications.For this reason there havebeen genuine advances made in very recent years in areas where there isa need, for example, for on-line analysis in the control of a continuous pro-duction line. The main problem here is the sampling process used, as thevast majority of sizing procedures require considerable dilution before theycan be applied. Sampling and analysis can be carried out automatically,but the final choice of the method of sizing has to be made on the ultimateapplication or use of the end product.Some recent advances in instrumentation are described, including theuse of scanning electron microscopy to characterise and identify particulatecontamination of the environment.In addition, the improvement broughtabout in the application of laser light to applications in which monochromaticlight was previously used is also described.Modern developments in the subject have been kept continually underreview by the Group since its foundation, including the organisation oftwo International Conferences, with a third scheduled for 1977. The childspawned by a healthy and interested parent is continuing to be blessed witha lusty and vigorous growth.M.J. GROVESPharmacy Department, Chelsea College, University of London, Manresa Road,London, S.W.3.Analyst, 1974, 99, 959-972December, 19741 THE ANALYST xixJOURNALSBOOKSMONOGRAPHSREPRINTSFrom January lst, 1975,orders for all publications atpresent published by the Societyfor Analytical Chemistry shouldbe sent direct or through abookseller toThe Publications Sales Officer,THE CHEMICAL SOCIETY,Blackhorse Road, Letchworth,Herts. SG6 1 HNANALOID compressed chemicalreagents offer a saving in the use oflaboratory chemicals.The range of over 50 chemicals in tabletform includes Oxidizing and ReducingAgents, Reagents for Colorimetric Analysisand Indicators for Complexometric titra-tions.Full details of all Analoid preparations freeon request from:RIDSDALE & GO.LTD.Newham Hall, Newby,Middlesbrough, Cleveland TS8 9EATelephone: Middlesbrough 372 16Annual Reports on AnalyticalAtomic SpectroscopyVolume 3,1973This comprehensive and critical report of developments in analytica I atomicspectroscopy has been compiled from nearly 1700 reports received fromworld-wide correspondents who are internationally recognised authorities inthe field and who constitute the Editorial Board. In addition to surveyingdevelopments throughout the world published in national or internationaljournals, a particular aim has been to include less widely accessible reportsfrom local, national and international symposia and conferences concernedwith atomic spectroscopy.324 pages Price f6.00 ISBN 0 85990 253 6Members of The Chemical Society may buy personal copies at the special price of f3.00Volumes 1 & 2, covering 1971 & 1972, are still availableObtainable from The Society for Analytical Chemistry,(Book Department), 9/10 Savile Row, London, W1 X 1 AF(From January 1st' 1975, a l l orders should be sent to The Pubfications SafesOfficer, The Chemical Society, Blackhorse Road, Letchworth, Herts.SG6 IHNXX SUMMARIES OF PAPERS I N THIS ISSUESome Modern Applications of Activation AnalysisApplications of neutron-activation analysis have considerably increasedin importance since the advent of high-resolution germanium (lithium) de-tectors. Complex spectra can indeed be analysed without the need forlengthy chemical separations. Obviously, applications are still mainlyorientated towards the determination of minor or trace constituents in a numberof fields.An area of application that has been increasingly used is the determina-tion of the inorganic composition of aerosols.By varying the differentparameters, such as irradiation time, decay time, thermal or epithermalneutron activation, over forty elements were quantitatively determined,down to the nanogram level. From comparative inter-laboratory tests onstandards it appeared that neutron activation was not only superior as faras sensitivity is concerned, but also in regard to accuracy of the results,compared with other instrumental methods.Neutron activation has also been a powerful aid in archaeology, especiallyin the determination of potsherds.Chemical analysis can provide informa-tion about the origin of the pottery, for instance to determine if it is of localor imported origin. Obviously an answer can only be found from the deter-mination of minor and trace elements, as they possibly allow one to dis-tinguish between samples of different origins or to link those with acommon origin. The neutron-activation technique applied to potsherds issimilar to that used for geological material. A combination of a large andlow-energy photon germanium (lithium) detector allows the determinationof about twenty-five minor and trace constituents. From the large amountof data obtained a classification must of course be obtained, leading to aconclusion of similarity or dissimilarity of origin.Procedures based onstatistical or cluster analyses have been developed for this purpose, whichlead to consistent conclusions.Considerable progress was also achieved in activation analysis with14 MeV neutrons, in which the most important application is still the oxygendetermination, either as a major constituent, for instance in rocks, or asa trace element in metals. By taking into account all the parameters thatcan cause systematic errors absolute standardisation procedures have beendeveloped leading to a precision and accuracy of approximately 1 per cent.relative.Development of relatively inexpensive isotopic neutron sources ascalifornium-252 and actinium-227 - beryllium has increased the interest inthe determination of major constituents.The advantages offered for a numberof elements such as fluorine, manganese, aluminium, silicon and silver areeither due to high speed, and/or precision of the analysis compared withother instrumental methods.J. Op de BEECK and J. HOSTEInstituut voor Nucleaire Wetenschappen, Rijksuniversiteit Gent, Proeftuin-straat 86, B-9000 Gent, Belgium.Analyst, 1974, 99, 973-993.[December, 197December, 19741 SUMMARIES OF PAPERS I N THIS ISSUEElectron Spectroscopy and the AnalystAuger electron spectroscopy, X-ray photoelectron spectroscopy andultraviolet photoelectron spectroscopy are surveyed from the point of viewof the analyst. Factors affecting the cost and performance of commerciallyavailable instruments and one home-made instrument are discussed.Prob-lems arising from use of the techniques are referred to. A number of examplesof applications are presented, viz., the analysis of surfaces of fracturedsteels, the analysis of pigments, a study of the wear of molybdenum(1V)sulphide lubricant, the analysis of simple mixtures by spectrum filling tech-niques and the quantitative analysis of various flavours. I t is also shownthat a gas - liquid chromatograph can be coupled directly to an ultravioletphotoelectron spectrometer and used as a controlled inlet system. Alterna-tively, the spectrometer can be used as a selective gas - liquid chromato-graphic detector.D. BETTERIDGEChemistry Department, University College of Swansea, ' Swansea, SA2 8PP.xxiAnalyst, 1974, 99, 994-1010.Analytical Chemistry in Inter- disciplinary Environmental ScienceThe traditional r61e of analytical chemistry in environmental sciencedeals with monitoring air, water and food for pollution, and the techniquesfor setting and enforcing legal pollution control standards. The purpose ofthis paper is to emphasise the importance of an expanded r61e for theanalytical chemist as a participant in inter-disciplinary research in environ-mental science.Such research may involve the major environmental units, namely air,soil, water, plants and animals, or subdivisions of those units into smallerand smaller sub-units down to the molecular level. At each stage, the analyti-cal chemist is called upon to answer increasingly detailed questions aboutenvironmental pollutants, including distribution on a macro- or micro-scale,the physical and chemical form of the pollutant, the nature of its interactionwith its substrate, and the rates of transfer from one location to another orfrom one form to another.A number of examples selected from the author's own experience andfrom the literature are presented to illustrate the depth and variety ofproblems confronting the analytical chemist in such research.H. A. LAITINENRoger Adams Laboratory, School of Chemical Sciences, University of Illinois,Urbana, Ill. 61801, U.S.A.Analyst, 1974, 99, 1011-1018

ISSN:0003-2654    

DOI:10.1039/AN97499BP141

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

DECEMBER, 1974 THE ANALYST Vol. 99, No. 1185 Centenary Celebrations of the Society for Analytical Chemistry The Centenary Anniversary of the foundation of the Society for Analytical Chemistry was marked by Celebrations and a scientific programme during the week of July 16th to 20th, 1974, when some 500 delegates and 200 accompanying guests from 26 different countries gathered in London. A full report of the Celebrations appeared in the September issue of the Proceedings of the Society. The Centenary Lecture, “One Hundred Years of Development in Analytical Chemistry,” by Professor H. hf. N. H. Irving, was delivered at the Opening Ceremony at the Royal Institution on Tuesday, July 16th. The scientific programme of lectures, centred at Imperial College of Science and Technology, consisted of three Plenary Lectures and over sixty Keynote Lectures and other lectures arranged in three parallel streams under a wide range of subject headings in analytical chemistry.This Centenary issue of The Analyst contains the full texts of the Centenary Lecture, the three Plenary Lectures and the 13 Keynote Lectures. It is also hoped that some of the other papers presented will be submitted to The Analyst in the usual way for publication in later issues. Readers will be aware, from the Editorial in the November issue of The Analyst, that the membership of the Society for Analytical Chemistry recently voted in favour of full amalgamation with the Chemical Society from January, 1975. Accordingly, this issue of The Analyst is the last to appear under the name of the Society for Analytical Chemistry, and it is perhaps fitting that it should contain the main papers presented at what could be considered the most important function to be held during the 100 years of its history. In the future, of course, The Analyst will become one of the primary journals published by the Chemical Society and will continue to flourish as The Analyst, the Analytical Journal of the Chemical Society. G. W. C. MILNER President, Society for Analytical Chemistry 785786 SAC CENTENARY CELEBRATIONS Professor H. M. N. H. Irving The Society f o r A vzalytical Chrnaistvy Ce?ate9aavy Lectuvev Pleizavy Lrctuvcvs Professor R. Belcher Mr. J. Markland Mr. C. Whalley

ISSN:0003-2654    

DOI:10.1039/AN9749900785

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

Analyst, December, 1974, Vol. 99, $p. 787-801 787 CENTENARY LECTURE One Hundred Years of Development in Analytical Chemistry BY H. M. N. H. IRVING (Department of Inorganic and Structural Chemistry, Leeds University, Leeds, LS2 9 JT) IT is a unique honour and a very heavy responsibility to have been entrusted with the task of delivering this Centenary Lecture under the title “One Hundred Years of Development in Analytical Chemistry,” but it is almost impossible, in the time available, to give a con- densed history of the discipline of analytical chemistry from 1874 until the present day. In a letter of February 5th, 1750, Lord Chesterfield wrote, “History is only a confused heap of facts,” but Henry Ford, giving evidence in his libel suit against the Chicago Tribune in July, 1919, was more succinct and even more disparaging when he stated, “History is bunk.” The historian of analytical chemistry can accept neither viewpoint, although he will realise that to do this vast subject justice he would need the synoptic view of a Sir Winston Churchill, the style and pungency of a Lytton Strachey and the sheer professionalism of an A.J. P. Taylor. In the event, I take some consolation for my own shortcomings from a typical remark of Oscar Wildel: “Anyone can make history. Only a great man can write it.” A really fascinating history of the last one hundred years could clearly be developed around the theme of successive discoveries and developments in equipment and techniques -on the lines of the enormously important and scholarly “History of Analytical Chemistry” by Ferenc Szabadv&ry.2 But could not an equally fascinating story be written around the personalities of those engaged in analytical chemistry, their social background and aspirations and their status in the society of their day? The education of the analytical chemist-or the lack of it-could also form a unifying theme though it might well be one in which the leitmotif expressed the continuing neglect of analytical chemistry as a subject worthy of encouragement and support by successive Governments and as an academically respect able and rewarding subject for study in many universities.The impact of new legislation on the need to develop new techniques or to improve on old ones can certainly be said to have been the major reason for the foundation of the parent Society of Public Analysts in 1874.This, and a great deal more besides, is fully recorded in the recently published History of the Society for Analytical Chemistry (1874- 1974) by R. C. Chirnside and J. H. Hamence with the title “The ‘Practising Chemists’.”3 A logical extension of this same theme could be used to interrelate the development in analytical activities resulting from the successive Factory Acts, the Food and Drug Acts of 1955 and earlier, the Consumer Protection Act of 1961, the Medicines Act of 1968, the Labelling of Food Regulations (1970), the Clean Air Act and many others. Throughout the ages, the frailties and cupidity of human beings have found expression in criminal acts and sharp practices in industry, in commerce and in our daily life.The adulteration of gold and silver in pre-Christian times, the constant pollution of the environ- ment, the adulteration of food and drugs, the doping of racehorses, of athletes and of the mentally sick, all these have engaged the attention and taxed the skills of the analytical chemist, Even so, the public a t large may gain its only insight into the applications of analytical chemistry to modern forensic science through the medium of television (for example, the series entitled “The Expert”). Some members of the public have even carried out analytical determinations themselves-under the supervision of a policeman and with a ‘ I breat h a1 yser . ” I would now like to call attention to the extraordinary neglect of the riile of the analytical chemist by writers of many fine books in which his activities should surely have merited at least a passing mention.Haber’s well known work “The Chemical Industry during the Nineteenth Century”* is a valuable textbook for economists, with excellent accounts of the @ SAC and the author.788 IRVING: ONE HUNDRED YEARS OF DEVELOPMENT [Analyst, VOl. 99 Leblanc soda industry and the manufacture of sulphuric acid, alkalis, bleaching agents and coal-tar dyestuffs. It rightly emphasises the gulf that separated academic scientists from chemical manufacturers in England and the growing exchange of ideas that made the latter less empiric and more scientific. Research is certainly mentioned, but not the rdle of the analytical chemist. The recent and important “History of Imperial Chemical Indu~tries,”~ produced by a team of professional historians, gives a fascinating account of the interplay of technological, political, economic and personality factors involved in the development of one vast industrial organisation; but there is no mention of analytical chemistry as having played any part whatsoever. Singer’s wonderful book6 on the economics and technology of the alum trade, devised for the Centenary of Peter Spence and Sons and luxuriously produced by the Folio Society, is equally reticent.The story of Allen and Hanburys Ltd. from 1715 to 1954 is told in the book “Through a City Archway.”’ Here, in a vivid account of an air raid on September 20th, 1940, we learn that an incendiary bomb “landed directly on the Library of the Analytical and Research Departments and the valuable collection of scientific works .. . was completely destroyed, as well as valuable apparatus used in the laboratories.” However, just what happened in the Analytical Department is never disclosed. It really does seem that the historian is unaware of the contributions made by the analytical chemist or perhaps regards him in the same light as the mechanic who services a typewriter or a television set, a car or an aeroplane-a technician whose services are clearly recognised as being indis- pensible but which would not rate a mention in any economic history of the communications or transport industries. As a preliminary to any survey of progress during the last hundred years, we must try to think back to 1874 and attempt to visualise the conditions under which our predecessors worked.England, once the foremost industrial giant of the world, was just beginning to lose her pre-eminence, owing to fierce and intelligent competition from Germany where the im- portance of research was more fully appreciated and encouraged by the close liaison between industry and the universities; there was also an increasing challenge from America with its vast natural resources and beckoning home markets. The out-pacing of British chemical industry by its foreign rivals has been ascribed to many factors. In the book “The Development of British Industry and Foreign Competition, 1875-1914,” edited by D. H. Aldcroft,8 inappropriate patent laws, high transport costs, a shortage of trained man- power, inadequate technical education and dissemination of knowledge, half-trained entre- preneurs relying on rule-of-thumb methods and reluctant to accept new ideas are all suggested as contributory factors. There is at least no mention of bad management - labour relation- ships, but this is scarcely surprising in an age when trade unions had yet to assume a significant rdle, where many in the large towns were living in dire poverty and it was still legal to force suitably small children to climb inside chimneys to sweep them.On the other hand, humani- tarian protests had succeeded in reducing the working hours of children below 9 years of age in mines and factories to a mere 10 hours a day. Environmental polIution was widespread and the adulteration of foodstuffs and medicines a matter for public scandal, which led to the establishment of public analysts and thence to the founding of the Society. At this time, in addition to problems involved in the analyses of food and drugs, chemical analysis was certainly required in the alkali, fertiliser and sulphuric acid industries as well as in the manufacture of iron and steel, of soap, bleaches, paper and textiles and in the exploitation of minerals, especially those from overseas.Much of this work was in the hands of private firms of consulting chemists, although some fell to Professors and staff in Universi- ties. I have heard tell that when W. H. Odling was Waynflete Professor of Chemistry at Oxford he would drive there from time to time in his coach, deliver samples of water to be analysed by his subordinates, give one of the University lectures required of him by Statute, and then drive back to his country estate (F.M. Brewer, personal communication). The training of the early analytical chemists was often by a process of apprentice- ship to established firms of consulting chemists or by diligent application after a full day’s work at evening classes in one or other of the forerunners of our modern technical colleges. Courses in chemistry, many of which included instruction in analytical chemistry, were given in a wide range of educational establishments. Chemical News of 1874 gives a very complete list of the prospectuses of eleven institutes and nine hospitals in London alone, and in additionDecember, 19741 IN ANALYTICAL CHEMISTRY 789 to the Universities of Oxford and Cambridge the provinces are credited with centres of chemical instruction at Birmingham, Blackburn, Bristol, Cirencester, Liverpool, Leeds, Harrogate, Newcastle, Sheffield and Stockbridge.Scotland was served a t Edinburgh and Glasgow, Ireland at Dublin, Belfast and Galway. Many of the larger provincial centres provided several institutions of varying size and reputati~n.~ The extent to which their courses were relevant for the training of analytical chemists is discussed in two excellent papers by Betteridge,loJ1 who comments that the output of honours graduates in chemistry had only just reached double figures in 1875 and even in 1920 was a mere 120. I feel bound to mention here that 1875 saw the founding of the technology-based York- shire College of Science from which, in due course, emerged the regional Universities of Leeds, Liverpool, Manchester and Sheffield. This reference to my own University of Leeds reminds me that on November 25th, 1872, the Leeds Sanitary Committee reported to the Council that “It is desirable to appoint a fit and proper person as Analyst under the Adulteration of Food, Drugs, etc.Act, 1872, at a salary of f150 per annum exclusive of any fees he may be entitled to receive from private individuals and that advertisements be inserted in the Newspapers for candidates to undertake the duties of the office.”12 Obviously, the City fathers did not believe that the adage “where there’s muck there’s brass” applied to the work of their Public Analyst.The munificent salary failed to attract any applicants and the post was re-advertised several months later at a salary of ,5100 per annum. On April 17th, 1873, “three gentlemen were examined by the Sanitary Committee” and one Thomas Fairley, who had received his training from Dr. Lyon Playfair at the University of Edinburgh, was appointed the first Public Analyst for the City of Leeds. It would appear from correspondence that he was having to pay out nearly half his annual salary “for costly apparatus, some of a very fragile nature, besides the chemicals and materials used up in the processes of analysis,” and some improvement in fees had to be negotiated. In Somerset, formal approval was given on February 21st, 1874, to the appointment as the first Public Analyst of a Mr. William Walter Stoddart,” a person professing competent medical, chemical and microscopical knowledge.”13 He, too, received ,Ill00 per annum plus a sum not exceeding f150 a year for “making and sustaining a suitable laboratory.’’ Six years later, his successor was a Dr.Alford of Taunton, who retained the post for a staggering 37 years, although his salary did rise to ,5200 per annum in 1901 and ,5240 per annum in 1913. The brochure entitled “100 Years of Public Analysis in Lancashire”14 contains some very human comments and anecdotes. Changes in scientific education and not least in working conditions from the tyrannical regime imposed by one Public Analyst not a hundred years ago are all recorded. Although the Chemical Society had been in existence for 33 years when the forerunner of the Society for Analytical Chemistry was founded, its membership certainly included what were then termed “amateur and theoretical chemists” and no doubt some “interested clergymen”; the gulf between them and the “academic chemists” and the considerable body of practising chemists described in the main as “analytical and consulting chemists” was no small reason for the success of the Society of Public Analysts when it came to be formed in 1874.3 We can envisage the nature of existing problems from published papers and infer others from the way in which chemical industry was developing.But if we are to secure a true historical perspective, we should know more about the analysts of the period, the chemical procedures available to them, the apparatus and chemicals they used and whence these were obtained.We certainly have biographical details of a number of the more prominent analysts of the period,3 but little enough is yet known even of the names of the rank and file who must have carried out much of the burdensome routine work. Painstaking research will be needed to uncover primary material and, however worthwhile this research may be, it has yet t o be carried out on any substantial scale. For example, in a weighty laboratory notebook kindly lent by Mr. C. Whalley of Laporte Industries Ltd., a barely decipherable label on the spine and various initialled entries identify the contributors as C. E. Waterhouse, I. P. Llewellyn, Thomas J. I. Craig and Mr. H. Spewen. Who were these men? We simply do not know.The first entry in this laboratory notebook (Fig. 1) is dated April 22nd, 1896, so that this document, the earliest that Laporte Industries still possess, dates from more What was analytical chemistry like in those days? What were their origin, training and capabilities?790 IRVING: ONE HUNDRED YEARS OF DEVELOPMENT [Analyst, VOl. 99 than two decades after the opening of our story and illustrates the difficulties that face any historian in tracking down earlier primary material. However, I cannot resist showing the last entry in this book (Fig. 2), which anticipates the industrial process in which the mineral ilmenite was taken up in concentrated sulphuric acid and treated with scrap iron after which iron(I1) sulphate was separated prior to the hydrolysis of the more soluble titanyl sulphate.The analyst of 1874 could obtain supplies of common acids and alkalis from many dealers, although for most analytical procedures the former had to be purified by redistillation. Less common chemicals and laboratory glassware were mainly imported from Germany and I can best illustrate the somewhat haphazard way in which our British trade developed by reference to the early history of a well known firm (P. Hallett, Chairman and Managing Director, A. Gallenkamp and Co. Ltd., personal communication). Adolph Carl Gottlieb Gallenkamp, born at Lippstadt, Westphalia, in 1844, came to England in 1872 and set up in business as a cigar importer with a retail shop in Cross Street, off Moorgate Street near the City and Guild Technical College.Staff and students of the College became his customers and they soon persuaded him to help with the importation from Germany of laboratory glassware and other apparatus. The cigar business was closed in 1880 and A. Gallenkamp and Co. became importers and distributors of laboratory glassware and other apparatus and moved in 1897 to 19/21 Sun Street, London, E.C.2, where the firm remained for 65 years. The first Gallenkamp Catalogue of 700 pages was published in 1900 and, in addition to general laboratory equipment, it listed a wide range of items for mineral prospecting and metallurgical assaying much in demand by prospectors and explorers overseas. I would have liked to have been able to show some typical extracts from this early catalogue but unfortunately, owing to a variety of factors including two World \Vars, a disastrous fire and relocation of premises, very few documentary records of these early days survive and indeed the earliest Gallerikamp Catalogue in the firm’s possession was that produced about 1930.Advertisements of the period enable us to learn what textbooks were available a hundred years ago.15 Watt’s “Dictionary of Chemistry” (five volumes for L7.3.0, with the first and second supplements a t Q.11.6) and Wanklyn’s “Milk Analysis” at 5s. Od were as well known as Fresenius’ important and influential “Anleitung zur qualitativen chemischen Analyse,” which first appeared in English translation in 1844. The companion volume on quantitative analysis was equally well knon 11, but Sutton’s “Volunietric Analysis” did not appear until later and Allen’s monumental “Commercial Organic Analysis’’ was not published until 1879. Also from advertisements we learn that “blr.Wanklyn has opened a laboratory at 117, Charlotte Street, Fitzroy Square, and is prepared to give practical instruction in chemical analysis to Medical Officers of Health and to persons proposing to undertake the duties of Public Analysts under the new Act.” Likewise, Mr. Henry Nottless, F.C.S., is “prepared to give instruction . . . and to carry out analyses” at 60, Gower Street, Bedford Square, and similar advertisements refer to services offered by a Dr. Medlock and Mr. Escourt.ls Provincial newspapers and journals provide a wealth of similar information regarding the widespread activities of our forefathers in analytical chemistry.Another typical advertisement of the period17 refers to the second edition of Griffins Catalogue (Fig. 3) and another name, still familiar to us, is seen when Phillip Harris and Co. of the Bull Ring, Birmingham, announced that their new Catalogue of Chemicals was now ready. Certainly the chemical historian of this period will lack no leads, although he may encounter many dead ends. By 1874, classical methods of gravimetric analysis were very well established and, although platinum apparatus was cheap and used extensively, the Gooch crucible had yet to be introduced. Good balances abounded and were relatively cheap, and Fig. 4 shows that the advantages of the short beam balance were beginning to be appreciated. The blowpipe was used extensively for field work and for confirmatory tests and although the use of spectroscopy as a qualitative tool had benefitted from the work of Bunsen and Kirchhoff, it did not become an important quantitative technique until the present century.Indeed, as late as 1910, H. Kayser, the author of the comprehensive “Handbuch der Spektroscopie,” expressed the opinion that “quantitative spectrum analysis is impracticable.” Separation methods in inorganic analyses generally followed the principles subsequently formalised (and, as some might feel, embalmed) in the familiar group analysis tables. Organic reagents for metals were completely unknown and liquid - liquid extraction was not practisedFig. 2. of titanium Last entry in the Laporte laboratory notebook anticipating the large-scale production from ilmeniteTaE ANALYBT.CHEAP CHEMICAL APPARATUS. NOW READY. SECOND EDITION OF GRIFFIN'S CATALOGUE, ENTIAELY RE VISED, A N D PUBLISHED AT QREATLY REDUCED PRICES. h i O K the Iirgnl, m a t towplde, and cbnprrt List oi Appnmtru cvor phred brlon (he Public. CHEMICAL HANDICRAFT, A CLrild md DR& ips C a h l v r of CHEHICAL AFPARA'rF% with errpiow E~phnatoq Solrs LIT JOHN J. O&FPIN, P.C.8. 1~ Dcmy 870. 472 pp, ilIuitnW by I,IW rocdrnU. Price U. h m d ia c W . Pdqt. 7d. Published by JOHN GRIFFIN 6 SON& 22, OABBICX STREET, COVENT QARDER, W.C. CHEMICAL AX'D PRILOSOPIIICAL INSTRUMENT MAKERS. BBRGOYNE, BURBIDGES, CVRIAY, & FARRIES, fionufacfuriry and Operatice Chcnii~ts, S 6 , UOLmMAN SST6LIIET.LOmDON. €XU., PRIZE MEDAL PAR15 EXH~EITION. 1867.) Manufacturers of every description of Pure Acids, Chemicab, and Ib-agents for AnliIytical Purposes and Scientiflc Research. Sole Agents for C . A. KAITLDAL\~, I k r l i i i . PRlCZ LLBTB AND BPLCXAL QUOTATIOns UPON APPLIGATIOW CHEMICAL & PHYSICAL APPARATUS, PURE CHEMICALS, HOT'I'LE~S, &c., For Manufacturers, Schoola, Private Students, Lc. Prim Lilt. Free. Carriage altored to so! It:iiiwnp Stotian in Englznd or Wales upon Ordcra of 4On. nnd upuaidq in taluc. Fig. 3. Mav, 1878 Advertisement taken from The Analyst, TBE AXALYST. WOLTE RS' B A LA NC E S . Fig. 5. Advertiserncnt for a colorirneter, taken from The Analysl, January, 1877December, 19741 IN ANALYTICAL CHEMISTRY 791 in the inorganic field, although E. P61igot18 had noted the ability of ether to extract uranyl nitrate from its solution in nitric acid as long before as 1842, and W.Skeylg had recently (1867) noted the solubility of various thiocyanates in ether and had proposed the use of solvent extraction to separate cobalt from nickel, gold from platinum, and iron from alkali metals, aluminium, manganese and also from uranium, platinum and nickel. It is curious that his proposals were never tested experimentally until R. Bock and W. Fischer began their classical investigations in 1942.20 It may surprise many to learn that electrogravimetric procedures for zinc, cadmium, lead, manganese and mercury had become well known since the pioneering work of C. Luckow in 1869, although it is not clear how extensively they were used in this country.Titrimetric analysis was very widely practised by 1874, although acid - alkali indicators of synthetic origin and of defined pK values were unknown.21 Indeed, the basic theory of titrimetry had yet to be formulated. The hardness of water could be determined by Clark’s process (1841) using a standard soap solution, reducing sugars with a copper(I1) salt, and the industrially important determination of iron was carried out with permanganate or chromate-the latter determination involving the use of an external indicator as internal redox indicators did not become available for another 50 years. In 1874, organic analyses for carbon and hydrogen were carried out by the methods developed by Berzelius, Gay-Lussac and Liebig.Halogens and sulphur were determined by Carius’ method. Nitrogen was determined gasometrically by Dumas’ method using Schiff’s azotometer or by the Varrentrap - Will process, for the highly important Kjeldahl method (1883) had yet to be discovered. Separation processes in organic chemistry were very unsophisticated and most reliance was placed upon distillation, sometimes at reduced pressures, and especially upon recrystal- lisation. Melting- and boiling-points were a principle method for establishing purity. Analysts of this period had access to a number of physical methods of analysis such as polarimetry and refractometry and, of course, specific gravity bottles and hydrometers were used, mainly to determine alcoholic strength ; microscopes were widely used in food analysis.Absorptio- metric determinations (“colorimetry”) were naturally restricted to coloured systems such as those between iron(II1) and thiocyanate, or copper(I1) and ammonia, and although Dehm’s colorimeter (1864) and the early Duboscq colorimeter (1870) were surely well enough known by then, it was still possible for less effective instruments to find their way on to the market, as illustrated in Fig. 5, taken from The Analyst of 1877. We can accept then that the analytical chemist of 1874 was not ill-equipped by training, apparatus or techniques to meet the challenges of his period, for this was still an era when it would not have been incorrect to describe the basic goal of analytical chemistry as answering the question, “What’s in it, and how much.” Labour was relatively cheap, the time available for analyses seldom prescribed by plant or economic conditions and-by modern standards at least-the analytical problems were fairly well defined and not too complex.The ensuing century brought many changes. Problems have become increasingly com- plex. There is an increasing demand for the determination of ever smaller amounts of material in matrixes of ever increasing diversity and complexity. There is an ever increasing demand for speed and throughput and multiple analyses on the same sample of material-especially so with clinical and biochemical determinations. Skilled labour becomes increasingly costly and harder to find. Above all, there is a shift from the simple criterion of “what’s in it, and how much” towards the realisation that the analyst is involved in determining not only what and how much is present (composition) but also what form (structure), how it i s bound (valence), where it i s spatially (location) and how uniformly it is distributed (homogeneity).Here I quote from W. Wayne Meinke,22 who also makes the point that these measurements are often required at both micro- and macro-levels as well as for surfaces, and that there are additional requirements for speed and adaptability to automation as well as for accuracy and precision. In addition, the analytical chemist must bring to the task of measurement a firm appreciation of the importance of statistical selection of the sample, for possible perturbations caused by sample preparation, and for the statistical evaluation of the data that have been obtained from it.22 Ralph Chirnside has also stressed the nature of the current analytical revolution and its impact on academic and industrial research in the Eighth Dunn Memorial Lecture.2a In connection with the Exhibition on the theme “You and Your Analytical Chemist”792 IRVING: ONE HUNDRED YEARS OF DEVELOPMENT [Analyst, Vol.99 at the Science Museum, the opening of which forms part of the Centenary Celebrations of the Society for Analytical Chemistry, I was asked to write a short booklet on the history of analytical teclinique~,~~ and in view of this I shall not give details here of the many changes which the last 100 years have wrought in the armoury of the analytical chemist. However, to recall some of these developments a few illustrations are given in order to exemplify the more striking growth points, although it would be remiss of me not to mention that some individuals such as Feigl, Heyrovsky, Kolthoff, Martin, Pregl and Schwarzenbach, to name only a few, have played exceptional r6les in expounding and popularising both theoretical and technical innovations.The dates given in the Tables enable us the better to appreciate those techniques which have been known for a long time and have been under constant development, and those which are comparatively recent. Sometimes an existing technique has been extended, refined or developed in response to a clearly expressed need for a particular kind of analysis. I n other instances, a new technique, such as nuclear magnetic resonance, has arisen primarily from the successful experimental confirmation of a phenomenon predicted academically, and analytical applications have been found subsequently as equipment became more generally available. Here we should pay tribute to the r61e of the present day manufacturer of sophisticated modern equipment for physical methods of analysis, for their work is no longer confined to reproducing in quantity apparatus whose worth has been demonstrated in some industrial or academic laboratory: their own research and development organisation often has resources far exceeding those of any small group of individuals.Their instruments not only fill an existing need but also facilitate and stimulate the development of new analytical procedures.In this context I am tempted to believe that two new Parkinson’s laws could be enunciated. Firstly, “any new development in technique will bring to light hitherto un- noted analytical problems which it is unable to handle,” and secondly, “the number of analytical samples will multiply to occupy all the time and apparatus available.” In the latter part of the 19th century, there was an increasing interest in naturally occurring organic compounds that often were available in only small amounts. The need to ascertain their composition and that of other synthetic laboratory products and to service the newer sciences of biochemistry, biology and physiology made it necessary to scale down organic analyses to amounts of sample of a few milligrams. This was made possible by the construction of microbalances by W.Kuhlmann sensitive to 0.01 mg and by Fritz Pregl’s meticulous and brilliant redesign of all the relevant analytical procedures. The oxygen flask method and rapid automatic carbon, hydrogen and nitrogen analysis represent more recent tendencies (Table I). TABLE I ORGANIC ANALYSIS Technique Date Determination of nitrogen . . .. .. Microbalance . . .. . . .. .. Micro-procedures . . .. .. .. . . Combustion in oxygen . . .. .. .. Direct determination of oxygen . . . . Automatic C, H and N analysis . . . . Relative molecular masses by solution methods (boiling-point, freezing-point, vapour pressure osmometry) Mass spectrometry . . .. .. .. Mass and abundance tables . . .. .. Infrared spectroscopy . . .. .. .. NMR spectroscopy .. .. .. .. Separations by partition .. .. .. Various techniques of chromatography J. G Kjeldahl, 1883 W. Kuhlnian, 1911 F. Pregl, 1910- W. Scheniger, 1955 ca. 1955 1930- J. H. Beynon and A. E. Williams, 1963 1936 1945- L. C. Craig, 1949 Earlier difficulties in determining the molecular formulae of solids and high-boiling liquids were resolved by the application of physical methods involving elevation of the boiling-point , depression of the freezing-point and, more recently, vapour-pressure osmometry . However, the really dramatic innovation came when it became possible by mass spectrometryDecember, 19741 IN ANALYTICAL CHEMISTRY 793 to determine a relative molecular mass with an accuracy of one part in 100000. From a consideration of the relative abundance of lines due to the various isotopes of carbon, hydrogen, oxygen and nitrogen and reference to the appropriate Tables of Mass and Ab~ndance,~5 it is generally possible to deduce a unique molecular formula or at least to limit it to one of a very few alt em at ives.It is impossible to overestimate the importance of ultraviolet, infrared and nuclear magnetic resonance spectroscopy for the qualitative identification and quantitative deter- mination of organic compounds, while the use of the various techniques of chromatography serve both as a means of separating the components of complex mixtures whether from micro- gram amounts of sample or on a preparative scale, and as a very rigorous means of estab- lishing homogeneity and ultimate purity. The use of organic reagents for inorganic analysis (Table 11) became really important only after the first specific reagent, dimethylglyoxime, had been introduced for the gravimetric determination of nickel and palladium.New reagents introduced subsequently proved valuable for absorptiometric and fluorimetric determinations, often in combination with solvent extraction techniques. Their popularity and importance became more widespread as good spectrophotometers and fluorimeters became commercially available. TABLE I1 ORGANIC REAGENTS FOR METALS (USED FOR PRECIPITATION, EXTRACTION, ABSORPTIOMETRY OR FLUORIMETRY) Reagent a-Nitroso-,%naphthol . . .. .. .. Spot tests . . .. ,. .. .. .. Dimethylglyoxime . . .. .. .. Cupferron . . .. .. .. .. .. 8-Hydroxyquinoline . . .. .. .. 2-Methyl-8-hydroxyquinoline .. .. .. Biquinol yl .. .. .. * . .. Morin .. .. .. .. .. .. Dithizone . . .. .. .. .. .. Date M. Ilinsky and G. von Knorre, 1884-86 F. Feigl, 1891- L. H. Tschugaeff, 1905 0. Baudische. 1909 R. Berg, 1938 L. L. Merritt and J . K. Walker, 1944 J . Hoste, 1963 E. B. Sandell, 1940 H. Fischer, 1926 Acid - alkali titrations (Table 111) benefitted enormously from the gradual introduction of a wealth of synthetic organic indicators, and when the basic theory had become firmly established the art took on more of the aspects of a science. Fluorescent indicators enjoyed a greater vogue in the 1930s than they do today, and the introduction of redox indicators eliminated the tedious and often messy operations with external indicators previously needed in many systems.With the introduction of hydrogen, metal and especially glass electrodes, a whole range of important potentiometric titrations became possible. As changes in elec- Technique End-point detection Titration methods TABLE I11 TITRIMETRIC (VOLUMETRIC) ANALYSIS Development Date Synthetic pH indicators- Phenolphthalein . . .. .. Methyl orange . . .. .. Sulphonphthaleins . . .. .. Theory of titrations . . .. .. Fluorescent indicators . . .. .. Redox indicators . . .. .. .. Hydrogen and glass electrodes . . .. Ion-selective electrodes . . .. .. End-point calculations . . .. .. Thermometric and catalytic end-points Conductivity titrations . . . . . . Coulometric titrations . . .. .. High-frequency titrations .. .. Non-aqueous titrations . . . . .. Complexometric titrations .. .. Titration of water .. .. .. Automatic titrimetry E. Luck, 1877 G . Lunge, 1877 W. M. Clark, 1917 N. J . Bjerrum, 1914; I. M. Kolthoff, 1926 C. Fajans, 1923 J . Knop, 1925 cu. 1920 E. Pungor, 1964 Gunnar Gran, 1960-52 F. W. Kuster and M. Griiters, 1903 L. SzebellCdy and 2. Somogyi, 1938 J. K. Foreman and D. J. Crisp, 1946; F. W. Jensen and A. L. Parrack, 1946 N. F. Hall and J . B. Conant. 1927 Karl Fischer, 1935 G. Schwarzenbach, 1940794 IRVING: ONE HUNDRED YEARS OF DEVELOPMENT [Analyst, VOl. 99 trical potential are the basic measurement, these procedures lend themselves to automatic recording, the automatic determination of the end-point by electronic devices and, by a natural extension, to plant control. The availability of other ion-selective electrodes, both for anions and cations, which have recently been introduced and are still under active development will certainly have repercussions on all sorts of potentiometric determinations.One of the most significant and rewarding innovations of recent years has been in the field of complexometric titrations, where we are indebted primarily to the genius of Professor Gerold Schwarzenbach.2s Many will recall the lecture demonstration he gave in this very lecture theatre of the Royal Institution in 1955, and on that occasion I acted as his lecture assistant and brought all the necessary chemicals and apparatus from my laboratory in Oxford. One especially bulky item was a 10-litre bottle of conductivity water which a porter helped me to lift carefully on to the train.In reply to his enquiry about why I was so careful with it, I replied, “Because it’s very pure water and it’s very heavy.” To my astonish- ment, when I arrived at Paddington Station I was met by a whole group of porters who had received instructions “to look out for a scientist from Hanvell who was taking a big bottle of Heavy Water to the War Office”! I t is a great pity that the important contributions to classical electrogravimetry made by H. J. S. Sand at the Sir John Cass Technical College have never been fully appreciated, although the procedures he developed are widely used. However, there can be no doubt that the innovations made by Heyrovskjr have made a most profound impact on both inorganic and organic analysis. Although there were many improvements in instrumentation during the period 1948-52, the next major breakthrough came from studies in a.c.polarography in which, by employing sophisticated electronic techniques, Barker and his collaborators at Harwell developed methods for determining materials at concentrations of M and below. This is a field in which many variations in procedure have been and still are being actively pursued. Electrical methods of analysis are listed in Table IV. TABLE IV ELECTRICAL METHODS OF ANALYSIS Technique Development Date Electro- Net and spiral electrodes .. . . deposition Controlled potential electrolysis . . Polarography New technique proposed . . . . .. First polarograph . . . . . . .. Derivative polarography . . .. .. Square-wave polarography . . .. Pulse polarography .. .. . . Cathode-ray oscillography . . .. Hanging-drop electrode . . .. .. Rotating platinum electrode . . .. Other Amperometric titrations procedures Chromopotentiometry Stripping volt nmmetry C. Winkler, 1899 H. J. S. Sand, 1908 J. Heyrovskf, 1922 J. Heyrovskg and M. Shikata, 1926 J. Heyrovskf, 1947 G. C. Barker ct id., 1962 G. C. Barker and A. W. Gardner, 1958 J. E. B. Randles, 1948; G. C. Barker, 1968 W. Kemula and 2. Kublik, 1957 H. A. Laitinen and I. M. Kolthoff, 1941 The supplementation of purely chemical methods of analysis by physical methods (Table V) gathered pace as the 19th century passed into the 20th, and the introduction of en tirely new physical principles extended the range of analytical determinations to an extent that the analyst of 1874 could never have conceived in his wildest flights of imagination.Developments in quantitative emission spectroscopy were bedevilled by matrix effects until Gerlach introduced the principle of internal standardisation, and there were rapid improvements in instrumentation during the second quarter of the present century. Lunde- ghdth showed that photocells could be used to advantage in place of the photographic plate and this led in due course to such instruments as the quantometer or polychromator with which a number of elements can be determined simultaneously. This instrument is of special value in the analysis of samples of alloy steel taken at regular intervals from a molten mass of perhaps 200 tons. A complete analysis can be performed in about 10 s with the analytical results printed out on an electric typewriter or interfaced with a computer.So far as ultraviolet and visible spectrophotometry are concerned, it is impossible to overestimate the debt that analysts owe to those firms which made good instrumentsDecember, 19741 Technique Spectro- graphy Ultraviolet and visible spectro- photometry Infrared spectro- scopy X-ray X-ray diffraction IN ANALYTICAL CHEMISTRY TABLE V PHYSICAL METHODS OF ANALYSIS 795 Development Homologous line-pairs . . .. . . Logarithmic sector . . .. . . Photoelectric recording . . .. . . Flame photometry . . .. .. Filter photometry for Na and K Atomic absorption .. .. . . Quantometer and polychromator . . .. Atomic fluorescence . . . . . . Raman spectroscopy Polarising attenuators .. .. .. Use of photo-cells .. . . . . Spekker absorptiometer, Beckman DU and Unicam SPSOO instruments Flow-through cells ; continuous monitoring ; automatic multicomponent analysis . . Characteristic absorption bands . . Determination of CO, in the air “Chopping” device . . . . . . Heat-detecting cell . . . . . . Work in the War years . . . . . . First commercial instrument . . . . First commercial double-beam instrument First double-beam and prism . . . . . . . . Studies of mixtures . . . . . . .. .. .. .. .. .. Discovery of phenomenon .. .. flubrescence Further studies . . .. .. . . Electron microprobe Electron microscope Auger electron spectroscopy ; ESCA Nuclear Demonstration of phenomenon . . . . magnetic resonance gravimetry Thermo- Mass spectro- Positive ions .. . . . . . . metry Isotopes . . .. . . . . .. Analyses of hydrocarbons . . . . Analyses of complex mixtures . . . . Replacement of low-temperature distilla- tion by mass spectrometry for up to 40 components . . . . . . . . Mass and abundance tables for mass spectra . . .. . . , . .. Use as adjunct to gas chromatography in flavour analysis: isotope dilution analy- sis; geochronology Instrumental advances . . . . . . Date W. Gerlach, 1925 G. Scheibe and A. Neuhausser, 1928 H. G. Lundeghdth, 1929 H. G. LundegArdth, 1928 W. Schuhknecht, 1937 A. Walsh, 1965 J. D. Winefordner and T. J. Vickers, 1964 ; T. S. West, 1968 P. Glan and C. G. Hbfner, 1877 R. Berg, 1911 1941- J. Lecompte, 1923 E. D. McAlister, 193G J. J . Fox and A. E. Martin, 1940-47 M. J.E. Golay, 1947 H. W. Thompson; G. B. B. M. Sutherland, ca. 1936 N. Wright and L. W. Herschel, 1947 A. J. P. Martin, 1955 1939-1946 W. H. and W. L. Bragg, 1913- C. G. Barkla and C. A. Sadler, 1907 H. N. Moseley, 1913; A. Hadding, 1923; G. von Hevesy, 1923; H. Friedman and L. S. Birks, 1948 E. M. Purceil, H. C. Torrey and R. V. Pound, 1945; F. Bloch. W. W. Hansen and N. Packard, 1945 W. Wien, 1898 J . J. Thomson, 1911 A. J . Dempster, 1918; F. W. Aston, 1919 0. Eisenhut and R. Conrad, 1930 H. Hoover and H. W. Washburn, 1940 ca. 1947 J . H. Beynon and A. E. Williams, 1963 available. In this country, the impact of the simple Spekker absorptiometer, which employed a set of glass filters to cover a range of wavelengths from 450 to 640 nm, was dramatic2’ and the later advent of the Beckman DU and the Unicam SP500 spectrophotometers certainly revolutionised the practice of absorpt iomet ry. Infrared spectroscopy started slowly at first, for the early workers were dependent upon their own equipment with comparatively poor heat-detecting cells, which necessitated the use of temperamental galvanometer-amplifiers and tediously slow point-by-point plotting of spectra.The Second World War saw a great increase in effort and in this country H. W. Thompson was able to use the technique to examine the composition of fuels from enemy aeroplanes and so provide information by which our bombing strategy could be guided.796 IRVING ONE HUNDRED YEARS OF DEVELOPMENT [Analyst, Vol. 99 Commercial instruments soon became available in ever increasing numbers-and dare I say of increasing reliability and simplicity of operation-and at a price that now makes it possible to put them in the hands of undergraduate students.Not more than passing references are possible to the immensely important technique of X-ray fluorescence or to the use of the electron microprobe which, by collimating an intense beam to a cross-section of about 1 pm, enables us to scan minutely across the surface of a sample so as to reveal concentration gradients, grain boundaries and inclusions of all types. The importance of X-ray diffraction has often been stressed, most effectively by Chirnside23,B in this country, and does not need to be emphasised here. Although the basic phenomenon of nuclear magnetic resonance was only discovered some 30 years ago, the intense activity of instrument manufacturers has made the technique very widely available and its analytical potentials are constantly being extended.I have already referred to mass spectrometry in connection with the determination of precise molecular masses in organic chemistry. In conjunction with a computer it is regularly employed for on-line analyses and plant control in petroleum refineries and is an indispensable adjunct to the gas chromatograph in, for example, flavour analysis. Its use in isotope dilution analysis and for geochronology is well known. TABLE VI RADIOACTIVITY Technique Date Geiger - Muller counter . . .. .. .. 1908-1928 Scintillation counting . . .. .. .. 1908-1947 Proportional counters, ratemeters, multi-channel “Labelling” (solubility of PbSO,) ... . G. von Hevesy and F. Paneth, 1913 Separation of Au from Pt . . .. .. . . 0. Erbacher and K. 2. Philipp, 1936 Radiometric titrations . . .. . . . . R. Ehrenberger, 1926; A. Langer, 1941 Isotope dilution analysis ; neutron activation analysis . . * . .. * . .. .. G. Von Hevesy and H. Levi, 1936. y-ray spectrometers, etc. Although many of the basic possibilities of radioactive isotopes were proposed and demonstrated experimentally with naturally occurring radionuclides forty and more years ago, it was the advent of intense neutron sources from nuclear reactors that made a whole range of artificial radioisotopes available (Table VI). Their impact on every aspect of chemical analysis cannot be overestimated. Here, too, the advances in electronics during and after TABLE VII SEPARATION PROCESSES* Type of separation Technique Depending on molecular size and geometry .. Depending upon volatility . . .. .. Depending upon surface activity . . .. Depending upon solubility . . .. .. ion-pairs . . . . .. .. .. Partition equilibria for uncharged species and Exchange equilibria for ions . . .. .. Properties of ions in solution . . .. .. Molecular sieves; gel filtration and permeation ; gaseous diffusion ; use of inclusion (clathrate) com- plexes ; ultrafiltration : electrophoresis (for charged species) Sublimation : distillation Foam fractionation ; absorption and gas - solid chromatography ; “scavenging” by colloidal pre- cipitates Crystallisation ; freeze separation ; zone-refining Liquid - liquid extraction; countercurrent extraction equipment (L.C. Craig, 1949) ; paper and thin-layer chromatography “Permutit” resins (R. Gans, 1905) : synthetic ion- exchange resins (B. A. Adams and E. L. Holmes, 1935) ; liquid cation and anion exchangers; inorganic salt exchangers Electrodeposition a t controlled potential : amalgam methods; complex formation, masking and de- masking * This list of methods and the examples given is not intended to be exhaustive.December, 19741 IN ANALYTICAL CHEMISTRY 797 the war years have played a possibly decisive r81e by providing a wide range of measuring instruments; the use of printed circuits and microminiaturisation have carried on the techno- logical advances. Nowadays, we have to deal with materials of increasing complexity, and under the influence of the biochemists, for whom the problem first became acute, much attention has been paid to separation procedures (Table VII). Very often the concentration of a desired constituent is too low for any existing analytical procedure to be applied directly and the determination stage has to be preceded by a stage of pre-concentration.= I t is fortunate that many of the methods available for separation will also serve for pre-concentration and I will only illustrate one of them in more detail.The first organic reagent used in liquid - liquid extraction (Table VIII) was introduced in 1900 for the absorptiometric determination of chromium( 111). With the introduction of dithizone, a new dimension appeared, for not only were its metal complexes readily extractable into organic solvents, but they were also highly coloured.Helmuth Fischer was a pioneer in devising a variety of colorimetric procedures and he established the basic methods of achieving selectivity by control of pH and the use of masking agents. The demands of the atomic energy industry led Reid and Calvin to devise TTA (trifluorothenoylacetone) as the best of a large series of organic extraction agents studied by them. Many other organic reagents are constantly being examined as extraction agents in a field that is steadily increasing in importance. TABLE VIII LIQUID - LIQUID EXTRACTION Technique FeCI, into ether . . .. .. .. .. .. .. GaC1, into ether . . .. .. . . .. .. . . Metallic chlorides, thiocyanates, nitrates, bromides and fluorides Cr(II1) with diphenylcarbazide .. .. .. .. .. Dithizone . . .. .. . . .. .. .. .. TBP (tributyl phosphate) . . . . .. .. . . .. Ph,As+ for Re0,- . . . . .. . . .. . . .. TTA (trifluorothenoylacetone) . . .. .. . . .. Phosphoric acids, phosphine oxides, long-chain liquid anion and cation exchangers Date J . W. Rothe, 1892 E. H. Swift, 1924 R. Bock et al., 1942-56 P. Cazeneuve, 1900 Helmuth Fischer, 1926 J. C. Warf, 1949 S. Tribalat, 1951 J . C. Reid and M. Calvin, 1059 Chromatographic techniques have had truly amazing effects, admittedly less in the inorganic than in organic and biochemical fields (Table IX). We all know how column chromatography was neglected and virtually forgotten for many years before its use was revived by Kuhn and Winterstein in 1931.We all know, too, how our own Nobel Prize winners introduced the world to the almost inexhaustible possibilities of paper liquid - liquid and gas-liquid chromatography. Some of us can still see vividly in our memory’s eye Dr. Martin’s home-made automatic burette working in the Dyson Perrins Laboratory during the First International Congress on Analytical Chemistry held at Oxford in 1952, and how we stared unbelieving as the graph showing the successive elution of a mixture of amines was plotted as we watched.30 Here, too, is a field in which instrumental and technical developments are constantly being reported. In that remarkable essay entitled “A Mathematician’s Apology,”3l G. H. Hardy made a great point of the aesthetic satisfaction to be derived from a beautiful mathematical theorem and its proof.I have often been struck by the beauty-and it seems to me the sheer elegance -of some analytical principles and procedures. Sometimes we must be almost overwhelmed by the sheer craftsmanship of a novel piece of equipment or by some manipulation on an ultramicro scale. Sometimes by the extension of a familiar idea to unfamiliar limits-such as very thin-layer chromatography in which nanogram amounts of certain metals can be separated as their dithizonates on an aluminium sheet that has been coated with a uniform layer of aluminium oxide a few micrometres thick by anodic oxidation.s2 But then all chromatographic separations of complex mixtures are matters for wonderment and rich satisfaction. The ingenious use of masking and demasking agents in the complexometric determination of mixtures of metals and even the devices whereby anions, organic acids and even alkaloids can be determined complexometrically excite admiration for the sheer in- genuity involved.26 I recall being immensely impressed by the brilliant idea of determining798 Type Inorganic separations Organic materials Thi n-layer chromato- P P h Y High-pressure chroma to- graph Y IRVING: ONE HUNDRED YEARS OF DEVELOPMENT [Analyst, VOl.99 TABLE IX CHROMATOGRAPHY Development NaCl from BaCI, or NH,+ from Fea+ on filter-paper . . .. Capillary analysis . . . . .. Group separations .. .. Alumina columns for cations . . First packed column . . .. Separation of petroleum fractions Separation of chlorophyll .. Separation of carotenoids ..Liquid - liquid chromatography . . Paper chromatography in one and two dimensions . . . . Gas - liquid chromatography . . Counter-current equipment . . Frontal and elution analysis . . Separation of hydrocarbons . . Separation of fatty acids up to C , , Displacement analysis . . .. Gradient elution analysis . . .. . . . . . . . . . . Chromatostrips for terpcncs . . Modern developments . . .. . . . . .. . . .. .. .. . . . . .. . . . . . . . . . . . . . . . . . . . . . . Date E. Fischer and E. Schmidmer, 1892 F. Gijppelsrijder F. H. Burstall, G. R. Davies, R. P. Lin- stead and R. A. Wells, 1960; F. H. Pollard and J. I;. W. McOmie. 1949- G. M. Schwab and K. Jockers, 1937; H. Flood, 1940 L. Reed, 1893 D. T. Day, 1897 M. Tswett, 1906 R. Kuhn, A. Winterstein and E.Lederer. A. J. P. Martin and R. L. M. Synge, 1941 R. Consden, A. H. Gorden and A. J. P. Martin, 1944 A. J. P. Martin and R. L. M. Synge, 1941 L. C. Craig, 1949 A. Tiselius, 1940, 1950 S. Claesson, 1946; C. G. Phillips, 1949 R. Alm and R. J. P. Williams, 1961 N. C. Turner, 1943 A. J- P. Martin and A. T. James, 1962 1931 N. A. Ismailof and N. S. Schreiber, 1938 J. M. Miller and J. G. Kirschner, 1963 E. Stahl, 1956 J. J. Kirkland, 1971 uranium in minerals and rocks in terms of the barium-140 produced from it by nuclear fission, thereby replacing some difficult chemical separations by one that is inherently simpler.33 From the same laboratory came that delightful illustration of the beauty of neutron activation analysis, viz., the determination of the arsenic content of a pea while it is still in its pod and protected by Nature from adventitious contamination.Hardy also makes the point that full aesthetic appreciation requires that a concept should have a general rather than a limited application, and in analytical terms I would instance the basic concepts of isotope dilution, sub-stoicheiometry, and even the principle of reversion.34 The use of radionuclides as tracers and, indeed, the whole concept of activation analysis underly many aesthetically satisfying procedures. The realisation that by correcting for the chemical yield in such procedures we are freed from the necessity of rigorously quanti- tative separations is one which I have always found to excite the grudging admiration of even the most uncommitted students.We really should not hesitate to take pride in such aspects of analytical expertise which could not have been conceived by our forebears in 1874. When I look up at the full moon I still find it very hard indeed to believe that modern technology ever made it possible for human beings actually to set foot on it.* However, long before that “first small step for man,’’ analytical chemists had been able to carry out exacting studies of the composition of the moon’s surface by using physical methods with equipment carried by unmanned spacecraft. The data could be telemetered back to earth, nearly a quarter of a million miles away, and interpreted there. I can give illustrations of only two such experiments. The back-scattering of a-particles (Fig. 6) provided quantitative estimates of aluminium, calcium, iron, magnesium, oxygen, silicon, sodium and titanium, which checked well with conventional analyses on samples brought back to earth by subsequent manned missions.In the X-ray fluorescence experiment (Fig. 7), measurements of magnesium, aluminium At this point, a colour slide was shown of Irwin on the moon’s surface with the Appenine mountains Ia the background (Apollo 16 mission).December, 19741 IN ANALYTICAL CHEMISTRY 799 Radioactive sources of 6.1 1-MeV a-particles from 200 mCi of 242Cm + I I I I I foil .ed Moon‘s surface (into which penetration by a-particles is about 0.03 mm) Fig. 6. The a-particle experiment. The instrument, contained in a 6-inch cubical box, was lowered from the unmanned Surveyor spacecraft on command from the Earth.Energy spectra from a- and proton-modes were separately binned into 128 channels and events (approxi- mately 2 s-1 for ct-particles and 2 min-f for protons) transmitted to Earth as they o c ~ u r r c d ~ ~ and silicon were carried out continuously as the command module traversed the planet and variations in the rates of the concentrations of aluminium and silicon could be monitored so as to reveal compositional changes between the maria and the highlands. Such analyses, in which sophisticated electronics and the use of -,computers play an integral part, indicate one direction in which analysis is moving today. Another example is provided by what is termed “total biochemical profiling,” in which about twenty different O=[ N- Moon’s surface Fig. 7.The X-ray fluorescence experiment. This was carried in the command module in Apollo 16.86 Adsorption edges (EK) are 1.37 keV for magnesium, 1.57 keV for aluminium and 1-85 keV for silicon800 IRVING: ONE HUNDRED YEARS OF DEVELOPMENT [Analyst, VOl. 99 analytical determinations are carried out sequentially on a small sample (less than 2 ml) of a patient’s blood by using an AutoAnalyzer capable of handling about 300 samples per hour. The analytical results are processed by a computer and the next and logical step will be for this computer to be interfaced with a memory bank of case histories and programmed to print out a diagnosis and even to prescribe a course of treatment. What would our forefathers of 100 years ago have thought of these incredible achieve- ments of analytical chemistry? What will be the problems of the next 100 years and how will they be handled by our successors? The philosopher Schlegel once wrote “Der Historiker ist ein ruckwarts gekehrter Prophet” (“A historian is a prophet looking backwards”), but I realise only too well that in this Centenary Lecture I have not done justice to the past or to the present.One thing is certain, however. The analytical chemist is still engaged in a never ending campaign to which there can be no ultimate victory, although there will be many outstanding successes and triumphs along the way. I am privileged to take this opportunity of expressing my sincerest thanks to many friends and colleagues who have given me the benefit of their specialised knowledge and experience and who have helped and encouraged me in the preparation of this lecture.Among these I can mention by name only A. J. Amos, A. C. Bushnell (County Analyst for the Lan- cashire County Council), R. C. Chirnside, P. Hallett (Chairman and Managing Director of A. Gallenkamp and Co. Ltd.), J. H. Hamence, D. W. Kent-Jones, and C. Whalley and Laporte Industries Ltd., to whom I am especially indebted for the loan of an early laboratory notebook (Figs. 1 and 2) and for the generous gift of a copy of “The Earliest Chemical Industry,” by C. Singer.s 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. REFERENCES Wilde, O., “Aphorisms,” cited in “Stevenson’s Book of Quotations,” Cassell & Co., London, 1935, Szabadvafy.F., “History of Analytical Chemistry,” translated by G. Svehla, Pergamon Press, Chirnside, R. C., and Hamence, J . H., “The ‘Practising Chemists.’ A History of The Society for Haber, L. F., “The Chemical Industry during the Nineteenth Century,” Clarendon Press, Oxford, Reader, My. J., “Imperial Chemical Industries. A History. Volume 1. The Forerunners, 1870- Singer, C., “The Earliest Chemical Industry,” The Folio Society, London, 1958. Chapman-Huston, D., and Cripps, E. C., “Through a City Archway,” John Murray, London, 1954. Aldcroft, D. H., Editor, “The Development of British Industry and Foreign Competition, 1876- Chemical News, 1875, 30, 123, Betteridge, D., “The Teaching of Analytical Chemistry in the United Kingdom before 1914,” -, “The Teaching of Chemistry in Victorian and Edwardian Times,” Royal Institute of Chemistry Dalley, R. A., “45th Annual Report on the Work of the City Analyst’s Laboratory,” Leeds, 1972. Peden, J. D., “Annual Report of the County Public Analyst for the Year 1973,” Somerset County “100 Years of Public Analysis in Lancashire,” The Lancashire County Analyst’s Department Chemical News, 1874, 29, 8. Ibid., 1874. 29, 48, 74 and 135. AnaZjist, 1878, 3, May. Pdligot, E., Annls Chim. Phys., 1842, 5 (3), 7. Skey, W., Chem. News, 1867, 16, 201. Cf., Irving, H. M. N. H., “William Skey (1835-1900); a Bock, R., and Fischcr, W,, Z. anorg. allg. Chem., 1942, 249, 146. Kolthoff, I. M., “Development of Analytical Chemistry as a Science,” Artalyt. Chem., 1973, 45, 24A. Meinke, W. W., “Analytical Chemistry-A Fading Discipline? No!,” Ibid., 1970, 42, 26A. Chirnside, R. C., “The Analytical Revolution-Its Impact on Academic and Industrial Research,” Irving, H. M. N. H., “The Techniques of Analytical Chemistry,” H.M. Stationery Office, London, Beynon, J. H., and Williams, A. E., “Mass and Abundance Tables for Use in Mass Spectrometry,” Schwarzenbach, G., and Flaschka, H., “Complexometric Titrations,” Second English Edition, p. 903. Oxford, 1966. Analytical Chemistry 1874-1974,” Society for Analytical Chemistry, London, 1974. 1958. 1926,” Oxford University Press, Oxford, 1970. 1914,” George Allen and Unwin Ltd., London, 1968. Talanta, 1969, 16, 995. Reviews, 1970, 3, 161. Council Health Committee, Taunton, 1974. (based on an information leaflet issued by the County Publicity Officer, 1970). Centenary in the History of Solvent Extraction,” Chem. G. Ind., 1967, 1780. Chem. 6 Ind., 1971, 893. 1974. Elsevier, Amsterdam, 1963. translated by H. M. N. H. Irving, Methuen, London, 1969,December, 19741 IN ANALYTICAL CHEMISTRY 801 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. Vaughan, E. J ., “The Use of the Spekker Photo-electric Absorptiometer in Metallurgical Analysis,” Chirnside, R. C., Cooper, B. S., and Rooksby, H. P., G.E.C. JL., 1950, 17, 3. Irving, H. M. N. H., “Separation and Pre-concentration,” 2. analyt. Chem., 1973, 263, 264. James, A. T., and Martin, A. J. P., Analyst, 1952, 77, 915. Hardy, G. H., “A Mathematician’s Apology,” Cambridge University Press, Cambridge, 1940. Lautenschlager, W., Pahlik, S., and Tolg, G., 2. anal. Chem., 1972, 260, 203. Smales, A. A., Analyst, 1952, 77, 778. Irving, H. M. N. H., Andrews, G., and Risdon, E. J., Nature, Lond., 1948, 161, 805. Turkevich, A. L., Accts Chcm. Res., 1973, 6, 81. Cf., Science, N . Y . , 1970, 167, 449. “Preliminary Science. Report of the National Aeronautics and Space Administration,” NASA Royal Institute of Chemistry Lecture Series, 1941. SP 289, Washington, D.C., 1972.

ISSN:0003-2654    

DOI:10.1039/AN9749900787

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

802 Analyst, December, 1974, Vol. 99, p$. 802-809 PLENARY LECTURE Analytical Chemistry and Education BY R. BELCHER (Department of Chemistry, Ureiversity of Birmingham, P.O. Box 363, Birmingham, B15 21T) CHEMICAL analysis has been taught in advanced institutes of learning for more than 200 years, but after the turn of the present century, analytical chemistry (as distinct from chemical analysis) also began to recci\re some attention and eventually became the dominant partner, even though it is now possible to find some establishments where there has been almost a return to the teaching of chemical analysis exclusively. As much of this paper is concerned with British Universities, it is not out of place to comment on the curious fact that, with one exception, this country did not have a Professor of Analytical Chemistry until 1958, whereas Chairs of this kind had been established for many years in both America and Europe; in some instances, even in the smallest countries, they had been established in the last century.In 1920, R. M. Caven was appointed as Professor of Inorganic and Analytical Chemistry at the Royal Teclinical College, Glasgow,” and held this position until his death in 1934. His work was much more concerned with inorganic rather than analytical chemistry; never- theless, he did valuable work in the teaching of analytical chemistry and produced a useful text on qualitative analysis on which most chemists of my age group were reared. One would like to know thc reasons that led to the foundation of this named Chair, but, more to the point, why the Chair was not continued after Caven’s death, for he had filled it with distinction.Another 24 years were to pass before the late Cecil Wilson was appointed to a Personal Chair in Analytical Chemistry at Queen’s University, Belfast. Many attempts have been made to find an explanation as to why Britain (and the former British Empire) deviated in this way and possibly the most thoughtful study of the situation has been made by Betteridgel: “Although several analytical chemists held Chairs, none had the influence of Playfair, Roscoe, Hofmann, Graham and Miilliamson in formulating policy. It was most un- fortunate that Fresenius and Will successively turned down the Chair at the Royal College of Science . . . and that Liebig was a Lutheran and thus ineligible for the Chair at King’s College, London.These failures of commission meant that no analytical research school was founded, that no analytical chemist played a major part in formulating the syllabus common to most universities, and that analytical chemistry was taught by people whose interest in the subject was secondary if it ever existed at all.” . In the Universities,? the study of analytical chemistry falls into two categories: (a) formal teaching, by which is meant lectures, tutorials and laboratory classes; and (b) research. At one time in Britain, the same categories would be exactly defined by the terms “undergraduate tuition” and “postgraduate tuition.” Nowadays there are postgraduate courses in which the more formal tuition predominates, and even in a research course the candidate is expected to attend a number of formal advanced lectures.* The Royal Technical College a t Glasgow was fornierly the Glasgow and West of Scotland Technical College and, before that, Anderson’s University and Anderson’s Institute. I t is now, of course, the Univer- sity of Strathclyde. Some noted analytical chemists occupied the Chair, e.g., Ure, Penny and Dittmar. Dittmar, who was a pupil of Bunsen, was Professor there from 1874 to 1892. He was author of a number of books on analysis and analysed samples for the Challenger Expedition. A contemporary of Dittmar at the College was Humboldt Sexton, Professor of Metallurgy, who also wrote books on qualitative and quantitative analysis. I t would seem, thcrcforc, that this particular institute was probably the first in Britain to become actively concerned with analytical chemistry and, with a few breaks, interest has been maintained to the present day.f In order to avoid unnecessary repetition, when Universities are referred to, other establishments of advanced education are also included. 0 SAC and the author.BELCHER 803 TEACHING Fifteen or so years ago, the teaching of analytical chemistry was confined almost ex- clusively to qualitative and quantitative inorganic classical analysis.* Possibly two or three instrumental exercises would be included. The situation has since changed completely; instrumental methods now generally predominate. Although some titrimetric methods and, to a lesser extent, gravimetric methods still remain, the number of exercises has been reduced significantly to make way for instrumentation.These changes in the practical courses necessi- tate radical changes in the teaching of theory. In addition to the physico-analytical back- ground, some account of the chemical development of the method was (and still is) needed; otherwise, students look on methods as they would on kitchen recipes. The expansion of instrumental methods in the courses necessitates the teaching of additional chemical and physical theory. Regardless of the advance of instrumentation, some pure reaction chemistry should still be included and lectures on sensitivity, selectivity, masking and de-masking, amplification, catalytic reactions, induced reactions, etc., cannot be without benefit.Where possible, such lectures should be supported by demonstrations.2 (A film was then shown, demonstrating selective masking of periodate in the presence of iodate with molybdate, and demasking with oxalic acid.) Qualitative analysis became very unpopular and has now virtually disappeared from most analytical courses. The separation tables were developed mainly by Fresenius and basically remained unchanged to the present day. I consider that this neglect of one of the most powerful teaching tools available is already having unfortunate consequences. Despite the theoretical background to analytical chemistry pioneered by Ostwald, little attempt was made in Europe immediately to develop the theoretical interpretations of quali- tative methods of analysis.Among the first interpreters was Stieglitz at the University of Chicago, around the turn of the century. All later teachers have followed the same pattern after making adjustments for developing knowledge. Some writers have shown as superficial a knowledge of physico-chemical interpretation as they have of the reactions. The great “show-window” of physico-analytical interpretation was sulphide precipitation. The interpretation purported to show why the sulphides fell into two distinct groups and why cadmium sulphide provided difficulties unless the acidity was strictly controlled. Cobalt, manganese, nickel and zinc are not precipitated in the acid sulphide group “because their solubility products are not exceeded.” Unfortunately, the table of solubility product constants provided (and generally inconveniently placed several pages away from the argument) showed that nickel, cobalt and zinc should, in fact, precipitate in the first sulphide group.To make things more difficult, the soIubility products of antimony and arsenic sulphides were never included and no explanation was provided; I suspect the authors did not know the reason. The upshot was that the earnest student checking these facts was left completely mystified. A favourite examination calculation was to show how much cadmium sulphide would escape precipitation if the acidity were raised from, say, 0.3 N to 0.6 N. Nobody bothered to take this calculation to its logical conclusion and so find out that even in 11 N hydrochloric acid, with the usual concentrations, more than 90 per cent.of the cadmium sulphide should theoretically still precipitate. Examiners stubbornly continued to set this type of question long after it had been pointed out that it was no more than an exercise in simple arithmetic.3 These effects can be interpreted theoretically, but they need a far more penetrating examination of all the factors than the textbooks provided. This shows the dangers of super- ficial interpretation; if it is to be done, it must be done thoroughly. On the other hand, I am not in full agreement with the extensive algebraic calculations on ionic equilibria that many teachers demand, even when they are based on solid ground (however, see the simplified Analytical chemistry became generally associated with inorganic chemistry, and this is reflected in the titles of some of the Chairs.Organic analysis, i.e., qualitative analysis and elemental and functional group analysis, were generally taught by the Division of Organic Chemistry. This led to a somewhat unnatural division between the two branches. In Birmingham University, although both organic and inorganic analysis is taught by the Division of Analytical Chemistry, the Division of Organic Chemistry has always taught its own qualitative analysis. Naturally, this situation has changed over the last decade. It is worth noting that in recent years some European Universities have created separate Chairs of Organic Analytical Chemistry and Inorganic Analytical Chemistry.804 BELCHER : ANALYTICAL CHEMISTRY [Analyst, VOl. 99 system devised by Freiser and Fernando4).They are repetitive, time consuming and, in my opinion, have little instructive value. Other experienced teachers have begun to think like- wise (discussion with Emeritus Professor F. Cuta and R. A. Chalmers, “Golem,” Prague, 1972). At one time, the most important reason for teaching qualitative analysis was to provide a means of identification, but there have been more convenient methods available for some considerable time and so this need has disappeared.* Despite this, there are still many advantages to be gained from teaching qualitative analysis and these have been enumerated elsewhere5 : concepts from physical chemistry can be applied; the student becomes acquainted with large numbers of reactions; he learns the basis of many separations and determinations; his deductive powers should be stimulated; and he learns the necessity for cleanliness and good technique.Chemistry is still an experimental science despite the attempts of some to make it otherwise. For better or worse, the new graduates know far less about chemical reactions than their predecessors. Yet a knowledge of reactions is still of major importance, not only from the standpoint of analysis but for application in any branch of chemistry. A few weeks before this paper was presented, Professor Philip West delivered his Fisher Award Address and made the following comments: “Chemistry students of the enlightened present are sheltered from laboratory tedium- they are being educated to be philosophers and theoreticians. Truly, the intellectual elite ! “Quantum chemistry, kinetics and thermodynamics.What powerful tools to put in the hands of freshmen! Think of a young MS majoring in home economics who knows all about the quantum levels of the sodium that is in the baking soda. . . . I’ll bet she never bakes a cake that falls flat-she will know too much kinetics to let that happen. “I did sense a bit of disdain for the experimentalist, but there was a determined resigna- tion to be noted whereby good theory was not to be wasted just because of bad data. For example, cited values for any given equilibrium constant may vary by a factor of 2, 5, 10 or 104--or lo1’ for Al(OH,). Such discrepancies, however, are easily disregarded and do not preclude the use of activity coefficients. Furthermore, it should be realised that activity coefficients have special value in helping eliminate some of the less active students.‘ I . . . I long at times for the good old days. It is hard for me to believe that everything we used to do was so bad that it all had to be replaced. Some chemical reactions are important to some people, surely, and why shouldn’t students be permitted to see what the colours are of salts of some of the transition metals?’’ I recommend this address for further reading, for Professor West makes many more telling points in the same inimitable style.* I should perhaps comment that it is not always a bad thing to have such variable values for constants. When the Midlands Association for Qualitative Analysis endeavoured to provide a theoretical explanation of our anion separation scheme, the precipitation of silver arsenate did not fit in. However, after a diligent search of the text-books, we eventually found just the solubility value we needed! The perpetuation of errors in written documents is a well known phenomenon, but there is less excuse for this in a scientific document than in any other.However, I doubt if any teaching manual on any subject contains as many errors as the books on qualitative analysis. An alarming number of the “standard” tests simply do not work and it is this fact more than any other, in my opinion, that has placed this subject under a cloud. The numerous books on qualitative inorganic analysis range from the simplest of tables for use in schools to the near-treatise.Despite the large number of texts available, many teachers, baffled by the unreliability of the standard tables, would prepare their own versions. These versions added to the confusion; they probably worked well under very limited condi- tions, but were hopeless when applied outside those limits. Some books are freer from‘ mistakes than others, but all of them contain tests that do not work. I t was for this reason that an Association was formed in the Midlands some 20 years ago to study in detail all’ these problems. There were so many problems that it was necessary for a large group of people to study them, for it was beyond the capabilities or life-time of single individuals. More than forty research papers have been published as a result of this work and tables have been evolved that are free from the faults of their predecessors.Nevertheless, certain identifications can be achieved much more rapidly and conveniently by simple chemical tests than by instrumental methods.December, 19741 AND EDUCATION 805 The Association is in the process of publishing a source book of chemical reactions, all of which have been thoroughly tested. This book should be the most comprehensive source of tested reactions that has ever been compiled. It is unfortunate that, at a time when these misleading and erroneous tables have been rectified, qualitative analysis should be on the verge of dying out in the advanced teaching establishments. However, I am sure that in the near future some enterprising teacher, becoming a little wearied by teaching his students reactions by numbers, will re-discover that the reactions can be systematised, that they fall into definite groups and that it is possible to formulate a systematic scheme of qualitative analysis ! It is perhaps of interest to provide some examples of the remarkable material that is to be found in text-books on qualitative analysis. The efect of borate-“.. . The presence of boric acid introduces no irregularities in the course of separation of the metals’’ (following a statement that all insoluble borates dissolve in ammonium chloride) .’ “Borates . . . of the metals of Groups IIIb and IV and of magnesium are insoluble . . . in ammoniacal solution and are therefore liable to be precipitated at this stage” (when the solution is made ammoniacal).“They may be removed. . . .’’8 In fact borate has to be removed, but not for the reason given, so both authors are wrong. The detection of carbonate and hydrogen carbonate-One would not expect such simple ions to provide problems. They are usually detected in the presence of each other by the use of calcium or magnesium salts, based on the fact that calcium and magnesium carbonates are insoluble and the hydrogen carbonates are soluble. If one considers the large number of text-books that are available, it is surprising how many authors evade the issue of dif- ferentiating between these two ions. Some ignore hydrogen carbonate completely, others give tests for the individual ions without specifying what should be done with mixtures; others give the tests already quoted.A film was then shown, demonstrating the precipitation reactions of carbonate and hydrogen carbonate with calcium and magnesium ions. Neither calcium nor magnesium is a suitable reagent for these anions. Calcium ions give a precipitate with hydrogen carbonate under most conditions, as can readily be calculated. The precipitate obtained with magnesium consists mainly of the hydroxide. In mixtures in the usual ratios, no precipitate is obtained because of the buffering effect of the hydrogen ~arbonate.~ Table I shows the reactions of mercury(I1) chloride with the same anions, as described in different text-books. No further comment is necessary, except to say that this reagent is useless for the purpose claimed. TABLE I REACTIONS OF MERCURY(I1) CHLORIDE WITH CARBONATE AND HYDROGEN CARBONATE Authors co,2- HC0,- Vogel .. . . .. , . Red - brown precipitate No precipitate Clowes and Colman . . . . Yellow precipitate Red precipitate Schimpf . . . . .. . . Red - brown precipitate White precipitate I have digressed at some length on qualitative analysis, because I think it is important to stress how many errors there are in the text-books and for how many years these passed unnoticed. RESEARCH Until a few years ago, there were some who doubted that Universities could make any notable contribution to analytical chemistry and, indeed, often asked what significant contributions had been made at all. The foundations of modern spectroscopy were developed in a University, as were polarography, electrogravimetric analysis, potentiometric and conductimetric titrations, mass spectrometry, chromatography and ion-exchange methods.806 BELCHER : ANALYTICAL CHEMISTRY [Analyst, Vol.99 Elemental organic analysis and its descendent microanalysis were developed in Universities. Substantial contributions have also been made from outside Universities, but the solid core of analytical chemistry, from the last century onwards has been developed from within the Universities. In more recent times, e.g., since the Second World War, most of the modern techniques have also been developed in Universities. As is well known, other countries made much earlier contributions, but I want to show that the Universities in Britain have made a substantial contribution to analytical chemistry, despite the handicaps that existed until shortly after the Second World War, and which still exist to some extent.Some University lecturers, interested in analytical chemistry, were able to make notable contributions. The work of T. B. Smith at the University of Sheffield is a good example. Smith never had a full-time research student, which provided some compensations, for he had more time to experiment himself. His book on the theoretical aspects of analytical chemistry, therefore, contained a vast amount of unequalled first-hand experience, which gave the book its special flavour. It was certainly the best of its day, and no more recent book has ever had so much influence. Notable work was carried out a t Edinburgh (Christina C. Miller), Glasgow (D. T. Gibson), Cambridge (A. J.Berry) and elsewhere. In case the criticism is raised that much of this work was “pure” analytical chemistry, it is timely to give the reminder that the rapid methods for the elemental analysis of coal and coke and the proximate methods of analysis were developed at the Department of Fuel Technology at Sheffield University (e.g., refs. 10 to 14). The work was unsponsored and not supported financially in any way, despite its “applied” nature. I t is nearly 40 years since this work was initiated. At that time, there had been virtually no change in the methods used for the analysis of coal and coke since the turn of the century. The “new” methods were based on different principles and reduced the time taken for the older methods from days and hours to a few minutes.These eventually became BSI and IS0 methods and so their origins and the investigations that led to their development have been forgotten. Long before this period, and probably at the start of this century, Dr. Fred Ibbotson* and some notable colleagues at the Department of Metallurgy, Sheffield University, developed methods of analysis for both ferrous and non-ferrous materials. Some of these methods are still used after the passage of more than half a century. These activities generally depended on the enthusiasm and initiative of individual workers and were not the policy of an established research school. It was not until after the Second World War that more Universities took a greater interest in the progress of academic analytical chemistry. The creation of Chairs was to be postponed for a considerable period, but more lectureships in the subject were created.Later these appointments developed into senior lectureships, readerships and, eventually, some Chairs were founded. At the beginning of 1974 there were three Professors of Analytical Chemistry in the British Isles; a fourth was appointed in June. Some of these University centres have tended to specialise, whereas others have main- tained a general approach; this is remarkable, especially when their resources are taken into consideration. Table I1 provides a summary of the work that has been in progress at some of the main centres in the British Isles. Research work in analytical chemistry in the Universities over the last decade has been mainly concerned with expanding knowledge on existing techniques, less often with developing entirely new techniques, possibly establishing new methods to meet a particular requirement or possibly studying reagents or reactions that behave anomalously.The last-named studies have their value even if they do not effect the improvement of a method. An explanation of such anomalies is still a contribution to knowledge and does further the progress of analytical chemistry. Examples in this area from our own work are the behaviour of phenylhydantoic acid,l5 the reactions of the rhodanines with silverls and the precipitation of calcium oxalate by urea hydr01ysis.l~ It should not be forgotten that a postgraduate student is being trained in the methods of research and the successful accomplishment of such training is really of more importance * The story is told that a student approached Ibbotson one day to complain that he had a bluebottle, Ibbotson advised him to catch another in his basic acetate separation.and to “do a blank.” He asked what he should do next.December, 19741 AND EDUCATION 807 than the development of entirely new techniques. This aspect must not be forgotten; the use of postgraduate students as technicians is now more rife than ever. When I conduct oral examinations for the Ph.D. degree, I am sometimes shocked by the limited knowledge of the candidates. It arises because they work on one instrument which churns out results, right or wrong. This should be countered either by preceding the Ph.D. course with a com- pulsory formal M.Sc.course or by including compulsory advanced lectures in the Ph.D. course. We are now concerned with a number of research programmes that are of a more “practical” nature, e.g., the monitoring of operating theatre atmospheres and analysis of the blood of medical and nursing staff exposed to anaesthetic vapours. In another investigation, the amount of lead in the teeth of children living near the Midlands Motorways is being examined. We are also concerned with determining drugs of abuse in clinical specimens. TABLE I1 RESEARCH IN PROGRESS AT BRITISH UNIVERSITIES University Aberdeen . . .. .. . . .. Belfast . . . . .. . . .. Birmingham . . .. .. . . Bristol . . .. . . , . . . Canterbury . . .. .. .. . . Chelsea College (London) . . .. .. Edinburgh .. .. .. . . .. Exeter . . .. .. .. .. Imperial College (London)-Chemistry . . Leeds-Chemistry , . .. . . . . Loughborough . . .. .. . . -Procter Labs. . . , . .. Royal School of Mines (Materials Analysis Salford . . .. .. .. . . Sheffield . . . . .. .. . . Research Group) . . . . .. . . Strathclyde . . . . . . .. .. UWIST (Cardiff) . . .. * . . . Swansea . . . . .. .. .. Nature of research General Submicro inorganic analysis, spectroscopy, polarography General inorganic and organic analysis General (special reference to chromatography) Ion exchange, radiochemistry, solvent extraction Polarography, ion-selective electrodes, thermal methods, analysis of drugs, polymers, etc. Organic functional groups. Application of infrared tech- niques. Natural products analysis Kinetics and mechanisms of titrimetric, indicator and electrode processes and induced reactions Electroanalytical and spectroscopic methods Trace and environmental analysis Atomic-absorption and atomic-fluorescence spectroscopy, molecular fluorescence, electrochemistry, trace analysis Complexing agents.Solvent extraction (theory and practice), viscometric titrations Analysis of food constituents Analytical biochemistry, electrochemistry, electron spec- troscopy, high-pressure liquid and other forms of chromatography, industrial and general Liquid chromatography of chelates, fluoride analysis, General Metallurgical analysis, especially atomic-absorption spec- Analytical atomic spectrometry, kinetic and catalytic Photoelectron spectroscopy, complexation reactions Ion-selective electrodes, fuel cell sensors, separation by ion exchange and electrophoresis, gas-chromatographic determinations gas-bubble electrification troscopy and gases in metals methods, electroanalytical methods We celebrated the quarter century of the Birmingham School last autumn. Over such a span of time, our interests have changed and in the earliest days we were mainly interested in new indicators, reagents and classical methods.This led to the development of many new indicators and reagents, some of which were then shown in a film demonstrating (a) the reactions of sulphate with Ba2+, fi-chloro-9’-aminodiphenyl hydrochloride and 2-aminoperi- midine hydrochloridel*Js; ( b ) the oxidation of dimethylnaphthidine (e.g., ref. 20) ; and (G) the reactions of 2,3-bis [2- (6-met h yl) pyridylquinoxaline and 2,3,5,6-tet rakis (2’-pyridyl) pyrazone (TPP) with Cu+ and Fe2+, respectively.21#22 We had various other interests, too numerous to mention, but now our main interests, apart from a few side-issues, are concerned with the gas - liquid chromatography of inorganic substances, candoluminescence spectroscopy and molecular emission cavity analysis (MECA spectroscopy).Nevertheless, to me the most fascinating part of chemistry lies in reactions and reagents. Our work in this area has had a new lease of life, paradoxically enough thanks to the development of newer instrumental techniques which combine well with many purely chemical techniques.808 BELCHER: ANALYTICAL CHEMISTRY [Analyst, VOl. 99 Our work in the field of inorganic gas - liquid chromatography has not been confined exclusively to chelate compounds ; we have had some success in determining chloride, bromide and iodide at remarkably low concentrations by reacting the halide with phenylmercury nitrate.The latter reacts instantaneously to form the phenylmercury halide, which can then be extracted into a suitable organic solvent. The phenylmercury halide is volatile and gives a characteristic peak in the gas - liquid chromatographic apparatus (e.g., ref. 23). Other methods of completing the determination are possible, e.g., spectrophotometry, polarography or atomic-absorption spectroscopy, but are not so sensitive as the gas - liquid chromatographic method. I mention this particular method, because it provides an excellent example of the perfect combination between reaction chemistry and instrumentation. Neither the reaction nor the instrument would be the slightest use alone for this determination, but in combination a remarkably simple and sensitive method results.Finally, I should say a few words about candoluminescence and MECA spectroscopy. These are very new techniques and some may not have heard of them yet, as they were first announced at Euroanalysis I less than 2 years ago. Candoluminescence is the term used to describe the luminescent emission from certain solid materials placed at the edge of a hydrogen diffusion flame (e.g., ref. 24). The emission is stimulated in the surface layers of the solid matrix (which is usually calcium oxide) only if they contain small amounts of certain ions (activators).The phenomenon was first noted as long ago as 1842, but no attempt had been made to apply it for quantitative purposes. Two attempts have been made to apply it in qualitative analysis (in 1913 and 1951), but no work has been carried out since then. The qualitative work was mentioned briefly by Feigl, but despite our familiarity with his book over a lifetime, it was only at the last reading that it was realised that the technique had possibilities. As little as 1 pg of bismuth can be determined in at least 100 times the amount of most other metals. Few other metals interfere at lower concentrations, and their interference can be overcome by various means. Trace amounts of bismuth can be determined in copper alloys and in lead oxide.A number of other metal ions can be determined: praseodymium, at 610 nm in the range 0.05 to 1.0 ng with a reproducibility of &6 per cent., and terbium, europium, scandium, antimony, lead and manganese. This work is still in its infancy and the determination of other metals and the use of other matrices is being studied at the present time. (A colour film was then shown, demonstrating the candoluminescent reactions of manganese, bismuth, praseodymium and antimony.) MECA spectroscopy was discovered about 2 years ago (eg., refs. 25 and 26). The sample is contained in a small cavity at the end of a rod, which is introduced into a hydrogen flame. The technique has many advantages over conventional molecular emission methods; it is more sensitive than nebulisation, very small samples can be used, there is the possibility of multi-element determination and emissions are obtained from elements that normally show nothing in the nebulisation technique.So far sulphur, phosphorus, halides (including fluoride), antimony, tin, copper, silicon, arsenic, boron, selenium and tellurium have been determined. The possibility of determining other elements is under investigation. For example, lead can be determined by precipitation of the sulphide, transference of the precipitate to the cavity, followed by measurement of the sulphur emission. It is also possible to determine certain sulphur-containing organic compounds by the same procedure, for different sulphur functions show characteristic emissions. MECA spectroscopy is so versatile that it can be run jointly with other techniques; for example, it should be possible to analyse fractions from thin-layer chromatographic separations or from gas chromatography. In some instances, chemical pre-treatment can be carried out in the cavity itself.This technique is also in its infancy but is being studied extensively and before long should come into general use for routine work. It is another interesting example of the effective combination of reaction chemistry with instrumentation. Some metals can be determined indirectly from the sulphur emission. CONCLUSION The Universities have played a prominent part in the development of analytical chemistry in the past, both in training analytical chemists and in developing new analytical techniques.December, 19741 AND EDUCATION 809 Because of the great advances that have been made in instrumentation, significant changes have had to be made in teaching courses.This step has been inevitable, but care should be taken to ensure that reaction chemistry receives due attention. For one thing, classical methods will be necessary, at least within the foreseeable future, for standardisation purposes and for separations; but both branches have much to offer each other and, by judicious combinations, more effective techniques can be evolved. A problem that might arise if analytical teaching is confined essentially to instrumentation is that the product of this form of training will become too specialised and often a one-instrument man. This is not noticeable so far because there are still many analytical chemists whose education was on a much broader basis.In any event, it should be borne in mind that the reactions of analytical chemistry are amongst the most sophisticated chemical reactions known. If chemistry is to survive as an independent discipline, these reactions should still be part of the University curriculum, otherwise chemistry as we know it will degenerate. Physicochemical inter- pretations should continue, but care must be taken to ensure that the theory is sound; extensive, repetitive calculations should be avoided. The nature of the research work has changed considerably and will continue to change. Nowadays, far more “applied” work has to be undertaken in order to obtain the necessary financial support.Nevertheless, it is essential that the apparently “useless” work continues. Thus, pioneering work in a possible new technique may not be of immediate application, but could be of value in the years to come. Even studies of reagents or reactions that appear to behave anomalously have their own value. It would be a tragedy if the “useless” research were eliminated entirely, for work of this kind can be a contribution to general knowledge and is not necessarily confined to analytical chemistry. Moreover, if it were discontinued in Universities, the quality of recruit- ment would be adversely affected, for first-class brains are not going to be satisfied with projects that do not stimulate initiative and original thinking. In that event, not only analytical chemistry but science as a whole would suffer. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 26. 26. REFERENCES Betteridge, D., Talanta, 1969, 16, 995. Belcher, R., and Townshend. A,, Analytica Chim. Acta, 1968, 41, 396. Belcher, R., J Z R. Inst. Chem., 1949, 101. Freiser, H., and Fernando, Q., “Ionic Equilibria in Analytical Chemistry,” John Wiley and Sons, Stephen, W. I., Educ. Chem., 1969, 6, 221. West, P. W., Fisher Award Address, American Chemical Society Spring Meeting, Los Angeles, Caven, R. M., “Systematic Qualitative Analysis,” Blackie and Son Ltd., London and Glasgow, 1926. Vogel, A. I., ‘*A Textbook of Qualitative Inorganic Analysis,” Longmans, Green and Co., London, Osborne, V. J . , and Freke, A. M., Micvochim. Acta, 1964, 790. Beet, A. E., and Belcher, R., Fuel Sci. Pvact., 1938, 17, 53. -- , Ibid., 1940, 19, 42. Belcier, R., Ibid., 1940, 19, 172. Belcher, R., and Spooner, C. E., Ibid., 1941, 20, 130. -- , Ibid., 1947, 26, 55. Bashar, A., and Townshend, A., Analyst, 1968, 93, 125. Stephen, W. I., and Townshend, A., J. Chem. SOC., 1965, 3738. Bashar, A., and Townshend, A., Talanta, 1966, 13, 1123. Belcher, R., Nutten, A. J . , and Stephen, W. I., J. Chem. Soc., 1953, 1334. Belcher, R.. PYOC. SOC. Analyt. Chem., 1970, 7, 61. Belcher, R., Nutten, A. J., and Stephen, W. I., J. Chem. SOC., 1951, 1620. Stephen, W. I., and Uden, P. C., Analytica Chim. Acta, 1967, 34, 357. Stephen, W. I., Talanta, 1969, 16, 939. Belcher, R., Majer, J . R., Rodriguez-Vasquez, J. A., Stephen, W. I., and Uden, P. C., AnaZytica Belcher, R., Bogdanski, S. L., and Townshend, A., Talanta, 1972, 19, 1049. Belcher, R., Bogdanski, S. L., Ghonaim, S. A., and Townshend, A., Analyt. Lett., 1974, 7, 133. New York and London, 1963. April 2nd, 1974. 1953. Chim. Ada, 1971, 67, 73. --- , , AnaZytica Chim. Acta, 1973, 67, 1.

ISSN:0003-2654    

DOI:10.1039/AN9749900802

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

810 Artalyst, December, 1974, Vol. 99, $9. 810-816 PLENARY LECTURE Analytical Chemistry in Public Service BY J. MARKLAND (The County Laboratory, County Ofices, Matlock, Derbyshive, DE4 3AG) IF one takes the literal meaning of public service, it is apparent that my topic would embrace most of analytical chemistry. Analytical chemistry in both education and industry must surely be public service. It is appropriate that I should acknowledge the great help received by those of us who work in what is more generally accepted as public service from analytical chemists in both education and industry. Indeed, when the wide spectrum of research organisations is considered, there is an obvious difficulty in deciding where to draw the lines between industry, education and public service. Therefore, in defining public service as I do, on a fairly narrow basis, it is only for the purpose of this paper.If I stray from my definition it is because I believe that if any dividing line exists, it varies from time to time. I take public service to mean that service which is more directly concerned with the needs of the public, as represented by elected bodies such as Parliament and Local Authorities and by nominated bodies such as Hospital and Water Boards. Even so, it would be pre- sumptuous to pretend that all aspects can be covered and my main theme must, of necessity, be based on that aspect of public service of which I have personal experience-namely Local Authority Public Service, as exemplified by the work of a Public Analyst. For this purpose we immediately go back to the origins of the Society for Analytical Chemistry.Analytical chemistry is just as difficult to define. The legal definition of Public Analyst provides little help as the Food and Drugs Act 1955 merely states that every Food and Drugs Authority shall appoint one or more persons to be analysts within its area and restricts such appointments to persons with approved qualifications. The Public Analysts Regulations 1957 made under the Act specifies this qualification. According to the Food and Drugs Act, “Analysis” includes microbiological assay but no other form of biological assay. It is sur- prising that until recently the law has not satisfactorily defined analysis. This omission has caused some debate, largely because analysis, as ordinarily understood, has been undertaken on behalf of Local Authorities by persons who are not Public Analysts and, indeed, who have no qualifications in analytical chemistry. The Agriculture Act 1970 remedied the defect as follows : “Analysis includes any process for determining any fact as to the nature, substance or quality of any material.” For the purpose of this paper, I treat analysis thus defined as synonymous with analytical chemistry.If we ignore Archimedes and his early use of a physical method for the analysis of gold, possibly the earliest control of commodities was made by the city Guilds, which indirectly was a public service. In the eighteenth and early nineteenth century, there was public concern about adulteration, mainly of food and medicines.Many of these hair-raising allegations were proved to be true, but some must have been exaggerated. How little human nature changes. The public still have fears, genuine and unfounded, many of which could be resolved by applying scientific methods to the probIem. Chemical and physical sciences were de- veloping rapidly and were applied to these consumer problems-to use a more fashionable term. A number of workers and authors contributed, not the least being Accum,l who gave his book on food adulteration a subsidiary title “There is death in the Pot.” These earlier workers must have given some inspiration to A. H. Hassall, who directed work on food adulteration for .The Lancet and not only published his findings but also, in 1857, published a book2 giving analytical methods for the detection of adulteration.Hassall was one of the founder members of this Society and must surely have good claim to be the first Public Analyst in the present context. Concurrent with the work on adulteration, some analysis was carried out for another public purpose. An Inland Revenue Laboratory had been started in 1842. Hassall criticised Surely, Accum was a potentially modem news reporter. @ SAC and the author.MARKLAND 81 1 this organisation in very forthright terms, but it is clear that he realised that the staff were working under restrictions imposed by their office, the purpose of which was the collection of revenue. It is well known that this inspection and testing service later developed into the Laboratory of the Government Chemist.All this initial work led to the Pure Food Act of 1860, in the event abortive, but it did create the post of Public Analyst and thus introduced into the law analytical chemistry in public service. A new Pure Food Act was enacted in 1872 and shortly afterwards the Society of Public Analysts was formed. It seems that there were two main difficulties. The first was the inexperience and shortage of analysts to carry out the work under the new Act. The second was the difficulty in defining adulteration. In defining adulteration, Hassall excluded the sale of one article in place of another-he called that substitution. He also excluded the presence of substances that were impurities in the raw materials, or foreign substances that were accidentally present, which is interesting in the light of modern attitudes towards such occurrences.Hassall’s view was that adulteration consisted in “the intentional addition to an article, for purposes of gain or deception, of any substance or substances, the presence of which is not acknowledged in the name under which the article is sold.” The Council of the Society decided that an article of food was deemed to be adulterated: (1) if it contained ingredients rendering the food harmful; (2) if it contained substances to increase the mass or bulk or to give it false value, unless such substances were necessary for manufacture or preservation or their presence was declared ; (3) if any important constituent had been abstracted without declaration at the time of sale; (4) if the material sold was an imitation of another material or was sold under the name of another article.Hassall listed some of the adulterants found in foods before the passing of the pure food laws. Among harmful ingredients said to have been found were copper salts, including the arsenite, Prussian blue, red lead, lead chromate and mercury sulphide, all of which were used as colours in a variety of foods; iron sulphate, sulphuric acid and even nux vomica, which were used as flavours! Spirits and beer were watered, a common enough allegation even now. Mutton fat was sold as lard; a variety of leaves and exhausted tea leaves were sold as tea; spices were diluted with starch; and milk was watered, artificially coloured and adulterated with starch and sugars. These, then, were the problems.In his book Hassall gave methods of chemical, physical and microscopical analysis. The chapter on milk deals with fat, total solids, ash, casein, lactose by a copper reduction method, specific gravity and specific gravity of the milk serum. He also mentions factors that cause variation in the composition of milk. Methods of analysis, including an interesting chapter on milk analysis, were given in a later book by Bell,3 the first “Government Chemist.” The polarimeter was used for deter- mining lactose and methods were given for sour milk analysis and for calculating the com- position from the total solids and specific gravity. In Bell’s book, microscopy, widely used in the analysis of coffee, tea and cocoa, was described. Apparent, then, are the concurrent advances in the two fields of public service.What a pity they could not have co-operated earlier than they did! Rather violent opinions were expressed on milk analysis, largely because the Government Laboratory and Public Analysts used different methods of analysis. The degree of co-operation now evident between the two branches of public service indicates how far we have advanced. For the obvious reason that the main concern of the public was food adulteration, analytical chemistry was greatly concentrated on food. The Society’s publication “Fifty Years of the Society of Public Analysts”* gives a summary of the activities and interests and, in those early days, food certainly predominated. There is mention here that before 1874, Hehner and Angel1 differentiated between soluble and insoluble fatty acids in butter- fat.How interesting to find that in 1968 the same principle is used but that the soluble fatty acids are measured by gas chromatography.K However, food was not the only interest. In observing some of the names mentioned we note that of Stevenson, a pioneer of toxicology, and of A. H. Allen, whose “Commercial Organic Analysis” is proof enough of his versatility as an analyst, or of Francis Sutton, who wrote the classic “Volumetric Analysis.” However, then there were more serious problems.812 MARKLAND ANALYTICAL CHEMISTRY [Analyst, Vol. 99 In the field of public protection, we note a very early report of a prosecution for adultera- tion of seeds, showing an early interest taken in agricultural work by Bernard Dyer, an interest still continued by his former practice.Voelcker, in his capacity as consultant to the Royal Agricultural Society, was another early Public Analyst actively engaged on agricultural work. Again, analytical chemists were agitating for legislation on fertilisers and feeding stuffs. Two unsuccessful Acts, in 1893 and 1906, were followed eventually by the Fertilisers and Feeding Stuffs Act of 1926, which has only just been replaced by the Agriculture Act of 1970. These early Public Analysts used their skills as advisory chemists to the agricultural industry. Indeed, together with agricultural colleges and some university departments, they were the only chemists available to carry out this work. Between the wars, Agricultural Education Departments were started by County Councils.Some agricultural advisory work was done by these departments in co-operation with colleges and universities. The National Agricultural Advisory Service now operates over a wide field and once again analytical chemistry is being applied to public service. Work on soils for the determination of major nutrients and trace elements, and on the effects of deficiencies and excesses of trace elements on plants and animals, are some of the invaluable features of their activities. I have digressed from Foods and Drugs and I return to drugs. The British Pharma- copoeia was first published in 1867. My earliest available reference is the 1885 edition6 The chemical drugs included were simple and there were many crude vegetable products.Surprisingly, the tests used did not seem to include microscopy and the methods prescribed for chemical analyses were very simple indeed. The activities of analysts from the pharma- ceutical industry, the Pharmaceutical Society and from Government and Local Authorities have contributed to the development of drug analysis, as partly exemplified by the present British Pharmacopoeia.' Attention is now paid to the possible drug impurities as well as to the percentage of the substance itself. Thus we now have ultraviolet and infrared spectro- photometry ; paper, thin-layer and gas chromatography ; biological and microbiological assay and quantitative microscopy, besides the more common chemical and physical analytical methods. These methods are used by Government, Local Authority and industrial analysts, all with the same purpose, the protection of the public. Consideration of drugs leads us to toxicological work.A founder member of this Society, Winter Blyth, wrote a textbook on this subject.* The third edition of his book, published in 1895, is remarkable for its breadth. In an example from the book, the celebrated Maybrick case in 1889 on arsenic poisoning, a list of fourteen articles, including a dressing gown, a handkerchief, contents of various bottles, and sediment from the trap of a water closet and lavatory drain, is given. Of course, this kind of work, which was commonly carried out by Public Analysts, is now mainly dealt with by the Forensic Science Laboratories. From the standpoint of an observer, Forensic Science Laboratories furnish an admirable example of combining a large number of sciences, with the object of giving a public service.In this field, analytical chemistry plays an important part. The methods used now are different, but the approach exemplified by the Maybrick case would no doubt be very similar. As the Society developed, water pollution became an active subject. We seem not to have changed much over the years as the subject is still an active one. Once again, the early members of the Society led the field. There were differences of opinion on analytical methods, but these chemists were strong and stubborn men. We have early books by Wank- lyn9 and by Frankland.10 Gradually, the various water undertakings employed their own chemists for analytical and other duties.Larger units were formed to control water supplies and sewage disposal, until we now have the new Water Authorities. Again, the thread of analytical chemistry is seen through the history of the Society up to its present use for this important public service. In 1878, papers on sulphur in coal gas4 were presented to the Society, and purification of this gas was suggested. Environmental pollution is also of modem interest and while gas has not for many years been a serious contributor to sulphur contamination, yet the sulphur problem is still with us. There is a degree of control by Factory Inspectors and Alkali Inspec- tors, but Government and Local Government analysts still carry out work on this subject. There has always been a need for the application of analytical chemistry to clinical work.The simpler chemical tests for urea, and for glucose in blood and urine, have long been per- All of these were examined for the presence of arsenic.December, 19741 IN PUBLIC SERVICE 813 formed in most hospitals, often by those who would not claim to be analytical chemists. The need for more and more diagnostic aids has led to a rapid growth of clinical biochemical work, usually by specialists in the hospital service. A need exists here for large numbers of analyses to be performed rapidly, and the various techniques of chromatography, spectrophoto- metry, spectroscopy and automatic analysis have been quickly taken up as they have been developed, thus constituting a very direct use of analytical chemistry for the benefit of the public.In developing these few themes on public service from the early workers in the field, I have been very selective. To be otherwise would involve too much detail and the present situation has to be discussed. So far, the Government Chemist and his work have been only briefly mentioned but in all of the aspects of analysis mentioned, he continues to be very active. Some time ago, the formation of the department was summed up thusll: “it exists to provide an analytical, investigatory and advisory service in all branches of chemistry for Government departments, civil and military, and for some quasi-Government grant-aided bodies, such as the Forestry Commission. Under a number of Acts of Parliament, such as the Food and Drugs Acts, the Government Chemist has statutory functions as an official analyst and as a referee in cases of disputed analyses.” I am sure that since then the department has developed further, but while the quotation gives a concise description of analytical chemistry in public service, it conceals a good deal of interesting detail.There is still the department of Customs and Excise, with its work on tobacco, hydro- carbon oils and alcoholic liquors, among its many other activities. One wonders how long we should have waited for accurate specific gravity tables for alcohol if financial considerations had not been involved. Analytically, it does not seem particularly important to have such precision. Similarly, more closely controlled apparatus for moisture determination has been improved by the need for repro- ducibility in Customs and Excise work.Perhaps these are two simple examples of a public service need, benefitting analytical chemistry. There is still the Government Chemist’s func- tion as a referee analyst under various statutes; work of this kind is dealt with later. Work is carried out on environmental health, involving pesticide levels in foods, waters, factory atmospheres and industrial pollution ; also forensic work on narcotic drugs ; radiochemistry ; bacteriological work; and quality control on Government stores to name but a few examples. The Government Chemist is represented on a variety of Advisory Boards and Committees and so gives public service by virtue of his knowledge of chemistry in general and analytical chemistry in particular.We thus have a department with extensive statutory duties and at the same time with scientific advisory duties covering a wide field. There has been a movement in the same direction in Local Government, but before considering this in greater detail, a further delve into history is appropriate. As long ago as 1881, Kingzettq recommended the desirability of extending the duties of the Public Analyst so that he would advise on gas and water supplies, sewage treatment and disposal, road materials and various other matters in which chemical knowledge is of major importance. This was obviously beneficial when the analyst was in fact appropriately trained but there were some who were not really capable of carrying out the statutory work. The Society, in 1890, suggested to the Government that proof of adequate qualification and training should be required.A t first, judgment on this require- ment was made by officers of the Local Government Board, but later this function was taken over by the then Institute of Chemistry, which set an examination. This examination system, somewhat modified, still remains a safeguard that analytical chemistry shall perform its public service competently. So far, we have dealt with the origins of the service and the early problems encountered. We have seen that for many years Public Analysts performed analytical and scientific duties, which gradually evolved until they became specialist fields of public service. In spite of this, Public Analysts have, in fact, tended to become what Kingzett suggested and are now being recognised as Scientific Advisers to the Local Authorities.The present Food and Drugs Act 1955 serves the same purpose as the old Act, but it has been clothed by many regulations. Nevertheless, the old problems appear in new forms. There is less gross adulteration; the deception can now be effected in more subtle ways by clever advertising and, moreover, is almost impossible to prove. In any event, the standards made by Regulations have eased the problems of gross adulteration and have eliminated But what precision was embodied in Thorpe’s work! l2814 MARKLAND : ANALYTICAL CHEMISTRY [Analyst, VOl. 99 the conflicts in court between experts with widely differing views. Differences due to the analytical methods used are not now common.While in this country there are few official methods of food analysis, there is a good deal of standardisation based on A.O.A.C. methods and on the many methods developed and published by the Society. In this sense, we have analytical chemistry, as represented by scientific bodies, clearly contributing to public service. The pattern of food and drug analysis is still one of analysis for composition and im- purities, but we also have analysis for additives and accuracy of labelling. It is necessary to determine by analysis the composition of milk, fish and meat products, soft drinks, preserves and a variety of other products, LabelIing of food is more strictly controlled and this, too, leads to analysis for composition. Many of the methods used are based on old analytical methods for determining moisture, fat, protein, carbohydrates and ash and individual constituents of the ash.The major difficulty facing the analytical chemist working in the field of public protection is that in analysing mixtures he very rarely has access to the raw materials used for preparing the product. Throughout the history of this work, the variation in composition of natural products has presented this difficulty. Earlier court cases on milk adulteration were littered with arguments that showed either inability or unwillingness to understand the elementary fact that a natural product such as milk could vary in composition and still be genuine. We seek a true constant, for each natural product, almost as the alchemists sought the philosopher’s stone or the elixir of life.Perhaps, gradually, we shall come to accept the statistically calculable consequences based on valid information on compositions of natural products. Of course, some constituents are more constant than others and for milk we do have a physical test, the freezing point, which was introduced as an analytical method by public servants for public service and is now used much more by industry with the ultimate result of public service. Meat composition and its variations have been well covered by Society publica- tions.13-ls The question of food additives leads us to regulations on preservatives, colouring matters and antioxidants. The regulations on colouring matters and antioxidants were made even though no methods were available for their enforcement. Such methods were developed and publi~hed~~9~8 by the Association of Public Analysts, an organisation that I had almost forgotten to mention.It was formed in 1953 as a separate body by Public Analyst members of the Society. Then there are the regulations on emulsifiers and stabilisers in food. I am sure that these regulations were necessary but they must have been devised by someone with a sadistic hatred of enforcement analysts. Was there also an alliance with some other branch of Government so that it could be stated that not only shall the regulations be made, but also that no funds will be made available for research on analytical enforcement methods? This is a serious general problem; there is a need for an open financial allowance by Local Authorities for research projects of this nature.Too much has been, and still is, achieved by individual officers in their own time with inadequate facilities. It is a chance for public service to repay some of the debt owed by it to analytical chemists. Over the past 15 years, analysts have been faced with increasing numbers of public complaints concerning the presence of foreign material in foods, many of which are an in- evitable result of present methods of food preparation and distribution. The materials found are difficult to classify and at times the work calls for application of disciplines other than analytical chemistry, An allied problem is that of insect infestation, from which follows work on residues of fumigants, but the most common cause of complaint is the development of mould.The subject of moulds leads naturally to the detection by the methods of analytical chemistry of mould metabolites in both human and animal feeds. The impurity problem is still with us. Lead compounds are not now deliberately used as colouring agents. The most recent problems with lead have arisen from contamination from sprays, from containers or sometimes from local pollution, A total of many thousands of food samples are examined each year for trace amounts of lead in the various p.;blic laboratories throughout the country. Life is somewhat easier in that the days have gone when harm attributable to each individual sample had to be proved. We have regulations limiting the amounts of lead and arsenic in food. These are not the only trace metals con- sidered; cadmium and mercury are also determined with some regularity.There has been public awareness of the potential dangers from these and other trace metals. However, I am not really sure which body should be celebrating its centenary. We trespass here into the field of microbiology.December, 19741 IN PUBLIC SERVICE 815 some analysts had anticipated this public concern and were already examining the problem before the need arose. The development of a variety of organic crop sprays has extended the problem of contamination. Public Analysts and Local Authorities throughout the country have co- operated in a series of national surveys on pesticide residues in food. Here we have an example of the detection, identification and extraction of substances present in fractions of a part per million made easily possible only by development of techniques of analytical chemistry.Some work could be done by biological testing, but paper, thin-layer and gas chromatography provided the tools for this service. Public Analysts have been working for some years on metal pollution of air, water, soil and crops, thus widening the scope beyond laboratory analytical chemistry to advice on the problem in general, particularly sampling. Contamination by potentially toxic pollutants is only a part of the problem. There is also aesthetic pollution in which there is a need to find the cause and the source of an aesthetic nuisance, which may vary from smells of organic chemicals to dust pollution from limestone quarries.Each problem needs a different analytical approach, again accepting that analysis must start with efficiently controlled sampling. Water analysis continues in spite of the fact that routine work is dealt with by the Water Authorities. Investigations carried out include consumer complaints, routine Local Authority checks on fluoride content, farm supply problems and not least swimming bath waters. Our laboratory records include a case of a bathing costume bleached by swimming bath water! The latest aspect of environmental work is poisonous waste disposal. Waste disposal problems are not new to Public Analysts but the Deposit of Poisonous Waste Act 1972 gave powers to Local Authorities which, if they were to be administered satisfactorily, necessitated the seeking of advice from a chemist.Analytical chemistry is involved in the identification of wastes and requires knowledge of methods used in the analysis of many industrial materials. This work, too, is a response of analytical chemistry to a public demand. Some minor statutory duties of Local Authorities logically fit in with matters relating to food contamination and general environmental pollution. Regulations under the Consumer Protection Act impose legal controls on the metal content of paints on toys, on pencils and crayons, and on cooking utensils. I t is interesting to note that Monier WilliamslQ dealt comprehensively with some cooking utensils 40 years ago. The Trade Descriptions Act has posed some new analytical problems in consumer pro- tection work, although many aspects of it have been dealt with in the ancilliary work under- taken by Public Analysts.Samples vary from concrete, clothing, ants’ eggs, soil, petrol,lS oil, and even scientific help on the servicing of cars is requested. There are no routine methods for much of this work. Unlike the Food and Drugs Act and nearly all of its regulations, the Fertilisers and Feeding Stuffs Regulations give detailed sampling instructions and many analytical methods. Some of the original methods for determining oil, protein, fibre, nitrogen, phosphate and potassium are retained. Some have been brought up to date but, most important, certain other substances, if present, have to be declared and therefore fuller analysis may be required. These sub- stances include antibiotics, vitamins, minerals and a variety of coccidiostats and anti- blackhead drugs.Methods prescribed for many of these are largely based on work carried out by the Analytical Methods Committee of this Society. The above, however, omits the analytical work required in an examination for the presence of deleterious ingredients. The comparison between official policy on foods and drugs and on fertilisers and feedingstuffs raises interesting questions on the desirability of official analytical methods prescribed by law. I suspect that the law is too slow and inflexible for this purpose and some other means should be found. The use of official methods presupposes that a particular method has been tried for all conditions, which cannot be so and occasions will arise when the method will not be successful.The difficulties here are obvious if legal action is involved. The British Pharmacopoeia gives many analytical methods that are official, but the problem is rather different from that with animal foods. These considerations lead us back to other work on drugs. The drugs element of the Food and Drugs Act remains and has been mentioned earlier. Most Public Analysts undertake analyses for blood-alcohol and for other drugs such as cannabis, either in the capacity of a private consultant or on behalf of coroners or hospitals. These food impurities are also liable to be present in the general environment. Most Public Analysts are also appointed as official Agricultural Analysts.816 MARKLAND Having established a department of analytical chemistry in order to fulfil duties that directly concern the public, any efficient Local Authority must refer to such a department when the authority acts as a purchaser of goods for its numerous establishments.The duties are not only for quality control of purchases but also to give advice on specifications and suitability for the purpose envisaged. This function is only partly exercised if the authori- ties do not consult the department at the earliest possible stage. Nevertheless, the Local Authorities who do make use of these analytical departments will usually show some profit from it. Before leaving the subject of analysts in Local Authorities, it is well to consider where the analyst’s function begins and where it ends. I strongly hold the view that these functions include sampling, analysis and interpretation.To some this may seem a truism but Govern- ment and Local Authorities are large administrative units and the scientific element is small. There is a lack of true understanding, which can lead to the use of analysts simply for labora- tory testing. In describing the work of a Public Analyst, I have deliberately not subdivided it into separate sections under appropriate headings. Instead, my comments have ranged from one subject to another and back again in order to show a connecting thread between the various duties. Often the connection is not just within one field, such as food and drugs, but cuts across those departmental lines when the subject is one of a contaminant occurring in the whole environment, or even of a particular analytical technique.I can only deal with general principles as they apply to my work. The number of samples involved in any particular analysis may be small and so make instrumen- tation uneconomic, but if instruments are chosen carefully for general purposes it is surprising how versatile they can be made. Not infrequently classical methods are used when other operators would make use of mechanisation. There is a risk in forgetting the old methods. Sometimes a combination of old and new techniques gives the best result. In this sense, perhaps public service is of some benefit to the profession of analytical chemistry, There is no doubt that analytical chemistry has contributed a great deal to public service. I often wonder if the public or their representatives in public service are aware of this fact.1 hope they are, but fear they are not. Perhaps it is because analytical chemistry is so fascinating that we forget to communicate it to the public in terms that they can understand. Ultimate interpretation is often done by others, which must be wrong. Other chemists are concerned with methods of analysis. I recognise virtue in a wide variety of activities. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 16. 16. 17. 18. 19. REFERENCES Accum, F. C., “A Thesis on Adulteration of Food and Culinary Poisons,”‘London, 1820. Hassall, A. H., “Adulterations Detected in Foods and Medicines,” Second Edition, Longman Green, Bell, T., “The Chemistry of Foods,” South Kensington Museum Art Handbook, London, 1883. Dyer, B., and Mitchell, C. A., “Fifty Years of The Society of Public Analysts,” Heffer & Sons, Phillips, A. R., and Sanders, B. J . , J . Ass. Publ. Analysts, 1968, 6, 89. British Pharmacopoeia 1885, Spottiswoode & Co., London, 1885. British Pharmacopoeia 1973, H.M. Stationery Office, London, 1973. Winter Blyth, A, “Poisons, Their Effect and Detection,” Third Edition, Chas. Griffin & Co., IVanklyn, J. A., “Water Analysis,” Eighth Edition, Kegan Paul, Trench Triibner & Co., London, Frankland, E., “Water Analysis,” Second Edition, Gurney and Jackson, London, 1890. Melville, H., “The Department of Scientific and Industrial Research,” George Allen and Unwin Thorpe, T. E., “Tables showing Relation between Specific Gravity of Spirits at 60°/60 O F and the Analytical Methods Committee, Analyst, 1961, 86, 557. -, Ibid., 1963, 88, 422 and 583. -, Ibid., 1964, 89, 630. -, Ibid., 1965, 90, 256, 679 and 681. “The Separation and Identification of Food Colours Permitted by The Colouring Matters in Food “The Detection and Determination of Antioxidants in Food,” Special Report No. 1, Association Monier Williams, G. W., “Reports on Public Health Subjects,” No. 29, 1925, and No. 73, 1934, Longman & Roberts, London, 1861. Cambridge, 1932. . London, 1895. 1891. Ltd., London, 1962. Percentage of Alcohol by Weight and Volume,” H.M. Stationery Office, London, 1918. Regulations, 1957,” Association of Public Analysts, London, 1960. of Public Analysts, London, 1963. H.M. Stationery Office, London.

ISSN:0003-2654    

DOI:10.1039/AN9749900810

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

Analyst, December, 1974, Vol. 99, fifi. 817-823 81 7 PLENARY LECTURE Analytical Chemistry in Industry BY C . WHALLEY (Laporte Industries Limited, General Chemicals Division, Moorfield Road, Widnes, Lancashirc) I WAS greatly honoured to be asked to give this Plenary Lecture at the Centenary Celebrations of the Society with which I have been associated for many years. I should say first, however, that it was intended that the late Mr. A. G. Jones, a Past President and one of the Society’s Gold Medallists, who had spent all his working life in industry, should have given this lecture and it is very sad that he died and was not able to do so. So I came in essence as the twelfth man and I would like later to continue to develop this cricketing simile a little further. \Vhen I was asked to give the lecture I was not given a remit, so I set my own, which is as follows: “to outline the contribution made by analytical chemists employed in industry to the advancement of basic knowledge and techniques and to emphasise the significant part that they have played in the general progress of industrial manufacturing processes.” I have tried to cover both aspects of this remit by saying a little about the contributions made by analysts in industry to the general advancement of the science and then something of what that contribution has meant to the actual operation of industrial processes.I wish now to continue my cricketing simile because as I bat almost last I have had the opportunity of attending a number of papers and seeing many of my more important points brought out in those sessions dealing with training, management and technical matters.Therefore, I had to look critically at what there was left to say which was new. However, it is true that although the good men went in first and batted and made their good scores, the man who comes in last really can have a fling around at the ball and this is what I am going to do. Professor Irving, in his Centenary Lecture, mentioned the difficulties that he had found in obtaining information about contributions that have been made by analytical chemists employed in industry in the very early days of the Society of Public Analysts. He showed what I had intended to call a magnificent leather-bound volume from Laportes, but which I think had better be referred to as a rather tatty and decrepit leather-bound volume, and mentioned how there was very little work described in it that was actually carried out on the development of analytical methods.If one reads the book “The Practising Chemists,” one finds that papers that appeared in The A9zalyst listed as being of industrial application are very few. If you look at the Journal of the Society of Chemical Industry in the late 19th century, there are very few papers that relate to work done by analysts in industry, and this does bear out what Professor Irving said. However, there are some interesting historical papers connected with Laportes to which I would like to refer. They date from some of the very early records of one of our manu- facturing companies, Peter Spence and Sons, which was operating about 1840.The first of these is a print of a paper given to the Manchester Philosophic and Literary Society by Peter Spence in 1857 on “Coal, Smoke and Sewage Scientifically and Practically Considered.” In this paper, he talks about how the general cleaning up of the atmosphere in Manchester might be achieved on a grand scale. I am sure those interested in pollution will appreciate the significance of this being reported in 1857. Peter Spence made analyses of the stack gases emitted from chimneys and made calculations that led to the proposition that all of the effluent from coal-burning Manchester houses and factories should be channelled along one common duct to a chamber, where they would react with the sewage which would also be channelled from all of the houses in Manchester.The heat of the gases would cause the sewage to dry and the sulphur dioxide in the gas would react with the ammonia in the sewage. He then proposed a 3W-fOOt stack to take the excess gases away from the atmosphere and to utilise the solid residue that remained as fertiliser. There are some analytical data in this paper, but no record of how the analyses were carried out. @ SAC and the author.818 WHALLEY: ANALYTICAL CHEMISTRY [Analyst, Vol. 99 Another paper given by Peter Spence to the same Society in 1869 on “Sulphuric Acid in the Air of Manchester” shows that the chemical industry, even at that time, was very concerned about pollution. In this paper, Peter Spence mentions the analytical tests that he made.They were only very simple tests of exposing litmus papers for various periods of time in different areas of Manchester, but on this basis he made some assessment as to how the sulphur dioxide pollution was distributed. In his final summing up he says, “I am still continuing the exposure and shall probably, in addition to this, attempt to measure the actual quantity of SO, on some day when Smedley (where he lived) has the benefit of the fullest sweep of the Manchester atmosphere.” There was therefore some record of analytical work carried out at that time. There is one other paper I would mention, which again was given by Peter Spence to the same Society. It is a paper on “The Manufacture of Sulphide of Ammonia” and it states, “Hydrosulphuret of ammonia or sulphide of ammonia is at present chiefly used in the labora- tory where it is a very useful 1-eagent for metallic and other analyses.It has often been thought it might be more extensively used if it could be made cheaply and of good quality.” He then describes how it would be made and then comes to a point which I think is a possible reason why much analytical data never reached the light of day at this time: “In communicating this plan to the Society I do it in the hope that it will be useful in the laboratories of those who produce some of their own reagents. The Society however must not give me too much credit for generosity for had I found a market for the article making it worth my while to make it largely, I should have held it secure by patent and would not be talking about it today.As it is not likely to receive this I make the gift to the Society for what it is worth. I have by this plan made the article to some extent for a London House and I have sent them some 30 to 40 carboys but the demand is only small and although they were highly satisfied with the quality they would not give me the price which I felt was satisfactory.” We might be saying this, I think, in the chemical industry today. I think this may account for some of the lack of information available at that time. Chemical manufacturers were reluctant to pass on information about their products and about what they did with their products, because of the business connotations applicable at the time. In some of the old Laporte record books I found one which was labelled “Analysis” and thought I had got a find, but it was not really a s valuable as I thought.I n it there were some cuttings that had obviously been taken from journals and I would refer to two or three of these for which I tried to find out the use to which they had been put. The first cutting was traced to an abstract in the Journal of the Society of Chemical Industry. It des- cribed a modified Kjeldahl apparatus for distillation of ammonia and was apparently used in the Spence laboratories about the turn of the century for determining ammonia in alum and other inorganic materials. The next cutting was more difficult, but I finally tracked it down to its use for the determination of ammonia in dilute aqueous solution. Finally, I traced the use of a third piece of apparatus, which was a kind of modified Dean and Stark in reverse, to the determination of boron by distillation.In fact, pieces of this apparatus were still in existence when I joined Laportes. In addition to description of these pieces of equipment I found one fascinating method that I could not resist describing. I t was a note about a method for the detection of free sulphuric acid in aluminium sulphate, and it gives the procedure in which the salt is added to a previously warmed mixture of two drops of Gurjum Balsam and 3 ml of acetic acid and warming. A bright blue colour for traces of acid or a dark blue colour in the case of larger amounts results. There was no comment as to whether this was a worthwhile method or whether it had been used or not.However, at least someone had tried this method about the turn of the century. There was also described in this book on analysis an account of a visit paid by the man who wrote it to one of the laboratories of a large dyestuffs manufacturer in Blackley on the occasion of the visit of the Society of Chemical Industry to Manchester for its annual meeting in 1897. In this description various comparisons are made, pointing out that the equipment in these laboratories was far ahead of that used for the same analysis in the writer’s laboratory and I presume, although it was not stated, that this large dyestuffs manufacturer in Blackley would be the forerunner of what eventually became ICI Dyestuffs Division. There was some interesting information about the equipment that was in the laboratories.December, 19741 I N INDUSTRY 819 I have said a little about one of the reasons why I think that in the early days the analytical chemists in industry did not make, or did not appear to make, a very important contribution.There was not a great deal of innovation and at this period there was not even a great deal of development of methods that had been proposed from other sources. In order to explain this, I think we have to look at what the r81e of the analyst was at that time, particularly in the chemical industry and, I think, possibly in other industries also. I believe the rale of the analyst then, and I call him the analyst rather than the analytical chemist, was circumscribed somewhat rigidly and could be given as follows: ( i ) to provide control measurement, which was the shift chemist’s job and a shift chemist activity; (ii) to be responsible for product acceptability, in other words to ensure that the material being manufactured was of satisfactory quality; (iii) to ensure adequate control of raw materials supplies, that is, to make sure that the starting materials were right; and (iv) to keep the processes working at maximum efficiency.Now, these criteria have not changed much today in the chemical industry and they are still the important areas that the analytical chemist must control. The result, however, is achieved in a different way now, but there is no doubt that control was the main job of the analyst and that there was no question of his trying out methods or looking at instruments, etc.This was the job he had to do and I think this may account for some of the reluctance or possible difficulties of management in our industry at that time to allow development or research work to be carried out on analytical methods. I would like now to progress to the 193040 era, which is the time that I started to become interested in analytical chemistry myself, both at University and subsequently in employment in industry. There was still, even at this later date, some slowness in the publication of analytical papers from industry. If one examines the American journal Industrial and Engineering Chemistry, which, if anything, ought to be industrially biased, few such industrial analytical papers are found. In fact, when the “Analytical Edition” was first published in 1929, it was published only four times a year and in the first two issues of that journal there were only six papers from industrial companies. Four of these papers dealt with viscosity and other physical properties of oils, so that even in the USA I think there was not much effort going into the development of analytical methods or the innovation of new ones by industrial laboratories.Most of the papers that were appearing in the Analytical Edition were coming from institutions and Universities. Professor Belcher said early in the first Plenary Lecture that in England there was not the same opportunity for analytical chemists in the Universities to play a similar part to their counterparts in the USA, and this is supporting evidence.Professor Belcher also mentioned Dr. T. B. Smith, who wrote an excellent book on analytical processes, which really was the very first and most readable and interesting book dealing with the applications of physical chemistry to analytical processes. I studied analyti- cal chemistry under Dr. T. B. Smith and we had to learn this book almost backwards. Professor Belcher also mentioned T. B. Smith and the experiments he used to do. Now, T. B. Smith had a certain reputation as a Lecturer in Sheffield University and it was almost always very difficult to gain much useful information from his lectures. He used to have the work-bench covered with experiments and flap around them. None of them ever worked or at least they only partially worked and therefore, although he was undoubtedly an analytical chemist of some considerable acumen and foresight, particularly in the applications that he described and about which he wrote, I think the President and myself are the only two of his students who actually became practising analytical chemists.After this period, I took my first post in metallurgical analysis and at that time we were beginning to receive the impact of contributions from industrial analytical chemists working out modifications to standard volumetric methods in particular. Mr. B. Bagshawe, one of the Society for Analytical Chemistry’s Gold Medallists, was responsible for many innovations in volumetric methods for the analysis of steel and similar compounds and, in my first employment, we used to use many of his methods, which were described as “Bagshawe’s methods.” Similarly, other chemists were making appreciable contributions to progress in what I would call a development of “neo-classical” methods, In Teesside, H.N, Wilson, the first Society for Analytical Chemistry Gold Medallist, was carrying out similar work on applying new ideas to the methods for the analysis of fertilisers, and I mention these two chemists as being typical of the individuals who made very great contributions a t this particular time. They were primarily interested in developing short-cut methods for820 WHALLEY : ANALYTICAL CHEMISTRY [Analyst, VOl. 99 obtaining answers quickly, because this speed was needed in order to achieve better control of processes. I can remember going to a steel laboratory for the first time and finding out that phos- phorus was determined by producing the yellow molybdophosphate precipitate, looking at it and assessing the phosphorus content by how yellow the precipitate was.Manganese was oxidised to permanganate and measured colorimetrically. Carbon was determined by a quick colorimetric method as well, and I think that in these days we would call these methods “guessometric.” When I started work, many of the analyses that we had to do were fairly difficult. Phosphorus was not an easy element to determine, nor was the determination of manganese by what we called the zinc oxide separation an easy procedure. However, there was a firm belief that the determination of carbon, which really consisted of placing drillings in a furnace, burning them and weighing the carbon dioxide produced, was the most difficult analysis of all.I well remember after I had done my stint on the “easier” determinations feeling particularly proud when the head of the laboratory was away and his deputy asked me to try carbon analysis. Two of us were employed on this analysis and one did the actual weighing of the absorption tubes while the other weighed the samples and stoked the furnaces. I was doing the latter, but I felt very proud to be asked to do it. The boss came back 2 days later, looked in the laboratory, called over his deputy and said, “what have you put him on carbOns for, I thought I told you before we must have good men on carbons-take him back,” but I went on to doing phosphorus and manganese and later to other analyses.Subse- quently, of course, I became involved with the development, as the President has said, of absorptiometric methods of analysis. This work, which was done under the direction of E. J. Vaughan by the President and by myself, had a great impact, first in the steel industry and later in other fields. In fact, the impact that the introduction of the Spekker absorptio- meter as an analytical instrument made was really very profound and went round England and round the world like wildfire. There was an immense proliferation of papers dealing with the absorptiometric determination of A in B, many of which came from industrial laboratories that were now starting to develop methods on a large scale. At the same time, we must not forget that there were other people working in industry on rather different analytical problems, and I would refer particularly to the work of Dr.K. C. Chirnside, another Society for Analytical Chemistry Gold Medallist. He worked on what I call the total analysis concept or the total problem concept : in other words, one should not be interested only in the amount of A in B, but in how A and B were distributed, how were they put together and what the effect of A was on B, i.e., solve the problem rather than determine simple analytical figures. Dr. Chirnside is another name from industry that we should add to those who have made a considerable contribution. We must now pass to the 1950-60 era, which I would call the “high days and holidays” of the development of analytical methods in industry.The immense growth and the utilisation of instrumentation that occurred in the 1950s and 1960s led to an increase in research activities within industry and in the build-up of analytical research laboratories generally. Professor Belcher mentioned that Universities at this time were not geared to doing some of this development work, which meant that analytical chemists in industry had to do it themselves. This naturally led to the build-up of analytical research groups in industry from which papers began to flow in an ever increasing stream. If we look at the number of graduates who have been employed in analytical research in the chemical industry] and I mention this because it is only the chemical industry for which I have figures and not the pharmaceutical industries] one can see what I mean.Taking 1945 as unity, for every graduate in 1945 there were five in 1950, twelve in 1955 and twenty in 1960, which was about the peak year. The numbers were maintained roughly at this level until about 1965 and then began to drop steadily in the 1970s. I shall talk a little about the reasons for this drop later, but it is the earlier figures that I want to emphasise first. This was the time when graduate chemists began to go in large numbers to work in analytical chemistry research in industry and it might be worth looking at what sort of work they were doing in such a research group. I would describe their activities as follows: (i) to develop methods to help research scientists in other disciplines to do their work better, i.e., to do support work for the research department generally; (ii) to make sure that all new products and processes are covered by appropriate control methods ; (iii) to up-date periodi- cally existing control methods, increasing efficiency in the light of new developments, newDecember, 19741 I N INDUSTRY 821 instrumentation, new publications, etc.; and (iv) to supplement customer service and process troubleshooting activities. All of these activities were carried on within the analytical research groups at this particular time and I myself had a group of about thirty people, and this was the sort of work that we used to do. In doing this, we believed that we were making a positive contribution to the running of the research department and to the better operation of the Company’s processes.The increase in these activities, however, led to the increase in specialisation in particular techniques and in particular instrumental operations, and led to the build-up within the analytical research group of the instrumental specialists. Some of these specialists, such as Dr. Willis and Dr. Dean from Imperial Chemical Industries, made very significant contributions to the progress of the science and to their techniques, but they never lost the outlook that they were part of an industrial team and that their specialisation was there to help the progress of the Company’s operations. hlr. G. E. Penketh, in his lecture in the Management Session, mentioned that the whole of the analytical activities should be directed to the business of the Company, and this is very true.There were, however, others that did not think in this way. They became what 1 would describe as techniques men, and became more interested in applying their particular techniques than solving the problem that existed, and this led to the build-up of compartments of specialists within the research and development group. Although I think these were the great years of analytical research in industry, the cloud, if I might call it that, was not far away. The sun was soon to be blackened slightly because there was a man called an accountant who, before very long, was going to exert very specific influences on research activities and analytical research activities in particular. Analytical instrumentation became increasingly expensive and industrial companies had more and more capital tied up in the analytical research groups or in process analysis and, to the accountant, capital tied up in this way was not very efficiently utilised.The return was nil and the write-off time far shorter than that for buildings or plant, and therefore to some extent I think analytical chemists in industry began to price themselves out of their own market and began to make themselves looked upon as something of a luxury. I think we had ourselves to blame in some way for this and for the fact that in a general research function analytical research was regarded as an overhead and, as a support function, contributed to it. We have heard a great deal in the course of this Symposium about analysis being a supporting activity for other branches of research and I think this also was one of the reasons why this cloud appeared.If we move from the late 1960s to the 1970s, the circumstances in industry changed considerably. We have had to learn to live with the accountant and to live with budgeting and with cost control in research techniques, and this applies in analytical techniques also. We have had to make a fairly drastic re-assessment of the part the analytical chemist has to play in the running of industrial processes. We have had to quantify more precisely the results of our work. We have had to change our ideas about being a primary support service. Although there must always be some element of support work within the framework of an analytical group in industry, this should not predominate.We have had to turn ourselves to quantify what we do and to justify our projects in ageneral research environment. I believe this has not been too bad an exercise, as one of the returns that has come from it is an increase in the status of the analytical chemist, certainly within the chemical industry. I think Mr. Penketh and Mr. Goulden in their talks in the Management Session were emphasising the same things as I am trying to emphasise now. We are able to put forward our projects in competition with the other research activities and to think out how we can make a positive contribution to the running of our affairs and to the running of our business. We can say this is a project which ought to be done; if we do it and are successful we are going to save the Company Ex.This will be either because the process will run more efficiently, or it is going to result in a better and more saleable product, or it is going to enable us to reduce the amount of labour in a particular situation. This change in emphasis means that we have changed the type of individual that we need to staff this new form of analytical research group. We are going to be much more concerned, I think, with processes and the operation of processes. We are going to participate in the operation of processes at a much earlier stage than we have done in the past and we are going to be planning our analytical work along with the other development of the process. We must not lose sight of the fact, however, that there must be some longer term non- committed work with which we ought to be concerned and thinking about within the frame-822 WHALLEY : ANALYTICAL CHEMISTRY [Analyst, VOl.99 work of the group, because this is one of the stimulating things we are able to offer to our staff. There must always be a place in industry for looking at something new and for bringing along some new technique and developing it, and we must have the flexibility of structure to allow us to do this. We have heard Mr. Greenfield talk about the plasma torch, which is a technique that is being developed primarily in an industrial laboratory and is the sort of work that is typical of what we wish to be able to do as well as the detailed quantified projects to which I have referred.Now, in industry, and in the chemical industry in particular, we are swinging over more to automation of analytical control, and by this I do not mean doing analytical chemistry automatically. To those of us concerned with the development of these control systems, to do analytical chemistry automatically is generally the last thing we attempt. We prefer to measure simple parameters during the running of the plant, and these must be parameters that can be measured easily and that can be used in order to control the running of the process. Only if there is no other way of obtaining the information we need do we turn to automatic chemistry. This means that we are looking for a different type of chemist within the analytical group, and this may have an impact upon educational institutions.There is one other area in which the analytical chemist in industry has a very positive rdle to play. This is in what I call the conservation activities, in the ambit of which we have to work. We have to work in conjunction with the Factory Inspectorate, with Local Authorities and with River Boards, and we have to be concerned very much about human safety. We must also be concerned about the disposal of our products or waste products in line with current legis- lation. This is an area in which I believe we as analytical chemists must take a more positive rale. I do not want to suggest that there is going to be another enormous dis- agreement between analytical chemists in industry and those in laboratories of the Govern- ment Chemist or other official bodies similar to that which occurred between the Public Analysts and the Government Chemist at the time of the founding of the Society. I do believe that there must be liaison between those of us in industry who are concerned with developing and progressing the analytical methods that are required and the political and public bodies whose requirements we in industry have to meet.This is happening, and we in our laboratories are liaising with authorities on the development methods for certain of our problems, and most industrial companies have such problems. We should eventually arrive at methods that will be satisfactory and meet all requirements. This is important because it is spelling out a new r61e for analytical chemists in industry and bringing them closer to the public authorities and official bodies.We are also going to liaise more with our friends in Universities, because much of the work that we in industry used to do can no longer be attempted. We must co-operate with the Universities and must put our problems to them and let them obtain the solutions for us. This consultation and co-operation has already shown satisfactory results and there are already Co-operative Awards in Pure Science and sponsored projects in analytical chemistry in the Universities. Professor Belcher referred to the build-up of expertise in University departments and their ability to tackle all types of problems, including the more specialised ones. I think that we inindustry shall make more use of this facility in the next 5 or 10 years.Now, I have covered a lot of ground in this paper and I have tried to show how the steady advancement of techniques and the development of analytical activities progressed in our industry and the increased importance of our profession in keeping the wheels of industry turning. We have had some set-backs and it would be idle to pretend that we have not, but I do not believe that the figures to which I referred earlier showing a decline in numbers mean that there is going to be no future or no place for the analytical chemist in our industry. I believe that we must maintain a flexibility of outlook and that this is critical. We must adapt ourselves to the changing needs that industry requires and we must maintain liaison with public bodies, public authorities and Universities. If we do this, I believe that when the Society for Analytical Chemistry comes to celebrate its 150th anniversary in 50 years time, there will be a lecturer speaking on behalf of industrial chemistry, He may be at present some young boy who will go and look at the Exhibition in the Science Museum and become interested in what analytical chemistry means and at a similar Conference will be showing the flag for us. We must advise our Company in the field of environmental control.December, 19741 I N INDUSTRY 823 We in industry are proud of the contribution that we have made to the progress of analytical chemistry in its widest sense. We are proud to be associated with our colleagues in academic institutions and public service in being members of this, our Learned Society. We are the “other analytical chemists,” if I might say so, of the original Society of Public Analysts and Other Analytical Chemists and we hope that we shall continue to play our part in the development of our Society. I conclude with these comments and hope that I have struck a note for the future.

ISSN:0003-2654    

DOI:10.1039/AN9749900817

出版商:RSC    

年代:1974

数据来源: RSC

摘要:

824 Analyst, December, 1974, Vol. 99, $9. 824-837 Bioavailability from Pharmaceutical Dosage Forms BY J. B. STENLAKE (Department of Pharmaceutical Chemistry, Univeyszty of Strathclyde, 204 George Street, Glasgow, G1 1XW) The last few years have witnessed a concentration of interest in the effectiveness of pharmaceutical dosage forms. This interest has arisen from a growing awareness that the efficacy of an otherwise acceptable drug can be severely affected by insufficient attention to the manner of its presentation for administration by different manufacturers. This has found expression in the concept of bioavailability. Strictly, bioavailability is only assessable in terms of availability of the drug substance a t the actual site of action. For various reasons, however, direct measurement of bioavailability is frequently not possible in human subjects. Its assessment, therefore, usually rests on the measurement of secondary parameters of which blood levels and urinary excretion data are the most common. The route of administration adopted for any drug depends on a com- bination of the clinical requirement, the physicochemical properties of the drug substance, and the extent to which these can be modified by formulation.Within the limitations imposed by such considerations, bioavailability de- pends principally on the skill of the formulator and his assessment of the physiological parameters that affect the absorption, transport, metabolism and excretion of the drug from the body. Once the product is formulated, standardisation of its production depends on the ability of the production pharmacist and his quality controller to specify and keep check on the parameters necessary to achieve uniformity from one batch to the next.Physiological factors, which affect blood levels and tissue availability of drug substances, are considered. These include plasma and tissue protein binding, cell binding, lipid deposition and metabolism, and assessment of the interplay between them. The physicochemical properties that affect their availability from oral dosage forms, aerosols and topical preparations are examined with particular reference to factors affecting rates of solution of substances with low water solubility. Crystallinity, polymorphism, particle size, wettability and ease of dissolution are examined from this point of view.USERS of the everlasting antimony pill of mediaeval times could have been in no doubt as to its clinical efficacy. Regurgitation along with the stomach contents that the pills had been sent to retch provided incontrovertible evidence of both bioavailability and clinical efficacy. Such demonstrable efficiency in any modern medicine would bring sheer joy to the clinical pharmacologist, whilst the economy of the process would surely gladden the heart of the conservationist. I do not need to remind you, however, that few of our modern medicines ever provide such clear-cut indications of clinical efficacy, or that, because of this, the term “bioavailability” has crept into use. It is relevant, therefore, to begin by examining the significance and limitations of the terms clinical efficacy and bioavailability.BIOAVAILABILITY-AN ESSENTIAL PARAMETER If we accept that clinical efficacy is the sine qua non of any modern medicine, as I think we do, then we should ask ourselves why other criteria for assessment of the effectiveness of medicines are necessary. Is the parameter bioavailability merely a substitute term for clinical efficacy, or does it have some special, different and perhaps complementary signifi- cance? Nobody doubts that the ultimate criterion is whether or not the patient benefits from treatment, and this applies irrespective of whether the medicine is prophylactic, palliative or actually curative. There are, however, two distinct sets of circumstances in which definitive criteria are essential.Thus, even when the observed clinical response provides clear evidence of the efficacy of the medicine, there are many other aspects of therapy that concern the physician. These aspects include assessment relative to other available treat- The first is a clinical set. @ SAC and the author.STENLAKE 825 ments, especially where medical contra-indications limit the choice of therapeutic agent, variability of response between patients owing to genetic or other effects, and drug inter- actions in circumstances where multiple therapy is essential to the continued welfare of the patient. Despite the many aids to precision now available, assessment of clinical efficacy is often still a matter for subjective judgment rather than precise measurement.The assess- ment of bioavailability, therefore, provides an additional parameter in the evaluation of particular treatments. Secondly, we have also become increasingly aware in recent years that the physician's problems are still further complicated by variations in the rate of release of the same drug from the same formulation, when prepared by different manufacturers, and even by the same manufacturer on successive occasions. Thus, Fraser and his co-workers' report substantial variation in dissolution profiles for eleven brands of Digoxin Tablets B.P., which correlate with the mean bioavailability (as expressed by the mean area under the serum concentration versus time graph). Similar conclusions can be drawn from our own (J. B. Stenlake and D. Watt, unpublished work) very much more extensive examination of 105 production batches manufactured by eighteen different companies in the United Kingdom during the period October 1972 to October 1973.Still further pharmaceutical problems of stability and availability are also created by the current vogue for extemporaneous addition of therapeutic agents to intravenous infusion fluids. All of these factors, therefore, combine to make the assessment of bioavailability an important parameter, not only in the control of drug therapy, but also in the standardisation of dosage forms. CONCEPTS AND CRITERIA OF RIOAVAILABILITY Various meanings can be attached to the term bioavailability. Unfortunately, like its counterpart, clinical efficacy, it is often not nearly so precise a term as many of its users would wish it to be.Although theoretically capable of precise definition, it is a parameter that is seldom capable of precise expression in quantitative terms. Ideally, by bioavailability we should strictly imply the amount of drug available at the actual site of action within a given period of time relative to its administration. In many instances, however, only the target organ is known and the precise site of physiological action is not fully identified. Even where particular target tissues, enzymes, invasive tissues or organisms can be identified, they may well not be localised, but scattered throughout the body. This is certainly the case with drugs designed to act on smooth or voluntary muscle, at the neuromuscular junction, at nerve synapses, and in the treatment of infections or invasive diseases, such as cancer.Even where the target organ or tissue is localised, as, for example, in thyrotoxicosis, bronchial asthma, heart disease and mental disorders, routine measurement to determine and control the levels of drug available are for the most part impracticable, if not impossible. Bioavailability can, therefore, be assessed only in terms of such secondary parameters as blood levels and urinary excretion kinetics-parameters which are more accessible and capable of measurement in the patient with the minimum of inconvenience and discomfort. Even this approach is only possible either in the course of clinical trials or, routinely, for small numbers of the more seriously ill patients for whom very precise control of drug therapy is essential, and then preferably restricted to a short period of adjustment at the commence- ment of therapy. For the vast majority of patients for whom precise dosage is a clinical necessity, however, and for the routine production of standardised products, suitably validated physicochemical evaluation methods must suffice.BLOOD LEVELS- The blood circulation is not only central to life support as the carrier of oxygen and nutrients, but is also the vehicle for conveying drugs to their site of action. This, together with the ease with which blood can be sampled, places measurement of blood levels and the half-life of drugs in a unique place in the assessment of bioavailability. From the andytical point of view, however, it must be remembered that blood concentrations of drugs are usually at the microgram, nanogram, or even picogram levels, and assays at the lower levels are subject to significant experimental error.Thus, to quote but one example, digoxin levels (of about 1 ng) measured by radioimmunoassay2 have an accuracy of only *lo per cent. Blood levels, also, are controlled by numerous factors, several of which are dynamic.826 STENLAKE BIOAVAILABILITY FROM [Amlyst, VOl. 99 Individual measurements of drug concentration, therefore, give only a somewhat imprecise record of bioavailability. A more accurate assessment of bioavailability can be obtained only by calculation of the area under the plasma concentration versus time graph plotted from successive measurements, standardised in terms of the patient’s body weight, according to the formula: Standard area = - c dt 75 0 in which W represents the patient’s body weight and c the concentration in pgml-1 h-1 or ng ml-1 h-1.Further, plasma volume is only about 2.9 litres, against a total soft tissue fluid volume of about 42 litres, which alone provides a potential driving force equivalent to a partition coefficient of 14 in favour of the tissues. The validity of such calculations can only be judged against clinical or clinical - bio- chemical criteria in those instances where the plasma itself is the target tissue, as, for example, blood glucose levels as a measure of the bioavailability of oral anti-diabetics. Thus, the study by Varley3 of the relative bioavailability of tolbutamide from two-tablet formulations showed a relative efficiency of 3-67, based on plasma tolbutamide levels, but a relative clinical efficiency of only 2.09, based on blood glucose measurements.Variability among patients, too, must always be kept in mind. For example, although a relatively constant relationship between the concentration in the plasma and the content of digoxin in the myocardium has been dem~nstrated,~ Coltart, Howard and Chamberlain5 have recently pointed out that there is a four-fold variation in this ratio between individuals. URINARY EXCRETION KINETICS- Measurement of urinary excretion rates can also be used to supply bioavailability data, which either supplements or complements blood-level studies. In contrast to sequential blood sampling, which is never pleasant for the patient, urine collection is usually much less disturbing, and apart from the inevitable time-lapse before excretion commences, periodic urine collection gives both a clear-cut measure of the variations in excretion rate with time and a precise measure of the percentage of the administered dose excreted by the kidney in any particular time period.Measurement of urinary excretion kinetics, therefore, affords a direct means of assessing the bioavailability of drugs acting directly on the kidneys or the urinary tract, or both. Thus, a direct measurement of the active-site drug concentrations available for the treatment of urinary tract infections is possible by microbiological assay. Similarly, the bioavailability of diuretics and drugs capable of affecting electrolyte balance through the excretion of sodium ions and water is capable of direct evaluation, as in the case of spironolactone.6 For drugs acting at other bodily sites, urinary excretion measurement merely represents a useful, indirect method of assessing the extent to which the drug has been absorbed.Urinary excretion rates are dependent on several factors; for instance, some 137 litres per day of plasma are filtered by the glomeruli in the kidneys. Plasma volume is maintained by tubular re-absorption, plus the normal daily fluid intake into the body of approximately 2-5 litres, which compensates for that lost by excretion via the urine (1500 ml), sweat (500 ml), faeces (100 ml) and via the lungs (400 ml). The total plasma volume of about 2.9 litres is, therefore, filtered and re-cycled some forty-seven times every 24 hours.In consequence, only those compounds with very high diffusion coefficients for re-absorption are retained at significantly high plasma levels for substantial periods of time, even when there is little or no diffusion into, and deposition in, other soft tissues. High lipid solubility, low water solubility and minimal metabolism resulting in more highly water-soluble metabolites, therefore, favour retention in the kidneys and the maintenance of high blood levels. High water solubility per se in some quaternary salts, or as a result of metabolism to glucuronides, sulphate esters and amino-acid conjugates, favours elimination and the rapid lowering of blood levels. PHYSIOLOGICAL FACTORS AFFECTING PLASMA LEVELS- Blood levels and the plasma half-life of drugs are affected by a large number of factors, some physiological, but mostly determined by the actual properties of the drug substance itself and the dosage form.Fig. 1 is an attempt to illustrate the interplay and extent ofDecember, 19741 PHARMACEUTICAL DOSAGE FORMS 827 interaction of the more important physiological and metabolic factors involved. From this diagram, it is evident that, setting aside for the moment the physical and other factors that affect absorption and urinary excretion, blood levels are determined mainly by : distribution of the drug between plasma and blood cells; protein binding of the drug in the plasma and muscles; metabolism; and deposition in fat of the drug.Blood Route of administration Urinary excretion Faecal excretion Fig. 1. Interaction of physiological and metabolic factors involved in drug assimilation, distribution and excretion Cell deposition- Some limited idea of the quantitative aspects of deposition in cells can be derived from the knowledge that the total blood volume in a normal adult man (weight 70 kg) is about 5 litres, of which only 2.9 litres consist of plasma, the remaining 2.1 litres consisting of blood cells. The cell membranes are lipid in c.haracter and semi-permeable and most lipid-soluble, neutral drugs, undissociated acids and un-ionised bases pass readily into the cells and reach concentrations that are in equilibrium with the free (unbound) drug in the plasma. Thus, 40 per cent. of the blood radioactivity from the antithyroid drug [35S]-methimazole (the plasma metabolite of carbimazole) is associated with the blood cells’ and a similar uptake of a number of other thioamide compounds has also been reported.8-11 The concentration and actual retention of some drugs in blood cells due to localised binding or metabolism has also been observed. Thus, sulphonamides have been found in blood cells several days after administration, at a time when they are no longer present in p l a ~ m a , ~ ~ . ~ ~ and the radioactive label from [2-14C]-methimazole, although not that from [S5S]-methimazole, shows a small, but distinct, concentration gradient in favour of the cells some 4 to 5 days after administration, indicative of drug metabolism.’4 In contrast, drugs such as carbenoxolone sodium, which are virtually 100 per cent.bound to plasma proteins, do not pass into the blood cells at all. Protein binding- Binding of drugs to plasma proteins markedly affects the amount of free drug available for equilibration with the rest of the system. Blood plasma normally contains on average about 6.72 g per 100 ml of protein, consisting of albumin (4.04 g per 100ml), globulins (2034g per 100ml) and fibrinogen (0.34g per 100ml) (Table I). Drugs are bound mainly to albumin, usually by processes that are relatively non-specific and readily reversible. Often, other plasma protein fractions are also involved, as with dicoumarol (Table 11),16828 Protein Albumin .. Globulins- a1 . . .. or, - - Y * . .. . . B - - .. Fibrinogen .. STENLAKE : BIOAVAILABILITY FROM TABLE I HUMAN PLASMA PROTEINS Normal concentration/ g per 100 ml of plasma .. 4-04 .. .. .. .. .. 0.3 1 0.48 0.81 0-74 - 2.34 0-34 - Total 6-72 [Afialyst, VOl. 99 Isoelectric point (approximate) 4.9 6.2 4.9 6.4 t o 6.8 6.8 to 8.2 6-2 whilst a number of steroid hormones, notably oestradiol,lg testosterone'' and hydrocortisonela~ls are specifically and preferentially bound to particular globulin fractions. Albumin, the principal binding protein, has an isoelectric point of about 4.9 and hence carries a net negative charge. It is, however, amphoteric at physiological pH (7.4) and is capable of binding both acidic and basic drugs.20 Neutral compounds, such as steroids, are also bound and examination of the solubilities of testosterone and methyltestosterone in model systems, such as the octapeptide angiotensin I1 amide and its constituent amino-acids, shows that both hydrophobic bonding and hydrogen bonding to individual amino-acids is involved (Table 111) .21 Thus, the significant increase in AGO values and association constants with temperature between 4 and 37 "C for the interactions of methyltestosterone with iso- leucine and valine indicates involvement of these amino-acid residues of the peptide in hydro- phobic bonding.Similarly, the extensive binding of methyltestosterone to tyrosine (as ethyl ester hydrochloride), and the fall in both A G O and the association constant with rise in temperature between 4 and 37 "C, is indicative of hydrogen bonding. Hydrophobic bonding also plays quite a significant r61e in the binding of acidic and basic drugs, including barbi- turates,Z2 penicillins23 and chlorpromazine.24 TABLE I1 BINDING OF DICOUMAROL TO PLASMA PROTEINS Protein fraction Dicoumarol bound to protein, per cent.(0-5 per cent. solution) Albumin .. . . .. . . 99 ,%Globulin . . . . . . . . 20 y-Globulin . . . . . . . . 20 OH OH D icou m aro I Reversible binding is a function of free drug concentration, taking the form of the Langmuir absorption isotherm, so that with rising drug concentration the protein approaches saturation. Thus, phenylbutazone, which has a pK, of 4.4 and hence is 99 per cent. ionised at pH 7.4, is bound to the extent of 98 per cent. at therapeutic levels (10 mg per 100 ml). At supratherapeutic levels, however, the fraction of total drug bound decreases as the protein approaches its saturation point (Table IV).Thus, a 2.5-fold increase in the total loading produces a fifteen-fold increase in the free drug concentration. Similar large changes in the free drug concentration can also occur as a result of drug displacement. In this respect, the dangers arising from the sudden enhancement of free plasma levels of anticoagulants (nicoumalone and warfarin) and oral antidiabetics (acetohexamide, chlorpropamide and tolbutamide) following treatment with aspirin, phenylbutazone, ibufenac, flufenamic acid and other strongly acidic anti-inflammatory drugs are well known. In contrast, changes in the total drug concentration of relatively weakly bound drugs,December, 19741 PHARMACEUTICAL DOSAGE FORMS TABLE 111 ASSOCIATION FREE ENERGY (AGO) AND APPARENT ASSOCIATION CONSTANTS (KB) FOR CONSTITUENT AMINO-ACIDS~' INTERACTION OF METHYLTESTOSTERONE WITH ANGIOTENSIN 11 AMIDE AND ITS 829 Solute Angiotensin I1 amide .. . . Arginine . . . . . . . . Proline . . . . . . . . Aspartic acid . . . . . . Histidine . . . . . . . . Isoleucine . . . . . . .. Phenylalanine . . . . .. Valine . . .. . . . . Tyrosine (as ethyl ester hydrochloride) Ko ( r l ) - 4 "C 37 "C . . 200 1600 . . 7.0 4.7 . . 8-4 3.5 . . 14 12 . . 6.8 8.8 . . 4.2 17 . . 14 8.8 . . 5.6 14 .. 214 55 AGO (kcal mol-I) & 4 "C 37 "C - 2.92 - 4-65 - 1.08 - 0.95 - 1.17 - 0.77 - 1.45 - 1.63 - 1.06 - 1.34 - 0.79 - 1-75 - 1.46 - 1.34 - 0.95 - 1.63 - 2.95 - 2.47 such as digoxin, which is only about 35 per cent.bound, produce changes in the free drug concentration that much more nearly parallel the change in total concentration. I t follows, therefore, that drug displacement of more weakly bound drugs such as digoxin by other drugs is unlikely to precipitate a sudden change in its bioavailability. Few substances that are used as medicines actually bind to plasma proteins by covalent bond formation. Aspirin, however, has been shown to acetylate human serum albumin and fibrinogen both in vitro and in v i m , with an uptake by albumin of one acetyl group per mole.25 A permanent increase in the binding of acetrizoic acid following therapy with aspirin has been demonstrated,26 indicating that a fundamental change has occurred in the properties of the protein as a result of combination with aspirin.TABLE IV BINDING OF PHENYLBUTAZONE TO HUMAN PLASMA PROTEINS AT THERAPEUTIC AND SUPRATHERAPEUTIC LEVELS Phenylbutazone concentrationsfmg per 100 ml f L > Fraction bound, Total Bound Unbound per cent. 10 9.8 0.2 98 15 14.5 2.0 96.6 22.5 20.5 2.0 01.8 25 22 3.0 89 Muscle protein, which accounts for some 30 kg of the total body weight in a normal adult, also foms an important natural dep6t site for some drugs. Thus, the long period (7 to 14 days) required to stabilise patients on digoxin therapy is due to extensive deposition of the drug in skeletal muscle protein in addition to heart muscle. Thus, Coltart, Howard and Chamberlain6 reported mean concentrations and standard deviations of 1.2 & 0.8 ng ml-1, 11.3 & 4.9 ng g-l and 77.7 43.3 ng g-l for plasma, skeletal muscle and cardiac muscle, respectively.General diffusion into muscle and other proteinaceous organs, together with fat deposition, clearly plays a very significant r61e in drug bioavailability, but as yet there are few other examples in which this factor has been assessed, other than by general drug distribution studies. Drug metabolism- Metabolic degradation in plasma itself is largely confined to hydrolysis of esters by plasma esterases. Circulating plasma concentrations of drugs, however, are also lowered by oxidative, hydrolytic and conjugative metabolism in the liver, thereby hastening excretion via the bile and gastro-intestinal tract, and via the kidney. With bile secretion at the normal rate of about 700 to 1200 ml day1, compared with a blood plasma volume of 2.9 litres, and the relatively slow passage of food through the gastro-intestinal tract, faecal elimination of absorbed drugs is often low and somewhat delayed compared with their much more rapid elimination by other routes (kidney and lungs).Drug metabolism rates vary enormously from compound to compound and, to a lesser but significant extent, from one patient to another. The rates are affected by numerous factors, including the age and sex of the patient,830 STENLAKE : BIOAVAILABILITY FROM [Analyst, VOl. 99 diet, and co-medication with potentiators such as phenobarbitone, which cause an increase in liver weight and hence in drug-metabolising tissue. Some compounds, notably esters like suxamethonium and urethanes (e.g., carbimazole) are metabolised so rapidly that little, if any, of the parent drug remains within minutes of reaching the blood stream.Others, including more stable quaternary compounds such as tubocurarine, are almost unaffected and are usually excreted unchanged. Isotope methods, which are widely used in metabolism and other phannacokinetic studies, are not entirely free from pitfalls. Not only must the isotope be in a biologically stable position, but the method of synthesis must also be free from ambiguity. Thus, it has been revealed that small amounts of 17-isoaldosterone in labelled aldosterone, used for the measurement of aldosterone secretion rates, give rise to erroneous results because of differences in the whole-body distribution of the two isomer^.^^^^ Thus, C-3 deuteration of N-methyl- diazepam reduces C-3 hydroxylation in the liver.Accumulation of its hydroxylated meta- bolite, oxazepam, in the brain is, therefore, reduced and its anticonvulsant effect (in mice) shortened from about 20 down to 5 hours.29 However, where the isotope is not placed in a metabolically critical position in the molecule, there is little evidence of any isotope effect in whole-body experiments. Nevertheless there are several examples on record of isotope effects leading to erroneous results, owing to unanticipated partitioning on columns and with other separation techniques.aOJ1 Fat deposition- Fatty tissues account for some 15 to 20 per cent. of body weight in the normal adult, but in obese individuals this can rise to as much as 50 per cent.The brain, spinal cord and nervous tissue together account for only about 1.6 kg of phospholipid tissue, whereas even in the average, lean 70-kg adult, something like 10 kg of other fatty tissue is present. Nervous tissue consists mainly of phospholipids. Other fatty tissues are mainly composed of tri- glycerides, together with small amounts of cholesterol fatty-acid esters. Neutral drugs with a high lipid solubility, e.g., general anaesthetics, for which the tissues of the central nervous system have a high affinity, are therefore also extensively deposited in body fat. The intra- venous anaesthetic thiopentone, which is almost instantaneous in its effect, is also slowly and steadily taken up by body fats, reaching a maximum concentration of some ten times the plasma concentration at about 3 hours after administration when levels in other tissues are falling rapidly.32 This factor accounts for the short duration of sleep, for the cumulative effects seen if dosage is repeated at a time when fat concentration is still high, and also for the persistent somnolence seen in some persons during the recovery period. Similarly, use of the X-ray contrast medium iophendylate in myelography is a result of the affinity which this long-chain fatty acid derivative has for the lipid tissues of the central nervous system.Pharmacokinetics- This paper is merely an attempt to identify the physiological factors involved in drug absorption and distribution. The interplay of such factors is complex, and it can only be determined by detailed analysis of pharmacokinetic data.This analysis calls for the con- struction of mathematical models33 that fit the data and, whenever possible, testing the validity of the model against further data so as to establish “goodness of fit.” PHYSICAL FACTORS AFFECTING BIOAVAILABILITY FROM ORAL DOSAGE FORMS The physical properties of the drug, the characteristics of the dosage form and the route of administration are three inter-related factors, which influence the rate of uptake of the drug by the blood. The route of administration is largely determined by clinical require- ments, but it may also be conditioned by the physical and chemical properties of the medica- ment. Intravenous injection is usually the preferred route where rapid systemic action is required, and is essential if the patient is unconscious.The medicament, however, must be water soluble in order to aid preparation of low-volume injection solutions. Less soluble compounds can be incorporated in large-volume intravenous infusions for administration by drip-feed injection, provided there is no incompatibility with the other constituents. Water solubility is less important in oral medicines, although a certain minimal water solubility is essential in all orally administered drugs that are required to act outside the gass tro-in testinal tract . Kinetic isotope effects also cannot be neglected.December, 19741 PHARMACEUTICAL DOSAGE FORMS 831 LIPID DIFFUSION- Uptake from the gastro-intestinal tract into the blood is by passive diffusion, according to Fick's law.The rate of absorption is, therefore, determined not merely by the concen- tration gradient, but also by the diffusion constant. This constant is dependent on a number of factors, including relative molecular mass, lipid solubility and steric configuration, and, if the drug is capable of ionisation, its pK,. Only neutral molecules readily penetrate bio- logical membranes. Diffusion into the blood stream of salts of acids and bases, therefore, depends on the lipid-solubility of the un-ionised acid or base and the degree of dissociation in the stomach (or intestine) and the plasma.34 Dissolution- Although adequate lipid solubility characteristics are essential for diffusion from the gastro-intestinal tract into the blood stream, water solubility in the gastro-intestinal tract is also an essential component of the transport factor, which can, if sufficiently low, be rate-limiting.Absorption must, therefore, be regarded as a two-step process in which dissolution becomes the rate-limiting step when it is the slower of the two. Aqueous GI medium Lipid membrane Drug Drug solution (aqueous) N Drug solution (plasma) k l k 2 There is abundant evidence of poor or slow absorption characteristics in a variety of medicaments, all of which have low water solubility in common. These include, among others, iopanoic acid,35 spironolactone,6 grise~fulvin,~~ phenylb~tazone,~~ t~lbutamide,~ p h e n y t ~ i n , ~ . ~ ~ nitrofurantoin40 and d i g ~ x i n . ~ ~ The solubility of a particular compound is a function of its solid-state characteristics.Fundamentally, this is dependent on two factors, lattice energy, which is a function of crystal packing, and solvation of the dissolved molecules or ions. Melting characteristics relate to crystal packing, and for this reason the melting-points of a group of chemically related compounds often parallel their solubilities (Table V). Compounds that are in the amorphous state might be expected to dissolve more readily than crystalline materials, as amorphous solids are not subject to the strong cohesive forces that exist between molecules in a closely packed crystal lattice. However, even when active ingredients are readily obtainable in an amorphous form, this is not always the more stable form, and reversion to a less soluble crystalline form could well occur in uivo, either prior to, or in parallel with, absorption.Thus, novobiocin, which is available in an amorphous form, is metastable in aqueous suspension and reverts to a crystalline form from which it is less readily available. The usual solid-state form of novobiocin calcium, on the other hand, is stable and therefore preferable in solid dosage products.42 TABLE V MELTING-POINTS AND AQUEOUS SOLUBILITIES OF SOME SULPHONAMIDES Sulphonamide Melting-point/"C Solubility in water (approximate) Sulphanilamide . . .. . . 165 to 186.5 1 in 170 Sulphamethoxypyridazirie . . 182 t o 183 1 in 700 Sulphapyridine . . . . . . 191 to 193 1 in 3000 Succinylsulphathiazole . . 192 to 195 1 in 5000 Sulphafurazole . . . . . . 195 to 198 1 in 7000 Sulphadiazine .. . . . . 252 to 250 1 in 13 000 POLYMORPHISM- The solubility of crystalline materials is dependent on crystal form and habit, and numerous examples of solubility differences due to polymorphism, including cortisone a ~ e t a t e , ~ ~ . ~ ~ s~lphathiazole,~~ sulphametho~ydiazine,~~ chloramphenic01~~~~~ and cephalori- dine,47 have been recorded. In general, the lower the thermodynamic activity of the polymorph, the lower is its apparent solubility and the slower its ab~orption.~~ Thus, the two chlor- amphenicol palmitate polymorphs, which differ in solution free energy (AG3,.J by some 774 cal mol-l, show a ten-fold difference in absorption rate.49 On the other hand, the sulpha- methoxydiazine (sulphametic) polymorph 11, which has a solution free energy ( AGao.J greater832 STENLAKE : BIOAVAILABILITY FROM [Analyst, VOl.99 than that of its less soluble polymorph I11 by 291 cal mol-1, has an absorption rate only 1.4 times that of polymorph III.46s50 Similarly, mefenamic acid polymorphs, which differ in solution free energy by 251 cal mol-l, show only small differences in their absorption rates.51 Cephale~in,~~ ~ephaloridine~~ and certain of the cortisone acetate p ~ l y m o r p h s ~ ~ ~ ~ ~ are really pseudopolymorphs, in which lattice strain arising from the inclusion of crystallisation solvents (water, methanol and ethanol) leads to enhanced solubility. This effect illustrates the need to standardise crystallisation solvents in the preparation of medicaments with poor water-solubility that are used in low doses in situations where dose levels are critical, as for example, digoxin, and oestrogens in oral contraceptive pills.SPECIFIC SURFACE AREA AND PARTICLE SIZE- Other important determinants of solution rate are specific surface area, often expressed in terms of particle size and wettability. A reduction in particle size, which increases the surface area exposed to the solvent, has been shown to increase the solubility in water and hence the absorption of a number of important medicaments. Thus, Duncan, MacDonald and Thorntonb4 have shown (Table VI) that doses of 0.6g of griseofulvin of surface area 0-35 m2 g-1 give blood concentrations in human subjects similar to those given by doses of 0-25 g of griseofulvin of surface area 1.5 m2 gl. Similarly, recent studies by Shaw, Carless, TABLE VI EFFECT OF SURFACE AREA OF GRISEOFULVIN PARTICLES ON ABSORPTION IN HUMAN VOLUNTEERS Surface Blood levels Formulation Dose area/ma g1 (0 to 49 h)/pg ml-1 h-1 Suspension .... 0.6 0.36 17 0.25 1.6 13.4 Tablets . . .. .. 0.6 0.36 20.8 0.26 1.6 17'2 Howard and Raymond55 have confirmed that particle size is an important factor in controlling plasma levels of digoxin administered in cachets. The rate of aqueous dissolution over a 2-hour period was some three times faster with powder of mean particle diameter 3.7 pm than with that of mean diameter 22 pm, and mean plasma digoxin levels in eight patients treated with a single daily dose for 1 week were 31 per cent. higher with 3-7 pm diameter powder compared with 22-pm diameter powder. It is perhaps significant that a ninth patient on the 3.7-pm diameter powder developed digoxin toxicity.Mean plasma - digoxin levels following single doses of 0.5 mg of digoxin of differing particle sizes are shown in Fig. 2. E 8 h Time after dose/h Fig. 2. Effect of particle size on solution rate of digoxin.6b Values in pm are mean particle diameters. (From T. R. D. Shaw, J. E. Carless, M. R. Howard and K. Raymond, Lancet, 1973, ii, 209)December, 19741 PHARMACEUTICAL DOSAGE FORMS 833 There is now some evidence to suggest that the method by which size reduction is achieved is also important. The usual method is milling, either alone or in admixture with a solid diluent. X-ray and other studies on digoxin before and after grinding56 indicate that control of particle size alone is not enough.Dissolution profiles (Fig. 3) show the appearance of a freely soluble, amorphous layer on the crystals, which is rapidly removed after about 30 minutes in the dissolution medium. Thereafter, the rate of solution decreases sharply as the remaining crystalline material dissolves much more slowly. This view is substantiated by the formation of an essentially amorphous product on ball-milling a micronised sample of digoxin for 5 hours. A comparison of milled and unmilled samples by X-ray diffraction shows differences that may be accounted for by differences in grain size or in crystallinity. Infrared spectra show the growth of a band of 1780 cm-1 on grinding (Fig. 4). The melting behaviour of digoxin samples also differs markedly, and samples that dissolve rapidly tend to have lower melting- points (Table VII). Differential thermal analysis traces of ground samples also show endo- thermic phase transitions at about 170 O C , well below the melting-points, which are not given by underground material and which could be accounted for by the presence of amorphous material (Fig.5 ) . T 5 8 k 4 7 a ; 3 0 7 .- w T ? 2 : ' .- 8 C .- .- n 0 20 40 60 80 100 120 140 160 180 Time/minutes 2000 1600 1200 Frequency, cm-' Fig. 3. Dissolution profiles of various samples of digoxin. Dissolution of digoxin samples (25 mg) into 250 ml of 0.006 per cent. polysorbate 80 stirred a t 37 & 0.2 "C. Closed symbols represent mortar-ground samples and open symbols Fig. 4. Infrared spec- original samples. 0, ., British Chemical Reference Sub- tra of milled (B) and stance; 0, 0, Swiss Standard (Courtin & Warner); A, A, unmilled (A) samples of Swiss micronised (ground) (Sandoz, through Courtin & digoxin Warner) Precipitation oi insoluble acids and bases from their water-soluble 'salts in a finely divided amorphous form offers an alternative method for the preparation of products with improved dissolution and bioavailability characteristics.Studies on the relative bioavail- ability of iopanoic acid, precipitated in vivo from sodium iopanate and from the crystalline TABLE VII MELTING-POINTS, EQUILIBRIUM SOLUBILITIES AND INITIAL SOLUTION RATES OF DIGOXIN SAMYLES~~ Sample Solubilityt/ Initial solution rates:/ Melting-point*/"C mg per 100 ml mg per 100 ml per minute British standard .. . . . . 235.5 British chemical reference standard 241 Swiss standard . . . . . . 228-5 Swiss standard, mortar ground . . - Swiss standard, micronised . . - . . 5.4 4.35 6 - 7 6 7.0 - 0.11 0.018 0.078 0.18 0.185 From differential scanning calorimetry traces. f Solubility after 6 days. 1 Rates of solution of 26 mg of digoxin in 250 ml of 0.006 per cent. of polysorbate 80 a t 37 "C between t = 0 and t = 10 minutes.834 STENLAKE BIOAVAILABILITY FROM [Analyst, Vol. 99 acid,35 have already shown that precipitation of an insoluble acid (or base) in a finely divided (amorphous) form from its more soluble salt in situ (by the action of gastric secretion in the gastro-intestinal tract itself) is a viable method of enhancing bioavailability. It is evident, therefore, that control of the pH of dissolution test media to something approaching gastric or intestinal conditions, or both, can also be an important factor in measurements of bio- availability from water-soluble salts if they are liable to precipitate an insoluble acid or base in vivo .Temperature/"C (rise of 5 "C min-1) Fig. 6. Differential thermal analysis of ground samples of digoxin : A, British Chemical Reference Standard (unground) ; B, Swiss micronised sample (ground); and C, British Chemical Reference Standard (ground) Liophilisation of solids from solution, which is used extensively in the preparation of powders intended for re-solution and injection, offers a further alternative method for the preparation of more readily soluble fonns of drugs, with an enhanced surface area for the incorporation of solid dosage forms.As has been commented elsewhere, however, particle- size measurements of powders prepared in this way are unlikely to offer a realistic means of assessing the increased solubility that is attained. The measurement of specific surface area is much more likely to be significant. The importance of specific surface area is also effectively demonstrated in a totally different way by the enhanced bioavailability of griseo- fulvin from a micronised oil in water emulsion compared with an oily or aqueous suspension.67 Mean plasma antibiotic levels are obtained that are some 1.5 to 2.3 times higher with the emulsion than from the suspension, with a 2.5-fold increase in bioavailability, as demonstrated by the area under the plasma concentration versus time graph.WETTABILITY- The dissolution rate of relatively insoluble substances can also be enhanced by the action of surface-active agents, such as sodium lauryl sulphate and polysorbates. Formulation with sodium lauryl sulphate is just as effective as reduction of particle size in enhancing the release of griseofulvin from tablets and increasing plasma levels in human subjecks8 Similarly, incorporation, of polysorbate 80 into spironolactone tablets gave a four-fold enhancement of peak plasma levekS BIOAVAILABILITY FROM CAPSULES AND COATED TABLETS Only somewhat limited studies of the factors affecting the release of drugs from capsules appear to have been made. The additional factor in bioavailability from soft capsules clearly resides in the properties of the capsule shell.Type B gelatin is mainly used for this purpose, and gel strength and pH are the most critical factors affecting release rates. Pepsin has little effect on fresh capsules, but it can hasten release from capsules that have been stored for substantial periods of time. Of the additives studied, the most pronounced effects on dissolution, and hence presumably, bioavailability, are shown by the salts of organic bases and organic acids.59December, 19741 PHARMACEUTICAL DOSAGE FORMS 835 BIOAVAILABILITY FROM AEROSOLS AND INHALANT CARTRIDGES Drugs administered by inhalation are primarily intended to have a direct effect in the lungs. A considerable proportion of the administered dose, however, is caught in the mouth and upper airway passages and is absorbed directly therefrom.One method of measuring the proportion of the administered dose actually penetrating the lungs is based on a com- parison of urinary excretion results for the same dose administered by inhalation and by intravenous injection.60,61 Thus, Cox et aL61 have calculated that only 8.2 per cent. of sodium chromoglycate administered from a spinhaler actually reaches the lungs, and is absorbed systemically. Much of the product is, therefore, deposited in the adaptor, the mouth, throat and trachea, from which it is not absorbed owing to tlie physicochemical characteristics of the material. In practice, however, it is usual to assess airway penetration by use of a compartment alised glass or plastic simulated lung apparatus, several of which have been described,61,62 which is coated internally with a suitable gel to trap the drug particles.The major physicochemical parameter of products administered from cartridge powder impellers is particle size. Theoretically, the smaller the particle size, the more effective is lung penetration, as larger particles are readily trapped in the mouth and upper airway passages. For aerosol suspensions, both droplet size and the particle size of the suspended solid are similarly important. A lower limit to particle size would seem to be desirable for all solid active ingredients that are administered by inhalation, because particles of less than 3 pm in diameter are more prone to aggregation due to electrostatic attraction. Bioavailability is also very much affected by the characteristics of the device and the mouth adaptor.BIOAVAILABILITY FROM TOPICAL PREPARATIONS DERMATOLOGICAL PREPARATIONS- The majority of factors affecting bioavailability from dermatological preparations are well known. The r81e of the vehicle in determining the extent of skin penetration has been clearly e~tablished.~~ Essentially, vehicles based on triglyceride fats and oils are more suited to ensure skin penetration of lipid-soluble medicaments than paraffin hydrocarbons whilst hydrophilic bases and aqueous creams assist absorption of water-soluble compounds. For example, a base from which fluocinolone acetonide is readily released and is clinically effective has been shown markedly to impair the release of the corresponding acetate, fluo~inonide.~~ Skin permeability is also favoured by the use of vehicles incorporating non-ionic surfactants, due to their effects on membrane structure.65 Irrespective of whether or not penetration of the skin is required, the bioavailability of insoluble medicaments is largely dependent on physical factors similar to those which influence the absorption of orally administered medicines.Solid-state characteristics generally are important, and extensive studies, particularly of corticosteroid preparations, have clearly established the importance of particle size. OPHTHALMIC PRODUCTS- Factors that influence the absorption of drugs through the cornea, including pH and isotonicity of solutions, and the hydrophilic and lipophilic characters of ointment bases, have been reviewed recently by Silvermamg6 In a recent work, Mikhelson, Chrai and Robinson67 have reviewed the factors affecting turnover, and drawn attention to effects that drug- protein binding in tears, cornea and aqueous humour can have on bioavailability.Protein levels, however, are lower by comparison with plasma (about 6.7 per cent.) in both lachrymal secretion (0-7 per cent., of which 0-4 per cent. consists of albumin) and aqueous humour (0.01 to 0-2 per cent. consisting of albumin, y-globulins and lysozyme). The total volume of eye fluids is also small, but turnover rates are significant. Only some 7 pl of lachrymal fluid is in contact with the cornea at any one time, and the volume of the aqueous humour is no more than 300 p1, while turnover rates are about 1 and 3 pl min-l, respectively, in the human eye.It has also been demonstrated in rabbitss8 that instilled solutions are rapidly drained from the eye, up to 50 per cent. of a FiO-pl drop being lost within 30 s, and over 80 per cent. within 3 to 4 minutes. With such high turnover rates, initial, but reversible, protein- binding could be a significant factor in drug retention and availability. 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ISSN:0003-2654    

DOI:10.1039/AN9749900824

出版商:RSC    

年代:1974

数据来源: RSC