dissolution FIP 1997

8/12/2019 dissolution FIP 1997

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flP Guidelines for issolutionTesting of Solid Oral ProductsJoint Report of the Section for O"icial laboratories

and Medicines Control Services and the Section ofIndustrial Pharmacists of the FIPIII 1981 FrP pllblisb,d Gllidelilles}or Dissoilltioll Testing ofSolid ami Prodllcts I l f If )oilll ' p01 ./ oftbe

Section for Official Lnbornwries find Medicines Coutrol Services fllld tbe Section oj 11dustrifll Pbn17l1ocists.Tlleseguitldillrs were il1ft'lltled flSsuggestionsprimflrilydirected to rompendifllc01J1mittees, working 011theillnwluctioll oJdissollltioll/ clellsc testsfor the rCJpcctive pl)(wlIlflcopoeius.

During tbe pflSt 15 years there bove befl11 1f1I1Ydevelopmems. Biopbflrlllflceliticsbns flttrflrled 7Jlllcb scien-tific liS well os politicnl imrrest. Dissollltioll test 1IIftbodology bos been introduced to 1I1011Y phu17llflcopoeioslind1I1l11111berofregulllfions IIl1dguidelines 011bioovnilnbiJity, bioeqllivnlt11fe and ill vitro dissolution terri11g hllvebeen ismednt IIntiOllfll lll1dill/ernntiollal level.

The joint working group 11 dissolution of/be two PIP sections tberejore decided to eSfflb/ish (llI ew dissolll-tioll guidelille, ttlkillg rill these developments illfo Ollsitiemtion bllt addiug proposfllsJorjil1'ther bflrmoJliu l-fiol/ fllldfor d('jillitiollS fllld pro(edures whieb (Ire 0t yt'f L Ovel'ed b1 imemntiollfll recommeudotiol1s.

PIP pI/bJis/wl tbe jillfll d/'llft version ill 1995 IIl1d co-sponsored fll1ll1fer'l1l1fiol1nlf.Vorksbop il1November 1996 to give collet1gllesfrom IIniversities, drug III1/horities, phfll1l1acopoeills find pbllrmoeellti(fllilldustries the o p p 0 1 1 l m i ~ yto contribute v.;itbtbeil' c01Jl7llellls o1'fil11ber i1Jlprove1llemof begllidelim textprior to tbis pllbJimtio11of tbe fi1l1l1 officiar veniol/.

The following guideline is tbe reSlllti1lgfil1a/ ojJid( vtf': ;ioll and ep,'csellfs tbe position find poliry ojFlP all DiJ'So/miol1 flSoj December 1996.

IntroductoryRemarks

The first GUIDELINES FOR DISSO LUT ION TE STI N G OFSOLID ORAL PRODUCT S werepublished in 1981 [I] as a joint

report of the Section for Official Laboratoriesand Medicines Control Services and me Section

of Industrial Pharmacists of the F.l.P. Th eseGu ide lines were intended as suggestions primarily directed to compendial cOlllmittees, workingon the introduction of dissolution/ release testsfor the respective Phannacopoeias.

Du ring the past decade, there have beenma ll}1 developments. Biopha rmaceutics hasattracted much interest scientifically as well 3Srega rding drug regulatory policies. Dissolutiontest methodology has been introduced to manyPhannacopoeias and a number of regulationsand guidelines on bioavailability, bioequivalenceand in vitro dissolmion testing have been issued

at national and international levels.Th ese updated Guidel ines (second edition)

are :he result of careful discussions of the joint0rking g roup of the two F.l.P. sections and are

based on recent developments. Descriptions o ftest methodo logy are no longer necessary,because they are already published elsewhere,officially or semi-officially. Differences betweenthe regulations of differem countries and compendias were iden tified and proposals for harmonisation are made.

s far as is reasonable for the purpose of theseGuidelines, rechnical terllls and definitions havebeen adopted from other hannonised recommentions and mainly correspond to USP-renninology. New tenns are in vitro-in ~ v ocomparison," Verification and "side batches. In

vitro-in vivo comparison" means any study collecting in vitro- and in vivo-data 011 the sallle setof test specimen to obtain information andunderstanding about how in vitro and in vivoperformance are related to each other, A significant in vitro-in vh'o correlation can be a result ofan in vitro-in vivo comparison study, hm valuableinfornlatioll could also be obtained when no correlation in a strict sense (e.g. USP levels) isachieved. 'I'Ver ification is used to define the invivo data set which provides evidence that a chosen in vitro test method and the proposed limitSare suitab le for the drug fonnu lation in tenns of

biophann3ceutical perfonnance. "Ver ification isproposed as a new tenllinus technicus to avoidthe extension of "validation on in vivo investigations. "Side batches') are batches of a givendnlg fonnulation which represent the intendedupper and lower dissolution limits. The) ' are preferrably to be derived from the defined manufacturing process by setting process parameterswithin the range of maximum variability expected frolll process validation studies. The termdissolution" itself is used for all dosage forms,

Tbe followingguideline'[vas elaborated by PIP '[vir/)COIIN'ibutiol1S i'om:J M AiIC'I , C/cl7lumt Pn7 lll1t,

N IIJ1 lI, 70kyo,H 111.1, Esrb/JonJ ,

J. lressall, F1'tI1lkfi01,H I . r l ~ l l Ll'Ve1'kusen,l I. GI'I_I, Rockville,i. GI'II, Rorkville,

p.. 11, 1'OlSboj,I . Nllert, Rod'Ville,1. 11,, -lllel , G enevn,J, lri.lr Escbborn, . IrislllSlI, Copenbllgell,F l l l l l l l er. fillSCl,l. l lISII , jV1olllVille,l. lelll , Rockville,J. U.'erl . Bedin,I McGllnraJ Oft l l L fI,

N Miller. Fnmkfllrt,S. Ilres'i , Otta wa,i . P.IIII , Rockville,

M Siewert, Fmnkj;wf,R l i l lr lr i , /JOIIII ,J. I. WlllersSll, Upi'mlll,I . Wlilel Kallsfls City,I. WirlilZkl, Frnnkjrm.

Iisso/llti o11Tecimoiogies/ O V M BE R 1997


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flP Guidelines conti.c. imlllediate-release (such as prompt drug releasing or convent ionaldosage fOfms) as well as lllodified-relc3sc products such 35 controlled,delayed, extended, modified, prolonged or sustained).

1. once pts o f D issol u tion TestingIn vitro dissolution testing serves as an important rool for chanlc

rerising the biopharll1:Jccuticalquality of a product at different stagesin its lifccycle. III early drug dcveloplllcm in vitro dissolution properties arc supportive for choosing between different alternative (annubtion candidates for further development and for evaluation of activeingredientv'drug 5ubst:1I1CCS. In vitro dissolution data are slipporti\,cin the evaluation and imerpretation of possible risks, especi;:dly in thec,lse of controlled/modified-release dosage fonns - e.g. as regardsdose dumping, food effects on bioavailibilityor interactio n with otherdrugs, which innuence g:lsrrointestinal environmenl;ll conditions.Biophannaceutical aspects are as important for stability concems asthey ,Ire for batch release after production, in vitro dissolution beingof high relevance in quality control and quality assurance. Last burnor least, in vitro dissolution data will be of great importance whenassessing ch'lIlges in production site, manufacturing process or forIllulation and assist in decisions conceming the need for bioavaibbility studies.

None of these purposes can be fulfilled by an in vitro test systemwithout sufficient reliability. Reliabilityhe re would be defined as thesystem being experimentally sound,yielding precise, accurate, repeatable results and with sufficient knowledge of the in vivo relevance ofthe dissolution data obt:lined.

telll design was adopted as firs( official method in USP XVIII in1970, described as rhe rotating basket (apparanlS I, USP).

The rotating basket and the paddle (apparatus 2, USP) devices

arc simple, robust and adequately standardised apparatuseswhich areused all around the world and thus arc supported by the widest experience of experilllemaluse. Jt is because of these advantages that rhepaddle and rotating hasket app:lranlses are recommended in variousguidelines as first choice for the in vitro dissolution testing of immediate as well as controlled/modified-release preparations.

I lowever, because of the "single container" nature of the paddle/hasket apparatusexperimental difficulties may ilrisc in tenn s ofrhe nced of a change in pH or of any other (p,lrtial) change in the testmcd ium during an investigation. Furthermore , difficulties arise for anumber of sparingly soluble dm gs and for some dosage fonns, particuhuly aerophilic multiple unit dosage fonns that, tend to float initially. Proposals h:lVe been made to increase solubility by addition of.1Il ;lppropri:ltcamount of surfactant.

lVith the flow-through cell apparatus 4, US P) the specimen isplaced in a small co lumn which is continuouslyflushed with a streamof fluid, simultaneously providing the medium and the mechanicalagit


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Table 2: Dissolution. Paddle and Basket Apparatus, Dimensions mm) of the Basket.

Item

asketShaft diameter

Wire thicknessOpeningsHeight of screenTotal height of basketInternal dia. of basketExternal dia. of basketExternal dia. of ringVent hole diamenterHeight of coupling disk

Positioning of the stjrring

Distance from the bottomDistance between shaft axisand vertical axis of the vessel

Stirring characteristics

EP

9.75 0.35)6A 0.1

0.2450.38127.0 136.8 320.2 122.2 125.4 325 1 0.5

5 25 2

Smoothlywithoutsignificantwobble

USP23Suppl. 5)

6 3 6 5 or9 4 10.1

0.254 or OA060.381 or 0.86427.0 1.036.8 3.020.2 1.022.2 1.025.4 325.1 0.5

25 25 2

Smoothlywithoutsignificantwobblemax. runout 1 mm)

JP XIII Proposal

9 750 35 or 9 4 10 16.4 0.1 corres. to shaft dia.of the paddle)

W 36 sieve 0.25

OA25 O.4001i27.0 1 27.0 1.036.8 3 37.0 3.020.2 1 20.0 1.022.2 1 22.0 1.025.4 3 25.0 3.02 2.0 0.55.1 0.5 5.0 0.5

25 2 25 25 2 5 2

No comment Smoothlywithout

significantwobblemax. runoutat the basis of

the basketlmm)

I I Test sieve 40 mesh) according to DIN ISONorm 331 Part 1): 1990 dimensions relevant for the plain wire cloth)

intern,ltional hannonisation is

strongly recolllmended 3S proposedin lilbles I and 2.

Anothersystem apparatus J) USPdescribes the reciprocating qrlinder.vVith these four apparatuses, dissolu-tion testing of most oral dmg prod-ucts should be possible on a reasoll-able basis. Neither too tight restrictions nor unnecessary proliferation ofalternative dissolution apparatusesshould be encouraged. If an individ-ual drug product cannot be accomo-dated by one of the apparatuses,described above, alternative modelsor appropriate modifications have tobe developed.However, in such a casesuperiority of the alternative or themodification has to be proven incomparison to the well establishedand standardised ilpparatuses. In thepast, many papers intended to justityan alternative model by proving thatin vitro dissolutionresultswere equivalentor similarto those obtained withe.g. the paddle method.According to the under-standing of these II

is.fOlutionTechn giesINOVEMBER 1997


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FIP Guidelines conIGuidelines, the latter p rovides clear evidence that the paddle methodshould be used'

Modification of the apparatus as described in the Ph;mnacopoeias

or the harmonisation proposals in T.1bles I and 2 can be intended forautomation e.g. of sampling procedure. in such cases, which couldpotentia lly have an influence on agitation characteristics [7], or anyother measure, it should be validated on a product-by-product basisthat results are equivalent with and without the modification.

The p H of the test medium should be set within pH I and 6.8. Ahigher p H needs to be justified on a case-by-casebasis and in general shuuld not exceed pH 8. For low pH in the acidic range He l

should be used (0.1 N I- el for pl-l I). If in a certain case, artificial gastric juice without enzymes (pH 1.2) is advantageous, this should bedcmollstT


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used for oral dosage fonns. Slightly increased test temperatures (e.g.(e.g.J8 0.5 C) are under consideration for special applications e.g.for rectal dosage forms, lower temperatures (e.g. 32 O.5'C) for

transdermal systems.Relevant parameters to be considered for the detinition of test

conditions are solubility and deaeration. In fonner Guidelines fsink conditions were requested. Sink was defined in different

ways e.g. as 10 t 20% [ or app roximately 30% [18J of solubilityconcentration to assure tl1


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flP Guidelines contpurposes, the respective dos.lge form h,15 to be thorough1r char


7/10

Recellri}" proposals have beenIlll1de [301 which in virro-in vi\'ocomparison results scientific:1l1y

:1lld formally cou ld suffice as vcrific.ltion of dissolution specificationof controlled/modified-releaseproducts. In C;lse of :1 signillcantquantitative co rrelation, dissolution limit


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flP Guidelines contcall be defined based on in \ ~ t r odata, obta ined during dmg develop- an in vitro-in vivo com parison study and should at least covermenr without an in vitro-in , ~ \ Ocomparison study. 14 hours.

Although in vitro - and in vivo- time a.xes need not he related in a The acceptance range for the dissolution p:ltfcm at the time

I: I ratio, the suggested dissolution time window corres ponds w typ- intcn 'als specined should he defined case-by-casc 011 the basis of theical gastric e mp tying times [31-331. in vitro-in vivo compariso n study and taking into consideration the

Imm ed iare co nvent ion- Table 5: Acceptance Tables According to DSP 23 < 111 > < 124 > c:lp:lbi lity of the lll"'lUfac-ai-release fonnul:mons W th ruring process ,mel the com-a speciRed dissolution time Sa: Immediate/ conventional-ReleaseDrug Products manly accepted range of 95of more than 30 minutes will 5tage NumberTested AcceptanceCriteria to 105% of state d amoumrequire an III Vit r O in VIVO 51 6 Each unit is not less than Q + 5 for the average conrenr ofcomparison srudy and disso- 52 6 Averageof 12 units (S1 + S2) is equal to or greater than Q. drug subsm nce. \,\'here

and no umt is less than Q - 15lurion profiles with several bo th upper and lower limi ts53 12 Averageof 24 units (S1 + 52 + 53) is equal to or greater(e . g. 3) poi nrs, obtained than Q. not more than 2 units are less than Q _15 %, are specified at ,lI1y timeduri ng deve lopm ent , to and no unit is less than Q - 25 point, the differencespecify s ingle point lim its. 5b: Modified (Extended-Release) Drug Products between them should usmll-Formulations with a speci- Stage Number Tested AcceptanceCnteria Iy not exceed 20% of thefied dissolution time of> 45 l1 6 No individualvalue lies outside each of the stated ranges labelled con ten t of drugminut es may requir e two and no individualvalue is less than the stated amount at substance ill the fonnula-

the final test tllnespecified dissolution times

L2 6 Theaverage value of the 12 umts (L1 + L2) lies withinfor quality control purposes. each of the stated ranges and is not less than the statedGastro-resisralll drug amount at the final test time; none is more than 10 of

labelled content outsideeach of the stated ranges; andproduct s should be treated none is more than 10 of labelled content belowthelike imm ediat e- release prod- staled amount at the final test timeucts for the purpose of spec- L3 12 The average value of the 24 units L1 + L2 + L3) lies within

each 01 the stated ranges, and is not less than the statedifying limits for the second amount at the final test time; not more than 2 of the 24dissolution test period, fol- units are more than 10 %of labelled content outside eachof

the stated ranges; not more than 2 of the 24 units are morelowing the initia l acidic test than 10 % of labelled content below the stated amount at thephase. final test lime; and none of the umts IS more than 20 of

labelled content outside eachof the stated ranges or moreFor modified-re lease for- than 20 of labelled content belowthe stated amount the

lTlulations (except debycd- final test timerelease) dissolution require- 5c: Gastro Resistant (Delayed-Release) Drug ProductsIllcnts should consist of at Acidic stageleast three points. The firstlimit is specified to prevent"dose dumping and therefore should be set after atesting interval of one to t\vohour s or correspondin g to ,}dissolved aillounr of 20 -30% of labelled dmg substan ce. Th e second limitshould define thc dissolutionpatt ern and thu s be setaround 50% release oflabelled drug substance. Thefinal limit is spec ificated toensure (almost) quantitative

Stage NumberTested6

6

12

Buffer stageStage

83

NumberT sted6

6

12

AcceptanceCriteriaNo individual value exceeds 10 % dissolvedAverageof 12 units (Al, + A2) is not more than 10dissolved. and no indiVidualunit is greater than 25 %dissolvedAverageof the 24 units (Al + A2+ A;l) is not morethan 10% dissolved. and no individualunit is greaterthan 25 dissolved

AcceptanceCriteriaEach unit is not less than Q + 5Averageof 12 units (B1 + Bll is equal to or greater thanQ, and no unit IS less than Q 15Averageof the units (Bt + 82 + 83 ) is equal to or greaterthan Q, not more than '2 units are less than Q - 15 ,and no unit is less than Q - 25

don unless limits have beenshown to provide reproducible and acceptable mvivo performance [13 .

8 Interpretation,Acceptlln ce Criteria

Dissolutio n test speci6-C'Jtions shou ld include thedefinition of limit s, thenumber of unit s to beexa min ed and respectiv eacceptance crite ria . Theprocedure of data interpretation should be harmonised inrernationally,the exist ing compend ialrequirements should beuniform .

As pharmacopoe ialapproaches are still not fullyhllrmonised it is recommended to follow Ule acceptance crite ria in acco rdancewith USP for immediateconventional-release products, modi fied-release(extended-release) productsand gast ro- resistant

drug release, which is gene lil y understood as ~ 8 0 .Thedissolution run in quality comrol therefo re should beextended for the tillle interval until ;It least 80% of drugsubstance is dissolved. Shoner test imerv.lls can be ,lcceptable in special cases but requir e just ification on the basis of

(delayed-release) products Crable 5). The approach with a maximumof three stages and individual units tested for deviation from statedranges corresponds well to requirements for coment unifomlity.Although there is preference ill common pnlctice in pharmaceuticalindustries {Q decide upo n batch release not later than stage 2, the three

Di sso /Illio7l7 ecim g iesINO V E M E R 1997


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step approa ch is th e best solution for fo rmal specification s especiallywhen referring to end-of-shelf life specification. Reference to labelledcontent docs not appl y for produ cts with int enti onal di fferent content

at tim e of manufacrur illg, Sich as n cases of sta bility overage.

9. Special ApplicationsA p c c i ~ ic valu e of dissoluti on testing is recognized in its applica

tions in sca le-up and manufacturin g changes for imm edia te/c on ventional - rel ease and l J l o d i ~e d r e le < l s e oral produ cts. Th eAAPS/FDA/USP Seale-up workshops 134, 151 recommend cCita intypes and ran ges of changes for which th e sam eness of in vivo pro duct p erforman ce is assullled, based on in vitro dissolurion dam. Inaddition, the Scale-Up and Post-Approval Change SUPA C document of FDA IJ6] defines the level of changes widl respcct to com

1451 Spccial test, h, ve ,Iso been suggested for consideration of specific situations, such as ilchlorhydric elderly patients 146].

J O. COllclusioll sIn ma ny interna tiona l d iscussions, Ill lillly ove r the years 1988 to1993, consensus was reached on some essenti al aspec ts, to whichth ese Guid elines refer. On th e oth er hand , man y aspects have eith ernot yet bee n sufficientl y explor ed or have not been harlll onised. Inthese cases, e.g. morc precise specifica tions of dissolut ion media andproposals for in vitro- in vivo compa riso n appr oaches and verifi cationof specifications for illlll1edi


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FIP ... rUllfll/lI(yi frolll prel'iollspllW

8. Slrickrr I-I (198-1)OptimimmgIImlJIIstit'l'llIIg tll'r l'errllrbs/mlillgulIgrll rOilill vitro-71'sts: Fmr pnvI"II/r i /r:'lIri:lIberriflll1gm. , /all PJJIII"III7rcblloJ30.1/3-/15

9. Stricker II (/976) 11l-t'lfro-SflfdiC'1/"':.11111Alljlosc- III/(/ R 'sorptiolln:erbtllll'lIoml i embreir/JfI'r tlr:'lIl'irrojJr IIlId die KOITt'IIWOIimit ,it>rbioloKiscbmVt7j",gbflrkeit. Pbllrm Illd 38, ]32 - 23

10. Dibbt'rII I-IW(198-1) Vnfiigbarkritspriifilllg in 'vitro: Portil'rllll gl'll.M.ig/icbkeitm, Grnl':.l'Il. P/){{rlllllld -16,38 1 - lS5

II . OilSSK. Gllptl/ ilK (1988) Silllll/Iltioll ofpbysiologim/pi1li1Hrprofi/r ill illvitro dissolutioll mul)': RI'/atiollsbip "etIm'll dissollltioll I"IItelIlId biolmri/llbiliryOfrailtrolled rell'lIse(Iosllgejim1l. Drug 0 1 1.11(1Phllrm N. 537 - H-I

12. Hlllllle H AliSL, SU'71.f/1.\1 (198-1)lur phlll7l11l:elltischmQUlllitiit 7. 011glibmritlmidh"/flg('IJF 'I1igl11"":'lII'imittdll.Pharm ltg 129,983 - 989

13. EEC NOlefor GuidI/lire (199I) Qlllllily of Prolol/ged Rdease Oml SolidDoslIgl'POI"IIIS

1-1.Glliddiues jar O 'sigl1 fllld E Ilillfltioll OfOm1SlIswilll'f/ Rrlr(1S('Dosl/gePorlll(1988). Millistry oj"II{'(1ltb fllld IVe/fflrr oj}tlPtlll. l1/kllskill-I-5

15. Il'orksbop Rt'f Ol1(1990) III Vitro llul III /lil'O 'resting IIIItICo,./"dtlfiOIlfa1'Oml CrJlltrollNJ/,\/ odijir(/-Rt/fl/se Dostlgt For1lls.PluwIII Rrs 7, 975 - 981

16. 51mb lIP, Kon('(/JJJJ. Et'el"ettRL. lrCllllolIgb IJ. Soorhiu/dJ :Ie. SJ:ellj'JP(1989) 111/fino Dissoilltloll Profile oj"lI11Ier-llIsollI"'e Drug 1)0sIIgeFOl7Ils illtbe PresellcrofSmjitrlfllltS.Pblmll R 's 6 (7) 611- 618

/7. Sbllb VI{ Gllrlilllg il l, NOQlY,/, Digb, S Ske//y]1' (199/) /ilf/llmre ofI ighl'r Rlltes ofl/gilllfioll011 Rd('flse Ptltten/s of11II1II1'dillll'-Rdl'lIse DrugProdllrts. J Pb(fl'111Sci 81 (6) 500 - 50J

IS. 11I-vihv IllIdill-iiil'Ot7.HtilltlfiOIlofdoslIgeforms (1995) USP 2J19. Quresbi SA lJ1 1 .leGi hll'm] lJ (199-1) Implltl of Dijji'I"I'1IfOellil"llrioll

Methot s 011 tbe USP D sso/lltioll APP(lJ"fIfIIS )lIil(f/Jilif)' 'Jest Critr/";II.Pbll1'1l11 01"/1111 20 (6) 8565 - 8566

10. So/tm RA, ll oover] 11, lOll"IT. Stllildisb ,II ( /98 9) EjjictsofSillkerSbllpes01/ Dissollllioll Plvjilrs. J Pblll'lJlSri 78. 35 - J9

21. U.S. Pb(fl'1llflrOpdlf23, SlIpplmullt I (1995): Dmg Reler/sl' 253522. FIP H'orkillg Grollp: -I OhSOlllioll tlild DisJolllfio l Spl'cij/mlion. lPPtl/"{ftw'

Sflitllbility7, .11 JOI Ibe fiJeraHbroltgbCell (pIIN.ill prep.)13. LnllgrlllJllcbrr F (1982): NIIIIII'rim/ com:ollltioll/decollvolllfirJIIIIJ (/ tool jar rOl'

re/millg ill vit1 O7:.'itbill t'ivo drug (lr.mlttbiliry. Pblmll. 1111.,-1-1-, 1166 - I 1-:2]-1. 1.IlJIgellll1lrberP (1981): /Jllp,vt'ed Iligorilb1lls rom-llI1mg/1(){/yrespollsr7l irb

drug il1plll,Pb(l1'Ili.Illd -1-1, 1275 - 117S.15. /11gller J IV, Nelsoll F (1963): P 'I1r1ll,,"sorbrd limr plots dn'iVt,1 ivm blood

it'Vt'Ior urillilry I'X(1"eliolltilltll.]' Pb(mJl. Sci., 57, 918 92826. 100]CK, Riegellllllllll S (1968): /t7J.1 metbodjar /"/I/cllilllillgtbe llf1'illsir

ahsorptioll mtl' ofdrug]. PbIlI"lJl. Sci., 57. 918 - 928.27. iJrocklllt'ier D l'oegeleD V()II IIl1ltillgbetX IIJI (1983): 11l1.}if1v-illVi'1'Ocor

,e/lltioll. IItime smJillg prob/I'II ?AI"":'lIeimittrljorsdJIIlIg n, 598 - 60128. 1.'011 1IIlftlllgbrrg 11,\ I (198-1): Il/ olIIl'lltell-Alllllysr1111111117.'itrolill1.'i1.'o

Korrrill1iol1,ACM Pblll7l1.Terimol . 30, 93 - 10129. Cllrdot J.\I, IJeyss(frF. (1993): I I vit/vlill vivo C'om'llItiolls: Scil'lllijic

ImplirtftioJlJ(fll" Stlllulllrdis(ltioli. EIII} Drug .\/t>ftI{,Pb(I17IJ1ICokillet18 I)113- /20

30. SiCiliC11M (I99';): / Vivo V"lid(ltiulI of11 Vitro Dissolutioll Jrsts fllldSpI'Cijimfiolls: rlpplimtiollfur COIlf1v/ledl.\ lodifirt Rell'IIse Prodlll1S.iJioillfernmiol1ld2 (293 - 299)

31 Obrrle RL, Cben T-S, UOJ'dC, /Jtl17tett JL, C f1L)'(lIIg. .lIry'rr

IJ. Amit/oll GL (1990): The illjlllenrr of be mterdigestfl.'e1111grtltmgmOlilityromp/I'xall tbe gflstrir emptyillgoflilJlllds. GlIstroellterolog;y

I 99, / 275 - 1181

/Jism//ltiollTedJll giesfNOVEMBER 1997

n. IJrellfr W -Ielldrix TR. ,\Ir1ll1gb PR (1981): Regulatioll oftbe gum-ir rmpf)'illg ofglllmre. GlIst7"Ol'IItrr%gJ' S5, :-6 - 81

33. ,\1111(1111111 II. Jl rCidlll1ll R.W, (1998-1): Tbr Pb)'siology 111111Phfllopbysiologyof GIISf1'irEmptylllg ill Ihmllllls. GIISf1"Or1lferologl,8616, 1592- 1610

H. IVorkshopRepol1(1993): Sm/I'-L"poj IlI/lIIl'dillte Rrifllse 01"111Solid Dos(lgeForms. Pbllrm. R 's. l(j. 313 - 316 IIl1dEII1: J. Pbarm. IJiopblll7J1.39 I). 40 - 43

J5. If'or/.:J/Jop II Rrport (1993): SCl/it'-Up ofOmI Ertell/led Rdetl.ff DosageFOI'IlIs.PbIlI7Jf. Res. 10, ISOO- IS05 IIl1dEm:J. PI}(m". /Jiopbll17l1.39 W/ 61- /67

J6. FDA 11IIlIIedillle Rdl'llse Smlr-up rllld Porr APP,vt'(f1 Change (SUP..4C)Expert /I arkil1g GIVUpof be Chemistl)' .\[allufartlll7l1g COIlf1VIsCoonlhultillg COlllmittel' of bl CrII/trfar Dmg Evaillmioll (lIIdResf(frr/J(199-1) IlIferim GllidllllU IlIlIImlill'l' ReleaseSolid Om/Dosage Ponl1s - Prefllld Pos,-Appl"01.,"1 Cb(lIIgl'S.

17. ,\I({lIml PK. PnmulllK, II'onlt)' IV, Sbiu GK, S k e / ~ )JP (1986) IlIfllleliu ofIIhighPit bretlkji/J 01/ tbt' bio(/"1.wilflbi/ityo l be o p J ~ )J / i l l fCOIlf7'oJ//'d-rr etlse)01'JIIulmiolls: 1111 ill vitro dt'mollstrtltiollOfllll illl,il'O ubsm.'IItioll. III:]. Pbll17l1.

Sci. 75. /105 - /]06JS. It I I r ~ .L. KJllilll. /, P /goneI: Strrirbt'rJ, Il'irklllllllil (1988) Pood-III/luud

TbeopbJ'"mr ReI('IfselAbsOlptioli OJIIl/gfSfiwl/ COlltrollel/-Rr/l'llseFOl7llflllltions:, I Propoml in I'itlv .\I{)(M.Drug D1.:I.IIItI. Pb"rlll. 1-1, 13 - 28

19. Karim II: Imp0l11111Ct'ofAsJt'ssiJlgFoodEffects in Et'll/l1l/tlllgCOIlf1vllrdRdl'llsr Furlllll/tlfiolls. (1988) I,,: )iltobi A /I/lt fllI/perin-Wfllegll E: OmlSiml/illcd Re('llsl' Formllllllio l. : I)r.l"igllll1/{/ Ev(dlllllioll. Pr1'gtllllol Preofs,,157- JNJ

-10. EI-A1'llliK. Shill GK. S k t / ~ yJ P (1990) T / ; e o p J ~ y l l i l l r - C o l l f l v l l dRr/ellsePrepllrtltiollJ a l l l i l t ~ ylifxul:;/11 ill 6f1vSIIUiyUsillg the Rowillg Di(Ii)'sisCell. Ph(ll111.Res. :-, 113-1- 11-1-0

-II.. Il1cbenfSP. Kouppafis ,lI . Jjllprollllis C (1986) Dmg dissoluti01lstflllirsi1llIIi//':Ifsmg tbl' IIIIfQIlIfltt'lJ}lerll' illjmjoll m'i,,/ ~ y l l ( l I I l i rdialysis tuhf/iqlfr. 1m.]. Pbllrm. 33 1]5 - /36

-12. JIIlIgillgl'r I E, VerbofvI'1IJ, Pt'scbi('r L]C (1990) E lle II/'/ICSill 'vinv-/Hot/rJl:lIr I r k t m l l l l l g7.'011 Wrdmltl'irkllllgm z,i.l'iscbenRrftmJl/rzneilllitte1I:wrom/l'lu /pplik"tiol/ IlIIdNlIlmmgsntittelll. Pb(wm. Ztg Wiss. 2, 53 - 58

-1-3. I\riimrrJ, Lilltitlllt'1"Re Sirv.'ert ,\/ , St,.irkt', /-I, /JIume II (/991) \tl'1ulrdRelel/seTbt'opbJllillf Altfl1l1lffl.'e / /'itro Dissollltio1l,\Iethotis.Elfr.J. Drug..\I elllb. Pbl/l7Jlflrakill. IN, r

-1-1.Sira't'11 .1I (1989): / t'itlV-O SSolllliollJerrillg ofOml COIlf1v/ledReleasePr{)(llIm. III: Glllllim-Rnn] U 1111(1,\/"IJel" II: Oml COllflvlled Rde(lseProdllm 7])cmp('lltic Il1dBiopblll'l)/(IwitirAssrss-mem.Wissellsrb(iftfirbe1't.'r/IlgsgeseJI.Kbtlfi, 139 - 1H

-15. Gali" E, Nitoillides I;, ReppllsC. DmS-III(f1lJ/J (1996): M. 'JJmedilldiscrimiIllite dissolmioll propmirs oIpoor(y soillble drugs. P )III7I1.RcSetllr/)13, 262

-16. Ogllt/l /-I et III, (198-1): DrvelopmclIIoJlwd tn'll/lIl11ioll ofa 1Il il perorfll test(lgml G/ /-Testjor IISSfS'lIIell1ofgas/1"lr lIrit/if]. J. Pbnl7llUroblO-DyIl7, 656-664

For COI7"I'Spol/(/fllce:

PIP JI'orkillg Group -I: Disso/litioIlIllU/D ssolutioll SprcijimtiollSD/: { Itmill Sil7 'l'rtdo Iloabst Mllrion ROIISS{'/,Building K 607, D-65926 Fmnklim

7],is jilllll "offici,,/", versioll of bl' PIP GllidelillfsfOl'Dissollltioll 'TerringojSo/i,1Oml Protillrts i ."llll/isobe pllblis/m/ill 11Itfl7lf1tiol/(t/ Pb(ll7)l(lry,Pb(ll'lJUlcoporinlForum, Die Pblll7J1f1':lItisrheIm/llmie IIIUJ PbUl7llllfflltiat/7frbJlology.

dissolution FIP 1997

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