[1
`
`CHAPTER 93
`
`Coating of Pharmaceutical DosQgeForms
`
`StuoN C Porter, PhD
`Vice ","",rden'. I\e"",rd\ ond P"""lop"","",
`Co\Ofa)(l, In<:
`W .... l'oInt. ·PA 194e6_
`
`Any introduction to t.a:blet coatlng-must be·prefaced by an
`were held_ at the end of a suction tube, dipped ana_then_the
`important questiori-"'Why coat tabletS?'''-sirice In_ mariy
`process:repeate,d for t he other side of the pill. Not surpris-'
`Instances, the coating is being applied to a' dosage fonn that
`ingiy, these_ techniques' often f",iled to produc~ a uniformly., .
`· coated produc.t.s
`.
`. . "'
`already is-functionally complete. In attempting to ap.swer ·
`Initially, the first sugar-coated pil)s seen in the US 'wen?
`.. this· question, if one ' examines the market, it will' become
`imported from France about 1842;5 while Warrier, a Philadel(cid:173)
`apparent that a significant proportion o{pharmaceutical solid
`phia pharmacist, becauie among the first indigenous manufac(cid:173)
`dosage forms are coated .. The reasons for this range' from
`turersin 1856. 6
`the esthetic to a desire to control the bi"c?availabili'ty .of the
`Rharmaceutical pall-coating processes ar, based on those
`dru$, ~nd include:
`used in the candy industry, where techniques were highly .
`1. Proteo:ting the drugJrom ilS SUrTounding environment (palticularly
`evolved, even in the Middle Ages. Today, while most coating
`air, moisture and U~t)with II. view to improving_stability.
`-
`pans are fabricated from stainless steel, early pans were made
`_.
`. 2. ' Masklng ofunple;asa,\t taste and odor.
`from copper, because drying waS effected_ by means of a(l
`3.
`l nc~as\ng the ease by means of which the produ'<l- can be ingesLed '
`extelllally appJied heat source. Current thinking, even with
`by the patienl.
`-
`conventional pans, is to dry the coated tablets with a supply of
`. 4. Improving product identity, from the manufacturing plant, through
`heated air, and remove the moisture and dust-Iad!'!n air fTom
`intermediaries and tuthe patient.
`_
`the vicinity of the pan by meallS of an air-extraction system .
`5. Facilitating l'Iar.dling, patticularly_ in high·speed packaging/filling
`. Pan-coating processes undeIW"ent little fuither change until
`lines', and automated Counters'in pharmacies, where-Hie coaling minimizes
`the late J 9405 and early 1950s; with the conventional pan'
`cros~:contaminll:tjOn due to dusl.elirnination.
`. .
`6. )ruprovingproductappearance, particularly ",here there are notice·
`being the rriainstay of all coatlng operations up to that time.
`able visible differences In tablet core ingredients fi-om batch to batch,
`However, iri.the_last ~O or 30 years 'there .have ,been;>omt";.
`7. Reducing the risk of interaction 'between incompatible-components.
`significant advam::es made in coatirig-pro"cess technology,
`This woul~ be' achieved by using coated fonns of one or mor~ of the
`mainly.-as a result of a steady evolution in pan design ~dits
`'offending ingredients (particularly actiye compounds).
`.
`associated 1'l.nciliary e'quipment.
`-8.
`Improving product mechani_cal integrity, since co_aied products gen(cid:173)
`It;lterestingly,, in tlie early ye;J.fS of this development, an
`erally are more resistant to rnishandling (abrasion, attrition, etc) ..
`· entirely 'newform oftechnology·evolved,. that of film coating;
`9. Mod.lfying drug rfllea..~e, as in enteric-coated; repeat·actio" and
`R'ecognizing the deficiencies of the sugar"coatin,g process,
`sustained-release products.
`advocates of filin coating were achi~ving success by using
`Evo"lut ion of the' Coating. Proces~ Tablet coating is
`· coating systems involving h,ighly volatile Qrgan!c _solvents.
`perhaps on!,:! of the oldest _pharnfuceutical processes still in
`'These circumvented' the problems aSsociated with the ineffi(cid:173)
`existence. Although a great deal has been written aboutthc
`ciency in the drying capabilities of.conventional equipment,
`materialS and methods used, the coating process is still often
`and 'enabled production 'quotas to be met .with significant
`recogniied to be more of an art than a science, a factor which
`reductions in proceSSing times and materials used. The_dis(cid:173)
`may be responsib!e for many of the problems tha~ can exist.
`advantage of this approach, however, always has been associ-,_
`Historically, the literature. cites Rhazes (850~932 AD) :as be(cid:173)
`ated with the solvent systems used, wtiich often employed'
`irig one of the earliest "tablet coati!rs," havii"tg used t.he lJIuc[(cid:173)
`flammable and toxic,materials.
`lage of psyllium seedS to coat pills·that had an offendmg taste;·
`The advances that occurred lVith equipment deSign, having
`Subsequently, Avic!,:!nna l was reported to have used gold and
`begun by the development Of the Wursterl process and co.ntin(cid:173)
`silver for p.ill coating. Since thenl there have peen rnaI}y
`uedbythe evolution of·side-vented pans, have'resulted in the .
`re(erences to the different m'aterials. used in "t.a:blet coating."
`gradual emergence 'of coating _processes. where drying effi(cid:173)
`tiency can be maximized" Thus; film coatirig began'as a(cid:173)
`White~ mentioned the use of fiIHily divided·talc in what was at
`one ~ime popuiafly known as "pearl cQating,': while Kremers
`process using inetficient drying equipment, relying Oil. highly
`and Urdang3 described the intn;)duction of the gelatin coating·
`volatile 'coating formulations for success, and evolved illto
`of pills byGarot'in·1838 .
`.
`one in which the processing equipmen~ is a major factor in
`An interesting,reference 4 reports the-use. of waxes to coat
`ensuring that rapid drying occurs.
`Improved drying capabili- .
`poison tabletS,
`l'hese waxes, being insoluble in all parts of
`ties have -permitted increased use of aqueous film-coating
`th~ gastr.oint.e~tipal .t[act, were intende'd to prevent aCcir,lental
`formulations.
`pOisoning (the contents could be _utilized by breaking the
`Advances-lri equipment design also have benefited. the sugar(cid:173)
`tabletprior to use).-
`.
`coating process, where, because of Current Good Manufactur(cid:173)
`While earlier coated,products were produced by individuals
`-ing Practices (CGMP) and to maintain product uniformity and
`wo rking' in. ph~rmacies, particulatly w.hen extemporaneous
`performance, the trend has been toward using fully automated
`-compom\.dingwas the order of the day, that responsibility now
`processes . . Nonetheless.- film coating tends to dominate as
`has oeen assumed by the pharmaceutical "industry_ The earli(cid:173)
`the' process of choice for tablet coating_
`est attemptS to apply coatings to pills yielded variab~e' results ._
`al1d usually required 'the handling of Single pills_ Such pills ' .
`w.ould have been mounted on a needle of held with a _pair of Pharm.aceutical Co~ting Processes '
`fo rceps andJiteraily dipped into the coating fl uid, a procedure
`which ,¥ould have to be repeated more than once to ensure
`that the pm was CQated completely_ Subseqmintly, ttle pills
`
`'Basically, there are four major techniques for applying coat(cid:173)
`ings .to pharmaceutical s?lid dosage forms:
`(I) sugar coat-
`
`· 1650
`
`p. 1
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`I I
`
`i'
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`SHIRE EX. 2013
`KVK v. SHIRE
`IPR2018-00290
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`

`1652.
`
`CHAPTER 93
`
`hl"lJuch a Connulation the powdered rna.t.eria.\.s responsible for
`(coating buildup have been dispersed in: a gum-based solution .
`. A -typiciJ.. fonnulation is shown in Table 3. This ·approach
`· al,!.ows. ~t: solids loiuting to be matched more closely to . the
`I)inding clpacity of the b.ase solution, and often permfts t.ke
`less-experienced coater to achieve satisfactQJ;1l results.
`Smoothlnl-:-Depending on ·how succe~·the subcmot
`was applied, it may be necessary to smooth out the tablet
`surface further prior to applicatio:n ot"lhe' co\or coating.
`Smoothing usually <;all be accoml?listted by the application of
`a simple ~p .solution (approximately 60 to 70% sugar sol· .
`. . . .
`.
`i~).
`.
`. . Often, the smoothing syrups contain a low percentage of .
`·titanium dioxide (l to 5%) as an opacifier. This can be
`particularly useful when the subsequent color-coating formu·
`Iatlon ·use!: water-soluble dyes as colorants, since it m·akes the
`sw'faee under.the color coating more refle:·ctive, resulting in a
`brighter,· cleaner final color.
`CoJor Coating-This stage often is the most critical in the
`successful completion of a sugar-coating process, and in(cid:173)
`·volves the mul~iple application of syrup sQlutions (60 to 70%
`sugar solids) containing the requisite coloring matter. The
`·types of coloring materials used can .be divided into two
`categories: dyes or. pigmentS. The distinction between the .
`two simply is one of "solubility in the· coating fluid.. Since
`water-soluble. dyes behave entirely dilTerentiy than water·
`insoiuble pigments, the application procedure used .m the
`color coating of tablets will depend on the type of colorant
`!Chosen.
`.
`.When useO by a skilled artisan,·water-soluble dyes produce·
`the most elegant of sugar·coated tablets, siTIce it is· possible to
`obtain a cleaner, brighter final color. However, since water.
`soluble dyes are migratory colorants (that is to say, moisture
`that is removed·from the coating on drying ~ill cause migra(cid:173)
`tion of the colorant, resulting· in a nonuniform appearance),
`great care ·must be exercised in their use, particularly when
`dark shades are requ.ired. This Can be· achieved by a,ppll'ing
`smaU quantities of colored syrup that arejust sufficient to wet
`the swface of every tablet in the batch, and then allowing the
`tablets to dry slowly.
`·It is essential tnat each application is
`allowed to ~ thoroughly before· subsequent applica~ions are
`made, othenyise moisture may become trappetfin the coating
`and may cause the tablets to "sweat" on standing.
`The final color obtained may result from up to 60 individual
`appliCations of colored sYruP. This factor, combined with"
`the need to dry each application slowly an~ thoroughiy, re(cid:173)
`sults:)n very long processing tim·es (eg, assuming 50 applica- ··
`tions are mad~ which take lletween 1 f? and ·SO minutes each,
`the coloring process can extend over a period of up to 25
`·hours).
`Tablet color coating with pigmenis, as advocated by Tucker
`·et at, 9 can preserit some sign"iticant advantages. First of all,
`since pigment colors are water-insoluble, they present no
`problems of migration since the colorant remains where it is
`In addition, if the pigment is Qpaque, or is com(cid:173)
`deposited.
`bined with an opacifier such as titanium dioxide, the desired
`i:olor can be.develope.d much !"flOre rapidJy, thus resulting in·a
`thinner· color coat. Since each ,<olor-syrup application now·
`can be dried more rapidly, feWer applications are required and .
`significant reductions can be ma~ in both processing times
`and costs.
`.
`
`Table 3-Typlcal SuspenslonSubco~lI~g Formulatlo."
`,
`
`Distilled water
`Suc rose
`Calcium carbonate
`Talc (aSbestos-free) ,
`Gum acacia (powdere·dj
`Titanjum dioxide
`
`%wlw
`
`25.0
`40.0
`20.0
`12.0
`2.0
`1.0
`
`A1though pigmerit:based color coatings are by no means·
`"foolproof, they will permit more abuse than a dye color(cid:173)
`coating approach, arid are more amenable for use by" less(cid:173)
`skilled coaters. Pharqlaceutically ac·ceptable pigmenls can
`be· classified either as inorganic pigments (eg, titaniutn diox·
`. Certified lakes are pro- ··
`ide, iron oxides) or certified lakes .
`duced from water-soluble dyes by means of a process known
`· as " laking," whereby the dye molecule becomes fixed to a
`suitable insoluble substrate· such asalumimlm hydroxide.
`~rtilied lakes, . particularly when used in corijunction with
`an opacilier·s uch as titanium dioxide, provide an excellent
`means rif colOring sugar coatings and permit a wide raJlge of
`shades to be achieved. However, the incorporation of pig(cid:173)
`ments into the .syrup solution is n.ot as easy as with water(cid:173)
`soluble dyes, since it is necessary to ensure that the pigment is
`wetted completely and dispersed unifonnly. Thus, tne use of
`pjgment color concentrates, which are commercially avail(cid:173)
`able, is usually beneficial.
`Polishing--Sugar-coated tabletS need to be polished in
`order to achieve a final gloss: Polishing·is achieved by apply-
`· ing mixtures of waxes (beeswax, camauba wax, candelila wax
`or hard paraffin wax) to the tablets in a polishing pan. Such
`wax mixtures may be applied as powders or as dispersions in
`various organic solvents.
`.
`·,Printing-II). order to·identifY sugar-cbal,ed tablets (in ad(cid:173)
`di't!on to shape, .size and color) .otten It is necessary to print
`thC"m, either before or after polishing, using pharmaceutical
`branding inks, by means of the process of offset rotogravure.
`Sugar-Coating Problem5--Various problems may be en(cid:173)
`co·untered during the sugar coating of tablets.
`It must be
`· remembered that any pr.ocess in which tablets are kept tum:··
`bUng constantly can present difficulties if the tablets are not
`strong enough to w:ithstand the applied stress. T8:~lets which
`.are too soft; or have a tendency to laminate, may break up.and
`the fragments adhere to the surface of otherwise good tablets.
`Sugar-coating pans exhibit inherently poor mixing·
`characteristi~s. If c3'l"e is not exercised dUring the applica(cid:173)
`tion of the various coatitlg fluids , nonuniform distribution of
`·coating material can occur, res~lting in·an unacceptable range
`of sizes of finished tablets within the batch.
`. .
`.
`· Ove~alous u~ of dusting powders, particularly during the
`·subcoating sl;age, may result in a coating b~ing fonned in
`which the quantitY of rulers exceeds the binding capacity of
`the polymer used in the formulation, creating so"ffcoatings or
`those with increased tendency to c·rack.
`Irregularities in appearance· are not uncommon, and occur
`either a,S the result of :color migration ' during drying .wben
`water-solubl~ dyes are used, or of "washing back" when over:
`dosing of colored syrups causes the previously dried coating
`layers to be·redissolved. Rough tablet surfaces "ill produce
`a "marbled" appearance during polishing, since wax buildup .
`occurs in the small d.epressions in the tablet surface.
`.
`
`Film Coo.ting of Solid Dosage Forms·
`
`Film cqating involves the deposition of a thin, but uniform,
`film onto the swface of ttJ-e substrate.. Unlike sugar coating,
`the flexibility afforded in film coating allows additional sub(cid:173)
`strates, other than just compressed tabletS, to be considered
`(eg, powder; granules, nonpareils, capsUles): Coatings essen(cid:173)
`tially are applied continuously to a moving bed of materiaJ,
`usually by means of a spray technique, although manual appli(cid:173)
`.
`cation procedures have been used.
`Historically, film coating was introduced in the early 1 ~50s
`in order to combat the shortcomings of tlie then pr~dominant
`sugar-coating pr9cess. Film coating has proved successful
`as a result of the many adv8;lltages ?tr:ered, incl.uding:
`i . Minimal. weight increase (typically 2 to 3% of lablet core weight).
`. 2. Signlfi<:;ant reductiorl in processing times.
`.
`.
`· 3.
`Incre...,.,d process efficiency and Output.
`. 4..
`increased nexib!lity in fonnula.tions.
`.
`5.
`improved resistance tochippingorthe coating.
`
`p. 3
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`1654
`
`CHAPTER 93
`
`The most extensively used synthetic polymer is cellulose ·
`ace~te ph·th:iiate.(CAP) which is ca~able offWlctioning effec(cid:173)
`tively as a.11 enteric coating. However, a pH greater than 6
`usually is require~ fo r solubililY and ·thus a aelay in drug
`release m:ur ensue. ' It alSo is relatively permeable to moL,>- .
`ture and. gastric fl uid compared to most entelic polymers.
`Thus it is susceptible to hydrolytic decoI"Qposition where
`phthalic and acetic acids are split off, resulting in·a change In
`. polymelic, and therefore entelic, properties:
`. , Another 'useful .polymer is polyvin'yl : acetate phthalate
`(PVA:P) whi d~ is leS$ permeable to moisture and gastric fluid,
`more .stable to hydrolys.is and able to ionize at a lower pH,
`resultiilg in earlier release of actives In the duodenwn.
`Other suitable enteric polymers include hydroxypropyl
`'methylcellulose phthalate (which hilS properties similar to
`·PVAP); methacrylic acid- methacryllc acid ester· copolymers
`(some of which have a high dissociation constant lJ ); celluloSe·
`acetatetriinellitate (CAT, which has properties similar to CAP);
`carboxymethyl ethylcell ulose (CMEC) and .hydroxypropyl
`methy1cellulose acetate succinate (HPMCAS).
`Various systems recently have been introduced that allow
`many ·of these · entelic polymers to be ·applied as aqueous
`. dispersions; thus· facilitating the use of aqueous film-co ating
`technology. for the enteric coating of pharmaceutical dosage
`forms.
`, .
`. SU8tained~ Rel e"ase Coatings-The concept of sustained
`·release fonn ulations was developed in order to eliminate the
`n·eed for rQultiple dosage regimens, particularly for those drugs
`requiring reasonably constant blood levels over a long period
`of time.
`In addition, it also has been aaopted for those drugs
`·which need to be administered in high doses, but where too.
`t~p id a rele1!Se is likely to cause undcsirable side effects (eg,
`the · l.Ilceration that·occurs when potassium chlOlide is re(cid:173)
`leased rapidly in the gastrointestinal tract).
`Fonnulation methods used to obtain the de.sired drug avail-·
`.. ability rate frQ.m ;mstained-actiopdosage forms incl ud ~
`I.. Incrcasing tllc particle size of tile drog.
`f:mbeddlng t.tie drug In a matrhr..
`.
`2.
`:J. , Coating the drug or do~age fonncontainlng the drug.
`4: Forming complexes or ·the drog with materials such a.~ ion·ex- .
`·c~~:nge resins.· .
`.
`Only th9se ~ethods which. ·involve some .fonn of ·co~ting fall
`within the "cope of this chapter. ·
`· Materials which have been found suitable for prod ucing
`sustained-release coatings include
`.MIxtures of . waxes (beeswaX: camauba wa~, etc) wi.th glyceryl morio(cid:173)
`I.
`·stearate, steariC acid·: palmitic .acid, glyceryl inonOP!llmiLate and cetyl ·
`akollol. Tllese provide coatings wllich are-dissolved slowly or broken
`dOY'n in tile G1 tract.
`.
`.
`· 2. Shellac·an d ~in-polymcrs wllich remain Intact· until tl)e PI-! of
`gastrointestinal COntenLS becomes Je5.'l acidic.
`3. Ethykellulose, whicll provides a membrane around the dosage form
`and remains int3<;t (hrciugllout tile gas\r'Olnte:atinal tr,.ct.' . However, It
`.does permIt water to permeate t!;le film, dis.~l,:e the drug an~ diffuse out
`again.·
`.
`. .
`4. Acrylic resins, which bella~e similarly to eth~lceliulose iI.s a diffuSion-
`.controlled drug- release coating material.
`o. Cellulose acetate (diacetatc and \riacctate).
`6. Silicone elastomers.
`As·with an enteric coating, moo:ty of the ·synthetic polymers
`suitable for sustained-release film coating have been prepared
`as a.queous pqlymer dispersL.ons (often called lat~xes or P$Cu(cid:173)
`dolatexes) that are commercially available and facilitate the
`use of aqueous-film-coating te·~ hnology fo r the preparation of.
`extended-release products.)(
`·
`.
`.
`.
`VariouS ·methods have been used to prepare sustained- ·
`release products using film-coating techniques. Examples
`(nelude the application of suitable film coat~gs to
`.
`I, Oneil grall\lles·(eitller irregular or spheronized).
`2. Drog-Ioaded beads:(or nonpareils).
`3. Drug crystals.
`. 4. Drug/ion-exchange·resin complexes. :
`· [;, 1'a.blels.
`
`In the first four · exam·ples, the final coated particles ·can
`either be ·filled into two-piece hard-gelatin capsules or com~ .
`pacted into tablets. Additionally, c"Oated drug/ion-exchange(cid:173)
`resin complexes may be dispersed in viscous liquids to create
`liqUid suspensions.
`.
`.
`. A ratlJer unique a!)plication of the fiJrn-coated, .s:ustair\ed.
`In this de(cid:173)
`r"lease .tablet is the elementary osmo~ic" pumP..
`vice, i> tablet lfore (formulated to contain osmotically active
`-ingredients) is film coated with a semipermeable roembrane,
`· which is subsequentiy "pierced" with a laser t6 create a deliv(cid:173)
`ery orifice. On the ingestion o"f such a device, the illflision of ·
`water g~nerat«s an osmotic pressure within the coated tablet
`that ··pumps" the drug in solution out through the orifice.
`With sustained-release products, one must remain aware
`COflstantly of the fact that the final (losage forms typically
`contain drug loadings that are s\lffidently high to cause prob- ..
`lems if the entire dose .is released quickly. This ph enotJ\~ ·
`eilOri, commoniycalled "dose:dumping," can be avoided only
`·if:
`I. The fjJrn" C()a(ing is mecllanically :lbund ilnd ·will rtslst rupture on
`i"g~si.ion of tile rlos:.ge ronn.
`.
`. z.. Suffielent coaling is applied uniformly across· tile ~urface oLtlle
`materialtllat is·to be coated , .
`. .
`.
`,
`
`--
`Film-Coating Problems
`.
`As with sugar coating, difficulties m~y develop durtllg,.or '
`suosequent to, the film-coaling process. . The tablets being ,
`coated r!lay hot be sufficiently robust, or may have "lIwn.de.ncy
`to lamina-Ie while be;ng coated. Since film ~oats are rela(cid:173)
`tively thin , their ability to hide defec.ts is signifitantly less than
`with sugar c.oating. Hence, tahlets which have poor resis(cid:173)
`tance to abrasion (ie, they exhibit high·friability characteris(cid:173)
`tics)·can be P"!"obiematic, since the impenections readily may·
`be· apparent after coating.
`It is· very important to identify
`tablets with suspect properties, whether mechanically or per(cid:173)
`formance related (eg, poor disSolution}, prior. to a coating
`process, since subsequent recovery or. reworking of.tablets .
`may be extremely difficult after (fcoating has beeri applied.
`Vario)ls process-rel;tted problems can occur.during the ap(cid:173)
`. One example is picking, whicp is
`plication of a film coating .
`a i=0nsequence of the fluid delivery rate exceediJ:tg the dlying
`capacity of the process, cal,lsmg tablets to stick together and
`subsequently .become broken aprut. Another (txampJe, or(cid:173)
`ange peel. or roughness, is usually .the result of premature
`· dryi.ng of atomiz~d droplt!ts of solution, or j~ may be a conse- .
`quence of spraying too viscous a coining solution such that ·
`effective atomizatlon is difficult.
`.
`.
`MoUling, or lack of color uniformity, can result ftom un(cid:173)
`even distril:iutio.n of COlQr in the coating, l!- problem Oft.en
`.related to the usc of soluble dyes in aqueous film coating;
`when color migration can occur, either by evolution of ·re-
`· sidual solvent. in the film, or by migration of plastic.izer. in
`which the colorant.may . b~ solu.ble. The use of pigments in .
`· th·e film-COaling process minifl.\izes ~he illcidence of this latt~r.·
`objection considerably. However, u~even color arso can re.(cid:173)
`suit from poof pigment dispersion in the coatiJ:tg solution .
`Pinally, s6ine major problems occur as the result of in!.ema1
`stress that develops within the film as it dries. One example
`is cracking, which occurs when this stress exceeds the tensile
`strength .of the film. This problem. may be. compounded by
`postcompaction stre·ss relaxation {a phenomenon that can
`occur with certa·in types of tabl.~t ~ormulations, such as those ·
`containi,ng ibuprofen, after ejection from lhe die), which causes ·
`tablets to expant;!. ' Another example is logo-bridging (i~,
`bridgmg of a· monogram present in the surface of the tab:let I
`core), which.o.ccurs when a component of the internal stress is
`able to overcome the aq.hesive bonds between the coating and .
`the tablet surface, caushlg the film to pull away so that legibil(cid:173)
`ity of the rrionoghm is lost. An understanding of the proper(cid:173)
`ties of the various ingredients. used in the film -coattng form u(cid:173)
`latiOI1, and ho ....... these. ingredients interact with olJe another,: ·
`can aUow the fonnulator to·avoid many of these intcrnal-stress- .
`rel.ated Pfoblems:15 .
`j
`.
`p. 5
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`

`

`COATING OF PHARMAC.EUTlCAL DOSAGE FORMS
`
`1659
`
`. .' I
`.
`.
`. . . • •. .
`.
`early, concerning the shelf-life of the produCt. Altltough use- .
`standp.oint, coated tablets must beshown to conform, where
`applicaole: to some color standard, otherwise the dispenser
`ful, highly exaggerated"conditions of storage can supply mis·
`.leading data for coated dosage forms . . 'Any change in drug
`and the consumer may assume that differences have occurred
`from previous lots,. signifying a changed or substandard .. release from the dosage fonn .is measured in vitro, but an in
`In addition, because of the physical abUSe that . Vivo measurement should· be 'tlSed to confirm that drug avail~
`product.
`· tablets, both in their uncoated and. coated f<?rms, refeive
`ability remain:<> within ~pccified limits over its stated shelf.life,
`during the coating prqcess, it i,s essential to check for defects This confirrn'ation can 'be' obtained.by testjhg: the 'product .
`initially for in vivo .availability and then repeating at intervals
`such as chipped. edges, picking, etc, and ensure they do not
`exceed predetennined limits.
`. during storage at normal conditions for itsestirnated shelf-life
`Qften, in order to' iden~ify the prodUCL'l, coated tablets may
`(or longer). .
`.
`be imprinted (particularly wit.h sugar-coated tablets) or bear a
`Interpretation of stability data for coated, modified-release
`monogram (corrunon1y seen with tablets that are film-coated).
`products should be undertaken with extreme care, since ·the·
`· 'The clarity and quality of sU¢h identifying features must be
`· d.ifI~ion charaCteristics of polymeric 61ms can change signifi(cid:173)
`assessed. The failure of a hatch of coated tablets to comply
`cantfy under exaggerated ternperature:. C:9nditions.· This
`with such preset standards may result ill 100% inspection . change may be COnfOWlding when trying to.predicttheir diffu(cid:173)
`being reg.uired or the need forthe batch to be reworked.
`sion characteristiCs under more moderate conditions and thus
`Batch-ta-batch reproducib ility for drug availability is of
`can provemisleadingwhenpredictingsheLflue.
`· paramount importance, consequently each batch of p~oduct When eleyated-temperature stability studies are conaucf.ed
`;-oifllroducls:' coated with-aqueous polymeric dispersio·r.s (la(cid:173)
`shQuld be submitted to some meaningful test such as adisso!u-
`tiontest. Depending on the chslacteristics of the tablet core . texes or ps~udol atexes), the data obtained might· be more '
`to be coated, tablet coatings . can modify the drug-release
`indicative ofm.orphological cliangesth;lt have occurred in the .
`film.' Su.::h~cha:nges may.result from'partialdest~tionofilie ,
`profile, even when not inten4ed (wilike' the case of .enteriC- or
`film \Vhen coated rnaterial adheres together it) the container
`controlled-release products). Since this behaltj.or may vary
`with each batch coate.d (being dependent, .for example, on
`and subsequentlr is brok~n apart; addition~lly, thpse changQIi '
`differences in processing conditions or variability in raw mate·. might result from further .coalescence .of the coating (which
`rials u~ed), it is essential that this parameter should be as-
`-can occur when .the coatiog is not coalesced completely dur-
`sessed, particularly in products that ar~ typically tJ9rderline
`.
`ing. ~e. coating procesS).
`(re:fer t6 Chapter 92).
`.
`Stability tests usUally are conducted on a pr'oduct at the
`'time of development, during th.e pilot phase and on represen(cid:173)
`tative lots of the commercial product. Stability testing must
`. continue for the commercial product as long as it remaiTIs or.
`the market because subtle changes in a manufactuting pro(cid:173)
`CeSS and/or a raw material'can have an impact on the shelf life .
`of a pr04uct . .
`
`Stability. Testing ~f Coaled P roduct~
`T~I stability-testing prOb'Tam for coated prQdu~ts ~n vary
`depe ding on the dosage form and its ·composition. Many .
`stab· .ity-testing programs are b"a..,>ed on studies which have
`disClosed the conditions a product may encOWlter prior to end
`use. Such conditions usually-are rderred 'to as normal.aqd
`'include ranges. in te!'lperature, humidity,' light and handling '
`I. Urdllng G:
`conditions. .
`' . \
`Limits of acceptability are established for eacti product for
`1945.
`2. WhiieRC: JAPhAl1 :345,1922.
`qualities such a.<: color, appearance, availability of drug for
`.3 . . ~~~me.Tf!. E, l!rdang G:' His/ory q[Phannacy: J,.ippincQLt. ~hil~~l'
`· absorption and drug content. T.he.time o"e~ which the prod- ·
`uct retains specified properties, when tested at normal condi-
`.ptil3, 2Qi319, 1940. ' .
`.
`' . .
`.
`. 4. Anon: JAMA 8-4: 829, 1920.
`· tions, may be defmed as the she({life. The container fortne'
`.
`l"or ex- : . 6: WarnerWRJr: . AmJPharl)1 74: 32, 1902.
`5 WiegilildTS: AmJPharm7.l!:33,1902.
`.
`product may be design~d 'to improve tile shelf-li.fe.
`~ple , if the color in the coating is light-sensitive, the: product
`7: Wu~t& DE:
`(Wisr.<)I~~in Alumni Research. Found~tfon.~) US Pat
`may tie packaged in an amber bottle and/or protected from
`2,648,609(1953): ' .
`.:-
`._ ............ -
`light by using a paper carton. , When the c9ating is friable,
`8. ~ignoTino CA: . US Pat 3, 738,952and3,741 ,195 (June,1973).
`resilient material· such· as cotton may belncorporated in both
`.9. Tud::erSJelaL' JAJ'hA 1/7:849, 1958.
`the top and bottom of th,e container, and if the product is
`10. SchwartzJB,Alvif1oTP: JPhary-nSci.6.5:572,1976.
`'affected adversely. by rTjoisture, a moisture.-resistant closure
`II. Pril!igEB: J.flw,mSci50: 1245, 1969.
`k
`12.
`l'orterSC: Pho.rmTec"'I,67,1980.
`· may.be used and/or a desiccant may be placed in the pac age.
`.13. DelpolteJP,Jarninet F:
`J PharmBelg 31: 38, 1976.
`· The shelf-life of the product is determin~d in the commercial
`14. Chan'g RK, HsiaQ CH, Robln~on JR: Pha'rm 7'ech J 1: 56, 1987.
`· p{lckage tested under normal conditions.
`15. Rowe RC:
`.
`,I Pho.n'llPhannacoI3!J:423, 1981.
`The stability. of the product also may be teste.d underexag-
`16'. HiiUin II ,OmgsMadein Germany28.' 147, 1985.
`gerated conditions. This uslially is done for the purpose of
`17. Prude OJ, ed: AlItama!ionqfPharrilaceulical Ope'mlioru, Ph&rm
`· accelerating changes so that an extrapolation can be m'ade
`Ter.h Publ, Sprin~~e1d OR,.19~.·
`.
`
`Referi':m:es
`What's NIlW, 19.43, pp 5-14; throughJAPhA 3-4: 135,.
`
`•
`
`p. 6
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`p. 7
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`

`

`

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`, .Easton, Pennsylvania 18042
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`p. 9
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