`

`Editor: Donna Balado
`Managing Editor: jennifer Schmidt
`Marketing Manager: Christine Kushner
`
`Copyright © 1999 Lippincott Wllliams & Wilkins
`
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`
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`
`All rights reserved. This book is protected by copyright. No part of this book may be re-
`produced in any form or by any means, including photocopying, or utilized by any infor—
`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—
`formation relating to general principles of medical care which should not be construed as
`specific instructions for individual patients. Manufacturers’product information and pack—
`age inserts should be reviewed for current information, including contraindications,
`dosages, and precautions.
`
`Printed in the United States ofAmerica
`
`Library of Congress Cataloging-in-Publication Data
`
`Ansel, Howard C., 1933—
`Pharmaceutical dosage forms and drug delievery systems / Howard C.
`Ansel, Lode. Allen, Jr, Nicholas G. Popovich. —— 7th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0—683—30572—7
`2. Drug delivery systems.
`1. Drugs—Dosage forms.
`11. 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
`
`1. Allen, Lode.
`
`99—17498
`CIP
`
`The publishers have made every effort to trace the copyright holders for borrowed material. Ifthey
`have inadvertently overlooked any, they will be pleased to make the necessary arrangements at
`the first opportunity.
`-
`
`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 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 01 02
`1 2 3 4 5 6 7 8 9 10
`
`AstraZeneca Exhibit 2095 p. 2
`
`

`

`
`
`Contents
`
`Preface
`
`Acknowledgments
`
`Section I. PRINCIPLES OF DOSAGE FORM DESIGN AND DEVELOPMENT
`
`I
`
`2
`
`3
`
`4
`
`5
`
`Introduction to Drugs and Pharmacy
`
`New Drug Development and Approval Process
`
`Dosage Form Design: Pharmaceutic and
`Formulation Considerations
`'
`
`Dosage Form Design: Biopharmaceutic and
`Pharmacokinetic Considerations
`
`Current Good Manufacturing Practices and Good
`Compounding Practices
`
`Section II. SOLID DOSAGE FORMS AND MODIFIED-RELEASE DRUG DELIVERY SYSTEMS
`
`6
`
`7
`
`8
`
`Powders and Granules
`
`Capsules and Tablets
`
`‘
`
`Modified~Release Dosage Forms and Drug Delivery Systems
`
`Section III. SEMI-SOLID AND TRANSDERMAL SYSTEMS
`
`9
`
`IO
`
`Ointments, Creams, and Gels
`
`Transdermal Drug Delivery Systems
`
`v
`
`vii
`
`1
`
`23
`
`60
`
`101
`
`142
`
`164
`
`179
`
`229
`
`_
`
`'244
`
`263
`
`ix'
`
`AstraZeneca Exhibit 2095 p. 3
`
`

`

`x
`
`Contents
`
`Section IV. PHARMAEEUTICAL INSERTS
`
`II
`
`Suppositories and Inserts
`
`Section V. LIQUID DOSAGE FORMS
`
`I 2
`
`I3
`
`S olutions
`
`Disperse Systems
`
`Section VI. STERILE DOSAGE FORMS AND DELIVERY SYSTEMS
`
`I 4
`
`I 5
`
`I6
`
`Parenterals
`
`Biologicals
`
`Ophthalmic Solutions and Suspensions
`
`Section VII. NOVEL AND ADVANEED DOSAGE FORMS, DELIVERY SYSTEMS, AND DEVIEES
`
`Radiopharmaceuticals
`
`Products of Biotechnology
`
`Novel Dosage Forms and Drug Delivery Technologies
`
`Systems and Techniques of Pharmaceutical Measurement
`
`I 7
`
`I8
`
`I9
`
`Appendix
`
`Index
`
`279
`
`296
`
`346
`
`397
`
`450
`
`469
`
`487
`
`503
`
`535
`
`552
`
`563
`
`AstraZeneca Exhibit 2095 p. 4
`
`

`

`' CAPSULES AND TABLETS
`
`
`
` Chapter at a Glance
`
`Capsules
`Hard Gelatin Capsules
`The Mamifacture of Hard Gelatin Capsule
`Shells.
`Capsule Sizes
`Preparation of Filled Hard Gelatin Capsules
`Developing the Emulation and Selection of
`CaPSUIESize
`Filling Hard Capsule Shells
`Capsule Seating
`Clearing and Polishing Capsules
`Soft Gelatin Capsules
`Preparation of Soft Gelatin Capsules
`Utilization of Soft Gelatin Capsules
`Compendial Requirementsfor Capsules
`Added Substances
`Containers for Dispensing Capsules
`Disintegration Test for Capsules
`Dissolution Test for Capsules
`Weight Variation
`Content Uniformity
`Content Labeling Requirement
`Stability Testing
`Moisture Permeation Test
`Ofi’icr‘al and Commercially Available Capsules
`Inspecting, Counting, Packaging, and Stor—
`ing Capsules
`Tablets
`
`Types ofTablEts
`Compressed Tablets (CI)
`Multiple Compressed Tablets (MEIR)
`Sugar-Coated Tablets (SCI)
`Film Coated Tablets (F.C.T.)
`Gelatin-Coated Tablets
`
`Effervescent Tablets
`Molded Tablets (M.T.)
`Tablet Trihnates CIT.)
`Hypoderrnic Tablets (rm)
`Dispensing Tablets (D.T.)
`Willa“! REJEQSE Tablas {LE-l
`Instant Disintegrating/Dissolvtng Tablets
`Extended Release Tablets (ER)
`Vaginal Tablets
`Compressed Tablets
`Quality Standards and Compendial Require-
`merits
`Compressed Tablet Manufacture
`Wet Granulation
`Allin-One Granulation Methods
`Dry Granulation
`Tableo'ng of Granulation
`Direct Compression Tableting
`Tablet Dedusting
`Chewable Tablets
`Molded Tablets
`Tablet Coating
`Sugamoating Tablets
`Film-coating Tablets
`Enteri: Coating
`Fluid-Bed or Air Suspension Coating
`Compression Coating
`Impact ofManufacturing Changes on Solid
`Dosage Forms
`Ofl'icz'ai and Commercially Available
`Tablets
`
`Packaging and Storing Tablets
`Oral Administrairhn ofSolid Dosage Forms
`Other Solid Dosage Formsfor
`Oral Administration
`
`Emerita-Coated Tablets (E.C.T.)
`Bugatti or Sublirrgual Tablet
`Lozenges
`Pills
`Chewable Tablets
`
`
`1'79
`
`AstraZencca Exhibit 2095 p. 5
`
`

`

`180
`
`Capsules and 'lhbleis
`
`WHEN M'EDICA'I'IONS are to be administered orally
`to adults, capsules and tablets usually are preferred
`because they are conveniently carried, readily iden-
`tified, and easily taken.
`Consider the convenience of apatient carrying a
`day’s, week’s, or month’s supply of capsules or
`tablets compared with equivalent doses of a liquid
`medication With capsules and tablets as dosing
`units, there is no need for spoons or other mea-
`suring devices, which sometimes may be inconve—
`nient and may result in less than accumte dosing.
`Also, most capsules and tablets are tasteless when
`swallowed, which is not the case with oral liquid
`medication.
`
`The characteristic shapes and colors of- capsules
`and tablets and the manufacturer’s name and prod-
`uct code number commonly embossed or imprinted
`on their surface make them readily identified. This
`enhances coulmunicafions-benveen the patient and
`health care providers, assists patient compliance
`and fosters safe-end effective medication use.
`
`Capsules and tablets are available formanymed—
`ications in a variety of dosage strengths thereby
`providing prescribing flaubflity to the prescribe:
`and accurate individualizad dosage for the patient.
`Some tablets are scored, or grooved. which allows
`them to be easily broken into two or more parts.
`This enables the patient to swallow smaller por—
`tions as may be desired, or when prescribed, it al-
`lows the tablet to be taken in reduced or divided
`dosage.Tablets- that are not scored are not intended
`to be broken or cut by the patient since they may
`have special Coatings andlor drug-release features
`that would be compromised by altering the tablets-
`physical integrity.
`From a pharmaceutic standpoint, solid dosage
`farms are efficiently and productively manufac-
`tured; they are packaged and shipped byrnanu-
`iacturers at lower cost and with less breakage than
`comparable liquid forms; and are more stable and
`have a longer shelf-life than their liquid counter-
`parts.
`As discussed later in this chapter, empty hard
`gelatin capsulesare often usedby the pharmacistin
`the attemporaneous compounding of preseriptions.
`On occasion, a pharmacist may use commercially
`available capsules and tablets as the source of a
`medicinal agent when it is not otherwisa available.
`In these instances, the pharmacr’St must take into
`account any excipients that are present in the com-
`mercial product to ensure campatibility with the
`other ingrediehts in the compounded prescription.
`Capsules and tablets designed to provide modified
`drug release are discussed in Chapter 8.
`
`Capsules
`
`Capsules are solid dosage forms in which medic-
`inal agents andlor inert substances are enclosed
`within a small shell of gelatin. Gelatin capsule shells
`may be hard or sofi‘ depending on their composition.
`Thevast majoo'ty offilled capsules are intended to
`be swallowed whole by the patient for the benefit of
`the medication contained therein. Howevm‘, it is not
`unusual practice in hospitals and extended care fia-
`foracaregiverto opencapsulea orcrush
`tablets to mix with food or ddnk, especially for chil-
`dren or other patients unable to swallow solid
`dosage icons. This should be done only with the
`concurrence of the phannacist since the drug release
`characteristics ofcertain dosage forms could be al-
`tered and adversely affect the patient’s welfare.
`Dosage forms that must be left intact include: en-
`teric coated tablets, designed to pass through the
`stomach for drug release and absorption in the in—
`testine; mended-release dosage forma, designed to
`provide prolonged release of the medication; and
`subllngual or buccal tablets, ionnulated to dissolve
`under the tongue or in the oral cavity (1]. In in-
`stances in which a'patient is unable to SWalIow an
`brtact solid dosage fonn, an altemafive product, such
`as a chewable tablet, instant dissolving tablet, oral
`liquid, suppository or injection may be employed.
`
`Hard Gelatin Capsules
`
`Hardgelafincapsuleshellsareusedto manufac-
`ture most ofthe commerciallyavallable medicated
`capsulesa They are also commonly employed in clin~
`ical drug trials,
`to compare the effects of an
`investigational drug to another drug product or
`placebo. Hard gelatin capsules also are used by the
`community pharmacist in the externporaneous com-
`pounding-of prescriptionsThe empty capsule shells
`aremadefromambchueofgelafin, sugarandweter.
`As such, they are clear, colorless, and essentially
`tasteless. They- may be colored with various PDdzC
`and Doc dyes and may be made opaque by adding
`agents such as titanium
`Most commercially
`available medicated capsules contain combinations
`ofcolorants and opaquants to make them distinctivo,
`many with caps and bodies of differentcolors.
`Gelatin is obtained by the par-Hal hydrolysis of
`collagen obtained from the skin, white connective
`tissue, and bones of animals. In commerce, it is
`available in the form of a fine powder, a coarse
`powder, shreds, flakes, or sheets (Fig. 7.1).
`Gelatin is stable in air when dry but is subject to
`microbial decomposition when it becomes moist.
`
`AstraZeneca Exhibit 2095 p. 6
`
`

`

`
`
`in the
`Fig. 7.1 Pork skin gelatin used as raw material
`manufacture of gelatin capsules. (Courtesy of SmithKiine
`Beccham.)
`
`Normally, hard gelatin capsules contain between
`13 and 16% of moisture (2). However, if stored in
`an environment of high humidity, additional mois-
`ture is absorbed by the capsules, and they may
`become distorted and lose their rigid shape. In an
`environment of extreme dryness, some of the mois~
`ture normally present in the gelatin capsules is lost
`and the capsules may become brittle and crumble
`when handled. Therefore, it is desirable to maintain
`
`hard gelatin capsules in an environment tree from
`excess humidity or dryness.
`Because moisture may be absorbed by gelatin
`capsules and affect hygroscopic agents contained
`within, many capsules are packaged along with a
`small packet of a desiccant material
`to protect
`against the absorption of atmospheric moisture.
`The desiccant materials most uSed are dried silica
`
`gel, clay, and activated carbon.
`Prolonged exposure to high humidity can affect in
`oitro capsule dissolution. Such changes have been
`observed in capsules containing tetracycline, chlor-
`amphenicol, and nitrofirrantoin (3). Because such
`changes could forewarn of possible changes in
`bioavailability, capsules subjected to such stress con-
`ditions must be evaluated on a case by case basis (3).
`Although gelatin is insoluble in cold water, it
`does soften through the absorption of up to ten
`
`vivo bioavaiiability for immediate-release products;
`(b) assessing the integrity and transit time of en—
`teric coated tablets through the stomach enroute to
`the intestines; and (c) drugldosage form evaluation
`in new product development
`(4—5). A separate
`technique, using a pit-sensitive, nondigestible, ra—
`diotelemetric device termed the Heidelberg cap-
`sule, the approximate size of a No. 0 gelatin cap-
`sule, has been used as a nonradioactive means to
`
`measure gastric pH, gastric residence time, and
`gastric emptying time of solid dosage forms in fast-
`ing and noniasting human subjects (6).
`As discussed in Chapter 4, drug absorption from
`the gastrointestinal tract depends on a number of
`factors, including the solubility characteristics of
`the drug substance, the type of product formulation
`(i.e., unmediate—release, modified-release, enteric
`coated), the gastrointestinal contents and intersub-
`ject diiferences in physiologic character and re—
`spouse.
`
`The Manufacture of Hard Gelatin
`
`Capsule Shells
`
`Hard gelatin capsule shells are manufactured in
`two sections, the capsule body and a shorter cap.
`The two parts overlap when joined, with the cap fit-
`ting snugly over the open end of the capsule body.
`
`AstraZeneca Exhibit 2095 p. 7
`
`Capsules and Tablets
`
`181
`
`times its weight of water. Some patients prefer to
`swallow a capsule wetted with water or saliva be-
`cause a wetted capsule slides down the throat more
`readily than a dry capsule. Gelatin is soluble in hot
`water and in warm gastric fluid a gelatin capsule
`rapidly dissolves and exposes its contents. Gelatin,
`being a protein, is digested by proteolytic enzymes
`and absorbed.
`
`A number of methods have been developed to
`track the passage of capsules and tablets thi'Ough
`the gastrointestinal tract to map their transit time
`and drug-release patternsAmong these is gamma
`scintigmphy, a noninvasive procedure which in-
`volves use of a gamma ray-emitting radiotracer in—
`corporated into the formulation with a gamma
`camera coupled to a data recording system (4-5).
`The quantity of material added to allow gamma
`scintigraphy is small and does not compromise the
`usual in vivo characteristics of the dosage form
`being studied. When scintigraphy is combined
`with pharmacokinetic studies, the resultant pharma-
`coscintogmphic evaluation provides information of
`the transit and drug release patterns of the dosage
`form as well as the rate of drug absorption from the
`various regions of the gastrointestinal tract (4).This
`method is particularly useful
`in:
`(a) identifying
`whether a correlation exists between in vitro and in
`
`

`

`182
`
`Capsules and Tablets
`
`The shells are produced industrially by the me-
`chanical clipping of pins or pegs of the desired
`shape and diameter into a temperature-controlled
`reservoir of melted gelatin mixture (Figs. 7.2, 7.3).
`The pegs, made of manganese bronze, are affixed
`to plates, each capable of holding up to about 500
`pegs. Bach plate is mechanically lowered to the
`gelatin bath, the pegs submerged to the desired
`depth and maintained for the desired period to
`achieve the proper length and thickness of coating.
`Then the plate and the pegs are slowly lifted from
`the bath and the gelatin dried by a gentle flow of
`temperanrre— and humidity-controlled air. When
`dried, each cap8ule part is trimmed mechanically to
`the proper length, removed from the pegs and the
`capsule bodies and caps are joined together. It is
`important that the thickness of the gelatin walls be
`strictly controlled so that the capsule’s body and
`cap fit snugly to prevent disengagement. The pegs
`on which the caps are formed are slightly larger in
`diameter than the pegs on which the bodies are
`formed, allowing the telescoping of the caps over
`the bodies. In capsule shell production, there is a
`continuous dipping, drying, removing and joining
`of capsules as the peg-cmtahungplates are rotated
`in and out of the gelatin bath. As noted earlier, cap-
`sule shells may be made distinctive by adding col-
`orants andi’or opaquants to the gelatin bath.
`A manufacturer also may prepare distinctive-
`
`looking capsules by altering the usaal rounded
`shape of the capsule—making pegs. By tapering the
`end of the body-producing peg While leaving the
`cap-making peg rounded, one manufacturer pre-
`pares capsules differentiated from those of other
`manufacturers (PULVULES, Elililly).Anotherman-
`ufacturer utilizes capsules with the ends of both the
`bodies and caps highly tapered (SPANSULE Cap-
`sules, SmithKline Beecham).Yet another innova-
`tion in capsule shell design is the SNAP-FIT, CONI—
`SNAR and CONIvSNAP SUPRO hard gelatin
`capsules depicted in Figures 7.4 and 7.5. The origi-
`nal SNAP-FIT construction enables the Mo halves
`
`of the capsule shells tobe positivelyjoined through
`locking grooves in the shellwalls. The two grooves
`fit into each other and thus ensure reliable closing
`of the filled capsule. During the closingprocess, the
`capsule body is inserted into the cap. With the
`high—capacity filling rates of the modern capsule
`filling machines (over 180,000 capsules per hour),
`capsule splitting ("telescoping") andfor denting of
`the capsule shell occurs with the slightest corrtact
`between the twn capsule-part rims when they are
`joined. This problem, which exists primarily with
`straight-Walled capsule shells, led to the develop-
`ment of the COM-SNAP capsule, in which the rim
`of the capsule body is not straight, but tapered
`slightly (Fig. 7.5). This reduces the risk of the
`capSule-rims touching on joining, and essentially
`
`
`
`ii i it
`
`.4
`
`:2.«it?!'!titllt‘lt'llli'liiiflw
`
`ww~__‘. .
`
`_ __
`
`Fig. 7.2 Body ofcapsules and their caps are shown as they move through automated capsule-making machete. Each machine is
`capable ofpmducing 30,000 capsules perilous it takes a 40-minute cycle to produce a capsule. (Courtesy omeitkKline Beautician.)
`
`AstraZeneca Exhibit 2095 p. 8
`
`

`

`
`
`Capsules and Tablets
`
`183
`
`amount of fill material to be encapsulated.'Ihe den-
`sity and compressibility of the fill will largely deter~
`mine to what extent it may be packed into a capsule
`shell (7). For estimation, a comparison may be made
`with powders of well—known features (Table 7.1)
`and an initial judgment made as to the approximate
`capsule size needed to hold a specific amount of ma-
`terial. However, the final determination largely may
`be the result of trial. For human use, empty capsules
`ranging in size from 000 (the largest) to 5 (the smali~
`est) are commercially available (Fig. 7.7). Larger cap~
`sules are available for veterinary use.
`For prescriptions requiring extemporaneous com-
`pounding hard gelatin capsules permit a Wide pre-
`scribing latitude by the physician. The pharmacist
`may compound capsules of a single medicinal agent
`or combination of agents at the precise dosage pre-
`scribed for the individual patient.
`
`Preparation of Filled Hard Gelatin Capsules
`
`The large-scale or small—scale preparation of
`filled hard gelatin capsules is divided into the fol~
`lowing general steps.
`
`Fig. 7.3 Capsules beingdippedfor coloringon automated cap»
`sole-making equipment. (Courtesy omeitliKline Beecliem.)
`
`eliminates the problem of splitting during large-
`scale filling operations. in the COM-SNAP SUPRO
`capsules, the upper capsule part extends so far over
`the lower part that only the rounded edge of the
`latter is visible (Fig. 7.5). Opening of such a filled
`capsule is difficult because the lower surface offers
`less gripping surface to pull the two halves apart.
`This increases the security of the contents and the
`integrity of the capsule.
`After filling, some manufacturers render their
`capsules tamper-evident through various capsule
`sealing techniques. Thesc methods are discussed
`later in this section. Capsules and tablets also may
`be imprinted with the names or monograms of
`the manufacturer, the assigned national drug code
`(NDC) number and other markings making the
`product identifiable and distinguishable from other
`products (Fig. 7.6).
`
`Capsule Sizes
`
`Empty gelatin capsules are manufactured in var-
`ious sizes, varying in length, in diameter, and capac~
`ity. The size selected for use is determined by the
`
`CONI-SNAP‘E
`
`.9
`
`I
`
`{0
`
`r'IOSL'd
`
`o'e closer!
`
`Open
`
`Fig. 7.4 Litre drawings of the COM-SNAP capsule in
`open, pre-closed, and closed positions. The tapered rims I)
`avoid telescoping; the indentations 2) prevent pretrialwe open-
`ing, and the grooves 3) lock the two capsule parts together af-
`ter the capsule hes beenfillert. (Courtesy ofCopsrlgel Division,
`Wenrer-anberl Co.)
`
`AstraZeneca Exhibit 2095 p. 9
`
`

`

`are performed to determine if all of the formulation’s
`bulk powders may be effectively blended together as
`such or if they require reduction of particle size or
`other processing to achieve homogeneity.
`A diluent or filler may be added to the formula—
`tion to produce the proper capsule fill volume. Lac-
`tose, microcrystalline cellulose and starch are
`commonly used for this purpose. In addition to pro-
`viding bulk, these materials often provide cohesion
`to the powders, which is beneficial in the transfer
`of the powder blend into capsule shells (2). Disin-
`tegrants are Erequently included in a capsule for-
`mulation to assist the break-up and distribution
`of the capsule contents in the stomach. Among
`the disintegrants used are pregelatinized starch,
`croscarrnellose, and sodium starch glycolate.
`To achieve uniform drug distribution, it is advan-
`tageous if the density and particle size of the drug
`and nondrug components are similar. This is par~
`
`
`
`
`
`A I
`
`I
`
`97:".
`
`Fig. 7.6 Examples of tablets and capsules marked with c
`letter-number code to facilitate identification. (Courtesy of Eli
`Lilly and Company.)
`
`184
`
`Capsules and Tablets
`
`CONIvSNAPQ
`
`com—snap sunnofi‘
`
`1|
`
`laurel! nm In amd telescon-ng
`lEcn.-Snap"‘3|
`?1 Drama: which lack Ihe Iwa halves
`Ingmar once Ih: capsule has been
`lulled {Snap-Film nnnonlcl
`3i Indenlalmns to prevent prenlalura
`opening
`
`Fig. 7.5 Line drawings of the COM-SNAP and CONT-
`SNAP SUPRO (rm right) capsules. The latter is designed to be
`smaller and to have the lower portion oflhe capsule shell cort-
`cealed exceptfor the rounded and. This makes separation ofilie
`1100 parts more difiicult and contributes to capsule integrity.
`(Caurtesy of Capsugel Division, WomenLambert Co.)
`
`1. Developing and preparing the formulation and
`selecting the size Capsule.
`2. Filling the capsule shells.
`3. Capsule sealing (Optional).
`4. Cleaning and polishing the filled capsules.
`
`Developing the Formulation and Selection of
`Capsule Size
`
`In developing a capsule formulation, the goal is
`to prepare a capsule with accurate dosage, good
`bioavailability, ease of filling and production, sta-
`bility, and elegance.
`In dry formulations, the active and inactive com-
`ponents must be blended thoroughly to ensure a
`uniform powder mix for the capsule fill. Care in
`blending is especially critical for low-dose drugs
`since lack of homogeneity could result in significant
`therapeutic consequences. Preformulat'ion studies
`
`AstraZeneca Exhibit 2095 p. 10
`
`

`

`Capsules and Tablets
`
`135
`
`Table 7.1. Approximate Capacity of Empty Gelatin Capsules
`
`Capsule Size
`
`volume (mil
`1.40
`0.95
`0.68
`0.50
`0.37
`0.30
`0.21
`0.13
`
`
`M Substance (mg?
`Quinine Sulfate
`650
`390
`325
`227
`195
`130
`97
`65
`Sodium Bicarbonate
`1430
`975
`715
`510
`390
`325
`260
`130
`
`
`
`
`
`
`
`
`1040 550 520 3'25 260 195 162Aspirin 97
`
`smount may vary according to the degree of pressure used in filling the capsules.
`
`ficularly important when a drug of low dosage is
`blended with other drugs or nondrug till (8). When
`necessary, particle size may be reduced by milling to
`produce particles ranging born about 50 to 1000
`rnicrorrs. Milled powders may be blended effec-
`fiver for uniform distribution throughout a pow—
`dermixwhen the drug’s dosage is 10 mg or greater
`(8). For drugs of10wer dose or when smaller parti-
`cles are required. micronizuliou is employed. De»
`pending on the materials and equipment used, mi—
`cronization produces particles ranging from about
`1 to 20 microns in size.
`
`In preparing capsules on an industrial scale using
`high-speed automated equipment, the powder mix
`or granules must be free-flowing to allow steady
`passage of the capsule fill from the hopper through
`the encapsulating equipment and into the capsule
`shells. The addition of a lubricant 0r glidant such as
`hinted silicon dioadde, magnesium stearate, calcium
`stearate, stearic acid, or talc (about 0.25—‘l%) to the
`powder mix enhances flow properties (2).
`When magnesium stearate is used as the lubri-
`cant,
`the water-proofing characteristics of this
`waterinsoluble material can retard penetration by
`the gastromtestinal fluids and delay drug dissolu-
`tion and absorption. The addition of Surface active
`agents, as sodium lauryl sulfate, to capsule and
`
`tablet formulations is used to facilitate wetting by
`the gastrointestinal fluids to overcome the problem
`(9). Even in instances in which a water-insoluble
`lubricant is not used, after the gelatin capsule shell
`dissolves, gastrointestinal fluids must displace the
`air that surrounds the dry powder and penetrate
`the drug before it can be dispersed and dissolved.
`Iibwders of poorly soluble drugs have a tendency to
`resist such penetration. Disimegration agents in—
`cluded in a capsule formulation facilitate the break
`up and distribution of the capsule’s contents.
`Whether it be the presence of a lubricant. sur-
`factant, disintegrating agent, or some other phar-
`maceulic endpient, formulation can influence the
`bioavailability of a drug substance and can account
`for differences in drug effects, which may be en-
`countered between two capsule products of the
`same medicinal substance. Pharmacists must be
`
`aware of this possibility when product-interchange
`is considered.
`
`Inserting tablets or small capsules within cap-
`sules is sometimes a useful technique in the com-
`mercial production of capsules and in a pharma-
`cist’s extemporaneous preparation of cap5ules
`(Fig. 7.8).This may be done to separate chemically
`incompatible agents or to add premeasured (as
`tablets) amounts of potent drug substances- Rather
`
`
`
`Fig. 7.7 Actual sizes ofhard gelatin capsules. From left to right, slaw 000. 00,0, 1,2. 3. 4,2nd 5.
`
`AstraZeneca Exhibit 2095 p. 11
`
`

`

`186
`
`Capsules and Thblets
`
`
`
`Fig. 7.3 Examples offill in hard gelatin capsules. 1, powder or grunulate; 2, pellet mixture; 3. paste: at. capsule; and 5, tablet.
`(Courtesy ofCapsugel, Division of Wamer=ermbcrtJ
`
`than weighing a potent drug, a pharmacist may
`choose to insert an available prefabricated tablet of
`the desired strength in each capsule. Other less po-
`tent agents and diluents may then we Weighed and
`added. On an industrial scale, coated pellets de-
`signed for modified-release drug delivery are also
`commonly placed in capsule shells.
`Gelatin capsules are unsuitable for the encapsu-
`lation of aqueous liquids because water softens
`gelatin and distorts the capsules, resulting in leak-
`age of the contents. However, some liquids such as
`fixed or volatile oils that do not interfere with the
`
`stability of the gelatin shells may be placed in locks
`ing gelatin capsules (or the capsules may be Sealed
`with a solution of gelatin thinly coating the inter-
`face of the cap and body) to ensure the retention of
`the liquid. Rather than placing a liquid in a capsole
`as such, the liquid maybe mixed with an inert pow-
`der to make a wetted mass or paste, which may
`then be placed in capsules in the usual manner
`(Fig. 7.8). Eutectic mixtures of drugs, or mbctures of
`agents that have a propensity to liquer when ad-
`mixed, may be mixed with a diluent or absorbent
`such as magnesium carbonate, kaolin, or light mag-
`nesium oxide to separate the interacting agents and
`to absorb any liquefied material which may form.
`In large-scale capsule production,
`liquids are
`placed in sofl‘ gelatin capsules that are sealed during
`the filling and manufacturing process. Soft cap-
`Sules are discussed later in this chapter.
`In most instances the amount of drug placed in
`a capsule represents a single dose of the medica-
`tion. In some instances, when the usual dose of the
`
`drug is too large to place in a single capsule, two or
`more capsules may be required to provide the de-
`sired dose.The total amount of formula prepared is
`that amount necessary to fill the desired number of
`capsules. On an industrial scale this means hun-
`
`dreds of thousands of capsules. In community prac-
`tice, an individual prescription may call for the
`preparation of only six or a dozen capsules. Any
`slight loss in fill-material during the preparation
`and capsule- filling process will not materially affect
`an industrial] size batch, but in the community
`pharmacy, a slight loss of powder would result in an
`inadequate quantity to fill the last capsule. To en-
`sure enough fill in the compounding of small num—
`bers of capsules, the community pharmacist may
`calculate for the preparation of one or two more
`capsules than is required to fill the prescription.
`However, this procedure may not be followed for
`capsules containing a controlled substance since
`the amount of drug used and that called for in the
`prescription must strictly coincide.
`The selection of the capsule siza for a commer-
`cial product is done during the product develop-
`ment stage. The choice is determined by require-
`ments of the formulation, including the dose of the
`active ingredient, and the density and compaction
`characteristics of the drug and nondrug compo-
`nents. If the dosc of the drug is inadequate to fill the
`volume of the capsule body, a diluent is added. In-
`formation on the density and compaction charac-
`teristics of a capsule’s active and inactive compo-
`nents and comparison to other similar materials
`and prior experiences can serve as a guide in se—
`lecting capsule size (7).
`Hard gelatin capsules are used to encapsulate be-
`tween about 65 mg and 1 g of powdered material.
`As shown inTable 7.1, the smallest capsule (No. 5),
`may be expected to hold 65 mg of powder or more,
`depending on the characteristics of the powder sub-
`stance. Oitentimes, in the externporaneous coma
`pounding of prescriptions, the best capsule size to
`use is determined by trial. Use of the smallest size
`capsule, properly filled, is preferredA properly filled
`
`AstraZeneca Exhibit 2095 p. 12
`
`

`

`capsule Shauld have its body filled with the drug
`mixture, not the cap. The cap is intended to fit
`snugly over the body to retain the contents.
`The following examples demonstrate the drug
`and nondrug contents of a few commercially avail-
`able capsules.
`
`'létmqeline Capsules
`Active ingredient:
`
`Filler:
`
`Tetracycline
`250 mg
`Lactose
`
`hydroddofide,
`
`Lubricantiglidant: Magnesium stearate
`Capsule colorants:
`FDt’cC Yellow No. 6, D&C
`Yellow No. 10, Duh-C Red
`No. 28, FDdrC Blue No. 1
`
`Capsule opaquant: Titanium dioxide
`
`Acetaminophen with Codeine Capsules
`Active ingredients: Acetanunophen, 325 mg
`Codeine phosphate, 30 mg
`Sodimn starch glycolate
`Magnesium stearate, stearic
`acid
`
`DisintEgrant.
`Lubricantlglidants:
`
`Capsule colorants:
`
`DSzC Yellow No. 10', Edible
`Ink, FD8:C Blue No. 1
`
`('FDdrC Green No. 3 and
`P'ch Red No. 40)
`
`Diphmhydmmine Hydrochloride Capsules
`Active ingredient Diphenhydramine HCL
`50 mg
`Cenfectioner’s sugar
`Filler:
`Lubricantst’glidants: Talc, colloidal silicon dioxide
`Wetting agent:
`Sodium Iauryl sulfate
`Capsule colorants:
`FDdrC Blue No. 1, mac Red
`No. 3
`
`Capsule opaquant: Titanium dioxide
`
`Filling Hard Capsule Shells
`
`When filling a small number of capsules in the
`pharmacy, the pharmadstuses the”punch”method.
`In this method, the phan'nacist takes the precise
`number of empty capsules to be filled from his
`stock container. By counting the capsules as the ini-
`tial step rather than taking a capsule from stock as
`each one is filled, the pharmacist guards against
`fillingan erroneous number of capsules and avoids
`contaminating the stock container with drug pow-
`der. The powder to be encapsulated is placed on a
`sheet of clean paper or on a glass or porcelain plate.
`Using the spatula, the powder mix is formed into a
`cake having a depth of approadmately one-fourth
`to one-third the length of the capsule body. Then
`an empty capsule body is held between the thumb
`
`Capsules and 'Iizblets
`
`137
`
`and foresfinger and “punched” vertically into the
`powder cake repeatedly until filled. Some pharma-
`cists wear surgical gloves or latex finger cots to
`avoid handling the capsules with bare fingers. Be-
`cause the amount of powder packed into a capsule
`depends upon the degree of compression, the phar-
`macist should punch each capsule in the same
`manner a