Pharmaceutical Suspensions

Alok K. Kulshreshtha ● Onkar N. Singh G. Michael WallEditors

Pharmaceutical Suspensions

From Formulation Development to Manufacturing

EditorsAlok K. KulshreshthaAlcon Research LtdForth Worth, TXUSAalok.kulshreshtha@alconlabs.com

G. Michael WallAlcon Research LtdForth Worth, TXUSAmichael.wall@alconlabs.com

Onkar N. SinghAlcon Research Ltd,Forth Worth, TXUSAonkar.singh@alconlabs.com

ISBN 978-1-4419-1086-8 e-ISBN 978-1-4419-1087-5DOI 10.1007/978-1-4419-1087-5Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2009937643

© AAPS 2010All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights.

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

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Preface

The suspension dosage form has long been used for poorly soluble active ingredi-ents for various therapeutic indications. Development of stable suspensions over the shelf life of the drug product continues to be a challenge on many fronts.

A good understanding of the fundamentals of disperse systems is essential in the development of a suitable pharmaceutical suspension. The development of a sus-pension dosage form follows a very complicated path. The selection of the proper excipients (surfactants, viscosity imparting agents etc.) is important. The particle size distribution in the finished drug product dosage form is a critical parameter that significantly impacts the bioavailability and pharmacokinetics of the product. Appropriate analytical methodologies and instruments (chromatographs, viscome-ters, particle size analyzers, etc.) must be utilized to properly characterize the sus-pension formulation. The development process continues with a successful scale-up of the manufacturing process. Regulatory agencies around the world require clini-cal trials to establish the safety and efficacy of the drug product. All of this develop-ment work should culminate into a regulatory filing in accordance with the regulatory guidelines. Pharmaceutical Suspensions, From Formulation Development to Manufacturing, in its organization, follows the development approach used widely in the pharmaceutical industry. The primary focus of this book is on the classical disperse system – poorly soluble active pharmaceutical ingredients sus-pended in a suitable vehicle.

After discussing various disperse systems, the theory of disperse systems and commonly used excipients, the remaining chapters in this textbook systematically explain the development of pharmaceutical suspensions, from the pre-formulation stage to clinical development, regulatory submission and commercial manufactur-ing. Additionally, the emerging area of nano-suspensions as applied to the pharma-ceutical field is also discussed. Each of the chapters in Pharmaceutical Suspensions was written independently by scientists who are skilled in their specific areas. Contributing authors represent a cross-sections of scholars from academic, indus-trial and governmental affiliations.

Pharmaceutical Suspensions, From Formulation Development to Manufacturing is organized in a total of ten chapters: Chapter 1 introduces various pharmaceutical disperse systems in-depth. Chapter 2 presents the general principles of suspension dosage form and Chapter 3 discusses commonly used excipients in pharmaceutical

vi Preface

suspensions. Chapter 4 systematically highlights steps involved in pharmaceutical development of suspension dosage forms. Chapter 5 focuses on preclinical devel-opment of suspension formulations. Analytical tools needed to characterize phar-maceutical suspensions dosage forms are discussed in Chapter 6. The clinical development aspects of suspension drug products are discussed in Chapter 7. Chapter 8 highlights scale up and technology transfer of the development of phar-maceutical suspensions. Chapter 9 reviews the science and regulatory perspectives of pharmaceutical suspensions. Finally, Chapter 10 deals with the pharmaceutical applications of nano-suspensions as nanomedicine, an emerging technology area.

Pharmaceutical Suspensions, From Formulation Development to Manufacturing should serve as a good resource for pharmaceutical scientists, process scientists and chemical engineers involved in the areas of research and development of pharma-ceutical suspension dosage forms, and for new and sustaining scientists of the pharmaceutical and chemical fields. The fundamental aspects together with the practical case studies should also make this a useful source for undergraduate and graduate education.

Forth Worth, TX Alok K. Kulshreshtha, Ph.D.Onkar N. Singh. Ph.D., M.B.A.

G. Michael Wall, Ph.D.

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Acknowledgements

We wish to acknowledge our families for their support and encouragement. We also wish to express our sincere gratitude to all the contributors who made this textbook possible. Their patience and perseverance throughout this process is greatly appreciated.

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Contents

1 Various Pharmaceutical Disperse Systems ........................................... 1Chandrasekar Manoharan, Ashwin Basarkar and Jagdish Singh

2 General Principles of Suspensions ......................................................... 39Mohammad T. H. Nutan and Indra K. Reddy

3 Commonly Used Excipients in Pharmaceutical Suspensions.............. 67R. Christian Moreton

4 Pharmaceutical Development of Suspension Dosage Form ................ 103Yusuf Ali, Akio Kimura, Martin J. Coffey, and Praveen Tyle

5 Preclinical Development for Suspensions ............................................. 127Sudhakar Garad, Jianling Wang, Yatindra Joshi, and Riccardo Panicucci

6 Analytical Tools for Suspension Characterization ............................... 177Alan F. Rawle

7 Clinical Trials of Suspension Drug Products ........................................ 231G. Michael Wall and Terry K. Wiernas

8 Scale Up and Technology Transfer of Pharmaceutical Suspensions .............................................................................................. 245Yashwant Pathak and Deepak Thassu

9 The Science and Regulatory Perspectives of Pharmaceutical Suspensions .............................................................................................. 265Abhay Gupta, Vilayat A. Sayeed, and Mansoor A. Khan

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10 Solid Nanosuspensions: The Emerging Technology and Pharmaceutical Applications as Nanomedicine ............................ 285Sudhir Verma and Diane Burgess

Index ................................................................................................................. 319

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Contributors

Yusuf Ali, Ph.D. Vice President, Santen Incorporated, Napa, CA, USA

Ashwin Basarkar, Ph.D. Pharmaceutical Sciences Department, North Dakota State University, Fargo, ND, USA

Diane Burgess, Ph.D. Professor of Pharmaceutics, University of Connecticut, School of Pharmacy, Storrs, CT, USA

Martin J. Coffey, Ph.D. Principal Scientist, Pharmaceutical Product Development, Bausch and Lomb, Inc., Rochester, NY, USA

Sudhakar Garad, Ph.D. Group Head, Novartis Institute for Biomedical Research, Cambridge, MA, USA

Abhay Gupta, Ph.D. Pharmacologist, Division of Product Quality Research, Office of Testing and Research, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

Yatindra Joshi, Ph.D. Vice President, Generic R&D, Teva Pharmaceuticals, North Wales, PA, USA (former Vice President, Novartis Pharmaceuticals, NJ, USA)

Akio Kimura Head of Pharmaceutical Development, Santen Incorporated, Osaka, Japan

Mansoor A. Khan, Ph.D. Director, Division of Product Quality Research (DPQR), Office of Testing and Research (OTR), Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD, USA

xii Contributors

Alok K. Kulshreshtha, Ph.D. Associate Director, Pharmaceutical Technology, Alcon Research Ltd., Fort Worth, TX, USA

Chandrasekar Manoharan, Ph.D. Pharmaceutical Sciences Department, North Dakota State University, Fargo, ND, USA

R. Christian Moreton, Ph.D. FinnBrit Consulting, Waltham, MA, USA

Mohammed T.H. Nutan, Ph.D. Irma Lerma Rangel College of Pharmacy, Texas A & M University, Kingsville, TX, USA

Riccardo Panicucci, Ph.D. Global Head, Novartis Institute for Biomedical Research, Cambridge, MA, USA

Yashwant Pathak, Ph.D. Assistant Dean of Academic Affairs, Professor and Chair, Pharmaceutical Sciences, College of Pharmacy, Sullivan University, Louisville, KY, USA

Alan F. Rawle, Ph.D. Divisional Manager, Malvern Instruments, Inc., Westborough, MA, USA

Indra K. Reddy, Ph.D. Professor and Dean, Irma Lerma Rangel College of Pharmacy, Texas A & M University, Kingsville, TX, USA

Vilayat A. Sayeed, Ph.D. Division of Chemistry, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD, USA

Jagdish Singh, Ph.D. Professor and Chairman, Pharmaceutical Sciences Department, North Dakota State University, Fargo, ND, USA

Onkar N. Singh, Ph.D., MBA Assistant Director, Development, Alcon Research Ltd., Fort Worth, TX, USA

Deepak Thassu, Ph.D., MBA Vice President of Pharmaceutical Development, PharmaNova Inc., Victor, NY, USA

Praveen Tyle, Ph.D. Senior Vice President and Global Head, R&D and BD&L, OTC, Novartis Consumer Health Care, Parsippany, NJ, USA

Sudhir Verma, Ph.D. University of Connecticut, School of Pharmacy, Storrs, CT, USA

xiiiContributors

G. Michael Wall, Ph.D. Senior Director, Alcon Research Ltd., Fort Worth, TX, USA

Jianling Wang, Ph.D. Senior Research Investigator, Novartis Institute for Biomedical Research, Cambridge, MA, USA

Terry K. Wiernas, Ph.D., MBA Vice President, Alcon Inc., Fort Worth, TX, USA

About the Editors

Alok K. Kulshreshtha, Ph.D., Associate Director, Pharmaceutical Technology at Alcon Research Ltd., Fort Worth, TX, has 20 years of experience in the devel-opment of sterile ophthalmic, contact lens care, and dry eye products. During this tenure in pharmaceutical industry, Dr. Kulshreshtha has worked on several sus-pension drug products in different stages of development. Dr. Kulshreshtha’s interest in the suspension area started almost 30 years ago when he began his doctoral dissertation on suspension rheology. Over the years, Dr. Kulshreshtha has worked on many new technologies for producing sterile suspensions. Dr. Kulshreshtha is the inventor/co-inventor of several patents and has authored many peer-reviewed publications. Dr. Kulshreshtha is a member of the American Association of Pharmaceutical Scientists (AAPS) and has been reviewer for AAPS abstracts screening for posters and symposia. Dr. Kulshreshtha holds a Ph.D. and M.S. in Chemical Engineering from Purdue University, and a Bachelor’s degree in Chemical Engineering from the Indian Institute of Technology, Kanpur, India.

Onkar N. Singh, Ph.D., M.B.A., Assistant Director, Development at Alcon Research Ltd., Fort Worth, TX, has over 16 years of experience in pharmaceutical product research and development of nasal, sterile ophthalmic, sterile otic, and parentral products. Dr. Singh is inventor/co-inventor of many patents related to formulations, process and formulation technology and has authored several peer-reviewed articles. Prior to joining Alcon Inc., Dr. Singh was Manager at Access Pharmaceuticals, Dallas, TX, leading efforts in the area of site-specific targeted drug delivery systems for diagnostic and therapeutic areas of cancer therapy. At Access Pharmaceuticals, Dr. Singh worked on nanoparticles, liposomes, emulsion formulations, protein pharmaceuticals and gene delivery technology. Dr. Singh served as Secretary/Treasurer of the “Ocular Focus Group of AAPS” from 2002 to 2005 and has been a reviewer for AAPS abstracts, posters and symposia. Dr. Singh is a member of the American Association of Pharmaceutical Scientists (AAPS) and currently serves as an editorial board member of American Pharmaceutical Review Journal. Dr. Singh holds a B.S. in Pharmacy, M.S. in

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xvi About the Editors

Pharmaceutics from Banaras Hindu University, India, Ph.D. in Pharmaceutics from University of Illinois at Chicago and M.B.A. from University of Texas at Arlington, TX.

G. Michael Wall, Ph.D., Senior Director of Pharmaceutical Products Development at Alcon Research, Ltd., Fort Worth, TX, has over 21 years of pharmaceutical industrial experience in the development of intranasal, sterile ophthalmic and otic drug products. Dr. Wall is author or co-author of two patents and over 100 publica-tions including peer-reviewed articles, abstracts, book chapters, book supplements and one book. Dr. Wall has led international, multidisciplinary teams in the devel-opment and approval of Ciprodex® Sterile Otic Suspension and Patanase® Nasal Spray, as well as other products in countries around the world. Dr. Wall is a Scientific Fellow of the American Academy of Otolaryngology – Head and Neck Surgery. He has also served the American Chemical Society as a member for 30 years. Dr. Wall received a B.S. degree in chemistry from Auburn University, a M.S. degree in medicinal chemistry from Auburn University School of Pharmacy, a Ph.D. in medicinal chemistry from the University of Mississippi School of Pharmacy, and completed the Advanced Management Program (168th session) of the Harvard Business School.