flP Guidelines for Dissolution Testing of Solid Oral Products Joint Report of the Section for O"icial laboratories and Medicines Control Services and the Section of Industrial Pharmacists of the FIP

III 1981 FrP pllblisb,d Gllidelilles }or Dissoilltioll Testing of Solid ami Prodllcts Ilf If )oilll " ' p01./ oftbe Section for Official Lnbornwries fi nd Medicines Coutrol Services fllld tbe Section oj l11dustrifll Pbn17l1ocists. Tllese guitldillrs were il1ft'lltled flS suggestions primflrily directed to rompendifll c01J1mittees, working 011 the illnwluctioll oJdissollltioll/"clellsc tests for the rCJpcctive pl)(wlIlflcopoeius.

During tbe pflSt 15 years there bove befl11!1f1I1Y developmems. Biopbflrlllflcelitics bns flttrflrled 7Jlllcb scien­tific liS well os politicnl imrrest. Dissollltioll test 1IIftbodology bos been introduced to 1I1011Y phu17llflcopoeios lind 1I1l11111ber ofregulllfions IIl1d guidelines 011 bioovnilnbiJity, bioeqllivnlt11fe and ill vitro dissolution terri11g hllve been ismed nt IIntiOllfll lll1d ill/ernntiollal level.

The joint working group 011 dissolution of/be two PIP sections tberejore decided to eSfflb/ish (llIew dissolll­tioll guidelille, ttlkillg rill these developments illfo cOllsitiemtion bllt addiug proposfllsJorjil1'ther bflrmoJliul­fiol/ fllld for d('jillitiollS fllld pro(edures whieb (Ire 110t yt'f L'Ovel'ed b)1 imemntiollfll recommeudotiol1s.

PIP pI/bJis/wl tbe "jillfll d/'llft" version ill 1995 II l1d co-sponsored fll1ll1fer'l1l1fiol1nl f.Vorksbop il1 November 1996 to give collet1glles from IIniversities, drug II I1/horities, phfll1l1acopoeills find pbllrmoeellti(fll illdustries the opp011lmi~y to contribute v.;itb tbeil' c01Jl7llellls fo1' fil11ber i1Jlprove1llem of tbe gllidelim text prior to tbis pllbJimtio11 of tbe fi1l1l1 "officiar veniol/.

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

Introductory Remarks

T he fi rst GUIDELINES FOR DIS­SOLUT ION TESTING OF SOLID ORAL PRODUCTS were published in 198 1 [I] as a joint

report of the Section for Official Laboratori es and Medicines Control Services and me Section of Industrial Pharmacists of the F.l.P. These Guide lines were intended as suggestions primar­ily directed to compendial cOlllmittees, working on the introduction of dissolu tion/ release tests for the respective Phannacopoeias.

During the past decade, there have been ma ll}1 developments. Biopharmaceutics has attracted much interest scientifica lly as well 3S

regarding drug regulatory policies. Dissolution test methodology has been introduced to many Phannacopoeias and a number of regulations and guidelines on bioavailability, bioequivalence and in vitro dissolmion testing have been issued at national and international levels.

These updated Guidel ines (second edition) are !:he result of carefu l discussions of the joint 1V0rking group of the two F.l.P. sections and are based on recent developments. Descriptions of test methodology are no longer necessary, because they are already published elsewhere, officially or semi-officia lly. Differences between the regulations of differem countries and com­pendias were identified and proposals for har­monisation are made.

As far as is reasonable for the purpose of these Guidelines, rechnical terllls and definitions have been adopted from other hannonised recom­mentions and mainly correspond to USP-renni­nology. New tenns are "in vitro-in ,~vo compar­ison," "Verification" and "side batches." "In vitro-in vivo comparison" means any study col­lecting in vitro- and in vivo-data 011 the sallle set of test specimen to obtain information and understanding about how in vitro and in vivo performance are related to each other, A signifi­cant in vitro-in vh'o correlation can be a result of an in vitro-in vivo comparison study, hm valuable infornlatioll could also be obtained when no cor­relation in a strict sense (e.g. USP levels) is achieved. 'I'Verification" is used to define the in vivo data set which provides evidence that a cho­sen in vitro test method and the proposed limitS are suitable for the drug fonnulation in tenns of biophann3ceutical perfonnance. "Verification" is proposed as a new tenllinus technicus to avoid the extension of "validation" on in vivo investi­gations. "Side batches') are batches of a given dnlg fonnulation which represent the intended upper and lower dissolution limits. The)' are pre­ferrably to be derived from the defined manufac­turing process by setting process parameters within the range of maximum variability expect­ed frolll process validation studies. The term "dissolution" itself is used for all dosage forms,

Tbe following guideline '[vas elaborated by PIP '[vir/) CO IIN'ibutiol1S fi'om: J, M, AiIC'I, C/cl7lumt Pn7"lll1t,

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

J. lressall, F1'tI1lkfi01, H. I. fril~ll , Ll'Ve1'kusen, l. I. GI'I_I, Rockville, i. GI'II, Rorkville, p. .'''11, B1'OIlSboj, I . Nllert, Rod'Ville, 1. 11,,-lllel, Genevn,

J, lri.lr, Escbborn, • . IrislllSlI, Copenbllgell, F. lllllll .. ler. fillSCl, l. llISII , jV1olllVille, l. lelll, Rockville, J. U.'erl. Bedin, I. McGllnraJ, Oftll7.L!fI,

N. Miller. Fnmkfllrt, S. Ilres'i, Ottawa, i. P.IIII, Rockville, M. Siewert, Fmnkj;wf, R. l illrlri' , /JOIIII,

J. I. WlllersSll, Upi'mlll, I. Wlilel .. , Kallsfls City, I. WirlilZkl, Frnnkjrm.

I Disso/lltio11Tecimoiogies/NOVEM BE R 1997

dx.doi.org/10.14227/DT040497P5

flP Guidelines ... cont. i.c. imlllediate-release (such as prompt drug releasing or conventional dosage fOfms) as well as lllodified-relc3sc products (such 35 controlled, delayed, extended, modified, prolonged or susta ined).

1. Concepts of Dissolution Testing In vitro di ssolution testing serves as an important rool for chanlc­

rerising the biopharll1:Jccutical quality of a product at different stages in 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 active ingredientv'drug 5ubst:1I1CCS. In vitro dissolution data are slipporti\,c in the evalua tion and imerpretation of possible risks, especi;:d ly in the c,lse of controlled/modified-release dosage fonns - e.g. as regards dose dumping, food effects on bioavailibility or in teraction with other drugs, which innuence g:lsrrointestinal environmenl;ll conditions. Biophannaceutical aspects are as important for stability concems as they ,Ire for batch release after production, in vitro dissolution being of high relevance in quality control and quality assurance. Last bur nor least, in vitro dissolution data will be of great importance when assessing 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 system without sufficient reliability. Reliability here would be defined as the system being experimentally sound, yield ing precise, accurate, repeat­able results and with sufficient knowledge of the in vivo relevance of the dissolution data obt:lined.

telll design was adopted as firs( official method in USP XVIII in 1970, described as rhe rotating basket (apparanlS I, USP).

The rotating basket and the paddle (apparatus 2, USP) devices arc simple, robust and adequately standardised apparatuses which are used all around the world and thus arc supported by the widest expe­rience of experilllemaluse. Jt is because of these advantages that rhe paddle and rotating hasket app:lranlses are recommended in various guidelines 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 apparatus experimental difficulties may ilrisc in tenns of rhe nced of a change in pH or of any other (p,lrtial) change in the test mcdium during an investigation. Furthermore, difficulties arise for a number of sparingly soluble dmgs and for some dosage fonns, par­ticuhu·ly aerophilic multiple unit dosage fonns that, tend to float ini­tiall y. Proposals h:lVe been made to increase solubility by addition of .1Il ;lppropri:ltc amount of surfactant.

lVith the flow-through cell (apparatus 4, USP) the specimen is placed in a small co lumn which is continuously flushed with a stream of fluid, simultaneously providing the medium and the mechanical agit<n-ion for dissolution of the drug substance. It can be nm as an open as well as a closed system. The open system design especially providcs several advantages in some of the difficult cases mentioned abm'e :md was adopted first by the Deutscher Arl.neimittelcodex (German Pharmaceutical Codex, DAC) in 198 I.

The now-through apparatus is currently monogf<lphed in USP, Ph.ElIr .• md Ph.J ap. Description of thc system is concordant world­wide. The paddle/basket system is described in USI~ rhe European, the.l 'lp'lnese ,Ind many other Pharmacopoeias. Some minor discrep­ancies are still found in details of the respective monographs. Full

Requirements for dissolution testing have been reviewed in the lit­erature 12 - 61. Since in vitro dissolution is a physical test, defined by convention ;md is of a destnlcti\,C nanlrc, proving reliabi li ty requires special attcntion. It therefore is within the scope of these

Table 1: Dissolution. Paddle and Basket Apparatus, Dimensions [mm) of the Vessel and the Paddle

Guidelines to define suitable testing equipment and experimental design as well as to suggest the background for adequate physical and allalytical validatioll, together Item EP III U5P23 IP XIII Proposal

with verification procedures according to the state of bio- ,---,---------------"'=="----------Vessel

(5uppl.5)

pharmaceutic]! science. Height The Guidelines arc primarily dedicated to solid or,,1 Internal diameter

16H 8 160 · 175 160 ·175 160 · 210 102 ± 4 98 · 106 98 · 106 102 ± 4

products. Il owever, the general concepts Ill,ly be adapt- "'P"ad""d"I.,---------------------------

ed to in vitro dissolution testing of dmg substances/po\\'- Shaft diameter ders, semi-solid oral products, suppositories and, with ~ distinct restrictions, to other non-oral products. Upper chord

2. A p/JfWatliS Large Ilumbers of different dissolution ,lpp,lranlses

<Ire described in the litenuure, but only some of them withstand critical methodological exam ination.

1\\'0 basic technical principles are ilpplied for in vitro dissolution resting: the "stirred heaker method " and the "flow through procedure," The "stirred beaker method" places the test specimen :lI1d a fixed volume of fluid in a large vessel, and stirring provides mechanical (hydrodynamic) agitation. This closed sys-II

Disso/lllioI7Tecbll% giesINOVEM BER 1997

lower chord Height Radius (disk) RadiUS (upper corners) Thickness

Positioning of the stirring device Distance from the bottom Distance between shaft ax.is and vertical ax.is of the vessel

Stirring characteristics

9.75 ± 0.35

74.0 ± 0.5 42.0 ± 1 19.0 ± 1 41.5 1.2 4.0 ± 1

25 ± 2

< 2

Smoothly wllhout significant wobble

9-1 ' 10.1 9.4·10.1 be are coating 9.4 · 10.1

74.0 · 75.0 74.0 · 75.0 74.0 ± 0.5 42.0 ± 1.0 42.0 42.0 + 1.0 19.0 ± 0.5 19.0 ± 0.5 19.0 ± 0.5 41.5 ± 1.0 41.5 41.5 ± 1.0 1.2 1.2 1.2 4.0 ± 1.0 4.0 ± 1.0 4.0 ± 1.0

25 ± 2 25 ± 2 25 ± 2

<2 < 2 < 2

Smoothly No comment Smoothly without without significant Significant wobble wobble

«0.5 mm)

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

Item

Basket Shaft diameter

~ Wire thickness Openings Height of screen Total height of basket Internal dia. of basket External dia. of basket External dia. of ring Vent hole diamenter Height of coupling disk

Positioning of the stjrring

~ Distance from the bottom Distance between shaft axis and vertical axis of the vessel

Stirring characteristics

EP III

(9.75 ± 0.35) 6A ± 0.1

0.245 0.381 27.0 ± 1 36.8 ± 3 20.2 ± 1 22.2 ± 1 25.4 ± 3 2 5.1± 0.5

25 ± 2

52

Smoothly without significant wobble

USP23 (Suppl. 5)

6.3·6.5 or 9.4. 10.1

0.254 or OA06 0.381 or 0.864 27.0 ± 1.0 36.8 ± 3.0 20.2 ± 1.0 22.2 ± 1.0 25.4 ± 3 2 5.1 ± 0.5

25 ± 2

5 2

Smoothly without significant wobble (max. runout ± 1 mm)

JP XIII Proposal

9.75·0.35 or 9.4.10.1 6.4 ± 0.1 (corres. to shaft dia.

of the paddle)

W 36 sieve 0.2511

OA25 O.4001i 27.0 ± 1 27.0 ± 1.0 36.8 ± 3 37.0 ± 3.0 20.2 ± 1 20.0 ± 1.0 22.2 ± 1 22.0 ± 1.0 25.4 ± 3 25.0 ± 3.0 2 2.0 ± 0.5 5.1 ± 0.5 5.0 ± 0.5

25 ± 2 25 ± 2

52 5 2

No comment Smoothly without

significant wobble

(max. runout at the basis of

the basket ±lmm)

I I Test sieve (40 mesh) according to DIN ISO·Norm 3310 (Part 1): 1990 (dimensions relevant for the plain wire cloth)

intern,ltional hannonisation is strongly recolllmended 3S proposed in lilbles I and 2.

Another system (apparatus J) USP describes the reciprocating qrlinder. vVith these four apparatuses, dissolu­tion testing of most oral dmg prod­ucts should be possible on a reasoll­able basis. Neither too tight restric· tions nor unnecessary proliferation of alternative dissolution apparatuses should be encouraged. If an individ­ual drug product cannot be accomo­dated by one of the apparatuses, described above, alternative models or appropriate modifications have to

be developed. However, in such a case superiority of the alternative or the modification has to be proven in comparison to the well established and standardised ilpparatuses. In the past, many papers intended to justity an alternative model by proving that in vitro dissolution results were equivalent or simi lar to those obtained with e.g. the paddle method. According to the under­standing of these II

Dis.fOlutionTechn%giesINOVEMBER 1997

FIP Guidelines ... conI. Guidelines, the latter provides clear evidence that the paddle method should 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 for automation e.g. of sampling procedure. in such cases, which could potentia lly have an influence on agitation characteristics [7], or any other measure, it should be validated on a product-by-product basis that results are equivalent with and without the modification.

The pH of the test medium should be set within pH I and 6.8. A higher pH needs to be justified on a case-by-case basis and in gener­al shuuld not exceed pH 8. For low pH in the acidic range Hel 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 be dcmollstT<lted. The use of simulated gastric juice (with pepsin) may be appropri'ltc for gelatine capsules.

In the pH-range of 4.5 to 8.0 USP buffer solutions are recom­mended, as sUlllmarized in T.1ble 3. A change of pH of dissolution

3. Experimental Testing Conditions Table 3: Proposed Dissolution Media

For all applications, in vitro dissolu­tion data should at least allow some inter­pretation with regard to in vivo biophar­maceutical performance. In order to

increase their predictive va lue, attempts have been made to adjust in vitro test con­ditions [8 - II [ as close as possible to physiologic conditions. Nevenheless, sev­eral examples demonstrate that such con­ditions can also lead to misinterpretations and are not able to guamntee in vitro results routinely relevant to the in vivo sit­uation [12].

In general, an aqueous medium should be used. It is not recommended to

Medium O.lN hydrochloric acid

Buffer solution pH 4.5

Simulated intestinal fluid without pancreatin pH 7.5

0.05M phosphate buffer solution of pH 5.8 to 8.0

Proposed Composition 3.636 g of Hel. corresponding to 8.3 ml hydrochloric acid 37% (m/m) per 1000 ml of aqueous solution

Acetate buffer solution pH 4.5:

2.99 g of sodium acetate trihydrate and 1.66 g of glacial acetic acid are dissolved in water to 1000 ml or Phosphate buffer solution pH 4.5:

13.61 g monobasic potassium phosphate are dissolved in 750 ml of water. After adjusting the pH to 4.5 with 0.1 N hydrochloric acid or O.lN sodium hydroxide. water is added to make 1000 ml

250 ml of a solution containing 6.8 g monobasic potassium phosphate + 190 ml of 0.2N sodium hydroxide + water to make 1000 ml

50 volumes of 0.2M monobasic potassium phosphate solution + specified volume of O.lN sodium hydroxide + water to 200 volumes

attempt to strictly mimic the physiologic gastroi n testi n a I en vi ronm ent (e.g. com _ .:.P,..H=_--,5:-.8::-----:6cc· 0:---:-6 . ..,2_-,-6.:-4::---:6-::. 6-,-_6".,..8 -:---:-7 .:-0-:---,7". 2:-::-_-::7".4-,-_7::.6:-:-_7,.-.:-8::--:-8 .:-0_ position of gastric or intestinal fluid) but NaOH 3.6 5.6 8.1 11.6 16.4 22.4 29.1 34.7 39.1 42.4 44.5 46.1

to choose the testing conditions as far as (volumes)

is reasonable, based on the physico-chemical characteristics of drug substance, within the range which a drug or dosage form could expe­rience after oral adm inistration. These following ranges were estab­lished based on several conferences and recommendations [e. g. 13 -LSI- There might be specific products for which no dissolution test can be established without exceeding the recommended ranges of test­ing conditions. In these cases, it should be clearly demonstrated that dissolution result~ obtained with other, more extreme testing condi­tions (e.g. pH > 8.0) allow for appropriate biophannaceutical inter­pretation.

For basket/paddle mecllOds the volume should be 500 to 1000 ml. 900 ml had been introduced historically; 1000 ml should be easier to handle in a metric system, th is volume being practicable with all equipment commercially available today. 1000 ml therefore should be considered for new drug products or in case of a revision of existing test procedures. This recommendation does not mean that 1000 Illi should be adopted to all existing test procedures and specifications.

Although larger vessels, such as up to 4,000 ml, could be

8 advantageous fo r poorly soluble dmgs, they are not described in compendia, and thus are not as well stan­dardised and therefore should be regarded as modification of a compendial method (see section 2.)

DisrollltiollTecim%gieslNOVEMBER 1997

medium during the test or a pH gradient may be appropriate for gas­troresistcnt formulations and products for which dissolution testing at one pH-levd or at different pH-levels in parallel does not give bio­pharmaceutically relevant results.

The use of water as dissolution medium bears the disadvantage that test condition details, such as pH and surface tension, can vary depending on the source of water and may be changed during the dissolution test itself, due to the influence of the dmg product and to the (re)absorption of carbon dioxide frolll air. \Nater therefore is recommended as dissolution medium only when it is proven, that the variations mentioned do not have influence on tl,e dissolution char­acteristics.

Further additives e.g. enzymes, salts or surfactants, could be con­sidered in specific cases. Their use should be justified as regards nature and concentration of additive [16J. Addition of organic sol­vents should be avoided.

Agitation typically should be obtained in the basket/paddle appa­ratus by stirring at 50 to 100 rpm and in general should not exceed 150 rpm. Although maximum discriminatory power should be obtained with lowest stirring rate, in Illilny cases experience with 75 rpm was feltto represent a reliable agitation for paddle equipment [17].

Regarding media temperature, 37 ± O.5'e should generally be

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 so lubility and deaeration. In fonner Guidelines f1 L "sink" conditions were requested. "Sink" was defined in different ways e.g. as 10 to 20% [II or approximately 30% [18J of sol ubility concentration to assure tl1<1t dissolution is not significantly influenced by solubility characteristics. Since "sink" conditions per se do not guarantee in vivo-in vitro associations and since reliable and pre­dictive in vitro profiles in certain cases can be obta ined by violating "sink" conditions, so lubility and drug substance concentrations during the test should be matter of verification studies to demonstrate that a chosen in vitro test metllOd yields biopharm3ceutically relevant results.

Case-by-case va lidation is also required regarding deaer,ltion since some formulations will be sensitive whereas others are robust in this concern, thus making deaeT<ltion unnecessary. 'fhe deaeration method has to be dearly characterised, since the method chosen can have impact on dissolution profiles [19J. It is noted that the flow rate in the flow-tluough ce ll (open circuit) is particularly sensitive to the presence of air in the medium.

Ph.jap. is currently the only Phannacopoei,l that requi res a spe­cific (very solid) sinker device for all capsule fonnulations. USP rec­ommends a few turns of wire helix when specimen tend to float. EFPIA harmonisation proposal suggests a similar one. Sinkers can significantly influence the in vitro dissolution protlle of a drug 120J. Since they are used especially with fonnulations causing problems during test performance, e.g. flmation, tlley will alter the dissolution profile, so that other recommendations liS] are not applicable.

The lise of sinkers therefore has to be part of case-by-case disso­lution validation as well as of in vi tro-Ln vivo comparison shldies. Any strict requirement on use of sinkers or specific sinker types lacks sci­cntific justification.

4. Qualification and Validation Due to the nature of the test method, quality by design is an

important qualification aspect for ill vitro dissolution test equipment. Besides the geometrical and dimensional accuracy and precision as described and commented in section 2 (including Tables I and 2), any irregularities such as vibration or undesired agitation by mechankal imperfection are to be avoided.

Besides the specification of the apparatus, qualification of dissolu­tion equipment has to consider critical parameters, e.g. temperature of test medium, rotation speed/flow rate, volume, sampling probes and procedures, to be monitored periodically during the periods of use.

Apparatus suitability test is a further important aspect of qualifica­tion and va lidation. The use of USP calibrator tablets (disintegrating as well as non-disintegrating) has been controversial for some time. However, it is the only standardised approach and has been helpful to

identify system or operator fililurcs. Since some individual drug prod­ucts might reveal similar or even higher sensitivi ty against technical variance in comparison to USP ca librator tablets, "in-house" stan­dards are judged acceptable as additional, or, if validated, equivalent for ca librator tablets.

The suitability test has to cover each individual apparatus. Paddle lind basket equipment, as well as 12 mm and 22.6 mill flow-tllrougb cells have to be qualified, unless only paddle or basket, or in the case of flow-through cells only small 0,. large ce ll is used in one specific piece of equipment. The system su itability test of USP Apparatus must be performed with both a multiparticubue and a monoparticu­late standard formulation. A system suitability test for flow-tllrough cells has just been established and will be soon published 1221.

Apparallls suitability tests are recolllmended to be performcd not less than twice per year per equipment and after any equipment change, significant repair or movement. However, a switching between paddle and basket, when the apparatus has been calibrated for both, should not require recalibration.

Additional validation aspects are precise product related operation instructions (e.g. deacration procedure). Disso lution results may be influcnced by the physical behaviour of the specimen stich as floating, adherence to the walls, etc. Thus, critical inspection and observation of test performance during thc test procedure is required. This approach is especially important to explain any "out-lying" results and it dearly limits the extent of automation for a number of drug formulations.

Validation of automated systems, either conceming the sampling and analytical part or also including media preparation and test per­formance, has to consider accuracy, precision and avoid com3lllina­£ion by any dilutions, transfers, cleaning or sample or solvent prepa­ration procedures. There should be proof thar there is no interfer­ence. This sha ll be evidence of no significant differences between data obtained with the lllanual dissolution equipment (see section 2) and the automated system, including manipulations sllch as pemla­nent sampling probes, additional valves, hollow shafts, etc. Since sen­sitivity to such modification may be fonnulation related, qualification and validation of automated dissolution equipment and testing has to be established on a case-by-case basis.

Validation of the analytica l procedures applied in dissolution test­ing, either automa ted or conventiona l, has to comply with "Va lidation of Analytical Procedures" (lCH) and "Y.1Iidation of Compendial Methods" (<1225>, USP). Validation aspects UlUS are accuracy, precision (repeatability, reproducibility), specificity, lineari­ty, range. Special care has to be taken regarding stability of the drug in test medium and sample solutions, since the test procedure often includes exposure to hydrolytic media at 37°C over significant time spans.

5. Formulation Cbamcte>"isation During development of the drug formulation, as a

basis for any in vitro-in vivo comparison srudy as well as for the final choice of test conditions for quality control

DissolutionTechnologieslNOVEMBER 1997

flP Guidelines ... cont. purposes, the respective dos.lge form h,15 to be thorough1r char<H:­tcri'ied in vitro widl respect to its biopharm:lcclltical performance. Special ancmion has ro be paid to controlled/modified-release prepa­rations, since sufficient information has to be gai ned about hO\\ Illllch the dosage form itse lt~ nlther than variations in test conditions, ~'co n­trol" the rate of dntg release.

Therefore, exrensivc dissolution tests ,lre necessary to l1nderst;lIld the delivery system and to have a rationale for the design of e,g. an in vitro-in vi \,o comparison study. The in vitro test profile will prefer­ahly consist of numerous individual di ssolut:ioll test>; under many dif­ferent rest conditiolls, involving the pH of test media and agimrion wi thin the ranges given in seerion 3. \ /a riarion of ionic strcngth, sur­fac t:lnts, enzymes or apparatus should be e\',llu,lted, if an influence 0 11

dissolu tion is expected for the individual fonnulation. For formulation characterisa tion, dissolution tests shou ld bc per­

form ed under the di ffere nt test conditions until actual di ssolution (e.g. mcan of six specimen) exceeds 80% of labelled amounl. \ \'hen, even with test prolonbration, results remain significantly below 80% and solubility is not the limiting parameter, recovery control should be performed to prevent misinterpretation of di sso luLion dar;l.

J\llost in vitro characteristics can be rehlted to physio logic,l l p;u'a­meters, such as pi I-profi le of test medi,l (gastric ,mel intestinal pi I), stirring or flow r:lt'e (gastfointestinallllotility, she:l ring forces), :lddi­tion of lipids, enzymes, surfacta nts (to simulate the physioiogicil cnvi­ronment). Thus, the information from formulation ch:lracrcrisarion in vitro can hc used later ;IS a tool to dcmonstnl te the rcliabiliry of;lJl in vi[ro-in vivo compari son, based on a distinct in vi tro model, as \\ell as for interpretation of all those examples where no or only a poor correlation of in vitro and in vivo data can be achieved. Ilo\\e\'er, it is obvious thilt ;1 meaningful in virro*in vivo col11l);}risoll (sec section 6) is [he more probable. the less affected in vitro dissol ution of a given drug formulation is by changes in the environmcntal tcst conditions.

6. In vitro-in vivo Comparison An in vitro test system for a given dmg fonnuhttion sen'es as the

tool as which it is dcsignated only, if it can disrjnguish hetween "good" and "bad" batches. "Good" here means "of accept<lble and reproducible hioph;lI'Inaccutical performance in vivo". Thus ill vivo rele\',l1lce of;1ll in vitro test system is sought. The purpose of in vi tro­in vivo comparison studies in ulis sense is the scientitic verific1tion of the in vitro tcst system and the respective specificarion limits for a given drug formulation.

Regarding extended-release dosage fonns the US!' /lSI has cate­go rised correlative methods, harmonised in a wide international con­sensus, as correlation b 'el A (I: I re lationship between in vitro and in vivo dissolution, calculated by numerical deconvolution [13, 141, according to \Vilgner-~Telson method 1251 or to Loo-Riegelmann

method [26]), correlation level B (sta tistical momenr

I an,l)'sis 117, 281) and correlation level C (single-point cor-

I relation of a dissolution time \'s. a phannacokinetic para­meter). Dcpending on the correlat:ion level finally obtained, in vitro di ssolution propcrties will be decisive

Disso/llliollTecim%gi('sINOVEM I3ER 1997

for the nccessiry of how Ill ,my ba tches should be included for a cor­re/ation shldy, c.g. for establishment of in vitro dissolution speci~ica­lion limi ts. According to recent recommendations, one single batch Ill;l)' be sufficient for il scientific111r ,md fonllally accepr'lble correla­tion 115 , [8], only in (,ISC of a correlation level A ,mel a product with a drug release, completely independent from environmental condi­t-ions, which then is represented hy only one di ssolution curve. Scientific ,md pr:l~l']llati c appro;lches for level A correla tions have heen proposed [19). '-11 case of:l le\'el A correlation , lll:lnUf<lChlrillg site changes, process and equipment changes, minor fonnulation l11odific;ltions, scale-up considerations and specific;ltion of dissolu­tion limi ts can he hased and justi fi ed without further in \~\'o-srudies.

In all other cases at Icast two or three different batches ha\'e to be used, offering differences ill their biopharmaccutical propelties, suf­ficient for correlation purposes. Nevertheless, these differences have to he 'effected' by only sllla li modifications of manufacUJring \'ari­;l bles within the r;1I1ges of the given process. In cases where differ­ences Clllllot be achieved by these va riations of the production process, major changes will he required to ohtain samples for in vi tro-in vivo comparison. Il owever, ;lIlY correlation rccei\tcd for dif­ferent forrnubtions bears the risk of being somewhat arbitrary. A tinal eva luatioll of type and influence of the changes in the lllanUE1 C­turing processes requires thorough in \'jtro dissolution tests ('bio­pharrnaccutical protllc'; see section 5) prior to an administration to human volunteers in a clinical srud y.

Concerning modified-releosl' prodll(f,f there is international consen­sus that levels A to C, \\ ilh ,1 quality ranking A > B > C, are accept­able for correlation e.g. for speci fications of dissolution limits. A

Table 4: Possible reasons lor poor In vlvo·ln vitro correlations

Fundamentals • in vivo dissolution IS not the rate limiting step for drug absorption • no In vitro test is able to model In vivo dissolution

Study design • inappropriate in vitro test conditions • inappropriate in vivo test conditions

Dosage form • drug release not controlled by the dosage form • drug release strongly affected by intestinal transport kinetics

Drug substance • non·linear pharmacokmetics (e.g. saturable first pass effect). absorption

wmdow. chemical degradation in the gastrointestinal tract • absorption of undissolved particles • large intralndivldual variability

Ilumber of different reasons (see "11lhle 4) could be responsible for "poor" or no correlation.

Even with highly sophisric:l(ed techniques it is oftcn difficult to

ohtain meaningful in vitro-in vivo comparisons, especially for bio­pharmaceutically very similar (hioequivalcnr?) products, such as b:ltches of one drug formulation, representing the upper and the lower di ssolution limits.

Recellri}" proposals have been Illl1de [301 which in virro-in vi\'o comparison results scientific:1l1y :1lld formally could suffice as vcri­fic.ltion of dissolution specification of controlled/modified-release products. In C;lse of :1 signillcant quantitative correlation, dissolu­tion limit<; can be derived hr inter­polation, when batches outside the specified biopharmaccutic:11 range are tested for in vitro- in vivo COI11-

parison. Thcll, at Ic,lst three hatches should be tested in vitro and in vivo. A qUi1litativc, i. e. rank-order correlation verifies ranges, whcn at least three batches arc tested in vivo flnd ill vitro and the dissolution dflt3 of two of the experimental ly investig;lted I)fltch­cs are concluded bioequiralent and their dissolurion chari1cteris­tics are speci/1ed as upper and lower dissolution limi ts (Fig. I).

\-\Th ere no correlation IS

obtained from an in vitro-in vivo comparison study, an alternative approach (Fig. 2) could consist of demonstrating bioequi\ralencc of the proposed formulation to for­mulations with dissolution profiles at the upper and lower limits of the specification [13 [.

The number of volunteers to

be included in such compara tive bioavailability snldies or in an in vitro- in vivo comparison stlJdy is to be defined on a case-by-case basis but in general should not be less than twelve.

The batch size of a fonnulation for in vitro-in vivo comparison srudies need not be of full produc­tion scale. Parameters for manu­facrure of these batches, especia lly of formulations representing the intended dissolu tion limits, should be defined frolll process va lidation

In -Vivo Verification of In-Vitro Test System and Dissolution Limits

Dissolution [~ o l

'00 r upper ' slde" batch

7S l[ I

target I . profile 50

25

o

?I' I j iower"slde" batch 1

I 2

SM OEIT 2 E

6 TImelhJ

Figure I

r 12

T,ma [hI

B

Dissolution Limits Verification low Correlation level Approach

In Vilro D,ssoiullOn

Figure 2

I)

T Examples for Verifica tion of Dissolution limits for -~ Immediate Release Dosage Forms with Dissolution Times

of >30 (left) or >45 min (right )

Dissolution 1%) In VIVO co~panson

'OO ~fl· i 1 1 i, ~~::f.7·: /"1 75 17:~U"0:t~' .. "--'~ -----=r l-poln1 • e.g 2-pomt

:: rJ d j="oo o 30 60 90 120 0 30 60 90 120

TIme [min] TIme [min]

Figure 3

two-way crossover between an oral solution and a fonnulation representing the (lower) specifi ed dissolution limit. (Fig. J).

7. Dissol1ltiol1 Limits The purpose of specifying dis­

solution limits is to ensure b;ltch­to-batch consistency within a range which !,'1Iarantecs acceptable biophal'lll:lceutical perfonmnce in vivo. Limits therefore have to be defined based on experience g;lined during the dmg develop­mcnt stage ~specia ll y regarding clinical de"elopmelll and/or bioe­quivalence snldies. In Illost cases deduction of limits requires thor­ough in vitro-in vivo comparison studies as described in section 6.

For illllllcdiate/conventional­rcie,lse formulations typically one limit is speci~i ed to ensllJ'e thin most of the active ingredient is released within the present time period. Regarding the deduction of limits, diffe rent procedures are recommended, depending on the individual dissolution characteris­tics. However, it is dearl}1 stated, that the following categorisation only concerns the specification verification process. It docs not qualify or disqualify dmg formula ­tions with dissolution properties, characterised by a specified time of > 15 minutes.

In case of velY fast drug releasc, single point dissolution data during cl,e de,'elopment period and a sin­gle point specifia1tion, consisting of ,1 pan1llletcr quantitating the extent and a parameter to define cl,e time, are judged sufficient. A formulation is in this concern understood as very fast releasing, when at least 80% of the drug sub­stance, corresponding

shldies according to the expected maxlInum variability of process parameters ("side batches").

to "Q" = 75% (see ~rabl e 5 a in section 8), is dissolved in about 20 - 30 minutes (including any lag times due to dis­solution of a tablet coating or capsules) under reasonable and justified test conditions. In th is case dissolution limits

Concerning immediate/conventional-release dosage fonns a suit­able design for an in vitro-in vivo comparison study could consist of a

Disso/litiollTecim%giesINOVEMBER 1997

flP Guidelines ... cont. ca ll be defined based on in \~tro data, obta ined during dmg develop- an in vitro-in vivo comparison study and should at least cover menr without an in vitro-in ,~\'O comparison 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 corresponds w typ- intcn'als specined should he defined case-by-casc 011 the basis of the ical gastric emptying times [31-331. in vitro-in vivo comparison study and taking into consideration the

Imm ed iare!convention- Table 5: Acceptance Tables According to DSP 23 < 111 > < 124 > c:lp:lbi lity of the lll"'lUfac-ai-release fonnul:mons WIth ruring process ,mel the com-a speciRed dissolution time Sa: Immediate/ conventional-Release Drug Products manly accepted range of 95 of more than 30 minutes will 5tage Number Tested Acceptance Criteria to 105% of stated amoum require an III VitrO- in VIVO 51 6 Each unit is not less than Q + 5 % for the average conrenr of comparison srudy and disso- 52 6 Average of 12 units (S1 + S2) is equal to or greater than Q. drug subsm nce. \,\'here

and no umt is less than Q - 15 % lurion profiles with several both upper and lower limi ts

53 12 Average of 24 units (S1 + 52 + 53) is equal to or greater (e. g. 3) poinrs, obtained than Q. not more than 2 units are less than Q _ 15 %, are specified at ,lI1y time duri ng development, to and no unit is less than Q - 25 % point, the difference specify single point lim its. 5b: Modified (Extended-Release) Drug Products between them should usmll -Formulations with a speci- Stage Number Tested Acceptance Cnteria Iy not exceed 20% of the fi ed dissolution time of> 45 l1 6 No individual value lies outside each of the stated ranges labelled con ten t of drug minutes may require two and no individual value is less than the stated amount at substance ill the fonnula-

the final test tllne specified dissolution times

L2 6 The average value of the 12 umts (L1 + L2) lies within for quali ty control purposes. each of the stated ranges and is not less than the stated

Gastro-resisralll drug amount at the final test time; none is more than 10 % of labelled content outside each of the stated ranges; and

products should be treated none is more than 10 % of labelled content below the like immediate- release prod- staled amount at the final test time ucts 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 stated ifying limi ts for the second amount at the final test time; not more than 2 of the 24 dissolution test period, fol- units are more than 10 % of labelled content outside each of

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

labelled content outside each of the stated ranges or more For modified-release for- than 20 % of labelled content below the stated amount the

lTlulations (except debycd- final test time release) dissolution require- 5c: Gastro Resistant (Delayed-Release) Drug Products Illcnts should consist of at Acidic stage least three poin ts. The first limit is specified to prevent "dose dumping" and there­fore should be se t after a testing interval of one to t\vo hours or corresponding to ,} dissolved aillounr of 20 -30% of labelled dmg sub­stance. The second limit should define thc dissolution pattern and thus be set around 50% release of labelled drug substance. The final limit is specificated to

ensure (almost) quantitative

Stage Number Tested 6

6

12

Buffer stage Stage

83

Number Tested 6

6

12

Acceptance Criteria No individual value exceeds 10 % dissolved Average of 12 units (Al, + A2) is not more than 10 % dissolved. and no indiVidual unit is greater than 25 % dissolved Average of the 24 units (Al + A2 + A;l) is not more than 10% dissolved. and no individual unit is greater than 25 % dissolved

Acceptance Criteria Each unit is not less than Q + 5 %

Average of 12 units (B 1 + Bll is equal to or greater than Q, and no unit IS less than Q • 15 %

Average of the units (B t + 82 + 83) is equal to or greater than Q, not more than '2 units are less than Q - 15 %, and no unit is less than Q - 25 %

don unless limits have been shown to provide repro­ducible and acceptable m vivo performance [13 [.

8. Interpretation, Acceptllnce Criteria

Dissolution test speci6-C'J tions should include the definition of limits, the number of units to be exa mined and respective acceptance criteria . The procedure of data interpre­tation should be har­monised inrernationally, the existing compendial requirements should be uniform .

As pharmacopoeial approaches are sti ll not fully hllrmonised it is recom­mended to follow Ule accep­tance criteria in accordance with US P for immediate! conventional-release prod­ucts, modi fi ed-release (extended-release) products and gastro-resistant

drug release, which is gene"lily understood as ~80%. The dissolution run in quali ty comrol therefore should be extended for the tillle interval until ;It least 80% of drug substance is disso lved. Shoner test imerv.lls can be ,lccept­able in special cases but require justification on the basis of

(delayed-release) products Crable 5). The approach with a maximum of three stages and individual units tested for deviation from stated ranges corresponds well to requirements for coment uni fomlity. Although there is preference ill common pnlctice in pharmaceutical industries {Q decide upon batch release not later than stage 2, the three

Disso/Illio7l7ecim%giesINOVEMBER 1997

step approach is the best solution for formal specifications, especially when referring to end-of-shelf life specification. Reference to labelled content docs not apply for products with intentional di fferent content at time of manufacrurillg, Stich as in cases of stability overage.

9. Special A pplications A spcci~i c value of di ssolution testing is recognized in its applica­

tions in scale-up and manufacturing changes for immediate/conven­tional-release and lJlodi~ ed - rel e<lse oral products. The AAPS/FDA/USP Seale-up workshops 134, 151 recommend cCitain types and ranges of changes for which the sameness of in vivo prod­uct performance is assullled, based on in vitro di ssolurion dam. In addition, the Scale-Up and Post-Approval Change (SUPAC) 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. COllclusiolls In many international discussions, Ill'lill ly over the years 1988 to

1993, consensus was reached on some essential aspects, to which these Guidelines refer. On the other hand, many aspects have either not yet been sufficiently explored or have not been harlllonised. In these cases, e.g. morc precise specifications of dissolution media and proposals for in vitro- in vivo comparison approaches and verification of specifications for illlll1edi<lte/conventional-releasc, delayed-release and modified-release preparations, the revi sed Guidelines will pro­vide contributions for reasonable standardization, while acknowledg­ing that for a numher of dnlgs e.g. wi th special physico-chemical or

ponenrs and composition, site of manufacturing, the sc,lle of ll1 ,lI1ufaculring, and process and equipment

Table G: Dissolution media that may reflect gastric conditions ,fasted: phann,lcokilletic proper­ties, case-by case develop­lTl ent is required. SGf) and conditions in small intestine ,fasted: faSSlf; fed: feSSlf)

changes in manufacturing ~~r 0.01 -0.05 N for an immediate- release o ral fo rmulari o n. Depending on the level of change, different Icvels of dissolution testing are rec-ommended to assure con-tinuing product qual ity and performance characteris-ti cs . Respectively, the docu-mentation needed to assure the product performance vari es, depending on thera-

Sodium lauryl sulfate Sodium Chloride Distilled Water

2.5 G 2.0 G qs. 1000 ml

peutic range, solubility and pemleabili ty fa ctors of the drug. For changes greater than the acceptable values in the scale-up workshop report, additional dissolution profile determinations in se\'eralmcdia are recommended for immediate-release products.

For major changes, that are likely to ha ve a significant impact on formulati on quality and performance, an in vivo bioequi v,llence study is recommended in addition to extensive dissolution profile resting. For manufacturing site change, scale-up, equipment changes <lnd minor process changes dissolution testing is deemed sufficient to assure product quality and performance.

[n vitro dissolution tests have also been used to try to simulate food-effects on bioavailability. So far, these different attempts 117 -41] ha ve had extremely limited success in prediction 1441 . Assuming that gastro-in testinal transit times are sif,rnificanrly contributing to

potential food-effects on bioavailabil ity, the va lue of an in vitro model for food-effects will be limited to an evaluation whether direct drug­food-interaction could be of relevance for the observed changes in bioava ilability in the in vivo srudy.

Test media that may refl ect gastric conditions (fasted) and intesti­nal conditions (fastedlfed) and thus may give additional infonnation for research and development purpose are summarised in Table 6

FaSSIF KH2 P04 NaOH NaTaurocholate Lecithin KCI Distilled Water

FeSSIF AcetiC acid NaOH NaTaurocholate lecithin KCI Distilled Water

0.029 M q.s pH 6.8 5mM 1.5mM 0.22 M q.s. 1000 ml

0.144 M q.s. pH 5 15 mM 4 mM 0.19 M Q.S. 1000 ml

These Guidelines should be helpful and ilppl icable for all involved in in vitro dissolution test­ing. However, there was special emphasis 0 11 pro­viding reliable guidance for industrial rese,nch and development, process vali ­dation .mel quality control , making the Guidelines especially applicable fo r industry, dmg authorities and control laboratories

but al so for universiti es, hospitals, phannilcies or others, when involved in (bio)pharmilceutical qllaliry eva luation.

til general these Guidelines should be understood as recommenda­tions based on scientific knowledge and experience. They should be helphll in the dialob~le with drug regula tory authorities. However they arc not intended to represent any offI cial requirements in this neld.

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12. Hlllllle H, Ali SL, SU'71.·f/1 .\1 (198-1) lur phlll7l11l:elltischm QUlllitiit 7."011 glibmritlmidh"/flg('IJ Ff'I1igl11"":'lII'imittdll. Pharm ltg 129,983 - 989

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16. 51mb lIP, Kon('(/JJ JJ. Et'el"ett RL •. \lrCllllolIgb IJ. Soorhiu/dJ :Ie. SJ:ellj' JP (1989) 111 /fino Dissoilltloll Profile oj" lI11Ier-llIsollI"'e Drug 1)0sIIge FOl7Ils ill tbe Presellcr of SmjitrlfllltS. Pblmll Rt's 6 (7) 611- 618

/7. Sbllb VI{ Gllrlilllg ill, NOQlY,/, Digb, S, Ske//y]1' (199/) /ilf/llmre of I fighl'r Rlltes ofl/gilllfioll 011 Rd('flse Ptltten/s of 11II1II1'dillll'-Rdl'lIse Drug Prodllrts. J Pb(fl'111 Sci 81 (6) 500 - 50J

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10. So/tm RA, lloover ],11, .lOll" IT. Stllildisb ,II (/989) EjjictsofSillker Sbllpes 01/ Dissollllioll Plvjilrs. J Pblll'lJl Sri 78. 35 - J9

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

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30. SiCiliC11 M (I99';): /" Vivo V"lid(ltiulI of 111 Vitro Dissolutioll Jrsts fllld SpI'Cijimfiolls: rlpplimtioll fur COIlf1v/ledl.\ lodifirt! Rell'IIse Prodlll1S. iJioillfernmiol1ld 2 (293 - 299)

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

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I 99, /275 - 1181

/Jism//ltiollTedJll%giesfNOVEMBER 1997

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H. IVorkshop Repol1 (1993): Sm/I'-L"p oj IlI/lIIl'dillte Rrifllse 01"111 Solid Dos(lge Forms. Pbllrm. Rt's. l(j. 313 - 316 IIl1d EII1: J. Pbarm. IJiopblll7J1. 39 (I). 40 - 43

J5. If 'or/.:J/Jop II Rrport (1993): SCl/it'-Up of Om I Ertell/led Rdetl.ff Dosage FOI'IlIs. PbIlI7Jf. Res. 10, I SOO - I S05 IIl1d Em: 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 GIVUp of tbe Chemistl)' .\[allufartlll7l1g COIlf1VIs Coonlhultillg COlllmittel' of tbl! CrII/t·rfar Dmg Evaillmioll (lIId Resf(frr/J (199-1) IlIferim GllidllllU IlIlIImlill'l' Release Solid Om/Dosage Ponl1s - Pre­fllld Pos,-Appl"01.,"1 Cb(lIIgl'S.

17. ,\I({lIml PK. PnmulllK, II'onlt)' IV, Sbiu GK, S'ke/~)' JP (1986) IlIfllleliu of II high Pit bretlkji/J! 01/ tbt' bio(/"1.wilflbi/ity oflbeopJ~)'J/illf COIl f7'oJ//'d-rr!etlse )01'­JIIulmiolls: 1111 ill vitro dt'mollstrtltioll Ofllll illl,il'O ubsm.'IItioll. III:]. Pbll17l1. Sci. 75. /105 - /]06

JS. It /'IIr~.' L. KJllilll. /, PI/gone I·: Strrirbt'rJ, Il'irklllllllil (1988) Pood-III/luud TbeopbJ'"mr ReI('IfselAbsOlptioli OJIIl/gfS fiwl/ COlltrollel/-Rr/l'llse FOl7llflllltions: , I Propoml in I'itlv .\I{)(M. Drug D(1.:I. IIItI. Pb"rlll. 1-1, 13 - 28

19. Karim II: Imp0l11111Ct' ofAsJt'ssiJlg Food Effects in Et'll/l1l/tlllg COIlf1vllrd­Rdl'llsr Furlllll/tlfiolls. (1988) I,,: )iltobi A /I/lt! fllI/perin-Wfllegll E: Oml Siml/illcd Rel('llsl' Formllllllioll.!: I)r.l"igllll1/{/ Ev(dlllllioll. Pr1'gtlllloll Preofs, , 157- JNJ

-10. EI-A1'llli K. Shill GK. Skt'/~y JP (1990) T/;eopJ~yllillr-Collflvlld Rr/ellse PrepllrtltiollJ alllll·ilt~y lifxul: ;/11 ill 6f1v SIIUiy Usillg the Rowillg Di(Ii)'sis Cell. Ph(ll111. Res. :-, 11 3-1- 11-1-0

-II .. \Il1cbenfS P. Kouppafis ,lI. Jjllprollllis C (1986) Dmg dissoluti01l stflllirs i1l lIIi//': Ifsmg tbl' IIIIfQIlIfltt'lJ }lerll' illjmjoll m'i,,/ l~yll(lIIlir dialysis tuhf/iqlfr. 1m. ]. Pbllrm. 33 , 1]5 - /36

-12. JIIlIgillgl'r I fE, VerbofvI'1I J, Pt'scbi('r L]C (1990) Eille II/'/ICS ill 'vinv-/Hot/rJl :lIr I~'rkt'mlllllg 7.'011 Wrdmltl'irkllllgm z,i.l'iscben RrftmJl/rzneilllitte/1I :wr om/l'lu/pplik"tiol/ IlIId NlIlmmgsntittelll. Pb(wm. Ztg Wiss. 2, 53 - 58

-1-3. I\riimrrJ, Lilltitlllt'1" Re Sirv.'ert ,\/, St,.irkt',· /-I, /JIume II (/991) £\·tl'1ulrd­Relel/se Tbt'opbJllillf Altfl1l1lffl.'e /11 /'itro Dissollltio1l ,\Iethotis. Elfr. J. Drug. .\Ielllb. Pbl/l7Jlflrakill. IN, r

-1-1. Sira't'11 .1I (1989): /11 t'itlV-OlSSollllioll Jerrillg of Oml COIlf1v/led Release Pr{)(llIm. III: Glllllim-Rnn] U 1111(1 ,\/"IJel" II: Oml COllflvlled Rde(lse Prodllm 7])cmp('lltic IIl1d Biopblll'l)/(Iwitir Assrss-mem. Wissellsrb(iftfirbe 1't.'r/IlgsgeseJI.Kbtlfi, 139 - 1 H

-15. Gali" E, Nitoillides I';, Repplls C. DmS-III(f1l J/J (1 996): M."'JJ medill discrimi­Illite dissolmioll propmirs oIpoor(y soillble drugs. P/)III7I1. RcSetllr/) 13, 262

-16. Ogllt/l /-I et III, (198-1): DrvelopmclII oJlwd tn'll/lIl11ioll ofa 1Il'il' perorfll test (lgml G//-Test jor IISSfS'lIIell1 ofgas/1"lr lIrit/if]. J. Pbnl7llUroblO-DyIl 7, 656-664

For COI7"I'Spol/(/fllce: PIP JI 'orkillg Group -I: Disso/litioIlIllU/ Dissolutioll SprcijimtiollS D/: {\ Itmill Sil7!'l'rt do Iloabst Mllrion ROIISS{'/, Building K 607, D-65926 Fmnklim

7],is jilllll "offici,,/", versioll of tbl' PIP Gllidelillfs fOl' Dissollltioll 'Terring oj So/i,1 Oml Protillrts i!."llll/iso be pllblis/m/ ill 11Itfl7lf1tiol/(t/ Pb(ll7)l(lry, Pb(ll'lJUlcoporinl Forum, Die Pblll7J1f1':£lItisrhe Im/llmie IIIUJ PbUl7llllfflltiat/ 7frbJlology.