HANDBOOK OF
`
`Pharmaceutical
`Manufacturing
`Formulations
`
`Uncompressed Solid Products
`VOLUME 2
`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 / Sarfaraz K. Niazi.
`p. cm.
`Includes bibliographical references and index.
`Contents: — v.2. Uncompressed solid products.
`ISBN 0-8493-1751-7 (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.
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`The consent of CRC Press LLC does not extend to copying for general distribution, for promotion, for creating new works, or for resale. Specific
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`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 0-8493-1751-7
`Library of Congress Card Number 2003051451
`Printed in the United States of America 1234567890
`Printed on acid-free paper
`
`UNIVERSITY LIBRARY
`11NIVFRSITY OF Al RFRTA
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`Dedication
`
`Dedicated to the memory of
`Takeru Higuchi
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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 drugs
`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 I 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.D.
`Deerfield. Illinois
`
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`Preface to the Volume
`
`Uncompressed solid products formulations comprise
`aggregates of powders, such as powders for topical appli­
`cation, for use as insufflations, and for extemporaneous
`suspensions, as well as hard gelatin capsules or any other
`form wherein the final form is not compressed. The ratio­
`nale for this clear demarcation of formulations based on
`their state of aggregation is important to understand.
`Whereas compressed solid products require formulation
`components to render them compressible while allowing
`free flow into compression cavities, such considerations
`are of lesser importance for uncompressed solid products.
`(The flow requirement nevertheless stays because the pow­
`ders must be forced into capsule shells or poured into
`bottles or other packaging forms.) Uncompressed solid
`products on the other hand offer their own set of formu­
`lation problems related to segregation of powders due to
`static charges, environmental contamination during the
`filling process, and inevitable problems in wetting and
`dissolution, thus leading to possible bioavailability prob­
`lems in vivo. In the series of steps that determine the
`ultimate dissolution of the product, however, uncom­
`pressed solid products are one critical step ahead of com­
`pressed solid products — disintegration. The formulator
`is advised to read Chapter 4 of this volume, which dis­
`cusses guidelines on the waiver of bioavailability require­
`ments. Substantial development costs can be reduced
`when a drug undergoes fast dissolution, and these consid­
`erations must therefore be part of any new formulation
`effort. The reader is also referred to Volume 1 of this series
`where current and proposed bioavailability guidelines are
`provided.
`Chapter 1 addresses the fundamental issues of good
`manufacturing practices (GMPs). The chapter provides
`access addresses to all major guidelines around the world
`and also highlights the U.S. Food and Drug Administration
`(FDA) guidelines. A discussion of the most recent changes
`in the philosophy of establishing the GMP guidelines
`based on risk assessment is addressed in this chapter as
`well.
`Chapter 2 presents a more recent discussion of how
`the U.S. FDA inspectors are supposed to conduct inspec­
`tions; this topic is of continuous importance to all drug
`manufacturers. Although it is included in this volume, the
`guidelines apply to all dosage forms.
`Chapter 3 discusses the topic of bioequivalence and
`bioavailability of solid products. Although this is dis­
`cussed more thoroughly in Volume 1, the emphasis in
`Chapter 3 is placed on the guidelines to request a waiver
`
`of bioavailability/bioequivalence testing; this is something
`of great importance to both the innovator and the generic
`drug manufacturer.
`Chapter 4 highlights the manufacturing aspects of
`uncompressed drugs as well as various topics of general
`and specific interest.
`Part II provides formulations for more than 400 phar­
`maceutical products. Included in part are not only the
`currently approved products, but also several innovative
`products such as small proteins, instantly liquefiable pow­
`ders, and nanoparticles. Formulators are strongly urged to
`review the methodologies described here to serve as a
`reference point for their own formulations. Some combi­
`nation products or dosage forms are described that are not
`currently approved by the FDA (i.e., not included in the
`Orange Book), and they may be in the development phase
`or in experimental phases. As is always the case, it is the
`responsibility of the manufacturer to ensure that the for­
`mulations used in the production do not violate any intel­
`lectual property or proprietary practice laws. The most
`effective means of establishing this is through a study of
`the Orange Book, which lists the exclusivities and unex­
`pired patents. The patent numbers provided in the Orange
`Book should then be searched for collateral patents, the
`FDA Freedom of Information (FOI) database, and other
`literature to ensure that the intellectual or proprietary prop­
`erty rights are not violated.
`Whereas coating solutions are not as important, as in
`the case of compressed solids, nevertheless, some capsules
`are coated and the granules that are filled in capsules for
`sustained or timed release are coated, utilizing nonpareil
`sugar beads most often. The coating solutions are
`described here, but the reader is further referred to
`Volume 1 for a detailed description of coating solutions
`that can be easily adapted to the product intended for
`formulation into a sustained release profile. Whereas some
`forms of powders are meant to be sterile, the sterility
`considerations are discussed in Volume 6.
`The subject of powder technology is vast, with appli­
`cations in many fields. The serious reader is referred to
`the journal Advanced Powder Technology
`(http://www.vsppub.com/journals/jn-AdvPowTec.html).
`Such advances as inhalation insulin in a powder form and
`the new science of nanoparticles opens a new phase of
`pharmaceutical research and development. Nanotechnol­
`ogy describes the ability to create new materials from
`building blocks the size of an atom cluster. Nanomaterials
`are powders and materials optimized at the nanoscale
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`(10 9 m or a billionth of a meter in size). Nanopowders
`consist of particles with dimensions that can be measured
`by x-ray crystallography to be a few hundred atoms in
`diameter.
`The formulations are presented in this volume with a
`scale for each unit: per capsule or per unit dose of powder.
`Quantities are expressed for 1000 units. Sometimes, how­
`ever, a different presentation is chosen for simplicity and
`clarity. It is often customary for manufacturers to scale
`formulae for a specific weight, such as 100 or 1000 kg to
`match the mixing vessel requirements. This can be done
`roughly by multiplying the weight of each capsule or unit
`powder by the quantity desired to calculate the size of the
`batch. The reader should be aware that the actual yield
`may be different because of differences in the scale and
`quantity due to differences in the chemical form of drugs
`used, excesses added, and loss of moisture during manu­
`facturing. Further, adjustment of quantity based on
`potency of raw material, where pertinent, changes the
`quantity requirements. Most of these products are identi­
`fied in this volume by a brief description before the listing
`of the Bill of Materials, which may not necessarily rep­
`resent the commercially available dosage form; the
`description includes details of the commercial product.
`A distinctive feature of this volume is the identifica­
`tion and inclusion of the most often approved capsules
`and powders in the U.S. It is noteworthy that in the prep­
`aration of an abbreviated new drug application (aNDA),
`it is important for both regulatory and scientific reasons
`to keep the selection of excipients as close as possible to
`the innovator’s product. The listing provided here includes
`every excipient used in the innovator listing and quantita­
`tive formulae in several instances. 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 a similar type
`should be sufficient for an astute formulator to develop
`quickly these formulations. Should there be a need for
`assistance in finalizing the formulations, however, the
`reader is invited, without any obligation, to write to the
`author at niazi@pharmsci.com. It should be emphasized
`that manufacturers frequently use colored capsule shells
`to identify their products and often imprint them with
`logos or other identification marks. It is important to
`understand that the coloring dyes are not universally
`approved and, in some instances, may form the basis for
`a trademark. The formulator is advised to investigate this
`aspect carefully; nevertheless, in most formulations, the
`dyes used are disclosed.
`Whereas the science and the art of formulations
`remain within the domain of experienced hands, the wide
`dissemination of information about drug formulation
`compositions and problems related to them makes it easier
`
`for one to design excellent benchmarked formulations.
`The Web site of the U.S. FDA (http://www.fda.gov)
`remains one of the best sources of information. At times,
`however, commercial sources of databases, particularly
`the details that come under the Freedom of Information
`Act can be more useful (e.g., http://www.foiser-
`vices.com/). No endorsement is intended here for any
`company or resource.
`I am grateful to CRC Press 1 LLC for taking the lead
`in publishing what is possibly the largest such work in the
`field of pharmaceutical manufacturing. It has been a dis­
`tinct privilege to have known Stephen Zollo, senior editor
`at CRC Press, for years. Stephen has done more than any
`editor I have known to encourage me to complete this
`work on a timely basis. The editorial assistance provided
`by the CRC Press staff was indeed exemplary, particularly
`the assistance of Erika Dery, Samar Haddad, and others
`at CRC Press. Though much care has gone into correcting
`errors, any remaining errors are altogether mine. The
`reader is encouraged to bring any errors to my attention
`so that 1 may make corrections in future editions of this
`volume (niazi@pharmsci.com).
`This book is dedicated to Takeru Higuchi. Higuchi
`was a university regents distinguished professor of phar­
`maceutical chemistry and chemistry at Kansas University,
`and the founding chair of the department of pharmaceu­
`tical chemistry. He was known for the first systematic
`application of chemical principles to drug design, delivery,
`and analysis. His scientific accomplishments earned him
`the informal title of "father of physical pharmacy.”
`Higuchi died in 1987. A famous quote of Tak Higuchi is:
`"It is merely a matter of orderly thinking ... and a little
`organization.” One of his admirers notes, "His uniqueness
`is that he can look into the future and see things and
`imagine things that most of us cannot. Higuchi has the
`ability to identify what will be important in the future —
`that is his genius.” I met Tak several times during my
`teaching career and heard a lot more about him from my
`colleagues and teachers who worked with him directly. (It
`was rumored that he wrote the entire logarithmic table
`when flying to Japan because he needed to solve an equa­
`tion.) I learned much of my science by reading Tak’s
`papers, which are full of insight and fresh approaches to
`old problems. He was also a good businessman and a
`wonderful role model for industry-academia partnership.
`His aura is inspiring, his presence overwhelming even
`though he is not among us any more. People like Tak
`Higuchi are rare in any profession; we were just lucky to
`have him.
`
`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 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).
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