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 Phannaceutical Compounding
`
`Nicholas G. Popovich, Ph.D.
`Professor and Associate Head
`Department of Pharmacy Practice
`School of Pharmacy and Pharmacal Sciences
`Purdue University
`
`'~LIPPINCOTT W ILLIAMS & WILKINS
`
`•
`
`A Wolters Kluwer Company
`Philadelphia • Baltimore • New York • London
`Buenos Ai res • Hong Kong • Sydney • Tokyo
`
`1
`
`EX 1013
`IPR of U.S. Pat. No. 7,829,595
`
`

`
`Editor: Donna Balado
`Ma11agi11g Editor: Jennifer Schmidt
`Marketi11g Ma11ager: Christine Kushner
`
`Copyright© 1999 Lippincott Williams & 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(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.
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`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 infonnation and pack(cid:173)
`age inserts should be reviewed for current inforrnation, including contraindications,
`dosages, and precautions.
`
`Printed in tl1e Llnited States of America
`
`Library of Congress Cataloging-in-Publication Data
`
`Ansel, Howard C., 1933-
`Phannaceutical dosage forms and drug delievery systems I Howard C.
`Ansel, Loyd V. Allen, Jr., Nicholas G. Popovich. - 7th ed.
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0-683-30572-7
`1. Drugs-Dosage forms. 2. Drug delivery systems.
`III. Title.
`11. Popovich, Nicholas G.
`[DNLM: 1. Dosage Forms. 2. Drug Delivery Systems. QV 785 A618i 1999]
`RS200.A57 1999
`615'.1-dc21
`DNLM/DLC
`for Library of Congress
`
`99-17498
`CII'
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`have i11adverte11tly overlooked any, they will be pleased to make the necessary arrangements at
`the first opport1111ity.
`
`l. Allen, Loyd V.
`
`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.
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`99 00 0102
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`
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`chapter 1
`"chapter
`
`2
`
`

`
`ass, color, odor,
`ition.
`r, appearance,
`ution.
`appearance,
`‘edispersibility
`)lutions)_
`h, color, odor,
`
`strength, de-
`umber of me—
`size distribu-
`
`weight dis-
`ray pattern.
`
`5), particle size
`sions, creams,
`rility_
`
`, appearance,
`tter, pH, vol—
`1 plastic con-
`ogenicity, and
`
`ange, appear-
`
`deliaery sysu
`rug reservoir,
`lembrane in—
`
`drug release
`
`' patient con—
`st bear an ap-
`identifies the
`
`Dosage Form Design: Pl1urmnceutic and Fomu.rJ'rrtimz Corrsiderutimrs
`
`8'7
`
`limits the time during which the product may be
`dispensed by the pharmacist or used by the patient.
`Prescriptions requiring extemporaneous corn-
`pounding by the pharmacist do not require the ex—
`tended shelf—life that commercially manufactured
`and distributed products do because they are in-
`tended to be used immediately on their receipt by
`the patient and used only during the immediate
`course of the prescribed treatment. However, these
`compounded prescriptions must remain stable and
`efficacious during the course of their use and the
`compounding pharmacist must employ formula-
`tive components and techniques which will result
`in a stable product (
`In years past pharmacists were confronted pri-
`marily with innocuous, topical prescriptions that
`required extemporaneous formulation. However,
`in recent years there has been a need to compound
`other drug delivery systems as well, e. g., progeste-
`rone vaginal suppositories, oral suspensions, from
`existing tablets or capsules. When presented with a
`prescription that requires extemporaneous com-
`pounding, the pharmacist is confronted with a
`difficult situation because the potency and the sta-
`bility of these prescriptions is a serious matter. Oc—
`casionally, the results of compatibility and stability
`studies on such prescriptions are published in sci—
`entific and professional journals. These are Very
`useful; however, there are also prescriptions for
`which stability and compatibility infonnation is not
`readily available. In these instances, it behooves the
`pharmacist to at least Contact the drug manufac-
`turer of the active ingredient(s) to solicit stability
`information. Also, a compilation of published stabil-
`ity information is included in Trissel's Stability of
`Compounded Formulations (8).The published stabil-
`ity data are applicable only to products that are pre-
`pared identically to the products that are reported.
`USP guidelines on stability of externporaneous
`compounded formulations state that, in the ab~
`sence of stability information that is applicable to a
`specific dmg and preparation, the following guide-
`lines can be utilized: nonaqueous liquids and solid
`formulations where the manufactured drug is the
`source of the active ing'redient—not later than 25%
`of the time remaining until the product's expiration
`date or 6 months, whichever is earlier; nonaqueous
`liquids and solid formulations where a USP or NF
`substance is the source of active ingredient—a be-
`yond—use date of 6 months; for water-containing
`formulations prepared from ingredients in solid
`form—a beyond—use date of not later than 14 days
`when stored at cold temperatures; for all other for-
`mulationsea beyond-use date ofthe intended du-
`
`ration of therapy or 30 days, whicheveris earlier (9).
`Thus, in the instance where an oral aqueous liquid
`preparation is made from an existing tablet or cap-
`sule formulation, the pharmacist should make up
`only at most a 14 days supply and it must be stored
`in a refrigerator. Further, the pharmacist must also
`dispense the medication in a container conducive
`to stability and use and must advise the patient of
`the proper method of use and conditions of storage
`of the medication.
`
`Finally, when compounding on the basis of
`extrapolated or less than concrete information it
`is best for the pharmacist to keep the formula-
`tion simple and not to shortcut but use the nec-
`essary pharmaceutical adjuvants to prepare the
`prescription.
`
`Pharmaceutic Ingredients
`
`Definitions and Types
`
`To prepare a drug substance into a final dosage
`form, pharmaceutic ingredients are required. For
`example, in the preparation of pharmaceutic solu-
`tions, one or more solvents are used to dissolve
`the drug substance, flavors mid sweeteners are used
`to make the product more palatable, colorants
`are added to enhance product appeal, preserva-
`tives may be added to prevent microbial growth
`and stabilizers, such as antioxidants and chelating
`agents, may be used to prevent drug decomposi-
`tion, as previously discussed. In the preparation of
`tablets, diluerits or fillers are commonly added to
`increase the bulk of the formulation, binders to
`cause the adhesion of the powdered drug and
`pharmaceutic substances, untiadherents or lubri~
`cunts to assist the smooth tableting process, disin-
`tegrating agents to promote tablet break—up after
`administration, and coatings to improve stability,
`Control disintegration, or to enhance appearance.
`Ointrnents, creams, and suppositories achieve their
`characteristic features clue to the pharmaceutic
`bases which are utilized. Thus, for each dosage
`form, the pharmaceutic ingredients establish the
`primary features of the product, and contribute to
`the physical form, texture, stability, taste and over-
`all appearance.
`Table 3.3 presents the principal categories of
`pharmaceutic ingredients, with examples of some
`of the official and commercial agents currently used.
`Additional discussion of many of the pharmaceutic
`ingredients may be found in the chapters where
`they are most relevant; for example, pharmaceutic
`materials used in tablet and capsule formulations
`
`3
`
`

`
`E68
`
`Dtistigr Form Desigai: l’lmnmicvtm'c rum‘ Pnniiulrzfiori Con5i:lemlim.*.¢
`
`Table 3.3. Examples of Pharmaceutic Ingredients
`
`iirgr‘en‘r't'iit if/pt‘
`rlcitiifyiiig Agcrit
`
`Drjfiiifiirm
`Used in liquid pieparations to pi-ovicie acidic meditlm for
`product stability.
`
`/\litnliiii:iii|e/1g;-iir
`
`Used in liquid pI'CpaL"uti0n5 to provide alkaline medium
`For product stabi iity.
`
`/ldsortimt
`
`Aerosnl Pmpellmit
`
`An agent capable of holding other molecule: onto its
`stirface by physical or chemical (Ci1cmi501'ption) means.
`Agent responsilsle for developing the pressure within an
`aerosol ccyntainer and expelling the product when the
`valve is opened.
`
`Air Disiilnmiient
`
`Agent employed to displace air in a hermetically
`sealed CDi1iZCLiD€I
`to enhance product stability.
`Aiitifimgnl‘ P2'vs:=miti'vt= Used in liquid and SEt‘nl'S0iiCi preparations to pievent the
`growth of l'ungi.The eftectiveness of the p-arabens is
`Llstmliy enhanced when they are used in combination.
`
`/tiJilIiJt(!’LJiJit1i
`Presm=riti'm'
`
`Used in liquid and e:emi—s0licl p1'eparation5 to prevent the
`growth or niicroorganisms.
`
`Ant/n.\'iri'mrt
`
`Agent that iriiiibits oxidation and thus is used to prevent
`the deterioration of prepmritions by the oxidative
`process.
`
`Buffi‘i'fii;g /igcrit
`
`Used to re "st change in pH upon dilution or addition of
`acid or alkali. potassiLim nietaphnspliate
`
`Emliiplvs
`
`Citric acid
`Acetic acid
`Fumaric acid
`ii_vdmchloric acid
`Nitric acid
`Ammonici solution
`Ammoniu n1 cnrinonate
`Diethanolamine
`Monoethanolamine
`Poteissi um hydi'oxide
`Sodium borate
`Sodium caiboiiate
`Sodium hydmxinle
`Ti'ietlmnol:imine
`T:-olamine
`Powdered cellulose
`Activated chnrco‘al
`Carbmi dioxide
`Dichlcimditluoroniethzme
`Dichio1'otetraF|uoroethane
`Trichlommomifltiorometliane
`Niti‘og,en
`Carbon dioxide
`l.%Lit_\jlpa1'abeii
`Eli'iyipLli'Llb|3H
`Meti1ylpm‘abei1
`Benzoic acid
`1-’i‘opylpai'abei'i
`Sodium benzoate
`Sodium pioinionzite
`Ben7aIl<onium chloride
`Benzethonium chloride
`Ben‘/.yl alcohol
`Cetylpyricllnium chloride
`Cliloi'<_1butaI1ol
`Phenol
`l"l1eiiylethy'i alcohol
`i’heh_vlmetcua‘ic nitrate
`Tliii‘net'o!-sail
`Ascorbic acid
`r'\_.=:corhyl palinitate
`B1.tl:)='iCItt‘Ci liytli'o\\-‘amis-ole
`Btll'\fiE‘tl.'CLi. it\’til‘0\\.'it7i'LlL‘i‘lC
`Hy'pUph0pi10t'L'ILIH acid
`Monothioglyccrol
`Propyl galinte
`Sodium :iscorbat'C
`Sodium bistiltite
`Sodium tot maldehvdc
`Sullox}/late
`Sodium inetnbisulfite
`P0i[!EwFlLll‘ti pliospliate,
`mmiobasic
`Sodium acetate
`Sor;liL1m citrate anli_vcii'otis
`and dih_\'d:‘at'e
`
`continrmi'
`
`Table 3.3. Examp
`
` _
`CHEM ting Agent
`
`Calomnt
`
`C1.m‘ifyingAgmr
`Eniufstjyia1gAggm
`
`Enmpsuln ting Agent
`
`Fiavonmt
`
`Humectant
`
`Lflligflflflig Aggjgf
`
`Oiniimiit Base
`
`Pinsticizer
`
`Solvent
`
`4
`
`

`
`jéjjjj
`l_-Tmrnplrts‘,j
`acid
`: acid
`ric acid
`ochloi ic acid
`: acid
`“mja 5-'.0lL'lilOI‘I
`mmum [a1'bfll‘liliL‘
`1 a nola mi ne
`ngi-hannlaminc
`ssnnn h_vdroxid0
`mu i‘:01‘Ell;E
`um carbonate
`ium hvcl|'oxi(lc
`:hanolammL‘
`amine
`rdcrecl cellulose
`i ated clniltml
`“hon dio\'lElC
`hloroclillunromcilia”?
`-hlorotetratlunroetlmnc
`3mm-umm‘\oFluoi‘ometl‘|Elm
`rrogen
`rbon dioxide
`jylparaben
`wylparabcn
`~tliylpa1‘ab0H
`Inzoic acid
`-0P_V-1pai'abc1i
`gdium hen7_oatC
`,,_jjl.n-. pi-opionalc
`3n‘/_CLll{Ol.1lLiI'i'| cli.lo1‘i€lC
`en’/.ethnmum chloride
`9,”) alcolwl
`_
`jglylpwicliriiiiiii cbl01'|dC
`Ihlm-obutanol
`’hcnol
`flmiwletlryl alcohol
`—‘|~.um}l1nercu1‘ic nitrate
`lhimemfifll
`I.\__;
`nic acid
`33¢“.-byl palmitate
`Butvlnlfld l1)"Cll'07‘l'm-ll*E’UlLV
`j'—3Uj_-/V|'L][[‘d hyd1'c).\‘ytoliIcnc
`j_j\,P(3Pl~juj_'»l‘lOl‘ULlS acid
`Monothioglvcliifil
`Pmpyl gflllflie
`Sodium ascorbate
`Sodium bisiiltile
`Soclium 'lormaldchydL'
`Stlltnxylate
`_
`Sodium metabisullite
`jjotagsiurfl pliosphate,
`mnnobasir
`Sodium acctfllv
`Soclium citrate anli}'“l"°uS
`and dilwdrate
`
`cmitilruerl
`
`Dosage Form Dcsign.'Pl1m':mrceLitic and Fammlation Considcmtimzs
`
`Table 3.3. Examples of Pharmaceutic Ingredients
`lTIg7‘r?dfEi1i Type
`Definitimi
`Clzelntii1gAge1it
`
`Colornm‘
`
`Substance that forms stable, water soluble complexes
`(chelates) with metals. Chelating agents are used in some
`liquid pharmaceuticals as stabilizers to complex heavy
`metals which might promote instability, in such use they
`are also called seqztestermg agents.
`Used to impart color to liquid and solid (e.g., tablets and
`capsules) pharmaceutical preparations
`
`Clnnfi/tug Agent
`Emulsifi/ingAge11t
`
`Used as a filtering aid because of adsorbent qualities.
`Used to promote and maintain the dispersion of finely
`subdivided particles of a liquid in a vehicle in which it
`isi1nmiscible.Tl1e end product may be a liquid emulsion
`or semisolid emulsion (e.g., a cream).
`
`Encapsulnting Agent
`
`Plnvortuzt
`
`Used to form thin shells for the purpose of enclosing a
`drug substance or drug formulation for ease of
`administration.
`Used to impart a pleasant flavor and often odor to a
`pharmaceutical preparation. In addition to the natural
`flavorants listed, many synthetic flavorants are also used.
`
`liimiectrml
`
`Levignffng Agent
`
`Ointinent Bnse
`
`Plnsticizer
`
`Solvent
`
`Used to prevent the drying out of preparati0ns—particula.rly
`ointrnents and creamsfidue to the agent's ability to
`retain moisture.
`
`Liquid used as an intervening agent to reduce the particle
`size of a drug powder by grinding together, usually in
`a mortar.
`
`Sernisolid vehicle into which drug substances may be
`incorporated in preparing medicated ointments.
`
`Used as a component of film—coating solutions to enhance
`the spread of the coat over tablets, beads, and granules.
`An agent used to dissolve another pharrnaceutic substance
`or a drug in the preparation of a solution. The solvent
`may be aqueous or nonacjueous (e.g., oleaginous).
`Cosolvents, such as water and alcohol (hydroalcoholic)
`and water and glycerin, may be used when needed.
`Solvents rendered sterile are used in certain preparations
`(e.g., injections).
`
`Examples
`Ede tic acid
`Edetate clisodjum
`
`FD&C Red No. 3
`FD&C Red No. 20
`FD &CYellow No. 6
`FD&C Blue No. 2
`D&C Green No.5
`D&C Orange No.5
`D &C Red N0. 8
`Caramel
`Ferric oxide, red
`Bentonite
`Acacia
`Cetornacrogol
`Cetyl alcohol
`Glyceryl monostearate
`Sorbitan monooleate
`Polyoxyethylene 50 stearate
`Gelatin
`
`Cellulose acetate phthalate
`Anise oil
`Cinnamon oil
`Cocoa
`Menthol
`Orange oil
`Peppennint oil
`Vanillin
`Glycerin
`Propylene glycol
`Sorbitol
`Mineral oil
`Glycerin
`
`Lanolin
`I-lydrophilic ointment
`Polyethylene glycol ointment
`Petrolatnm
`
`Hydrophilic petrolaturn
`White ointment
`Yellow ointment
`Rose water ointment
`Diethyl phthalate
`Glycerin
`Alcohol
`Corn oil
`Cottonseed oil
`Glycerin
`Isopropyl alcohol
`Mineral oil
`Oleic acid
`Peanut oil
`Ptuitied water
`Water for injection
`Sterile water for injection
`Sterile water for irrigation
`continued
`
`5
`
`

`
`9U
`
`Dnsrrgc Form Dtzsfgii: Plim'iiiircem‘it mid Frimnilutioir Cnrrsrricmtimts
`
`Table 3.3. Examples of Pharmaceutic Ingredients
`Dcfiiiitloii
`li‘lg‘l‘i'3(‘l!t’lJl 'li;pt’
`Str]’}‘cmii_i{ /\gt=rrt
`
`Used to increase the thickness or hardness of a
`pharmaceutical preparation, usually an ointment.
`
`Srrppnsi'ftir'_i; Base
`
`Surfactmrt
`(slirfiice active rigcirt)
`
`Used as a vehicle into which drug substances are
`incorporated in the preparation of suppositories,
`Substances that absorb to surfaces or interfaces to reduce
`surface or intertacial tension, May be used as wetting
`agents, detergents or emulsifying agents.
`
`Susprvidilrg Agent
`
`A viscosity increasing agent used to reduce the rate of
`sedimentation ot (dnig) particles dispersed throughout
`a vehicle in which they are not soluble.The resultant
`suspensions may be formulated for use orally,
`parenterally, ophthalmically, topically, or by other routes.
`
`SEl’L‘(‘lt‘i .1 it re /lLi_\"[’t1r‘
`
`Used to impart sweetness to a preparation.
`
`Tlrlrlct Aiirirrzilivr-t=iils
`
`"lirlilot l3mrrlr-rs
`
`Agents that prevent the sticking of tablet formulation
`ingredients to punches and dies in a tableting machine
`during production.
`Substances used to cause adhesion of powder particles in
`tablet Le-_ranulations.
`
`Wiblwt mid Capsule
`Dilrreiit
`
`lnert substances used as fillers to create the desired bulk,
`flow properties, and compression characteristics in the
`preparation of tablets and capsules.
`
`Exiimplcs
`
`Cetyl alcohol
`Cetyl esters wax
`Microcrystallirie wax
`Paraffin
`Ste-aryl alcohol
`White wax
`Yellow \-vax
`Cocoa butter
`
`Polyethylene glycols (in i:<lurcsl
`Benzall<oniuni chloride
`Nonoxynol '10
`Oxtoxynol 9
`Polysorbate 80
`Sodium lauiyl sulFatc
`‘Sorlcritan monopalrnitate
`Agar
`Bentonite
`Carborner (e.g., Carlaopol)
`Catboxyinetliylcellulose
`sodium
`
`I-lyd toxye thyl cellulose
`lrlyclroxypropyl cellulose
`l-lydrox_\-pi'opyl rnethylccllulose
`Kaolin
`Methylcellulose
`Tra ga ca :1 th
`Veegum
`Aspartasne
`Dextrose
`Glycerin
`Mannitol
`Saccharin sodium
`Sorbiiol
`Sucrose
`Magnesium stearate
`Talc
`
`Acacia
`
`Alginic acid
`Carboxymethylcellulose
`sodium
`
`Compressible srigar (e.g., Nu—Tab)
`Ethylccllulose
`Gelatin
`Liquid glucose
`lvicthylcellulose
`ljovidnnc
`
`Pregelatinizcd starch
`Dibaslc calcium phosphate
`Kaolin
`Lactose
`Mannitol
`lvlicrocrystalline cellulose
`Powdered cellulose
`Precipitated calcium carbonate
`Sorbttol
`Starch
`
`cmitiiincti
`
`Table 3.3. Ex;
`
`Tflblet C0t1tf2iqAg
`
`Sugar c0n.'ing.'
`
`Film corrtiiig:
`
`Eizteric coating:
`
`Tablet D:';r*cCf
`Campress:"0iz Exc;
`Tlibler Disirztegmn;
`
`Tablet Giidmrt
`
`Tablet Lubricant
`
`Tablet/Cnpszile
`Opaqumzf
`Tlzblet Polz'sht'7igAge;-
`
`Tfliiicily Aggiqf
`
`6
`
`

`
`Dosage Form Desig1‘i: Pl'rrri'inricr=ir!icnm1’ F0."l'.‘l‘!.'l[1fl0iJ Coirsideiimoiis
`
`Table 3.3. Examples of Pharmaceutic Ingredients
`Iiigi'edi'cnt Ti/pa
`Definition
`
`Exziiizples
`
`Tablet Coritz'ngAgei-it
`
`Sugar corn‘mg:
`
`Film coating:
`
`Eizteric coating.-
`
`Yhblct Direct
`Conipressioii Excipiem‘
`Tablet Disiiitegmm‘
`
`Used to coat a formed tablet for the purpose of protecting
`against drug decomposition by atmospheric oxygen or
`humidity, to provide a desired release pattern for the
`drug substance after administration, to mask the taste
`or odor of the drug substance, or for aesthetic purposes.
`The coating may be of various types, including
`sugancoating, film coating, or cnteric coating. Sugar
`coating is watevbased and results in a thickened covering
`around a formed tablet. Sugar—coated tablets generally
`start to break up in the stomach. A film coat is a thin
`cover around a formed tablet or bead. Unless it is an
`enteric coat, the film coat will dissolve in the stomach.
`An enteriocoatccl tablet or bead will pass through the
`stomach and break up in the intestines. Some coatings
`that are water—insoluble (eg, ethylcellulose) may be
`used to coat tablets and beads to slow the release of
`drug as they pass through the gastrointestinal tract.
`
`Used in direct compression tablet formulations.
`
`Used in solid dosage forms to promote the disruption of
`the solid mass into smaller particles which are more
`readily dispersed or dissolved.
`
`Tlzblet Glirimit
`
`Tablet Liibricmit
`
`Agents used in tablet and capsule formulations to improve
`the flow properties of the powder mixhire.
`
`Substances used in tablet formulations to reduce friction
`dming tablet compression.
`
`Tablet/Capsule
`Opaqirrmt
`Tablet P0lE5lringAgem‘
`
`Used to render a capsule or a tablet coating opaque. May
`be used alone or in combination with a colorant.
`Used to impart an attractive sheen to coated tablets.
`
`lbriicity Agent
`
`Used to render a solution similar in osmotic dextrose
`characteristics to physiologic fluids. Ophthalmic,
`parenteral, and irrigation fluids are examples of
`preparadons in which tonicity is a consideration.
`
`Liquid glucose
`Sucrose
`
`I-Iydroxyethyl cellulose
`Hyclroxypropyl cellulose
`Hyclroxypropyl methylcellulose
`Methylccllulose
`(e.g., Methocel)
`Ethylcellulose (e.g., Ethocel)
`Cellulose acetate phthalate
`Shellac (35% in alcohol,
`(‘pharmaceutical glaze")
`Dibasic calcium phosphate
`(e.g., Ditabj
`Alginic acid
`Carboxyinethylcellulose
`calcium
`
`Microcrystalline cellulose
`(e.g., Avicel)
`Polacrilin potassium
`(e.g., Amberlite)
`Sodium alginate
`Sodium starch glycollate
`Starch
`Colloidal silica
`Cornstarch
`Talc
`Calcium stearate
`Magnesium stearate
`Mineral oil
`Stearic acid
`Zinc stearate
`Titanium dioxide
`
`Camau ba wax
`White wax
`Sodium chloride
`
`confliiued
`
`L‘.\'miiplr.
`
`lcohol
`stcrs‘ wax
`
`rystallinc wax
`l
`
`alcohol
`
`ylene glycols (mixtures)
`konium chloricle
`
`n lauryl sulfate
`in monopalmitate
`
`iitc
`
`ner (cg, Carbopoll
`qrmcthvlcellulose
`um
`
`xyethyl cellulose
`xypropyl cellulose
`xyi_1i'opyl mctliylcellulosc
`
`lcell u lose
`anth
`
`itol
`nrin sodium
`
`ixymetl1ylCtTllLIlL)SC
`ium
`
`nressiblc sugar (e.g., l\lu--Tab)
`rellulose
`in
`
`fl glucose
`ylccllulosc
`one
`latinizccl starch
`iic calcium phosphate
`o
`iitol
`
`ns
`
`iciystallinc cellulose
`cred cellulose
`aitatcd calcium carbonate
`
`h
`
`coiitr'm:L’il
`
`7
`
`

`
`92
`
`Dosage Farm Dcsigii:
`
`Pimriimwiitir imri Feriiiiiliitizm Criiisi'dcniti:ms
`
`Table 3.3. Examples of Pharmaceutic Ingredients
`lrigrciiicnt T_lipt*
`D(‘_i"iHifiOJ'i
`drug sul::stance.They are used in
`c
`\/ciiiclc
`A carrying agent for a
`Osage for oral and
`torniulating a variety of liquid cl
`al administration. Generally, oral liquids are
`parenter
`or hydro-alcoholic
`aqueous preparations (as syrups)
`. Parenteral solutions for intravenous use are
`[as elixirs)
`ar injections may be
`aqueous, whereas intramusctil
`aqueous or oleaginousr
`
`Fliizinrcd/Swiwtciicri
`
`Oit‘rT_QilIIW5
`
`\/iscesiti; liicrciisine
`/'ig{’i1l
`
`ie consistencv of a preparation to render
`Used to change tl
`it more resistant to flow.
`er sedimentation, in ophthalmic
`Used in suspensions to clot
`ct i;imc (e g., inetliylcellulnse),
`solutions to enhance cont-a
`to thicken topical creams, etc,
`
`Eriiiiiplcs
`
`;\cacia S}-‘i up
`f\l'U|1Tfl[lL' Syrtip
`Aromatic Elixir
`Cherry S} TU p
`Cocoa Syrrip
`Orange Syrti p
`Syrup
`Corn Oil
`l\*lincral Oil
`Peanut Oil
`Sesame Uil
`hacl'erios|.atic Sodium
`chloricle iniection
`liacteriostatic Water’ tor
`lniection
`,'\le,inic acid
`Bentnnite
`Carbnnier
`Cai‘boxymctln=|cellLilose
`Socliuni
`h‘lClli\*lCL‘lltIlt7Ht‘
`Povidone
`Socliuin algiiiate
`Tragacanth
`
`are discussed in Chapter 7, Capsules and Tablets
`and Chapter 8, Modi|iied—l{elease Dosage Forms
`and Drug Delivery Eiysteiiis.
`
`,Hfl11dbO0l( of
`Plmrnmceutical Excipimts
`The reader should also be aware of the I-laiiiilinulr
`of Plmrnmccirtinil E.\'cipiciits (10), which presents
`200 excipicnts used in pl‘iar~
`monographs on over
`ation.
`lncludecl
`in
`maceutical dosage form prepar
`each monograph is such information as: nonpro~
`]J1‘l@l€|1‘_\_~', chemical, and commercial names; enipiri~
`cal and chemical formulas and molecular weight;
`pharinaceutic specifications and chemical and phys-
`ical properties; incompatibilities and interactions
`with other excipients and clrug substances; i‘egrila—
`tory status; and applications in pharmaceutic for»
`mulation or technology.
`
`Hm'monizati0n of Staruicirds
`rently-i
`in the internae
`There is great interest cur
`tiona
`l”harnionizatinn" ol‘ standards applicable to
`pharmaceutical
`excipients. This
`is due to the
`tact that
`the pharmaceutical
`industry is multina-
`tional, with major companies having facilities in
`more than a single coriiitni, with products sold in
`markets worldwide, and with regulatory approval
`for these prod Licls required in each inclividual coun-
`try. Standards for each drug substance and excipient
`used in pharmaceuticals are contained in pharrna—
`copeias~or, tor new agents, in an application tor
`reg1ilat'oiy approval by the FDA or another n ation's
`governing authority. The four pharmacopcias with
`the largest international use are the l.liiitci1‘ States
`Plummicripciir/Niitiuiml Fnniiiilrii‘_i,- (LJSl’.lNf), Brilisli
`l’lim'iiincnpciii (B13), Eurripcim Plmi‘iiiirrnpcin (l:iF’), and
`the ]irpimr'sc i”lii7i'iimcnpi‘ia tjl’). Uniform standards
`for exci
`picnts in these and other pharmacopeias
`
`would facil
`
`marketing (
`ternationall
`
`pharmaceu-
`harmonizat
`Ccirporate re
`fOIy authori
`A few or
`pharmaceui
`flavors, colt
`here.
`
`App
`
`Although
`unpalatable
`modern pha
`to the patier
`tractive to t]
`ties, which ,
`have Virtual"
`
`many patier
`agreeable oc
`tiveness of tc
`to acquire th
`of acciclenta
`
`among child
`tic appca1_
`There is st
`and the ode
`preparation t
`have its mos
`
`and taken pr-
`bination of F1
`ceutical prod
`
`Flavoring a;
`The flavciri
`
`ily to liquid (1.
`tration. The 1
`roof of the in
`receptor cells
`with moleculu
`positive or Tic
`liquid form ol
`rect Contact vi
`
`Flavoring age,
`able taste of
`Drugs placec
`tablets may b
`Contact betwe
`
`Containing dr-
`may remain 1
`them with wa
`sirable drug I
`
`8
`
`

`
`Res
`
`rnd
`ech
`
`eri(cid:173)
`and
`
`~ter-
`993;
`
`cas-
`
`: raw
`sizer
`
`arikh
`a ti on
`-150.
`
`CAPSULES AND TABLETS
`
`Chapter at a Glance
`
`Capsules
`Hard Gelatin Capsules
`The Manufacture of Hard Gelatin Capsule
`Shells
`Capsule Sizes
`Preparation of Filled Hard Gelatin Capsules
`Developing the Formulation and Selection of
`Capsule Size
`Filling Hard Capsule Shells
`Capsule Sealing
`Cleaning and Polishing Capsules
`Soft Gelatin Capsules
`Preparation of Soft Gelatin Capsules
`Utilization of Soft Gelatin Capsules
`Compendia[ Requirements for Capsules
`Added Subs tances
`Containers for Dispensing Capsules
`Disintegration Test for Capsules
`Dissolution Test for Capsules
`Weight Variation
`Content Uniformity
`Content Labeling Requirement
`Stability Testing
`Moisture Permeation Test
`Official and Commercially Available Capsules
`Inspecting, Counting, Packaging, and Stor(cid:173)
`ing Capsules
`Tablets
`Types of Tablets
`Compressed Tablets (C.T.)
`Multiple Compressed Tablets (M.C.T.)
`Sugar-Coated Tablets (S.C.T.)
`Film Coated Tablets (F.C.T.)
`Gelatin-Coated Tablets
`Enteric-Coated Tablets (E.C.T.)
`Buccal or SubLingual Tablets
`Chewable Tablets
`
`Effervescent Tablets
`Molded Tablets (M.T.)
`Tablet Triturates (T.T.)
`Hypodermic Tablets (H.T.)
`Dispensing Tablets (D.T.)
`Inunediate Release Tablets (1.R.)
`Instant Disintegrating/Dissolving Tablets
`Extended Release Tablets (E.R.)
`Vaginal Tablets
`Compressed Tablets
`Quality Standards and Compendia I Require-
`ments
`Compressed Tablet Manufacture
`Wet Granulation
`All-in-One Granulation Methods
`Dry Granulation
`Tableting of Granulation
`Direct Compression Tableting
`Tablet Dedusting
`Chewable Tablets
`Molded Tablets
`Tablet Coating
`Sugarcoating Tablets
`Film-coating Tablets
`Enteric Coating
`Fluid-Bed or Air Suspension Coating
`Compression Coating
`Impact of Manufacturing Changes 011 Solid
`Dosage Forms
`Official and Commercially Available
`Tablets
`Packaging and Storing Tablets
`Oral Administration. of Sol id Dosage Forms
`Other Solid Dosage Forms for
`Oral Administration
`Lozenges
`Pi Us
`
`179
`
`9
`
`

`
`180
`
`Capsules and Tablets
`
`WHEN MEDICATIONS are to be administered orally
`to adults, capsules and tablets usually are preferred
`because they are conveniently carried, readily iden(cid:173)
`tified, and easily taken.
`Consider the convenience of a patient 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(cid:173)
`suring devices, which sometimes may be inconve(cid:173)
`nient and may result in less than accurate 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(cid:173)
`uct code number commonly embossed or imprinted
`on their surface make them readily identified. This
`enhances communications between the patient and
`health care providers, assists patient compliance,
`and fosters safe and effective medication use.
`Capsules and tablets are available for many med(cid:173)
`ications in a variety of dosage strengths thereby
`providing prescribing flexibility to the prescriber
`and accurate individualized 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(cid:173)
`tions as may be desired, or when prescribed, it al(cid:173)
`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 and/or drug-release features
`that would be compromised by altering the tablet's
`physical integrity.
`From a pharmaceutic standpoint, solid dosage
`forms are efficiently and productively manufac(cid:173)
`tured; they are packaged and shipped by manu(cid:173)
`facturers 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(cid:173)
`parts.
`As discussed later in this chapter, empty hard
`gelatin capsules are often used by the pharmacist in
`the extemporaneous compounding of prescriptions.
`On occasion, a p harmacist may use commercially
`available capsules and tablets as the source of a
`medicinal agent when it is not otherwise available.
`In these instances, the pharmacist must take into
`account any excipients that are present in the com(cid:173)
`mercial product to ensure compatibility with the
`other ingredients 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(cid:173)
`inal agents and/or inert substances are enclosed
`within a small shell of gelatin. Gelatin capsule shells
`may be hard or soft depending on their composition.
`The vast majority of filled capsules are intended to
`be swallowed whole by the patient for the benefit of
`the medication contained therein. However, it is not
`unusual practice in hospitals and extended care fa(cid:173)
`cilities for a caregiver to open capsules or cnish
`tablets to mix with food or drink, especially for chil(cid:173)
`dren or other patients unable to swallow solid
`dosage forms. This should be done only with the
`concurrence of the pharmacist since the dnig release
`characteristics of certain dosage forms could be al(cid:173)
`tered and adversely affect the patient's welfare.
`Dosage forms that must be left intact include: en(cid:173)
`teric coated tablets, designed to pass through the
`stomach for drug release and absorption in the in(cid:173)
`testine; extended-release dosage forms, designed to
`provide prolonged release of the medication; and
`sublingual or buccal tablets, formulated to dissolve
`under the tongue or in the oral cavity (1). In in(cid:173)
`stances in which a patient is unable to swallow an
`intact solid dosage fom1, an alternative product, such
`as a chewable tablet, instant dissolving tablet, oral
`liquid, suppository or injection may be employed.
`
`Hard Gelatin Capsules
`Hard gelatin capsule shells are used to manufac(cid:173)
`ture most of the commercially available medicated
`capsules. They are also commonly employed in clin(cid:173)
`ical drug trials, to compare the effects of an
`investigational dnig to another drug product or
`placebo. Hard gelatin capsules also are used by the
`community pharmacist in the extemporaneous com(cid:173)
`pow1ding of prescriptions. The empty capsule shells
`are made from a mixture of gelatin, sugar and water.
`As such, they are clear, colorless, and essentially
`tasteless. They may be colored with various FD&C
`and D&C dyes and may be made opaque by adding
`agents such as titaniwn dioxide. Most commercially
`available medicated capsules contain combinations
`of colorants and opaquants to make them distinctive,
`many with caps and bodies of different colors.
`Gelatin is obtained by the partial 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.
`
`Fig. 7.1 Pork i
`manufacture of
`Beecham.)
`
`Normally, ha
`13 and 16% c
`an enviromm
`ture is absor
`become distc
`enviromnent
`ture normall}
`and the caps
`when handle
`hard gelatin 1
`excess humic
`Because II
`capsules and
`within, man)
`small packej
`against the
`The