SECOND EDITION Pharmaceutical Preformulation And
DRUGS AND THE PHARMACEUTICAL SCIENCESVOLUME 199SECOND EDITIONPharmaceuticalPreformulation andFormulationA Practical Guide from Candidate Drug Selection to Commercial Dosage Formedited byMark Gibson
PharmaceuticalPreformulation andFormulation
DRUGS AND THE PHARMACEUTICAL SCIENCESA Series of Textbooks and MonographsExecutive EditorJames SwarbrickPharmaceuTech, Inc.Pinehurst, North CarolinaAdvisory BoardLarry L. AugsburgerUniversity of MarylandBaltimore, MarylandJennifer B. DressmanUniversity of Frankfurt Instituteof Pharmaceutical TechnologyFrankfurt, GermanyAnthony J. HickeyUniversity of North CarolinaSchool of PharmacyChapel Hill, North CarolinaAjaz HussainSandozPrinceton, New JerseyJoseph W. PolliGlaxoSmithKlineResearch Triangle ParkNorth CarolinaStephen G. SchulmanHarry G. BrittainCenter for Pharmaceutical Physics Milford,New JerseyRobert GurnyUniversite de GeneveGeneve, SwitzerlandJeffrey A. HughesUniversity of Florida Collegeof PharmacyGainesville, FloridaVincent H. L. LeeUS FDA Center for DrugEvaluation and ResearchLos Angeles, CaliforniaKinam ParkPurdue UniversityWest Lafayette, IndianaJerome P. SkellyAlexandria, VirginiaUniversity of FloridaGainesville, FloridaElizabeth M. ToppYuichi SugiyamaUniversity of KansasLawrence, KansasUniversity of Tokyo, Tokyo, JapanGeoffrey T. TuckerUniversity of SheffieldRoyal Hallamshire HospitalSheffield, United KingdomPeter YorkUniversity of BradfordSchool of PharmacyBradford, United Kingdom
For information on volumes 1–149 in the Drugs and PharmaceuticalScience Series, please visit www.informahealthcare.com150. Laboratory Auditing for Quality and Regulatory Compliance, Donald Singer,Raluca-Ioana Stefan, and Jacobus van Staden151. Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation,edited by Stanley Nusim152. Preclinical Drug Development, edited by Mark C. Rogge and David R. Taft153. Pharmaceutical Stress Testing: Predicting Drug Degradation, edited bySteven W. Baertschi154. Handbook of Pharmaceutical Granulation Technology: Second Edition,edited by Dilip M. Parikh155. Percutaneous Absorption: h Edition, edited by Robert L. Bronaugh and Howard I. Maibach156. Pharmacogenomics: Second Edition, edited by Werner Kalow, Urs A. Meyerand Rachel F. Tyndale157. Pharmaceutical Process Scale-Up, Second Edition, edited by Michael Levin158. Microencapsulation: Methods and Industrial Applications, Second Edition,edited by Simon Benita159. Nanoparticle Technology for Drug Delivery, edited by Ram B. Gupta andUday B. Kompella160. Spectroscopy of Pharmaceutical Solids, edited by Harry G. Brittain161. Dose Optimization in Drug Development, edited by Rajesh Krishna162. Herbal Supplements-Drug Interactions: Scientific and Regulatory Perspectives,edited by Y. W. Francis Lam, Shiew-Mei Huang, and Stephen D. Hall163. Pharmaceutical Photostability and Stabilization Technology, edited byJoseph T. Piechocki and Karl Thoma164. Environmental Monitoring for Cleanrooms and Controlled Environments,edited by Anne Marie Dixon165. Pharmaceutical Product Development: In Vitro-In Vivo Correlation, edited byDakshina Murthy Chilukuri, Gangadhar Sunkara, and David Young166. Nanoparticulate Drug Delivery Systems, edited by Deepak Thassu, MichelDeleers, and Yashwant Pathak167. Endotoxins: Pyrogens, LAL Testing and Depyrogenation, Third Edition,edited by Kevin L. Williams168. Good Laboratory Practice Regulations, Fourth Edition, edited by AnneSandy Weinberg169. Good Manufacturing Practices for Pharmaceuticals, Sixth Edition,edited by Joseph D. Nally170. Oral-Lipid Based Formulations: Enhancing the Bioavailability of PoorlyWater-soluble Drugs, edited by David J. Hauss171. Handbook of Bioequivalence Testing, edited by Sarfaraz K. Niazi172. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes,edited by Robert O. Williams III, David R. Taft, and Jason T. McConville173. Clean-in-Place for Biopharmaceutical Processes, edited by DaleA. Seiberling174. Filtration and Purification in the Biopharmaceutical Industry, Second Edition,edited by Maik W. Jornitz and Theodore H. Meltzer175. Protein Formulation and Delivery, Second Edition, edited by EugeneJ. McNally and Jayne E. Hastedt
176. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, ThirdEdition, edited by James McGinity and Linda A. Felton177. Dermal Absorption and Toxicity Assessment, Second Edition, edited byMichael S. Roberts and Kenneth A. Walters178. Preformulation Solid Dosage Form Development, edited by Moji C. Adeyeyeand Harry G. Brittain179. Drug-Drug Interactions, Second Edition, edited by A. David Rodrigues180. Generic Drug Product Development: Bioequivalence Issues, edited byIsadore Kanfer and Leon Shargel181. Pharmaceutical Pre-Approval Inspections: A Guide to Regulatory Success,Second Edition, edited by Martin D. Hynes III182. Pharmaceutical Project Management, Second Edition, edited byAnthony Kennedy183. Modified Release Drug Delivery Technology, Second Edition, Volume 1,edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts,and Majella E. Lane184. Modified-Release Drug Delivery Technology, Second Edition, Volume 2,edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts, andMajella E. Lane185. The Pharmaceutical Regulatory Process, Second Edition, edited byIra R. Berry and Robert P. Martin186. Handbook of Drug Metabolism, Second Edition, edited by Paul G. Pearson andLarry C. Wienkers187. Preclinical Drug Development, Second Edition, edited by Mark Rogge andDavid R. Taft188. Modern Pharmaceutics, Fifth Edition, Volume 1: Basic Principles and Systems,edited by Alexander T. Florence and Juergen Siepmann189. Modern Pharmaceutics, Fifth Edition, Volume 2: Applications and Advances,edited by Alexander T. Florence and Juergen Siepmann190. New Drug Approval Process, Fifth Edition, edited by Richard A.Guarino191. Drug Delivery Nanoparticulate Formulation and Characterization, edited byYashwant Pathak and Deepak Thassu192. Polymorphism of Pharmaceutical Solids, Second Edition, edited by Harry G. Brittain193. Oral Drug Absorption: Prediction and Assessment, Second Edition, edited byJennifer J. Dressman, hans Lennernas, and Christos Reppas194. Biodrug Delivery Systems: Fundamentals, Applications, and Clinical Development,edited by Mariko Morista and Kinam Park195. Pharmaceutical Process Engineering, Second Edition, edited by Anthony J. Hickeyand David Ganderton196. Handbook of Drug Screening, Second Edition, edited by Ramakrishna Seethala andLitao Zhang197. Pharmaceutical Powder Compaction Technology, Second Edition, edited byMetin Celik198. Handbook of Pharmaceutical Granulation Technology, Dilip M. Parikh199. Pharmaceutical Preformulation and Formulation: A Practical Guide from CandidateDrug Selection to Commercial Dosage Form, Second Edition, edited byMark Gibson
PharmaceuticalPreformulation andFormulationSecond EditionA Practical Guide from Candidate Drug Selection to Commercial Dosage Formedited byMark GibsonAstraZeneca R&D CharnwoodLoughborough, Leicestershire, UK
Informa Healthcare USA, Inc.52 Vanderbilt AvenueNew York, NY 10017# 2009 by Informa Healthcare USA, Inc.Informa Healthcare is an Informa businessNo claim to original U.S. Government worksPrinted in the United States of America on acid-free paper10 9 8 7 6 5 4 3 2 1International Standard Book Number-10: 1-4200-7317-6 (Hardcover)International Standard Book Number-13: 978-1-4200-7317-1 (Hardcover)This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted withpermission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publishreliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materialsor for the consequence of their use.No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, orother means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any informationstorage or retrieval system, without written permission from the publishers.For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923,978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. Fororganizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only foridentification and explanation without intent to infringe.Library of Congress Cataloging-in-Publication DataPharmaceutical preformulation and formulation: A practical guide from candidate drugselection to commercial dosage form / edited by Mark Gibson.—2nd ed.p. ; cm. — (Drugs and the pharmaceutical sciences ; 199)Includes bibliographical references and index.ISBN-13: 978-1-4200-7317-1 (hb : alk. paper)ISBN-10: 1-4200-7317-6 (hb : alk. paper) 1. Drugs—Dosage forms.I. Gibson, Mark, 1957- II. Series: Drugs and the pharmaceuticalsciences ; v. 199.[DNLM: 1. Drug Compounding. 2. Biopharmaceutics—methods. 3.Dosage Forms. 4. Drug Discovery. 5. Drug Evaluation. W1 DR893B v.1992009 / QV 778 P53535 2009]RS200.P425 20096150 .1—dc222009012458For Corporate Sales and Reprint Permissions call 212-520-2700 or write to: Sales Department, 52 Vanderbilt Avenue,16th floor, New York, NY 10017.Visit the Informa Web site atwww.informa.comand the Informa Healthcare Web site atwww.informahealthcare.com
PrefaceThe first edition of this book published in 2001 has been more successful than I ever imagined,as indicated by the excellent reviews it has received, the continued demand, and impressivesales! I believe that the main reasons for its popularity are that there was a significant gap inthe literature and also that the information presented was based on the extensive experiencesof the various contributors who were all actively working in the industry and were willing toshare “best practice” from their knowledge and experiences. The book is intended to be apractical guide to pharmaceutical preformulation and formulation to be used as a referencesource or a guidance tool to those working in the pharmaceutical industry or relatedindustries, such as biopharmaceuticals or medical devices, or anyone wanting an insight intothe subject area. Indeed, this book has also proved to be a valuable text for undergraduate andpostgraduate courses in industrial pharmacy and pharmaceutical technology. A second editionis required because preformulation and formulation technology continues to develop and alsobecause 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, tolllprovide a logical and structured approach to product development, with key stagesidentified and the preformulation, biopharmaceutics, and formulation activities andtypical issues at each stage discussed, wherever possible with real or worked examples,emphasize what practical studies need to be undertaken for what reasons and duringwhat key stages of the drug development process, andprovide separate chapters on the formulation development of each route and type ofdosage 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 fewerregistrations year on year. Having a structured approach and doing the right things first timeare essential elements for achieving this. The chapters on product design and productoptimization 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 leanmanufacturing 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 areshifting from developing small molecules to developing biopharmaceuticals to treat a widerange of diseases, and today approximately one in four drugs introduced to the market is abiopharmaceutical. Since the majority of biopharmaceuticals will be delivered by injection orinfusion, the chapter on parenteral dosage forms has been updated to reflect this. Focus hasbeen given to the steps after purification, formulation, and subsequent fill-finish. Consideration has also been given in the other chapters for handling and developing biopharmaceuticaldosage forms where there is some potential for drug delivery, for example, intranasal dosageforms.Elsewhere in the second edition, there are updates throughout the book to reflect onsome omissions and developments since the first edition and make it up-to-date; for example,to reflect emerging “cutting-edge” technologies such as polymorph and salt selection and
viiiPrefaceprediction, molecular modeling and automation in preformulation studies, and more consideration 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 inproducing this updated version. I am also indebted to my wife, Alison, and my family for theirsupport and understanding during the time I have been busy working on this book.Mark Gibson
ContentsPrefaceContributorsviixi1. Introduction and PerspectiveMark Gibson12. Aiding Candidate Drug Selection: Introduction and ObjectivesMark Gibson113. Preformulation Investigations using Small Amounts of Compound as an Aid toCandidate Drug Selection and Early Development17Gerry Steele and Talbir Austin4. Biopharmaceutical Support in Candidate Drug SelectionAnna-Lena Ungell and Bertil Abrahamsson5. Early Drug Development: Product DesignMark Gibson1291726. Preformulation as an Aid to Product Design in Early Drug DevelopmentGerry Steele7. Biopharmaceutical Support in Formulation DevelopmentBertil Abrahamsson and Anna-Lena Ungell8. Product OptimizationMark Gibson2899. Parenteral Dosage Forms325Joanne Broadhead and Mark Gibson10.Inhalation Dosage FormsPaul Wright34811.Oral Solid Dosage FormsPeter Davies36712.Ophthalmic Dosage FormsMark Gibson431247188
Contentsx13. Aqueous Nasal Dosage FormsNigel Day45614. Topical and Transdermal DeliveryKenneth A. Walters and Keith R. BrainIndex527475
ContributorsBertil AbrahamssonAstraZeneca, Mölndal, SwedenTalbir Austin AstraZeneca R&D Charnwood, Loughborough, Leicestershire, U.K.Keith R. BrainCardiff University, Cardiff, U.K.Joanne Broadhead AstraZeneca R&D Charnwood, Loughborough, Leicestershire, U.K.Peter DaviesShire Pharmaceutical Development Ltd., Basingstoke, U.K.Nigel Day AstraZeneca R&D Charnwood, Loughborough, Leicestershire, U.K.Mark GibsonGerry SteeleAstraZeneca R&D Charnwood, Loughborough, Leicestershire, U.K.AstraZeneca R&D Charnwood, Loughborough, Leicestershire, U.K.Anna-Lena UngellAstraZeneca, Mölndal, SwedenKenneth A. Walters An-eX Analytical Services Ltd., Cardiff, U.K.Paul WrightAstraZeneca R&D Charnwood, Loughborough, Leicestershire, U.K.
1Introduction and PerspectiveMark GibsonAstraZeneca R&D Charnwood, Loughborough, Leicestershire, U.K.INTRODUCTIONThis book is intended to be a practical guide to pharmaceutical preformulation and formulation.It can be used as a reference source and a guidance tool for those working in the pharmaceuticalindustry or related industries, for example, medical devices and biopharmaceuticals, or anyonewanting an insight into this subject area. The information presented is essentially based on theextensive experiences of the editor and various other contributors who are all actively working inthe industry and have learned “best practice” from their experiences.There are various excellent books already available that cover the theoretical aspects ofdifferent types of pharmaceutical dosage forms and processes. A variety of books are also availablethat focus on the drug development process, business, and regulatory and project managementaspects. The popularity of the first edition of this book, Pharmaceutical Preformulation and Formulation:A Practical Guide from Candidate Drug Selection to Commercial Formulation, confirms my opinion thatthere is a need for a pragmatic guide to pharmaceutical preformulation and formulation with anemphasis on what practical studies need to be undertaken, for what reasons, and during what keystages of the drug development process. Preformulation, biopharmaceutics, and formulation are allimportant for candidate drug selection and through the various stages of product development asshown in Figure 3. This book has been written to try and address this need.A logical approach to product development is described in the book, with the key stagesidentified and the preformulation, biopharmaceuticals, and formulation activities and typicalissues at each stage discussed. Wherever possible, the book is illustrated with real or workedexamples from contributors who have considerable relevant experience of preformulation,biopharmaceuticals, and formulation development.Jim Wells’ book on preformulation (Wells, 1988) made a strong impact on trainees andpharmaceutical scientists (including myself) working in this field of the pharmaceuticalindustry when it was introduced two years ago. It describes the important concepts andmethods used in preformulation with the underlying theory. To his credit, Wells’ book is stilluseful today, but sadly, the book is now out of print, and existing copies are hard to obtain. Italso requires updating to include the abundance of modern preformulation instrumentaltechniques that have emerged, such as thermogravimetric analysis (TGA), hot-stage microscopy (HSM), X-ray powder diffraction (XRPD), Raman and infrared spectroscopy, and solidstate nuclear magnetic resonance (NMR). These techniques can be used to provide valuableinformation to characterize the drug substance and aid formulation development using theminimal amounts of compound.Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate DrugSelection to Commercial Formulation covers a wider subject area than just preformulation. Topicsinclude biopharmaceutics, drug delivery, formulation, and process development aspects ofproduct development. The book also describes a logical and structured approach to theproduct development process, recommending at what stages appropriate preformulation,biopharmaceutics, and formulation work are best undertaken.DRUG DEVELOPMENT DRIVERS, CHALLENGES, RISKS, AND REWARDSIt is important that the reader is aware of the nature of pharmaceutical research anddevelopment (R&D) to appreciate the importance of preformulation and formulation in theoverall process.
Gibson2Table 1 Major Hurdles to Successful Product Registration and SaleActivityRequirementsResearchNovel compound (Is it patentable?)Novel biological mechanism (Is it patentable?)Unmet medical needsPotent and selectiveHigh margin of safetyNontoxic (not carcinogenic, tetratogenic, mutagenic, etc.)Tolerable side effects profileEfficaciousAcceptable duration of actionBulk drug can be synthesized/scaled upAcceptable formulation/pack (meets customer needs)Drug delivery/product performance acceptableStable/acceptable shelf lifeRobust clinical trial process, which can be scaled up and transferred into operationsQuality of data/documentationManufacturableAcceptable cost of goodsAble to pass preapproval inspectionCompetitiveMeets customer needsValue for moneyCommercial returnSafetyClinicalDrug ing/commercialIn simple terms, the objective of pharmaceutical R&D can be defined as “converting ideas intocandidate drugs for development” and the objective of product development as “converting candidatedrugs into products for registration and sale.” In reality, these goals are extremely challenging anddifficult to achieve because of the many significant hurdles a pharmaceutical company has toovercome during the course of drug development. Some of the major hurdles are listed in Table 1.The high risk of failure in drug discovery and development throughout the pharmaceutical industry statistically shows that, on average, only 1 in 5000 compounds screened inresearch will reach the market. For those that are nominated for development, the failure ratewill vary from one in five to one in ten compounds that will achieve registration and reach themarketplace. Most failures in early development are due to drug toxicity or safety issues,whereas a lack of efficacy is the primary reason for late-stage attrition (Lowe, 2008). Therelatively high attrition rates of new medicines is a major challenge, particularly when they areexpensive phase III clinical failures that have occurred in recent years. Regulators are beingmore selective in what they approve, and they are demanding more data on efficacy and sideeffects. Only about 20 new drugs are now approved every year, down from 40 or 50 a decadeago and despite an approximate 70% increase in R&D investment over the last 10 years. On topof this, there is a significant commercial risk from those that are marketed; only 3 out of 10 arelikely to achieve a fair return on investment. The products that give poor return on investmentare often the result of poor candidate drug selection (the compound does not have the desiredproperties of safety, selectivity, efficacy, potency, or duration) and/or poor productdevelopment (the development program does not establish the value of the product). Thelatter scenario should, and can be, avoided by careful assessment at the “product design” stageof development. Product design is discussed further in chapter 5.There has been a recent worrying trend of marketed products being withdrawn a fewyears after launch. This may be because once it is used by many thousands, or even millions, ofpeople, rare but significant side effects can emerge. For example, Merck’s blockbuster arthritisdrug, Vioxx, was approved in 1999 but withdrawn five years later when linked to increasedcardiovascular risks. Another example is the surprise announcement by Pfizer when itwithdrew the world’s first inhalable insulin product, Exubera, from the market in 2007following disappointing sales. It would seem that the company had failed to appreciate thecustomer requirements well enough during the product design phase of development.
Introduction and PerspectiveFigure 13Product life cycle.To be successful and competitive, research-based pharmaceutical companies mustensure that new discoveries are frequently brought to the market to generate cash flow. This isrequired to fund the next generation of compounds to meet the therapeutic needs of patients,and of course, to benefit the shareholders. This cycle of events is sometimes referred to as the“product life cycle” and is further illustrated in Figure 1.The overall costs of drug discovery and development to bring a new medicine to themarket are increasing at an alarming rate. It is currently estimated that US 1 billion is requiredto recoup the costs of research, development, manufacturing, distribution, marketing, andsales for a new chemical entity (NCE). Cost estimates are even higher for a newbiopharmaceutical product at US 1.2 billion and take longer to develop than a NCE, buttend to enjoy much greater success rates (DiMari and Grabowski, 2007). A significantproportion of this total is for the cost of failures, or in other words, the elimination ofunsuccessful compounds. R&D expenditure tends to increase substantially as the compoundprogresses from drug discovery research through the various clinical trial phases ofdevelopment. The pivotal phase III patient trials are usually the largest, involving thousandsof patients, and hence the most expensive. To reduce development costs, some companiesselectively screen and eliminate compounds earlier in the drug development process on thebasis of results from small-scale, less expensive studies in human and progress fewer, morecertain compounds to later clinical phases.In spite of the high risks and high costs involved, there is still a huge incentive forpharmaceutical companies to seek the financial rewards from successful marketed products,especially from the phenomenal success of the rare “blockbuster” (reaching sales of US 1 billionper year). This can earn the company significant profits to reinvest in research and fund theproduct development pipeline.Another factor, the risk of delay to registration and launch, can also have a significantimpact on the financial success of a marketed product. McKinsey & Company, a managementconsultancy, assessed that a product that is six months late to market will miss out on onethird of the potential profit over the product’s lifetime. In comparison, they found that adevelopment cost overspend of 50% would reduce profits by just 3.5%, and a 9% overspend inproduction costs would reduce profits by 22% (McKinsey & Co., 1991). The loss of product
Gibson4revenue is often due to competitor companies being first to market, capturing the marketshare, and dictating the market price, in addition to the loss of effective patent life. Hence, theimportance of accelerating and optimizing drug discovery and development, and getting tothe market first with a new therapeutic class of medicinal product, cannot be underestimated.The second product to market in the same class will usually be compared with the marketleader, often unfavorably.The average time from drug discovery to product launch is currently estimated to be 10to 12 years. Several factors may have contributed to lengthening development times over theyears, including an increase in the preclinical phase to select the candidate drug and also anincrease in the duration of the clinical and regulatory period required for marketing approvalbecause regulatory agencies are requesting comparator efficacy studies and extensive safetyprofiling. Benchmarking studies show wide gaps between industry average or worstperformance compared with what is achievable as best practice performance (Spence, 1997).On average, the preclinical phase currently takes four to six years to complete, whereas thetime from candidate drug nomination to regulatory submission takes on average six to eightyears, and longer for treatments of chronic conditions. Most forward-looking pharmaceuticalcompanies are aiming to reduce these times by reevaluation and subsequently streamlining thedevelopment process, for example, by introducing more effective clinical programs and moreefficient data reporting systems, forward planning, and conducting multiple activities inparallel. However, this in turn may put formulation development and clinical supplies on thecritical path, with pressures to complete these activities in condensed time scales. Suggestionsare offered throughout this book on how preformulation, biopharmaceuticals, and formulationcan be conducted in the most efficient way to avoid delays in development times.Any reduction in the total time frame of drug discovery to market should improve thecompany’s profitability. In a highly competitive market, product lifetimes are being erodedbecause of the pace of introduction of competitor products, the rapid introduction of genericproducts when patents expire and move to “over-the-counter” (OTC) status. Successfulpharmaceutical companies are focusing on strategies for optimum “product life cyclemanagement” to maximize the early growth of the product on the market, sustain peaksales for as long as the product is in patent, and delay the post-patent expiry decline for as longas possible. This should maximize the return on investment during a product life cycle toenable the company to recover development costs and make further investments in R&D.Figure 2 shows a classic cash flow profile for a new drug product developed and marketed.Figure 2Product life cycle management.
Introduction and Perspective5During development there is a negative cash flow, and it may be some time after launch beforesales revenue crosses from loss to profit because of manufacturing, distribution, andadvertising costs. Profits continue to increase as the market is established to reach peaksales, after which sales decrease, especially after the primary patent expires and genericcompetition is introduced.Throughout the life span of a product, it is in a company’s interest to ensure the bestpatent protection to achieve the longest possible market exclusivity. Prior to the primary patentexpiring (normally for the chemical drug substance), it is imperative to introduce newindications, formulations, manufacturing processes, devices, and general technology, whichare patent protected, to extend the life of the product and maintain revenue. A patent generallyhas a term of about 20 years, but as development times are getting longer, there will be alimited duration of protection remaining once the product is marketed (the effective patentlife). A comparison of effective patent life for pharmaceutical NCEs in various countriesaround the world shows the same downward trend between the 1960s and the 1980s (Kariaet al., 1992; Lis and Walker, 1988). In the EU, products typically enjoy 10 years of patentexclusivity, whereas in the United States, it is typically only 5 years.Getting to the market quickly is a major business-driving force, but this has to bebalanced with the development of a product of the appropriate quality. There is a need togenerate sufficient information to enable sound decisions on the se
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, Jonath
liquid oral or parenteral.Fundamental preformulation properties include - Solubility, dissociation constant (pKa), . studies, wherein the physical and chemical stability of the drug molecule is studied in presence of excipients. Obviously, the choice of excipients is dictated by the type of dosage form to be developed. .
Formulation & Evaluation of Naringin Nanoethosome by Cold Method Ashish Y. Pawar1*, Khanderao R. Jadhav2, Komal Naikwade1 . Finally, the formulation is stored under refrigeration [3,4,9,10]. 2.3 Characterization 2.3.1 Preformulation studies [14-16] Preformulation is that the initiative in designing or
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BIOS INSTANT NOTES Series Editor: B.D. Hames, School of Biochemistry and Microbiology, University of Leeds, Leeds, UK Biology Animal Biology, Second Edition Biochemistry, Third Edition Bioinformatics Chemistry for Biologists, Second Edition Developmental Biology Ecology, Second Edition Genetics, Second Edition Immunology, Second Edition
156 varun arora pharmaceutical organic chemistry –ii 157 devala rao inorganic pharmaceutical chemistry 158 siddiqui inorganic pharmaceutical chemistry 159 chatwal pharmaceutical chemistry inorganic 160 huneely inorganic chemistry 161 mohammed ali tb of pharmaceutical chemistry inorgan
Preface to the Second Edition Modern Pharmaceutical Drug Analysis essentially involves as a necessary integral component even greater horizons than the actual prevalent critical analysis of not only the active pharmaceutical substances but also the secondary pharmaceutical product(s) i.e., the dosage forms having either single or multi-component formulated product.
Pharmaceutical Biotechnology: Fundamentals and Essentials. The present volume is effectively a second edition of this textbook and is designed to provide an update of a subject that has developed into a major component of current pharmaceutical research. The decision to pro
The new industry standard ANSI A300 (Part 4) – 2002, Lightning Protection Systems incorporates significant research in the field of atmospheric meteorology. This relatively new information has a pro-found impact on the requirements and recommendations for all arborists who sell tree lightning protection systems. Since there are an average of 25 million strikes of lightning from the cloud to .
