SEVENTH EDITION
`
`PHARMACEUTICAL
`DOSAGE FORMS
`AND DRUG
`DELIVERY SYSTEMS
`
`Howard C. Ansel, Ph.D.
`Professor and Dean Emeritus
`College of Pharmacy
`The University of Georgia
`Loyd V. Allen, Jr., Ph.D.
`Professor Emeritus
`College of Pharmacy
`University of Oklahoma/ and
`Editor-in-Chief
`International Journal of Pharmaceutical Compounding
`
`Nicholas G. Popovich, Ph.D.
`Professor and Associate Head
`Department of Pharmacy Practice
`School of Pharmacy and Pharmacal Sciences
`Purdue University
`
`4~ LIPPINCOTT WILLIAMS & WILKINS
`~ A Wolters Kluwer Company
`Philadelphia • Baltimore • New York • London
`Buenos A ires • Hong Kong • Sydney • Tokyo
`
`Cosmo Ex 2020-p. 1
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`Editor: Donna Balado
`Managing Editor: Jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright© 1999 Lippincott Williams & Wilkins
`
`351 West Camden Street
`Baltimore, Maryland 21201-2436 USA
`
`227 East Washington Square
`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright. No part of this book may be re(cid:173)
`produced in any form or by any means, including photocopying, or utilized by any infor(cid:173)
`mation storage and retrieval system without written permission from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence, or otherwise)
`for any injury resulting from any material contained herein. This publication contains in(cid:173)
`formation relating to general principles of medical care which should not be construed as
`specific instructions for individual patients. Manufacturers' product information and pack(cid:173)
`age inserts should be reviewed for current information, including contraindications,
`dosages, and precautions.
`
`Printed in the United States of America
`
`Library of Con gress Ca taloging-in-Publication Data
`
`Ansel, Howard C., 1933-
`Pharmaceutical dosage forms and drug delievery systems I Howard C.
`Ansel, LoydV. Allen, Jr., Nicholas G. Popovich. -7th ed.
`em.
`p.
`Includes bibliographical references and index.
`ISBN 0-683-30572-7
`1. Drugs-Dosage forms. 2. Drug delivery systems.
`II. Popovich, Nicholas G.
`III. Title.
`[DNLM: 1. Dosage Forms. 2. Drug Delivery Systems. QV 785 A618i 1999]
`RS200.A57 1999
`615'.1-dc21
`DNLM/DLC
`for Library of Congress
`
`I. Allen, Loyd V.
`
`99-17498
`CIP
`The publishers have made every effort to trace the copyright holders for borrowed material. If thea;
`have inadvertently overlooked any, thea; will be pleased to make the necessary arrangements at
`the first opportunity.
`
`The use of portions of the text ofUSP23/NF18, copyright 1994, is by permission of the USP
`Convention, Inc. The Convention is not responsible for any inaccuracy of quotation or for
`any false or misleading implication that may arise from separation of excerpts from the
`original context or by obsolescence resulting from publication of a supplement.
`
`To purchase additional copies of this book call our customer service department at (800)
`638-3030 or fax orders to (301) 824-7390. International customers should call (301)
`714-2324.
`
`99 00 0102
`1 2 3 4 5 6 7 8 9 10
`
`Cosmo Ex 2020-p. 2
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`170
`
`Powders and Granules
`
`Physical Pharmacy Capsule 6.2
`
`Particle Size Reduction
`
`Comminution, the process of reducing the particle size of a solid substance to a finer state of subdivision,
`is used to facilitate crude drug extraction, increase the dissolution rates of a drug, aid in the formulation
`of pharmaceutically acceptable dosage forms, and enhance the absorption of drugs. The reduction in
`the particle size of a solid is accompanied by a great increase in the specific surface area of that sub(cid:173)
`stance. An example of the increase in the number of particles formed and the resulting surface area is
`as follows.
`
`EXAMPLE
`Increase in Number of Particles
`If a powder consists of cubes 1 mm on edge, and it is reduced to particles 1 0 f..l. on edge, what is the
`number of particles produced?
`
`1 . 1 mm equals 1 000 f..l.·
`2. 1000 J..~,/1 0 f..l. = 100 pieces produced on each edge, i.e., if the cube is sliced into 100 pieces, each
`1 0 f..l. long, 1 00 pieces would result.
`3. If this is repeated in each of the other two dimensions, i.e., to include the x, y and z axes, then there
`would be 100 X 100 X 100 = 1,000,000 particles produced, each 10 f..l. on edge, for each orig(cid:173)
`inal particle 1 mm on edge. This can also be written [(1 02)3 = 1 06].
`Increase in Surface Area
`What is the increase in the surface area of the powder by decreasing the particle size from 1 mm to
`10 f..l,?
`1. The 1 mm cube has 6 surfaces, each 1 mm on edge. Each face has a surface area of 1 mm2. Be(cid:173)
`cause there are 6 faces, this is 6 mm2 surface area for this one particle.
`2. Each 10 f..l. cube has 6 surfaces, each 10 f..l. on edge. Each face has a surface area of 10 X 10 =
`100 f..l.2. Because there are 6 faces, this is 6 X 100 f..l.2, or 600 f..l.2 surface area for this one particle.
`Since there are 106 particles that resulted by comminuting the 1 mm cube into smaller cubes, each
`1 0 f..l. on edge, there would be 600 f..l.2 X 1 06 or 6 X 1 os f..l.2 surface area now.
`3. To get everything in the same units for ease of comparison, we convert the 6 X 1 os f..l.2 into mm2 as
`follows.
`4. Since there are 1,000 J..~,/mm, there must be 1,0002, or 1,000,000 f..l,2/mm2. This is more appropri(cid:173)
`ately expressed as 106 f..l.2/mm2,
`
`6 X 1 08f..l,2
`1 06J..~,2/mm2 = 6 X 102 mm2
`
`As is evident here, the surface areas have been increased from 6 mm2 to 600 mm2 by the reduction in
`particle size of cubes 1 mm on edge to cubes 10 f..l. on edge (i.e., a hundred-fold increase in surface
`area). This can have a significant increase in the rate of dissolution of a drug product.
`
`"figure 8" track is commonly used to incorporate
`the materials. Mineral oil and glycerin are com(cid:173)
`monly used levigating agents.
`
`Blending Powders
`When two or more powdered substances are to
`be combined to fonn a unifonn mixture, it is best to
`reduce the particle size of each powder individually
`before weighing and blending. Depending upon
`the nature of the ingredients, the amount of pow-
`
`der to prepare, and the equipment available, pow(cid:173)
`ders may be blended by spatulation, trituration,
`sifting, and tumbling.
`Spatulation is a method by which small amounts
`of powders may be blended by the movement of a
`spatula through the powders on a sheet of paper or
`an ointment tile. The method is not suitable for
`large quantities of powders or for powders con(cid:173)
`taining potent substances, because homogeneous
`blending is not as certain as through other meth(cid:173)
`ods. Very little compression or compacting of the
`
`Cosmo Ex 2020-p. 3
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`powder results from this method. This method is
`especially suited to the mixing of solid substances
`that form eutectic mixtures (or liquify) when in
`close and prolonged contact with one another.
`Substances that form eutectic mixtures when com(cid:173)
`bined include phenol, camphor, menthol, thymol,
`aspirin, phenylsalicylate and other similar chemi(cid:173)
`cals. To diminish contact, a powder prepared from
`such substances is commonly mixed in the pres(cid:173)
`ence of an inert diluent such as light magnesium
`oxide or magnesium carbonate to separate physi(cid:173)
`cally the troublesome agents.
`Trituration may be employed both to comminute
`and to mix powders. If simple admixture is desired
`without special need for comminution, the glass
`mortar is usually preferred. When a small amount
`of a potent substance is to be mixed with a large
`amount of diluent, the geometric dilution method
`is used to ensure the uniform distribution of the
`potent drug. This method is especially indicated
`when the potent and the nonpotent ingredients are
`of the same color and a visible sign of mixing is
`lacking. By this method, the potent drug is placed
`on an approximately equal volume of the diluent in
`a mortar and mixed thoroughly by trituration. Then
`a second portion of diluent equal in volume to the
`mixture is added, and the trituration repeated. This
`process is continued by adding equal volumes of
`diluent to the powder mixture and repeating until
`all of the diluent is incorporated. Some pharmacists
`add an inert colored powder to the diluent before
`mixing to permit visual inspection of the mixing
`process.
`Powders may also be mixed by passing them
`through sifters like those used in the kitchen to sift
`flour. Sifting results in a light fluffy product. This
`process is not acceptable for the incorporation of
`potent drugs into a diluent powder.
`Another method of mixing powders is tumbling
`the powder enclosed in a rotating container. Spe(cid:173)
`cial small-scale and large-scale motorized powder
`blenders have been developed which mix pow(cid:173)
`ders by a tumbling motion (Fig. 6.2). Mixing by this
`process is thorough, although time-consuming.
`Such blenders are· widely employed in industry as
`are mixers that utilize motorized blades to blend
`powder contained in a large mixing vessel.
`
`Medicated Powders
`Some medicated powders are intended to be
`used internally; others externally. Most powders for
`internal use are taken orally after mixing with wa(cid:173)
`ter. Some powders are intended to be inhaled into
`the lungs for local and systemic effects. O ther dry
`
`Powders and Granules
`
`171
`
`Fig. 6.2
`Industrial size solid state processor or "twin
`shell" blender used to mix solid particles. (Courtesy of Abbott
`Laboratories.)
`
`powders are commercially packaged for constitu(cid:173)
`tion with a liquid solvent or vehicle, some for ad(cid:173)
`ministration orally, others for use as an injection,
`and still others for use as a vaginal douche. Med(cid:173)
`icated powders for external use are dusted on the
`affected area from a sifter- type container or applied
`from a powder aerosol. Powders intended for ex(cid:173)
`ternal use should bear an EXTERNAL USE ONLY or a
`similar label.
`Medicated powders for oral use may be intended
`for local effects (e.g., laxatives) or systemic effects
`(e.g., analgesics) and may be preferred over coun(cid:173)
`terpart tablets and capsules by patients who have
`difficulty swallowing solid dosage forms. Oral pow(cid:173)
`ders for systemic use may be expected to result in
`faster rates of dissolution and absorption than solid
`dosage forms since there is immediate contact with
`the gastric fluids; however, the actual advantage in
`terms of therapeutic response may be negligible or
`only minimal depending upon the drug release
`characteristics of the counterpart products. A pri(cid:173)
`mary disadvantage to the use of oral powders is the
`undesirable taste of the drug.
`There are some medications, notably antibiotics
`for pediatric use, which are intended for oral ad-
`
`Cosmo Ex 2020-p. 4
`Mylan v Cosmo
`IPR2017-01035
`
`