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Analytical Profiles

of

Drug Substances

and

Excipients
 EDITORIAL BOARD

Abdullah A. Al-Badr Gunawan lndrayanto

Alekha K. Dash David J. Mazzo

Klaus Florey Leroy Shervington

 Ana Iytica I Profiles
of Drug Substances
and Excipients
Volume 29
edited by

Harry G. Brittain

Center for Pharmaceutical Physics

10 Charles Road
Milford, New Jersey 08848

Founding Editor:
Klaus Florey

ACADEMIC PRESS
An imprint of Elsevier Science

Amsterdam . Boston . London . New York Oxford . Pans

San Diego . San Francisco Singapore . Sydney Tokyo
This book is printed on acid-free paper. 8

0 2002 Elsevier Science (USA)

All rights reserved.

No part of this publication may be reproduced or transmitted in any form or

by any means, electronic or mechanical, including photocopy, recording, or
any information storage and retrieval system, without permission in writing
from the Publisher.

The appearance of the code at the bottom of the first page of a chapter in this
book indicates the Publisher’s consent that copies of the chapter may be made
for personal or internal use of specific clients. This consent is given on the
condition, however, that the copier pay the stated per copy fee through the
Copyright Clearance Center, Inc. (222 Rosewood Drive, Danvers,
Massachusetts 01923), for copying beyond that permitted by Sections 107 or
108 of the U.S. Copyright Law. This consent does not extend to other kinds of
copying, such as copying for general distribution, for advertising or
promotional purposes, for creating new collective works, or for resale. Copy
fees for pre-2002 chapters are as shown on the title pages. If no fee code
appears on the title page, the copy fee is the same as for current chapters.
1075-6280102 $35.00

Explicit permission from Academic Press is not required to reproduce a

maximum of two figures or tables from an Academic Press chapter in another
scientific or research publication provided that the material has not been
credited to another source and that full credit to the Academic Press chapter is
given.

Academic Press
An Elsevier Science Imprinr
525 B Street, Suite 1900, San Diego, California 92101-4495, USA
h ttD:N\rww.academicoress.com

International Standard Book Number: 0- 12-260829-1

PRINTED IN THE UNITED STATES OF AMERICA

02 03 04 05 06 07 9 8 7 6 5 4 3 2 1
 CONTENTS

Affiliations of Editors and Contributors vii

1. Profiles of Drug Substances, Excipients, and 1

Related Methodology
Harry G. Brittain

2. Aspartame 7
Richard J. Prankerd

3. Edetic Acid (EDTA) 57

F. Belal and Abdullah A. Al-Badr

4. Etodolac 105
Ketan P. Shah, Kavita Gumbhir-Shah, and Harry G.
Brittain

5. Eugenol 149
Mochammad Yuwono, Siswandono, Achmad Fuad
Hafid Achmad Toto Poernomo, Mangestuti Agil,
Gunawan Indrayanto, and Siegfried Ebel

6. Mandelic Acid 179

Harry G. Brittain

7. Pantoprazole 213
Adnan A. Badwan, Lina N Nabulsi, M M A1 Omari,
Nidal H. Daraghmeh, Mahmoud K. Ashour, Ahmad M
Abdoh. andA. M Y. Jaber

8. Spironolactone 26 1
Badraddin M H. Al-Hadiya, Fathalla Belal, Yousif A.
Asiri, and Othman A. Gubara

Cumulative Index 32 1

V
This Page Intentionally Left Blank
 AFFILIATIONS OF EDITORS AND CONTRIBUTORS

Ahmad M. Abdoh: The Jordanian Pharmaceutical Manufacturing

Company Ltd., Na’or, Jordan
Mangestuti Agil: Faculty of Pharmacy, Airlangga University, J1.
Dharmawangsa dalam, Surabaya 60286, Indonesia
Abdullah A. Al-Badr: Department of Pharmaceutical Chemistry, College
of Pharmacy, King Saud University, P.O. Box 2457, Riyadh-1 1451,
Saudi Arabia
Badraddin M.H. Al-Hadiya: Department of Clinical Pharmacy, College
of Pharmacy, King Saud University, P.O.Box 2457, Riyadh 11451,
Kingdom of Saudi Arabia
M.M. A1 Omari: The Jordanian Pharmaceutical Manufacturing Company
Ltd., Na’or, Jordan
Mahmoud K. Ashour: The Jordanian Pharmaceutical Manufacturing
Company Ltd., Na’or, Jordan
Yousif A. Asiri: Department of Clinical Pharmacy, College of Pharmacy,
King Saud University, P.O.Box 2457, Riyadh 11451, Kingdom of
Saudi Arabia
Adnan A. Badwan: The Jordanian Pharmaceutical Manufacturing
Company Ltd., Na’or, Jordan
Fathalla. Belal: Department of Pharmaceutical Chemistry, College of
Pharmacy, King Saud University, P.O. Box 2457, Riyadh-1 1451,
Saudi Arabia
Harry G. Brittain: Center for Pharmaceutical Physics, 10 Charles Road,
Milford, NJ 08848-1930, USA
Nidal H. Daraghmeh: The Jordanian Pharmaceutical Manufacturing
Company Ltd., Na’or, Jordan
Alekha K. Dash: Department of Pharmaceutical & Administrative
Sciences, School of Pharmacy and Allied Health Professions,
Creighton University, Omaha, NE 68 178, USA
Siegfried Ebel: Department of Pharmacy, University of Wiirzburg, Am
Hubland, D-97074 Wiirzburg, Germany

vii
Klaus Florey: 151 Loomis Court, Princeton, NJ 08540, USA
Othman A. Gubara: Department of Clinical Pharmacy, College of
Pharmacy, King Saud University, P.O.Box 2457, Riyadh 1 1451,
Kingdom of Saudi Arabia
Achmad Fuad Hafid: Faculty of Pharmacy, Airlangga University, J1.
Dharmawangsa dalam, Surabaya 60286, Indonesia
Gunawan Indrayanto: Faculty of Pharmacy, Airlangga University, J1.
Dharmawangsa dalam, Surabaya 60286, Indonesia
A.M.Y. Jaber: Chemistry Department, King Fahd University of
Petroleum and Minerals, Dhahran 3 1261, Saudi Arabia
David J. Mazzo: Preclinical Development, Hoechst Marion Roussel, Inc.,
Route 202-206, P.O. Box 6800, Bridgewater, NJ 08807, USA
Lina N. Nabulsi: The Jordanian Pharmaceutical Manufacturing Company
Ltd., Na’or, Jordan
Achmad Toto Poernomo: Faculty of Pharmacy, Airlangga University, J1.
Dharmawangsa dalam, Surabaya 60286, Indonesia
Richard J. Prankerd: Victorian College of Pharmacy, Monash
University, Parkville, VIC 3052, Australia
Ketan P. Shah: Schering-Plough Corporation, NJ Quality Laboratories,
1011 Morris Avenue, Union, NJ 07083
Kavita Gumbhir-Shah: PharmaConsult, Inc., 23 Honeyman Road,
Basking Ridge, NJ 07920
Leroy Shervington: Pharmacy Faculty, Applied Science University,
Amman 11931, Jordan
Siswandono: Faculty of Pharmacy, Airlangga University, J1.
Dharmawangsa dalam, Surabaya 60286, Indonesia
Mochammad Yuwono: Faculty of Pharmacy, Airlangga University, J1.
Dharmawangsa dalam, Surabaya 60286, Indonesia

...
Vlll
 Profiles of Drug Substances, Excipients,
and Related Methodology

Harry G . Brittain

Center for Pharmaceutical Physics

10 Charles Road
Milford, NJ 08848 U.S.A.

In 1970, scientists from the Pharmaceutical Analysis Section of the

Academy of Pharmaceutical Sciences began to plan a cooperative venture
to compile and publish a series of volumes entitled the Analytical Profiles
ofDrug Substances. The aim of the series was to provide information not
available in the official compendia1monograph of a drug substance, such
as physical or chemical data, methods of synthesis, and pathways of
physical or biological degradation and metabolism. Klaus Florey became
the first editor of the series, and between 1972 and 1991 he edited the first
20 volumes in the Analytical Profiles series.

In 1992, I assumed the role of editor for the Analytical Profiles, and
expanded the scope of the series to include profiles of additional materials.
Consequently the series title changed slightly to that presently used,
Analytical Profiles of Drug Substances and Excipients. Although the
content of individual profiles differed from substance to substance, the
basic content of most profile chapters contained six main sections:
1. Description
2. Methods of Preparation
3. Physical Properties
4. Methods of Analysis
5. Stability
6. Drug Metabolism and Pharmacokinetics
This format has characterized all of the volumes I have edited (21 -29),
which were published over the time period of 1992 to 2002.

I have been considering another expansion of the scope of the series for
some time, and with the acquisition of Academic Press by the Elsevier

ANALYTICALPROFILESOF DRUG SUBSTANCES 1 Copyright Q 2002 Elrevier Science (USA)

AND EXCPIENTS - VOLUME 29 All rights reserved.
1075-6280/02$35.00
2 HARRY G. BRlTTAIN

Publishing Company it is now appropriate to set these designs into action.

Beginning with volume 30, the name of the series will be changed to
Profiles of Drug Substances, Excipients, and Related Methodology. The
traditional profile chapters will, of course, still be acceptable for
publication, but it is envisioned these contributions will be augmented by
publication of critical review chapters that summarize information related
to the characterization of drug substances and excipients.

Contributions to the Projles series will generally fall within one of the
following six categories of review articles:
A. Physical profiles of drug substances and excipients
B. Analytical profiles of drug substances and excipients
C. Drug metabolism and pharmacokinetic profiles of drug
substances and excipients
D. Methodology related to the characterization of drug
substances and excipients
E. Methods of chemical synthesis
F. Reviews of the uses and applications for individual drug
substances, classes of drug substances, or excipients
More detailed descriptions of the chapter content anticipated for each
category are summarized in the following sections. The scope of
described topics is illustrative in nature, since it is fully realized that the
actual content of any given chapter will vary somewhat according to the
compound or methodology being reviewed.

A. Physical Profiles of Drug Substances and Excipients

1. General Information
1.1 Nomenclature
1.1.1 Systematic Chemical Name
1.1.2 Nonproprietary Names
1.1.3 Proprietary Names
1.2 Formulae
1.2.1 Empirical Formula, Molecular Weight, CAS Number
1.2.2 Structural Formula
1.3 Elemental Analysis
1.4 Appearance
 PROFILES OF DRUG SUBSTANCES, EXCIPIENTS, 3
AND RELATED METHODOLOGY

2. Physical Characteristics
2. l- Ionization Constants
2.2 Solubility Characteristics
2.3 Partition Coefficients
2.4 Optical Activity
2.5 Particle Morphology
2.6 Crystallographic Properties
2.6.1 Single Crystal Structure
2.6.2 X-Ray Powder Diffraction Pattern
2.7 Hygroscopicity
2.8 Thermal Methods of analysis
2.8.1 Melting Behavior
2.8.2 Differential Scanning Calorimetry
2.8.3 Thermogravimetric Analysis
2.9 Spectroscopy
2.9.1 UVNIS Spectroscopy
2.9.2 Vibrational Spectroscopy
2.9.3 Nuclear Magnetic Resonance Spectrometry
2.9.3.1 'H-NMR Spectrum
2.9.3.2 I3C-NMRSpectrum
2.10 Mass Spectrometry

3. Stability
3.1 Solid-state Stability
3.2 Solution-Phase Stability
3.3 Stability in Biological Fluids
3.4 Incompatibilities with Functional Groups

B. Analytical Profiles of Drug Substances and Excipients

1. Compendia1 Methods of Analysis

1.1 Identification
1.2 Physical Methods of Analysis
1.3 Impurity Analyses
1.4 Assay Methods

2 Titrimetric Methods of Analysis

2.1 Aqueous Titration Methods
2.2 Non-Aqueous Titration Methods
4 HARRY G . BNTTAIN

2.3 Potentiometric Titration

2.4 Miscellaneous Titration Methods

3 Electrochemical Methods of Analysis

3.1 Voltammetry
3.2 Amperometry
3.3 Coulometry
3.4 Polarography

4 Spectroscopic Methods of Analysis

4.1 Spectrophotometry
4.2 Colorimetry
4.3 Fluorimetry

5 Chromatographic Methods of Analysis

5.1 Paper Chromatography
5.2 Thin Layer Chromatography
5.3 Gas Chromatography
5.4 High Performance Liquid Chromatography
5.5 Ion-Exchange Chromatography
5.6 Supercritical Fluid Chromatography
5.7 Capillary Electrophoresis

6 Determination in Body Fluids and Tissues

6.1 Radio-immunoassay Methods
6.2 Enzyme-immunoassay Methods
6.3 Chromatoaauhic Methods

C. Drup Metabolism and Pharmacokinetic Profiles of Drug

Substances and Excipients
1. Uses, Applications, and Pertinent History
2. Adsorption
3. Distribution
4. Metabolism
5. Elimination
6. Pharmacological Effects
 PROFILES OF DRUG SUBSTANCES, EXCIPIENTS, 5
AND RELATED METHODOLOGY

D. Methodolow Related to the Characterization of Drug

Substances and Excipients
1. Introduction
2. Apparatus and Instrumentation
3. Principles of Operation
4. Illustrative Examples of the Methodology
5. Summary and Indications for Future Work

E. Methods of Chemical Svnthesis

1. Historical Overview
2. Preparative Chemical Methods
3. Preparative MicrobiologicalMethods

F. Uses and Applications for Individual drug substances, classes

of drug substances, or excipients
1. Historical Overview
2. Uses and Applications - format largely dependent on the nature of
the substance(s) being reviewed

The change in series scope and title is not being effected merely for the
sake of change, but to allow the series to better meet the needs of the
pharmaceutical community. The time for publication of simple data
compilations seems to be passing, and it is equally clear that the need is
growing for publication of more critical evaluations of data, information,
and methodology. The revised series title Profiles ofDrug Substances,
Excipients, and Related Methodology reflects this emerging trend, and
future volumes in the series will attempt to better meet the information
needs of the drug development community.
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