PHARMACEUTICAL PREFORMULATION AND - ajprd

610 Pages·2003·15.72 MB·English

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PHARMACEUTICAL
PREFORMULATION
AND
FORMULATION
A Practical Guide from
Candidate Drug Selection to
Commercial Dosage Form
Mark Gibson
Editor
IHSfi Health Group
An IHSfi GROUP Company
Your Enterprise Solution to (cid:31)
Global Healthcare Knowledge
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CONTENTS
Preface vii
Contributors ix
1. Introduction and Perspective 1
Mark Gibson
Drug Development Drivers, Challenges, Risks and Rewards 2
Current Trends in the Pharmaceutical Industry 6
Lessons Learnt and the Way Forward 8
Scope of the Book 10
References 11
PART I: Aiding Candidate Drug Selection
2. Aiding Candidate Drug Selection:
Introduction and Objectives 15
Mark Gibson
Stages of the Drug Discovery and Development Process 15
Summary 20
References 20
3. Preformulation Predictions from Small Amounts of Compound
as an Aid to Candidate Drug Selection 21
Gerry Steele
Initial Physicochemical Characterization 22
Initial Solubility 28
Initial Stability Investigations 34
Crystallinity 41
Crystal Morphology 46
Hygroscopicity 48
Salt Selection 49
Methods for Evaluating Physicochemical Properties 58
Concluding Remarks 87
Acknowledgements 88
References 88
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iv Pharmaceutical Preformulation and Formulation
4. Biopharmaceutical Support in Candidate Drug Selection 97
Anna-Lena Ungell andBertil Abrahamsson
Drug Dissolution and Solubility 100
Luminal Interactions 111
Absorption/Uptake over the GI Membranes 117
Models for Studying the Absorption Potential of Drugs 118
Permeability Coefficients versus F 134
a
In VivoTechniques for Studies in Man 135
Vehicles for Absorption Studies 139
Functional Use of Absorption Models 141
References 143
PART II: Early Drug Development
5. Early Drug Development: Product Design 157
Mark Gibson
The Importance of Product Design 157
Product Design Considerations 158
Concluding Remarks 173
References 173
6. Preformulation as an Aid to Product Design in Early Drug Development 175
Gerry Steele
Solid Dosage Forms 175
Solution Formulations 196
Freeze-Dried Formulations 210
Suspensions 214
Topical/Transdermal Formulations 215
Inhalation Dosage Forms 217
Compatibility 223
References 228
7. Biopharmaceutical Support in Formulation Development 239
Bertil Abrahamsson andAnna-Lena Ungell
In VitroDissolution 241
Bioavailability Studies 257
In Vitro/In VivoCorrelations 269
Animal Models 276
Imaging Studies 279
References 289
PART III: From Product Design to Commercial Dosage Form
8. Product Optimisation 295
Mark Gibson
Product Optimisation Purpose and Scope 295
Excipient and Pack Optimisation Considerations 296
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Contents v
Sources of Information 304
Expert Systems 305
Experimental Design 309
Stability Testing 313
Developing Specifications 316
Process Design, Process Optimisation and Scale-Up 319
Validation and Launch 323
Acknowledgements 327
References 327
9. Parenteral Dosage Forms 331
Joanne Broadhead
Guiding Principles for Simple Parenteral Solutions 332
Choice of Excipients 334
Sterility Considerations 336
Strategies for Formulating Poorly Soluble Drugs 336
Strategies for Formulating Unstable Molecules 340
Strategies for the Formulation of Macromolecules 342
Liposomal Delivery Systems 343
Sustained-Release Parenteral Formulations 343
In Vitroand In VivoTesting Methods 346
Packaging of Parenteral Products 347
Manufacturing of Parenteral Products 348
Administration of Parenteral Products 350
Parenteral Products and the Regulatory Environment 351
References 353
10. Inhalation Dosage Forms 355
Paul Wright
Lung Deposition 356
Particle Sizing 357
Dry Powder Inhalers 361
Metered Dose Inhalers 364
Nebulisers 372
Standards 374
Future 375
References 376
Bibliography 378
11. Oral Solid Dosage Forms 379
Peter Davies
Powder Technology 381
Powder Flow 382
Mixing 388
Compaction 390
Solid Dosage Forms 403
Tablets 403
Hard Gelatin Capsules 441
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Soft Gelatin Capsules 453
Summary 455
References 456
12. Ophthalmic Dosage Forms 459
Mark Gibson
Ocular Topical Drug Delivery Issues and Challenges 460
Drug Candidate Selection 464
Product Design Considerations 465
Product Optimisation Considerations 473
Processing Considerations 482
Concluding Remarks 486
References 488
13. Aqueous Nasal Dosage Forms 491
Nigel Day
Nasal Anatomy and Physiology 494
Formulation Selection Considerations 496
Device Selection Considerations 499
Regulatory Aspects 506
Special Considerations for Peptide Nasal Delivery 508
References 511
Additional Reading 513
14. Topical and Transdermal Delivery 515
Kenneth A. Walters andKeith R. Brain
The Skin and Percutaneous Absorption 516
Drug Candidate Selection and Preformulation 534
Formulation 543
Concluding Remarks 567
Bibliography 567
References 569
Index 581
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PREFACE
In my industrial career,I have gained broad experience working on many different pharma-
ceutical development projects and dosage forms,spanning candidate drug selection through
technology transfer to production and subsequent launch.With this background and with
Gerry Steele’s encouragement and rich experience in preformulation studies, I planned a
book that would emphasize what practical studies need to be undertaken,for what reasons
and during what key stages ofthe drug development process.In addition to preformulation,
I considered it essential to include biopharmaceutics (an area of emerging importance) as
well as formulation aspects.I soon realized I could not commit the time to writing all the
chapters in such a book,and,indeed,I considered the book would be more comprehensive by
involving other contributors and adding their special knowledge and experiences.
I am extremely grateful to all the contributors in this book,who have given up so much
of their time to create their specialised chapters.I would specially like to thank Anna-Lena
Ungell and Bertil Abrahammson for the two biopharmaceutics chapters,and also Jo Broad-
head for stepping in at the final hour and writing the chapter on parenterals.Without these
chapters,the book would have been incomplete.
In the past few years,I have written internal company guidelines and given seminars ex-
ternally on a logical approach to product development and technology transfer. This ap-
proach emphasises the importance of starting development of an NCE with product design
prior to commencing product and process optimisation, scale-up and technology transfer.
Two people I would particularly like to thank for their input and support for these concepts
are Gordon France and Mike Dey.This logical approach to ensure that products are devel-
oped efficiently and moved speedily to market is part ofmy own contribution to the chapters
in this book.
Preparing this book took longer than anticipated,and it contains more pages than ex-
pected.I have many vivid memories ofone-finger typing on my laptop in airport lounges and
hotel rooms and at home late in the evenings or on weekends.While my typing has become
considerably faster,I hasten to add that I have progressed only to two-finger typing! I am in-
debted to my secretarial support, particularly Hayley Pruden, who has much better typing
skills than I,to complete the figures and tables for this book.
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viii Pharmaceutical Preformulation and Formulation
This book should prove to be a useful guide to practitioners working in the pharmaceu-
tical industry,including R&D scientists,technicians and managers.In the words of Francis
Bacon (1561–1626):
Some books are to be tasted,others to be swallowed,and some few to be
chewed and digested:that is,some books are to be read only in parts;oth-
ers to be read but not curiously;and some few to be read wholly,and with
diligence and attention.
I would like to think that this book might fit any ofthe above descriptions,depending on the
reader’s need.
Finally,I would like to thank my wife Alison for her love,understanding and support over
the time I have spent preparing this book.Now that the book is finished,I should have more
time to spend with her and my three children,Laura,Joanna and David.
Mark Gibson
May 2001
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Contributors
MARK GIBSON
Mark Gibson,BPharm,PhD,CChem,MRSC,MRPharmS,is currently responsible for par-
enteral and oral solid dosage form development at AstraZeneca R&D Charnwood,which is a
division of AstraZeneca.His experience includes formulation and preformulation develop-
ment,both as a bench scientist and a manger,at Cyanamid (Lederle) for six years,Fisons Par-
maceuticals for six years,Astra Pharmaceuticals for four years and AstraZeneca for two years.
He has worked on a variety ofdosage forms and routes ofdelivery,including inhalation,oral,
nasal,ophthalmic,parenteral and transdermal,resulting in some patents or marketable prod-
ucts.Dr.Gibson is a member ofthe UK Academy ofPharmaceutical Sciences,the Parenteral
Society and the Aerosol Society.
BERTIL ABRAHAMSSON
Bertil Abrahamsson,PhD,leads pharmaceutical and analytical research and development at
AstraZeneca R&D Mölndal.His experience is in in vitro/in vivocorrelations,in vitrodissolu-
tion,in vivoimaging of dosage forms and drug absorption.Dr.Abrahamsson has published
more than 20 articles in clinical pharmacology.
KEITH R. BRAIN
Keith Brain,BPharm,PhD,is head of the drug delivery research group at Cardiff Univer-
sity.His major responsibilities are in molecular recognition research and skin research.He
is also CEO of An-eX, a university-based spinoff company formed in 1988, which
specialises in confidential contract research and development for international clients.He
has organized several international conferences on skin research and workshops on molec-
ular imprinting.
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