ISSN:0003-2654    

DOI:10.1039/AN99621FX041

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

GEOANALYSIS 97 3rd International Conference on the Analysis of Geological and Environmental Materials 1-5 June 1997 Vail Cascade Hotel & Club, Vail, Colorado USA The 3rd International Symposium on the Analysis of Geological and Environmental Materials will be held in the Colorado Rockies. The meeting provides an opportunity for analytical chemists, spectroscopists, and hydrologists working in the geosciences to: (1) share specifics of their analytical techniques with others in their field, (2) explore measurement problems that currently limit usehlness of their data in specific studies, and (3) learn more about the geoscience research applications of their data. topical geoscience investigations that make use of the analytical data rather than around individual analytical techniques.The focus of contributed papers should be the analytical methods themselves, any measurement problems that recently have been or still need to be solved to make the data most suitable for use, and procedures used to assure data quality. of analytical chemistry: Most sessions are being organized around the Contributed papers include the following areas Technical Sessions Poster Sessions Analyses supporting: > Geostandards > Climate Change Studies P Quality Assurance/ > Environmental Monitoring Quality Control + Mine-site Reclamation > Sampling > Mineral Exploration *Analyses using: > Ore Genesis NAA + Geochronology ICP-MS P Petrogenesis XRF > Elemental Speciation ICP-AES + Aqueous Geochemistry Microprobe Specialty Methods For information, please contact the General Chair: Belinda Arbogast, U.S.Geological Survey, Federal Center, Box 25046, MS 973, Denver, CO 80225 e-mail: geo97@helios.cr.usgs.gov Tel.: 303-236-2495 Fax: 303-236-3200 Participation in the symposium is open to analysts and laboratory managers in all fields of the geosciences, and to other interested scientists who use analytical laboratory data routinelyin perfbrmingtheirown investigations.Theq$tmtio~ fee will cover the Ml cost of attendance, including sessions and special events, coffee breaks, meals and l+ng, Book o Abstracts, and the symposium proceedings volume to be published as a special issue of TheAnalyst. Response Card Please send me hture announcements and informa- tion about the GEOANALYSIS 97 Symposium. Name: 0 rgan iza t io n : Address: Postal Country: Code: Tel.: Fax: k-mail: +ti+ Current Sponsors +t+ Sustaining Sponsor: Contributors: ACTLABS, INC.ENVIRONMENTAL RESOURCE ASSOCIATES GEOANALYSIS 94 ORGANIZING COMMITTEE Organized and Cosponsored by the United States Geological SurveyGEOANALYSIS 97 3rd International Conference on the Analysis of Geological and Environmental Materials 1-5 June 1997 Vail Cascade Hotel & Club, Vail, Colorado USA The 3rd International Symposium on the Analysis of Geological and Environmental Materials will be held in the Colorado Rockies. The meeting provides an opportunity for analytical chemists, spectroscopists, and hydrologists working in the geosciences to: (1) share specifics of their analytical techniques with others in their field, (2) explore measurement problems that currently limit usehlness of their data in specific studies, and (3) learn more about the geoscience research applications of their data.topical geoscience investigations that make use of the analytical data rather than around individual analytical techniques. The focus of contributed papers should be the analytical methods themselves, any measurement problems that recently have been or still need to be solved to make the data most suitable for use, and procedures used to assure data quality. of analytical chemistry: Most sessions are being organized around the Contributed papers include the following areas Technical Sessions Poster Sessions Analyses supporting: > Geostandards > Climate Change Studies P Quality Assurance/ > Environmental Monitoring Quality Control + Mine-site Reclamation > Sampling > Mineral Exploration *Analyses using: > Ore Genesis NAA + Geochronology ICP-MS P Petrogenesis XRF > Elemental Speciation ICP-AES + Aqueous Geochemistry Microprobe Specialty Methods For information, please contact the General Chair: Belinda Arbogast, U.S.Geological Survey, Federal Center, Box 25046, MS 973, Denver, CO 80225 e-mail: geo97@helios.cr.usgs.gov Tel.: 303-236-2495 Fax: 303-236-3200 Participation in the symposium is open to analysts and laboratory managers in all fields of the geosciences, and to other interested scientists who use analytical laboratory data routinelyin perfbrmingtheirown investigations.Theq$tmtio~ fee will cover the Ml cost of attendance, including sessions and special events, coffee breaks, meals and l+ng, Book o Abstracts, and the symposium proceedings volume to be published as a special issue of TheAnalyst.Response Card Please send me hture announcements and informa- tion about the GEOANALYSIS 97 Symposium. Name: 0 rgan iza t io n : Address: Postal Country: Code: Tel.: Fax: k-mail: +ti+ Current Sponsors +t+ Sustaining Sponsor: Contributors: ACTLABS, INC. ENVIRONMENTAL RESOURCE ASSOCIATES GEOANALYSIS 94 ORGANIZING COMMITTEE Organized and Cosponsored by the United States Geological SurveyGEOANALYSIS 97 3rd International Conference on the Analysis of Geological and Environmental Materials 1-5 June 1997 Vail Cascade Hotel & Club, Vail, Colorado USA The 3rd International Symposium on the Analysis of Geological and Environmental Materials will be held in the Colorado Rockies.The meeting provides an opportunity for analytical chemists, spectroscopists, and hydrologists working in the geosciences to: (1) share specifics of their analytical techniques with others in their field, (2) explore measurement problems that currently limit usehlness of their data in specific studies, and (3) learn more about the geoscience research applications of their data. topical geoscience investigations that make use of the analytical data rather than around individual analytical techniques. The focus of contributed papers should be the analytical methods themselves, any measurement problems that recently have been or still need to be solved to make the data most suitable for use, and procedures used to assure data quality.of analytical chemistry: Most sessions are being organized around the Contributed papers include the following areas Technical Sessions Poster Sessions Analyses supporting: > Geostandards > Climate Change Studies P Quality Assurance/ > Environmental Monitoring Quality Control + Mine-site Reclamation > Sampling > Mineral Exploration *Analyses using: > Ore Genesis NAA + Geochronology ICP-MS P Petrogenesis XRF > Elemental Speciation ICP-AES + Aqueous Geochemistry Microprobe Specialty Methods For information, please contact the General Chair: Belinda Arbogast, U.S. Geological Survey, Federal Center, Box 25046, MS 973, Denver, CO 80225 e-mail: geo97@helios.cr.usgs.gov Tel.: 303-236-2495 Fax: 303-236-3200 Participation in the symposium is open to analysts and laboratory managers in all fields of the geosciences, and to other interested scientists who use analytical laboratory data routinelyin perfbrmingtheirown investigations.Theq$tmtio~ fee will cover the Ml cost of attendance, including sessions and special events, coffee breaks, meals and l+ng, Book o Abstracts, and the symposium proceedings volume to be published as a special issue of TheAnalyst.Response Card Please send me hture announcements and informa- tion about the GEOANALYSIS 97 Symposium. Name: 0 rgan iza t io n : Address: Postal Country: Code: Tel.: Fax: k-mail: +ti+ Current Sponsors +t+ Sustaining Sponsor: Contributors: ACTLABS, INC. ENVIRONMENTAL RESOURCE ASSOCIATES GEOANALYSIS 94 ORGANIZING COMMITTEE Organized and Cosponsored by the United States Geological SurveyGEOANALYSIS 97 3rd International Conference on the Analysis of Geological and Environmental Materials 1-5 June 1997 Vail Cascade Hotel & Club, Vail, Colorado USA The 3rd International Symposium on the Analysis of Geological and Environmental Materials will be held in the Colorado Rockies.The meeting provides an opportunity for analytical chemists, spectroscopists, and hydrologists working in the geosciences to: (1) share specifics of their analytical techniques with others in their field, (2) explore measurement problems that currently limit usehlness of their data in specific studies, and (3) learn more about the geoscience research applications of their data.topical geoscience investigations that make use of the analytical data rather than around individual analytical techniques. The focus of contributed papers should be the analytical methods themselves, any measurement problems that recently have been or still need to be solved to make the data most suitable for use, and procedures used to assure data quality. of analytical chemistry: Most sessions are being organized around the Contributed papers include the following areas Technical Sessions Poster Sessions Analyses supporting: > Geostandards > Climate Change Studies P Quality Assurance/ > Environmental Monitoring Quality Control + Mine-site Reclamation > Sampling > Mineral Exploration *Analyses using: > Ore Genesis NAA + Geochronology ICP-MS P Petrogenesis XRF > Elemental Speciation ICP-AES + Aqueous Geochemistry Microprobe Specialty Methods For information, please contact the General Chair: Belinda Arbogast, U.S. Geological Survey, Federal Center, Box 25046, MS 973, Denver, CO 80225 e-mail: geo97@helios.cr.usgs.gov Tel.: 303-236-2495 Fax: 303-236-3200 Participation in the symposium is open to analysts and laboratory managers in all fields of the geosciences, and to other interested scientists who use analytical laboratory data routinelyin perfbrmingtheirown investigations.Theq$tmtio~ fee will cover the Ml cost of attendance, including sessions and special events, coffee breaks, meals and l+ng, Book o Abstracts, and the symposium proceedings volume to be published as a special issue of TheAnalyst. Response Card Please send me hture announcements and informa- tion about the GEOANALYSIS 97 Symposium. Name: 0 rgan iza t io n : Address: Postal Country: Code: Tel.: Fax: k-mail: +ti+ Current Sponsors +t+ Sustaining Sponsor: Contributors: ACTLABS, INC. ENVIRONMENTAL RESOURCE ASSOCIATES GEOANALYSIS 94 ORGANIZING COMMITTEE Organized and Cosponsored by the United States Geological Survey

ISSN:0003-2654    

DOI:10.1039/AN996210X043

出版商:RSC    

年代:1996

数据来源: RSC

ISSN:0003-2654    

DOI:10.1039/AN99621BX047

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Analyst, October- 1996, Vol. 121 (9/K-IOOK) 9lR Analytical Challenges in the Development of Modified-release Oral Solid Dosage Forms A Review Michael J. Bowker Analytical Cheniistw Department, RhBne-Poulenc Roru Ltd., Du~qridzam, Esw-t-, UK RMIO 7XS Summary of Contents In trod-uct i on and Definitions Scope Analytical Involvement in the Development Process for Modified-release Dosage Forms Product Concept Preformulat ion Studies Formulation Development Studies and Design of the Tablet Core Establishment of the Need for a Film-coat and Optimization of the Coating Level to Achieve the Required Release Rate Formulation Development Studies Leading to a Pelleted Product Probe Stability Studies and Establishment of the Preliminary S he1 f- 1 i fe Specifications Scale-up Studies and Production of the Validation Batches Stability Studies on the Validation Batches Technology Transfer to Quality Control Post-approval Studies Conclusions References Keywords: Modified, delayed, prolonged and extended release; tablets; pellets and c.apsrtles; dissolution testing; I-eiyiew Introduction and Definitions Modified-release oral solid dosage forms encompass a wide range of types of pharmaceutical finished products with different types of drug-release mechanisms.Over the past 30 years, there has been a plethora of different names applied to such products in order to attempt classification of their release mechanisms. As often happens in such situations, different names have been adopted in different countries and confusion abounds. Within Europe, there have been proposals in a guideline by the Committee on Proprietary Medicinal Products to define the categories of ‘Modified Release’ in two main groups: ‘Delayed Release’ and ‘Prolonged Release’.At the draft guideline stage, it was originally proposed to sub-divide the latter further into ‘Slow Release’ and ‘Extended Release.’ However, as this was resisted by a significant body of opinion in the pharmaceutical industry, this attempt at further sub-division was abandoned in the final guideline. In 1984, the United States Pharinacopeial Convention revised2 its published definition of Modified-Release dosage forms, Extended-Release dosage forms and Delayed-Release dosage forms in the Pharmacopeial Forum. It has recently3 again revised its definition of an Extended-Release dosage form.In 1092, a working party co-ordinated by the Italian Association of Industrial Pharmacists published proposals for guidelines on modified release doyage forms.4 These proposals also included definitions. Surprisingly, there are no definitions of these types of dosage forms in the Japanese Pharmaco- poeia. ( I ) Definitions proposed by the CPMP Working Party on Quality of Medicinal Products: Modfied Release-‘This term is defined in the European Pharmacopoeia as a modification of the rate or place at which active ingredient is released. Modified release products cover a wide range of rdease models, the principal types of which would include “delayed release” and “prolonged relea4e” products. ’ Deluyed Releus-‘ A modified release product i n which the release of active substance is delayed for a finite “lag time,’‘ after which release is unhindered (e.g., enteric coated or ‘&gastro resistant” (Ph.Eur.) oral tablets or capsules which remain intact in the stomach and only disintegrate in the higher pH of the small intestine. Delayed release rewlts in a longer t,,,,,, but with C,,,,, ’ and elimination half life unchanged.’ PI-olongcd Release---‘A product in which the rate of release of active substance from the formulation after admini5tration has been reduced. in order to maintain therapeutic activity, to reduce toxic effects, or for some other therapeutic purpose.’ (2) Definitions proposed by the Unitcd States Pharmacopeial Convention: Modified Releu.se2-‘Products for which the drug-relcasc characteristics of time cour\e and/or location are chosen to accomplish therapeutic objectives not offered by conventional dosage forms.’ Dcluyed Releuse2-‘Products that release a diw-ete por- tion(s) of drug at times other than promptly after administra- tion.’ Extended Releux-‘An extended-release dosage form is defined as one that allows a therapeutically beneficial reduction in dosing frequency.’ (3) Definitions proposed by a working party co-ordinated by the Italian Association of Industrial Pharmacists: Modified Release-’Modified releax pharmaceutical dosage forms are capable of modifying the rate, and/or the time and/or the location of drug release.They make it possible to achieve therapeutic objectives beyond the scope of conventional do\age forms administered viu the same route.’ Deluyed Release or Reputed Relcwse--‘Delayed- or re- peated-release dosage forms release the dose, or a portion (or portions) of the dose, at a time (or timeh) other than soon after administration.’ Extended Release or Pi-oloiiged Kclcuse-These forms release the active component from the formulation more slowly than does the corresponding conventional do\age form that is intended for the same route of administration. The prolonged- or The various definitions proposed are as follows: ~~ ~ ~- Incoriectly vtated i n the giudelines A\ T,,,,,.92R Airalyst, Oc.tohei- I996, Vol. 121 extended-release dosage form releases the drug at a given rate for a given time.’ Scope It is the author’s intention to focus on the two main categories of modified-release products and not to cover other forms, such as buccal or chewable products, even though many of the issues and principles raised may also need to be considered or addressed in the development of these specialized dosage forms.Over the past 25-30 years, there has been a wide coverage in the literature of different dissolution testing methodologies and strategies; it is proposed also not to focus specifically on these aspects. The reader is directed to three pivotal text books5 7 which give an excellent insight into the principles and practice of dissolution testing and stability enhancement. Those aspects involving dissolution testing which are not considered to be adequately addressed in the analytical and pharmaceutical literature, especially those with a significant analytical bias, will be discussed in this review.Analytical Involvement in the Development Process for Modified-release Dosage Forms There are normally several discrete phases in the development process; these can be conveniently classified into the following: (i) the product concept; (ii) preformulation studies; (iii) formulation development studies and design of the tablet core; (iv) establishment of the need for a film-coat and optimization of the coating level to achieve the required release rate; (17) formulation development studies leading to a pelleted product; (I?) probe stability studies and establishment of the preliminary shelf-life specifications; (Irii) scale-up studies and production of the validation batches; (Iyiii) stability studies on the validation batches; ( i - ~ ) technology transfer to quality control; and (1-) post- approval studies.Product Concept Many drug substances have pharmacokinetic or physico- chemical properties which make them inappropriate for the preparation of modified-release products. Cabana8 provided a rationale for the development of such dosage forms: (i) the toxicity and occurrence of adverse reactions is decreased; (ii) there is better control on the rate and site of release of the drug substance; (iii) there is a more uniform concentration in the blood due to the provision of a more predictable delivery of drug; (iv) such a form provides much greater convenience and/ or better patient compliance; (v) there is better utilization of drug. For the majority of drug substances intended for oral administration, an immediate release product is developed and marketed first.For a small percentage of these drug substances it may be considered more beneficial to develop and market a delayed-release (e.g., enteric-coated) product first. Either of these can then be followed some time later with the prolonged/ extended release form. The pharmacokinetic monitoring of human clinical trials conducted during the product development phase of the immediate release product generates a wealth of information and data on the fate of the drug substance and its metabolites. These data can often be used to judge approximately the likely theoretical in L ~ L W profile required and the dosage strength for the modified release form. In some cases.these data can be used directly to compute more accurately the required in viiw profile (and sometimes also the corresponding iFz t1iti-o profile). There are, however, very few examples of this latter approach to formulation design in the literature.’-17 In parallel with these considerations of the likely in vivo and in \it?-o characteristics, there should be a rapid evaluation of the various types of dosage form most suited to the drug substance, bearing in mind its physico-chemical characteristics. Will the required in iivo profile be best achieved by a simple or complex tablet or an encapsulated pelleted product‘? If it is a tablet, will it require film-coating or enteric-coating? It is here that the analyst may be expected to advise on issues such as: (i) What are the likely physico-chemical changes that the drug substance might undergo in the formulation? (ii) What will be the likely chemical stability of the drug substance in the formulation‘? (iii) Will there be any photo-instability problems for either the drug substance or any of the dyes which may be proposed for use in the film-coat (if a film-coat is necessary)? Preformulation Studies Preformulation studies are a combination of simple or short- term studies, often involving a high thermal, photochemical or mechanical stress. They are designed quickly to force changes that would otherwise be slow to appear. If an immediate-release dosage form has been previously developed to modem standards, then much information would already have been generated on the likely requirements for the particle size distribution of the drug substance and the basic physico- chemical and stability characteristics of the drug substance. l 4 This would include a full evaluation of the lability of the molecule to the various stresses outlined above and an in-depth study of the relative stabilities of any polymorphs which may have been previously discovered.If the drug substance was substantially amorphous, the potential for crystallization under compression, using pressures which are representative of those in a tabletting press or capsule filling machine, should also have been evaluated. If the immediate-release product was a simple capsule and a modified-release tablet is being considered, it may be advantageous to repeat part of the compression studies at significantly higher pressures.Relatively simple studies on many drug substances’s-32 have shown that mechanical stress such as compression, grinding or micronization can have a profound effect on the crystalline form of the drug substance, often resulting in a complete change of polymorphic state. Preformulation studies directed towards immediate-release and modified-release formulations are normally undertaken on binary or tertiary mixtures of the drug substance and a range of possible excipients that might be considered for use in the formulation. The aim of these screening studies is to permit the rapid identification of those excipients with which the drug substance is chemically or physically incompatible. This incompatibility can manifest itself as a significant chemical change (e.g..drug substance decomposition and loss of potency) or a significant physical change (e.g., a colour change, a polymorphism change or the formation of a eutectic mixture). Various approaches are undertaken within different organi- zations;33 some groups simply prepare 1 + 1 mixtures of the active ingredient as a loose, but uniform, powder, and store samples under a variety of accelerated conditions for periods which usually exceed 1 month. Others compress the mixtures using one or more different pressures in a tabletting press or 1R (potassium bromide) disk press normally used in TR spectrome- try and then store the pellet and/or loose compacts under a variety of conditions. The pivotal tests undertaken on these stored samples usually involve HPLC, for the detection of decomposition products, and an evaluation of more subtle physical changes using differential scanning calorimetry (DSC), occasionally reinforced by other thermal analytical techniques, such as thermogravimetric analysis (TGA) and hot- stage microscopy, and X-ray powder diffraction (XRPD).Analyst, 0ctolx)r- 1996, Vol.121 93R With these early studies using HPLC. it is normal to use only a partially validated method which is known to separate the major decomposition products formed during preliminary accelerated stress studies on the drug substance. Validation can be restricted to linearity of response for the drug substance and one or two major decomposition products, an assessment of the limit of quantification and an assessment of excipienl inter- ference.It is always advantageous to have samples of the stressed excipients as a method blank since they can occasion- ally be used to identify correctly spurious peaks on an HPLC trace. There are excellent texts available on the use of a wide range of techniques which are used in preforinulation and compatibil- ity studiesj4 and for the specific use of thermoanalytical techniques.3’ The results from DSC thermograms should be interpreted with care as there are a few excipients which invariably create a variety of changes to the thermogram of the drug substance. it is our experience that magnesium stearate, s t e a k acid and the various oligoniers of polyethylene glycol modify the thermograms of most candidate drug substances.With the frequency of changes seen with these three excipients, it might be expected that they would be rarely used. This is not the case, however, and many perfectly acceptable and stable oral solid dosage forms contain these excipients at low concentrations. We have also observed changes occasionally with various grades of polyvinylpyrrolidone, talc and colloidal silicon dioxide with some candidate drug substances. If these early studies show evidence of the formation of alternative polymorphs of the drug substance, that excipient should be abandoned or studied in much greater detail using a wider range of techniques such a s XRPD, isothermal calorimetry, intrinsic dissolution studies and IR and Raman spectrotnetry in order to confirm the observation.It is imperative that significant physical changes are detected at a very early stage to save the huge costs in time and money wasted and expensive clinical studies to be repeated. There are a few publications where different polymorphs have been detected well after develop- ment and stability studies have finished on those marketed products. ih-.iX Formulntion Development Studies and the Design of the Tablet Core Once the results from the preformulation studies have been assessed and the range of acceptable excipients agreed, it i s possible for the forniulation team to finalize their ideas for the proposed dosage form and present them to the marketing organization for prioritization and approval. For example, the product may be proposed as one of the many forins of prolonged-release tablets (swelling matrix, erodible matrix, tablet with rate controlling membrane, etc.) or it may be a simple tablet core coated with a membrane imparting delayed- release (gastro-resistant) properties.The expected dose(s) of the drug substance may limit the formulation team in their choice of formulation approach. Highly active (potent) drug substances will generally allow more freedom in the choice of dosage form since the ratio of excipients to drug substance will be high. This may allow the choice of excipients which are suitable for a direct compression producl since any adverse drug substance properties can be outweighed by the appropriate choice of excipients with very advantageous properties. As the potency reduces, generally, the amount of drug substance required per unit dose increases and any adverse physico-mechanical properties of the drug sub- stance may start to predominate.This gradually forces the formulation towards a granulated product (or a pelleted product). Eventually, a limit is reached where even pelletization becomes impossible owing to the restrictions on capsule volume unless multiple capsules are acceptable as a unit dose. When the finished dosage form is known and the range of excipients has been chosen, the analyst and the formulator together must consider the acceptability (or otherwise) of the excipient specifications. For many products, the different grades and sources may markedly affect the dissolution process. This is especially so for the polymeric excipients chosen for their rate-controlling properties.Generally, pharmacopoeia1 monographs are inadequate for full control and additional tests should be considered. These may measure directly, or indi- rectly, the molecular mass distribution, degree of cross-linking, crystallinity, particle size, moisture content, glass transition temperature, ctc. As different batches are used in development trials, many of the key properties of each excipient become apparent and a database of information is developed. It is becoming apparent that excipient ‘fingerprinting’ using NIR spectrometry will bc extremely useful to help define the boundaries between acceptable and unacceptable batches of excipient or sources of excipient, where they are available from more than one source.In modern processing equipment, the sampling of the intermediate powder blend or granule prior to compression into a tablet is often judged unnecessary and tablets are often compressed directly without this in-process control. For modern products, a specification needs to be established for the tablet core, even though it may be considered as an intermediate en route to the product intended for marketing. For the regulatory filing, the specification for the tablet cores would be expected to contain most of the following possible tests: appearance (general colour and shape; presence of breakline); key dimen- sions and column height; hardness; identity test for the active ingredient; average weight and/or uniformity of mass; assay and/or uniformity of content; impurities/decomposition prod- ucts; disintegration time (or a test for the absence of disintegra- tion, if appropriate); and dissolution rate.In many cases, it is advisable to monitor other parameters as ‘in-house tests’. Tests that may be considered in this category are friability; water (or solvent) content; and microbial contamination. Many of these are standard tests for the pharmaceutical analyst; requirements and specification limits for many of the tests are given in the British or United States Pharmacopoeias. It is important to monitor hardness (together with friability on occasions) especially when those products are intended for film- coating. It is also important to determine the uniformity of mass at the tablet core stage if the product is to be film-coated, since the film-coat applied may vary slightly from tablet to tablet and mass uniformity may otherwise be difficult to determine accurately later once the product has been coated.Prior to film- coating it is often useful to determine the dissolution rate, whether disintegration does or does not occur (it may be designed not to occur) and whether the assay and/or uniformity of content are correct. Products intended for sale in the European Community (EC) must comply with an assay limit of +S% of nominal, unless otherwise justified. The uniformity of content requirements for tablets intended for sale in the EC and the USA differ considerably. The EC requirement to undertake uniformity of content testing applies if the individual tablets contain 2 mg or less of drug substance or 2% m/m or less of drug substance.The requirement in the USA is invoked if the tablets contain 50 mg or less of drug substance. Undertaking a significant amount of testing on tablet cores before film-coating does often permit their recovery if any individual test result is outside specification. Recovery can often be achieved by grinding down the tablets back to a granular state. This is usually impossible if a film-coat has been applied (at considerable cost!). For the uncoated tablet cores, there must be a specification, for which the analyst must develop and validate the methodology to be used in the following specification tests: (i) identity; (ii) assay (drug substance content per tablet of average mass); (iii) uniformity ofcontent of i n d i \, id 11 a 1 t ii b 1 e t s : ( i 19) i in p u ri t i e s/decom po s it i on products; ( 1 9 ) the dissolution rate test conditions and the analytical method used for assessing the content and stability of drug substance released into the dissolution medium; and (vi) water (or solvent) content.I t is not the author’s intention to detail the means by which each of these tests can be validated since these are adequately addressed in many texts and i n a recent draft documentj9 arising through the International Conference on Harmonisation proc- ess. TI‘ the tablet is intended for film-coating, an extra dimension of complexity is added for the analyst, especially when the coating also is designed to modify the rate of‘ release of‘the drug substance in the dissolution test.EstablisIii?terzt of the Need j o r a Film-coat and Optimization of the Coating Level to Achieve the Required Release Hate Delayed release tablets are tlie simpler of the two forms as they are usually a relatively standardized tablet core which is coated with ;I game-resistant film-coat. Celliilose acetate phthalate is the mo\t frequently used film-coating agent; to aid the coating process and to yield a more durable tablet, a plasticizing additive is used. These additives arc norrnally phthalates or other polyerters and a coat mass adding approximately 2% m/m to the tablet mass is usually necessary to impart resistance to the acidic environment of the stomach. This level of coating is usually rapidly di\solved away in the more alkaline environ- ment of the large intestine, leaving the tablet to dicintegrate and the drug substance to diswlve prior to absorption through the intestine wa 11.The film coaling is frequently achieved using a mixture of organic solvents such as methanol and drchloromethane and the tablet is dried. Test\ for residual solvents40.4i and decomposi- tion products are iiwally undertaken as an in-proces\ control for t hi operat ion. Cellulo~e acctate phthalate may contain up to 3% (6% in the USA) of unreacted phthalic acid, which would be expected t o diswlve in ;i solvent for extraction of the drug substance from the matrix; the diethyl phthalate or other plasticim- alro may be soluble in the solvent used Ihr extraction of the drug substance and impurities from the matrix. Detail\ of studies using thin- layer chromatographic detection of some coiiinioii plasticizers have been publis1ied.J’ Unles\ additional validation is under- taken for thcce soluble excipients at an early \tage, there is a danger that they could be misinterpreted a s unidentified related substance\ of the drug substance.Obviously, they are best incorporated into one comprehensive method developmelit and validatioii programme once the core tablet and film-coating formulae are known. The detailed evaluation of a compre- hen,ice range of physical properties of coated tablets has been de\cribed.4 i-J‘’ The presence of ;I fi Im-coat also adds extra complications for the analyst who may wish to follow the RP method for grinding down ;I representative sample of 20 tablets and assaying a portion equivalent to the average mass of one tablet.It is almo\t impossible to grind down many of the film-coats to the same sizc range as that which can be achieved with the tablet corc. Significant errors are introduced into the sampling process if partially broken sheets of film-coat rernaiii in the powdered tablet mix. IJnder these circumstances, we adopt a procedure where 10 or 20 tablets are added to a large flask and allowed to disintegrate and dissolve in a large volume of extraction solvent . An identity tect is required for each of the colouring agents, including ‘TiO? used in the film-coating formulation. This identity test mu\t be validated for use on the finished product. Pro1 ong ed/e x t e nde d- re I e asc tab 1 e t \ in ay be con1 pre s sed di - rcctly from a mixture 01’ excipients ( c .~ . , cellulose derivatives) such that the tablet exerts its own rate controlling mechanism. During the formulation development phase. a range of tablet batches with different amounts of the main rate-controlling excipients can be prepared. Alternatively. for some products, it may be more appropriate to produce a range of tablet batches using different compression forces. These can be tested i n either dogs or human volunteers to determine the optimum formula- tion. The two common types are a swellable matrix and an erodible matrix. The former is the more popular and is based on the properties of certain cellulosic derivatives which can swell slowly in aqueous media. As it swells, micro-channels form in the matrix; the dissolution medium permeates these channels and dissolves the active ingredient.Erodible tablets are designed to disintegrate slowly. present- ing a constantly renewable surface to the dissolution mediuni. Generally, it is not necesw-y to film-coat these types of tablets with an additional rate-controlling membrane, although they may be coated with a rapidly dissolving film-coat to aid recognition, for marketing reasons, to reduce friability or to protect the product from photodecomposition. Analytical controls similar to those described earlier are usually sufficient for the analysis of these types of tablets. The specification for the dissolution test would be expected to comprise at least a three-point control which limits both rate and extent of release within a relatively narrow ‘window’ over the range 10-80% of the release.Limits are normally expected for both minimum and maximum amount released after 10-20% and 40-60% release. An additional control to limit only the minimum amount released is usually specified at 70-85% of nominal released. In setting these limits, it is standard practice to manufdcture a range of tablets with different release rates and to test these in dog\, together with the immediate release product to generate the pharmacokinetic profile of each product. Froin the range of dissolution data and their corresponding pharmacokinetic profiles, it is normally possible to choose at least three candidate formulations which may be expected to be: (i) slightly faster releasing than would normally be acceptable; (ii) the idcal release profile; and (iii) slightly slower releasing tlian would normally be acceptable.Typical dissolution profiles for the immediate-release prod- uct and tlie three experimental products, together with their corresponding typical pharmacokinetic profiles are given in Figs. 1 4 . 110 100 90 80 1 E 70 E $- 60 2 50 a, 40 h Q, v) - 30 20 10 0.0 / i t i / Fig. I Typical dissolution profile for an immediate-release product.These formulations should be fully characterked analytically and also evaluated in human volunteers. It is occasionally necessary to refine the formulations slightly on the basis of the human pharmacokinetic data obtained. Following these mod- ifications, additional clinical studies are normally necessary to confirm the profiles are optimized and the dissolution 'win- dows' must be set such that batches of tablets with unacceptable profiles are always excluded. These pharrriacokinetic evaluations should be augmented ideally by evaluations of how the optimized product releases in the presence of food, especially a meal with high fat content.This is necessary because of the dramatic changes in the pH of the stomach contents and the potential modification to the drug absorption process as a result of the fat content of digestive fluids. The determination of pH values, typical volumes of fluid ,0150 r -i .0140 ,0130 ,0120 ci I Y .0050 ,0040 ,0030 .0020 .0010 s \ i Ti m e/m i n Typical ill l-irw profile for an immediate-relcase pioduct. Fig. 2 110 r 100 90 80 - 701 E 30 20 10 A involved and average residence times in the various regions of the digestive tracl has been the subject of several publica- tions;"'- j7 typical ranges are given in Table I .Some 01' the potential interaction\ with food can be studied using isothermal m icrocal o rime t r y , fol1 ow i tip pu bl i ca t i on o f t he1 r in i t 1 a1 s t ud i es by Buckton and co-workers,5x-.50 or by other forms o i modcl- liiig.6O.h' Various workers and companies have also used gamma scintigraphy in order to probe the tran\it of a finished Fadiolabelled tablet down the intestinal tract.(12 O7 There i \ one additional type of study where the analy\t can make a significant coiitribution. A small number of controlled- release tablets have been de\igned with a breakline and, occasionally, there may be a need to 'blind' a competitor'\ product as a comparator product for use in a clinical trial.One common means of blinding the products is to encapsulate them in a strongly coloured capsule shell. Some tablet\ do not fit into a convenient sized capsule \hell and it has been the practicc to consider breaking the tablets in half. To stop the products rattling to difierent extents it may be nece\sary to con\ider filling the void remaining inside the capsule with an inert and rapidly dissolving agent. Lactose and inannitol are frequently used for this purpwe. The analyst should investigate the dissolution properties of half tablets in compariwn with the intact product.68 (jC) Data should be generated on the dissolution properties of' tablets with a breakline and on potential clinical comparators as half tablets.Formulation Development Studies Leading to a Pelleted Product The decision between the developrnent 01. the drug substance as a modified release tablet or as multiple units (pellets) is a difficult one. 'Tablets generally are cheaper to produce i n bulk ,0060 r .0010 1 p I Ti me/mi n Fig. 4 and C me as in Fig. 3. Typical 111 rV\v protiles for prolonged-release product\. whcre A, R, Table 1 Typical physiological environnients o.OL-Li-. I.. _ i - I I _ I L _ L . - L . _ J 0 0 0 0 0 0 0 0 0 0 0 0 0 o n J ! b c D c o o N d c D c o O N d c u F l * c O b " O r n g n J ~ ~ Timelm i n Fig. 3 Typical dissolution profiles for prolonged-release products, where product releasing at: A. upper range of acceptability; B, middle of range of acceptability: and C, lower range o f acceptability.Region pH Stomach 1.1-2 7 (facting) 1.1-3.5 (aftel food) 1.92 (men) 2.92 (women) 4.5-5.8 (after food) Small intestine 4.7-7.3 (fasting) Large inte\tinc 7.0-8.0 (tasting) A verdge re3 idence ti me /h 0.5 -0 75. 3 Illax. Vo I ume/ni 1 Mem SO Range 0 I80 ( f o r \olid\) (at ter tood) S--lOO max. 4.5-6 50.- I 0 0 tnax. 8-1 2 ' Defined as half of the time required for total discharge.96R Amlyst, Oc-tohci- 1996. Vol. 121 and can be coated, if required, with a high degree of confidence in currently available commercial coating equipment. Their ir? vivo performance, however, is sometimes erratic owing to differences in physiological factors from one patient to another.Pelleted products are generally more difficult to produce and they usually need to be coated. The pellets invariably require to be filled into capsules, although as a fairly recent innovation microcapsules may be tabletted70-7x by normal processer such as direct compression. The benefit of pelleted or micro- encapsulated products arises from there being normally at least 100 individual dosage units which can quickly spread through- out the gastrointestinal tract. The advantages of multiple unit delivery are discussed in excellent papers by Bechgaard,79 Bechgaard and Nielsenxo and Davis.67 The mechanisms by which various dosage forms, including pelleted products, are distributed throughout the gastrointestinal tract have been followed by radiolabelling57 and gamma scintigraphy.As may be -expected, depending on the drug substance and other excipients chosen, considerable differences in density can be achieved. The density and pellet size should be considered as important factors.xl.x’ There are two commonly adopted procedures for formulating pellets with modified-release prop- erties. For most of the products currently marketed, the pellet diameter is normally close to I mm. Pellets of this size can be conveniently manufactured directly by extrusion and spher- onization, then filled into capsules. In this process, a ‘wet mass’ is prepared with the drug substance evenly distributed at the required concentration and the ‘wet mass’ is extruded through a screen of the appropriate diameter (about 1 mm). The extrudate is chopped automatically to give cylinders with a length of approximately 1 mm and these are rolled whilst still damp until they are approximately spherical; the pellets are then dried.These pellets normally require coating with a rate controlling, insoluble membrane such as ethylcellulose or an acrylate derivative in conjunction with soluble component, such as hydroxypropylmethy Ice1 lulose. ‘The second commonly employed process involves spraying a solution or suspension of the drug substance. normally in combination with excipients. on to an inert core. The inert cores commonly used are confectionary-grade non-pareil seeds.xi By this procedure and with careful balancing of the spraying rate to the drying rate in the coating pan, the pellet is gradually built up to the required size range.Because there is disproportional build-up, it is usually necessary to sieve the product regularly to remove those pellets at (or above) the required size; the undersize pellets are returned to the coating pan for additional applications of coating. Alternatively, the cores may be rendered tacky by spraying with polyvinylpyrrolidone or shellac and the dry drug substance particles fed into the vessel at a rate such that they adhere to the core surface. By alternating the addition, a pellet is gradually built up. Because of the totally different mechanisms of production. the development studies, analytical controls and amount of involvement by the analyst differ considerably for these two processes. For the extrusion/spheronization/drying process, the unifor- mity of distribution of drug substance from pellet to pellet and within each pellet is virtually guaranteed; simple assays on both individual pellets and multiples of pellets from throughout the bulk should confirm this.It should be noted that the drug content should be 2-3% higher than theoretical if the pellets are to be coated. Depending on the lability of the drug substance, a determination of the content of degradation products and an assessment o f the polymorphic form of the drug substance would be expected to be considered, at least for the first few batches produced. Because the pellets are extruded from a ‘wet mass’ and dried, they normally have a rough surtxe texture, they are generally porous and have a partial honeycombe structure internally.The initial film-coating layers may be expected to be at least partially absorbed into the pores and surhce defects. As the pellets are rolled or tumbled in the coating apparatus or as they collide with each other in the fluid bed coater, the rougher edges and defects tend to be at least partially abraided, creating a new surface which may have a slightly lower level of coating at the end of the process. As the coating proceeds, the mass of coating applied can be calculated and occasionally confirmed by a determination of the mass increase; often it is necessary to use spectroscopy to determine indirectly the coat mass through the measurement of coat thickness. Samples should be taken at regular intervals, quickly dried to constant or equilibrium mass and tested for release rate.For in-process control purposes, it is useful to consider a set of conditions for the dissolution test which give results more rapidly than those which might be expected to be in the finished product specification. Additional samples should be examined by microscopy and/ or electron microscopy. As the coating procedure reaches the end-point in terms of assay and dissolution profile, smaller applications of film-coat, more frequent analytical in-process control checks and the use of the dissolution test intended for regulatory and quality control use are necessary. IJsing this process, it is possible to consider manuficturing several batches with slightly or significantly different dissolution profiles and blending them in appropriate proportions to give a final batch with exactly the required dissolution profile.Alternatively, it is possible to mix two or more batches with release maxima several hours apart to give a product which gives ‘pulsatile’ release.x3 Mixing different batches requires careful analytical study to ensure that there is the required number of pellets of each type in each capsule. In the alternative process, the diameter of the pellets is usually built up over several hours or days. After several applications of coating, the pellets should be dried to an appropriate water or residual solvent content before further coating is allowed to proceed. The outer surfaces of the pellets are usually more perfectly coatcd than those produced by extrusion/spheronization and it is more difficult to dry ade- quately the water or solvent from the interior if a thick layer of coating has been applied.As with the pellets produced by the extrusion/spheronization process. it is necessary to undertake frequent in-process controls on assay and dissolution rate. Because the rate of build-up varies from pellet to pellet, controls on the pellet dimensions are critical for this type of product. If the pellet build-up process involves spraying a suspension of drug particles, or if dry drug substance is fed into the coating apparatus. larger crystals of drug substance may not be bound into the growing surface. If this occurs, it is possible to create nuclei from these drug crystals, which are themselves capable of being coated. The pellets which are produced from a crystal seed have a much higher drug content but usually they have a significantly lower diameter. They can be easily removed by sieving before their size increases to a significant extent.By careful monitoring of pellet dimensions, drug content and residual water or solvent content at regular intervals, it is possible to create a batch with uniform appearance, size distribution, dissolution rate and drug content when sampled at the nominal content mass of the encapsulated product. If the pellets produced require additional film-coating, perhaps using an enteric coat, because the surface of the pellets is more uniform after build-up than by spheronization, the amount of coating required to give the required release characteristics is usually small. A coated, pelleted product gives the formulator ample opportunity to produce a range of small batches with different release characteristics if samples are reserved from the bulk after each application of film-coat.As with the tabletted products discussed earlier, it is possible to choose batches withAnalyst, October 1996, Vol. 121 97R appropriate dissolution profiles and evaluate their pharmaco- kinetic characteristics in animals or human volunteers. Even- tually a range of acceptable and unacceptable profiles can be obtained by evaluation in humans. The in ititro dissolution profiles from acceptable batches can then be used to establish an appropriate dissolution specification range for further batches. The pellets produced by either process are considered as an intermediate product and require full control testing.An appropriate regulatory specification must be established; it should contain most of the following tests: appearance of the pellets; typical size range; identity test for active ingredient; density of the pellets; assay; impurities/ decomposition products; and dissolution rate. As discussed previously for tablets, other parameters that may be considered as 'in-house' tests, and that may be usefully monitored, at least for the first few batches, are: water (or residual solvent) content; and microbial contamination. The pellets can then be filled into capsules for establishment of the finished product release specification which would be expec'ted to contain most of the following tests: appearance of capsule shell and contents; dimensions of the capsule; typical size range of the pellets; identity tests for the active ingredient and capsule colouring agents; density of the pellets; average mass and/or uniformity of content mass; assay and/or unifor- mity of content; impurities/decomposition products; disinte- gration time; dissolution rate; and water (or solvent) content.Microbial contamination may be monitored as an 'in-house' test. Validation requirements are the same as those for the methods used for the analysis of tablets. Probe Stability Studies and Establishment of the Preliminary Shelf-life Specifications Once the production of moderately large batches of tablet cores and coated tablets or pellets and encapsulated pellets has been achieved, their preliminary stability profiles should be deter- mined.Stability studies should incorporate the requirements of the recent ICH Guidelines.xs The stability parameters evaluated in these probe studies can range from an evaluation of changes likely to be observed in the results from the pivotal tests (appearance, disintegration, assay, decomposition products and dissolution rate) to a full evaluation of all probable specification tests and others that are likely to be stability-indicating. The objective of these probe stability studies is to confirm quickly that the formulation chosen is likely to be stable in the packaging intended for marketing before extensive resources are poured into the product to allow scale-up and the eventual transfer of the product to the manufacturing or industrialization group.Stability should be ensured also before major commitments are made for larger (Phase 111) clinical trials. Stability information generated in these early studies is also invaluable when used to establish the preliminary end of shelf-life specifications for the intermediates and finished products. Stability studies on these early batches should be continued for at least 12 months. There have been several reports in the literature of the types of changes which may be detected with enteric coated tablets,86>87 film-coated tablets,x6-x7 and pellets.g5,96 Also, over the last few years, it has been determined that some of the changes seen in the disintegration and dissolution characteris- tics of hard gelatin capsules may be due to cross-linking of gelatin by aldehyde~~7,')~ or, less frequently, by hydrogen bonding to colouring agents9X399 in the gelatin shell.HPLC,l~)O~lO' fluorimetricl02 and colorimetric microdiffusion methods103 are available, if required, for the determination of traces of formaldehyde and acetaldehyde in gelatin products. It is imperative that documented specifications are estab- lished before moving to the next phase where scale-up studies are initiated. Scale-up Studies and Production of the Validation Batches Once the product developed on a small scale has been demonstrated to be suitably stable for marketing, a larger-scale manufacturing process must be developed and validated. The scale-up studies involve the preparation of a small number of batches, typically for tablets, or a larger number of batches, typically for pellets.These studies usually initiate the handover of responsibility for manufacture to the manufacturing or industrial operations group and individuals from both develop- ment and industrial operations contribute usually to the manufacturing of these batches. This stage should also be the initiation of handover of analytical responsibility from develop- ment to QC personnel. The QC personnel should start to become involved in project meetings and planning at the start of scale-up studies and should ideally be prepared to contribute to any of the analytical methodology changes and decisions that are made. The scale-up studies themselves require extra vigilance on the part of the analyst, who should be prepared to test many samples, especially during the coating stages.Coating larger batches generally gives a more uniform coat to the products but balancing the drying as the coating progresses is often problematic in the early stages. As confidence is gained in the larger scale manufacture of the finished products, planning of the validation batches is usually initiated. The analyst contributes to the establishment of sampling protocols and final acceptance protocols for these validation studies. Also, at the stage immediately prior to the initiation of validation batch manufacture, the analyst should consider undertaking an in-depth evaluation of the validation that has been completed on the various analytical methods that have been developed. If additional validation is considered necessary, it should be completed and thoroughly documented as a new, comprehensive, validation report.If not already sent, copies of the methodology and validation reports should be given to QC personnel to contribute to their familiarization process. Once all the appropriate documentation (analytical metho- dology, testing protocols and stability protocols) is in place, the manufacture of the validation batches should commence. There are usually a minimum of three batches required, each involving different batches of drug substance. Consideration should be given also to using at least two different batches of each excipient. The purpose of the three-batch campaign is to confirm that the process can be operated on a large scale to manufacture batches within specification and with uniform properties.Each batch of intermediate tablet core or pellet and each batch of finished tablet or encapsulated pellets must be tested in full to the proposed specification. If all batches are satisfactory in all respects they can be forwarded for packag- ing. If the analytical testing on the validation batches indicates an unexpected result or a failure to meet the requirements of the proposed specification for any batch, the manufacture of a replacement batch must be planned whilst the cause of rejection or problem is investigated and fully documented. Stability Studies on the Validation Batches The three validation batches of each formulation should be submitted for stability evaluation in each of the packs intended for marketing.For tablets and capsules, these are normally a blister pack and a random pack such as a plastic or glass bottle. The protocol setting out the aims of the study, the packs andstorage conditions to be used and the criteria of stability to be evaluated should be issued before the study starts. The protocol should also specify what form of statistical evaluation will be used on the results in order to establish a meaningful shelf-life statement. The core conditions of temperatures and humidity are now storage conditions used but not in terms of the range of tests employed. It is normal to store production batches at the recommended maximum labelled temperature (25 f 2 "C and 60% RH k 5%) and only one other accelerated condition. Post-approval Studies specifiedx' at: 25 TL: 2 "C/60% RH k 5% (long-term testing); 40 k 2 "C/75% RH k 5% (accelerated testing). Where tl 'significant change' is seen during the first 6 months of storage at 40 k 2 "C/7S% RH k 5%, additional testing at an intermediate condition such as 30 k 2 "C/60%) KH k 5% is permitted.Obviously it is sensible to initiate storage on samples at this third temperatiire/humidity condition as a fall-back position in case unpredicted changes are detected. It is also advantageous to include storage of samples under a small range of other conditions. Typically, these would include 4-8 "C for the full duration of the \tudy and 40 "C/ambient RH and 45 or SO "C/ambient RH for a shorter duration (c.s.. 6-12 months maximum). The regulatory submission can proceed with a minimum of 12 months' data generated at 25 TL: 2 "C/60% RH k 5% and 6 months under the acceleratcd condition(s) for products prepared from previously unregistered drug substances. If the modified release product is a new dosage form (line extension) of an existing inimediate-release product or an alternative route of administration, it is possible to justify a reduction in storage time ( c .~ . , 6 months' data at 25 k 2 "C/60% RH k 5% and under the accelerated cotiditions) before the data can be submitted. When the stability data are collated, the assay results and the results from the evaluation of decomposition products and total impurities should be analysed statistically, preferably ufing a programme acceptable to the FDA.8' The stability data should also be used to finalke the shelf-life specifications for the drug substance and drug product(.;).Technology Transfer to Quality Control If not already initiated or under way, at the time of submission, discussions should commence with the appropriate QC person- nel on training programmes for their analysts, the content and acceptance criteria for the technology transfer protocol and the collaborative studies needed to ensure a well documented transfer. We have found that this training can be achieved successfully by demonstration of all methods and procedures to all the QC analysts by a well trained development analyst. The QC analysts then try the method on the same equipment under one to one tuitions. before thcy try the procedure on their equipment again with a development analyst standing by as the different steps are completed.The next phase is a collaborative 5tudy. testing samples of the same batch at exactly the same time in the two laboratories. The results are then evaluated statistically and the whole study is documented fully. If differences between the results obtained by the two groups are large, compared with the proposed tolerance in the specifica- tion, the causes should be investigated and the collaborative study should be repeated. If there is a significant time delay between the date training was completed and the date that the first batches for sale are manufactured and due to be tested, consideration should be given to a short period of retraining. When the first batches for testing by QC personnel arrive, consideration should be given to seconding thc trainer temporarily into the QC laboratory to help if problems arise. As more batches are prepared to give an adequate launch stock, the increased involvement by QC personnel is normally matched by a decreased involvement by the development group.It is standard practice that the first three production batches o f each dosage strength are placed on stability trial by the QC stability group. The stability protocol for these batches can be considerably reduced in terms of There are several types of studies that occur post-approval when the product(s) are marketed. Some involve the QC analysts (complaints and returned samples, counterfeit products, re- quests from hospital pharmacists for information on the likely stability of the product under 'abnormal' storage conditions, modifications to the existing methodology or evaluation of new methodology, etc.), others are referred back to the development section.Typical of the changes to analytical methodology which may be considered is the use of NIR for identity testing for packaged products.104 There has been a substantial increase in the number of pharmaceutical companies investing in NlR in the last few years to permit the rapid identity testing and release of excipients, packaged clinical trials materials and packed finished products for sale. It seems likely that the use of NTR by QC groups will increase substantially over the next few years because of its sensitivity to crystal form, particle size distribu- tions and source of supply of excipients.With all major pharmaceutical products, it is normal for generic copies to appear in the marketplace soon after the patent expires. A worrying trend is also the increase in the number of counterfeit copies which have appeared over the last decade. Generic copies of modified-release oral solid dosage forms are obviously more difficult to produce than the equivalent immediate-release product. The natural reaction of the market- ing department as soon as generic copies appear is to instigate an investigation to determine how closely the originator product has been copied. Often this is linked to an evaluation of the source of the drug substance and whether drug substance process patents may have been infringed. One procedure that we have used successfully to determine the abnormal dissolution characteristics of generic copies of a modified release product is topographical dissolution characterization.105,IOh In this proce- dure, samples of the generic copy and the originator's product are separately tested for dissolution rate using a range of media of different pH values for 8-24 h. We typically use media of pH 1.5, 4.5, 6.6, 6.8, 7.2 and 7.5 and monitor the dissolution rate continuously. Three-dimensional plots are then constructed of amount dissolved against pH and against time. This procedure often gives an indication of 'dose dumping' which is more readily seen using this technique than by using single-pH dissolution tests. Examples of typical dissolution 'surfaces' obtained using this technique are given in Figs.5,6 and 7 for the RPR product, a generic copy which partially 'dose dumps' and a close generic copy, respectively. We have also made good use of this technique for the comparison of batches of the same RPR product made at two different sites and were able to use the information to help to convince regulatory authorities that both sites were able to produce products which gave identical dissolution profiles over a wide range of pH values. Conclusions The development of modified-release oral solid dosage forms is a lengthy process which continues to attract regulations and guidelines from the various regulatory bodies world-wide. In the recent spirit of international harmonization, there is adequate scope for harmonization of the definitions of such dosage forms and hopefully this might lead to greater harmonization of the guidelines for their development and clinical evaluation.The analytical contribution to the development programmes for such products, as exemplified in this text, must be of theAncrlyst, October 1996, Vol. 121 99R 0 Fig. 5 product. Topographical dissolution characterization surface for RPR UK Fig. 6 which ‘dose dumps.’ Topographical dissolution characterization surface for generic copy highest calibre if the project is to succeed and achieve expectations. The analytical team must be continually aware of the changing regulatory environment and must be ready to incorporate and adapt to new requirements. They must anticipate trends in regulatory requirements.Looking to the future, it is to be hoped that the various regulatory bodies world-wide will become more familiar with the emerging technique of NIR spectrometry. This is now proving to be a valuable method for the identification of all types of oral dosage forms, the identification and characteriza- tion of excipients, film-coats and even the core tablets. Supported by sound science, it will prove to be of great value to the analysts involved in the development of the modified- release solid oral dosage forms of the future. 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Plzarm. frat., 19x6, 2, 202. Thoma, K.. and Oschmann, R., Plzarmuzie, 1991, 46, 331. Cordes, G., Pliurm. lid., 1969, 31, 566. Thoma, K., and Heckenmueller, H., Pharmazie, 1987, 42, 837.Sheen, P. C., Sabol, P. J., Alcom, G. J., and Feld, K. M., Drug Dei). Ind. Phat-m., 1992, 18, 85 1. Everett, M. R., Medical Biochemistry, Hamish Hamilton Medical Books, New York, 1946. Geigy Sr,ientific Tables, ed. Lentner, G., Ciba-Geigy, Bask, 8th edn., 1981. Wilkinson, R., Cliemical Metlzods in Clinical Medicine, London, Wagner, J. G.. Drug Intell.. 1968, 2, 30. Rein, H., Eiqf in die Physiologir lies Menschen, Berlin, 1964. Hofmann, A. F., Pressman, J. H., and Code, C. F., Drug Dev. Ind. Pharm., 1983. 9, 1077. Wilson, C. J., Parr, G. D., Kennerley, J. W., Taylor, M. J., Davis, S. S., Hardy, J. G., and Rees, J. A., Int. .I. Phar-m., 1984, 18, 1. Wilson, C. G.. and Washington. N., Manuf. Chem., 1985, February, 37. Ashby, I,. J., Beezer, A.E., and Buckton, G.. Int. J . Pharm., 1989,51, 245. Buckton, G., Beezer, A. E., Chatham, S. M., and Patel, K. K., Int. J . Plzarm., 1989, 56, 151. El-Arini, S. K.. Shiu, G. K., and Skclly, J. P., Int. J . Pharm., 19X9,55, 25. Macheras, P., Koupparis, M., and Apostolelli, E., Int. J . Phurm., 1987, 36, 73. Hunter, E., Fell, J. T., and Sharma, H., Drug Dev. Ind. Pharm.,1982, 8, 751. Davis, S. S., Hardy, J. G., Taylor, M. J., Whalley, D. R., and Wilson, C. G., Int. .I. PIzarm., 1984, 21, 167. Davis, S. S., Hardy, J. G., Taylor, M. J., Whalley, D. R., and Wilson, C. G., Int. .I. Phurm.. 1984. 21, 331. May, H. A., Wilson, C. G., and Hardy, J. G., Int. .I. Pharm., 1984,19, 169. Davis, S. S., Khosla, R., Wilson. C. G., Washington, N., and Malkowska, S., Int. J .Pharm., 1990, 60, 191. Davis, S. S., S.T.P. Phai-ma, 1987, 3, 412. Shah, V., Yamamoto, L. A,, Schuirman, D., Elkins, J., and Skelly, J. P., Phurmi. Res., 1987, 4, 416. 1974, p. 454. 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 Bachiller, M., Goni Leza, M., and DeNo Lengaran, C., Farm. Clin., 1986, 3, 144. Eskilson, C., Manuf. Chem., 1985, March, 33. Chan, R. K., and Rudnic, E. M., Int. J . Phurm., 1991, 70, 261. Sakr, A., and Oyola, J. R., Phurm. Ind., 1986, 48, 92. Akbuga, J., Plzurmazie, 1992, 47, 128. Dahlstrom, H., and Eriksson, S., Acta Pharm. Suec., 1971, 8, 505. Takenaka, H., Kawashima, Y., and Lin, S. Y., J . Pharm. Sci., 1980, 69, 1388. Nixon, J. R., Jalsenjak, I., Nicolaidou, C. F., and Harris, M., Drug Dev. Ind. Pharm., 1978, 4, 117. Gumy, R., Buri, P., Sucker, H., Guitard, P., and Leuenberger, H., Phurm. Acta Helv., 1977, 52, 247. Juslin, M. Turakka, L., and Puumalainen, P., Pharm. ind., 1980, 42, 829. Bechgaard, H., Acta Pharm. Technol., 1982, 28, 149. Bechgaard, H., and Nielsen, G. H., Drug Dev. Ind. Pharm., 1978, 4, 53. Clarke, G., Newton, J. M., and Short, M. D., Int. J . Phurm., 1993,100, 81. Husson, I., Leclerc, B., Spenlehauer, G., Veillard, M., and Couarraze, G., Int. J . Pharm., 1992, 86, 113. Friedman, M., Donbrow, M., and Samuelov, Y., J . Phurm. Pharma- col., 1979, 31, 396. Giunchedi, P., Maggi, L., Conte, U., and Caramella, C., Int. .I. Phnrnz., 1991, 77, 177. ICH Hurmonised Tripurtite Guideline: Stability Testing of New Drug Substances and Products. Step 4 Dorunzent, issued October 27th, 1995; ICH Dru@ Harmonised Tripartite Guideline: Stability Testing: Requirements ,for New Dosage Forms. Step 2 Document, signed off November 29th. I995. ICH Draft Hurmonised Tripartite Guideline: Stability Testing: Photostability Testing. Step 2 Document, signed off November 29th, 1995. Hoblitzell, J. R., Thakker, K. D., and Rhodes, C.T., Pharm. Actu Hell>., 1985, 60, 28. Thoma, K., and Oschmann, R., Pharmazie, 1992, 47, 595. Dahl, T. C., and Sue, I. T., Drug Dev. Ind. Pharm., 1990, 16, 2097. Murthy, K. S., and Ghebre-Sellassie, I., J. Pharm. Sci., 1993, 82, 113. Dahl, T. C., Sue, I., Lan, T., and Yum, A., Pharm. Res., 1991, 8, 412. Munday, D. L., and Fassihi, A. R., Drug Del.. Ind. Phurm., 1991, 17, 2135. Raggi, M. A., Cavrini, V., and Di Petra, A. M., Boll. Chim. Farm., 1980,119,663. Schwartz, J. B., and Alvino, T. P., J . Pharm. Sci., 1976, 65, 572. Chowhan, Z. T., Amaro, A. A.,. and Chi, L. H.. Drug Dev. Ind. Phurm., 1982,8, 713. Goracinova, K., and Simov, A., Plzai-muzie, 1992, 47, 801. Canafe, K., and Duman, G., Pharmazie, 1993, 48, 935. Chafetz, L., Hong, W., Tsilifonis, D. C., Taylor, A. K., and Philip, J., J . Pharm. Sci., 1984, 73, 1186. Murthy, K. S., Enders, N. A., and Fawzi, M. B., Pharm. Technol., 1989, 72. Cooper, J. W., Ansel, H. C., and Cadwallader, D. E., J . Pharm. Sci., 1973,62, 1156. Swarin, S. J., and Lipari, F., .I. Liy. Chromatog., 1983, 6, 425. Pina, E., Sousa, A. T., and Brojo, A. P., .I. Liy. Chromatogr., 1995,18, 2683. Belman, S., Anal. Chim. Acta, 1963, 29, 120. Hollander, V. P., Dimowro, S., and Pearson, 0. H., Endocrinology, 1951, 49, 617. Dempster, M. A., MacDonald, B. F., Gemperline, P. J., and Boyer, N. R., Anal. Chim. Acta, 1995, 310,43. Skelly, J. P., Yamamoto, L. A., Shah, V. P., Yau, M. K., and Barr, W. H., Drug Dev. Ind. Pharm., 1986, 12, 1159. Skelly, J. P., Yau, M. K., Elkins, J. S., Yamamoto, L. A., Shah, V. P., and Barr, W. H., Drug Dev. Ind. Phurm., 1986, 12, 1 1 17. Paper 610359YJ Received May 23, 1996 Accepted June 18,1996

ISSN:0003-2654    

DOI:10.1039/AN996210091R

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Analyst, October 1996, Vol. 121 143N Book and Software Reviews AAS SoftBook By Cognitive Solutions Ltd. Revised and Updated. January 1995. Price f295.00 (plus VAT); US$ 529.00 This is a software-based text on AAS which takes the novice from basic theory through to a number of applications. The software is very simple to install, aided by the manual which takes the operator through a step-by-step procedure. The manual itself contains no subject matter, but is a well written guide to the structure and operation of the software package. Once installed, the operator is then given the option to go straight into the programme or to run through a tutorial, which explains such things as how to use a mouse, the basic concepts of using Windows-based software and a brief explanation of how the software works.Once the tutorial has been completed, the user is returned to the home page. If the main body of the software is then opened, one of four discrete modules may be chosen. These are ‘Theory of AAS’, ‘AAS Instrumentation’, ‘Analysis with AAS’ and ‘Questions and Answers’. Any of these modules may be opened by clicking on the appropriate icon. It will then load, producing a module overview page. Each module is comprised of 20-30 topic areas. These topic areas may be accessed individually by clicking on the appropriate icon, or alternatively may be accessed in series by clicking on one and then repeatedly clicking on the ‘next’ icon. In many of the topic pages there are so-called ‘hotwords’. If clicked upon, these will reveal a further page explaining more about the specific hotword.Some of the topic areas also have demonstration buttons. An example is a demonstration of the avalanche effect that occurs in a photomultiplier tube. Simple demonstrations such as this are a good use of this media and save substantial effort reading through reams of text. When finished with a particular topic, the user can return to the module overview page by clicking on the home icon at the bottom of the screen. Once the user finishes the last topic area the program will state that the module has been finished and will give the option of returning to either the main menu or to the home page of the module. If required, the next module may then be investigated in a similar fashion. When using the package, clear and concise instructions appear in boxes on most pages to aid the user.The questions and answers module is somewhat limited (only 10 questions for theory and a further 10 for applications) but does give the user an opportunity for self assessment. There is also an option to print a certificate of achievement! A pass mark is given at 50% for both the theory and applications tests. It must be said that this computer program is easy to follow and is very user friendly. Some of the material is, however, rather thin. In the monochromators section, for example, the Czerny-Turner style is shown, but there is no mention of the other types (e.g., Littrow and Ebert). Little detail is given about Zeeman background correction, and although the fundamental theory is probably unnecessary for this program, there is no mention that the magnetic field can be applied to either the atom cell or the source, or in a longitudinal or transverse manner.The program explains (nicely) how a hollow cathode lamp works, but fails to mention anything about electrodeless discharge lamps. But perhaps most importantly there is a complete absence of the use of isothermal operation (i.e., platforms or probes) in ETV. Since many applications use isothermal operation (and other elements of the STPF concept), I feel this really should have been included. Omissions aside, the program is refeshingly free of errors although the equation hidden under ‘photons’ in the electromagnetic radiation part of the theory section is expressed as E = h/v rather than E = hv. Overall, I feel this is a useful and well structured teaching package.It would benefit from a more comprehensive questions and answers section, perhaps interactive with the main text and suggesting further reading. However, overall the package is good value for money and I am sure it will prove popular with students and trainees who respond to material in this format and who wish to know more about the fundamentals of AAS. Steve Hill 5199074C University of Plymouth Selective Detectors. Environmental, Industrial and Bio- medical Applications Edited by Robert E. Sievers. Volume 737 in Chemical Analysis: A Series of Monographs on Analytical Che- mistry and its Applications. Series editor J. D. Wine- fordner. Pp. xxi + 262. Wiley. 1995. Price f49.95. ISBN 0-47 1-01 343-9.Although the title suggests that this book provides a com- prehensive review of selective detectors and their application in chemical analysis, it focuses on some of the more recent developments and is therefore a text for the specialist rather than the novice chromatographer seeking an overview of the subject. Overall there is too much emphasis on atomic (rather than molecular) detectors and I was surprised to see no contribution on molecular mass spectrometric or infrared detection systems. However, the book is well produced with clear illustrations and the balance between the operational principles and applications of the detectors described is good. The first two chapters deal with sulfur-selective chemilu- minescence (CL) detection and concentrate on ozone-induced CL.In the first contribution the authors describe two detectors they have developed, one of which converts sulfur compounds dissolved in aqueous solutions to SO using high temperatures and pressures and has been employed for selective detection in analytical and preparative HPLC systems. The second chapter is devoted to flameless sulfur CL detection and describes applications of this detector in combination with GC and SFC. Most of the third chapter covers applications of detectors employing the NO-ozone CL reaction. These include the analysis of N-nitroso compounds; organonitrogen species in petroleum samples; nitrate and nitrite ions in water and foodstuffs; and nitric oxide, nitrogen dioxide and ammonia in the atmosphere. Indirect analysis, by measuring the NO produced when samples are oxidized by nitrogen dioxide, is also discussed.‘it focuses on some of the more recent developments and is therefore a text for the specialist rather than the novice chromato- grapher seeking an overview of the subject’ The oxygen-sensitive flame ionization detector (0-FID), the recent development of which has been catalysed by the need to determine oxygenated hydrocarbons in fuel, is the subject of chapter four. The major application areas of 0-FID (i.e., oxygenates in automotive petroleum and flavours and fra- grances in natural products) are outlined and the chapter concludes with some useful remarks on 0-FID operation which should help the newcomer to avoid many of the pitfalls experienced by the author.144N Analyst, October 1996, Vol.121 Chapter five is essentially a paper describing the experimen- tal optimization of a metal-selective FID for the determination of elements such as aluminium, iron, tin, lead and manganese. This contribution contains little information on applications of the detector and will be of interest to only a few readers. GC-atomic (plasma) emission spectroscopy is described in chapter six, which concentrates on the widely used microwave- induced helium plasma. A good list of references is given to papers where GC-atomic emission detection has been used to determine metallic and non-metallic elements, and the author concludes with the view that this detection technique will be used increasingly as commercial instrumentation becomes more widely available.The following chapter continues the theme of plasma sources but deals with mass spectrometric (MS) detection. The great analytical power available from the combination of chromatography (for speciation) with in- ductively-coupled plasma (1CP)-MS (for selectivity and sensi- tivity) is emphasized, and the significance of this combination illustrated with a brief account of the biological significance of different chemical forms of a range of ‘environmentally sensitive’ elements. HPLC rather than GC is most frequently combined with KP-MS, as witnessed by the variety of HPLC separations reported in this chapter. The concluding sections of this comprehensive account focus on the combination of GC and SFC with ICP-MS detection systems. The penultimate chapter deals with peroxyoxalate CL detection and somewhat overstates the sensitivity of this technique compared with fluorescence.Following a fairly detailed account of the mechanism of the peroxyoxalate reaction, the remainder of this contribution deals with the design and optimization of instrumentation for peroxyoxalate CL and describes some applications of the technique. The book concludes with a fascinating chapter which is essentially a mini-autobiography of James Lovelock’s scientific career. This pioneer of selective detection provides a fascinating insight to how some of the analytical devices that we nowadays take for granted have their origins in completely different areas. He also emphasizes the value of regular personal contact between supervisor and trainee, which is something we frequently overlook in these days of increased workloads and reduced staff numbers.S. Forbes 5190044A Shell Research Limited Chester Modern Infrared Spectroscopy By Barbara Stuart. Analytical Chemistry by Open Learn- ing. Edited by David J. Ando. Pp. xx + 180. Wiley. 1995. Price f 17.95. ISBN 0-471-95917-0. Modern Infrared Spectroscopy is one of the latest books in the ACOL (Analytical Chemistry by Open Learning) series. In common with the other texts the book concentrates on a limited area of analytical chemistry and then aims to make it accessible to readers who may be following a course, doing a self-tuition programme, or are otherwise new to the area. For readers unfamiliar with Open Learning, the text follows a pattern established by bodies such as the Open University.Thus a complex set of ideas is presented in a series of well- defined blocks. Each block is broken into smaller segments which allows the student to make effective use of even small increments of study-time. Regular use of self-assessments related to the material helps the student gain confidence in how much has been assimilated during their study. Dr. Barbara Stuart of the University of Technology, Sydney, deserves congratulations for writing a very readable and interesting book on modem infrared spectroscopy. The empha- sis of the book is on the choice of effective sampling methods. The main instrumental method is almost assumed to be FTIR, although sufficient information on dispersive systems is included. There is a section on the identification of unknown materials via correlation charts and typical vibrations, but this does not form the bulk of the text as it might have done a few years ago.There are a lot of clear drawings and some good-quality spectra to assist the novice in all stages of infrared analysis. Background theory, including signal processing, is integrated into the text in a readily assimilated format. All the major sampling methods are discussed and critical appraisals given of their strengths and weaknesses. There are also about 30 original problems in the book. These range from simple numerical conversions through to complex questions involving calibration graphs and the identification of unknowns. These problems form the core of the self-assessment process and so fully worked answers are provided.In comparison with some of the courses provided by instrument manufacturers, ACOL texts offer a cost-effective resource which can be used to produce in-house training packages. There are also courses run by the RSC which can lead to the award of LRSC. J . E . Newbery 5190098K Greenwich University Practical Gamma-ray Spectrometry By Gordon Gilmore and John Hemingway. Pp. viii + 314. Wiley. 1995. Price f60.00. ISBN 0-471-95150-1. This book is based on notes used for a series of practical gamma-ray spectrometry courses run by the authors at the Universities Research Reactor at Risley. The authors’ intention was to provide more of a workshop manual than an academic treatise. In this they have eminently succeeded. The book contains all the information which a newcomer to the technique of gamma-ray spectrometry would need to understand the principles underlying the technique and to set up and run a practical operating system for real applications.Chapters are included on radioactive decay and the origin of gamma- and X-rays; interactions of gamma radiation with matter; semiconductor detectors for gamma-ray spectrometry; electronics; counting statistics; spectrometer calibration; co- incidence summing; computer analysis of spectra; scintillation spectrometry; choosing, setting up and checking the specifica- tion of a detector; resolution; troubleshooting; low-count rate systems; high-count rate systems; and ensuring quality in gamma-ray spectrometry. Five appendices provide useful sources of further information, decay data for detector calibra- tion standards, data on background gamma-rays including those from Chemobyl fallout, a list of chemical names and symbols and details of suppliers of spectrometry equipment.‘would be invaluable for anyone setting up, or operating, a gamma-ray spectrometry system for practical applications, Much of this material is, of course, also contained in other texts and comparison can be made with, for example, ‘Gamma- and X-ray Spectrometry with Semiconductor Detectors’ (K. Debertin and R. G. Helmer, North-Holland, 1988). The strength of Gilmore and Hemingway’s book lies in the wealth of practical information and advice which appears throughout the text and which is collected together at the end of each chapter in a section entitled ‘Practical Points’.Their chapters on scintilla-Analyst, October 1996, Vol. 121 145N tion spectrometry (still important for many applications) and on troubleshooting do not appear in the Debertin and Helmer text. The latter book is a detailed treatise on gamma- and X-ray spectrometry and one would expect to find it on the shelves of radionuclide metrologists and nuclear physicists. The Gilmore and Hemingway book, on the other hand, would be invaluable for anyone setting up, or operating, a gamma-ray spectrometry system for practical applications such as neutron activation analysis, environmental monitoring or measurements related to the nuclear fuel cycle. The chapter on low count rate systems, for example, will be particularly relevant to measurements on environmental radioactivity; whilst that on high count rate systems will have particular relevance to measurements of nuclear fuel.The book must be highly recommended to anyone involved with gamma-ray spectrometry. Desmond MucMuhon 5190045 J Imperial College NMR Techniques in Catalysis Edited by Alexis T. Bell and Alexander Pines. Pp. viii + 432. Marcel Dekker. 1994. Price $165.00. ISBN 0-8247-9173-8. Nuclear magnetic resonance (NMR) spectroscopy has emerged as a powerful technique to investigate the structure of solid materials. in view of the importance of heterogeneous catalysis to modern chemical processes, it has proved to be a major growth area for the application of solid state NMR techniques. As well as providing unique information on the chemical environment of specific nuclei in catalysts or species adsorbed on the catalysts, NMR can monitor the connectivities and dynamics of these environments and species.This book is the first that has attempted to cover the many diverse applications of NMR in heterogeneous catalysis. After a brief introduction, by the editors, to basic NMR concepts and the type of information that can be obtained from modern techniques, the book comprises six chapters written by leaders in the field (Maciel, Karger, Fyfe, Haw, Eckert and Haddix) on the application to specific areas in heterogeneous catalysis. These include zeolites and related areas, molecular diffusion, in situ measurements, bulk oxide catalysts, silica and alumina surfaces and layered materials (clays, aluminophos- phates and metal sulfides).The chapters highlight the major role 29Si and 27A1 NMR play in the characterization of aluminosili- cates, the growing number of other catalytically-important nuclei that can be investigated by NMR (e.g., 3lP, 17O,5lV) and the key role of lH, l3C and 31P in probing adsorbed species and acidity (Bronsted and Lewis acid sites), together with the skill and ingenuity that has gone in to providing information on diffusion and in situ measurements. The final chapter of the book provides a very brief overview of emerging techniques. ‘the book represents a valuable and unique reference source on the application of NMR techniques to heterogeneous catalysis’ Although under the themes chosen for the chapters, it is clearly impossible to include every application of NMR to catalytic science, there are relatively few omissions.Perhaps a chapter devoted specifically to NMR could have brought together more of the work on adsorbed species and the importance of the technique for characterizing catalytic coke. Some of the overlap between the different chapters on the presentation of essential theory for the various applications covered (particularly cross-polarisation, magic-angle spinning) could have been avoided by having an expanded introductory chapter. The final chapter of the book is somewhat disappoint- ing in that the reader not conversant with NMR is left with barely a superficial understanding of the emerging techniques. Further, no attempt has been made to cross-reference these techniques to where they appear in other chapters and the other chapters, particularly those covering aluminosilicates, could have been intergrated to a greater extent.Putting aside these relatively minor criticisms, the book represents a valuable and unique reference source on the application of NMR techniques to heterogeneous catalysis and its purchase is highly recom- mended for those working in the field. Colin E. Snupe 41901 06A University oj Strathclyde ICUMSA. International Commission for Uniform Meth- ods of Sugar Analysis By ICUMSA. Pp. xxxvi + 438. ICUMSA Publications. 1995. Price f42.00; ISBN 0-905003-14-4. The proceedings of the twenty-first session of the International Commission for Uniform Methods of Sugar Analysis (ICUMSA), held in Havana in May of 1994 is published by ICUMSA itself, and runs to xxxviii pages of introduction, followed by 424 pages of the proceedings of the meeting, accompanied by an index.The introductory pages incorporate a revealing blow-by-blow account of the structure, politics, allegiance, and financial viability of ICUMSA itself. Discussion of the last point dwells considerably on the substance and construction of this very volume; its cost and the likely return against those costs. Whilst of minimal curiosity value to the general reader, none of these topics is of general interest and would be better reported, in the opinion of this reviewer, internally to the ICUMSA as minutes to relevant management committee meetings. Regrettably that style is maintained throughout this produc- tion. Its content can be briefly described as being a mixture of ICUMSA’s definitions of the requirements for sugar analysis, accompanied by elaborate internal disucussion as to how to establish those criteria.The text covers many, but not all, of the required categories. Those that it does deal with are, to the credit of the authors, presented in clear and acceptable format. They range widely from raw sugar determination to chromatographic techniques for sugars. The principal drive is, however, directed not to analysis itself, but to the formulation of particular protocols for sugar analysis, the intention being their adoption as self-imposed internal regulatory controls, and presumably directed to the general acceptance, by others, of those protocols. It is clear that ICUMAS’s efforts would be well served by a wider view of the development of the science, by others, in each of those many categories covered by this text.Instead the organisation takes an introspective view, and at length, tends only to discuss and report those analytical developments conducted by its own members, in the period between this and their previous report. This reviewer is of the opinion that this text will be of considerable value to the delegates of the meeting in question, of some minimal interest to those in the sugar industry, but only of curiosity value to anyone working in the wider fields of carbohydrate chemistry and their analysis. in summary, this text will necessarily appear to the general reader as a peculiarly introspective account of a meeting held by just another vested interest group.Ivor Lewis 51 90068I King’s College London146N Analyst, Octohei. 1996, Vol. 121 Advances in Chromatography. Volume 36 Edited by Phyllis R. Brown and Eli Grushka. Pp. xvii + 444. Marcel Dekker. 1995. Price $175.00. ISBN 0-8247-9551-2. After 35 volumes this series can certainly be called well established. Like previous volumes it contains a series of chapters across a broad spectrum of interest. This volume is no exception and covers mathematical methods and detection principles as well as more mainstream topics. This diversity make(; reviewing difficult as many of the eight topics covered are of a highly specialist nature. The first chapter, by Cserhiiti and Forgiics (Central Research Institute for Chemistry, Budapest, Hungary) on the use of multivariate methods for the evaluation of retention data focuses heavily on the applications of a variety of techniques and assumes that the reader has at leust a reasonable working knowledge of the methods used although references to more detailed works are given as well as to data sources.Chapter 2 is a very readable account of the liquid chromatography of the fullerenes by Jinno and Saito (Toyoha\hi University of Technology, Japan). It is well illustrated and gives an excellent insight into liquid-crystal bonded phases. The next 2 chapters and chapter 8 concern themselves with the application of capillary electrophoresis (CE) to biomolecules. Cohen, Smis- mek and Wang (Hybridon. USA) describe the use of CE-MS in sequencing of oligonucleotides whilst Oda, Madden and Landers (Mayo Foundation/Mayo Clinic, Rochester, USA) cover the analysis of glycoproteins and glycopeptides.Lunte and Lunte (University of Kansas, USA) discuss microdialysis sampling in pharmacological studics and its applicability to HPLC and CE. Whilst specialist in nature, they are all well written and well referenced. ‘Overall, this volume continues the tradition and standards set by previous volumes in the series and will find a place in many library collections a Chapter 5 is somewhat different as it is a detailed review of LC methods (413 references) for the screening of biological fluids for drugs of abuse (Binder. Bio-Rad Laboratories, Hercules, USA). It covers specific drug separations as well as broad spectrum screening.It is very readable as well as being most informative. The role of electrochemical detection for molecules of biological interest is the subject of the next chapter by Chen, Woltman and Weber (University of Pittsburgh, USA). The application of electrochemical methods for detection of a wide variety of moleculec at low levels of concentration is discussed and the conflict of sensitivity and specificity is explored. Chapter 7, by Lindon (Wellcome Research Laboratories), Nicholson (Birkbeck College) and Wilson (Zeneca Phar- maceuticals) tJK, discusses the development and application of the hybrid technique of HPLC-NMR. After discussion of the basic theory and experimental aspects, its application to drug metabolism studies and biochemical analysis is discussed.Overall, this volume continues the tradition and standards set by previous volumes in the series and will find a place in many library collections. C . R ui;qes s 619001 2G Co. Dur-ham Encyclopedia of Nuclear Magnetic Resonance. Volume 1. Historical Perspectives Edited by D. M. Grant and R. K. Harris. Pp. xii + 814. Wiley. 1996. Price f125.00; ISBN 0-471-93871-8. ~~~~ ~~~~ ~~~~ ~~ ~ ~~~ I find that students at all levels respond enlhusiastically to the teaching of NMR spectroscopy via an historical perspective: the failure of Gorter to detect nuclear resonance in the 193Os, the success of Felix Bloch and co-workers at Stanford and of Edward Purcell and colleageus at Harvard in the 1940s, followed by the unexpected discovery of the chemical shift and of spin-spin coupling, phenomena which we all take for granted these days.Then there was Albert Overhauser, the young (in 1953) theoretician who predicted that, in a metal, the saturation of the ESR resonance of the electrons should lead t o an enormous increase in nuclear polarization; nobody believed him (his presentation to the American Physical Society went down like a lead balloon!) until Charles Slichter demonstrated it to be so later that year. Without the (nuclear) Overhauser effect, we would not now be using multinuclear NMR methods to solve the structures of proteins as big as 25 kDa. ‘definitely the volume for introducing all aspects of NMR to students’ NMR spectroscopy is one of the few techniques which has continued to evolve; almost every year useful new advances in the instrumentation or pulse sequences (but remember the days of continuous wave NMR) seem to appear. A large number of research workers have made important contributions and most of them are detailed in this volume, not only for high resolution spectroscopic studies of liquids but also for solids (e.g., the major impact of magic angle spinning introduced by Raymond Andrew in Nottingham in 1960), and imaging. Paul Lauterbur says that ‘The invention of NMR imaging (MRI) can be traced back through a variety of specific incidents to a set of underlying interests developed in my childhood.’: enough to arouse the curiosity of any reader! This is a heavy volume, one for the library and not for carrying home very often, but definitely the volume for introducing all aspects of NMR to students. I can see a market for a slimmer version which can be carried home (and is affordable), perhaps a fifth the size, with just the key people (can we agree on them?). As Silvio Aime pointed out in hi\ contribution ‘The personal pathway sketched in this brief report may closely resemble the story of many (hundreds, thousands‘?) of researchers who had the fortune to meet the splendid armoury of NMR spectroscopy early in their career.’ Long may the good fortune continue. Peter J . Sadlei- 6190035 F Ut?iversity of Loidon

ISSN:0003-2654    

DOI:10.1039/AN996210143N

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Analyst, October 1996, Vol. 121 147N Conference Diary Date Conference 1996 November Location 4-6 3-8 12-15 13 13-15 13-15 14-15 17-22 19-20 20-22 20-22 21 24-30 26-27 26-28 ISPPP '96: 16th International Symposium on the Separation and Analysis of Proteins, Peptides and Polynucleotides Luxembourg International Symposium on the Industrial Application of the Mossbauer Effect Johannesburg, South Africa International Exhibition and Conference for Chemical Technology, Analytical Technology and Biotechnology Capillary Electrophoresis Meeting Hertfordshirc, Basel, S witzrland UK Quality Control Laboratory CGMP Zurich, Compliance and Auditing Switzerland 13th Montreux Symposium on Liquid Chromatography-Mass Spectrometry Switzerland Montreux, US Generic Drug Approval System Series. GMP, GLP and FDA Inspections for Generic Drugs 1996 Eastern Analytical Symposium Zurich, Switzerland Somerset, NJ.USA Safety of Biopharmaceutical Products and Processes: Validation and Testing Switzerland Basel, ICP/NZ Trace Elements Groups Joint Conference New Zealand Hamilton, TAS '96, 2nd International Symposium on Micro Total Analysis Systems Switzerland Basel, Spectroscopic Detection in Process Analysis (11) UK Hull, 4th Rio Symposium on Atomic Spectrometry Buenos Aires, Argentina Hiopharmaceuticals: Analytical, Formulation, Basel, Product Development Process and Regulatory Switzerland Issues 7th National Symposium on Mass Gwalior, Spectrometry India Contact Secretariat ISPPP '96, B.O. Conference Service, P.O. Box 100 78, S-750 10 Uppsala, Sweden Tel: +36 18 I65 060.Fax: +46 18 304 074. E-mail: bengt.osterlund@seuppbt.pharmacia.sc. Herman Pollak, Mossbauer Laboratory, University of the Witwatersrand, Private Bag 3, WITS 2050, Johannesburg, South Africa Tel: +27 1 I 7 16 4053/2526. Fax: +27 11 339 8262. E-mail: isiame@physnet.phy$.wits.ac.za. L. E. Loew, ilmac96, Messc Bassel, CH-4021 Basel, S witLerland Tel: +4l 61 686 2707. Fax: +41 61 686 2188. Mrs Gill Caminow, The Chromatographic Society, Suite 4, Clarendon Chambers, 32 Clarendon Street, Nottingham, UK NGl 5JD Tel: +44 (0) 1 15 950 0596. Fax: +44 (0) 1 15 950 0614. Programme Division, Technomic Publishing AG, Missionstrasse 44, CH-4055 Basel, Switzerland Tel: +41 61 381 5226. Fax: +41 61 381 5259. M. Frei-Hausler, Postfach 46. CH-4123 Allschwil 2, Switzerland Tel: +41 61 481 2789.Fax: +41 61 482 0805. Programme Division, Technomic Publishing AG, Missions trasse 44, CH-405 5 Base I, Switzerland Tel: +41 61 381 5226. Fax: +41 61 381 5259. EAS, P.O. Box 633, Montchanin, DE 197 10-0633, USA Tel: +1 302 738 6218. Fax: +1 302 738 5275. Programme Division, Technoinic Publishing AG, Missionstrasse 44, CH-4055 Basel, Switzerland Tel: +41 61 381 5226. Fax: +41 61 381 5259. Dr. Peter Robinson, Conference Secretary, R. J. Hill Laboratories Ltd., P.O. Box 4048, Hamilton, New Zealand Tel: +64 7 855 2266. Fax: +64 7 854 9886. E-mail: Peter@rjhill.co.nz. Secretariat, Mrs E. Muller, Corporate Analytical Research, K-127.1.54, Ciba Inc., CH-4002 Basel, Switzerland Tel: +41 61 696 2571. Fax: +41 61 696 4504. Dr. ,J. S. Lancaster, BP Chemicals, Hull Research Centre, Saltend, Hull, UK HU12 8DS Tel: +44 (0)1482 894803.Fax: +44 (0)1482 892171. Osvaldo E. Troccoli, Quiniica Analitica, Facultad de Ciencias Exactasy Naturales, Ciudad Universitaria, (1428) Buenos Aires, Argentina Tel: +54 1 783 3025. Fax: +54 1 782 0441. E-mail: troccoli@trazas.uba.org or batiston@cena.edu.ar. Programme Division, Technomic Publishing AG, Missionstrasse 44, CH-4055 Basel. Switzerland Tel: +41 61 381 5226. Fax: +41 61 381 5259. Dr. Suresh Aggarwal, Fuel Chemistry Division, Bhabha Atomic Research Center, Bombay 400 085, India E-mail: hejain@magnurn.baretl.ernet.in or Dr. G. Sudhakar Reddy, The University of Michigan, OSEH, 1655 Dean Road, Ann Arbor, MI 48109, USA148N Analyst, October 1996, VoE. 121 Date Conference 27 North West Analytical Science 28-29 Process Validation from A to Z: An International Perspective December 3 2nd Young Scientists Research Symposium-Current Research Trends in UK Air Quality Location Contact Salford, UK University of Salford, Salford M5 4ET, UK Tel: +44 (0)161 745 5000.Fax: +44 (0)161 745 5999. E-mail: d. w .m. arrigan@ chemistry. salford.ac. uk. Programme Division, Technomic Publishing AG, Miss ions tras se 44, CH-405 5 B asel, Switzerland Tel: +41 61 381 5226. Fax: +41 61 381 5259. Basel, Switzerland London, UK SCI Conference Department, 14/15 Belgrave Square, London SWlX SPS, UK 17-20 1st Asia-Pacific International Symposium on Hong Kong APCE '96, c/o Dr. Sam F. Y. Li, Department of Chemistry, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Republic of Singapore Tel: +65 772 2681.Fax: +65 779 1691. E-mail: chmlify s@ leonis .nus. sg . - Capillary Electrophoresis and Related Techniques 1997 January 4-9 The Fourth International Symposium On: Giza, New Trends in Chemistry The Role of Egypt Analytical Chemistry in National Development Analysis-ICFIA 97 USA 12-1 6 International Conference on Flow Injection Orlando, 12-17 1997 European Winter Conference on Plasma Gent, Spectrochemistry Belgium 20-24 First Asia-Pacific EPR/ESR Symposium Hong Kong 26-30 9th International Symposium on High Anaheim, Performance Capillary Electrophoresis and USA Related Microscale Techniques February 2-6 The Australian and New Zealand Society for Hobart, Tasmania, Mass Spectrometry 16th Conference Australia (ANZSMS 16) 3-5 2nd Symposium on Macromolecules Used as Stockholm, Pharmaceutical Excipients-New Sweden Opportunities, Characterization and Applications Professor Dr.M. M. Khater, Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt ICFIA 97, Sue Christian, P.O. Box 26, Medina, WA Fax: +1 206 454 9361. E-mail: sue@flowinjection.com. L. Moens, Secretariat, 1997 European Winter Conference, Laboratory of Analytical Chemistry, University of Gent, Proeftuinstraat 86, B-9000, Gent, Belgium Tel: +32 9 264 66 00. Fax: +32 9 264 66 99. E-mail: plasma97@ rug.ac. be. Professor C. Rudowicz, Chairman, LOC & IOC, City University of Hong Kong, Department of Physics and Materials Science, 83 Tat Chee Avenue, Kowloon, Hong Kong Tel: +852 2788 7787.Fax: +852 2788 7830. E-mail: apsepr@cityu.edu.hk. Shirley Schlessinger, Symposium Manager, HPCE '97, 400 East Randolph Street, Suite 1015, Chicago, IL 60601, USA Tel: +1 312 527 2011. 98039-0026, USA Mures Convention Management, Victoria Dock, Hobart, TAS 7000, Australia Tel: +61 002 312121. Fax: +61 002 344464. E-mail: mures@hba.trumpt.com.au; WWW: http://www .csl.edu.au/ANZSMS/ anzsms 16.html. The Swedish Academy of Pharmaceutical Sciences, P.O. Box 1136, S-111 81 Stockholm, Sweden Tel: +46 8 723 50 00. Fax: +46 8 20 55 11. E-mail: academy@swepharm.se or visit http://www.swepharm.pharmsoft.se.Analyst, October 1996, Vol. 121 149N Date Conference 18-1 9 Inbio '97 Industrial Biocatalysis: The Way Ahead March 9-14 CANAS '97 Colloquium Analytische Atomspektroskopie 16-21 48th Pittsburgh Conference on Analytical .Chemistry and Applied Spectroscopy 23-27 April 13-17 14-19 19-22 2 1-25 28-29 30-2/5 May 4-8 11-15 Electrophoresis '97 213th American Chemical Society National Meeting Genes and Gene Families in Medical, Agricultural and Biological Research: 9th International Congress on Isozymcs Scanning 97 Seventh International Symposium on Biological and Environmental Reference Materials (BERM-7) Computer & Process Validation in the Location Manchester, UK Freiberg/Sachsen, Germany Atlanta, GA, USA Seattle, WA, USA San Francisco, CA, USA Texas, USA Monterey , CA, USA Antwerp, Belgium Manchester, Pharmaceutical and Fine Chemical Industries UK Flavours and Fragrances Warwick, UK PBA '97,Sth International Symposium on Pharmaceutical and Biomedical Analysis USA Orlando, FL, 5th European Workshop on Modern Torquay, Developments and Applications in Microbeam UK Analysis Contact Spring Innovations Ltd., 185A Moss Lane, Bramhall, Stockport, Cheshire, UK SK7 1BA Tel: +44 (0)161 440 0082.Fax: +44 (0)161 440 9127. G. Werner, Universitat Leipzig, Institut fur Analytische Chemie, Linnestrasse 3, D-04103 Leipzig, Germany Tel: +49 0341 973 6101. Fax: +49 0341 973 6115. Linda Briggs, The Pittsburgh Conference, 300 Penn Center Blvd., Suite 332, Pittsburgh, PA 15235-5503, USA Tel: +1 412 825 3220, +I 800 825 3221. Fax: +1 412 825 3224. David Wiley, Electrophoresis Society, P.O. Box 1987, Lawrence, KS 66044-8897, USA Tel: +1 913 843 1221. Fax: +I 913 843 1274. E-mail: dwiley@allenpress.com. Department of Meetings, American Chemical Society, 1155-16th St. NW, Washington, DC 20036, USA Tel: + I 202 872 4396.Fax: +1 202 872 6128. E-mail: natlmtgs@acs.org. Mrs. Janet Cunningham, Ban- Enterprises, 101 20 Kelly Road, P.O. Box 279, Walkersville, MD 21793, USA Tel: +I 301 898 3772. Fax: +1 301 898 5596. Mary K. Sullivan, FAMS Inc., SCANNING 97 Program Committee, Box 832, Mahwah, NJ Tel: +1 201 818 1010. Fax: +1 201 818 0086. E-mail: fams@holonet net; Internet: http://www .scanning-fams.org. J. Pauwels, Institute for Reference Materials and Measurements, Retieseweg, B-2440 Geel, Belgium. Tel: +32 14 571 722; or Wayne Wolk, US Department of Agriculture, 10300 Baltimore Blvd, Beltsville, MD 20705, USA Tel: +1 301 504 8927. Spring Innovations Ltd,, 185A Moss Lane, Bramhall, Stockport, Cheshire, SK7 1BA Tel: +44 (0)161 440 0082.Fax: +44 (0)161 440 9127. Elaine Wellingham, Conference Secretariat, Field End House, Bude Close, Nailsea, Bristol BS19 2FQ, UK Tel: +44 (0)1275 853311. Fax: +44 (0)1275 853311. E-mail: confsec@dial.pipex.com. 07430-0832, USA Shirley E. Schlessinger (Symposium Manager), Suite 1015, 400 East Randolph Drive, Chicago, IL, 60601, USA EMAS Secretariat, University of Antwerp, Department of Chemistry, Universiteitsplein 1, G-2610 Antwerp-Wilrijk, Belgium Fax: +32 3 820 2376. E-mail: vantdack@uia.ua.ac.be.150N Analyst, October 1996, Vol. 121 Date 12-13 12-16 18-22 27-28 June 1 -5 2-5 3-5 15-2 1 16-20 22-27 30-3/7 July Conference Chiral USA '97 European Symposium on Photonics in Manufacturing I11 19th International Symposium on Capillary Chromatography and Electrophoresis IInd Miniaturisation in Liquid Chromatography versus Capillary Electrophoresis Conference Location Boston, USA Paris, France Wintergreen, VA, USA Ghent, Belgium Geoanalysis '97,3rd International Conference Vail, CO, on the Analysis of Geological and Environmental Materials 6th Annual Course on Practical Methods of Digestion for Trace Analysis LIMS '97, 11th International LIMS Conference and Exhibition International Conference on Analytical Chemistry European Symposium on Environmental Sensing 111 HPLC '97, 21st International Symposium on High Performance Liquid Phase Separations and Related Techniques 6th European ISSX Meeting USA Amherst, MA, USA The Hague, Netherlands Moscow, Russia Munich, Germany Birmingham, UK Gothenburg, Sweden Contact Spring Innovations Ltd, 185A Moss Lane, Bramhall, Stockport, Cheshire, UK SK7 1BA Tel: +44 (0)161 440 0082. Fax: +44 (0)161 440 9127 or Brandon Associates, PO Box 1244, Merrimach, NH 03054, USA.Tel and Fax: +1 (630) 424 2035. Francoise Chavel, Executive Secretary, European Optical Society, B.P. 147-91403 Orsay Cedex, France Tel: +33 1 69 85 35 92. Fax: +33 1 69 85 35 65. E-mail: francoise.chavel@iota.u-psud.fr. Joy Wise, P.O. Box 4153, Frederick, MD 21705-4153, USA Tel: + 1 301 473 8311. Fax: +I 301 473 8312. E-mail: Wisejoy@aol.com. Prof. Dr. Willy R. G. Baeyens, Chairman MINI-LC 11, University of Ghent, Faculty of Pharmaceutical Sciences, Department of Pharmaceutical Analysis, Laboratory of Drug Quality Control, Harelbekestraat 72, B-9000 Ghent, Belgium Tel: +32 9 264 80 97.Fax: +32 9 264 81 96. E-mail: willy . baeyens@ rugac. be Belinda Arbogast, USGS, Dever Federal Center, Box 25046, MS 973, Denver, CO 80225, USA Tel: +I 303 236 2495. Fax: +1 303 236 3200. E-mail: plamothe@helios.cr.usgs.gov. Beverly Lissner, Questron Corporation, 4044 Quakerbridge Rd., Mercerville, NJ 08619, USA Tel: +1 609 587 6898. Fax: +1 609 587 0513. Conference Secretariat, LIMS 97, 45 Hilltop Avenue, Hullbridge, Hockley, Essex, UK SS5 6BL Tel: +44 (0)1702 231268. Fax: +44 (0)1702 230580. E-mail: 10 1320.16 17@compuserve.com. Dr. L. N. Kolomiets, Scientific Council on Chromatography of the Russian Academy of Sciences Leninsky Prospect 3 1, 117915 Moscow, Russia Tel: +7 95 952 0065. Fax: +7 095 952 0065.E-mail: Iarionov@Imm.phyche.mk.su. Frangoise Chavel, Executive Secretary, European Optical Society, B.P. 147-91403 Orsay Cedex, France Tel: +33 1 69 85 92. Fax: 33 1 69 85 33 65. E-mail: francoise.chavel@iota.upsud.fr. HPLC '97 Symposium Secretariat, ICC, Broad Street, Birmingham B1 2EA, UK Tel: +44 121 200 2000. Fax: +44 121 643 0388. Meeting Secretariat, 6th European ISSX Meeting, c/o The Swedish Academy of Pharmaceutical Sciences, P.O. Box 1136, S-11 1 81 Stockholm, Sweden Tel: +46 8 723 5000. Fax: +46 8 20 551 I. 2 1-25 4th International Conference on Laser Monterey, CA, Richard E. RUSSO, Lawrence Berkeley Laboratory, Ablation USA MS 90-2024, Berkeley, CA 94720, USA Tel: +I 510 486 4258. Fax: + I 510 486 4260. E-mail: renxsso@ 1bl.gov; http://cola97 .om1 .gov.Analyst, October 1996, Vol.I21 151N Date Conference 23-26 4th International Conference on the Biogeochemistry of Trace Elements August 10-1 5 11th International Conference on Fourier Transform Spectroscopy 25-28 VII Flow Conference 25-29 IMSC '97-14th International Mass Spectrometry Conference September 7-1 1 7-1 1 7-1 2 8-12 8-12 15-19 2 1-26 111th AOAC International Annual Meeting and Exposition 214th American Chemical Society National Meeting 1 1th International Conference on Secondary Ion Mass Spectrometry (SIMS XI) 4th International Conference on Nanometer Scale Science and Technology Biomedical Optics V Location Berkeley, CA, USA Athens, GA, USA Aguas de Sao Pedro-Piracicaba, Brazil Tampere, Finland San Diego, CA, USA Las Vegas, NE, USA Orlando, FL, USA Beijing, China Poland 3rd International Symposium on Speciation Port Douglas, of Elements in Biological, Environmental Queensland, and Toxicological Sciences Australia XXX Colloquium Spectroscopicum Melbourne, Internationale Au s tr a1 ia October 5-10 4th international Symposium on Environmental Geochemistry Vail, CO, USA Contact I.K. Iskandar, U.S. Army Cold Regions Research and Engineering Laboratory, 72 Lyme Rd., Hanover, NH 03755, USA Tel: +1 603 646 4198. Fax: + I 603 646 4561. E-mail: iskander@crrel.usace.army.mil. James A. de Haseth, Department of Chemistry, University of Georgia, Athens, Georgia 30602-2556, USA Tel: +1 706 542 1968. Fax: +1 706 542 9454. E-mail: dehaseth@dehrsv.chem.uga.edu. Henrique Bergainin Filho, CENA-USP, Caixa Postal 96, 13400-970 Piracicaba, SP, Brazil Tel: +55 194 335122.Fax: +55 194 228339. E-mail: flow97@aguia.cena.usp.br. 14th IMSC Congress Secretariat, c/o Congress Management Systems, P.O. Box IS 1, SF-00 I4 1, Helsinki, Finland Margreet Lauwaars, P.O. Box 153, 6720 AD Bennekom, The Netherlands. Tel: +31 318 418725; Fax: +3 1 3 18 4 18359; or Derek Abbott, 80 Chaffers Mead, Ashtead, Surrey, UK KT2 1NH Tel: +44 372 274856. Fax: +44 372 274856. Department of Meetings, American Chemical Society, 1 155- 16th St. NW, Washington, DC 20036, USA Tel: +I 202 872 4396. Fax: +1 202 872 6128. E-mail: natlmtgs@acs.org. SIMS XI, 1201 Don Diego Ave., Santa Fe, NM 87505, USA Tel: + I 505 989 4735. Fax: +1 505 989 1073. Shijin Pang, Beijing Laboratory of Vacuum Physics, Chinese Academy of Sciences, P.O. Box 2724, Beijing 100080, People's Republic of China Tel: +86 10 256 8306. Fax: +86 10 255 6598. E-mail: pang@ image .blem. ac .cn. Francoise Chavel, Executive Secretary, European Optical Society, B.P. 147-9 1403 Orsay Cedex, France Tel: +33 1 69 85 35 92. Fax: +33 1 69 85 35 65. E-mail: francoise.chavel@iota.u-psud.fr. Dr. J. P. Matousek, Department of Analytical Chemistry, University of New South Wales, Sydney, NSW 2052, Australia Tel: +61 2 3854713. Fax: +61 2 3856141. E-mail: j .matouseke unsw.edu.au. The Meeting Planners, 108 Church Street, Hawthorn, Victoria 3 122, Australia Tel: +61 3 9819 3799. Fax: +61 3 9819 5978. E-mail: http://www.latrobe.edu.au/CSIconf/XXXCSI.html. R. C. Severson, U.S. Geological Survey, Federal Center, Box 25046, MS 973, Denver, CO 80225, USA Tel: +1 303 236 5514. Fax: +1 303 236 3200. E-mail: keg@ helios .cr.usgs .gov.

ISSN:0003-2654    

DOI:10.1039/AN996210147N

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

152N Analyst, October 1996, Vol. 121 Courses Date Conference 1996 November 6-10 Interpretation of Infrared Spectra 16-17 GC and GC-MS for Beginners 19 Spectroscopic Techniques for Extrusion Cooking 25-29 Quality Management Short Course 30 Pesticide Maximum Residue Levels December 9-12 An Introduction to ICP Spectrometry; An Introduction to ICP-MS Spectrometry 10-13 Introduction to Mass Spectrometry 1997 January 14 ICP-MS Instrumentation 14 Quality Assurance and Quality Control 14 Plasma Spectrometry and Speciation Trends 14 High Resolution ICP-MS Location Seer Green, UK Duisburg, Germany Campden, UK Loughborough, Leicestershire, UK Campden, UK Omaha, NE, USA Warwick, UK Gent, Belgium Gent, Belgium Gent, Belgium Gent, Belgium Contact Ms M. Pope, Course Administrator, Perkin-Elmer Ltd., Post Office Lane, Beaconsfield, Bucks, UK HP9 1QA Mrs.Fliehmann, Shimadzu Europe, GmbH, Albert-Hahn Strasse 6-10, D-472689 Duisburg, Germany The Training Department, Campden & Chorleywood Food Research Association, Chipping Campden, Glos., UK GL55 6LD Tel: +44 (0)1386 842104. Fax: +44 (0)1386 842100. Dr. B. L. Sharp, Department of Chemistry, Loughborough University, Loughborough LEI 1 3TU, UK Tel: +44 (0) 1509 222 572/575. Fax: +44 (0) 1509 223 925. E-mail: B.L.Sharp@lboro.ac.uk. The Training Department, Campden & Chorleywood Food Research Association, Chipping Campden, Glos. GL55 6LD, UK Tel: +44 (0)1386 842104. Fax: +44 (0)1386 842100. Robyn Castleman, Continuing Education Administrator, CETAC Technologies, 5600 S. 42nd St., Omaha, NE 68107, USA Tel: +1 402 733 2829, +1 800 369 2822.Fax: +1 402 733 5292. Dr. P. Tebbutt, Department of Chemistry, University of Warwick, Coventry, UK CV4 7AL Secretariat 1997 European Winter Conference, Luc Moens, Laboratory of Analytical Chemistry, University of Gent, B-9000 Gent, Belgium Tel: +32 9 264 6600. Fax: +32 9 264 6699. E-mail: plasma97@rug.ac.be. Secretariat 1997 European Winter Conference, Luc Moens, Labortory of Analytical Chemistry, University of Gent, B-9000 Gent, Belgium Tel: +32 9 264 6600. Fax: +32 9 264 6699. E-mail: plasma97@rug.ac.be. Secretariat 1997 European Winter Conference, Luc Moens, Laboratory of Analytical Chemistry, University of Gent, B-9000 Gent, Belgium Tel: +32 9 264 6600;. Fax: +32 9 264 6699. E-mail: plasma97@rug.ac.be. Secretariat 1997 European Winter Conference, Luc Moens, Laboratory of Analytical Chemistry, University of Gent, B-9000 Gent, Belgium Tel: +32 9 264 6600. Fax: +32 9 264 6699. E-mail: plasma97@rug.ac.be. Entries in the above listing are included at the discretion of the Editor and are free of charge. If you wish to publicize a forthcoming meeting please send full details to: The Analyst Editorial Office, Thomas Graham House, Science Park, Milton Road, Cambridge, UK CB4 4WF. Tel: +44 (0)1223 420066. Fax: +44 (0)1223 420247. E-mail:Analyst@RSC.ORG.

ISSN:0003-2654    

DOI:10.1039/AN996210152N

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

Analyst, October 1996, Vol. 121 153N I COPIES OF CITED ARTICLES Future Issues Will Include Rapid 90Sr Determination in Environmental Samples by Single Cerenkov Counting Using Two Different Colour Quench Curves-Montserrat Llaurado, J. M. Torres, J. F.Garcia, G. Rauret Gas Chromatographic Analysis of Chlorophenolic, Resin and Fatty Acids in Chlorination and Caustic Extraction Stage Effluent From Kahi Grass-S. Kumar, Chhaya Sharma, S. Mohanty, N. J. Rao High-performance Liquid Chromatography Methods for Deter- mination of Marine Biotoxins-A. Gago-Martinez, M. Comesana-Losada, J. M. Leao-Martines, J. A. Rodriguez- Vazquez Thermometric Determination of Copper(I1) Using Acid Urease-Bengt Danielsson, Claudia Preininger Simultaneous Spectrophotometric Determination of o-Cresol and rn-Cresol in Urine by Use of the Kinetic Wavelength Pair Method-Dolores Perez-Bendito, Maria Lopez Carreto, Loreto Lunar, Soledad Rubio New Technique and Support for Microorganism Immobiliza- tion.Application to Trace Metals Enrichment by Flow Injec- tion-Atomic Absorption Spectrometry-Angel Maquieira, Hayat A. M. Elmahadi, Rosa Puchades The Analysis of Halogens, with a Special Reference to Iodine, in Geological and Biological Samples Using Pyrohydrolysis for Preparation and ICP-MS and Ion Chromatography for Measure- ment-B. Schnetger, Y. Maramatsu Polymer Agglutination-based Piezoelectric Immunoassay for the Determination of Complement 111-Guo-Li S hen, Xia Chu, Ru-Qin Yu A Comparative Study of the Performance of Micellar and Hydro-organic Mobile Phases in Reversed-phase Chromato- graphy for the Analysis of Pharmaceuticals Containing Beta- blockers and Other Antihypertensive Drugs-M.C. Garcia Alvarez-Coque, I. Rapado-Martinez, R. M. Villanueva- Camanas Continuous Monitoring of Ozone in Air by Reflectiometry- Nobuo Nakano, Akihiro Yamamoto, Kunio Nagashima Determination of Cur1 by Anodic Stripping Voltammetry by Means of a Flow-through System-Peter R. Fielden, A. Economou Electroanalysis for the Purpose of Environmental Monitoring and Specimen Banking-Is There a Future?-Hendrik Emons, Peter Ostapczuk Time-resolved Resonance Raman Spectroscopy-A Tutorial Review-Steven Bell Single-piece All-solid-state Calcium-selective Electrode Based on Polyaniline. Part 11: An Impedance Spectroscopic Study- Ari Ivaska, Tom Lindfors, Johan Bobacka, Andrzej Lewenstam Statistical Aspects of Proficiency Testing in Analytical Labor- atories.Part 1 : Ranking of Participants Scores-Michael Thompson, Philip J. Lowthian Statistical Aspects of Proficiency Testing in Analytical Labor- atories. Part 2: Testing for Sufficient Homogeneity-Michael Thompson, Philip J. Lowthian Statistical Aspects of Proficiency Testing in Analytical Labor- atories. Part 3: Confirmatory Tests for Scheme Organizers- Michael Thompson, Philip J. Lowthian Electrothermal and Thermal Behaviour of New Calcium Ion- selective Membranes-Arthur K. Covington, Eugenia Totu Hot Wire Electrodes: Voltammetry above the Boiling Point- Peter Grundler, Andreas Kirbs, Tadesse Zerihun Effect of Different Experimental Parameters on the Potentio- metric Evaluation of Blood Electrolytes Using K+ as a Test Cation-M. J. F. Rebelo, Cristina M. R. R. Oliveira, M. F. Camoes The Royal Society of Chemistry Library can usually supply copies of cited articles. For further details contact: The Library, Royal Society of Chemistry, Burlington House, Piccadilly, London W1V OBN, UK. Tel: +44 (0)171-437 8656. Fax: +44 (0)17 1-287 9798. Telecom Gold 84: BUR2 10. Electronic Mailbox (Internet) LIBRARY@RSC.ORG. If the material is not available from the Society’s Library, the staff will be pleased to advise on its availability from other sources. Please note that copies are not available from the RSC at Thomas Graham House, Cambridge.

ISSN:0003-2654    

DOI:10.1039/AN996210153N

出版商:RSC    

年代:1996

数据来源: RSC

摘要:

154N h u l y s t , Oc*toher. 1996, Vol. 121 Technical Abbreviations and Acronyms The presence of an abbreviation or acronym in this list should NOT be read as a recommendation for its use. However, those defined here need not be defined in the text of your manuscript. AAS ac A D ADC ANOVA AOAC ASTM bP BSA BSI CEN CPrn CMOS c.m.c. CRM CVAAS cw CZE dc DRIFT DELFIA DNA EDTA ELISA emf ETAAS EXAFS EPA FAAS FAB FAO-WHO FIR FT FPLC FPD GC GLC HGAAS HPLC ICP id INAA IR ISFET iv im IGFET IS E LC LED LOD LOQ dpm atomic absorption spectrometry alternating current analogue- to-digital analogue-to-digital converter analysis of variance Awxiation of Official Analytical Chemists American Society for Testing and M ateri a1 s boiling point bovine serum albumin British Standards Institution European Committee for Standardimti on counts per minute complementary metal oxide silicon critical micellization concentration certified reference material cold vapour atomic absorption spec troinetry continuous wave capillary zone electrophoresis direct current disintegrations per minute diffuse reflectance infrared Fourier transform spectroscopy diwxiation enhanced lanthanide fluorescence immunoassay deoxyribonucleic acid ethylenediaminetetraacetic acid enzyme linked immunosorbent assay electromotive force electrothermal atomic absorption spectrometry extended X-ray absorption fine structure spectroscopy Environmental Protection Agency flame atomic absorption spectrometry fast atom bombardment Food and Agriculture Organization, far- infrared Fourier transform fast protein liquid chromatography flame photometric detector gas chromatography gas-liquid chromatography hydride generation atomic abwrption high-performance liquid inductively coupled plasma internal diameter instrumental neutron activation infrared ion-selective effect transistor intravenous intramuscular insulated gate field effect transistor ion-selective electrode liquid chromatography light emitting diode limit determination limit of quantification World Health Organization spectroscopy chromatography analy\i c "P MRL mRNA M s NIK NMR N IST od OES PBS PCB PAH PGE PIXE PPt PPb PPm PTFE PVC PDVB QC QA REE rf RIMS rm s rpm RNA SCE SE SEM SIMS SIMCA S/N SRM STM STP TIMS TLC TOF TGA TMS tris TRIS uv uv/vrs VDU XRD XRF Y AC melting point maximum residue limit messenger ribonucleic acid mass spec trorne t ry near-infrared nuclear magnetic resonance National Institute of Standards and Technology outer diameter optical emission spectrorne t ry phosphate buffered saline polychlorinated biphenyl polycyclic aromatic hydrocarbon platinum group element part i c le/p ro t on - i nd Liceif X-ray parts per trillion (10'2; pg g--i) parts per billion ( 1W; ng g 1 ) parts per million (loh; pg g-I) poly(tetrafluoroethy1ene) poly(viny1 chloride) poly(diviny1 benzene) quality control quality assurance rare earth element radiofrequency resonance ionization mass spectrometry root mean square revolutions per minute ribonucleic acid saturated calomel (reference) electrode standard error scanning/surface (reflection) electron microscopy secondary-ion mass spectrometry soft independent modelling of class signal-to-noise ratio Standard Reference Material scanning tunnelling (electron) standard temperature and pressure thermal ionization mass spectrometry thin-layer chromatography time-of-fl ight thermogravimetric analysis t r imeth y Is i 1 ane 2 -am in 0-2 -( 11 y dro x ym e t h y I ) - propane-l,3-diol (ligand) 2-amino-2-( hydroxymethy1)- propane-l,3-diol (reagent) ultraviolet ultraviolet-vi si ble visual display unit X-ray difirac tion X-ray fluorescence yttrium aluminium garnet emission analogy microscopy Commonly Used Symbols M molecular mass Mr relative molecular mass 1- correlation coefficient 7 standard deviation U atomic mass

ISSN:0003-2654    

DOI:10.1039/AN996210154N

出版商:RSC    

年代:1996

数据来源: RSC

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Analyst, October 1996, Vol. 12I (1359-1365) 1359 Resolution of Partially Overlapped Signals by Fourier Analysis. Application to Different ial-pulse Polarog rap h ic Responses Davide Allegri“, Giovanni Moria and Renato Seeberb* Fisirw, Uniiw-Jitu di Pal-niu, Vide delle Scienze, 431 00 Pal-ma, Italy Risoi-giniento, 4 , 40136 Bologna, Ituly Dipartiniento di Cliiniica Geneiule e Inoi,gunic.a, Chimica Analitica e Chimica Dipai-timento di Chiniica Fisicu e Inorgunicu, Universitd di Bologna, Vide del An analysis of the first harmonic components of the sequence resulting from a suitable deconvolution operation on a response composed of single partially overlapped signals allows the resolution of the over-all response into the individual signals. Ideally, it is possible to reduce the original response to single impulses with suitable height and location. If the number, n, of single signals is known, the first n - 1 harmonic components of the spectrum of the deconvoluted response, plus the continuous term, need only be computed.On the other hand, if the over-all response includes an unknown number of single signals, a method is suggested that requires the calculation of only a few harmonic components in order to build up a suitable form of the whole spectrum of the deconvoluted signal. The effectiveness of the proposed procedures, which are suitable for the treatment of responses from different analytical techniques, was tested on simulated responses, both in the absence and presence of noise, and on experimental data, viz., differential-pulse polarographic responses recorded on solutions containing two metals that were reduced at similar potentials.Keywords: Signal processing; digitul ,filtei*ing; i-csolutioiz of signals; Forri-iei- aiialysis; decon\vlution; se~-~e~~oii~oliiti(jri; diffei-ential-pulse polarogi-aphy Introduction The problem of obtaining the maximum possible information from composite signals, i.e., of defining the single components with respect to position, height and shape, has been the subject of many studies in the field of electrochemistry, spectroscopy, chromatography, and any type of detection procedure that can be thought of as a multicomponent analysis.1-22 Different approaches have been followed, the most popular and effective of which appear to be self-deconvolution based on Fourier transform, direct curve fitting, or a combination of the two techniques.It has been emphasized, however, that Fourier self- deconvolution, in spite of being, in principle, the procedure of choice, presents the serious drawback of involving divisions between very small, non-significant numbers, which leads to instability of the system: small amplitudes are common to the medium-high frequency portion of the signals usually encoun- tered in an analytical context and, consequently, of the corresponding deconvoluting sequences; hence, spurious fre- quencies often pollute the signal resulting from deconvolution. On the other hand, a simple boxcar truncation, i.e., the application of a rectangular frequency low-pass filter, causes * To whom coirespondence should be addressed. spurious oscillations due to the Gibbs phenomenon.Z3 In order to damp the oscillations as much as possible, variou\ apodiza- tion functions have been studied and proposed;4-”l2J4 however, the problem has still to be solved satisfactorily. In view of the difficulties encountered in following classical approaches to deconvolution of partially overlapped signals, we turned our attention to a more accurate analysis of the spectrum of the deconvoluted signal.On the basis of the properties of the first harmonic components of the spectra obtained from both simple and composite signals, two different procedures have been established. The first can be followed when the number of individual signals comprising the over-all response is not known; the second can be applied when the number of individual signals is known in advance.As a benchmark for the proposed algorithms, this paper considers simulated and experimental responses in differential-pulse polarography (DPP). It is well known that in this electroanalytical tech- nique,2s.26 the sensitivity of the measurement increases on increasing the amplitude of the potential step; on the other hand, this may lead to poor resolution with the presence of more than one single peak in a narrow potential range. Experimental Experimental DPP responses were recorded on aqueous solutions prepared by dilution of commercial standards. The potentiostat was a Princeton Applied Research (PAR) (Prin- ceton, NJ, USA) Model 174A equipped with a PAR Model 303 stand. The working, auxiliary and reference electrodes were a 0.5 mm diameter mercury drop, a platinum foil and an Ag- AgC1-KCl(sat.) electrode, respectively.Pulse heights of 5 (cadmium and lead solutions) or 10 mV (lead + thallium mixture) were superimposed on the potential, which was varied linearly at a scan rate of 10 (former case) or 5 mV s-1 (latter case). Solutions of 0.1 moll-’ KC1 or 1 mol 1 - I NaF were used as supporting electrolytes. Basic Theory Let us consider two finite sequences, x{ n } and z{ n ) , with equal length. The convolution sequence, y{ n }, can be conveniently computed by taking advantage of the convolution theo- rem:27.28 y { n ) = x ( n ) * z { n } = F - ’ ( F [ x { n } ] x F [ z ( n } ] ) ( I ) where the symbol * indicates the convolution operation; F and F- I indicate direct and inverse Fourier transform, respec- tively.Conversely, z is defined as the deconvolution sequence of y by x: (2) z { n } = y { n } * - ’ x In} = F-1(F[y(n}]/Flx(ii)])1360 Analyst, October 1996, VoE. 121 where the symbol *- 1 indicates the deconvolution operation. If x coincides with y in shape, but not necessarily in position, deconvolution becomes a self-deconvolution. z is, in this case, a unit impulse 6{ n ) , equal to zero over the whole interval of definition, but in a single point:29 ( 3 ) 6 ( n * a ) = x(n * a } *-I x{n) a being a constant, either equal to, or different from, zero. The unit impulse function, 6, is defined as: (4) 0 when n f a 1 when 11 = a 6 { n + a } = By considering a normalized sequence, x, basis of a vector space, a linear combination generates the generic vector v( n } : v{n) = c x{n+o,} x (‘, ( 5 ) so that deconvolution of v by x can be considered as the transformation of v into a vector space generated by 6: Hence, if the signal can be represented by deconvolution by x leads to a linear combination of 6 sequences with the same values for the coefficients a, and ‘;.The discrete Fourier transform operation on a finite sequence x consisting of N points is defined as: x{n*a,) X C17 c (7) X{ k ) = x{ x e-J(?xlwkn 0 5 k < N x ,1=0 where k is the index of a given harmonic component ( = 0 for the continuous component). In particular, the Fourier transform of 6 leads to: I . P . , Deconvolution Procedures Procedure 1 Fig. l(h) and ( c ) shows the vectorial representation of the different harmonic components relative to an impulse function, 6 [Fig.l(a)]. It consists of a sequence of unitary modulus vectors with phase angles given by: (10) Eqn. (10) can be utilized in order to establish an effective procedure to describe the signal using only a small portion of the relevant spectrum. Since the result of eyn. (8) can be viewed as Ok = (2n/N) X ka; 0 < k < N a rotation, defined by the 01, sequence, of every point of 6, a key point in the analysis of the spectrum consists in ascertaining whether the N-element sequence of the angles between two subsequent vectors is composed of equal sub-sets, each consisting of M elements. A further point is to establish if M is small enough with respect to N . An analysis of a large number of different situations allowed us to confirm that an affirmative answer can be given to both questions, M being defined by the following equation: @ A ( L ) .4 ( k + M ) = 2nM/N ( 1 1) which is valid for 0 I k < N - M ; <p is the angle between two vectors that are M indices far from each other. The advan- tageous conclusion is that M harmonic components are suitable to describe the signal completely. By properly ‘copying’ (see the procedure reported below) the first M-element part of the spectrum over the whole range of frequencies, the whole spectrum of the signal is constructed. Through this operation the signal retains fully the information content at low frequencies and discards that at higher frequencies, without the inconven- ience of the usual filtering operations.In particular, the impulse in Fig. 1 (a), located at the 200th point of a I024 point sequence, is described by the first four harmonic components reported in Fig. l(c) (M = 4). A different index for the location of the impulse leads to different situations with respect to the position of subsequent vectors on the imaginary wrsus real component plot on the vectorial plane and, consequently, to the value of M . Once a vector A { h } (0 I h I M ) has been computed, the whole spectrum A{ k } can be re-constructed as follows: A{ k } = A{ h } for 0 I h I Mi. e., for the first M + I indices k A(k} = A{m + p x M } = A{m + ( p - 1) x M}e-lv; l < m < M ; l < p < i n t [ - for k > M (12) where cp G @ in eqn. (1 1). Of course, additional A terms with respect to A(N - 1) should be disregarded.The original sequence, 6, is re-obtained by: 6 ( n } = F ’ (A{k)) (13) For two generic impulses, the sequence to be transformed can be written as: = 0 when n # aI and # ar = p when n = u1 = ‘c when n = a2 (14) d{n} = p6, { n k u1 1 + z6, { n k a 2 ) I Taking advantage of the linearity property of Fourier trans- form27 one obtains: A( k ) = F(pa1 { n ) + -&( n ) ) = p e-I(2n/W~~l + ‘c e-/(*Jr/WLu2 (15) i.e., A(N - 1) = p e-/(2n/N)(N - 1 )a1 + e- /(2x/N)(& - 1 )~2 (16) It is evident that a simple normalization on eqn. (14) can lead either p or ‘c to be unitary, so that only one of the two modulus in eqns. (14)-( 16) assumes a non-unitary value. More complex patterns for the vector representation of the spectrum of the signal may be encountered.Apart from theAnalyst, Octobei- 1996, Vol. 121 1361 1 - 0.9 0.8 0.7 > 0.6 0.5 ' 0.4 c. .- m w computation of M through a simple algorithm written to find the solution of eqn. ( 1 I ) , the possibility of identifying sub-sets composed of M elements inside the whole N-element frequency sequence implies that notable geometric properties are charac- teristic of the sequence of vectors. It follows that the whole N- component spectrum is obtained by a 2x rotation of a polygon defined by just M vectors. An example is given in Fig. 2. Two impulses at the 76th and 300th points of a 1024 point sequence, respectively, with relevant heights of 2.5 : 1 [Fig. 2(u)] lead to an N-point spectrum [Fig. 2(h)] that can be obtained by subsequent rotations of the first M ( = 14) harmonic components.Fig. 2(d) shows the result of two subsequent rotations of the elemental polygon in Fig. 2(c). The procedure described can be extended to consider complex responses consisting of more than two individual signals. Fig. 3 shows the results obtained with a system of three impulses: the original sequence (u) is reconstructed on the basis of the first ten harmonic components (h). When dealing with an analytical response, cleaned of any noise, described by a sequence s { I I } , the previous discussions for x can be extended to s. Notationally: s ( n ) = x ( n + a ) (17) s { n } k ' X { I 1 ) = b { n + a ) (18) In view of eqn. (3) one can write: If the response consists of two individual signals, eventually partial 1 y over1 apped: (4 - - - - - - 0.3 0.2 0.1 - - - 0 200 400 600 800 1000 1200 index E 0.2 8 .e -0.2 (d OI L 0.4 -0.6 1 -0.8 1 so that: s { n } *-' x(n) = & ( n + a , } x ('I +6{n+a*} x ('2 (20) The result of the deconvolution by x should hence consist of two impulses with heights equal to c I and c2 and locations at a l and u2, respectively.This pattern can be correctly built up by calculating a deconvolution sequence A{ h } limited to the first M harmonic components, as discussed above. Defining: S { k } = F ( s { n } ) (21) one can compute: and then re-construct the whole spectrum, A, as described in eqn. (1 2). Finally: d{ / I } = F-'(A{ k ) ) (23) Procedure 2 The method reported above does not require the a priori knowledge of the number of impulses in the sequence, because the evaluation of M through eqn.(1 1) is directly performed on the spectrum of the signal. On the other hand, in those cases in which the number of individual component signals is known, a m a -0.6 - 0 8 -1 Real component L a, C 0.4 - 0 Q - 8 L. 0 - - k - 0 4 - c a - 1 - m -1 -05 0 0.5 Real component Fig. 1 Unit impulse ( ( I ) with thc vectorial representation of the relevant spectrum (h). The first four harmonic components are shown in ( c ) \ 1I362 Analvst, Omher 1996, Vol. I21 further simplification of the procedure is possible. Considering the sequence expressed by eqn. (14), which consists of two generic impulses, the continuous and the first harmonic components can be obtained by Fourier transform [see eqns.( I 6)]. Expressing A( 1) directly in the form of a single vector resulting from the vectorial sum of two p and 'c modulus vectors, respcctively, one obtains: where 0 and (2n/N)I7 represent modulus and phase, respec- tively: where 1111 = imaginary and Re = real. A( I), a s well a s A(0), are explicitly computed: N O ) = S(O)/X(O) A(1) = S(I)/X(l) (5 and h. as well as the sum p + T, become known quantities from which p, t, a l and 0 2 have to be computed. By normalizing the response with respect to the height of one of the two impulses, e.g., by setting p to 1, -c can be computed as A(0) - p. The 0 + c - 0.4 0.3 0.2 0.1 0 200 400 600 800 1000 1200 Index .. -1 0.5 0 0.5 1 1.5 Real component locations of the two impulses, given by u1 and u2, respectively, are hence the only unknowns: a system of two independent equations, representing the projection and the Carnot theorems, respectively, can be written: Solving the equation system (28) leads to: N 2n (29) u, = h - - arcos a2 = h + - arcos [; - N 0 0 2 - t 2 + p 2 2 n 20-c Hence, starting from a two-peak response s ( k ) , it is only necessary to calculate S(0) and S( I), as well as X(0) and X( I ) of the deconvoluting function [see eqn. (27)].Any additional individual signal only requires the consider- ation of one additional harmonic component, i.e., of two additional unknowns and of two additional equations in the system. It follows that very complicated responses can be analysed by considering in any case a small number of harmonic components. 1 + c ? 0.5 E L. Q 8 0 S 0) .- -0.5 E - 1 I -1.5 -1 - 0 5 0 0.5 1 1.5 Real component Real component Fig.2 components, respectively. Two impulses ( [ I ) together with the vectorial representation of the relevant spectrum (h); (c.) and (4 show the first A4 (= 14) and 3 X A4 harmonicAnalyst, October 1996, Vol. 121 I363 Application to Signals Synthetic Signals The first problem to solve when dealing with experimental situations is the presence of superimposed noise. If the ~ ( n } sequence accounts for the deviations from the theoretical 'clean' response, s, the signal sequence, r, can be expressed by: r ( n ) = s { n } + ~ { n } (30) Deconvoluting r by x, i.e., the sequence representing a single 'ideal' response [see Fig. 5(b) as an example], leads to a sequence p { n } : p{n} = r { n ) *-I x(n) (3 1) Performing the deconvolution operation by the usual self- deconvolution algorithms, it is usually difficult to extract 6 [or 61 + .. . an] from p because of the problems discussed above. On thk other hand, according to the arguments discussed previously, even if the number of individual signals is unknown, the number, M , of harmonic components necessary to describe the proper impulse, or series of impulses, can be computed on the basis of the vectorial representation of the spectrum of the sequence resulting from deconvolution. Assuming that, as regards the first M components, the frequency content of E is negligible, it is possible to extract the spectrum of 6 [or of 6 l + 62 + . . . 6,] from that of p. The procedure is outlined in detail below for two individual signals.R(k1 = F ( r { n l ) (32) and 0.3 1 0.2} O.' 0 0 L 200 (b) 1 400 600 Index I 800 lo00 1200 -1.5 -1.5 -1 -0.5 0 0.5 1 1.5 Real component Fig. 3 components are shown in (h). Three impulses ( a ) lead to a spectrum whose first 1 1 harmonic X ( k } = F(x(nJ) (33) Defining: P,{ h } = R{ k } / X { k } limited to 0 S k d A4 (34) the remaining part of the PI( k } spectrum, which is obviously different from P ( k } = F(p{nj), is re-constructed in a way similar to eqn ( 12): P,(k} = Pl{h} P,{k}=P,(m+p x M } = P , ( n z + ( p - l ) ~ h ' } e - ' ' ~ ; for 0 5 11 I M i.e., for the first M + 1 indices k I I m I M ; l < p _ < i n t [:*)fork - > M Finally, the sequence we are seeking, relative to a single signal or to the sum of two individual signals, can be computed: ( 3 5 ) On the other hand, if it is known in advance that two signals compose the over-all response, we have only to compute the continuous and first harmonic components by relationships similar to eqn.(27). The evaluation of the quantities character- izing the deconvoluted signals is then straightforward by applying eqns. (25)-(29). Synthetic DPP Responses It is apparent that the deconvolution procedures described retain full validity independently of the measurement technique and can hence, in principle, be applied to the responses of different analytical methods. As an example of their application, let us consider a sequence representing a simulated differential-pulse polarogram relative to a single reversible uncomplicated one- electron charge transfer, the oxidized and reduced forms both being soluble in the solution phase:2s-.-70 where 6i is the measured quantity, GA and o are exponential functions of the electrode potential.E , and of the potential step, respectively, T and z' the times at which the current is sampled and the other symbols have their usual meming.25 An example of the application of the described procedures to the self- deconvolution of a simulated DPP system of two peaks representing the reduction of two species present in the solution at a relative concentration of 2.5 : 1 and with equal diffusion coefficients, is given in Fig. 4. The potential separation between the relevant formal potentials is about 120 mV. No significant differences between the results obtained with the two proce- dures are apparent.Fig. 5 illustrates the same sequence as that in Fig. 4, but this time affected by noise consisting of a linear combination of sinusoids with amplitudes proportional to the signal intensity: both deconvolution procedures give satisfactory results [Fig. 5(a) and (b) for procedures 1 and 2, respectively]. Procedure 1 preserves the location and height of the individual signals with an accuracy of about 5%, while the results of procedure 2 are affected by errors lower than 1%. Spurious spikes are clearly detectable in the result of procedure 1 [Fig. 5(a)]. The choice of the number of harmonic components to use in order to reconstruct the whole spectrum of the deconvoluted signal (i.e., the value of M) is critical, so much so that, when dealing with signals that are very far from being 'ideal', the useful signal can be completely hidden by spurious1364 Analyst, October- 1556, Vol. I21 spikes.This is a consequence of the fact that M increases on increasing the noise. Acceptable results can, however, also be obtained with low M values in the presence of noise as high as that in Fig. 5 . The result of the elaboration of this signal is not trivial, because the application of a conventional filtering technique to a noisy signal can, on the one hand, be capable of reducing the random noise efficiently but, on the other hand, can introduce into the signal a much more subtle noise, i.e., a type of marked Index Fig. 4 result of the deconvolution performed according to procedure 1. Two partially overlapped simulated DPP signals, together with the 1.2r g o 200 400 600 800 1000 1200 0 200 400 600 800 1000 1200 Index Fig.5 Sequence shown in Fig. 4 with superimposed noise, together with the result of deconvolution by procedure I (a> and procedure 2 (h), respectively. ‘distortion’, which is the cause of the problems encountered in the usual self-deconvolution operations. Experimental Signals The procedures outlined above were tested in different experimental situations, i.e., for signals recorded under condi- tions that are far from ‘ideal’, e.g., not completely reversible charge-transfer processes, signals distorted by ‘ faradaic’ and ‘charging current’ effects,’6 and the use of relatively high values for the linear potential scan on which the pulses are superimposed. In this case, the responses do not fit the theoretical eqn.(37), resulting in a peak width different from that expected on the basis of the electronicity (the number of electrons involved in the charge transfer) of the process and asymmetric (distorted) in shape. The procedures were also tested for two signals representing processes with different electronicity. In this case, the deconvoluting function cannot be correctly evaluated by eqn. (37): the operation is no longer one of self-deconvolution. We have verified that for symmetrical peaks, satisfactory results are obtained by using appropriate values c.g., eventually non-integer numbers, for 12 in eyn. (37), provided that they lead to a particular criterion being satisfied. such as, for example, a good fit with a portion of the experimental curve.Furthermore, asymmetry is well accounted for by convolution of the peak with a suitable sequence, typically an exponential decay. These additional elaborations involve implementing the algorithms described here in more complete and flexible procedures. This aspect is currently under study in our laboratories. Two examples are given here to illustrate how a single-step-signal-treatment based on the proposed methods works. An example of the result obtained with deconvoluting functions using appropriate values for n in eqn. (37) is also provided. Fig. 6 displays the sum of DPP responses recorded for 1 ppm cadmium and lead nitrate solutions. The individual respomes have been shifted so that their maxima coincide with each other and, subsequently, the response of cadmium has been further shifted at lower abscissa indices to an extent of 40 mV; the final response has been normalized.The individual peak heights are actually in a ratio of 1 : 0.83 and appear almost equal to each other only because of the tailing of the first (cadmium) peak. The application of the second proposed procedure leads to the signals shown in Fig. 6. The results can be summarized as follows: ‘impulse’ height ratio = 0.6 (theoretical value 0.83); location of cadmium response: index 67 (theoretical value 57); 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 ’ 0.1 ’ c .- a, c-’ 0 50 100 150 200 250 0 Index Fig. 6 Elaboration, i.e., displacement and sum, of DPP responses recorded for 1 ppm cadmium(1rj and lead(ii), 1 mol I-’ NaF aqueous solutions, respectively, together with the result of deconvolution.An index difference of 1 corresponds to I mV.Analyst, October 1996, Vol. I21 1365 300 350 400 450 Index 500 550 Fig. 7 -Experimental DPP response recorded for a 9 ppm lead(r1) f 10 ppm thallium(i), 0.1 mol 1-1 KCl, aqueous solution, together with the result of deconvolution. An index difference of 1 corresponds to 1 mV. location of lead response: index 115 (theoretical value 97). By using an n value of 2.3 instead of 2.0, the following results are obtained: ‘impulse’ height ratio = 0.838; location of cadmium response: index 62; location of lead response: index 112. Fig. 7 shows the DPP response recorded for a solution of lead(1r) and thallium([) at a relative concentration ratio of 9 : 10, together with the result of treating the signal by either of the proposed procedures.An intermediate value between the electronicity of thallium and lead reductions was used to define the deconvoluting function. The position of the peaks was located with an accuracy of about 10 mV; the relative height of the impulses was accurate to within 10%. Partial financial support of MURST (40% and 60%) is acknowledged. D.A. was supported by a fellowship from Barilla S.p.A. and Parmalat S.p.A., Parma, Italy. References 1 2 3 Grabaric, B. S., O’Halloran, R. J., and Smith, D. E., Anal. Chim. Acta, 198 1, 133, 349. Kauppinen, J. K., Moffatt, D. J., Mantsch, H. H., and Cameron, D. G., Anal. Chem., 1981, 53, 1454. Toman, J. J., and Brown, D. S., Anal.Chem., 1981, 53, 1497. 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Kauppinen, J. K., Moffatt, D. J., Cameron, D. G., and Mantsch, H. H., Appl. Opt., 1981,20 1866. Kauppinen, J. K., Moffatt, D. J., Mantsch, H. H., and Cameron, D. G., Appl. Spectrosc., 198 1, 35, 27 1. Caster, D. M., Toman, J. J.. and Brown, D. S., Anal. Chem., 1983,55, 2143. Dyke, J. T., and Fernando, Q., Tulanla, 1985, 32, 807. Engblom, S. O., and Ivasaka, A. U., in Elec.trcic.hemistry, Sensors und Analysis, eds. Smyth, M. R., and Vos, J. G., Analytical Chemistry Symposium Series, vol. 25, Elsevier, Amsterdam, 1986, pp. 49-54. Mittlefehldt, E. R., Gardella, J. A., Jr., and Salvati, L., Jr., Anal. Clzim. Acta, 1986, 191, 227. Lacey, R. F., Anal. Chem., 1986, 58, 1404. Muller, K. H., and Plesser, Th., Thermochim. Actu, 1987, 119, 189. James, D. I., Maddams, W. F., and Tooke, B. P., Appl. Spectrosc., 1987,41, 1362. Englom, S. O., J . Electroanal. Chem., 1990, 296, 371. Perdih, M., and Zupan, J., Vestn. Slov. Keni. Drus., 1990, 37, 13 1. Pierce, J. A., Jackson, R. S., Van Every, K. W., Griffiths, P. K., and Hougjin, G., Anal. Chem., 1990, 62, 477. Pizeta, I., Lovric, M., and Branica, M., J . Electi-ourzal. Chem., 1990, 296, 395. Palys, M., Korba, T., Bos, M., and van der Linden, W. E., Tulunra, 199 1, 38, 723. Englom, S. O., J . Electroanal. Chem., 1992, 332, 73. Rotunno, T., Fuesenius’ J . Anal. Chem., 1993, 345, 490. Economou, A., Fielden, P. R., Gaydecki, P. A., and Packham, A. J., Analyst, 1994, 119: 847. Felinger, A., Anal. Chem., 1994, 66, 3066. Economou, A., Fielden, P. R., and Packham, A. J., Analyst, 1996, 121, 97. Oppenheim, A. V., and Schafer, R. W., Digitnl Signal Processing, Prentice-Hall, Englewood Cliffs, NJ, 1975. Hamming, R. W., Digiral Filters, Prentice-Hall, Englewood Cliffs, NJ, 3rd edn., 1989. Bard, A. J . , and Faulkner, L. K., Elrc.trochemic~a1 Methods. Fundamentals und Applications, Wiley, New York, 1980. Bond, A. M., Modern Polarogruphic Merhods in Analytical Chem- istry, Marcel Dekker, New York, 1980. Brigham, E. O., The Fast Foi~iei. Transform, Prentice-Hall, Englewood Cliffs, NJ, 1974. Bracewell, R. N., The Fourier Transform and Its Applications, McGraw-Hill, New York, 2nd edn., 1978. Weaver, H. J., Applications of Discrete and Continuous Fourier Analysis, Wiley, New York, 1983. Pizeta, I., Jeren, B., and Aleksic-Maslac, K., J . Electroanuf. Chem., 1994,375, 169. Paper 61032 17F Received May #, I996 Accepted July 16, I996

ISSN:0003-2654    

DOI:10.1039/AN9962101359

出版商:RSC    

年代:1996

数据来源: RSC