Pharmaceutical Chemical Analysis: Methods for Identification and Limit Tests

155 Pages·2006·3.394 MB·English

by  Ole Pedersen

Pharmaceutical Chemical Analysis:
Methods for Identification
and Limit Tests
Ole Pedersen
© 2006 by Taylor & Francis Group, LLC
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International Standard Book Number-10: 0-8493-1978-1 (Hardcover)
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Library of Congress Cataloging-in-Publication Data
Pederson, Ole.
Pharmaceutical chemical analysis : methods for identification and limit tests / Ole Pederson.
p. ; cm.
Includes bibliographical references and index.
ISBN 0-8493-1978-1
1. Drugs--Analysis--Laboratory manuals. 2. Drugs--Standards--Laboratory manuals. 3.
Pharmaceutical chemistry. I. Title.
[DNLM: 1. Pharmaceutical Preparations--analysis--Laboratory Manuals. 2. Pharmaceutical
Preparations--standards--Laboratory Manuals. 3. Drug Compounding--standards--Laboratory
Manuals. 4. Quality Control--Laboratory Manuals. 5. Reference Standards--Laboratory Manuals. QV
25 P371p 2005]
RS189.P39 2005
615'.1901--dc22 2005052909
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Preface
The obvious potential severity of wrongfully giving an already weak patient
the wrong medication, or giving medicine with a harmful content of
unwanted substances, led relatively early (compared to other industries) to
formal governmental demands on the quality of pharmaceutical products
and pharmaceutical ingredients. One aspect of these demands includes
chemical tests specified in pharmacopeias defining requirements on identity
and chemical purity with which raw materials bound for pharmaceutical
dosage from production must comply. The methodology of the tests adapted
has in principle reflected the current knowledge and technological expertise
of the pharmaceutical society at the time of adaptation of the test methods
in question. Early monographs relied largely on appearance, taste, and smell
as well as microscopic characterizing, whereas recently adapted monographs
are often based on sophisticated and expensive analytical techniques such
as capillary electrophoresis, X-ray spectroscopy, and an extensive use of high-
performance liquid chromatography.
There is, however, some tardiness in the process of replacing methods
relying on outdated analytical techniques with more modern ones for several
reasons. First, the pharmaceutical industry is in general a rather conservative
one with respect to bringing in new technology, again for several reasons.
Huge economical interests are at stake so no one wants to jeopardize the
product development time line by using technology that has not already
proven its quality. So, newer methods are often run in parallel with older
ones for a long time, thereby not fully releasing its cost saving and knowl-
edge enrichment potential. In addition, the pharmaceutical industry has
increasingly been the subject of goods manufacturing procedure (GMP)
requirements, and are therefore, the subject of periodic inspections. Also,
one must justify methodology used when filing for approval of a new drug
product. Obviously it will be easier to prove the validity of a well known
and widely used technique and a manufacturer could be tempted not to
spend time and effort in justifying the capability of novel techniques to
ensure consistent and sufficient drug product quality. Also, it is a substantial
bureaucratic maneuver to effect the change in a European Pharmacopoeia gen-
eral test referendum referenced in many individual monographs in a super-
national organization like the European Pharmacopoeia Commission. A last
reason for not replacing old methods is that some tests actually perform
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quite well and one could question why something simple and economical
should be replaced with expensive instrumental techniques.
This, however, leaves us with a number of rather old chemical methods,
which are based on analytical principles, like colorimetry, using selective
reagents and precipitation-based techniques, which have largely been aban-
doned in modern analytical chemistry. The basic assumptions and theoretic
background of these techniques are to only a limited extent a part of the
training of the contemporary and very instrumentally orientated analytical
chemist. Even less likely will he or she have enough knowledge about
specific color reagents. The literature dealing with the techniques is so old
that nothing is found in an electronic literature search and information is
therefore less accessible. The specific knowledge collected by national medic-
inal agencies is to a large extent closed to the public.
The past few decades have seen a massive increase in GMP requirements,
and this has been reflected in recruitment especially in the analytical quality
control laboratory. Very often, within the department, job candidates have
been screened for their GMP experience and attitude as compared to ana-
lytical chemistry skills. The prerequisites of the typical quality control ana-
lytical chemist are to understand the tests performed and thereby being
capable of solving any occurring problems, which very often does not equal
the outside pressure and potential economic implications an unsolved ana-
lytical problem might cause. This book is intended to aid the quality control
chemist, but also in general to make knowledge about these tests easily
accessible to academics and technicians working with these tests. It is orga-
nized into two parts dealing with the tests of European Pharmacopoeia 2.3.1
and 2.4, identification and limit tests, respectively. Each part contains three
general chapters where subjects relevant to all the pharmacopoeial identifi-
cation/limit tests are discussed, and then the individual tests are described
and discussed in sections organized and named as in the European Pharma-
copoeia. The test sections start with a few short remarks about the purpose
and rationale of the tests, followed by a review of the physical and chemical
characters of the ion or compound that is the target of the test. Then the
chemical background and logic of the individual procedural steps of the test
are described, with formulas and reaction, including remarks about the
strengths and weaknesses in terms of specificity, ruggedness, and potential
procedural pitfalls. All chapters include a list of references that could be the
starting point of further investigations.
The methods of the two European Pharmacopoeia general test chapters are
among the oldest in the pharmacopoeia. Many of the tests on the simple
inorganic ions are based on selective precipitation using only simple inor-
ganic reagents. Many of these tests were developed in response to the needs
of the mining industry in the nineteenth century. A wealth of information
on the specificity, strengths, and weaknesses of these techniques can be found
in older inorganic qualitative and quantitative analytical chemistry litera-
ture, but very often it is not possible to find evaluations on methods carried
out exactly as adapted by the pharmacopoeia. The use of colored derivatives
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began in the early 20th century, gained much attention with the development
of more sophisticated optical equipment during the middle of the century,
until their application declined dramatically toward the end of the century
as a result of the success of chromatographic techniques. Such methods are
dealt with in analytical chemistry handbooks and also in scientific journals
published prior to the 1980s.
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Acknowledgment
The author wishes to thank
Tina, QC GEA 2002–2004, and Albert Bentz.
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About the Author
Ole Pedersen is a pharmacist of the Danish University of Pharmaceutical
Sciences and has throughout his career worked with various aspects of
analytical chemistry in the pharmaceutical industry. His work led to his
broad expertise in the fields of analytical quality control and analytical
development, and a thorough knowledge of GMP and regulatory affairs
requirements.
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Table of Contents
Part I: Identifications
Chapter 1 Precipitation in identifications......................................................3
Precipitate selectivity..............................................................................................3
Precipitate appearance...........................................................................................5
Chapter 2 Color reactions in identifications.................................................9
Chapter 3 Tests .................................................................................................11
3.1 Acetates (European Pharmacopoeia 2.3.1)...................................................12
3.2 Acetyl (European Pharmacopoeia 2.3.1)......................................................14
3.3 Alkaloids (European Pharmacopoeia 2.3.1).................................................16
3.4 Aluminum (European Pharmacopoeia 2.3.1)..............................................18
3.5 Amines, primary aromatic (European Pharmacopoeia 2.3.1)...................20
3.6 Ammonium salts (European Pharmacopoeia 2.3.1)...................................22
3.7 Ammonium salts and salts of volatile bases (European
Pharmacopoeia 2.3.1).....................................................................................24
3.8 Antimony (European Pharmacopoeia 2.3.1)................................................25
3.9 Arsenic (European Pharmacopoeia 2.3.1)....................................................26
3.10 Barbiturates, non–nitrogen substituted (European
Pharmacopoeia 2.3.1).....................................................................................28
3.11 Benzoates (European Pharmacopoeia 2.3.1)................................................31
3.12 Bismuth (European Pharmacopoeia 2.3.1)...................................................33
3.13 Bromides (European Pharmacopoeia 2.3.1).................................................34
3.14 Calcium (European Pharmacopoeia 2.3.1)...................................................39
3.15 Carbonates and bicarbonates (European Pharmacopoeia 2.3.1)..............41
3.16 Chlorides (European Pharmacopoeia 2.3.1)................................................43
3.17 Citrates (European Pharmacopoeia 2.3.1)....................................................47
3.18 Esters (European Pharmacopoeia 2.3.1).......................................................50
3.19 Iodides (European Pharmacopoeia 2.3.1).....................................................52
3.20 Iron (European Pharmacopoeia 2.3.1)..........................................................54
3.21 Lactates (European Pharmacopoeia 2.3.1)...................................................57
3.22 Lead (European Pharmacopoeia 2.3.1).........................................................60
3.23 Magnesium (European Pharmacopoeia 2.3.1).............................................62
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3.24 Mercury (European Pharmacopoeia 2.3.1)...................................................63
3.25 Nitrates (European Pharmacopoeia 2.3.1)...................................................66
3.26 Phosphates (Orthophosphates) (European Pharmacopoeia 2.3.1)...........68
3.27 Potassium (European Pharmacopoeia 2.3.1)...............................................71
3.28 Salicylates (European Pharmacopoeia 2.3.1)...............................................73
3.29 Silicates (European Pharmacopoeia 2.3.1)...................................................75
3.30 Silver (European Pharmacopoeia 2.3.1)........................................................76
3.31 Sodium (European Pharmacopoeia 2.3.1)....................................................77
3.32 Sulfates (European Pharmacopoeia 2.3.1)....................................................80
3.33 Tartrates (European Pharmacopoeia 2.3.1)..................................................82
3.34 Xanthines (European Pharmacopoeia 2.3.1)................................................86
3.35 Zinc (European Pharmacopoeia 2.3.1)..........................................................89
Part II: Limit tests
Chapter 4 Precipitation in limit tests...........................................................93
Chapter 5 Color reactions in limit tests.......................................................97
Chapter 6 Tests ...............................................................................................103
6.1 Ammonium (European Pharmacopoeia 2.4.1)..........................................104
6.2 Arsenic (European Pharmacopoeia 2.4.2)..................................................107
6.3 Calcium (European Pharmacopoeia 2.4.3).................................................110
6.4 Chlorides (European Pharmacopoeia 2.4.4)..............................................113
6.5 Fluorides (European Pharmacopoeia 2.4.5)...............................................116
6.6 Magnesium (European Pharmacopoeia 2.4.6)...........................................119
6.7 Magnesium and alkaline-earth metals (European
Pharmacopoeia 2.4.7)...................................................................................122
6.8 Heavy metals (European Pharmacopoeia 2.4.8).......................................126
6.9 Iron (European Pharmacopoeia 2.4.9)........................................................132
6.10 Phosphates (European Pharmacopoeia 2.4.11)..........................................135
6.11 Potassium (European Pharmacopoeia 2.4.12)...........................................137
6.12 Sulfates (European Pharmacopoeia 2.4.13)................................................139
6.13 Sulfated ash (European Pharmacopoeia 2.4.14)........................................140
6.14 Total ash (European Pharmacopoeia 2.4.16)..............................................143
6.15 Free formaldehyde (European Pharmacopoeia 2.4.18)............................145
6.16 Alkaline impurities in fatty oils (European Pharmacopoeia 2.4.19).....149
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Part I
Identifications
© 2006 by Taylor & Francis Group, LLC