Essentials of Pharmaceutical Preformulation E-Book

Simon Gaisford

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 360

Veröffentlichungsjahr: 2012

Beschreibung

Essentials of Pharmaceutical Preformulation is a study guide which describes the basic principles of pharmaceutical physicochemical characterisation. Successful preformulation requires knowledge of fundamental molecular concepts (solubility, ionisation, partitioning, hygroscopicity and stability) and macroscopic properties (physical form, such as the crystalline and amorphous states, hydrates, solvates and co-crystals and powder properties), familiarity with the techniques used to measure them and appreciation of their effect on product performance, recognising that often there is a position of compromise to be reached between product stability and bioavailability.

This text introduces the basic concepts and discusses their wider implication for pharmaceutical development, with reference to many case examples of current drugs and drug products. Special attention is given to the principles and best-practice of the analytical techniques that underpin preformulation (UV spectrophotometry, TLC, DSC, XRPD and HPLC). The material is presented in the typical order that would be followed when developing a medicine and maps onto the indicative pharmacy syllabus of the Royal Pharmaceutical Society of Great Britain

Undergraduate-level pharmacy students and R&D / analytical scientists working in the pharmaceutical sector (with or without a pharmaceutical background) will find this text easy to follow with relevant pharmaceutical examples.

• Essential study guide for pharmacy and pharmaceutical science students
• Covers the pharmaceutical preformulation components of the Royal Pharmaceutical Society of Great Britain’s indicative syllabus
• Easy to follow text highlighted with relevant pharmaceutical examples
• Self-assessment assignments in a variety of formats
• Written by authors with both academic and industrial experience
• Companion website with further information to maximise learning

Leseprobe

Contents

Cover

Companion website

Title Page

Copyright

Dedication

Preface

List of Abbreviations

Chapter 1: Basic Principles of Preformulation Studies

1.1 Introduction

1.2 Assay design

1.3 Concentrations

1.4 UV spectrophotometry

1.5 Thin-layer chromatography (TLC)

1.6 High-performance liquid chromatography

1.7 Differential scanning calorimetry

1.8 Dynamic vapour sorption

1.9 Summary

References

Answer to study question

Additional study questions

Chapter 2: Ionisation Constants

2.1 Introduction

2.2 Ionisation

2.3 Buffers

2.4 Determination of pKa

2.5 Summary

References

Answers to study questions

Additional self-study questions and answers

Chapter 3: Partition Affinity

3.1 Introduction

3.2 Partitioning

3.3 Summary

References

Answers to study questions

Chapter 4: Solubility

4.1 Introduction

4.2 Intrinsic solubility

4.3 Summary

References

Answer to study question

Additional self-study questions and answers

Chapter 5: Dissolution

5.1 Introduction

5.2 Models of dissolution

5.3 Dissolution testing

5.4 Summary

References

Answers to study questions

Chapter 6: Salt Selection

6.1 Introduction

6.2 Salt formation

6.3 Salt solubility

6.4 Dissolution of salts

6.5 Partitioning of salts

6.6 Summary

References

Answers to study questions

Chapter 7: Physical Form I – Crystalline Materials

7.1 Introduction

7.2 Crystal formation

7.3 Crystal structure

7.4 Polymorphism

7.5 Pseudopolymorphism

7.6 Polymorph screening

7.7 Characterisation of physical form

7.8 Summary

References

Answers to study questions

Chapter 8: Physical Form II – Amorphous Materials

8.1 Introduction

8.2 Formation of amorphous materials

8.3 Ageing of amorphous materials

8.4 Characterisation of amorphous materials

8.5 Processing and formation of amorphous material

8.6 Amorphous content quantification

8.7 Summary

References

Answers to study questions

Chapter 9: Stability Assessment

9.1 Introduction

9.2 Degradation mechanisms

9.3 Reaction kinetics

9.4 The temperature dependence of reaction kinetics

9.5 Stress testing

9.6 Summary

References

Answers to study questions

Chapter 10: Particle Properties

10.1 Introduction

10.2 Microscopy

10.3 Particle shape

10.4 Summary

References

Answer to study question

Chapter 11: Powder Properties

11.1 Introduction

11.2 Powder flow and consolidation

11.3 Compaction properties

11.4 Summary

References

Answers to study questions

Index

Companion website

This book is accompanied by a companion website at:

http://www.wiley.com/go/gaisford/essentials

Visit the website for:

Figures and tables from the bookMultiple choice questions

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Library of Congress Cataloging-in-Publication Data

Gaisford, Simon. Essentials of pharmaceutical preformulation / Simon Gaisford and Mark Saunders. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-97635-7 (cloth) – ISBN 978-0-470-97636-4 (paper) I. Saunders, Mark, 1976 Sept. 18- II. Title. [DNLM: 1. Drug Compounding–methods. 2. Drug Discovery–methods. QV 779] 615.1′9–dc23 2012027538

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

Cover design: Gary Thompson

First Impression 2013

For Yasmina and Oliver

Preface

The inspiration for this book came when Michael Aulton asked me to take over his preformulation module on the PIAT course of the University of Manchester. The existing module was based on the excellent textbook (Pharmaceutical Preformulation) written by Jim Wells in 1988 and thus a perfect opportunity to write both an updated module and an updated book presented itself.

The majority of the text was written while I was on sabbatical leave at the Monash Institute for Pharmaceutical Sciences (MIPS) in Melbourne, Australia, in the summer of 2011. I am hugely grateful to Prof. Bill Charman, Prof. Peter Stewart, Marian Costelloe and Marian Glennon for arranging the visit and to MIPS as a whole for the welcoming, friendly and stimulating environment they provided. I would also like to mention many of the wonderful people that I met, including Anne, Ben, Carolyn, Chris, Colin, David, Ian, Hywel, Iliana, Joe, Laurence, Mercedes and Michelle. Special thanks are reserved for Richard Prankerd, who took the time and effort to talk with me about many aspects of the text while I was at MIPS and also to review the whole text before publication; the book is immeasurably better for his input and advice. Thermal analysts are indeed a special breed!

Equally, the book would never have been finished were it not for several other special people. Nicole Hunter undertook the weighty tasks of reviewing the whole text and providing constant support and encouragement while Hamid Merchant cast his expert eye over the dissolution chapter. My group of amazing PhD students (Alice, Asma, Garima, Jawal, Jip, Luis, Mansa, Mustafa and Rin) provided many of the data and examples that populate the text while my academic colleagues, particularly Prof. Abdul Basit, Prof. Anthony Beezer and Prof. Kevin Taylor, have been constant sources of advice and support. I also acknowledge all of the wonderful students who I have taught on the MSc in Drug Delivery and who are such an inspiration to me.

Of course, no book would be possible without a publisher, and I am extremely grateful to Fiona Seymour and Lucy Sayer for editorial advice and encouragement.

Finally, I must acknowledge the constant support of my family, especially Joanne and Oliver, who keep me sane!

S GaisfordApril 2012

List of Abbreviations

AbbreviationMeaningMolar absorption coefficientθAngle of reposeσNormal stressτShear stressASurface areaAFMAtomic force microscopyARAspect ratioBCSBiopharmaceutical Classification SystemBPBritish PharmacopoeiaCConcentrationCRMCertified reference materialDDiffusion coefficientDSCDifferential scanning calorimetryESEMEnvironmental scanning electron microscopyFDilution factorFaSSIFFasted state simulated intestinal fluidFDAUS Food and Drug AdministrationFeSSGFFed state simulated gastric fluidFeSSIFFed state simulated intestinal fluidFTIRFourier transform infraredGGibb's free energyGRASGenerally regarded as safehThickness of boundary layerHEnthalpyHPLCHigh-performance liquid chromatographyHSMHot-stage microscopyICHInternational Conference on HarmonisationIDRIntrinsic dissolution rateIRInfraredIUPACInternational Union of Pure and Applied ChemistrykRate constantKEquilibrium constant or stress ratioMTDSCModulated temperature DSCnReaction orderNANumerical apertureNIRNear infraredpNegative logarithmPhEurEuropean PharmacopoeiaRIRefractive indexSEntropySoIntrinsic solubilitySEMScanning electron microscopySGFSimulated gastric fluidTTemperatureTEMTransmission electron microscopyTGAThermogravimetric analysisTLCThin-layer chromatographyUHPLCUltra high-performance liquid chromatographyUSPUnited States PharmacopoeiaUVUltravioletVVolumeWWeightxMole fractionXRPDX-ray powder diffraction

1

Basic Principles of Preformulation Studies

1.1 Introduction

The worldwide market for pharmaceutical sales is large and has grown consistently year-on-year for much of the past decade (Table 1.1). The advent of computer-based drug design programmes, combinatorial chemistry techniques and compound libraries populated with molecules synthesised over many decades of research and development means there is a vast array of compounds with the potential to become drug substances. However, drug substances are not administered to patients as pure compounds; they are formulated into drug products. The selection of a compound, its development into a drug substance and, ultimately, drug product is a hugely time-consuming and expensive process, which is ultimately destined for failure in the majority of cases. As a rough guide, only 1 out of every 5–10 000 promising compounds will be successfully developed into a marketed drug product and the costs involved have been estimated at ca. $1.8 billion (Paul et al., 2010).

Table 1.1 Total market sales in the pharmaceutical sector from 2003 to 2010 (data from IMS Health).

While it is tempting to assume that all drug products are financial blockbusters, approximately 70% never generate sufficient sales to recoup their development costs. Table 1.2 shows the top 20 medicines by sales worldwide (and the percentage of revenue they generate for their respective companies). It is apparent that a significant percentage of income is generated from these blockbuster products, and the financial health and prospects of the originator company are largely dependent upon the extent of patent protection (allowing market exclusivity) and new drug products in the development pipeline.

Table 1.2 Top ten drugs by sales worldwide in 2010 (data from IMS Health).

These numbers imply that development of a drug product in the right therapeutic area can result in significant income, but the costs involved in reaching market are such that only a few potential drug substances can be considered for development. How best to select a compound for development from the myriad of chemical structures that may be available? It is tempting to think that the decision reduces to efficacy against a biological target alone, but in practice physicochemical properties affect how a substance will process, its stability and interaction with excipients, how it will transfer to solution and, ultimately, define its bioavailability. The compound showing greatest efficacy may not ultimately be selected if another compound has a better set of physicochemical properties that make it easier to formulate and/or manufacture. It follows that characterising the physicochemical properties of drug substances early in the development process will provide the fundamental knowledge base upon which candidate selection, and in the limit dosage form design, can be made, reducing development time and cost. This is the concept of preformulation.