Pharmaceutical
`Dosage Forms
`and Drug
`Delivery Systems
`
`Howard C. Ansel, Ph.D.
`,.
`Panoz Professor of Pharmacy, Department of
`Pharmaceutics, College of Pharmacy
`The University of Georgia
`
`Nicholas G. Popovich, Ph.D.
`Professor and Head, Department of Pharmacy
`Practice, School of Pharmacy and Pharmacal
`Sciences
`Purdue University
`
`Loyd V. Allen, Jr., Ph.D.
`Professor and Chair, Department of Medicinal
`Chemistry and Pharmaceutics, College of
`Pharmacy
`The University of Oklahoma
`
`SIXTH EDITION
`
`A Lea & Febiger Book
`
`Williams & Wilkins
`
`&ALIIMORE • •H LADELPHIA • HONGKONG
`LONDON • MUNICH • S•DNEY • JOKYO
`
`A WAVF. R LY CO M PANY
`
`1995
`
`

`

`Executive Editor: Donna M. Balado
`Developmental Editor: Frances M. Klass
`Production Coordinator: Peter J. Carley
`Project Editor: Jessica Howie Martin
`
`Copyright © 1995
`Williams & Wilkins
`200 Chester Field Parkway
`Malvern, PA 19355 USA
`
`All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form
`or by any means, including photocopying, or utilized by any information storage and retrieval system without
`written permission from the copyright owner.
`Accurate indications, adverse reactions, and dosage schedules for drugs are provided in this book, but it is pos(cid:173)
`sible they may change. The reader is urged to review the package information data of the manufacturers of the
`medications mentioned.
`Printed in the United States of America
`
`Library of Congress Cataloging in Publication Data
`
`94 95 96 97 98
`1 2 3 4 5 6 7 8 9 10
`
`Ansel, Howard C., 1933-
`Pharmaceutical dosage forms and drug delivery systems / Howard C.
`Ansel, Nicholas G. Popovich, Lloyd V. Allen, Jr.-6th ed.
`P· cm.
`Includes bibliographical references and, index.
`ISBN 0-683-00193-0
`1. Drugs-Dosage forms. 2. Drug delivery systems.
`I. Popovich, Nicholas G.
`II. Allen, Loyd V.
`III. Title.
`[DNLM: 1. Dosage Forms. 2. Drug Delivery Systems. QV 785 A618i
`1995]
`.
`RS200.A57 1995
`615'.1-dc20
`DNLM/DLC
`for Library of Congress
`
`94-22471
`CIP
`The use of portions of the text of USP23/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 publica(cid:173)
`tion of a supplement.
`
`PRINTED IN THE UNITED ST A TES OF AMERICA
`
`Print No. 4 3 2 1
`
`

`

`Oral Suspensions, Emulsions, Magmas, and Gels
`
`255
`
`These main features of a suspension, which
`depend upon the nature of the dispersed phase,
`the dispersion medium, and pharmaceutical ad(cid:173)
`juncts, will be discussed briefly.
`
`Sedimentation Rate of the Particles of a
`Suspension
`
`The various factors involved in the rate of velocity
`of settling of the particles of a suspension are embodied
`in the equation of Stokes' law, which is presented in
`the accompanying Physical Pharmaci; Capsule.
`Stokes' equation was derived for an ideal situ(cid:173)
`ation in which uniform, perfectly spherical parti(cid:173)
`cles in a very dilute suspension settle without
`effecting turbulence in their downward course,
`without collision of the particles of the suspen(cid:173)
`soid, and without chemical or physical attraction
`or affinity for the dispersion medium. Ob(cid:173)
`viously, Stokes' equation does not apply pre(cid:173)
`cisely to the usual pharmaceutical suspension in
`which the suspensoid is irregularly shaped, of
`various particle diameters, and not spherical, in
`which the fall of the particles does result in both
`turbulence and collision, and also in which there
`may be a reasonable amount of affinity of the
`particles for the suspen~ion medium. However,
`the basic concepts of the equation do give a valid
`indication of the factors that are important to the
`suspension of the particles and a clue to the pos(cid:173)
`sible adjustments that can be made to a fonnula(cid:173)
`tion to decrease the rate of particle sedimenta(cid:173)
`tion.
`From the equation it is apparent that the veloc(cid:173)
`ity of fall of a suspended particle is greater for
`larger particles than it is for smaller particles,
`all other factors remaining constant. By reducing
`the particle size of the dispersed phase, one can
`expect a slower rate of descent of the particles.
`Also, the greater the density of the particles, the
`greater the rate of descent, provided the density
`of the vehicle is not altered. Because aqueous
`vehicles are generally used in pharmaceutical
`oral suspensions, the density of the particles is
`generally greater than that of the vehicle, a desir(cid:173)
`able feature, for if the particles were less dense
`than the vehicle, they would tend to float, and
`floating particles would be quite difficult to dis(cid:173)
`tribute uniformly in the vehicle. The rate of sedi(cid:173)
`mentation may be appreciably reduced by in(cid:173)
`creasing the viscosity of the dispersion medium,
`and within limits of practicality this may be
`done. However, a product having too high a vis(cid:173)
`cosity is not generally desirable, because it pours
`
`with difficulty and it is equally difficult to redis(cid:173)
`perse the suspensoid. Therefore, if the viscosity
`of a suspension is increased, it is done so only
`to a modest extent to avoid these difficulties.
`The viscosity characteristics of a suspension
`may be altered not only by the vehicle used, but
`also by the solids content. As the proportion of
`solid particles is increased in a suspension, so is
`the viscosity. The viscosity of a pharmaceutical
`preparation may be determined through the use
`of a Brookfield Viscometer, which measures vis(cid:173)
`cosity by the force required to rotate a spindle
`in the fluid being tested (Fig. 7-3).
`For the most part, the physical stability of a
`pharmaceutical suspension appears to be most
`appropriately adjusted by an alteration in the
`dispersed phase rather than through great
`changes in the dispersion medium. In most in(cid:173)
`stances, the dispersion medium is supportive to
`the adjusted dispersed phase. These adjustments
`mainly are concerned with particle size, uni(cid:173)
`fonnity of particle size, and separation of the par(cid:173)
`ticles so that they are not likely to become greatly
`larger or to form a solid cake on standing.
`
`Physical Features of the Dispersed Phase of a
`Suspension
`Probably the most important single considera(cid:173)
`tion in a discussion of suspensions is the size of
`the drug particles. In most _good pharmaceutical
`sus ensionsJ the_par.tick diameter is between 1
`ind 50 µm.
`Particle size reduction is generally accom(cid:173)
`plished by dry-milling prior to the incorporation
`of the dispersed phase into the dispersion me(cid:173)
`dium. One of the most rapid, convenient, and
`inexpensive methods of producing fine drug
`powders of about 10 to 50 µm size is micropulveri(cid:173)
`zation. Micropulverizers are high-speed, attrition
`or impact mills which are efficient in reducing
`powders to the size acceptable for most oral and
`topical suspensions. For still finer particles,
`under 10 µm, the process of fluid energy grinding,
`sometimes referred to as jet-milling or microniz(cid:173)
`ing, is quite effective. By this process, the shear(cid:173)
`ing action of high velocity compressed air
`streams on the particles in a confined space pro(cid:173)
`duces the desired ultrafine or micronized parti(cid:173)
`cles. The particles to be micronized are swept
`into violent turbulence by the sonic and super(cid:173)
`sonic velocity of the air streams. The particles
`are accelerated into high velocities and collide
`with one another, resulting in fragmentation and
`a decrease in the size of the particles. This
`
`