Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Products (Volume 1 of 6) PDF
Preview Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Products (Volume 1 of 6)
H A N D B O O K O F Pharmaceutical Manufacturing Formulations Compressed Solid Products V O L U M E 1 © 2004 by CRC Press LLC Handbook of Pharmaceutical Manufacturing Formulations Volume Series Sarfaraz K. Niazi Volume 1 Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Products Volume 2 Handbook of Pharmaceutical Manufacturing Formulations: Uncompressed Solid Products Volume 3 Handbook of Pharmaceutical Manufacturing Formulations: Liquid Products Volume 4 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products Volume 5 Handbook of Pharmaceutical Manufacturing Formulations: V O L U M E 1 Over-the-Counter Products Volume 6 Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products © 2004 by CRC Press LLC H A N D B O O K O F Pharmaceutical Manufacturing Formulations Compressed Solid Products V O L U M E 1 Sarfaraz K. Niazi CRC PR ESS Boca Raton London New York Washington, D.C. © 2004 by CRC Press LLC Library of Congress Cataloging-in-Publication Data Niazi, Sarfaraz, 1949– Handbook of pharmaceutical manufacturing formulations: compressed solid products / Sarfaraz K. Niazi. p. cm. Includes bibliographical references and index. Contents: — v.1. Compressed solids. ISBN 0-8493-1746-0 (alk. paper) 1. Drugs—Dosage forms—Handbooks, manuals, etc. I. Title RS200.N53 2004 615'19—dc21 2003051451 This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage or retrieval system, without prior permission in writing from the publisher. The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific permission must be obtained in writing from CRC Press LLC for such copying. Direct all inquiries to CRC Press LLC, 2000 N.W. Corporate Blvd., Boca Raton, Florida 33431. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation, without intent to infringe. Visit the CRC Press Web site at www.crcpress.com © 2004 by CRC Press LLC No claim to original U.S. Government works International Standard Book Number 0-8493-1746-0 Library of Congress Card Number 2003051451 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper © 2004 by CRC Press LLC Dedication to the memory of Sidney Riegelman © 2004 by CRC Press LLC Preface to the Series No industry in the world is more highly regulated than dosage forms. These types of considerations have led to the pharmaceutical industry because of potential threat to the classification of products into these six categories. a patient’s life from the use of pharmaceutical products. Each volume includes a description of regulatory fil- The cost of taking a new chemical entity (amortized over ing techniques for the formulations described. Also the cost of all molecules racing) to final regulatory included are the current regulatory guidelines on cGMP approval is a staggering $800 million, making the phar- compliance specific to the dosage form. Advice is offered maceutical industry one of the most research-intensive on how to scale up the production batches. industries in the world. In the year 2004, it is anticipated It is expected that formulation scientists will use this that the industry will spend about $20 billion on research information to benchmark their internal development pro- and development. The generic market of drugs as the new tocols and cut the race to file short by adopting formulae entities come off patent is one of the fastest growing that have survived the test of time. Many of us who have segments of the pharmaceutical industry, with every major worked in the pharmaceutical industry suffer from a close multinational company having a significant presence in paradigm when it comes to selecting formulations — “not this field. invented here” perhaps reigns in the mind of many sea- Whereas many stages of new drug development are soned formulations scientists subconsciously when they inherently constrained with time, the formulation of drugs prefer to choose only a certain platform for development. into desirable dosage forms remains an area where expe- It is expected that with the quick review of possibilities diency can be practiced with appropriate knowledge by available to formulate made available in this book, scien- those who have mastered the skills of pharmaceutical for- tists will benefit from the experience of others. mulations. The Handbook of Pharmaceutical Manufactur- For the teachers of formulation sciences, this series ing Formulations is the first major attempt to consolidate offers a wealth of information. Whether it is a selection the available knowledge about formulations in a compre- of a preservative system or the choice of a disintegrant, hensive, and by nature a rather voluminous, presentation. the series offers a wide choice to study and rationalize. The book is divided into six volumes, based strictly Many have assisted me in the development of this on the type of formulation science involved in the devel- work that has taken years to compile, and I thank scores opment of these dosage forms: sterile products, com- of my graduate students and colleagues for their help. A pressed solids, uncompressed solids, liquid products, work of this size cannot be produced without errors, semisolid products, and OTC products. The separation of although I hope that these errors do not distract the reader OTC products even though they may easily fall into one from the utility of the book. I would sincerely appreciate of the other five categories is made to comply with the if readers point out these mistakes for corrections in future industry norms of separate research divisions for OTC editions. products. Sterile products require skills related to steril- ization of product, and of less importance is the bioavail- Sarfaraz K. Niazi, Ph.D. ability issue, which is an inherent problem of compressed Deerfield, Illinois © 2004 by CRC Press LLC Preface to the Volume Compressed solids present one of the greatest challenges volume, we highlight what the manufacturers need to be to formulation scientists, as they offer remarkable market- aware of in establishing a manufacturing process based on ing opportunities to marketers. A solid oral dosage form the formulations presented. is easy to ingest, is relatively more stable than other dosage In other volumes of this series, details are provided forms (longer shelf life), and with it, opportunities to on various other issues that pertain to the manufacturing design delivery profiles to meet specific therapeutic of compressed solids, including validation issues, compli- requirements are offered. As a result, almost two-thirds of ance with cGMP, laboratory guidelines, etc. The reader is all dosage forms fall into this category. The challenge in referred to the other volumes for further understanding of formulating these products includes finding an optimum the subject matter. medium of compromises that will ensure releases of an Compressed solids or tablets are usually applied with active drug at the most desired and consistent rate. The coatings, mainly aqueous film coatings, for many reasons, formulation components and process of manufacturing from aesthetics to imparting higher physical–chemical sta- thus take pivotal importance. As a result, the formulations bility. Coating technology is a separate science. Fortu- provided in this volume offer a rare opportunity for for- nately, the major suppliers of equipment, such as Accela- mulators to start with an optimal composition. Described Cota® and Glatt® and coating materials such as Colorcon® in this volume are formulations for over 200 of the most and Röhm®, are very helpful in establishing coating widely used drugs for all types of release profiles. parameters and choosing the right coating materials and The most significant issues in the formulation of com- formulations. A large number of coating formulations are pressed solids are related to bioequivalence. Over the past listed in the Appendix, including sugar coating, film coat- quarter of a century, the science of evaluating equivalence ing, and enteric coatings. With such a wide variety avail- of products has taken a greater emphasis on testing in able, coating steps are omitted from all formulations human subjects. Although they are expensive to conduct, where coating is recommended. Instead, the reader is such trials are now routine, requiring frequent evaluation referred to the Appendix to make an appropriate choice. during the development phases and before marketing new The formulations are presented with a scale for each entities. Most frequently, trials are required when estab- unit, per tablet; and quantities are expressed for 1000 lishing generic equivalences. The U.S. FDA may require tablets. It is customary for manufacturers to scale formulas additional biostudies if there is a change in the manufac- for a specific weight, such as 100 or 1000 Kgs, to match turing site or even a change in the specification of a raw mixing vessel requirements. This can be done roughly by material. This aspect of formulation development clearly multiplying the weight of each tablet by the quantity differentiates the compressed solids category; as a result, desired to calculate the size of the batch. Remember that Chapter 1 in the book deals with the guidelines for bio- the actual yield may be different because of differences availability and bioequivalence testing of pharmaceutical in the scale and quantity, due to differences in the chemical products. Noteworthy are the changes proposed in this forms of the drugs used, excesses added, and losses of guideline from what is the currently accepted methodol- moisture during manufacturing. Further, the adjustment of ogy; for example, what was long considered necessary, quantity based on the potency of the raw material, where the multiple-dose studies of modified release products, pertinent, changes the quantity requirements. will yield to single-dose studies, which are considered A distinctive feature of this volume is the identifica- more discriminating. The manufacturers are particularly tion and inclusion of the most popular prescription prod- reminded to understand the changes in the requirements ucts. The 200 most widely prescribed drugs (by brand of bioavailability and bioequivalence studies that are on name) are marked with a bracketed number to indicate the horizon. their rankings. These data are derived from over 3 billion The formulation of compressed solids involves a highly prescriptions filled during 2002 in the U.S., comprising intricate series of events, from the characterization of the the majority of the U.S. prescription market. Because in active pharmaceutical ingredient, to the choice of excipi- some instances more than one brand name is prescribed, ents, to the selection of processing, compression, and coat- only the top brand is listed; therefore, the total number of ing equipment and packaging systems appropriate for the chemical equivalents is less than 200. The compressed specific drug and the dosage form. In Chapter 2 of this solids represent more than an 80% share of this list, © 2004 by CRC Press LLC therefore expounding the need to elaborate this list in this Journal of the American Pharmaceutical Association particular volume. Obviously, for a generic manufacturer, under the major heading of “The Kinetics of Rectal it would be advantageous to enter the market with products Absorption.” For these studies, Sid was awarded the Ebert that have a wide market, not necessarily the largest margin, Prize in 1959, which recognized Sid’s publications as the and this list will further help in the selection of products. best work published in the journals of the American Phar- It is noteworthy that in the preparation of an ANDA maceutical Association during the year 1958. Sid’s con- (Abbreviated New Drug Application), it is important for tributions to pharmaceutical sciences, particularly in the both regulatory and scientific reasons to keep the selection field of pharmacokinetics, earned him a revered place in of excipients as close as possible to the innovator’s prod- the profession. On April 4, 1981, Sid drowned while scuba uct. The listing provided here includes every excipient diving with his wife at Salt Point, California, a coastal used in the innovator listing. Whereas, in most instances, area just north of San Francisco. At the University of sufficient details are provided to assist in the formulation California, a plaque is dedicated to Sid “by his graduate of a generic equivalent with exact quantities of excipients students, who honor his scientific achievements and excel- and conditions appropriate for processing, the examples lence, his inspirations and contagious enthusiasm in provided for other drugs of similar types should be suffi- research and teaching. We shall always remember Sid as cient for an astute formulator to quickly develop these our mentor, scientific father and most importantly, as our formulations. However, should there be a need for assis- beloved friend and confidant.” tance in finalizing the formulation, the reader is invited, I had the distinct privilege, both during my graduate without any obligation, to write to the author at studies and later as a faculty member teaching biophar- [email protected]. maceutics and pharmacokinetics, to interact with Sid. I am grateful to CRC Press for taking this lead in When my book, Textbook of Biopharmaceutics and Clin- publishing what is possibility the largest such work in the ical Pharmcokinetics, was published, Sid called to con- field of pharmaceutical products. It has been a distinct gratulate me. It was like receiving a call from God — that privilege to have known Mr. Stephen Zollo, the senior is how he was revered in the profession. I remember editor at CRC Press, for many years. Stephen has done vividly how he would argue in seminars while appearing more than any editor can to encourage me to complete to be dozing off during the presentation. Sid was a giant: this work on a timely basis. The editorial assistance pro- a scientist, a scholar, and, above all, a loving human being. vided by the CRC Press staff was exemplary, particularly When a professional crisis arose, I called Sid for advice. the help given by Erika Dery, Joette Lynch, and others at Instead of telling me what I should do, Sid told me a story CRC Press. Though much care has gone into correcting about his childhood: “Sarf, my brother was much stronger errors, any errors remaining are altogether mine. I would than I and every time he would run into me, he would appreciate it if the readers bring these errors to my atten- take a jab at me, and when I would return his jab, he would tion so that they can be corrected in future editions of this knock me down. I complained about this to my father, and volume ([email protected]). my father advised me not to return the jabs. My brother This book is dedicated to Sidney Riegelman, who was became so frustrated, he started jabbing others.” I have born July 19, 1921, in Milwaukee, Wisconsin. He attended never forgotten his advice. the University of Wisconsin, graduating with a Bachelor of Science degree in pharmacy in 1944 and a Ph.D. in Sarfaraz K. Niazi, Ph.D. pharmacy in 1948. Following his graduate work, Sid Pharmaceutical Scientist, Inc. joined the faculty of the School of Pharmacy at the Uni- 20 Riverside Drive versity of California at San Francisco. In 1958, Sid pub- Deerfield, Illinois 60015 lished a series of papers with graduate student Wilfred Crowell, which appeared in the scientific edition of the © 2004 by CRC Press LLC About the Author Dr. Sarfaraz K. Niazi has been teaching and conducting research in the pharma- ceutical industry for over 30 years. He has authored hundreds of scientific papers, textbooks, and presentations on the topics of pharmaceutical formulation, biophar- maceutics, and pharmacokinetics of drugs. He is also an inventor with scores of patents and is licensed to practice law before the U.S. Patent and Trademark Office. Having formulated hundreds of products from consumer products to complex bio- technology-derived products, he has accumulated a wealth of knowledge in the science of formulations and regulatory filings of Investigational New Drugs (INDs) and New Drug Applications (NDAs). Dr. Niazi advises the pharmaceutical industry internationally on issues related to formulations, pharmacokinetics and bioequivalence evaluation, and intellectual property issues (http://www.pharmsci.com). © 2004 by CRC Press LLC Table of Contents Part I Regulatory and Manufacturing Requirements in Compressed Solid Dosage Forms Chapter 1 Bioavailability and Bioequivalence Studies for Orally Administered Drug Products I. Introduction II. Background A. General B. Bioavailability C. Bioequivalence 1. INDs/NDAs 2. ANDAs 3. Postapproval Changes III. Methods to Document BA and BE A. Pharmacokinetic Studies 1. General Considerations 2. Pilot Study 3. Pivotal Bioequivalence Studies 4. Study Designs 5. Study Population 6. Single-Dose/Multiple-Dose Studies 7. Bioanalytical Methodology 8. Pharmacokinetic Measures of Systemic Exposure B. Pharmacodynamic Studies C. Comparative Clinical Studies D. In Vitro Studies IV. Comparison of BA Measures in BE Studies V. Documentation of BA and BE A. Solutions B. Suspensions C. Immediate-Release Products: Capsules and Tablets 1. General Recommendations 2. Waivers of In Vivo BE Studies (Biowaivers) D. Modified-Release Products 1. NDAs: BA and BE Studies 2. ANDAs: BE Studies 3. Waivers of In Vivo BE Studies (Biowaivers): NDAs and ANDAs 4. Postapproval Changes E. Miscellaneous Dosage Forms VI. Special Topics A. Food-Effect Studies B. Moieties to Be Measured 1. Parent Drug vs. Metabolites 2. Enantiomers vs. Racemates 3. Drug Products with Complex Mixtures as the Active Ingredients © 2004 by CRC Press LLC
The list of books you might like
