PHARMACEUTICAL
`,T E C H N O L O G y ...-.
`
`VOLUME 7
`
`Page 1 of 18
`
`KVK-TECH EXHIBIT 1025
`
`

`

`124
`
`PHARMACEUTICAL TECHNOLOGY, Seplember 1
`
`3
`
`The forgotten dosage form:
`enteric-coated tablets
`
`WALTER G . C HAMBLISS
`
`T HE RECENT INTROD UCTION of
`
`transdcm1al dcl ivery sy tcms and other
`controlled-release dosage fom1s has demon(cid:173)
`strated the ingenuity of the pharmaceutical
`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 fom1 thar appears to have been
`forgotten: the enteric-coated tablet.
`An enteric-coa1ed tablet is designed le> re(cid:173)
`sist the desrructive acrion of the gastric nuid
`and Lo disintegrate in the intcslinal tract.'
`Reason
`for apply ing an cmeric coa1 to a
`drug produc1 include: '"'
`• preventing the drug's de !ruction by ga ·(cid:173)
`tric enzymes o r by the acidi ty of gastric
`tluid
`• preventing nausea and vomi ling caused
`by the drug's irr ilali on of th e gastri c
`muco a
`• delivering the drug to its local si te of
`acti on in the inte tine
`• providing delayed actio n
`• delivering a drug primarily ab ·orbcc.l in
`the intestine Lo that site at the highest po -
`si ble concentratio n.
`This presentation will review the history of
`this dosage form and exami ne the reasons
`for its apparent demi e.
`
`Basic Studies
`In 1965, Schroeter published a review of
`over 60 materials that have been used as en(cid:173)
`teric coating materials,' referri ng to studies
`that found both favorab le and un favorable
`in vivo performances fo r tablets coated with
`those materials. T he four basic types of en(cid:173)
`tcric coaling materials are water-resistant
`films. pH-sensitive film . materials digest(cid:173)
`ed by intesti nal nuid, and materials that
`lowly swell and dissolve after expo ure to
`moisture. : The pH-se nsitive films have re(cid:173)
`ceived the most attention in the literature.
`Indeed, enteric products introduced recen t(cid:173)
`ly eem to be manufac tured exclusively
`with this type of coating .'
`
`pH- ensitive Films
`As the name im pl ies, pH-sensi 1ivc film is
`di rectly affected by the pH of the GI tract.
`
`The film must be insoluble in gastric llu icl
`bu t dissolve rapid ly in inrcstinal nuid . Table
`I lists pH val ues fo und in the G I 1ract." The
`usual pH of gastric llu id range from 1.0 to
`3.5 . Fasting generally reduces the pH va lue
`to a level between 1.2 and 1.8. and G I dis(cid:173)
`eases and drugs such as hista mine H-2 an(cid:173)
`tagonisrs, ant icholinergics. and antacids are
`also know n to affect pH .7
`Enteric fi lms that are pH-sens itive consist
`of a long-chain polymer with ioni zab lc car(cid:173)
`boxyl g roups . In the low-pH environment
`of the ga tric tluid . the acid groups a rc un (cid:173)
`ionized and arc therefore poorly water solu(cid:173)
`ble. When the tablet empties from the stom(cid:173)
`ach into th e s mall in tes tine . a drama ti c
`change in pH occurs: ionization of the acid
`group and, therefore, increased water . ol(cid:173)
`ubili ty occ urs in th e intestinal trac t as
`shown in Lhc fo llowing eq uation:
`
`T he eq uili bri um co nstant for th· rc11ctiun is
`a functio n of Lhe pH of the medium and the
`apparent pK. of Lhe film .' The Henderson(cid:173)
`Hasselbach equation may be used to predict
`the ratio of the concent ration of the ionized
`10 un-ionized acid groups based upon the
`pH of the medium and the pf(, of the film :'
`
`concent ration (ionized)
`K _ 1
`pH - P • - ogconcentration (un-ionized)
`
`Enteric films that are pH -sensi tive sh uld
`have a pK. between 4 and 6. At a pH level
`two unit s below lhe pK, of the acid groups.
`for instance, only I % of the ac id groups on
`the polymer wi ll be ionized - which ex(cid:173)
`plains the low solubility oft heentcric mate-
`
`7bble I: Range of p H values in the GI tmct.
`
`GI Arca
`
`tomach
`Duodenum
`Jej unum
`Ileum
`olon
`Rectum
`
`pH Value
`
`1.0- 3 .5
`6.5- 7.6
`6 .3- 7 .3
`7.6
`7.9- 8.0
`7.8
`
`rial in the gastric lluicl . As pH b in rca~e<...1.
`f lhc reaction s hifts to th -
`the equilibrium
`rig ht , and 1hc percentnge or ionized a ·i.__t
`groups increa cs.
`intestine, pl-I exceeds the pK., ofth ,
`In th
`acid group by two to four unit ·. the pcrcc n t.
`age of ionized g ro ups approac hes I 00 ''.(cid:173)
`and the polymer making up th<.· film be(cid:173)
`come · water soluble .1 Io nizatio n of th<' aciu
`g roups cau ses a charge repul sion wi th in th
`polymer. leading 10 a . tret hing of 1he pol .'- ,
`mer chain .8 Stretching the chain allows w~~ (cid:173)
`ter to penetrale to the table! core. rcsu lt in ~
`in 1ablct disi ntegration .'
`The p H-sensi t ive fi lms tha t hav e bc~·rt
`studied include shella ." cellulose ace tat
`phthalatc , "' 10 cellulose acetate succi natc. ,.,.
`half-c ·tcr · of the copolymer p lyvin I
`me rhy l e th er/ muleic anhydride, " mc th _
`acrylic acid/methy l methacrylatc copn l _
`mer. ''' polyv iny l acetate phthalatc /'' and h _
`d roxy propy l meth y lccllulose phthalatc .:
`Two of thcs · polymers -
`sh Ila and ·ellu _
`lose acetate phthal;itc - will be discuss •d in
`detai l in 1hc fo llowing sections.
`Shellac. Shellac, a long- hain polym rt>f
`esters ofalcuritic acid , was introduced as an
`e nte ric coat ing material b Wrubl c in
`I 930. 9 Although once used ex te nsive!
`in
`the industry. shellac is no longer the pol) -
`mer of c hoi ce for e nt e ri -coa ted tablet, .
`She llac has a n apparent pK. between 6 . 9
`and 7 .5. and this high va lue leads to J)(l(>r
`so lub ilit y of the film in the duodenum .
`where the pH is generally
`lightl y ac idic :
`de layed intestinal rclea e of the drug may
`therefo re occur.'
`The stabili ty of shellac has also been criti(cid:173)
`·izcd . Luce reported that marked clwngc,
`in di sintegra rion rimes occurred in shcll:K·(cid:173)
`coa tcd dica lcium phosphat e tablets afta
`storag at room temperature for one year
`Before ·toragc, tablets disi ntegrated in in(cid:173)
`testinal ll u id within 50 min : after sto rage .
`1hcy failed to dis int grate with in 120 min
`The stability of the do age fom1 ma also Ile
`innuenced by the grade of shellac : ~ever:11
`grades a re comme rcia ll y available . SP
`recogn izes two basi grades: o range . hc llac
`(wax o r dewaxed) , and bleached o r refined
`
`Page 2 of 18
`
`

`

`Eastman C-A-P™
`• e 1vers.
`t
`
`,ng Material
`
`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 readily dissolve in intestinal 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™
`
`NI ....
`
`< I
`
`lf.t'.,., a
`
`J,,r .,,~, .
`
`Circle Reader Service Cord No. 74
`
`Page 3 of 18
`
`

`

`126
`
`shellac (wax or dcwa11ed)." h has been rc(cid:173)
`poned that alcoh I soluti ns or orange hcl(cid:173)
`lae arc more stable than arc corresponding
`s lutions of bleac hed hella ; bleached
`to csterify fa te r because re(cid:173)
`shellac tend
`sidual chlorine lowe rs the pH . :u (The tablet~
`in th e study by Luce c ited curlie r used
`bleached he lla .)
`Cellulose acetate phthalate.
`ellulose
`acetate phthalatc ( AP
`i a white. free(cid:173)
`no wing powder prepared by reacting a par(cid:173)
`tial acetate ester of cellulose with phthalic
`anhydride. The cellulose pol yme r used in
`the rca tion has a molec ular weight be(cid:173)
`tween 2000 a nd 000, and the finul product
`contains 30 % to 36 % combined phthalyl
`and 19 % to 23 .5 % combined acctyl. Ap(cid:173)
`proximately one-half of the avai lable hy(cid:173)
`droxy gr up in the cellulose chain arc acct(cid:173)
`ylatcd ; one-fourth a rc esteri 1ed with o ne
`of the two phtha lic acid groups ."' Figure I
`shows the structure of cellulo
`and a rcpre(cid:173)
`scmative structure fCAP_:,
`AP, the mo ·t widely used e nteric coat(cid:173)
`ing material. wa, introduced by Hiatt in
`1940 . 11 Cuuvrcur conducted an ex tensive
`f enteric c ating of rnblct and con(cid:173)
`study
`cluded that CAP combined all of the quali (cid:173)
`ties required o a true enteric oa ting. In (cid:173)
`deed,
`uvrcur found th at AP was the
`only material tested that responded exactly
`to the requirement . u
`Z,nzand Kn wle stud ied the effect of pH
`on AP monomers.
`rum pH 2 to pH 4 . the
`AP monomers we re bservcd to be in a
`compact form . A the pH changed from 4 to
`6, however. ioniza1i n of the acid groups
`occurred ; the greatest effect on film stabil i(cid:173)
`ry was seen at pH 6. ' '
`A c ntrovcrsy ha developed in the litera(cid:173)
`ture concerning th
`role f pan rcatic estcr(cid:173)
`ases in the disi ntcgra1jon of AP-coated
`tabl ets . Baue r and Masucci attributed disin(cid:173)
`in sligh1ly
`tegrntion of CAP-coated tablet
`fluid 10 1hc hydrolytic
`alkali ne panc rcati
`effect of th e tcra. c a nd not 10 a pH ef(cid:173)
`fect," while Payn · found thal a panc reatin
`concen tra1io n of g/ L had no significant ef(cid:173)
`fect n the in vitro disi ntegrmion time of
`AP-coated tablet .1'
`Long-term toxiciry studies in rat s and
`dogs performed as early as 1944 showed
`that AP wa · very safe . Rais h.id depressed
`growth r tcs, but no f'ataliti we re aurib(cid:173)
`utcd 10 ingcsti n of AP. ogs fed 10 g of
`AP daily howed no adve rse affects after
`one ycar.2b
`1 rage of AP-coated di al ci um ph11·(cid:173)
`phate 1ablcts at room temperature for 12
`months caused no significant change in dis(cid:173)
`integration time .. '" Blythe ct al. , however.
`type of disi ntcgrant incor(cid:173)
`reported thal th
`porated into the tablet core affc 1ed the ta·
`bili1y
`f the do age~ nn . n 1hc one hand.
`th y fou nd 1ha1 AP-coated aspirin 1ablc1s
`co ntainin g starc h as
`th e disintcgrant
`
`PHARMACEUTICAL TECHNOLOGY,
`
`pt mber 1983
`
`showed marked changes in both in vitro and
`in vivo di integration times after 18 months
`in storage. On the othe r hand , no c hange in
`disintegration time~ was observed after
`storage of AP-coated a~pirin tablets on(cid:173)
`taini ng guar gum as th disintegram :''
`
`Met hods of 'oati ng
`The old M me1hod of entcric coaung in(cid:173)
`volves manual pan coating. Convc111ional
`coating pans a re co nstructed of s1ainlcss
`steel and ra nge in diameter from 12 in. Ill 60
`in. Pans arc available in d ughnut , pear,
`and hexagonal shapes, and most arc
`equipped wilh an ex hau st sy. tem a ntl a
`hu midity-co ntrolled air source .' The ungle
`of the a is and the rotation speed may be ad (cid:173)
`ju tcd a · needed for a panicular product. "
`The conventional pan has a
`inglc front
`opening through whic h processi ng air e n(cid:173)
`idc-vented pan · provide a unidirec(cid:173)
`ters.
`tional !low o f air thr ugh the bed and the
`pan's pe r ora ti o ns. increasing coa ting
`cflicicncy. :M
`o.uing solution · muy be added to the p,111
`by ei ther intermittent or continu o u~ prn(cid:173)
`ccssc.~. and new spray systems have largely
`replaced the conventional ladle technique for
`solution addition. A dusting powd ·r such as
`talc or mugncsium stearatc may be added to
`1he bed to prevent tablet sticking. The thick(cid:173)
`ness of the coat depends upon the nature of
`the oating mm.' the physical propcnies of
`the specific tablet ," ,md the desired in vitro/
`in vivo release profile .
`The air ~uspens ion oate r de eloped by
`Wurster uspcnds tab lets in an air tream ::,,
`the coating solution is sprayed onto the sus(cid:173)
`pended tablets a nd is then dried by warming
`1hc airstream . Th major disadvanwgc of
`th is coa ter is breakage and attntio n of the
`tablets . Table t coated in thi s way mu st
`therefore have suflicicn1 hardness to wi th(cid:173)
`tand coll ision with the walls of th coating
`chamber and with other tublcts. 2
`
`ernturc.thecarli•stb Toplbin 1915 ." Thc
`pH of these nuid s hav • ranged from I w
`va lue~ or 6 .8" and 6.9" lO a high o f 8 .5."
`till. the only official simulmed imestinal
`nuid that is acidic (pH 6 .8) i, found in the
`British Plwrmacopneia ."
`A large numbe r or rcpom fou nd in the lil (cid:173)
`eratu re dcmunstrn tc that good in
`ivo pcr(cid:173)
`forn1ance b an ent ·ri -coa1ed mblct i. nm
`cn~urcd sim ply by vi nuc r passi ng the U P
`dis1111egratillll ICSl. "'"0 T:tbl ClS that ha C
`pa 'Sed the test have 0111 'limcs been ob(cid:173)
`served to be c crctcd un ·hanged in th ' c (cid:173)
`cc, of normal human ubjc ·t~ ."'
`thcr tab(cid:173)
`le t~ ha e dcmon~t ratcd p, or rc la1 ivc
`hiuavailability as co mpared to the un ·omcd
`Lablcll,."' '' '° Wag n r a nd colleague ·. using
`P disintegration apparatu., and a pH
`1he
`6. 9 buffer. fount! no direc t rclat ion~hip he(cid:173)
`tween in vivo and in vi1rn di si ntegration
`time~ ."·"'·" Ra~m usscn. ho, • e r. rep< ncd
`a direct proponionality between in vi tro and
`ivu disintegration tim s. ind pendent of
`in
`tabl et site and composi tion ."
`Virtu .ill
`11<1 aucntiun ha~ been gi e n In
`the u~c of a dii.~olu tion te~ l for cn tcr k
`coa ted tablets: indeed. th · lat ·~l SP doc,
`1101 contain an oflicial method ofcval ua1i11g
`the dissolution behavior of ·n1c ric-cl1:ncu
`tahlct.-. ." In a study by Embil a nd Torosi:i n.
`P procedu re for uncoated tablet~ wa,
`the
`;1daptcd to study the dissolution of cntcric(cid:173)
`cmncd aspirin mblets. The authors rccom
`me nded a pretreatment p-riod o f 15 min in
`~intulatcd ga.stri · flu id. followed b di~so
`lution in
`irnulatcd imc tin:1 1 nuid . Thi.'
`~tud showed thai longer pre treatment peri(cid:173)
`ods did not s ig nificantly :il l ·r the dissolu(cid:173)
`tion profile."
`In a Mud performed recent! b 1hc au(cid:173)
`thor and co-workers . the di,~ulu tion of dif(cid:173)
`fere nt en te ri c-coa tcd formu lati o ns , as
`·tudicd at pH 1.2. pH 6.0. and pH 8.0. 11
`Th• following criteria , ere established to
`help in the. election of the best coati ng ma-
`
`Eva lua tion of Ent r ic-Coated Tablets
`Irr vitro l e ts. The SP disi nteg ration test
`for e ntcric-coatcd table!~ first appcurcd in
`1955 in USP XV."' It was modified in the
`second supplement to USP XV a nd ha~ ~ince
`remained unchanged . The test spec ifics that
`the tablets mu t remain intact in simulated
`gastric nuid T at 37 • · for I hr. then disin(cid:173)
`tegrate in ~i mulated inte ·tinal nuid TS n1
`37 ° within a rime period not 10 xcccd the
`limit ~pcci fi cd in the individual mon graph
`for the uncoated tablet plus 2 hr. 11
`As cMly a 1948. invc ·tigators reponcd
`that th pH <>f sim ulat ed intestinal fluid
`sh ulcl he slightly acidic to correspond tu
`the pH of i111cstirrnJ fluid in the duodenum ."
`oncthclcss. the pH of simulated inle~tinal
`in USP XX ( 1980) is alkulin · (pH
`nuid T
`7 .5) . 11 A variety of ah •rnativc anificia l in(cid:173)
`testinal lluids have been de. cribcd in 1hc lit-
`
`.. . -. ~
`
`.. .. -
`
`0
`I
`c110CCt1
`
`c.--C) 6 C©I
`
`¢
`
`CHOCCH
`I
`0
`
`Fii;rire I: hemi/'11 / .\lruc·111rt•s of ce/111 /o."'
`(A) mu/ ce/111/<m• at·(•tatl! p/11/wlau,
`( AP) (8 ).
`
`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 coal should not alter diss lu(cid:173)
`tion of the tablet at pH 6.0; there should
`be no significant diffe rence in percentage
`of drug remai ning between the coated and
`uncoated tablets at selec ted sampling
`times
`• the enteric coat should not alter dissolu(cid:173)
`tion of the tablet al 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 10 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
`fi rst to mention lhe importance of evaluating
`lhe in vivo perfom1ance of an enteric-coated
`product.' 1 In 1933 I.hey developed a fluoro(cid:173)
`scopic melhod of determining in vivo disin(cid:173)
`tegration time. Bukey and Bliven reported by
`1936 that the fluoroscopic method was inae(cid:173)
`c u rate :46 they introduced the radiographic
`technique, which has been used successfully
`by many investigator ."·"·n·- 9 The enteric
`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 e ntcric(cid:173)
`coated tablets. Endoscopic examination of
`patients taking enteric-coated aspirin tab(cid:173)
`lets revealed that they suffered significantly
`less gastric and duodenal muco a damage
`than did patients taking plain or buffered a -
`pirin tablcts .l()-;, Investigatio ns with thi
`technique also revealed that potassium
`chloride released from entcric-coated tab(cid:173)
`lets caused lesions in the ·mall bowe\.s,
`The most precise method of evaluating
`enteric-coated products is through d i reel
`detection of the drug in the body. Recent de(cid:173)
`velopments in drug analysis have greatl y in(cid:173)
`creased the numbe r of pharmacological
`agents that can be detected in biological fl u(cid:173)
`ids. This method of evaluating in vivo per(cid:173)
`fo rmance of coated drugs has been used by
`many investigato rs.'' s,
`Physical methods of evaluating the in vi(cid:173)
`vo perfonnance of cnteric-coated tablets
`have also been introduced . Husa and Magid
`used a combination of calcium sultide and
`methylene blue in the dosage form .s• Disin(cid:173)
`tegration of the tablet in the stomach caused
`regurgitation of hydrogen ·ultide; disinte(cid:173)
`gration in the intestinal tract was revealed
`by the appearance of methylene blue in th
`urine. Peppem1int C>il and carbonated water
`were used in another study; eructation of
`peppermint indicated 1ablc1 disintcgra1jon
`in the stomach.'°
`
`PHARMACEUTICAL TECHNOLOGY. September 1983
`Factors Affecting In Vivo Performance
`Properties of t/1e film . Cohesion is the
`ability of a tilm m no\aycr to form a trong
`bond 1ba1 resists separation. To obtain a co(cid:173)
`hesive film. adjoining monomers must coa(cid:173)
`lesce on contact. forming a unifom1. non(cid:173)
`laminated matrix . Strong cohesive forces.
`however, can impart both desirable and un(cid:173)
`desirable properties in an cnteric film . Al(cid:173)
`though a strongly cohesive film become
`more compact and less permeable to mois(cid:173)
`ture. strong cohesion leads to fi lm brittle(cid:173)
`ness and inflexibility.
`The 1ruc1ure and geometric shape of
`polymeric molecule affect the strength of
`the film . Branched macromolecules with
`regular, unhindered shapes fo rm th most
`cohesive lilms. Cellulose acetate pbtha\a1c.
`for example . fo rms a st rong. cohesive film
`because of its rigid ring structure and the
`large number o f fu nctional groups able to
`form hydrogen bonds. The film's strength is
`also affected by the ·o\vem ystem u ed
`during application. olvation occurs when
`the solvcm -po lymer combinations arc
`formed . Adhesive forces must exceed the
`cohesive solvent-solvent and polymer(cid:173)
`polymer forces . In genera\. the greater the
`degree of solvation, the str nger the result(cid:173)
`ing film .
`As the so\v nl evaporate . a polymeri
`gel form . The orientation o f molecules in
`the gel -
`and hence in the linal dry film -
`is a fun 1ion of the solvent-polymer Orienta-
`
`Granulation Dryers
`THAT PASS THE TEST
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`THAT PASS THE TEST
`
`Designed, built. and tested 10 meet
`your requ irements. The latest in single(cid:173)
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`ers. and explosion-resistan t drye r .
`Custom enginening for any shape or
`size. Fu ll y-welded structu ra l steel
`frames. Steam, gas, or electrica lly
`heated. Free information kit.
`
`The latest CG MP designs ensure validation with ± 5° uni·
`formi1y and fa tory tun ed and tested air t1ow to ± 20 FMP.
`175° steri lization a nd 250° depyrogenation in sh~·lfand tru ck(cid:173)
`load inR units. ustom engineering for any sh ape or size.
`Fully -welded structural stee l framework. omplc-tc informa(cid:173)
`tion packet avai\abk.
`
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`
`t) GRUENBERG OVEN COMPANY
`. ~
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`P.O._Box3246, 2121 ~<!ll~~ahvas op,e G~ruenberg
`WIiiiamsport. PA 1770Jt. the NlM and ma be
`_________ ,
`Subj en US CopVrig t Laws
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`Williamsport, PA 17701
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`Page 6 of 18
`
`

`

`SUSTAINED RELEASE
`
`dissolution
`
`II , ,
`
`studies
`
`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
`• MEDIA REPLACEMENT TO MAINTAIN FLASK VOLUME
`• DILUTION AND REAGENT ADDITION CAPABILITY
`• CONVENIENT HPLC ("WISP" ) INTERFACE
`
`~
`HANSON
`
`RESEARCH CORPORATION
`eadvv.,
`·n d,t-Molu;Ci.on t.ec.hnotugy
`19727 Bahama St., Northridge, CA 91324 USA
`213/882-7266
`* VISTRIBUTORS WORLV-WIV E *
`fhis materia l was copied
`Clrcle,,Ruilll!M £$'11'1~.Card No. 78
`Subject US Copyrlr;ht Laws
`
`tlx:182-344
`
`Page 7 of 18
`
`

`

`130
`lion . It is usually desirable to have a rapid
`rate of solvent evaporation in order lo re(cid:173)
`duce the required coating time .' Rapid
`evaporntion , however, promotes the fo rma(cid:173)
`tion of a rou gh, "orange peel .. coal. ' The
`permeability of the film also may be affect(cid:173)
`ed by the rate of evaporation. 8
`A plasticizer may be added lo a polymeric
`film to reduce brittlenes ·, increa e flexibili(cid:173)
`ty, and improve flowability. Plasticizers are
`low-volatile liquids that change the physical
`and mechanical propenics of the polymer.'
`One theory holds that a plasticize r interferes
`with the polymer-polymer attachments. thus
`reducing molecular rigidity. The film 's cohc-
`
`r Introducing a
`'
`faster, safer way
`of screening
`ingredients
`
`PHARMACEUTICAL TECHNOLOGY, September 1983
`·
`Ra. smussen ob-
`Thickness of I 1e coat.
`siveness is reduced, with a resultant increase
`J
`served a direct rclauons 1P
`h' bc1ween ihc
`·
`h
`in flexibility and 1oughness.
`1e p as1Jc1ze r must e m1sc1 e wu
`t e
`Tl
`I
`1l11·ck11ess· of the CAP C(1at on tablets and t de
`· ·
`b
`·
`'bl
`· h h
`. .
`·
`he blood an
`polymer and usually is related closely in
`appearance of qu1111ne 111 1
`structure 10 1he p<.llymer.' The type of plasti-
`. -limiting
`uri ne. '''
`.
`,
`Gastric emptymg rate. 1 he r,ite
`cize r used will affect lhe moisture-vapor
`d
`·
`f ·
`· nteric-coate
`.
`step in the absorpimn o ~n "
`1ransmission rate through the film and theo-
`iimc.
`drug producl is the gastric emptymg d
`retically will af~ ct the in vivo disintegra-
`resentc 10
`Once 1he dosagc form has cen P
`lion time. Luce, however, reported that
`d , b-
`b
`the in1e. tinal 1ra t, disintegratio n an .daly
`plasticizcrs have little effec1 on in vi1ro dis-
`Id
`ur rap•
`·
`integra1ion 1i111es. 1 The most common plas-
`sorption of 1hc drug shou occ
`.d nee
`i
`· ·
`I
`stric res• c
`llc1zers used in the pharmaceutical industry
`Any fac1or that affects 11e ga.
`d·-
`·11 therefore 1
`d-
`ar phthalatc esters. glycerin , casto r oil ,
`time of the dosage fo rm wi
`of the pro
`rcctly affect the performance
`h 1
`propylene glycol, and low molecul ar
`aJ facl rs l a
`..•
`weight polyethylene glycols.
`uc1.' Maycrsohn listed sever,
`2
`· humans. in
`.
`inlluence gastric empt y mg 111
`, 1 the
`d type of mca ·
`.
`cludmg the volume an
`·ous
`ntcn1s van
`·
`physic:il slate of gastric co
`·
`sition ,
`drugs, several disease stales. body f
`and the extent of' physical excrci e.
`the
`.
`•. either in
`11
`An crueric-coated 1a i cl 15
`or
`.
`.
`~ , bsorpuon,
`stomach and not available or a
`.
`raphic
`it is in the intestinal tract. Radiog f iimc
`. d he length o
`.
`s1ucl1es have determine
`t
`. d ·
`the
`· eta1nc 111
`an enteric-comcd table! 1 r
`Bukey
`stomach 14.•7.•• An extensive study by
`f
`d shape 0
`·
`·
`and Brew found 1ha1 the size an .'
`time.
`·
`ff
`I empt ying
`the 1ablc1 did 1101 a cc
`.
`stiga-
`9 I •• Other inve
`wh ich averaged 5. 1r.
`piyi ng
`to rs reported that the average cm
`. ob-
`time was 4 hr.'8 Blythe an °
`lleaguc~
`d
`7 hr."
`served a range from 1.5 hr 10 ow.rB k ,y·
`• ry lO
`IJ C
`Wagner reponcd 1ha1 , comra
`tablet
`I
`,• e of l 1e
`.
`h
`and Brew's lindmgs, I e siz
`reovcr,
`· ,c· 1110
`time
`.iffec1ed the residence un • .
`I •
`11p1y1ng
`Wag ne r observed l ial _e,'
`1
`iying
`obeyed the laws of probability. .
`1· gastnc emP
`• 1 •
`The unprcdictab1 ny o
`·
`. d , niagc
`.
`, d1sa v <1
`ti me is oflen seen as a unique
`·
`drugs
`of cntcric-coated table1s; howeve~, ornach
`1ha1 arc poorly abso rbed fro m th~. ~acior. 7
`1.1.
`d by 1h1s
`arc also greatl y a ectc
`.. , water
`I, ss ol JC1'
`cd tab·
`R itschel suggested 1hat a g •1 •
`1cric-coat
`·
`"
`should be iaken with an en
`tying.
`I ap-
`let to ensure rapid stomach cn_,p
`difl e ren
`d
`Wagne r rccommend e n
`timU Ol
`proac h observin g 1ha1 the op iho ·c
`uld be
`'
`·
`emeric-coatcd dosage forms wo
`. ules
`icd gran
`f
`in which a large number o coa
`,
`. d . , capsule,
`or pilules were comamc
`111 a
`
`illCUU~
`IINr
`
`----------...
`
`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 automatically 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 ~t the Vac -U-Max test lab using
`your own material, cal l or write Vac-U-Max, 37 Rutgers St
`Belleville, N.J. 07109. (201) 759-4400.
`··
`
`d '(llblCIS
`f in
`Reliability of Enteric-Coate
`p0rtS 0
`had 1cd
`Cooper staled that frequent re
`tcd iablelS
`.
`.
`f
`,
`.. is!ll bY
`vivo fa ilures o entenc-coa
`f
`. .
`d . 1·vc cr111c
`10 susp1 ion among an a 1
`. . g o
`. . .
`h
`escnb1n
`.
`clim ·ia ns faced w11h t e pr ·
`i·,craiu re
`"' The 1
`emcric-comed do. age fomis.
`·ng 1hC
`, d monstrall
`.
`••'
`contams many account
`c
`,.,.J9.lll·'
`n thC
`unreliab ility of the dosage for~,;
`be wn11cn o
`51 of LhC
`very lillle. however, has
`en
`subject in the recent litcraiurc. Mo970 and
`nega1ive reports appeared before 1 ~ no•
`·
`d
`s that a
`several of those concerned ru~
`forms in
`available in enteric-coated dosage
`1he United States.
`1, nations
`There arc ·evcral possible exp a
`
`Page 8 of 18
`
`

`

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`POWDER FILLING
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`
`Page 9 of 18
`
`

`

`132
`for the recent decline of reported in vivo
`failures involving enteric-coatc~ tablets in
`the United States. The most obvious rca on
`is that the number of products available in
`this dosage form ha · declined. In 1930 an
`estimated 3.3 % of all prescriptions were
`written for enteric-coated drug product · .68
`Statistics arc not available concerning the
`use of this dosage form today; nevertheless,
`the percentage is certainly much lower. To(cid:173)
`bie U contains a list of the diminishing num(cid:173)
`ber of drugs available in enteric-coated tab(cid:173)
`lets in the United States in 1981. 69
`The early reports of in vivo failures had the
`benefit of leading to the elimination of many
`
`a
`
`ber 1983
`PHARMACEUTICAL TECHNOLOGY. Sept~ _,, 10
`e not
`unacceptable enteric coating materials. Re-
`til recently, tablet coat mg w
`as cons1derou
`.
`formulation of an enteric-coated aspirin tab-
`be an art and sc1cnt11ic pnnci
`con·
`·
`'pies wer
`.
`.
`950S
`let, for instance, occurred in the l960s after
`rigid ly applied. Wagner an
`•
`d colleagues
`1
`frequent reports of poor in vivo perfor(cid:173)
`·n the late
`d.
`f large
`ducted a series of stu 1cs I
`mance. l'-''·" Most of the entcric-coaied tab(cid:173)
`·alJY
`designed 10 determine the causes O
`lets introduced to the market in the past fow
`.
`.
`. commcrc1
`I They dis·
`batch-to-batch v;mat1ons In
`years have been coated with CAP.' This ma(cid:173)
`available enteric-coatcd tablets. f he final
`terial has been studied for more than 40 years
`covered that the performance O I
`vert
`and has been shown to be highly reliable in
`d b
`lmost e
`do age fonu was affectc Y a
`·ons of
`vivo. ll.30,,..•2·" Acceptance of CAP as the cn(cid:173)
`f
`ss Observau
`.. h
`.
`cd'
`·
`mgr 1ent m t c proce
`ount o
`teric coating material of choice may be re(cid:173)
`tablet coaters r vealed that Lhe am radded
`sponsible for improved in vivo perfonnance
`coating material and dus~ing ?°;d:oatcr to
`for enteric-coated tablets. 2
`to a batch of tablets vaned tro
`he s{lllit
`The process of manufacturing cnteric(cid:173)
`coater - and from day to day for 1
`coatcd tablets must also be considered . Un-
`ent Good
`coater.
`The 1977 revisions m the Curr
`d the
`·n1roduce
`.
`'d -011 bas
`Manufacturing Practice 1
`JO Val, Oil
`•
`term process validatton ·
`.
`. n of (he
`been delined as the " detcrmi~auo ,aoufac·
`· luation °
`f
`·
`· ·
`h
`· ·cal step m 8 11
`rcliab1h1y of eac cn!I
`turing process involving an eva
`terials,
`(men ma
`.
`the elements of qualny
`' h'nerY) at
`methods and equipment and m~c I should
`J'dauon ·
`e tenn11rt
`each stcp ." 71 Process va I
`quicklyeliminateapplicationoflh h ingre(cid:173)
`t of cac
`to tablet coating. The amoun
`ow be
`. mu t n
`ed' a re-
`client added in the process
`d document
`.
`' · o
`carefully monitored an
`1 1 variaUO
`sultant decrease in tablet-Lo-tab e r· bili!Y,
`cd ·11 vivo re 13
`•
`should result in improv
`b'l'ty stud1
`I
`· 'la I I
`·
`.
`••
`The emergence of b1oav,u
`the rel1
`effect on
`has also h·td a tremendous
`e forn1·
`, d dosag
`•
`.
`ability of the entenc-coate
`r def1nt
`·c
`ufaciure
`FDA requires that a