PHARMACEUTICAL
`,TE C H N O L O G Y
`
`voLu
`ME 7 NUMBER 9
`
`SEPT 1983
`
`$4 . 00
`
`Page 1 of 18
`
`KVK-TECH EXHIBIT 1025
`
`

`

`r=== ==-===================== === ===a.;;;;--------------------------------=:ar.s~......--
`PHARMACEUTICAL TECHNOLOGY, September 198 3
`124
`
`The for gotten dosage form:
`enteric-coated tablets
`
`WALTER G . C HAMBLISS
`
`T HE RECENT INTRODUCTION of
`
`transdennal delivery systems and other
`controlled-release dosage forms has demon(cid:173)
`strated the ingenuity of the pham1aceutical
`development scientist. The number of poten(cid:173)
`tial dosage forms available for a new drug
`has never been higher. There is, however,
`one dosage form that appears to have been
`forgotten: the coterie-coated tablet.
`An entcric-coated tablet is designed to re(cid:173)
`sist the dcst ructive act ion of the gastric nu id
`and to disintegrate in the intestinal tract. '
`Reasons for applying an ente ric coat to a
`drug product include:' ..
`• preventing the drug's destruction by gas(cid:173)
`tric enzymes or by the acidity of gastric
`fluid
`• preventing nausea and vomiting caused
`by the drug's irritation of the gastric
`mucosa
`• delivering the drug to its local s ite of
`action in the intestine
`• providing delayed action
`• delivering a drug primarily absorbed in
`the intestine to that site at the highest pos(cid:173)
`s ible conce ntration.
`This presentation will review the history of
`this dosage form and examine the reasons
`for its apparent demise.
`
`Basic Studies
`Jn 1965, Schroeter published a review of
`over 60 materials that have been used as en(cid:173)
`teric coating matcrials,4 referring to studies
`that found both favorable and unfavorable
`in vivo performances for tablets coated with
`those materials. The four basic types of c n(cid:173)
`tcric coating materials are water-resistant
`fiJms, pH-sensitive films. materials digest(cid:173)
`ed by intestinal nuid , and materials that
`s lowly swell and dissolve after exposure to
`moisture. 2 The pH-sensitive films have re(cid:173)
`ceived the most attention in the literature.
`Indeed , e nteric products introduced recent(cid:173)
`ly seem to be manufactured exclusively
`with this ty pe of coating.'
`
`pH-Sensitive Films
`As the name implies, pH-sensitive film is
`directly affected by the pH of the GI tract.
`
`The film must be insoluble in gastric tluid
`but dissolve rapidly in intestinal tluid. Table
`I lists pH values found in the G I tract.'' The
`usuaJ pH of gastric f1uid ranges from I .0 to
`3.5. Fasting generally reduces the pH value
`to a level between I .2 and 1.8. and G I dis(cid:173)
`eases and drugs such as histamine H-2 an(cid:173)
`lagonisLs, amichol inergics, and antacids are
`also known to affect pH. 7
`Enterie films that are pH-sens itive consist
`of a long-chain polymer with ionizable car(cid:173)
`boxyl groups. In the low-pH environment
`of the gastric fluid, the acid g roups arc un(cid:173)
`ionized and arc therefore poorly water solu(cid:173)
`ble. When the tablet empties from the stom(cid:173)
`ach into the sma ll intestine, a dramatic
`change in pH occurs: ionization of the acid
`groups and , therefore, increased water sol(cid:173)
`ubility occurs in the intestinal tract as
`shown in the following equation:
`
`R - COOH + OH" ... R - coo· + H2O
`
`The equilibrium constant for Lhe reaction is
`a function of the p H o f the medium and the
`apparent PK. of the film . 1 The Hende rson(cid:173)
`Hasselbach equation may be used to predict
`the ratio of the concentration of the ionized
`to un-ionized acid groups based upon the
`pH oflhe medium a11d the pK. of the film :7
`
`K _
`pH - P O -
`
`concentratio n (ionized)
`1
`og concentration (un-ionized)
`
`Enteric films that are pH-sensitive should
`have a pK, between 4 and 6. At a pH level
`two units below the pK. of the acid groups.
`for instance, only I % of the acid groups on
`the polyme r will be ionized - which ex(cid:173)
`plains the low solubi lity of the cote rie mate-
`
`Tbble I: Range of pH values i11 the Gt tmct.
`
`GI Area
`
`Stomach
`Duodenum
`Jejunum
`Ileum
`Colon
`Rectum
`
`pH Value
`
`1.0- 3.5
`6.5- 7.6
`6.3- 7.3
`7.6
`7.9- 8.0
`7.8
`
`r ial in the gastric fluid . As p H is incrcase<.:l_
`the equilibrium of the reaction shifts to th -
`right. and the percentage of ionized aci<.J
`groups increases.
`In the intestine, pH exceeds Lhe pK11 of th~
`acid group by two to four units. the pcrccn t_
`age of ionized g roups approaches I 00 %
`a nd the polymer making up the film b~ .
`comes water soluble . 2 Ion izat io n of the aciu
`groups causes a charge repulsion within th~
`polymer. leading to a stre tching of the po l} - _
`mer chain. 8 Stretching Lhc chain a llows w ._'t. _
`ter to penetrate to the tablet core. resulting,
`in tablet disintegration.'
`The pH-sensi tive film s that have been
`studied include shellac .0 ce llulose ace tate:
`phthalme. "1
`0 cellulose acetate succ in;ite . ,..,.
`'
`half-e sters of the co polymer po lyvin y l
`methyl e ther/ maleic anhydride. '~ mcth _
`acrylic acid/ methyl methacryh1te copol _
`mer, '0 polyvinyl acetate phthalatc.~' und hy _
`droxypropyl methylccllulosc phthalatc . ~
`Two of these polymers -
`shellac and cl!! I u -
`lose acetate phthalate - will be discussed i 11
`detail in the fo llowing sectio ns.
`Shellac. Shellac, a long-chain polymer of
`esters of aleuriticacid. was introduced as an
`enteric coating material by Wruble i 11
`1930. 9 Although once used extensively in
`the industry. shellac is no longer the poly(cid:173)
`mer of c hoice for entc ric-coated tablet~.
`Shellac has an apparent pKJ between 6. 9
`and 7.5, a nd this high value leads to poor
`solubility of the film in the duodenum .
`where the pH is genera lly slightly acidic:
`delayed intestinal release of the drug may
`therefore occur.z
`The sta bility of shellac has also been crit i(cid:173)
`cized. Luce reponed that marked change:-.
`in disintegration times occurred in she llac(cid:173)
`coated dicalcium phosphate tablets aft..:r
`storage at room te mperature for one year.
`Before storage, Lablcts disintegrated in in(cid:173)
`testinal fluid within 50 min: a fter storage .
`they fa iled to disintegrate within 120 min .
`The stability of the dosage form may also be
`intluenced by the grade of shellac; ~everal
`grades arc commerc ially ava ilable. USP
`recognizes two basic grades: orange shellac
`(wax o r dcwaxed), and bleached or refi ned
`
`Page 2 of 18
`
`

`

`Eastman C-A-P™
`•
`e 1vers.
`
`Enteric Coating Mater1al
`
`Eastman C-A-P-Cellulose Acetate Phthalate-as an
`enteric coating can give your tablets an elegant, appealing
`finish. But there's more to the effectiveness of this free(cid:173)
`flowing white powder than meets the eye.
`Because of their excellent enteric properties, coat(cid:173)
`ings of C-A-P withstand prolonged contact with gastric
`juices but readi ly dissolve in intestina l fluids. So, one coat(cid:173)
`ing material delivers both elegance and protection.
`Also, impressions made in the tablet are visible
`through the finish, thus eliminating the need for printing
`the coated tablets.
`For more information about C-A-P for enteric coat(cid:173)
`ings, contact Gunther Doerfert, 615-229-3797, or write
`him at Eastman Chemical Products, Inc., a subsidiary of
`Eastman Kodak Company, Kingsport,Tennessee 37662.
`
`Eastman~ C-A-P™
`
`t I • Hid A •• "' 1" J ,. ,, Id,
`
`I
`
`IJ.••
`
`Circle Reader Service Card No. 74
`Thu; m ateri al wu copied
`
`Page 3 of 18
`
`

`

`PHARMACEUTICAL TECHNOLOGY September 1983
`
`126
`
`shellac (wax or dewaxed).21 It has been re(cid:173)
`ported that alcohol solutions of orange shel(cid:173)
`lac arc more stable than arc corresponding
`solutions of bleached shellac: bleached
`shellac tends to estcrify faster because re(cid:173)
`sidual chlorine lowers the pH_ n (The 1ablc1s
`in the study by Luce c ited ea rlie r used
`bleached shellac .)
`Cellulose acetate phthalate. Cellulose
`acetate phthalate (CA P) is a white, free(cid:173)
`fl owing powder prepared by reacting a par(cid:173)
`tial acetate ester of cellulose with phlhalic
`anhydride. The cellulose polymer used in
`the reaction has a molec ular weight be(cid:173)
`tween 2000 and 8000. and the final product
`contai ns 30% to 36% combined phthalyl
`and 19% to 23.5% combined acctyl. Ap(cid:173)
`proximately one-half of the available hy(cid:173)
`droxy groups in the cellulose chain arc acct(cid:173)
`ylated; one-fourth arc estcrified with one
`of the two phthalic acid groups. 1° Figure I
`shows the structure of cellulose and a repre(cid:173)
`sentative structure o f CAP. n
`CAP. the most widely used cnicric coal(cid:173)
`ing material . was introduced by Hiatt in
`1940. 11 Couvrcur conducted an extensive
`study o f cnteric coating o f tablets and con(cid:173)
`cluded that CAP combined all of the quali(cid:173)
`ties required of a true e nteric coating. In(cid:173)
`deed. Couvreur found that C AP was the
`only material testccl that responded exactly
`to the requirements . u
`Zatz and Knowles studied the effect of pH
`on CAP monomers. From pH 2 10 pH 4, the
`CAP monomers were observed 10 be in a
`compact form . As the pH changed from 4 10
`6. however. ionization of the acid groups
`occurred; the greatest effect o n film stabili(cid:173)
`ty was seen at pH 6. 24
`A controversy has developed in the litera(cid:173)
`ture concerning the role of pancreatic ester(cid:173)
`ascs in the disintegration of CAP-coated
`tablets. Bauer and Masucci attributed disin(cid:173)
`tegration of CAP-coated tablets in slightly
`alkaline pancreatic fluid to the hydrolytic
`e ffect of the cstcrascs and not to a pH cf.
`fcct, " while Payne found thai a pancreatin
`concentration of 3 g/L had no signi(icant ef(cid:173)
`fect on the in vitro dis integration time of
`CAP-coated tablcts. 1
`'
`Lo ng-te rm toxic iry studies in rats and
`dogs performed as early as 1944 showed
`that C AP was very safe . Rats had depressed
`growth rates, but no fatalities were a11rib(cid:173)
`u1ed to ingestion of CAP. Dogs fed IO g of
`CAP daily showed no adverse affects after
`o ne year. 2
`•
`Storage of CA P-coated dicalcium phm,(cid:173)
`phatc tablets at room temperature for 12
`months caused no s ignificant change in dis(cid:173)
`integration times.'~ Blythe ct al. . however.
`reported that the type of disintcgrant incor(cid:173)
`porated into the tablet core affected the !lta(cid:173)
`bility of the dosage form. On the one hand.
`they found that CAP-coated aspirin tablets
`containing starc h as the dis intcgrant
`
`showed marked changes in both in vitro and
`in vivo disintegration times after 18 months
`in storage. On the other hand. no change in
`disintegration times was observed afte r
`storage of CAP-coated aspi rin tablet~ con(cid:173)
`taining guar gum as the disintcgrant. n
`
`Methods of Coating
`The oldest method of c ntcric coating in(cid:173)
`volves manual pan coating. Conventional
`coating pans are constructed of stainless
`steel and range in diameter from 12 in . tu 60
`in . Pans arc available in doughnut , pear,
`and hexagonal shapes. and most arc
`equipped with an exhaust syia c tn and a
`humidity-controlled air sourcc. 2 The angle
`o f the axis and the rotation speed may be ad(cid:173)
`justed as needed for a particular product.!>
`The conve ntional pan has a single front
`opening th rough which processing ai r en(cid:173)
`ters. Side-vented pans provide a unidirec(cid:173)
`tional flow of air through the bed and the
`pan's pe rforations . increasing coating
`c fficicncy.1
`M
`Coating solutions may be added to the pan
`by either inte rmittent or continuou~ pro(cid:173)
`ccssc.~. and new spray systems have largely
`replaced the conventional ladle technique for
`solution addition. A dusting powder such as
`talc or tnagncsium stcaratc may be added to
`the bed to prevent tablet ~ticking. The thick(cid:173)
`ness of the coat depend~ upon the nature of
`the coating lilm.1 the physical properties of
`the specific tablet," and the desired in vitro/
`in vivo release profile.
`The air suspension coater developed by
`Wurster i.uspends tablets in an ai rstrcam::-.
`the coating solution is sprayed onto the sus(cid:173)
`pended tablets and is then dried by warming
`the airstrcam . T he major disadvanwgc of
`this coater is breakage and attrition of the
`tablets . Tablets coated in this way must
`therefore have sufficient hardness to with(cid:173)
`stand collision with the walls of the coating
`chamber and with other tablets . i
`
`Evaluation of Enteric-Coated Tablets
`/11 vitro tests. The USP disi ntegration test
`for entcric-coated tablets first appeared in
`1955 in USP XV.'° It was modified in the
`second supplement to USP XV and has since
`remained unchanged . The test specifics that
`the tablets must remain intact in simulated
`gastric nuid TS at 37 °C for l hr. then disin(cid:173)
`tegrate in s imulated intestinal fluid T S at
`37 °C within a time period not 10 exceed the
`limit specified in the individual monograph
`for the uncoated tablet plus 2 hr. 11
`As early as 1948. investigators reported
`that the pH of simulated intestinal nuid
`should he slightly acidic to correspond to
`the pH of intestinal fluid in the duodenum. 14
`Nonetheless. the pH of simulated intc:.tinal
`fluid TS in USP XX ( 1980) is alkaline (pH
`7 .5). '2 A variety of alternati ve artificial in(cid:173)
`testinal fluids have been described in the lit-
`
`l o
`
`a
`
`• • •
`
`-
`
`craturc. the earliest by To pli:. in I 9 15. " The
`pH of these lluids have ranged from low
`values of 6 .8 .. and 6 .9 " tu a high of 8.5. 11
`Still. the only official simulated intc:.tinal
`fluid that is acidic (pH 6.8) i, found in the
`Brirish Pharmacopoeia.,..
`/\ large numbe r o f repo rts fou nd in the lit(cid:173)
`e rature demonstrate that good in vivo per(cid:173)
`formance by an cntcric-coatcd tablet is not
`ensured simpl y by virtueofpa:.~ing the USP
`di~intcgrat ion test. "' 40 Tablets that have
`passed the test have sometimes been oh(cid:173)
`:,ervcd to be excreted unchanged in the fc(cid:173)
`cc~ of normal human subject~."' Other tab(cid:173)
`le t:. have demonst ra ted poor relative
`hioavailability as compared to the uncoated
`tablets."' '~·''' Wagner and colleagues. u:.ing
`the USP disintegration apparatu, and a pH
`6 . 9 buffer. found no direct relationship be(cid:173)
`tween in vivo and in vitro disintegration
`times. '1
`" '·" ' Rasmussen. however. reported
`a direct proportionality between in vitro and
`in vivo disintegration time:.. independent of
`tablet size and composition."
`Virtually no attention has been given to
`the use of a dis:.olution tc:.t for e nteric(cid:173)
`coatcd tablets : indeed. the latci.t USP doc,
`not contain an official method of evaluating
`the dissolution behavior of cntcric-coatcd
`tablets . '1 In a study by Emhil and Torosian.
`the USP procedure for uncoated tablets wa,
`adapted to study the dissolution of cntcric(cid:173)
`coatcd aspirin rnblcts. The authors recom(cid:173)
`mended a pretreatment period of 15 min in
`:.imulated gastric fluid. followed by db:.o
`lution in simulated intc:.t inal lluid . The
`Mudy showed that longer pretreatment p.:n(cid:173)
`ods did not significantly alte r the dissolu(cid:173)
`tion profile."
`In a study performed recently by the au(cid:173)
`thor and co-worke rs. the di:.M>lution of dif(cid:173)
`fe re nt c ntc ric-coatcd formu latio ns wa:.
`studied at pl-I 1.2, pH 6 .0. and pH 8.0.4 '
`The following c riteria were c,tablishcd to
`help in the selection o f the bc,1 coating ma-
`
`n
`
`CII OII ~ H
`
`0
`I
`CII OCCII
`
`0
`
`c-<5
`6 COOH
`
`m,
`
`¢
`O C
`©rCOOft
`
`CHOCCH
`I
`0
`
`"
`
`Fig11re I : Chemical Mmcr11res of ce/f11/o.11•
`(A) and celfulo.ve acew re p/11/wlmc
`(CA P) (B).
`
`Page 4 of 18
`
`

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`Page 5 of 18
`
`

`

`128
`terial and the ideal number of coats:
`• less than 10% of the drug should be re(cid:173)
`leased after 4 hr of dissolution testing at
`pH 1.2
`• the enteric coat should not alter dissolu(cid:173)
`tion of the tablet at pH 6.0; there should
`be no significant difference in percentage
`of drug remaining between the coated and
`uncoated tablets at selected sampling
`times
`• the enteric coat should not alter dissolu(cid:173)
`tion of the tablet at pH 8.0; there should
`be no significant difference in percentage
`of drug remaining between the coated and
`uncoated tablets at selected sampling
`times.
`Dissolution at pH 6.0 proved to provide the
`most information about a formulation. For(cid:173)
`mulations that performed well at pH 1.2 and
`pH 8.0 showed drastically different dissolu(cid:173)
`tion profiles at pH 6.0.
`In vivo tests. Losinski and Diver were the
`first to mention the importance of evaluati.ng
`the in vivo perfom1ance of an enteric-coated
`product. 45 ln 1933 they developed a fluoro(cid:173)
`scopic method of determining in vivo disin(cid:173)
`tegration time. Bukey and Bliven reported by
`1936 that the fluoroscopic method was inac(cid:173)
`curate :~ they introduced the radiographic
`technique, which has been used successfully
`9 The enteric
`by many investigators. 12
`11
`21
`•
`•
`·..,...
`material was usually applied to barium sul(cid:173)
`fate tablets; the progress of the tablet through
`the GI tract was followed by periodic X-ray
`
`analysis.
`Clinical evaluation has been used to de(cid:173)
`termine the in vivo performance of enteric(cid:173)
`coated tablets. Endoscopic examination of
`patients taking enteric-coated aspirin tab(cid:173)
`lets revealed that they suffe red significantly
`less gastric and duodenal mucosa damage
`than did patients taking plain o r buffered as(cid:173)
`pirin tablc ts . .so·52 Investigatio ns with this
`technique also revealed that po tass ium
`chloride released fro m enteric-coated tab(cid:173)
`lets caused lesions in the small bowel. sJ
`The most precise method of evaluating
`enteric-coatcd products is through direct
`detection of the drug in the body. Recent de(cid:173)
`velopments in drug analysis have greatly in(cid:173)
`creased the number of pharmacological
`agents that can be detected in biological llu(cid:173)
`ids. This method of evaluating in vivo per(cid:173)
`formance of coated drugs has been used by
`many investigators.s•-ss
`Physical methods of evaluating the in vi(cid:173)
`vo performance of coterie-coated tablets
`have also been introduced. Husa and Magid
`used a combination of calcium sulfide and
`methylene blue in the dosage form.59 Disin(cid:173)
`tegration of the tablet in the stomach caused
`regurgitation of hydrogen sulfide; disinte(cid:173)
`gration in the intestinal tract was revealed
`by the appearance of methylene blue in the
`urine. Peppem1int oil and carbonated water
`were used in another study ; eructation of
`peppermint indicated tablet di~intcgration
`in the stomach.60
`
`PHARMACEUTICAL TECHNOLOGY, September 1983
`Factors Affecting In Vivo Performance
`Properties of tlte film. Cohesion is the
`ability of a lilm monolayer to fom1 a strong
`bond that resists separation. To obtain a co(cid:173)
`hesive film. adjoining monomers must coa(cid:173)
`lesce on contact. forming a unifonn, non(cid:173)
`laminated matrix . Strong cohesive forces.
`however. can impart both desirable and un(cid:173)
`desirable properties in an enteric film. Al(cid:173)
`though a strongly cohesive film becomes
`more compact a nd less pcm1eable to mois(cid:173)
`ture. strong cohesion leads to film brittle(cid:173)
`ness and innexibility.
`The struc ture and geometric shape of
`polymeric molecules affect the stre ngth of
`the film . Branched macromolecules with
`regular, unhindered shapes form the most
`cohesive films. Cellulose acetate phthalate,
`for e xample. forms a strong, cohesive film
`because of its rigid ring structure and the
`large number of functional groups able to
`form hydrogen bonds. The film 's strength is
`also affected by the solvent system used
`during application. Solvation occurs when
`the solve nt-polymer combinations are
`formed. Adhesive forces must exceed the
`cohesive solve nt-solvent a nd polymer(cid:173)
`polymer forces. In gene ral. the greater the
`degree of solvation, the stronger the result(cid:173)
`ing film.
`As the solvent evaporates. a polymeric
`gel forms . The orientation of molecules in
`the gel - and he nce in the final dry film -
`is a functio n of the solvent-polymer Orienta-
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`was opie G~ruenberg
`P.0 : Box3246,2121 ~cfPA&iaI
`P.O. Box3246,2121 Reach Road
`- - - - - - - - -~ Williamsport, PA 17701
`WIiiiamsport, PA 177<:)!t the NLM and ma be
`717-326-1755
`717-326·1755
`Subj ect USCopyrig t Laws
`-A Lunalra Company
`
`See us at INTERPHEX - Booth 1206
`
`Page 6 of 18
`
`

`

`SUSTAINED RELEASE
`
`dissolution
`
`I
`
`saf,
`
`studies
`
`11 ..
`r il T !'
`116:c: e -. • • t e a
`\I
`•
`\I,
`.
`I
`•
`, ~ \
`•
`~ I, •
`I
`
`~
`
`• ,
`
`I
`
`VERSATILE FEATURES IN MODULAR FORM
`
`• HANSON FULLY EQUIPPED TEST STATION
`• MICRO-PROCESSOR CONTROLLED AUTOMATION
`• VARIABLE SAMPLE TIMES (5 min, - 24 hr.)
`• AUTO-PROBE ELIMINATES PROBE DISTURBANCE IN FLASK
`• AUTOMATED ABSORBANCE DETECTION AND PRINT-OUT
`• PH CHANGE (up to 250 ml) ON PROGRAMMED COMMAND
`• MED IA REPLACEMENT TO MAINTAIN FLASK VOLUME
`• DILUTION AND REAGENT ADDITION CAPABILITY
`• CONVENIENT HPLC ("WI SP"®) INTERFACE
`
`~
`HANSON
`
`RESEARCH CORPORATION
`teadeAI.> ~n fu~olu;t.,<.on teehnotogy
`19727 Bahama St, J NorthridgeJ CA 91324 USA
`213/882-7266
`* VISTRI BUTORS WORLV-WIV E *
`This material was copied
`ClrclaiReCilfllaf £EiJ1f!~.Card No. 78
`Subject US Copyright Laws
`
`tlx:182-344
`
`Page 7 of 18
`
`

`

`PHARMACEUTICAL TECHNOLOGY. September 1983
`siveness is reduced, with a resultant increase
`R ·mussen ob·
`Thickness of the coat. as
`h
`in flexibility and toughness.
`h' between t e
`.
`served a direct relations 1P
`h
`The plasticizer must be miscible with the
`thickness o f the CAP coat on tablets and I de
`polymer and usually is related closely in
`the blood an
`. .
`.
`appearance of qummc in
`. w
`structure to the polymer. 8 The type of plasti(cid:173)
`l'miting
`urrnc.
`cizer used will affect the moisture-vapor
`Gastric emptyi11g rale. The rate- 1
`d
`transmission rate through the film and theo(cid:173)
`ntcric-coate
`.
`f
`.
`step in the absorption o an c
`.
`retically will affect the in vivo disintegra(cid:173)
`pty rng ume.
`.
`drug product is the gastric em
`d
`tion time. Luce, however, reported that
`rescntc to
`b
`Once the dosage form has cen P ·
`d . b-
`plasticizers have little effect on in vitro dis(cid:173)
`thc intestinal tract. disintegration an .;ly
`integration times. 15 The most common plas(cid:173)
`sorption of the drug should occur ~api
`·
`ticizers used in the pharmaceutical industry
`. c residence
`Any factor that affects the gastn
`d·-
`arc phthalatc e~tcrs. glycerin. castor oil .
`·11 therefore 1
`d-
`time of the dosage form wi
`propylene glycol . and low molecular
`f the pro
`rcctly affect the performance O
`• that
`weight polyethylene glycols.2
`1 · d , veraJ factors
`'
`uct. • Maycrsohn 1ste se
`.•
`.
`. humans, in
`influence gastric emptying in
`the
`I
`d pe of mea'
`.
`eluding the volume an
`ty
`·ous
`ntcnts van
`·
`physical state of gastric co
`'
`sition,
`
`130
`tion. It is usually desirable to have a rapid
`rate o f solvent evaporation in order to re(cid:173)
`duce the required coating time. 8 Rapid
`evapora'tion, however, promotes the forma(cid:173)
`tion of a rough, " orange peel" coat. 2 The
`permeability of the film also may be affect-
`.
`8
`ed by the rate of evaporatton .
`A plasticizer may be added to a polymeric
`film to reduce brinleness, increase flexibili(cid:173)
`ty, and i mprove flowability. Plasticizers are
`low-volatile liquids that change the physical
`and mechanical propenies of the polymer. 2
`One theory holds lhat a plasticizer interferes
`with the polymer-polymer anachments, thus
`reducing molecular rigidity. The film's cohc-
`
`I Introducing a
`'
`faster, safer way
`of screening
`ingredients
`
`'mCUUlol
`IINf
`
`/
`
`MATERIAL []
`
`This new check sieving package, combining the Russell Siv
`and a Vac-U-Max va_c~um transfer system, is a major break(cid:173)
`through to more eff1c1ent, safer processing. The completely
`closed system enables you to automatical ly transfer material
`to your process and check sieve in the same operation. No
`dust, no loss, no hazard, no contamination. Vacuum in(cid:173)
`creases throughput many fold, yet eliminates manual opera(cid:173)
`tion, and greatly reduces housekeeping. For further details or
`to arrange for demonstration at the Vac-U-Max test lab using
`your own material, call or write Vac -U -Max, 37 Rutgers St
`iBelleville, N.J. 07109. (201) 759-4400.
`·•
`
`drugs. several disease states. body r
`
`the
`.
`and the extent o f physical exerci_se.
`· · either in
`bl
`or
`An enteric-coated ta ct is
`.
`. 1 fi absorptron'
`stomach and not ava1lab e or
`raphic
`.
`. 1 tra· ct Rad1og
`.
`.
`.
`I
`.
`11 1s in t 1e rntestrna
`·
`h
`f time
`studies have determined the len~t 0
`the
`.
`· etained 1n
`an enteric-coated tablet is r
`b BukeY
`40 An extensive SIUdy Y
`4
`47
`f
`stomach. 2
`•
`•
`d shape o
`.
`and Brew found that the size an .
`time
`.
`rr
`emptying
`'
`the tablet did not a cct
`.
`tiga-
`9 h •• O1her inves
`which averaged 5.
`r.
`ptying
`.
`tors reported that the average em
`. ob·
`d olleagucs
`time was 4 hr: 8 Blythe an c
`hr 25
`7
`I 5 hr to over
`·
`served a range from
`key's
`·
`8
`trary to u
`Wagner reported that, con
`h
`tablet
`and Brew's findings, the size of I creovcr.
`· e· mo
`affected the residence t1m ·
`.
`time
`. mpty rng
`Wagner observed that e
`1
`tying
`obeyed the laws of probability.
`•
`.
`. .
`r astnc emP
`The unprcd 1ctabrlrty o. g •
`.. dvaniage
`time is often seen as a unrque disa
`drugs
`o f enteric-coated tablets; howevc~, omach
`b d r om the st
`1
`r
`.
`that arc poorl y absor e
`factor.
`arc also greatly affected by thf,~ e, water
`lass O IC
`ed tab-
`Ritschel suggested that a g '· ·
`tcric-coat
`••
`. h
`should be taken wrt an en
`.
`tying.
`let to ensure rapid stomach emP
`ap·
`d' ffercnt
`I
`Wagner recommended a
`tirnum
`thc
`proach, observing
`that
`~those
`emcric-coated dosage forms wou
`·,nules
`f atcd gr,
`in which a large number o co
`,
`1
`. d . a capsu c.
`.
`or prlules were comarnc 1n
`
`1;
`
`d •rablelS
`•
`Reliability of Enten c-Coate
`fin
`Ports o
`, d 1ed
`Cooper stated that frequent re
`ed tablets ha
`.
`.
`.
`... ·rn bY
`vivo failures of entcnc-coat
`.
`crruc1s
`. . g of
`to suspicion among and acuve
`escrrb1n
`clinicians faced with the pr
`i·ierature
`,6l The 1
`.
`.
`cnterrc-coated dosage forms.
`-
`g thC
`11
`d onstrat1
`,,,
`contains many accounts cm
`.1<>.J9.S11·•'
`unreliability of the dosage for~,; on thC
`very little however, has been written of (he
`.
`'
`.
`Most
`and
`subJcct in the recent literature.
`970
`d before 1
`'
`negative reports appcarc
`h t arc not
`several of those concerned dru~s t arorms in
`available in enteric-coated dosage
`the United States.
`nations
`1
`There are several possible exp a
`
`Page 8 of 18
`
`

`

`CAPSULE MA NUFACTURING
`
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`
`R&O LABORATORIES
`
`STORAGE & PACKAGING OF
`HYGROSCOPIC M ATERIAL
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`HEAT-SENSITIVE
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`AMPULE FILLING
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`TABLET COATING
`
`POWDER FILLING
`
`COMPOUNDING
`
`DOESYOUR
`fHARMACEUTICAL PLANT
`4VE HUMIDITY PROBLEMS?
`
`quali ty systems guarantees years of low
`mainte11cmce and the support or a 24-hour
`service Hot Line.
`To learn how a Cargocaire Industrial
`Dehumidification System can eliminate
`your humidity control problems call Boris
`Elisayeff, Market Manager, (617) 388-0600
`or attach your business card to this ad and
`mail it to Cargocaire today.
`
`ma~~rn humidity causes pharmaceuticaJ
`more ac~urers quality control problems (cid:173)
`for so~~i more they look to Cargocaire
`Th
`ons.
`for d~ ~·s b~cause our systems are known
`manuf ivenng conditioned air that meets
`Wheth acturers' specifications consistently.
`dew p ~r you require delivered air wit/1
`minus om!5 of 1- 40°F or dew points of
`5~ F or anywhere in between, a
`Car
`O
`appfi/at!re system can meet your critical
`S a 10 11 needs.
`Plai rem~ve humidity as a variable in your
`rate
`7nvironment and improve the drying
`0
`Proble heat~sensitive materials, eliminate
`
`ing, po mJ wi~h _compounding, encapsulat-
`
`And w er f1llmg or tablet coating.
`Cargo/~ the leader in dehumidification,
`cant l aire can show you how dry desic(cid:173)
`signifi~chnology can save your company a
`
`dificati ur sa_r e, dry, non-corrosive dehum1-
`
`costs. 0nt ~ercentage of its pr~sent energy
`Pharrn °~ ll~lls offer capaci ties to meet any
`Produc~ce~tical processor's need with units
`Produc;ng fO to 40,000 SCFM, and systems
`steam ng 50 to 15,000 SCFM. You choose
`the de~?as or electric power supply. And
`ign leadership of our industrial
`
`~
`Gocl\lflEEN
`GiNEEAiNGc
`OFlPORATtON • Ot:PT 310 W. p O BOX 640 . AMESBURY. M ASS 01913 • TEL 6 17-388-0600 • TELEX 94-7496 • CABLE CARGOCAIRE
`
`Clrcle Reo~r c:..rvtce Card. No. 80
`s ~re riarw,ucop,ed
`at the NLM and
`
`Page 9 of 18
`
`

`

`132
`,
`the recent decline of reported in vivo
`,m
`b
`.
`failures involving enteric-coated ta lets m
`the United States. The most obvious reason
`is that the number of products available in
`this dosage form has declined. In 1930 an
`estimated 3.3 % of all prescriptions were
`written for enteric-coated drug products.611
`Statistics are not available concerning the
`use of this dosage form today; nevertheless,
`the percentage is certainly much lower. Ta(cid:173)
`ble D contains a list of the diminishing num(cid:173)
`ber of drugs available in enteric-coatcd tab(cid:173)
`lets in the United States in 1981. 69
`The early reports of in vivo failures had the
`benefit ofleading to the elimination of many
`
`i,er1983
`ed 10
`PHARMACEUTICAL TECHNOLOGY, Septe~
`ot
`unacceptable entcric coating materials. Re-
`11! recently. tablet coaling was
`. consider
`.
`.
`.
`. les weren
`be an art, and scientific pnncip
`ues con·
`formu lation of an enteric-coated aspirin tab-
`50s
`let, for instance, occurred in the 1960s after
`rigidly applied. Wagner and colleag
`f
`f
`19
`requent reports o · poor in vivo perfor-
`
`
`
`. n the late f large d. ducted a series o stu ,es I
`.
`f
`38
`58
`designed to determine the causes O rciallY
`Most of the enterie-coated tab-
`mance.
`~"
`I
`• ·n comrne
`.
`. •
`ets introduced to the market in the past few
`, TheY dis-
`batch-to-batch vana11ons 1
`years have been co