Table Of ContentDRUGS AND THE PHARMACEUTICAL SCIENCES VOLUME 199
S E C O N D E D I T I O N
Pharmaceutical
Preformulation and
Formulation
A Practical Guide from Candidate Drug Selection to Commercial Dosage Form
edited by
Mark Gibson
Pharmaceutical
Preformulation and
Formulation
DRUGS AND THE PHARMACEUTICAL SCIENCES
A Series of Textbooks and Monographs
Executive Editor
James Swarbrick
PharmaceuTech, Inc.
Pinehurst, North Carolina
Advisory Board
Larry L. Augsburger Harry G. Brittain
University of Maryland Center for Pharmaceutical Physics Milford,
Baltimore, Maryland New Jersey
Jennifer B. Dressman Robert Gurny
University of Frankfurt Institute Universite de Geneve
of Pharmaceutical Technology Geneve, Switzerland
Frankfurt, Germany
Jeffrey A. Hughes
Anthony J. Hickey University of Florida College
University of North Carolina of Pharmacy
School of Pharmacy Gainesville, Florida
Chapel Hill, North Carolina
Vincent H. L. Lee
Ajaz Hussain US FDA Center for Drug
Sandoz Evaluation and Research
Princeton, New Jersey Los Angeles, California
Joseph W. Polli Kinam Park
GlaxoSmithKline Purdue University
Research Triangle Park West Lafayette, Indiana
North Carolina
Jerome P. Skelly
Stephen G. Schulman Alexandria, Virginia
University of Florida
Gainesville, Florida Elizabeth M. Topp
University of Kansas
Yuichi Sugiyama Lawrence, Kansas
University of Tokyo, Tokyo, Japan
Peter York
Geoffrey T. Tucker University of Bradford
University of Sheffield School of Pharmacy
Royal Hallamshire Hospital Bradford, United Kingdom
Sheffield, United Kingdom
For information on volumes 1–149 in the Drugs and Pharmaceutical
Science Series, please visit www.informahealthcare.com
150. Laboratory Auditing for Quality and Regulatory Compliance, Donald Singer,
Raluca-Ioana Stefan, and Jacobus van Staden
151. Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation,
edited by Stanley Nusim
152. Preclinical Drug Development, edited by Mark C. Rogge and David R. Taft
153. Pharmaceutical Stress Testing: Predicting Drug Degradation, edited by
Steven W. Baertschi
154. Handbook of Pharmaceutical Granulation Technology: Second Edition,
edited by Dilip M. Parikh
155. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,
Fourth Edition, edited by Robert L. Bronaugh and Howard I. Maibach
156. Pharmacogenomics: Second Edition, edited by Werner Kalow, Urs A. Meyer
and Rachel F. Tyndale
157. Pharmaceutical Process Scale-Up, Second Edition, edited by Michael Levin
158. Microencapsulation: Methods and Industrial Applications, Second Edition,
edited by Simon Benita
159. Nanoparticle Technology for Drug Delivery, edited by Ram B. Gupta and
Uday B. Kompella
160. Spectroscopy of Pharmaceutical Solids, edited by Harry G. Brittain
161. Dose Optimization in Drug Development, edited by Rajesh Krishna
162. Herbal Supplements-Drug Interactions: Scientific and Regulatory Perspectives,
edited by Y. W. Francis Lam, Shiew-Mei Huang, and Stephen D. Hall
163. Pharmaceutical Photostability and Stabilization Technology, edited by
Joseph T. Piechocki and Karl Thoma
164. Environmental Monitoring for Cleanrooms and Controlled Environments,
edited by Anne Marie Dixon
165. Pharmaceutical Product Development: In Vitro-In Vivo Correlation, edited by
Dakshina Murthy Chilukuri, Gangadhar Sunkara, and David Young
166. Nanoparticulate Drug Delivery Systems, edited by Deepak Thassu, Michel
Deleers, and Yashwant Pathak
167. Endotoxins: Pyrogens, LAL Testing and Depyrogenation, Third Edition,
edited by Kevin L. Williams
168. Good Laboratory Practice Regulations, Fourth Edition, edited by Anne
Sandy Weinberg
169. Good Manufacturing Practices for Pharmaceuticals, Sixth Edition,
edited by Joseph D. Nally
170. Oral-Lipid Based Formulations: Enhancing the Bioavailability of Poorly
Water-soluble Drugs, edited by David J. Hauss
171. Handbook of Bioequivalence Testing, edited by Sarfaraz K. Niazi
172. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes,
edited by Robert O. Williams III, David R. Taft, and Jason T. McConville
173. Clean-in-Place for Biopharmaceutical Processes, edited by Dale
A. Seiberling
174. Filtration and Purification in the Biopharmaceutical Industry, Second Edition,
edited by Maik W. Jornitz and Theodore H. Meltzer
175. Protein Formulation and Delivery, Second Edition, edited by Eugene
J. McNally and Jayne E. Hastedt
176. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Third
Edition, edited by James McGinity and Linda A. Felton
177. Dermal Absorption and Toxicity Assessment, Second Edition, edited by
Michael S. Roberts and Kenneth A. Walters
178. Preformulation Solid Dosage Form Development, edited by Moji C. Adeyeye
and Harry G. Brittain
179. Drug-Drug Interactions, Second Edition, edited by A. David Rodrigues
180. Generic Drug Product Development: Bioequivalence Issues, edited by
Isadore Kanfer and Leon Shargel
181. Pharmaceutical Pre-Approval Inspections: A Guide to Regulatory Success,
Second Edition, edited by Martin D. Hynes III
182. Pharmaceutical Project Management, Second Edition, edited by
Anthony Kennedy
183. Modified Release Drug Delivery Technology, Second Edition, Volume 1,
edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts,
and Majella E. Lane
184. Modified-Release Drug Delivery Technology, Second Edition, Volume 2,
edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts, and
Majella E. Lane
185. The Pharmaceutical Regulatory Process, Second Edition, edited by
Ira R. Berry and Robert P. Martin
186. Handbook of Drug Metabolism, Second Edition, edited by Paul G. Pearson and
Larry C. Wienkers
187. Preclinical Drug Development, Second Edition, edited by Mark Rogge and
David R. Taft
188. Modern Pharmaceutics, Fifth Edition, Volume 1: Basic Principles and Systems,
edited by Alexander T. Florence and Juergen Siepmann
189. Modern Pharmaceutics, Fifth Edition, Volume 2: Applications and Advances,
edited by Alexander T. Florence and Juergen Siepmann
190. New Drug Approval Process, Fifth Edition, edited by Richard A.Guarino
191. Drug Delivery Nanoparticulate Formulation and Characterization, edited by
Yashwant Pathak and Deepak Thassu
192. Polymorphism of Pharmaceutical Solids, Second Edition, edited by Harry G. Brittain
193. Oral Drug Absorption: Prediction and Assessment, Second Edition, edited by
Jennifer J. Dressman, hans Lennernas, and Christos Reppas
194. Biodrug Delivery Systems: Fundamentals, Applications, and Clinical Development,
edited by Mariko Morista and Kinam Park
195. Pharmaceutical Process Engineering, Second Edition, edited by Anthony J. Hickey
and David Ganderton
196. Handbook of Drug Screening, Second Edition, edited by Ramakrishna Seethala and
Litao Zhang
197. Pharmaceutical Powder Compaction Technology, Second Edition, edited by
Metin Celik
198. Handbook of Pharmaceutical Granulation Technology, Dilip M. Parikh
199. Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate
Drug Selection to Commercial Dosage Form, Second Edition, edited by
Mark Gibson
Pharmaceutical
Preformulation and
Formulation
Second Edition
A Practical Guide from Candidate Drug Selection to Commercial Dosage Form
edited by
Mark Gibson
AstraZeneca R&D Charnwood
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Pharmaceuticalpreformulationandformulation:Apracticalguidefromcandidatedrug
selectiontocommercialdosageform/editedbyMarkGibson.
—2nded.
p.;cm.— (Drugsandthepharmaceuticalsciences;199)
Includesbibliographicalreferencesandindex.
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I. Gibson,Mark,1957-II. Series:Drugsandthepharmaceutical
sciences;v.199.
[DNLM: 1. DrugCompounding. 2. Biopharmaceutics—methods. 3.
DosageForms. 4. DrugDiscovery. 5. DrugEvaluation. W1DR893Bv.199
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Preface
Thefirsteditionofthisbookpublishedin2001hasbeenmoresuccessfulthanIeverimagined,
as indicated by the excellent reviews it has received, the continued demand, and impressive
sales! I believe that the main reasons for its popularity are that there was a significant gap in
the literature and also that the information presented was based on the extensive experiences
of the various contributors who were all actively working in the industry and were willing to
share “best practice” from their knowledge and experiences. The book is intended to be a
practical guide to pharmaceutical preformulation and formulation to be used as a reference
source or a guidance tool to those working in the pharmaceutical industry or related
industries, such as biopharmaceuticals or medical devices, or anyone wanting an insight into
thesubjectarea.Indeed,thisbookhasalsoprovedtobeavaluabletextforundergraduateand
postgraduatecoursesinindustrialpharmacyandpharmaceuticaltechnology.Asecondedition
isrequiredbecausepreformulationandformulationtechnologycontinuestodevelopandalso
because there are bound to be some gaps and improvements to be filled.
The second edition still meets the main objectives of the first edition, that is, to
l provide a logical and structured approach to product development, with key stages
identified and the preformulation, biopharmaceutics, and formulation activities and
typicalissuesateachstagediscussed,whereverpossiblewithrealorworkedexamples,
l emphasize what practical studies need to be undertaken for what reasons and during
what key stages of the drug development process, and
l provide separate chapters on the formulation development of each route and type of
dosage forms.
The pressure to accelerate the drug development process, shorten the development timelines,
and launch new pharmaceutical products is even more intense than before, with fewer
registrations year on year. Having a structured approach and doing the right things first time
are essential elements for achieving this. The chapters on product design and product
optimization are still very relevant but have been updated to include the quality by design
(QbD) and International Conference on Harmonisation (ICH) Q8 (product development),
ICH Q9 (quality risk management), process analytical technology (PAT), and lean
manufacturing principles that aim to link regulatory expectations to good science.
Another significant change since the first edition is the growth of biopharmaceuticals,
compared with small molecules, that deserves more attention. Pharmaceutical companies are
shifting from developing small molecules to developing biopharmaceuticals to treat a wide
range of diseases, and today approximately one in four drugs introduced to the market is a
biopharmaceutical. Since the majority of biopharmaceuticals will be delivered by injection or
infusion, the chapter on parenteral dosage forms has been updated to reflect this. Focus has
been given to the steps after purification, formulation, and subsequent fill-finish. Consider-
ationhasalsobeengivenintheotherchaptersforhandlinganddevelopingbiopharmaceutical
dosage forms where there is some potential for drug delivery, for example, intranasal dosage
forms.
Elsewhere in the second edition, there are updates throughout the book to reflect on
some omissions and developmentssince the first editionand makeit up-to-date; forexample,
to reflect emerging “cutting-edge” technologies such as polymorph and salt selection and
viii Preface
prediction, molecular modeling and automation in preformulation studies, and more consider-
ation for packaging technology during development of the various dosage forms.
Once again I am indebted to all the contributors for giving up their time and energy in
producingthisupdatedversion.Iamalsoindebtedtomywife,Alison,andmyfamilyfortheir
support and understanding during the time I have been busy working on this book.
Mark Gibson
Contents
Preface vii
Contributors xi
1. Introduction and Perspective 1
Mark Gibson
2. Aiding Candidate Drug Selection: Introduction and Objectives 11
Mark Gibson
3. Preformulation Investigations using Small Amounts of Compound as an Aid to
Candidate Drug Selection and Early Development 17
Gerry Steele and Talbir Austin
4. Biopharmaceutical Support in Candidate Drug Selection 129
Anna-Lena Ungell and Bertil Abrahamsson
5. Early Drug Development: Product Design 172
Mark Gibson
6. Preformulation as an Aid to Product Design in Early Drug Development 188
Gerry Steele
7. Biopharmaceutical Support in Formulation Development 247
Bertil Abrahamsson and Anna-Lena Ungell
8. Product Optimization 289
Mark Gibson
9. Parenteral Dosage Forms 325
Joanne Broadhead and Mark Gibson
10. Inhalation Dosage Forms 348
Paul Wright
11. Oral Solid Dosage Forms 367
Peter Davies
12. Ophthalmic Dosage Forms 431
Mark Gibson
