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
`
`Complex Innovations 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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`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)
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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
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`99 00 0102
`12345678910
`
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`

`
`Dosage Form Design: Pharmaceutic and Fommirrtion Crmszdcrations
`
`8'7
`
`limits the time during which the product may be
`dispensed by the pharmacist or used by the patient.
`Prescriptions requiring extemporaneous coin-
`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 (7).
`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 information 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 extemporaneous
`compounded formulations state that, in the ab-
`sence of stability information that is applicable to a
`specific drug and preparation, the following guide-
`lines can be utilized: nonaqueous liquids and solid
`formulations where the manufactured drug is the
`source of the active ingredient-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-
`mulations—a beyond-use date of the intended du-
`
`ration of therapy or 30 days, whichever is 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 and sweeteners are used
`to make the product more palatable, colorants
`are added to enhance product appeal, preser'va-
`fives 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, diliients or fillers are commonly added to
`increase the bulk of the formulation, binders to
`cause the adhesion of the powdered drug and
`pharmaceutic substances, mititrdherciits or lubri-
`cants 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 due to the pharrnaceutic
`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
`pharrnaceutic ingredients, with examples of some
`of the official and commercial agents currently used.
`Additional discussion of many of the pharrnaceutic
`ingredients may be found in the chapters where
`they are most relevant; for example, pharrnaceutic
`materials used in tablet and capsule formulations
`
`r, appearance,
`ution.
`appearance,
`‘edispersibility
`)lutions).
`h, color, odor,
`
`strength, de-
`umber of me-
`size distribu-
`
`rarance, odor,
`weight dis-
`ray pattern.
`solutions, and
`
`,, appearance,
`ersibility (sus-
`jgenicity, and
`
`, appearance,
`tter, pl-L vol-
`1 plastic con-
`‘ogenicity, and
`
`ange, appear-
`
`patient con-
`at bear an ap-
`identifies the
`
`)8 expected to
`ble under the
`
`xpiration date
`
`3
`
`

`
`88
`
`Drisiigr Ftiriii Drsigii: l)lit7i'lll1iL‘t’!FFlt‘t'lHt'lFOF‘fli‘t'll1ifl[)Fl CtJlT5l{'lt‘J‘i‘Ti'i‘(lJlF
`
`Table 3.3. Examples of Pharmaceutic Ingredients
`Dijfiiiitioii
`liigreiiiriit llfpt’
`rtciiiifitiiiig Agent
`
`Used In liquid piepai'at'ioiis to provide acidic medium tor
`prciduct stability
`
`/'\ll<iiliiii:iiig/lgeiit
`
`Used in liquid preparations to pi‘rJv'icle alkaline iiieditim
`for product stability.
`
`Ailsni’liciit
`
`Aernsril Pi-nprlliiiit
`
`An agent Capable of holding other iiiolecules onto its
`surface by physical or chemical (Cl'lCtT|lHUT]JtlUl1) tiieaiis.
`n
`l-
`L
`Awent res ‘tOI15llJl€
`for develo iii
`the _ressure within an
`aerosol container and expelling the product when the
`valve is opeiied.
`
`Air Disiiliiceiiieiit
`
`_
`c
`Aiitifiiiiqiil P)'t’5t’f't7l'!l‘l?.)t’
`
`Ageiil ernployed to displace air iii a hermetically
`sealed container to enhance product Stability.
`Used in liquid and SE1‘fll-SOllCl preparatitins to prevent the
`growth of lungi.Tlie effectiveiiess of the parabeiis is
`LlSL1i‘tll_V eiihaiiced when they are used in miiihiiiation.
`
`Aiitiiiiicrolriiil
`Pi‘csi*rtIiifr'm*
`
`Used in liquid and ~'.emi—t:0lid preparations tn prevent the
`growth of microorgaiiisiiis.
`
`/liiIin.i'iri'iiiit
`
`Acrent that inliibits oxidation and tl1L|F.lS used to irevent
`D
`_
`l
`l
`l
`,
`the detei'i:ii'atioii oi vie iaraticins ‘by the iixiclative
`iiiiicess.
`
`Biiffri mg /"||Qt‘lli‘
`
`Used to resist change in pH upon dilution or addition of
`acid or alkali. imtassiiim iiietaplinsapliate
`
`E.\iiirriilrs
`
`Citric acid
`Acetic acid
`Fuiiiaric acid
`ll_vdmchloi‘ic acid
`Nitric acid
`Arnnicinia sc,iluti0n
`1\I‘lWiTlUl'll'L|i“ Cfll'lJOl7r.llL‘
`Diethannilaniine
`Nlminethanolaniine
`Potassium livcli'0:<ide
`Sodium Litirate
`Sodittiii earl_i«_iiiate
`Scidiuiii l1}t'l!'O>{lL'lL‘
`Trietliaiiiilaiiiine
`Ti-nlamine
`Powdered cellulose
`.'\cEivated Cl'1Clt‘C0‘Jl
`Carbon dioxicle
`Dichlcimditltitirmiietliane
`Diclil:iroteti'a‘E|uuroetliaiie
`'ll‘iehlommoiinfltitimtiietliaiie
`Nitrogen
`Carbon dioxide
`Bu tylpam bun
`Ell'\_VlpDI'£tl3L‘iW
`Metliylparabeii
`Benzoic acid
`Pia pylpai alaen
`Sodium l”\en'/,0ate
`Sodium pi npiunate
`l3en7all<c'iniu1ii chloride
`BL‘I“IZ.L'.‘lZl‘lDl‘tittt11 chlnride
`Beii'/.yl alcnlicil
`Cetylp_vi'icliiiiuiii cliloride
`Cl1lUl'OlJLIlfll‘Ii)l
`Phenol
`l-‘lieii_\_-'letliyi tilcnlitil
`l’lieii\/liiiet'cLii'iC nitrate
`Tliiiiie
`"al
`A
`rbir acid
`H\SC(1tb)‘l paliiiitate
`Butylated lt\,-'Ll['LTtX_\"L‘t[1l!-iUlC
`Btitylated l1_ydi‘0\\ tnltienc
`Hypuplitipliui'i'ii.I>: acid
`Mniititliiugl_Vcei‘0l
`l’i':‘)p_vl gallate
`Sodium a5cm'l:iatC
`Sndiuni liiatiltiie
`Sodium lormalclelivde
`Sul!'o.~,_vlate
`Sodium iiietaliisullite
`Potassitiiii pliosiiliate,
`iiioiitibasiic
`Sodium acetate
`Suclitiiii citrate aiili_V«;li'iitis
`and dili_vda'ate
`
`coiitiiiiiuii'
`
`Table 3.3. Examp
`
`_
`Chcln ting Agem
`
`Colomiit
`
`Clrzrifying Agent‘
`Eiiiiilsifyii1gAggm
`
`Eiicizpsuln ring Agent
`
`l:.l'LIU07‘£IJ1f
`
`Himiectaiit‘
`
`Lmigntiiig Agent
`
`Ofn tmeiii Base
`
`Pizisiicizer
`
`Solvent
`
`4
`
`

`
`(aim;
`E.wruplr*5;ej
`acid
`: acid
`tic acid
`ochloiic acid
`: acid
`“mm _c.olution
`mnium carbomllt‘
`mnolaminc
`oetlianolaminc
`isjum hyclrnxidc
`um horzltt‘
`um carbonate
`LLll‘ll h\_-‘cl roxirlc
`:h:inUlaWlHL‘
`amine
`adored cellulusc
`ivated Charcoal
`‘hon dioxide
`hjomdilluorometliflllfi
`hlorotetrafluoroethM10
`3hlmolimnoFluni‘0!‘n€tl1EmC
`:togcn
`1-hon dioxide
`iyiparabcn
`1ylparal:>cn
`311).-[psi rabcn
`inzoic acid
`Om-1p;ii'ribe1i
`_.CliU[]‘[ benzoatc
`1L‘lll|lT| plvplvllfllt‘
`an‘/_alkoniLnn chlo1‘ld0
`emctlionium chl0!‘iCl0
`Ojmyj alcohol
`jcwl
`riclinium chl01‘lLl@
`ililhi r hutanol
`‘henol
`:hCm_ijgtli\'l. alcohol
`-‘hemjlmeI'curic nitratfl
`i‘hime1'osal
`’\scoi'hic acid
`.\_,»Cmby-1 palmitatc
`Butylated ll_\’Cll'Ll,‘{\'UlllEt!lC
`Brilylatecl hydi'o.\[\_-itoliiciic
`j_j\,Pj ,P]mplio1‘mis acid
`Ivlonuthloglvcctol
`pmpyl gnllate
`Sodium ascorbfllt‘
`Sodium bisiiltitc
`Sodium iiwinaliiehydu
`Silltoxylalk‘
`_
`Sodiuin metabisuliite
`Potassiiiiii pl“)-“-l‘ll”m'
`mnnobaslt
`Sodium acct‘-ILU
`Sodium citrate :II1ll,V"l"Ol‘lS
`and dil1_vclr£Il'E
`cuuiiliiiecl
`
`Dosage Form Design: Pharimzceiitic and Fommlrition Considemfions
`
`Table 3.3. Examples of Pharmaceutic Ingredients
`l71g7‘€i'llL’i1ll:jp€
`Definition
`Clzelrttingflgertt
`
`Substance that forms stable, water soluble complexes
`(chelates) with metals. Chelating agents are used in some
`liquid pharrnaceuiicals as stabilizers to complex heavy
`metals which might promote instability. In such use they
`are also called sequestering agents.
`Used to impart color to liquid and solid (e.g., tablets and
`capsules) pharmaceutical preparations.
`
`Clarifi/ii1gAgci1t
`Eiiiiilfitflflrtg/lgfiif
`
`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
`is l1TllT|lSCll3l6.TllE‘ end product may be a liquid emulsion
`or semisolid emulsion (e.g., a cream).
`
`Enmpsii lntfiig Agent
`
`Flnvormzt
`
`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.
`
`Humectrmt
`
`Lcvigrtfing Agent
`
`Oiiitme1itBnsc
`
`Plasticfzer
`
`Solvent
`
`Used to prevent the drying out of preparati0ns—particularly
`ointments and crearnsfidue 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.
`
`Semisolid 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
`Ecletic acid
`Edetate disodium
`
`FD&-C Red No. 3
`FD&C Red No. 20
`FD &rCYz-llow No. 6
`FD&C Blue NO. 2
`D&C Green No.5
`D&C Orange No.5
`D&C Red No, 8
`Caramel
`Ferric oxide, red
`Bentonite
`Acacia
`Cetomacrogol
`Cetyl alcohol
`Glyceryl nionostearate
`Sorbitan rnonooleate
`Polyoxyethylene 50 stearate
`Gelatin
`Cellulose acetate phthalate
`Anise oil
`Cinnamon oil
`Cocoa
`Menthol
`Orange oil
`Peppermint oil
`Vanillin
`Glycerin
`Propylene glycol
`Sorbitol
`Mineral oil
`Glycerin
`
`Lanolin
`Hydrophilic ointment
`Polyethylene glycol ointment
`Petrolatum
`Hyclrophilic petrolaturn
`White ointment
`Yellow ointment
`Rose water ointment
`Diethyl phthalate
`Glycerin
`Alcohol
`Corn Oil
`Cottonseed oil
`Glycerin
`lsopropyl alcohol
`Mineral oil
`Oleic acid
`Peanut oil
`Piuifiecl water
`Water for injection
`Sterile water for injection
`Sterile water for irrigation
`continued
`
`5
`
`

`
`9U
`
`Dosage Form L7csfgrr: Plrimmrccutzt mid l"immrlm‘ioii Cm1siri'er'rii'imrs
`
`Table 3.3. Examples of Pharmaceutic Ingredients
`li‘igf‘Erll(’f1l’T_l[;7[’
`Drjfmifioiz
`Used to increase the thickness or hardness of a
`St[ffi*:iiii_=,7 /-lgerrt
`pharmaceutical preparation, usually an ointment.
`
`Siippnsitmjif Base
`
`Srrijfirctmrt
`(siiijliw cictivc rigmt)
`
`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.
`
`Siispmidiirg Agmt
`
`A viscosity increasing agent used to reduce the rate of
`sedimentation of (dmg) particles dispersed throughout
`a vehicle in which they are not soluble.The resultant
`suspensions may be forinulated for use orally,
`parenterally, ophthalmically, topically, or by other routes.
`
`Sthcctcniii_q /\_ee'ni‘
`
`Used to impart sweetness to a preparation.
`
`Tiililcf Azrtimiliemils
`
`Tiilalct Bmrlers
`
`Agents that prevent the sticking of tablet forrnulation
`ingredients to punches and dies in a tableting machine
`during production.
`Substances used to cause adhesion of powder particles in
`tahlct Le,-ranulations.
`
`l'nbli=tnm1‘Ciipsiilc
`Dilucut
`
`lnert substances used as fillers to create the desired bulk,
`Flow properties, and compression characteristics in the
`preparation of tablets and capsules.
`
`E.\umplc5
`
`Cetyl alcohol
`Cetyl esters wax
`t\/Iicrocrystalline wax
`Paraffin
`Ste-aiyl alcohol
`White wax
`Yellow wax
`Cocoa butter
`
`Polyethylene glycols (inixturesl
`Benzalkoniuin chloride
`Nono>.'ynol '10
`Oxtoxynol 9
`Polysoi bate 80
`Sodium lauiyl sulfate
`Sorbitan monopalmitate
`Agar
`Bentonite
`Carbomer (e.g., Carbepol)
`Carlooxyrnethylcellulosc
`sodium
`
`I-lydroxycthyl cellulose
`l-lydroxypropyl cellulose
`Hydi'ox}api'c)pyl n1cth_ylccllulose
`Kaolin
`Methylcellulose
`Tragaca n th
`Veegum
`Aspartame
`Dextrose
`Glycerin
`Mannitol
`Saccharin sodium
`Sorbitol
`Suci use
`Magnesium stcarate
`Talc
`
`Acacia
`
`/’\lginic acid
`Carboxymetl‘iyl.cellulose
`sodium
`
`Coniprcssilale sugar (e.g., Nu—Tab)
`Ethylccllulosc
`Gelatin
`Liquid glucose
`Mcthylccllulose
`Povidone
`
`Pregelatini7.ed starch
`Dihasic calcium phosphate
`Katalin
`Lactose
`Man nitol
`l\xlicrociystalline cellulose
`Pow«;|ered cellulose
`Precipitated calcium carbonate
`Soibitol
`Starch
`
`cniitiiiimi
`
`Table 3.3. Ex;
`
`Tablet Coating: Ag
`
`Sugar coating."
`
`Film coating:
`
`Emfewi: mating:
`
`Tablet Direct
`Comprcssi'mz Exc;
`7l‘il71€!Disi11teg1'n;gf
`
`Tablet Glidmrt
`
`Tablet Lubricimt
`
`Thblef/Capsyfg
`Opaquam
`T:ib1etPoIr'shirrgAge;
`
`Trmiciry Aggmc
`
`6
`
`

`
`Dosage Form Design: Plmrmacmtic mm‘ Formiiiafiaii Ctnisidenitioris
`
`Table 3.3. Examples of Pharrnaceutic Ingredients
`li1gi‘ediciitT_i;pc
`Definition
`
`Exairipies
`
`Tablet CaatingAgent
`
`Sugar coating.'
`
`Film coating:
`
`Enteric coating.-
`
`Tabiei Direct
`Compression Excipieiif
`Tablet Disiiitegmnt
`
`Used to coat a formed tablet for the purpose of protecting
`against dmg 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
`srigarcoating, film coating, or enteric coating. Sugar
`coating is water—based 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 enteriocoatcd tablet or bead will pass through the
`stomach and break up in the intestines. Some coatings
`that are water—insoluble (e.g., 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.
`
`Tablet Gliriimt
`
`Tablet Lubricant
`
`Agents used in tablet and capsule formulations to improve
`the flow properties of the powder mixture.
`
`Substances used in tablet formulations to reduce friction
`dining tablet compression.
`
`Tablet/Capsule
`Opaqiiant
`Tablet Poiisliingfligem‘
`
`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.
`
`Toiiicity Agent
`
`Used to render a solution si.milar in osmotic dextrose
`characteristics to physiologic fluids. Ophthalmic,
`parenteral, and irrigation fluids are examples of
`preparations in which tonicity is a consideration.
`
`Liquid glucose
`Sucrose
`
`l-lydroxyethyl cellulose
`Hydroxypropyl cellulose
`Hyclroxypropyl methylcellulose
`Methylccllulose
`(e.g., Methocel)
`Ethylcellulose (e.g., Ethocel)
`Cellulose acetate phthalate
`Shellac (35% in alcohol,
`(‘pliarmaceutical glaze"
`Dibasic calcium phosphate
`(e.g,, Ditab)
`Alginic acid
`Carbopgnnethylcellulose
`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
`
`Carnau ba wax
`White wax
`Sodium chloride
`
`contiiiaeri
`
`.\'nmpiws
`
`lcoliol
`sters wax
`
`rystallinc wax
`l
`
`alcohol
`
`ylene glycols (mixtuI‘L‘S)
`i<onium chloride
`
`“bate 80
`n lauryl sulfate
`in monopalmitate
`
`‘.g., Carbopol)
`9.1-ncthylcellulose
`LllTl
`
`methyl cellulose
`xypropyl cellulose
`xypropyl metliylcellulnst‘
`
`lcellulose
`
`esium stearate
`
`1
`c acid
`ixymethylcellulose
`ium
`
`wessible sugar (e.g., Nu ~Tab)
`relluloso
`in
`i glucose
`ylccllnilosc
`one
`latinized starcli
`tic calcium phosphate
`e
`iitol
`iciystallinc cellulose
`cred cellulose
`Jitated calcium carbonatk‘
`
`ns
`
`coiitiiiiivii
`
`7
`
`

`
`Dosage Form Dcsigii: i’lmriiiri(critir mid Fnmiiiiii
`
`titm Ctwsiiicmfioizs
`
`Table 3.3. Examples of Pharmaceutic Ingredients
`lflg'i“£’tl.l(-‘iii Ti/pt’
`Dcjiiiitioii
`agent for a drug substance.They are used in
`i/ulziclr
`A carnr-ing
`liquid dosage for oral and
`lorniulating a variety of
`i administration. Generally, oral liquids are
`parentera
`or lrvdioalcoholic
`aqueous preparations (as syrups)
`. Parenteral solutions for intravenous Lise are
`(as elixlrs)
`ctions may be
`aqueous, whereas intramuscular inie
`aqueous or oieaginous,
`
`Flrivmcd/Sttti'ctcut‘47'
`
`Oitneiiiivirs
`
`ViSL‘ilSll’_l/ lJifl'L‘tib‘liif.{
`Agmi’
`
`Used to change t
`he consistency of a preparation to render
`it more resistant to flow.
`sedimentation, in ophthalmic
`Used in suspensimls to deter
`ct time (e.g., methylcellulnse),
`solutions to enhance conta
`to thicken topical creams, etc,
`
`[\CElL‘ld S}-‘rup
`:‘\i'oIna tic Sytiip
`Aromatic ‘lixir
`Clicriy '¥\-rup
`Cocoa Syrup
`Orange S_\-‘cup
`S}.-"l'Llp
`Corn Oil
`iviineral Oil
`Peanut‘ Oil
`Sesame Oil
`Eacl'ci'iostatic Socllum
`chlni ide injection
`l'%actci'iostatic Water tor
`injection
`Alginic acid
`Bentonite
`Carhnmcr
`Cai‘box_\_'rnctlr\_ lcellulose
`Sodium
`l\‘icthvicelltiliisi*
`i-‘oviclone
`Sodium aleinatc
`'li‘ag,acan th
`
`are discussed in Chapter 7, Capsules and Tablets
`and Chapter 8, M0di|"ied—1'{clease Dosage Forms
`and Drug Delivery Systems.
`
`Hmidboolc of
`Plmrimlcezitical Excipients
`
`The reader should also be aware of the H[TIlr'li70(Jl\
`of i’litirrm7ccirticr7i EXL‘lpit‘iliS (10), which presents
`monographs on over 200 excipients used in phat»
`maceutical dosage Form preparation. Included in
`each monograph is such information as nonpro~
`prietani, chemical, and commercial name_, empiri—
`cal and chemical formulas and molecular weight;
`pharmaceu tic specifications and chemical and phys—
`ical properties; incompatibilities and interactions
`with other excipients and drug substances i‘egula~
`tony status; and applications in pharmacet
`ic tor»
`'|'il.l.llaii0'll U1" it‘Cl‘tll0lOg'}’.
`
`Hariironizcition of Stamlm'ds
`
`There is great interest currently in the interna-
`n’’ of standards applicable to
`tional "harmonizatin
`due to the
`is
`pharmaceutical
`excipieiits. This
`fact that the pharmaceutical
`indtistiy is multina-
`tional, with major companies having facilities in
`more than a single country, with products sold in
`markets worldwicle, and with I'e_e,Lilatoiy approval
`for these products required in each individual court»
`try. Standards for each drug substance and e,\'cipient
`used in pharmaceuticals are contained in pharma—
`c0peias—or, For new agents, in an application for
`at by the FDA or another nations
`i'e_g1ilat‘oi'y approv
`pharmacnpeias with
`governing authority. Th e tout
`the largest international use are the Limited Stm‘t"s
`Plumrritmpciii/Natitinui Fui'iiiirlm‘_i,r (l.JSl-‘IND, l3’riiisli
`i’lim'im1cnpciii till’), Eiirnpctm l]iI(li‘}litTt'{1‘ti[‘lli (l:1P),ancl
`the ]i7,t7imi'st' Piiiinirurapcizi tji"). Uniform standards
`for excipients in these and other pharmacopeias
`
`would tacit
`
`marketing 1
`temationall
`
`pharmaceu‘
`harmonizat
`Corporate re
`tory authori
`A few of
`pharmaceui
`flavors, col:
`here.
`
`App
`
`Although
`unpalatable
`modern pha
`to the patjel
`tractive to t]
`ties, which 5
`have virtual’
`many patter
`agreeable oc
`tiveness of tc
`
`to acquire th
`of accidenta
`
`among child
`tic appeal.
`There is st
`and the ode
`preparation (
`have its mos
`
`and taken pi-
`bination of El
`
`ceutical prod
`
`Flavoring an
`The flavoti
`ily to liquid (1,
`tration. The 1
`root of the in
`
`receptor cells
`with moleculu
`positive or 111
`liquid form oi
`rect Contact vt
`
`flavoring age,
`able taste of
`Drugs placec
`tablets may b
`contact betwe
`
`Containin g 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