Separation Methods in Drug Synthesis and Purification (Handbook of Analytical Separations)

613 Pages·2000·38.77 MB·English

by  Valko

Separation Methods
in Drug Synthesis
and Purification
HANDBOOK OF ANALYTICAL SEPARATIONS
Series Editor: ROGER M. SMITH
In this series:
Vol. 1" Separation Methods in Drug Synthesis and Purification
Edited by K. Valk6
HANDBOOK OF ANALYTICAL SEPARATIONS VOLUME 1
Separation Methods
~n Drug Synthes~s
and Purification
Edited by
P p
KLARA VALKO
Physical Sciences, Glaxo Wellcome Medicines Research Centre,
Gunnels Wood Road, Stevenage, Herts. SG1 2NY, United Kingdom
2000
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First edition 2000
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Editor's preface
In the pharmaceutical industry our aim is to discover and develop drugs in a cost-
effective way. The new technologies such as combinatorial chemistry, high throughput
screening, and robotics have made it possible to synthesise millions of molecules for
thousands of screens. We need efficient methods to check the quality and the quantity of
the new molecular entities, and this is where separation science plays an important role.
The process of selecting candidate molecules needs to be accelerated and the number
of molecules failing in a later stage of the development process has to be reduced.
Separation science can help in selecting molecules for further development, in greater
productivity of compound progression, to shorten drug development cycles and to build
in better quality at an early stage. For all of the above-mentioned purposes we need
separation techniques that are readily available, easily implemented and reproducible
with instrumentation that is well developed and supported by the manufacturer. The
objective of this book is to provide a critical rather than a comprehensive review of
the analytical separation methods and techniques used in the pharmaceutical industry.
We shall concentrate on to the applied separation science and technologies used across
the early stages of drug research, synthesis, and purification. We do not intend to cover
the separation methods used in quality control, formulation, toxicology, and pharmaco-
kinetic studies, although very similar techniques and methods can be used in these
areas.
The academic contributors will provide guidance to the various separation methods,
their relative value and advantages and their pitfalls. They provide a source of estab-
lished and potential methods based on the literature that can be consulted by the reader.
The contributors from industrial backgrounds reveal the aspects of various methods
from the industrial viewpoint and will focus on discussing useful technologies, such
as automation, cost impact and organisational issues in conjunction with the separation
methods. Therefore this book can be used as a reference to methods frequently used
in pharmaceutical research and development. Some of these methods may be very new
and may not have been published before but they have been tested in everyday work.
Although many of the industrial contributors are my colleagues at GlaxoWellcome we
do know that in other pharmaceutical companies similar approaches and technologies
are used with very similar aims. The most widely discussed technique throughout this
book is high performance liquid chromatography. The reason for this is that there are
many advanced applications of this technique to a wide selection of problems bring-
ing also the benefit of automated analysis. The theoretical background and practical
solutions of the gradient method will be highlighted together with the hyphenated tech-
niques (i.e. HPLC with mass spectrometry or NMR). The comparison of isocratic and
gradient methods, which is crucial when we want to use information from one method
or the other, will be discussed. To avoid the time taken for method development for
VI Editor's preface
every compound going through quality control, generic methods have been developed
using fast gradient reversed-phase chromatography. Generic methods developed for high
throughput quality information generation will be presented. The most important factors
for the column selection and gradient conditions will be compared with the information
gained, time and cost. Similarly genetic methods can be developed for capillary elec-
trophoresis in drug analysis. The recently emerged new separation technique, capillary
electro-chromatography has received great attention in the pharmaceutical industry and
will be discussed in this volume. The various separation and hyphenated analytical
techniques are widely applied in combinatorial assays. A fully automated so-called
"walk up" HPLC-UV-MS system will be also described. The optimisation of separation
concerning the time, solvent consumption is very important when the same samples are
to be analysed in process research. The various optimisation strategies in HPLC and
CZE are also presented and the basic principles of the available expert systems and
knowledge based systems are discussed.
The application of preparative and scale up chromatography and the strategies for
the development of process chromatography as a unit operation will be discussed in
detail. The development and application of an automated preparative HPLC system for
purification of small amounts of research compounds by the chemists themselves will
be also described.
The enantioseparation represents a unique and very important field of separation
science and is more and more frequently used in the analysis and purification of
potential drugs.
Thin layer chromatography is still used in pharmaceutical research and development
as a very simple and cost effective technique. A chapter is devoted to summaries the
basic principles of thin layer chromatography and the pharmaceutical applications of the
technique.
At the end of this volume the application of separation techniques in quantitative
structure retention relationship studies and measurement of physical properties are
discussed. This represents a special field of separation science where the results can be
used directly in drug research and optimisation of the lead compound or can be fed
back to method development for other separation problems, characterising not only the
solutes but also the stationary phases.
I hope that this volume will present an example of the success of the amalgamation of
separation sciences and technologies in the pharmaceutical industry and that the readers
will enjoy the mixture of different aspects from the academic and industrial contributors.
The value of information as a function of cost and time are more important parameters
in industrial research than applying immediately new scientific achievements. However,
new scientific achievements driven by the motivation of the pharmaceutical industry get
their reward by quick application in delivering good medicines to patients.
Finally I would like to thank all the contributors for the hard work and enthusiasm
required putting this volume together. I am also very grateful to all of my colleagues
who supported me in writing up their achievements and provided me with interesting
results as a personal communication. I would like to thank to Dr. Derek Reynolds for
his scientific support and for encouraging colleagues in the Physical Sciences Unit in
GlaxoWellcome Medicines Research Centre to contribute to this book. I am indebted
Editor's preface VII
to Dr. David Ashton, School of Pharmacy, University of London, for his invaluable
technical and emotional support in reviewing and revising most of the chapters in this
book.
Kldlra Valk6
March 2000
This Page Intentionally Left Blank
IX
Series editor's preface
This volume on Separation Methods in Drug Synthesis and Purification is the first in
what will grow to be the Handbook of Analytical Separations. It reflects the dominance
of separation methods for the analysis of drug substances, the wide range of techniques
that are employed, and how this field is still rapidly developing and changing to face the
challenges of combinatorial chemistry, high-throughput screening, the high selectivity
required by enantiomeric separations and the demands of quality control and regulatory
requirements.
The Handbook of Analytical Separations will be a comprehensive work, which
is intended to recognise the importance of the wide range of separation methods in
analytical chemistry. Since the first report of chromatography almost a 100 years ago,
separation methods have expanded considerably, both in the number of techniques and
in the breadth of their applications. The objective of the Handbook is to provide a
critical and up-to-date survey, rather than a detailed review, of the analytical separation
methods and techniques used for the determination of analytes across the whole range
of applications. The Handbook will cover the application of analytical separation
methods from partitioning in sample preparation through gas, supercritical and liquid
chromatography to electrically driven separations. The intention is to provide a work
of reference that will provide critical guidance to the different methods that have been
applied for particular analytes, their relative value to the user and their advantages and
pitfalls. The aim is not to be comprehensive but to ensure a full coverage of the field
weighted to reflect the acceptance of each alternative method to the analyst.
The individual self-contained volumes will each encompass a closely related field of
applications and will demonstrate those methods which have found the widest applica-
tions in the area. The emphasis is expected to be on the comparison of published and
established methods which have been employed in the application area rather than the
details of experimental and novel methods. The volumes will also identify future trends
and the potential impact of new technologies and new separation methods. The volumes
will therefore provide up-to-date critical surveys of the roles that analytical separations
play now and in the future in research, development and production, across the wide
range of the fine and heavy chemical industry, pharmaceuticals, health care, food pro-
duction and the environment. It will not be a laboratory guide but a source book of estab-
lished and potential methods based on the literature that can be consulted by the reader.
I am pleased to acknowledge that the value of the Handbook will be dependent
on the volume editors and the contributors that they will bring to each topic. It is
their experience and expertise that will provide the insights into the present and future
development of separation methods.
Roger M. Smith
Editor