DISPENSING OF
`MEDICATION
`
`Formerly HuscI's Pharmaceutical Dispensing
`
`A Manual on the Formulation of Pharmaceutical Products,
`the Dispensing of Prescriptions, and
`The Professional Practice of Pharmacy
`
`EDITOR
`
`ERIC W. MARTIN PhC,B3c,MS,PhD,
`
`Adjunct Pzufesso): of Biomedical Communicefion, Columbia Univermity
`College of Pharmaceutical Sciences; Director of Medical Commlmication,
`Lederrle Lnbmainriea, Division of Amazixmn Cyanamid Company. Formerly
`Editor, Jofimd of
`the American PM Association, Emecufive
`Eclibor, Pfize:’s Spectrum, Eclihm-in-Chief, Remington's Phannaoeutfml
`Sciances; flutbor of TEeIr.mLqu£-.s of Meflimfiorg Hamrds of Medimtiarg and
`some 80 01:116.’ biomedical publications; licensed p in Canada and
`the United States; Founder: and finzt Preaidantlz, Drug Inforniation Aaaocinu
`tion; President, American Medical Wflbem Asaendafion, 19'?0—-1971; Fellow
`AAAS, American Medical Wfibem Aaaudafiom, and Internafianfll Academy
`of Law and Science, etc.
`
`SEVENTH EDITION
`
`211.:-.'.=.«x
`
`
`
`
`
`Amerigen Ex. 1060, p. 1
`Amerigen Ex. 1060, p.
`
`MACK PUBLISHING COMPANY
`
`
`
`1971
`
`

`
`
`
`
`
`©Copyright1971by
`
`MACK PUBLISIIING COMPANY
`Easton, Pennsylvania
`
`All Rights Reserved
`This book or any part thereof must
`not be reproduced in any form without the
`written permission of the publisher.
`
`Printed in the United States of America
`
`LibraryofCongrewCatalogCardNumber:
`
`'?{)—165831
`
`I ‘
`
`1'
`
`I ‘
`
`I
`
`Amerigen Ex. 1060, p. 2
`
`

`
`
`
`
`
`
`
`CHAPTER 20
`
`
`Cooling
`
`
`
`Chapter preparation by
`James R. Mccowan, PhD
`Professor of Pharmaceutics
`School of Pharmacy
`University of Arkansas, Medical Center
`Little Rock, Arkasusae 72201
`
`The coating of pills has been performed
`since antiquity, and with the advent of
`tablets and capsules, methods have been
`devised for coating these dosage forms
`also.
`
`Tablets and caps_ules may be coated
`for various reasons:
`to protect the in-
`gredients from light or air to insure
`stability of the medicinal, to mask an
`objectionable taste or odor, or to improve
`the appearance of
`the dosage form.
`Such coatings readily disintegrate or
`dissolve in the stomach and are not in-
`
`the activity of the
`tended to alfect
`medicinal
`following
`administration.
`Coatings used to mask taste and odor or
`to improve appearance are primarily
`used to gain patient acceptance of the
`dosage form.
`-
`A special type of coating, referred to
`as an anteric coating, may be applied to
`tablets and capsules. Coatings of this
`type do not disintegrate in the stomach
`but will disintegrate or dissolve in the
`intestinal fluids. Enteric coating may be
`utilized to control the site of drug re-
`lease,
`to protect
`the activity of the
`medicinal from the gastric pH or
`to
`
`812
`
`prevent nausea or gastric irritation
`caused by the uncoated medicinal.
`Various techniques and coating ma-
`terials may he employed to allow the
`medicinal to be released from the tablet
`
`in such a manner as to give a delayed
`action, a repeat action, or a sustained
`action. Compression coating, or dry
`coating, may be utilized to prevent
`incompatibilities by putting one drug in
`a tablet core and compressing a dry
`coating containing another drug around
`the tablet core. Products of this type are
`frequently referred to as
`a “tablet
`within a tablet.” Repeat action or sus-
`tained action may also be obtained with
`compression coating.
`
`1
`
`Butisol Sodium R.A- (McNeil)
`D.T.D. No. 21
`Sig: One three times a day
`
`30 mg
`
`2
`
`. No. 100
`Pabirin Buffered tablets (Dorsey)
`Sig: Two tablets every four hours
`
`Fig ED-l—S‘to kes’ tz
`
`Sugar Cooling
`
`Probably thi
`coating for
`ta
`scale is a sugar
`sive thin layeri
`are applied to 1
`and tumble in
`
`3
`Q
`
`;
`
`pans are avail:
`shapes but are
`sels, usually m:
`steel and are I
`shaft so thatth 5
`Polishing pane
`pans that have
`they may be
`sugar coating :
`by adding the
`tion or suspens
`
`equipped with
`cold air throu
`
`drying. Exhau
`move moisture
`See Fig 20-1 tc
`Tablets whi
`made with con
`
`a spherical sh
`diflicult to coa
`should be re:
`
`placed in the (
`The usual s
`
`(1) waterprooi
`of moisture in
`
`ing to fill out
`(3) smooth cu
`smooth surfac
`
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`
`
`
`
`
`
`Amerigen Ex. "106 1 p. 3
`Amerigen Ex. 1060, p. 3
`
`

`
`
`
`
`Coating
`
`813
`
`to obtain the desired color, and (5) pol-
`ishing to give the finished product a high
`gloss.
`Waterproofing—Since the vehicle for
`sugar coating is water, most tablets re-
`quire an initial sealing coat to prevent
`moisture from penetrating the tablet and
`destroying the ingredients of the tablet.
`This is accomplished by applying one or
`two coats ocli arsenic-free shellac, cellulose
`derivatives such as ethylcellulose, or sili~
`cones. Waterpmofing materials must be
`applied sparingly since excess material
`may retard disintegration time of the
`coating and even result in an unwanted
`enteric coating.
`Subcoating——As the tablets rotate
`in the coating pan, a heavy syrup usually
`containing acacia and sugar in water is
`added The tablets should tumble freely
`in the pan until they become sticky. A
`dusting powder consisting of starch and
`powdered sugar is then applied and rota-
`tion of the pan is continued until the tab-
`lets have dried. Precipitated chalk, pow-
`dered acacia or talc may also be added to
`the subcoating powder. The process of
`adding the solution and powder is re-
`peated until the edges of the tablets are
`sufficiently covered and rounded.
`SmootI1iI1g—Following subcoating, a
`heavy sugar syrup is added to the tablets
`rotating in the pan. The smoothing
`syrup is added slowly to moisten the
`tablets and warm air is used to hasten
`drying. _A dusting powder may or may
`
`
`
`Abbott
`
`Fig 20-2—Tab'|et coating pans.
`
`H;
`
`.
`Amerigen Ex. 106i), p
`Amerigen Ex. 1060, p. 4
`4i:
`EU:I:.
`lS
`.
`
`Fig 20-1—~Stokes' tablet coating pans.
`
`Sugar Coating
`
`Probably the most commonly used
`coating for
`tablets on a commercial
`scale is a sugar coating in which succes-
`sive thin layers of the coating material
`are applied to the tablets as they rotate
`and tumble in the coating pan. Coating
`pans are available in various sizes and
`shapes but are essentially spherical ves-
`sels, usually made of copper or stainless
`steel and are mounted on the end of a
`
`shaft so that they may be made to rotate.
`Polishing pans frequently are coaiing
`pans that have been lined with canvas, or
`they may be canvas drums- Since the
`sugar coating of tablets is accomplished
`by adding the coating material in solu-
`tion or suspension form, coating pans are
`equipped with air blowers to force hot or
`cold air through the pans to facilitate
`drying. Exhaust ducts are used to re-
`move moisture and dust from the pans.
`See Fig 20-1 to 20-6.
`Tablets which are to be coated are
`
`made with convex surfaces approaching
`a spherical shape since flat tablets are
`difficult to coat. Dust and broken tablets
`should be removed before tablets are
`
`placed in the coating pan.
`The usual stages of coating consist of
`(1) waterproofing to prevent penetration
`of moisture into the tablet, (2) subcoat-
`ing to fill out and build up the tablets,
`(3) smooth coating to produce a hard
`smooth surface, (4) coloring and finishing
`
`

`
`
`
`814
`
`Coating
`
`not be used in conjunction with the
`syrup. A sufficient number of coats are
`applied to give a smooth surface and to
`build the tablets to a specific size.
`CoIoring—To avoid a mottled ap-
`pearanci, color is built up gradually by
`the use of diluted colored
`syrups.
`Colored syrups are made by dissolving
`certified water-soluble dyes in syrup and
`then several difierent dilutions of color
`
`are made by adding plain syrup to the
`colored syrup. Several coats of the light-
`est colored syrups are applied, then sev-
`eral coam of the next dilution are applied.
`The other dilutions are added in order,
`with the undiluted colored syrups being
`applied last. Drying is necessary between
`each coat and it is customary to dry the
`last coat very slowly by manually turn-
`ing the pan every few minutes to prevent
`the tablets from sticking together and to
`promote the slow drying.
`PoIishing—wAi'ter the coloring coats
`have been applied,
`the coated tablets
`are then polished by rotating them in the
`polishing pan with lulnps of wax or with
`‘the addition of a solution of the wax in a
`volatile solvent. See Fig 2041.
`Since in the standard sugar coating
`procedure much time is spent in sealing,
`rounding and smoothing the tablet and
`overcoming the white background during
`the coloring phase, a revised procedure
`has been advanced.‘ An undercoating ad—
`hesive suspension consisting essentially
`
`
`
`8'! Cor
`Fig 2fl—3—Weighing operation and polishing
`room.
`
`
`
`Lily
`Fig 2|]-4»-Tablet coating pans. Polishing pans
`are similar but are lined with canvas.
`
`of acacia, gelatin, sucrose and water is
`mixed with a stock coating formulation
`of dioctyl sodium sulfosuccinate,
`insol—
`uble coloring material, titanium dioxide,
`and syrup. This undercoatin g suspension
`is applied to the rotating tablets and fol-
`lowed by dusting of the tablets With pow-
`dered acacia. The procedure is repeated
`once- The tablets are then sealed with
`one coat of a material such as shellac and '
`
`are then Tnished by the application of
`approximately 25 coats of the stock coat~
`ing formulation diluted with coating
`syrup. The tablets are then polished in
`the usual fashion. With this procedure,
`colored coatings
`can be applied to
`the subcoating and the application of
`smoothing coats is eliminated.
`The process of tablet coating has long
`been recognized as an art dependent
`upon the experience and skill of the per—
`"i
`
`
`
`J States 00110
`Fig2{]~5—Coatingtablets at Wyeth Laboratories.
`
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`
`
`
`
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`
`
`
`...¢....a-...~.3......
`
`Amerigen Ex. 1060,
`Amerigen Ex. 1060, p. 5
`
`
`
`Fig 2!]-fi——Tabl
`the end of the
`from the table
`
`'
`
`sonnel. Hov
`been devise:
`cedures to 1'
`
`to
`formity,
`cycles and
`ables.’- 3
`
`Film Cc-aIi'
`
`A more re
`a soluble fil)
`or films are
`
`ing and smo
`coating tim
`terials may
`solution in
`and waterp
`coating is
`their origin
`original sizu
`with solubl-
`the use of 1
`titanium di
`
`

`
` Coating
`
`Of the materials for film coating, cellu-
`losic high polymers such as sodium car-
`boitymethylcellulose have been used to
`mask taste and odor effectively.‘ A suit-
`able coating can be obtained by the use
`of
`a polyethylene glycol, Carbowax
`6000,‘ and a combination of carboxy-
`methylcellulose and Carbowax 6000 has
`also been utilized to give a_ suitable coat-
`ing.° Film coating employs coating pans,
`such as those used for sugar coating, and
`the tablets are_ tumbled in the pan and
`the solution of the coating material is
`added to the tablets. The solution may
`be poured or sprayed onto the tumbling
`tablets.
`-
`
`Fig 20-6—TabIets are coated over a 16-hour period in theselarge, giohular,_5tain|ess steel pans, At‘
`the end of the process, each tablet has 35 layers which rneasure altogether about 0.025 in. thick
`from the tahIet‘s cent er.
`
`Pfizer
`
`
`
`
`
`sonnel. However, several methods have
`been devised for automated coating pro—
`cedures to improve batch to batch uni~
`formity,
`to give reproducible coating
`cycles and to reduce operator vari-
`ables.*- 3
`
`Film Coating
`
`A more recent type of coating employs
`a soluble film to coat tablets. Thin coats,
`or films are sufficient and since subcoat—
`
`ing and smooth coatings are unnecessary,
`coating time is quite rapid. Coating ma—
`terials may be applied to the tablets as a
`solution in volatile, anhydrous vehicles
`and waterproofing of the tablet prior to
`coating is unnecessary. Tablets retain
`their original shape and essentially the
`original size. The films may be colored
`with soluble dyes or rendered opaque by
`the use‘ of pigments or materials such as
`titanium dioxide.
`
`Compression Couiirig
`Compression coating is also referred
`to as “dry coating” since the coating in
`the form of a fine granulation is com-
`pressed around the tablet by punches.
`
`
`Amerigen Ex. 1060, p. 6
`Amerigen Ex. 1060, p’.
`
`

`
`
`
`-
`
`solubility in acid
`in"alkaline solutir
`contents are somi
`it is advantageo
`coating of such a
`tegration is not er
`alkalinity of the
`siderable evidenc
`nal contents ran
`7.9. To insure the
`tegrate soon afte g
`testine, some re
`enteric coated ta} 5
`
`_
`
`atapHaslowaé
`In addition to ‘-
`‘
`materials to ol
`other materials 1
`plish this purp
`slowly soluble, r
`enzymes in the
`cause the coatir
`
`passes through tl
`When a releas
`
`5
`
`period of time i
`tlon or repeat 2
`be prepared by 11'
`core tablet whic '
`soluble sugar
`I
`medicament
`f0]
`Another method
`obtain a sustai
`coating many SI
`cament with var ‘
`a certain amom
`leased at diiferei
`tinal tract. The
`
`§
`
`.
`
`in these pellets :
`the pellet core I
`form which is sf
`as an initial cos
`
`are generally eil
`or compressed Ill
`
`Dexaroyl Spansul
`Dispense No
`Sig; Take one
`
`Coatings may
`laminated tabl
`structed with :
`medicament arc
`
`persed medicarr
`
`
`
`
`
`__‘__~____)__,___W.~_____'“__;,_._._,_,___,,_._,-__.‘_._.T,_..,_,.,...:........-........_..v_..—.---emu-__
`
`
`
`
`
`
`
`
`
`816
`
`Coating
`
`This method may be utilized when water;
`as used-in the sugar coating operation,
`causes decomposition or degradation of
`the tablet ingredients. Incompatible ma-
`terials may also be combined by placing
`one material in the core tablet, an inert
`material compressed on the core and a
`second coat containing the other incom-
`patible material may be compressed on
`the core and first coat. Repeat action or
`sustained action tablets may be pro-
`duced by coating the core tablet with an
`appropriate material-
`
`Compression coating may be applied
`by feeding previously compressed core
`tablets into the dies of a specially de-
`signed tablet press used as a coating ma-
`chine. Each die has previously received a
`measured amount of the coating ma-
`terial, the core tablet is fed onto this and
`another measured amount of coating ma-
`terial is fed into the die. The tablet is
`then compressed between the punches of
`the press. Compression coating may also
`be produced by coupling two or three tab-
`let presses together so that the first press
`produces the core tablet and transfers it
`to the second press which presses the
`coating material on the tablet. The
`coated tablet may then be transferred to
`a third press for the application of the
`second coating. See Fig 20-7.
`
`Air Suspension
`
`A rapid method of coating drug parti-
`cles of various sizes and shapes has been
`developed by Wurster.7 The process con-
`sists of supporting particles or tablets in
`a vertical column with an upwardly mov-
`ing airstream during which time the
`coating solution is sprayed onto the sus-
`pended particles. The coating chamber
`consists of a vertical column constricted
`_at the bottom and expanded at the top.
`Air velocity in the constricted area is
`suficiently strong so that tablets enter-
`ing this area are propelled upwards. In
`the upper, or expanded area,
`the air
`velocity is greatly decreased so that the
`velocity will not support the tablets and
`they fall to the bottom. of the chamber.
`
`Upgohn
`Fig 29-7--Pressure coater used in the manufac-
`ture cf 3: tablet within a tablet.
`
`This process may be used to apply
`various types of coating materials such
`as suspensions of insoluble materials in
`
`coating solutions as well as fi.lm—type
`coating materials dissolved in volatile-
`solvents. It is not readily adaptable to
`the typical sugar coating. Coating time
`with air suspension is very rapid and
`batch uniformity is readily achieved.
`
`Enieric Coating
`
`Dosage forms such as tablets that are
`to be enteric coated are processed in a
`manner dependent upon the material to
`be used. The general process for tablets
`includes waterproofing the tablet by
`coating with shellac in a coating pan and
`then adding the enteric coating material -
`to the rotating tablets to build up the
`coat. A sugar coating may be applied
`over the enteric coating. Some coating
`materials may be applied by other meth-
`ods such as spraying the coating material
`on the tablets or by air suspension.
`Formerly, materials used for enteric
`coating were selected because of their in-
`
`
`
`
`
`.-Fr-.*.'*-'*—--“'---.-'
`
`
`
`
`
`
`
`
`
`Amerigen Ex. 1060, p. 7
`Amerigen Ex.
`p. 7
`
`

`
`solubility in acid solution and solubility
`in alkaline solution. Since the intestinal
`contents are sometimes acid in reaction,‘
`it is advantageous to have an enteric
`_coating of such a composition that disin-
`tegration is not entirely 'lependent on the
`alkalinity of the intestinal juices. Con-
`siderable evidence indicates that -intesti-
`nal contents range from pH 3.6 to pH
`7.9. To insure that enteric coatings disin—
`te grate soon after reaching the small in-
`testine, some researchers“ believe that
`enteric coated tablets should disintegrate
`at a pH as low as 3.7.
`In addition to the use of pH dependent
`materials to obtain enteric coatings,
`other materials Inay be used to accom-
`plish this purpose because they are
`slowly soluble, undergo degradation by
`enzymes in the intestinal tract, or be-
`cause the coating may _be eroded as it
`passes through the intestinal tract.
`_
`When a release of medicament over a
`
`period of time is desired, sustained ac-
`tion or repeat action medications may
`be prepared by utilizing an enteric coated
`core tablet which is then coated with a
`soluble sugar coating containing the
`medicament
`for an immediate dose.
`Another method of utilizing coatings to
`obtain a sustained action consists of
`coating many small pellets of the medi-
`cament with Varying thicknesses so that
`a certain amount of medicament is re-
`leased at different locations in the intes-
`tinal tract. The medicament contained
`
`in these pellets may either be located in
`the pellet core or may be in a solution
`form which is applied to the pellet core
`as an initial coating. The coated pellets
`are generally either enclosed in capsules
`or compressed into tablets.
`3
`
`Dexamyl Spansules (SKI?)
`Dispense No. 28
`Sig: Take one capsule at breakfast
`
`No. 2
`
`Coatings may also be used to prepare
`laminated tablets,
`ie,
`a
`tablet
`con-
`structed with a coated,
`inner core of
`medicament around which a shell of dis-
`
`persed medicament is added. This type
`
`Coating
`
`817
`
`of tablet is designed to present an im~
`mediate release of the drug from the shell
`and a subsequent release from the core
`as the coating disintegrates or djssolVe3_
`4
`
`Pyribsrizainine Lontabs (Ciba)
`Dispense No. 20 '
`'
`Sig: One tablet a.1n. and at night
`
`150 mg
`
`For further information regarding sus-
`tained action medications, see Chapter
`2'? on Prolonged-Action Medications.
`
`Materials for Enieric Coating
`Scientific journals are a rich source of
`information concerning materials uged
`for the enteric coating of tablets and
`capsules. Many materials have been ob-
`tained from the field of synthetic or de-_
`rived" polymers. The student is advised to
`peruse the literature to advance beyond
`the scope of this text.
`is
`Shellac———'1‘his
`resinous material
`soluble in aqueous solutions whichlare
`alkaline but not
`in those which are
`neutral or acid. An alcoholic solution of
`
`arsenic—free shellac may be sprayed on
`tablets or capsules in a coating pan and
`the solvent evaporated by means of a
`current of
`A mixture of five parts of
`shellac and one part of castor oil dis-
`solved in alcohol has been used-” Arn-
`moniated shellac, as well‘ as combinations
`of shellac with other coating substances,
`gives effective coatings. Shellac is also
`used to waterproof tablets prior to sugar
`coating to prevent moisture in the syrups
`from reacting with the tablet and when
`used for this purpose, care must be exer.
`(zised to avoid forming an enteric coating
`on the tablets.
`
`Cellulose Acetate Phthalate (CAP)
`—-This coating material has been found
`to have considerable merit as an enteric
`coating and is used commercially for this
`purpose- It disintegrates due to.
`the
`hydrolytic effect of intestinal esterases,
`even when the intestinal contents are
`acid.“ It has been "found to withstand
`the action of artificial gastric juice for a
`long period of tinie but will readily disin-
`tegrate in intestinal juice.” Antonides
`
`Amerigen Ex. 1060, p. 8
`
`

`
`
`
`..._...¢-.....-.-......—...-.-.\..,.7...~.on...\.1¢n.»\-g.,9.u...-.--.-we-p~
`
`
`
`
`K"-\-ur......o-_-.....\.:_...._..-..m:_..f.:.._..._.._.q_«m-.»_-'.-o.-_
`
`
`
`818
`
`Coating
`
`and DeKay have reported that CAP
`gives excellent results in all tests for
`enteric properties.”
`Cellulose acetate phthalate is applied.
`to tablets as a solution in volatile organic
`solvents" such as ethylacetate-BA "de-
`natured alcohol solution.” Tablets that
`have been coated with this material may
`be sealed with a coating of wax to i_m-
`prove water irnpermeability. Cellulose
`acetate phthalate when combined with
`polyethylene glycol has also been used as
`a water soluble filrn coating. The use of
`starch and amylose acetate phthalate as
`an entericcoating material has also been
`reported,“
`Lipids—These have been combined
`with other ingredients to give favorable
`enteric coatings One such combination is
`a mixture of myristic acid, hydrogenated
`castor oil, castor oil, cholesterol and
`sodium taurocholate.“ The. mixture is
`dissolved in ethylene dichloride, benzene,
`absolute ethyl alcohol for application.
`Coating mixtures _containing lipids such
`as waxes or hydrogenated oils in com-
`binations with fillers may be_ granulated
`and applied to core tablets by compres-
`sion coating.
`'
`Synthetic Resins--—Resins have been
`applied as enteric coatings on a com-
`nierical basis and in general are applied
`as a solution in volatile solvents Among
`the "resins that have been proposed as in-
`gredients in various coating formulations
`are polyvinyl acetate -phthalate; phenolic
`anhydride, styTene—maleic acid copoly-
`liners, and poly (methylvinyl ether) X
`maleic anhydride.
`
`swelling, are incorporated to bring about
`disintegration in 6-8 hours. ‘7
`A comprehensive compilation of pro-
`cedures
`materials suitable for pro.
`ducing sustained release and timed re-
`lease dosage forms and based on patent,
`literature is available to the student. 18
`
`Exiemporuneous Melhocls
`
`Wlfile the coating of dosage forms such I
`as tablets is a process best performed by
`manufacturing companies, it is possible
`for the pharmacist to coat these dosage
`forms extemporaneously if the pr-ope};
`materials and methods are used.
`Some traditional methods, such as the
`use of phenyl salicylate (salol) or the
`dipping of capsules‘ into formaldehyde
`solution for the extemporaneous enteric
`coating of capsules, have fallen into dis-
`favor because of the unreliability of the
`coatings.
`'
`For a convenient and satisfactory ex-
`temporaneous enteric coating for tablets,
`capsules, or pills, the following process”
`may be used. A mixture composed of n-
`butyl stearate (.45 parts), carnauba wait
`(30 parts), and stearic acid (25 parts), is
`heated on a water bath to 75°C. The
`tablet, pill, or capsule is held at one end
`with tweezers and dipped into the liquid.
`As the object is Withdrawn, the coating
`solidifies rapidly. After the coating of
`each of the capsules, or other dosage
`form, in this manner, the uncoated end.
`is then dipped in the melted mixture to a
`depth that will give an overlap of the
`coating material over
`the previously
`coated end. Two coats are suflicient. In
`
`Approximately
`tion per 25 ca}:
`sules in a 400
`then swirled ur
`and become ta:
`of the coating s
`ing of the bea
`cedure is repes
`been applied.
`tossed onto ga-
`to air dry for
`This techniqut
`withstand imrr
`fluid TS for 3 I
`lated intestine
`hour.
`
`Ammonium Cli
`(Enteric co
`DTD NI
`1 tab ti
`
`Sig:
`
`Aspirin
`M ft enter.
`Dispense
`Sig: One q -
`
`En-seals Sodiuri
`DTD N
`Sig: One ta
`
`'l'e-sling and
`Coated do:
`
`by in vitro an
`disintegratior
`With the pres
`logical availa
`forms, it is 1
`effect of a coa
`
`by both in vi"
`Particularl
`lease coating
`ment among
`the relative
`coating mate
`ment is due '
`materials, ti
`and to the
`used to dete
`
`coatings. Ph
`stomach em]
`
`Materials for Timed Disiniegraiion
`
`Coatings which disintegrate.a:i'ter a
`certain length of time in the gastrointes-
`tinal tract regar_dless of the acidity or
`alkalinity of h the digestive fluids are
`readily utilized for timed release or sus-
`tained action dosage forms. One such
`coating is composed of stearic acid,
`carnauba wax, petrolatum, powdered
`agar,
`pow-dered elm bark. The elrn
`bark and agar, because of their property
`of absorbing moisture with resultant
`
`‘
`
`addition to the use of tweezers, a needle
`may be used to dip capsules or pills into
`the melted mixture, care being taken to
`insure a complete coverage of the capsule
`or pill after the" needle is removed.
`Another extemporaneous method for
`enteric coating of capsules utilizes poly-
`vinyl acetate polymers. 1" The recom—
`mended formula is:
`
`Vinac ASB-10 or Gelva 0-3
`Castor Oil
`Acetone
`
`10-12%
`10% 0/”
`so~7s% v/v
`
`,.:¢,r.§3h¢..<.:9..~i4gam!.(.-'-.;¢L...-an:-.—-;—mI.L.v-\.v\:~I..'.w-m£¢r_=:h.-2.
`
`Amerigen Ex. 1060, p. 9
`Amerigen Ex. 1060 9
`
`
`

`
`Approximately 2 ml of the coating solu-
`tion per 25 capsules is added to the cap-
`sules in a 400-600 ml beaker which is
`then swirled until the capsules are coated
`and become tacky. A second 2 ml portion
`of the coating solutiof. is added and swirl-
`ing of the beaker is repeated. The pro-
`cedure is repeated until 8-10 coats have
`been applied. The capsules are then
`tossed onto gauze or a towel and ‘allowed
`to air dry for 8-12" hours or overnight.
`This technique produced capsules which
`withstand immersion in simulated gastric
`fluid TS for 3 hours and dissolve in simu-
`lated intestinal fluid TS in less than 1
`hour.
`
`5
`
`Ammonium Chloride
`(Enteric coated tablets)
`DTD No 30 .
`1 tab tid
`
`Sig:
`
`'6
`
`gr viiss
`
`Aspirin
`M ft enteric coated capsules
`Dispense 25 such capsules
`Sig: One q 4 hours as needed
`
`7
`
`Enseals Sodium Salicylate (Lilly)
`DTD No. 30
`Sig: One tablet two times a day
`
`griiss
`
`grx
`
`Testing and Evaluation
`
`Coated dosage forms may be tested"
`by in vitro and in viva methods for both
`disintegration and dissolution
`rates.
`With the present emphasis on the physio-
`logical availability of drugs from dosage
`forms, it'is necessary to determine the
`effect of a coating on the release of a drug
`by both in vitro and in viva methods.
`Particularly with enteric and timed re-
`lease coatings,
`there is some disagree-
`ment among various investigators as to
`the relative value of different types of
`coating materials. Much of the disagree-'
`ment is due to variations in the coating
`materials,
`the methods of application,
`and to the dissimilarity of techniques
`used to determine the efliciency of the
`coatings. Physiological factors such as
`stomach emptying time and absorptive
`
`Coating
`
`819
`
`sites of the gastrointestinal tract also
`contribute to disagreements in the evalu-
`ati on of enteric coatings.
`To insure batch uniformity in control
`procedures, in. vitro methods may be used
`to determine disintegration and dissolu-
`tion rates and automated methods for
`prolonged determination of dissolution
`rates have been devised“ which may be
`adapted for this purpose.
`- Determination of
`the efficiency of
`coatings by in vitro tests involves the use
`of simulated digestive fluids. An official
`test for plain coated and enteric coated
`tablets is provided in the USP. Plain
`coated tablets are first immersed in water
`for 5 minutes then immersed in simulated
`
`gastric fluid for 30 minutes. If the plain
`coated tablets have not disintegrated fol-
`lowing the exposure to simulated gastric
`fluid they are then immersed in simu-
`lated intestinal fluid. The tablets should
`disintegrate in a total tinle equal to the
`time specified for plain coated tablets in
`the USP monograph plus 30 minutes.
`Enteric coated tablets should show no
`evidence of disintegration or solution
`when subjected to simulated gastric fluid
`for 1 hour. They should, however, disin-
`tegrate when subjected to simulated in—
`testinal fluid for a time equal to 2 hours
`plus the time specified in the oflicial indi-
`vidual monograph for the plain coated
`tablet or, where only an enteric coated
`tablet is recognized, for the time limit
`specified in the monograph.
`Simulated gastric fluid of the USP has
`a pH of about 1.2 and is composed of
`sodium chloride, pepsin, hydrochloric
`acid and distilled water. Simulated in-
`testinal fluid of the USP contains mono-
`basic potassium phosphate, pancreatin,
`distilled water, and 0.2 N sodium hy-
`droxide. It is adjusted to a pH of 7.5.
`The USP also provides an official pro-
`cedure for the determination of dissolu-
`
`tion rates for tablets and capsules. Vari-
`ous methods, similar in nature to the
`USP method, have been devised to mea-
`sure dissolution of drugs from coated tab-
`lets and capsules which in turn permit
`the evaluation of the specific coating ma-
`
`Amerigen Ex. 1060, p. 10
`
`

`
`
`
`820
`
`Coating
`
`terials. In general, the various methods
`have modifications in the dissolution
`
`medium and in the extent and type of
`agitation.
`The i_.t_nportance of in vivo disintegra-
`tion time of
`tablets whether
`sugar -
`coated or- enteric coated, as related to
`the active ingredient has been shown by
`the fact that riboflavin in sugar coated
`tablets requiring two hours for in vitro
`disintegration by the USP test does not
`guarantee that it will be fully physio-
`logically available to all people.”
`Snce barium sulfate is opaque to X-
`rays, it may be used in experimental
`enteric coated products so that the be-
`havior of the product in the gastroin-
`testinal
`tract may be deterrnined by
`roentgenoscopy or roentgenography. At
`various time intervals the position and
`condition" of the enteric coated product
`may be determined with disintegration
`being indicated by a scattering of the
`barium sulfate. This procedure is quite
`suitable for comparative testing of differ-
`ent enteric coating materials.
`An in vivo method utilizing radioactive
`sodium in the form of sodium chloride
`
`has been reported.“ Passage of enteric
`coated capsules containing the radio-
`active material
`through the gastroin-
`testinal tract can be followed with a
`Geiger counter. Since disintegration of
`the coated product is determined by the
`appearance of radioactivity in the hand
`of the subject, the site of disintegration
`cannot be well defined.
`
`In. vino disintegration tests are suitable
`for comparative evaluation of coating
`materials but further in oiuo tests must
`be conducted to determine the influence
`
`of the coating on the absorption or physi-
`ological availability of the drug. This
`testi_ng includes such methods as the
`measurement of the concentration of a
`
`drug in the blood at periodic time inter-
`vals or the measurement of urinary ex-
`cretion of a drug.
`
`Dispensing Couied Products
`
`Coated tablets or capsules should be
`dispensed in glass or plastic vials to pro—'
`tect
`them from the atmosphere and
`hL1.midity. Particularly in the case of ex-
`temporaneously coated products, proper
`care should be taken to avoid either
`cracking or breaking the coating.
`
`References
`
`1. Tucker SJ, Rednick AB: JAPhA, Sci
`Ed 493738, 1950.
`2. Lachman L, Cooper J: J Pharm, Sci 52:
`490, 1963.
`3. Mody DS, Scott MW, Lieberman HA:
`J Pharm Sci 53:949, 1964.
`4. Doerr DW, Serles EH, Deardorff DL:
`JAPhA, Sci Ed 43:433, 1954.
`5. Gans EH, Chavkin L: JAPhA, Sci Ed
`43:483. 1954.
`6. Golod WH, Huyclr CL: Drug Cos Incl
`77:620, 1955.
`7. Wurster DE: JAPhA, Sci Ed 483151,
`1959.
`8. Wruble M: JAPhA 24:570, 1935.
`9. Wagner JG, Ryan GW, Kubiak E,
`Long S: JAPRA, Sci Ed 49:133, 1950.
`10. Goorley JT, Lee CO: JAPhA 27:379,
`1933.
`11. Bauer CW, Masucci PE: JAPhA, Sci
`Ed 37:124. 1948.
`12. Hodge HC, Forsyth IIH, Jr, Ramsey
`GII: J Pharmacol Exptl Ther 80:241, 1944.
`13. Antonides IIJ, De.Kay HG: Drug Std
`21:205, 1953.
`14. Huyck CL: JAPhA, Prac Ed 7:86,
`1946.
`
`15. Wagrier JA, Brignall TW, Long S:
`JAPhA_. Sci Ed 43:244, 1959.
`16. Maney PV, Kuever RA, JAPhA, Sci
`Ed 30:276. 1941.
`17. Worton AG, Kempf GF, Burrin PL,
`Bibbius FE: JA.Ph.A 27:21, 1938.
`18. Williams A: Sustained Release Phar-
`maceuticals. Park Ridge NJ, Noyes Develop-
`ment Corp, 1969.
`19. Stoklosa MJ, Ohmart LM: JAPhA, Pr
`Eol 14:507, 1953.
`20. Cook CI-I, Webber MG: Am J Hosp"
`Pharm 22:95, 1965.
`21. Schroeter LC, Hamlin WE: J Pharm
`Sci 52:811, 1963.
`22. Morrison AB, Chapman DG, Camp-
`bell JA: JAPIFIA, Sci Ed 48:634, 1959.
`23. La.rk—I-Iorovitz K, Lang HR: JAPhA,
`Sci Ed 31 :99, 1942.
`
`Amerigen Ex. 1060, p. 11
`Amerigen Ex. 1060, p.
`L,,....
`
`:11
`
`Derm
`
`
`
`Dermatologi:
`are applied t
`protective fi
`
`Dermatolt
`
`liquid, solid,
`rations.
`
`Liquid Derl
`
`From a 1
`liquid dermz
`any other l
`they may 83
`or colloidal
`
`and supplen
`ous, hydroal
`ally oily) v
`liquids are
`permits a s
`vehicles. Fr
`
`polyethylen
`isopropanol
`ethyl ethei
`
`.4...~,.-.-,..:we-»..u.wa.n,i.¢«9.»u.u.,m«»..-:.w~3«._.-—a..—-1..-«r.-=-