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:
`Over-the-Counter Products
`
`Volume 6
`Handbook of Pharmaceutical Manufacturing Formulations:
`Sterile Products
`
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`

`HANDBOOK OF
`
`Pharmaceutical
`Manufacturing
`Formulations
`
`Compressed Solid Products
`
`VOLUME 1
`Sarfaraz K. Niazi
`
`CRC PRESS
`Boca Raton London New York Washington, D.C.
`
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`

`

`Library of Congress Cataloging-in-Publication Data
`
`Niazi, Sarfaraz, 1949-
`Handbook of pharmaceutical manufacturing formulations: compressed solid products / Sarfaraz K. Niaz.i.
`p. cm.
`Includes bibliographical references and index.
`Contents: — v.I. Compressed solids.
`ISBN 0-8493-1746-0 (alk. paper)
`I. Drugs—Dosage forms—Handbooks, manuals, etc. 1. 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 23456789 0
`Printed on acid-free paper
`
`UNIVERSITY LIBRARY
`UNIVERSITY OF ALBERTA
`
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`

`

`Dedication
`
`to the memory1 of Sidney Riegelman
`
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`

`

`Preface to the Series
`
`No industry in the world is more highly regulated than
`the pharmaceutical industry because of potential threat to
`a patient's life from the use of pharmaceutical products.
`The cost of taking a new chemical entity (amortized over
`the cost of all molecules racing) to final regulatory
`approval is a staggering $800 million, making the phar­
`maceutical industry one of the most research-intensive
`industries in the world. In the year 2004, it is anticipated
`that the industry will spend about $20 billion on research
`and development. The generic market of drugs as the new
`entities come off patent is one of the fastest growing
`segments of the pharmaceutical industry, with every major
`multinational company having a significant presence in
`this field.
`Whereas many stages of new drug development are
`inherently constrained with time, the formulation of drags
`into desirable dosage forms remains an area where expe­
`diency can be practiced with appropriate knowledge by
`those who have mastered the skills of pharmaceutical for­
`mulations. The Handbook of Pharmaceutical Manufactur­
`ing Formulations is the first major attempt to consolidate
`the available knowledge about formulations in a compre­
`hensive. and by nature a rather voluminous, presentation.
`The book is divided into six volumes, based strictly
`on the type of formulation science involved in the devel­
`opment of these dosage forms: sterile products, com­
`pressed solids, uncompressed solids, liquid products,
`semisolid products, and OTC products. The separation of
`OTC products even though they may easily fall into one
`of the other five categories is made to comply with the
`industry norms of separate research divisions for OTC
`products. Sterile products require skills related to steril­
`ization of product, and of less importance is the bioavail­
`ability issue, which is an inherent problem of compressed
`
`dosage forms. These types of considerations have led to
`the classification of products into these six categories.
`Each volume includes a description of regulatory fil­
`ing techniques for the formulations described. Also
`included are the current regulatory guidelines on cGMP
`compliance specific to the dosage form. Advice is offered
`on how to scale up the production batches.
`It is expected that formulation scientists will use this
`information to benchmark their internal development pro­
`tocols and cut the race to file short by adopting formulae
`that have survived the test of time. Many of us who have
`worked in the pharmaceutical industry suffer from a close
`paradigm when it comes to selecting formulations - "not
`invented here’’ perhaps reigns in the mind of many sea­
`soned formulations scientists subconsciously when they
`prefer to choose only a certain platform for development.
`It is expected that with the quick review of possibilities
`available to formulate made available in this book, scien­
`tists will benefit from the experience of others.
`For the teachers of formulation sciences, this series
`offers a wealth of information. Whether it is a selection
`of a preservative system or the choice of a disintegrant,
`the series offers a wide choice to study and rationalize.
`Many have assisted me in the development of this
`work that has taken years to compile, and I thank scores
`of my graduate students and colleagues for their help. A
`work of this size cannot be produced without errors,
`although 1 hope that these errors do not distract the reader
`from the utility of the book. 1 would sincerely appreciate
`if readers point out these mistakes for corrections in future
`editions.
`
`Sarfaraz K. Niazi, Ph.I).
`Deerfield, Illinois
`
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`Preface to the Volume
`
`Compressed solids present one of the greatest challenges
`to formulation scientists, as they offer remarkable market­
`ing opportunities to marketers. A solid oral dosage form
`is easy to ingest, is relatively more stable than other dosage
`forms (longer shelf life), and with it. opportunities to
`design delivery profiles to meet specific therapeutic
`requirements are offered. As a result, almost two-thirds of
`all dosage forms fall into this category. The challenge in
`formulating these products includes finding an optimum
`medium of compromises that will ensure releases of an
`active drug at the most desired and consistent rate. The
`formulation components and process of manufacturing
`thus take pivotal importance. As a result, the formulations
`provided in this volume offer a rare opportunity for for-
`mulators to start with an optimal composition. Described
`in this volume are formulations for over 200 of the most
`widely used drugs for all types of release profiles.
`The most significant issues in the formulation of com­
`pressed solids are related to bioequivalence. Over the past
`quarter of a century, the science of evaluating equivalence
`of products has taken a greater emphasis on testing in
`human subjects. Although they are expensive to conduct,
`such trials are now routine, requiring frequent evaluation
`during the development phases and before marketing new
`entities. Most frequently, trials are required when estab­
`lishing generic equivalences. The U.S. FDA may require
`additional biostudies if there is a change in the manufac­
`turing site or even a change in the specification of a raw
`material. This aspect of formulation development clearly
`differentiates the compressed solids category: as a result.
`Chapter 1 in the book deals with the guidelines for bio­
`availability and bioequivalence testing of pharmaceutical
`products. Noteworthy are the changes proposed in this
`guideline from what is the currently accepted methodol­
`ogy: for example, what w-as long considered necessary,
`the multiple-dose studies of modified release products,
`will yield to single-dose studies, which are considered
`more discriminating. The manufacturers are particularly
`reminded to understand the changes in the requirements
`of bioavailability and bioequivalence studies that are on
`the horizon.
`The formulation of compressed solids involves a highly
`intricate series of events, from the characterization of the
`active pharmaceutical ingredient, to the choice of excipi­
`ents. to the selection of processing, compression, and coat­
`ing equipment and packaging systems appropriate for the
`specific drug and the dosage form. In Chapter 2 of this
`
`volume, we highlight what the manufacturers need to be
`aware of in establishing a manufacturing process based on
`the formulations presented.
`In other volumes of this series, details are provided
`on various other issues that pertain to the manufacturing
`of compressed solids, including validation issues, compli­
`ance with cGMP, laboratory guidelines, etc. The reader is
`referred to the other volumes for further understanding of
`the subject matter.
`Compressed solids or tablets are usually applied with
`coatings, mainly aqueous film coatings, for many reasons,
`from aesthetics to imparting higher physical-chemical sta­
`bility. Coaling technology is a separate science. Fortu­
`nately, the major suppliers of equipment, such as Accela-
`Cota® and Glatt ’ and coating materials such as Colorcon4
`and Rohm . are very helpful in establishing coating
`parameters and choosing the right coating materials and
`formulations. A large number of coating formulations are
`listed in the Appendix, including sugar coating, film coat­
`ing. and enteric coatings. With such a wide variety avail­
`able. coating steps are omitted from all formulations
`where coating is recommended. Instead, the reader is
`referred to the Appendix to make an appropriate choice.
`The formulations are presented with a scale for each
`unit, per tablet: and quantities are expressed for 1000
`tablets. It is customary for manufacturers to scale formulas
`for a specific weight, such as 100 or 1000 Kgs, to match
`mixing vessel requirements. This can be done roughly by
`multiplying the weight of each tablet by the quantity
`desired to calculate the size of the batch. Remember that
`the actual yield may be different because of differences
`in the scale and quantity, due to differences in the chemical
`forms of the drugs used, excesses added, and losses of
`moisture during manufacturing. Further, the adjustment of
`quantity based on the potency of the raw' material, where
`pertinent, changes the quantity requirements.
`A distinctive feature of this volume is the identifica­
`tion and inclusion of the most popular prescription prod­
`ucts. The 200 most widely prescribed drugs (by brand
`name) tire marked with a bracketed number to indicate
`their rankings. These data are derived from over 3 billion
`prescriptions filled during 2002 in the U.S., comprising
`the majority of the U.S. prescription market. Because in
`some instances more than one brand name is prescribed,
`only the top brand is listed; therefore, the total number of
`chemical equivalents is less than 200. The compressed
`solids represent more than an 80% share of this list,
`
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`therefore expounding the need to elaborate this list in this
`particular volume. Obviously, for a generic manufacturer,
`it would be advantageous to enter the market with products
`that have a wide market, not necessarily the largest margin,
`and this list will further help in the selection of products.
`It is noteworthy that in the preparation of an ANDA
`(Abbreviated New Drug Application), it is important for
`both regulatory and scientific reasons to keep the selection
`of excipients as close as possible to the innovator’s prod­
`uct, The listing provided here includes every excipient
`used in the innovator listing. Whereas, in most instances,
`sufficient details are provided to assist in the formulation
`of a generic equivalent with exact quantities of excipients
`and conditions appropriate for processing, the examples
`provided for other drugs of similar types should be suffi­
`cient for an astute formulator to quickly develop these
`formulations. However, should there be a need for assis­
`tance in finalizing the formulation, the reader is invited,
`without any obligation, to write to the author al
`niazi@pharmsci.com.
`I am grateful to CRC Press for taking this lead in
`publishing what is possibility the largest such work in the
`field of pharmaceutical products. It has been a distinct
`privilege to have known Mr. Stephen Zollo, the senior
`editor at CRC Press, for many years. Stephen has done
`more than any editor can to encourage me to complete
`this work on a timely basis. The editorial assistance pro­
`vided by the CRC Press staff was exemplary, particularly
`the help given by Erika Dery. Joette Lynch, and others at
`CRC Press. Though much care has gone into correcting
`errors, any errors remaining are altogether mine. 1 would
`appreciate it if the readers bring these errors to my atten­
`tion so that they can be corrected in future editions of this
`volume (niazi@pharmsic.com).
`This book is dedicated to Sidney Riegelman, who was
`born July 19, 1921, in Milwaukee, Wisconsin. He attended
`the University of Wisconsin, graduating with a Bachelor
`of Science degree in pharmacy in 1944 and a Ph.D. in
`pharmacy in 1948. Following his graduate work, Sid
`joined the faculty of the School of Pharmacy at the Uni­
`versity of California at San Francisco. In 1958, Sid pub­
`lished a series of papers with graduate student Wilfred
`Crowell, which appeared in the scientific edition of the
`
`Journal of the American Pharmaceutical Association
`under the major heading of “The Kinetics of Rectal
`Absorption.” For these studies, Sid was awarded the Ebert
`Prize in 1959, which recognized Sid’s publications as the
`best work published in the journals of the American Phar­
`maceutical Association during the year 1958. Sid’s con­
`tributions to pharmaceutical sciences, particularly in the
`field of pharmacokinetics, earned him a revered place in
`the profession. On April 4, 1981. Sid drowned while scuba
`diving with his wife at Salt Point, California, a coastal
`area just north of San Francisco. At the University of
`California, a plaque is dedicated to Sid "by his graduate
`students, who honor his scientific achievements and excel­
`lence. his inspirations and contagious enthusiasm in
`research and teaching. We shall always remember Sid as
`our mentor, scientific father and most importantly, as our
`beloved friend and confidant.”
`1 had the distinct privilege, both during my graduate
`studies and later as a faculty member teaching biophar­
`maceutics and pharmacokinetics, to interact with Sid.
`When my book. Textbook of Biopharmaceutics and Clin­
`ical Plwnncokinetics, was published, Sid called to con­
`gratulate me. It was like receiving a call from God — that
`is how he was revered in the profession. I remember
`vividly how he would argue in seminars while appearing
`to be dozing off during the presentation. Sid was a giant:
`a scientist, a scholar, and. above all, a loving human being.
`When a professional crisis arose, 1 called Sid for advice.
`Instead of telling me what I should do, Sid told me a story
`about his childhood: "Sai f', my brother was much stronger
`than I and every time he would run into me, he would
`take a jab at me. and when I would return his jab. he would
`knock me down. I complained about this to my father, and
`my father advised me not to return the jabs. My brother
`became so frustrated, he started jabbing others.” I have
`never forgotten his advice.
`
`Sarfaraz K. Niazi, Ph.D.
`Pharmaceutical Scientist, Inc.
`20 Riverside Drive
`Deerfield, Illinois 60015
`
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`About the Author
`
`Dr. Sarfaraz K. Niazi has been teaehing 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, phannacokinetics and bioequivalence
`evaluation, and intellectual property issues (http://www.pharmsci.com).
`
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`72
`
`Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Products
`
`Cefadroxil Dispersible Tablets (250 mg)
`
`Item
`1
`2
`3
`4
`tz_____ _
`
`Bill of Materials
`Scale (mg/tablet)
`250.1)0
`2.00
`—
`: 77.(X)
`I 93.50
`13.00
`1.50
`0.45
`0.05
`4.00
`5.00
`5.00
`1.. -9s
`
`6
`7
`8
`9
`10
`11
`12
`_____ j 13
`
`Material Name
`Cefadroxil. use cefadroxin anhydrous
`PVP potassium 30
`Isopropyl alcohol
`Lactose monohydrate
`Starch (maize)
`Aspartame
`Aerosil 200
`Methyl paraben
`Propyl paraben
`Starch (maize)
`Magnesium stearate
`Talc
`Water, purified
`
`Quantity/1000 Tablets (g)
`268.65
`2.00
`10.80
`77.00
`93.50
`13.00
`1.50
`0.45
`0.05
`4.00
`5.00
`5.00
`QS
`
`MANUFACTURING DIRECTIONS
`
`1. Charge Items 2 and 3, and prepare a binding
`solution.
`2. Sift Item 1 through a 250-pm sieve.
`3. Add Step 1 into Step 2. and prepare a wet mass.
`4. Spread granules on trays, and dry in a dehu­
`midified room.
`5. Pass dried granules through a 595-|im sieve.
`6. Prepare a paste of Item 5 using purified water.
`
`7. Sift Items 4 and 6 into 9 through a 250-pm
`sieve. Mix for 15 min.
`8. Add the paste from Step 6, and mix until a wet
`mass is obtained without lumps.
`9. Dry the granules obtained in Step 8 in a fluid­
`bed dryer at 50°C for 2 h.
`10. Mix granules from Step 5 and Step 9, and
`charge into a tumble mixer.
`11. Sift Items 10 to 12 through a 250-jim sieve, add
`to Step 10, and blend for 2 min.
`12. Compress 630 mg using 11.3-mm punches.
`
`Cefdinir Tablets (300 mg)
`
`Item
`
`Bill of Materials
`Scale (mg/tablet)
`300.00
`2
`29.20
`29.20
`3
`3.70
`4
`0.90
`5
`4.40
`6
`15.00
`7
`J5:60_____________ LL_
`
`Material Name
`Cefdinir bulk powder
`Microcrystalline cellulose (Avicel PH 101)
`L-HPC (LH-21. Shin-Etsu Chemical)
`Polyvinylpyrrolidone (Kollidon 30)
`Silicic acid light anhydorus (Aerosil 200)
`Magnesium stearate
`Saccharin sodium
`Strawberry flavor
`
`Quantity/1000 Tablets (g)
`306.80
`29.20
`29.20
`3.70
`0.90
`4.40
`15.00
`5.60
`
`MANUFACTURING DIRECTIONS
`
`1. Charge Items I to 4 after passing through a 250-
`pm mesh into a mixing vessel. Mix for 10 min.
`2. Add Items 5 to 8, one at a time, and blend for
`1 min each time.
`3. Compress 395 to 400 mg.
`
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