Pharmaceutical Research, Vol. 6, No. 7, 1989
`
`Report
`
`In Vitro Dissolution Profile of Water-Insoluble Drug Dosage
`Forms in the Presence of Surfactants
`
`Vinod P. Shah, 1•5 John J. Konecny, 2 Richard L. Everett, 3 Bruce McCullough, 4
`A. Carol Noorizadeh,I and Jerome P. Skelly1
`
`Received September 7, 1988; accepted February 7, 1989
`
`The determination of the in vitro release profile of water-insoluble drug products requires dissolution
`media different from those used for water-soluble drug products. Since the relevance of drug disso(cid:173)
`lution in organic solvents is questionable, we investigated the use of surfactants to determine the
`dissolution profiles of water-insoluble drug products. In most cases, the drug dissolution rate and
`extent increased as the surfactant concentration in the aqueous dissolution medium increased. Suitable
`dissolution profiles were obtained in the presence of sodium Iaury! sulfate (SLS) for water-insoluble
`drug products, such as griseofulvin, carbamazepine, clofibrate, medroxyprogesterone, and cortisone
`acetate. These findings recommend the use of surfactants for determining the aqueous dissolution of
`water-insoluble drug products rather than adding organic solvents to the dissolution medium.
`
`KEY WORDS: dissolution of water-insoluble drugs; dissolution of griseofulvin, carbamazepine, clofi(cid:173)
`brate, medroxyprogesterone, cortisone acetate; dissolution with sodium Iaury! sulfate; dissolution
`with surfactants.
`
`INTRODUCTION
`
`Dissolution of drugs from solid oral dosage forms is a
`necessary criterion for drug bioavailability, i.e., the drug
`must be solubilized in the aqueous environment of the gas(cid:173)
`trointestinal (GI) tract in order to be absorbed. Therefore,
`the dissolution test for solid oral drug products has emerged
`as the single most important control test for assuring product
`uniformity and batch-to-batch bioequivalence once its bio(cid:173)
`availability has been defined (1). For water-soluble drugs
`suitable dissolution media are water, dilute buffer solution,
`simulated gastric fluid, and/or simulated intestinal fluid with(cid:173)
`out enzymes. For drugs that are practically water insoluble
`(solubility less than 0.01%), an appropriate dissolution me(cid:173)
`dium/or method needs to be developed.
`Attempts have been made to conduct dissolution testing
`for sparingly water-soluble drugs by using a large volume of
`the dissolution medium or by removing the dissolved drug
`(2-5). While both these procedures are intended to provide
`sink conditions, they are cumbersome. Another approach
`involves increasing the drug solubility with the use of hy(cid:173)
`droalcoholic dissolution media (6,7). Additionally disintegra-
`
`1 Division of Biopharmaceutics, Center for Drug Evaluation and
`Research, Food and Drug Administration, Rockville, Maryland
`20857.
`2 Philadelphia District Lab, FDA, Philadelphia, Pennsylvania 19106.
`3 Baltimore District Lab, FDA, Baltimore, Maryland 21201.
`4 Chicago District Lab, FDA, Chicago, Illinois 60616.
`5 To whom correspondence should be addressed.
`
`tion tests have been used in lieu of dissolution tests. The use
`of disintegration or dissolution in alcoholic media as a qual(cid:173)
`ity measure is questionable for the following reasons: (i) the
`use of a hydroalcoholic medium has no relevance to the
`physiological milieu in which the drug dissolves, and (ii) the
`disintegration test is not a good quality-control procedure
`and is not predictive of drug bioavailability (8,9).
`Because of the increasing number of water-insoluble
`solid dosage forms, it is necessary to develop an in vitro
`dissolution test as a quality-control procedure to assure
`batch-to-batch product bioequivalence once bioavailability
`has been established. A simple approach is described here to
`determine the dissolution of the water-insoluble drug prod(cid:173)
`ucts, griseofulvin, carbamazepine, cortisone acetate, clofi(cid:173)
`brate, and medroxyprogesterone acetate.
`
`MATERIALS AND METHODS
`
`Materials
`
`Attempts were made to obtain all brands and strengths
`of approved and marketed dosage forms for the drugs stud(cid:173)
`ied.
`
`Sodium lauryl sulfate (SLS; Fisher Scientific, King of
`Prussia, Pa.), sodium cholate, sodium dehydrocholate, so(cid:173)
`dium deoxycholate, sodium taurocholate (Pfaltz and Bauer,
`Waterbury, Conn.), bile salts (Sigma Chemical Co., St.
`Louis, Mo.), sodium oleate, dioctyl sodium sulfosuccinate,
`Tween 20 [polyoxyethylene (20) sorbitan monolaurate], Brij
`35 (polyoxyethylene lauryl ether; Fisher Scientific), and so-
`
`0724-8741/89/07()().()612$06.00/0 © 1989 Plenum Publishing Corporation
`
`612
`
`0001
`
`PSG2008
`Catalent Pharma Solutions v. Patheon Softgels
`IPR2018-00422
`
`

`

`Dissolution of Water-Insoluble Drugs
`
`613
`
`Producta
`
`I
`
`II
`
`TABLE I. Effects of Surfactants on Dissolution of Griseofulvin Dosage Forms
`
`Aqueous solution containing
`
`60 min
`
`90 min
`
`% dissolution
`
`I% sodium dehydrocholate
`1% sodium desoxycholate
`2% sodium desoxycholate
`4% sodium desoxycholate
`2% sodium desoxycholate and 0.54% SLS
`1% sodium taurocholate
`4% sodium taurocholate
`6% sodium desoxycholate (4 parts)
`and sodium cholate (6 parts)
`1% Tween 20
`0.6% Brij 35
`1% dioctyl Na sulfosuccinate
`4% sodium oleate
`0.2% sodium bistridecyl sulfosuccinate
`0.54% sodium Iaury! sulfate
`1.0% sodium Iaury! sulfate
`2.0% sodium Iaury! sulfate
`4.0% sodium Iaury! sulfate
`1% sodium cholate
`1% sodium cholate and 0.54% SLS
`4% sodium oleate
`0.54% sodium Iaury! sulfate
`1.08% sodium Iaury! sulfate
`2% sodium Iaury! sulfate
`4% sodium Iaury! sulfate
`
`10.7
`15.5
`24.3
`42.6
`36.2
`7.7
`15.7
`50.4
`
`13.3
`9.7
`27.2
`98.5
`9.6
`74.9
`94.0
`99.3
`102.0
`15.1
`52.2
`69.5
`54.2
`63.5
`74.9
`82.8
`
`10.9
`15.4
`25.3
`43.2
`37.9
`8.7
`16.7
`52.4
`
`13.3
`9.2
`27.5
`100.9
`9.6
`79.4
`98.6
`102.0
`102.0
`15.4
`57.7
`72.7
`59.3
`72.2
`79.8
`87.6
`
`a I, 500 mg, manufacturer C; II, 500 mg, manufacturer A.
`
`dium bistridecyl sulfosuccinate (American Cyanamide Co.,
`Wayne, N.J.) were used as received. All reference standards
`were obtained from the USP (USP Convention, Inc., Rock(cid:173)
`ville, Md.) and used as received.
`
`an aqueous medium containing gradually increasing concen(cid:173)
`trations of sodium lauryl sulfate.
`
`Procedure
`
`Dissolution Medium
`
`For griseofulvin several surfactants and bile acids, in
`various amounts and combinations, were studied. The dis(cid:173)
`solution profile of the other drug products was determined in
`
`All dissolution tests were performed using the USP XXI
`apparatus 2 (paddle method) at 37°C. The dissolution appa(cid:173)
`ratus was calibrated using USP prednisone and salicylic acid
`calibrators as well as DDA (Division of Drug Analysis,
`CDER, FDA, St. Louis, Mo.) prednisone performance
`
`%DISSOLVED
`
`100
`
`%DISSOLVED
`
`80
`
`60
`
`40
`
`20
`
`0
`
`!OOf
`
`80 f-
`I
`
`60
`
`40
`
`20
`
`0
`
`15
`
`30
`
`60
`45
`TIME (MIN)
`
`75
`
`90
`
`15
`
`30
`
`45
`60
`TIME (MIN)
`
`75
`
`90
`
`-+-
`0.54% SLS
`1.08% SLS
`2% SLS
`-&- 4% SLS
`-li<-
`Fig. 1. Dissolution profile of 250-mg griseofulvin tablets (manufac(cid:173)
`turer A) in sodium Iaury! sulfate solution.
`
`0.54% SLS
`
`1.08% SLS
`
`-+-
`Fig. 2. Dissolution profile of 500-mg griseofulvin tablets (manufac(cid:173)
`turer C) in sodium Iaury! sulfate solution.
`
`--ll<-
`
`2% SLS
`
`-&- 4% SLS
`
`0002
`
`

`

`614
`
`% DISSOLVED
`
`100
`
`BO
`
`60
`
`40
`
`20
`
`Shah et al.
`
`% Dissolved
`'
`i
`BO '
`I
`
`'
`
`60
`
`40
`
`15
`
`30
`
`60
`45
`TIME (MIN)
`
`75
`
`90
`
`0~----~-----L----~------------~-----
`0
`30
`60
`90
`120
`!50
`lBO
`Time (Minutes)
`
`-~-~ ~~~~ ~~-~ -~~~
`"'""*-- C. 500 mg
`Fig. 3. Dissolution profile of 250- and 500-mg griseofulvin tablets in
`4% sodium Iaury! sulfate at 100 rpm by the paddle method.
`
`--- Water
`
`-i-- O.lN HCl
`
`--6- 0.5'7. SLS
`
`-4---
`2% SLS
`Fig. 5. Dissolution profile of 200-mg carbamazepine tablets in dif(cid:173)
`ferent dissolution media by the paddle method at 50 rpm.
`
`standard, before initiating the studies. The dissolution re(cid:173)
`sults were found to be within specified limits with all three
`calibrators.
`The dissolution studies were conducted using a paddle
`speed of 50, 75, or 100 rpm in 900--1000 ml of the dissolution
`medium. Several dissolution media were studied for a given
`drug product. Samples were analyzed at frequent time inter(cid:173)
`vals to obtain the dissolution profile of the products.
`
`Griseofulvin
`
`Dissolution studies were carried out at 75 and 100 rpm in
`1000 ml of the medium. A 20-ml aliquot was removed at 15,
`30, 60, and 90 min. Each aliquot was replaced with fresh
`medium. A syringe with a stainless-steel cannula was used to
`draw up the test solution. The aliquot was forced through an
`0.8-J.Lm porosity membrane ftlter (Type AA, Millipore Corp.,
`Bedford, Mass.). The first 10 ml was discarded to wash the
`ftlter free of material that might interfere with the assay and
`to saturate the filter with drug. A measured portion of each
`of the ftltered aliquots was diluted with a solution of meth(cid:173)
`anol and water (4: 1) and compared to a standard in the same
`medium at the wavelength of maximum absorbance (about
`293 nm). A UV blank of dissolution medium was prepared in
`
`% DISSOLVED
`
`the same manner. This solution was read at 293 nm and any
`absorbance value was subtracted from that of the sample
`absorbance.
`The solubility of griseofulvin was determined in water,
`2% SLS in water, and 4% SLS in water. An excess amount
`of griseofulvin USP reference standard was shaken in 100 ml
`of the medium at room temperature (25°C) for 8 hr, then
`allowed to stand overnight, and the amount of drug dissolved
`was determined by UV procedure. This procedure was re(cid:173)
`peated until the last two UV measurements gave the same
`results.
`
`Carbamazepine
`
`Dissolution profiles of 200-mg carbamazepine tablets
`were studied using the paddle method at 50, 75, and 100 rpm
`in water, 0.1 N HCl, simulated intestinal fluid (SIF) without
`enzymes, and 0.5-2% SLS. Products A (Ciba-Geigy) and B
`(Colmed) were also studied using the paddle method at 75
`and 100 rpm and a medium containing 10.5% alcohol and
`0.1% Tween 20 (10). After establishing the dissolution test
`parameters using the Ciba-Geigy product, all marketed 200-
`mg carbamazepine tablets (A, Ciba-Geigy; B, Colmed; C,
`Inwood; D, Lemmon) were evaluated using the paddle
`method at 75 rpm in 1% SLS. Dissolution samples were
`analyzed by the UV method at 285 nm.
`
`Clofibrate
`
`Dissolution of clofibrate capsules from two manufactur(cid:173)
`ers (A, Ayerst; B, Geneva) were determined in 1000 ml of
`water and in increasing amounts of SLS by the paddle
`method at 75 rpm. All samples were analyzed by a high(cid:173)
`performance liquid chromatographic (HPLC) procedure
`with detection at 226 nm. The HPLC procedure employed a
`10-J.Lm C18 column (30 em x 4 mm) and an isocratic mobile
`phase of methanol and water (80:20).
`
`TIME (MIN)
`
`-~-~ ~~~~ ~~-~ -~~~
`"'""*-- C. 500 mg
`
`Medroxyprogesterone Acetate
`
`Fig. 4. Dissolution profile of 250- and 500-mg griseofulvin tablets in
`4% sodium Iaury! sulfate at 75 rpm by the paddle method.
`
`Dissolution profiles of three marketed brands (A, Up(cid:173)
`john; B, Camick; C, Reid Provident) of medroxyprogester-
`
`0003
`
`

`

`Dissolution of Water-Insoluble Drugs
`
`615
`
`Table II. Dissolution of Carbamazepine Tablets Using the Paddle Method and a Hydroalco(cid:173)
`holic Mediuma
`
`100 rpm
`
`75 rpm
`
`Manufacturer
`
`A. Ciby-Giegy
`B. Colmed
`
`1hr
`
`68.6 ± 2.2b
`93.7 ± 1.3
`
`3 hr
`
`%.5 ± 2.4
`101.6 ± 0.6
`
`1 hr
`
`63.5 ± 4.0
`88.2 ± 3.1
`
`3 hr
`
`89.6 ± 4.1
`100.8 ± 1.2
`
`a 10.5% 3A alcohol and 0.1% Tween 20.
`b Mean of six tablets ± %CV.
`
`one acetate tablets were determined by the paddle method at
`50 rpm in 900 ml of water and 0.5 and 1% SLS. Samples were
`removed at 15, 30, 45, 60, 90, and 120 min and analyzed by
`the UV method at 240 nm.
`
`Cortisone Acetate
`
`Dissolution profiles of nine brands of marketed corti(cid:173)
`sone acetate tablets were studied. All dissolution samples
`were analyzed by the UV method at 240 nm. All samples
`were also tested using the official USP XXI method, which
`requires a medium containing 30% isopropyl alcohol in wa(cid:173)
`ter.
`
`RESULTS
`
`Griseofulvin
`
`The role of surfactants in the release of sparingly soluble
`drugs from the tablet matrix (11) and their ability to solubi(cid:173)
`lize water-insoluble materials are well described (12,13), and
`considerable work has been done to study the dissolution of
`griseofulvin products. Bile salts (sodium deoxycholate) and
`surfactants such as SLS and sodium oleate have been shown
`to increase significantly the dissolution rates of griseofulvin
`over that in water alone (12).
`For comparison of the solubilization of microsized
`griseofulvin, solutions of all the bile salts and surfactants
`were tested on two commercial tablet samples. Dissolution
`results are given after 60 and 90 min (Table I). The dissolu(cid:173)
`tion values observed represent the combined effect of the
`
`solubilizing property of the surfactant and nature of the for(cid:173)
`mulation itself. Because offormulation effects, two products
`may show different dissolution profiles in spite of the same
`solubilizing effect of the surfactants. Examination of the dis(cid:173)
`solution data show that SLS and sodium oleate were the
`most efficient solubilizers. A dissolution medium containing
`6% bile salts (60 parts sodium cholate and 40 parts sodium
`desoxycholate) resulted in about 50% dissolution within 60
`min, whereas as little as a 0.54% solution of SLS resulted in
`75% dissolution. Solubility of griseofulvin using the USP
`reference standard was found to be 0.00908g/liter in water,
`1.915g/liter in 2% SLS aqueous solution, and 3.535g/liter in
`4% SLS aqueous solution. The solubilizing properties of
`other bile salts such as sodium glycochenodesoxycholate,
`sodium glycodesoxycholate, sodium taurochenodesoxy(cid:173)
`cholate, and sodium taurodesoxycholate were also consid(cid:173)
`ered. Because of the observed low solubilization properties
`(Table I) and the relatively high cost of these bile salts, it was
`decided to terminate further testing of bile salts. In these
`experiments sodium lauryl sulfate and sodium oleate were
`found to be better solubilizers than the other surfactants.
`However, solutions of sodium oleate gave high UV absor(cid:173)
`bance and interference at 293 nm, the maxima at which gris(cid:173)
`eofulvin is spectrophotometrically determined. Therefore,
`sodium lauryl sulfate was selected for all other additional
`studies.
`The concentration of SLS in the dissolution medium
`was progressively increased from 0.54 to 4% in order to
`study the rate and extent of dissolution of griseofulvin tab(cid:173)
`lets. The dissolution of all products was initially studied us-
`
`% Dissolved
`
`% Dissolved
`
`100 c
`
`;
`80-
`
`40 ~
`j
`
`I
`
`I I .
`I I
`ji
`I;
`':~
`
`0
`
`10
`
`30
`20
`40
`Time (Minutes)
`-+- B
`---*- C
`A
`D
`--€l-
`Fig. 6. Dissolution profile of marketed 200-mg carbamazepine tab(cid:173)
`lets in 1% SLS by the paddle method at 75 rpm.
`
`50
`
`60
`
`3
`4
`Time (Hours)
`--+- 3% SLS
`-+--
`---*'""" 6% SLS
`-
`0.3% SLS
`4% SLS
`5% SI.S
`-8--
`Fig. 7. Dissolution profile of clofibrate soft gelatin capsules in dif(cid:173)
`ferent dissolution media by the paddle method at 75 rpm.
`
`0004
`
`

`

`616
`
`Shah etal.
`
`Table III. Dissolution Profile of 500-mg Clofibrate Capsules: Paddle Method; 75 rpm; 5% SLS
`
`% dissolveda in
`
`Manufacturer
`
`A. Ayerst
`B. Geneva
`
`30 min
`
`33 (10)
`29 (19)
`
`60min
`
`57 (6)
`53 (11)
`
`120 min
`
`180 min
`
`240 min
`
`75 (5)
`73 (8)
`
`85 (4)
`83 (6)
`
`91 (4)
`89 (5)
`
`a Mean of six capsules (%CV).
`
`ing the paddle method at 100 rpm (the USP-recommended
`agitation). The results of the griseofulvin tablet dissolution
`are summarized in Figs. 1, 2, and 3. The dissolution coeffi(cid:173)
`cient of variation at each time interval was less than 10% in
`all cases. The more rapid dissolution of griseofulvin tablets
`from manufacturers B and C than of tablets from manufac(cid:173)
`turer A may be due to the formulation of the products and
`the interaction of the surfactant with the formulation. The
`dissolution studies for these dosage forms were also carried
`out in 2 and 4% SLS aqueous solutions using the paddle
`method at 75 rpm. The results indicate that there was no
`significant increase in rate and extent of dissolution with an
`increase in agitation from 75 to 100 rpm (Figs. 3 and 4).
`Tablets from manufacturers A and C disintegrated rapidly
`(1-3 min) compared to tablets from manufacturer B (10 min).
`The results in Figs. 3 and 4 indicate that there is no necessity
`for conducting dissolution studies at a high agitation (100
`rpm). The high agitation intensity may reduce the discrimi(cid:173)
`native power of the dissolution test as a quality-control pro(cid:173)
`cedure for detecting any manufacturing-process changes.
`Using the paddle method at 75 rpm and 4% SLS, all grise(cid:173)
`ofulvin microsize tablets achieved not less than (NLT) 75%
`dissolution in 60 min. On the basis of these studies, the USP
`has now accepted a dissolution medium with 4% SLS for
`griseofulvin tablets.
`
`Carbamazepine
`Dissolution of 200-mg Tegretol (carbamazepine) tablets
`was initially studied by the paddle method at 50, 75, and 100
`rpm using water, 0.1 N HCl, simulated intestinal fluid, and
`increasing amounts of SLS (0.5, 1, and 2%) as the medium.
`
`% Dissolved
`
`100
`
`80
`
`60
`
`40
`
`20
`
`/;
`I
`
`The results are shown in Fig. 5. Again, the rate and extent of
`dissolution increased with an increase in SLS. Four mar(cid:173)
`keted brands of carbamazepine were studied using the pad(cid:173)
`dle method at 75 rpm in 1% SLS. The in vitro dissolution
`studies were also conducted using 10.5% alcohol and 0.1%
`Tween 20 in water by the paddle method at 75 and 100 rpm
`for products A (Ciba-Geigy) and B (Colmed) and by the pad(cid:173)
`dle method at 75 rpm in 1% SLS. From the results, Table II
`and Fig. 6, respectively, it is clear that SLS can be used as
`a dissolution medium for carbamazepine tablets. The results
`of all four brands of carbamazepine tablets are shown in Fig.
`6. The Colmed product showed the fastest dissolution, 95%
`in 30 min. Using the paddle method at 75 rpm and 1% SLS,
`all four brands of carbamazepine tablets dissolved NLT 75%
`in 60 min.
`
`Clofibrate
`The dissolution profile of two marketed clofibrate cap(cid:173)
`sules was determined in water and in increasing amounts of
`SLS. Clofibrate is available as a soft gelatin capsule formu(cid:173)
`lation. Following the capsule rupture, dissolution of the drug
`is required as a condition of drug absorption. For clofibrate
`also, the dissolution increased with increases in SLS con(cid:173)
`centration (Fig. 7). It was necessary at 75 rpm (paddle
`method) to increase the amount of SLS to 5% in order to
`obtain at least 70% dissolution in a 2-hr time period. The
`results are shown in Table III. The USP has no dissolution
`test requirement for this product; however, in a recent
`Stimuti article (14) the USP has proposed a first-case (Ap(cid:173)
`paratus 2) dissolution requirement for soft gelatin capsules
`using water as the medium.
`
`Medroxyprogesterone Acetate
`Dissolution profiles of medroxyprogesterone acetate
`tablets in water and in 0.5 and 1% SLS are shown in Fig. 8.
`Dissolution significantly increased with increasing concen(cid:173)
`trations of SLS. There was a slight increase in the rate of
`dissolution in 1% SLS, compared to the profile in 0.5% SLS.
`The dissolution profiles (0.5% SLS) for all approved mar(cid:173)
`keted medroxyprogesterone acetate tablets are shown in Ta(cid:173)
`ble IV. The USP has no dissolution test requirements for this
`product.
`
`0
`
`0
`
`15
`
`30
`
`-
`
`Water
`
`45
`60
`75
`Time (minutes)
`--*-
`-+--- 0.5% SLS
`
`90
`
`105
`
`120
`
`1.0% SLS
`
`Fig. 8. Dissolution profile of medroxyprogesterone acetate tablets
`in different media by the paddle method at 50 rpm.
`
`Cortisone Acetate
`The current USP procedure requires the use of 30%
`isopropyl alcohol in water as the dissolution medium. Dis(cid:173)
`solution profiles of cortisone acetate tablets in water and 0.5
`
`0005
`
`

`

`Dissolution of Water-Insoluble Drugs
`
`617
`
`Table IV. Dissolution of 10-mg Medroxyprogesterone Acetate Tablets: Paddle Method; 50 rpm;
`0.5% SLS
`
`% dissolveda in
`
`Manufacturer
`
`A. Upjohn
`B. Carnick
`C. Reid Provident
`
`15 min
`
`54 (4)
`53 (II)
`70 (6)
`
`30 min
`
`74 (2)
`88 (3)
`91 (l)
`
`45 min
`
`84 (2)
`93 (2)
`98 (3)
`
`60 min
`
`89 (2)
`96 (3)
`100 (2)
`
`90 min
`
`96 (l)
`98 (3)
`100 (l)
`
`a Mean of six tablets (%CV).
`
`and 1.0% SLS are shown in Fig. 9. An increase in the rate
`and extent of dissolution was observed with increasing SLS
`concentrations. A concentration of 0.5% SLS was found to
`be adequate to obtain 75-80% dissolution in less than 1 hr.
`All marketed cortisone acetate products were studied under
`these conditions as well as by the official USP procedure.
`The results in Table V show that all products dissolve readily
`in 0.5% SLS when dissolution testing is carried out by the
`paddle method at 50 rpm. Only one product showed a poor
`dissolution profile under these conditions. The results de(cid:173)
`scribed here, using the paddle method at 50 rpm and 0.5%
`SLS, can be correlated with the current USP method. How(cid:173)
`ever, working with aqueous surfactant media causes fewer
`problems for the analyst than working with organic solvents.
`
`DISCUSSION
`
`In order to assure that a dosage form will release the
`drug completely, the FDA generally requires 75-80% disso(cid:173)
`lution of the declared labeled amount of drug in 1 hr, but the
`time period may be adjusted according to the bioavailability
`data. In developing dissolution tests, attempts are made to
`design test parameters that are sensitive to manufacturing/
`process/formulation changes. Whenever possible, the disso(cid:173)
`lution medium should be physiologically meaningful and
`simple. The determination of dissolution profiles of water(cid:173)
`insoluble drug products requires dissolution media different
`from those normally used for water-insoluble drug products.
`The dissolution of water-insoluble drug products has been
`carried out in hydroalcoholic media, primarily to increase
`
`45
`
`60
`
`--e- Co. D
`
`~ CO.H
`
`Fig. 9. Dissolution profile of cortisone acetate tablets by the paddle
`method at 50 rpm (I liter 0.5% SLS).
`
`the drug solubility. The use of surfactants in the dissolution
`system for water insoluble drugs may be physiologically
`more meaningful, because of the presence of natural surfac(cid:173)
`tants, bile acids, bile salts, and lecithin in the gastrointestinal
`tract.
`The ability of surfactants to accelerate the in vitro dis(cid:173)
`solution of poorly soluble drugs has been attributed to wet(cid:173)
`ting, micellar solubilization, and/or detlocculation. The mi(cid:173)
`cellar solubilization occurs when the dissolved surfactant is
`present at concentrations exceeding its critical micelle con(cid:173)
`centration. The use of dissolution media with supramicellar
`concentrations of surfactant enhances the solubility of the
`sparingly soluble drugs (12,13). Such dissolution media are
`similar to intestinal fluid, in which mixed micelles of bile
`salts and lecithin are capable of solubilizing insoluble sub(cid:173)
`stances. Buri and Hainbert-Droz (15) have shown that the
`natural surfactants (sodium cholate and sodium taurochol(cid:173)
`ate) can be interchanged with synthetic surfactant such as
`SLS for solubilizing purposes. The water-insoluble drug
`products are most likely solubilized by naturally occurring
`surfactants and micellar medium in the gastrointestinal tract.
`The dissolution studies in the presence of SLS may mimic,
`to some extent, the process that occurs in in vivo (16). It is
`concluded that the use of a surfactant system, such as aque(cid:173)
`ous SLS solutions, in studying dissolution of water-insoluble
`drug products may be more relevant to the in vivo situation
`than the use of cosolvents or hydroalcoholic media.
`Surfactants enhance the dissolution rate of poorly wa(cid:173)
`ter-soluble drug products, even when present at a level be(cid:173)
`low the critical micelle concentration. This may be due to a
`reduction in the interfacial tension as well as a possible as(cid:173)
`sociation between the drug and/or excipients and the surfac(cid:173)
`tants. Low levels of surfactants in the dissolution medium
`have been recommended, as this seemed to give a better
`correlation between in vitro and in vivo data (17). With the
`use of surfactants as solubilizing agents, complete dissolu(cid:173)
`tion of water-insoluble drug products such as griseofulvin,
`carbamazepine, medroxyprogesterone acetate, clofibrate,
`and cortisone acetate was achieved in 900-1000 ml of the
`dissolution medium. The rate and extent of dissolution in(cid:173)
`creased with increasing concentrations of SLS. Our results
`show that solutions with supramicellar surfactant concentra(cid:173)
`tion are realistic alternatives to the employment of the dis(cid:173)
`integration test or other dissolution media presently used for
`very poorly soluble drugs. Surfactants, such as SLS should
`be tested with additional water-insoluble drug products to
`establish meaningful dissolution specifications to assure lot(cid:173)
`to-lot quality and bioequivalence of the product.
`
`0006
`
`

`

`618
`
`Shah etal.
`
`Table V. Dissolution of Cortisone Acetate Tablets: 0.5% SLS; Paddle Method, 50 rpm; and
`USPXXI Procedure
`
`Manufacturer
`
`15 min
`
`30min
`
`45 min
`
`60min
`
`USP XXIb
`
`% dissolveda
`
`A.
`
`Merck
`
`B.
`
`c.
`
`D.
`
`E.
`
`F.
`
`G.
`
`Heather (U.R.L.)
`
`Richlyn
`
`Chelsea (Rugby)
`
`Upjohn
`
`Upjohn (10 mg)
`
`West-Ward
`
`West-Ward (Purepac)
`
`H. W. T. Paulsen
`
`62.2
`(14.1)
`95.6
`(2.6)
`60.3
`(3.3)
`88.9
`(8.1)
`66.2
`(2.4)
`71.7
`(3.5)
`95.7
`(0.4)
`95.3
`(1.2)
`34.1
`(8.3)
`
`80.4
`(11.6)
`100.6
`(1.4)
`76.5
`(2.2)
`102.5
`(0.9)
`82.2
`(0.8)
`88.1
`(1.8)
`98.3
`(0.3)
`97.0
`(1.2)
`66.2
`(2.0)
`
`90.6
`(7.6)
`100.9
`(1.7)
`84.1
`(2.0)
`103.2
`(0.8)
`89.6
`(0.5)
`93.7
`(1.1)
`98.5
`(0.4)
`97.3
`(1.3)
`76.3
`(1.6)
`
`95.3
`(5.4)
`101.0
`(1.6)
`88.7
`(1.7)
`101.9
`(0.1)
`93.3
`(0.7)
`%.8
`(0.9)
`98.9
`(0.4)
`97.5
`(1.3)
`84.4
`(1.6)
`
`89.5
`(4.1)
`%.2
`(4.0)
`80.0
`(2.8)
`103.9
`(1.5)
`89.5
`(2.3)
`88.6
`(2.4)
`98.1
`(2.3)
`98.4
`(1.2)
`66.4
`(2.7)
`
`a Mean of six tablets (%CV).
`b Basket, 100 rpm; 900 ml of 30% isopropanol in 0.01 N HCl (%dissolution in 30 min).
`
`REFERENCES
`
`I. J. P. Skelly. J. Clin. Pharmacal. 16:539-543 (1976).
`2. M. Gibaldi and S. Feldman. J. Pharm. Sci. 56:1238-1242 (1967).
`3. B. Katchen and S. Symchowicz. J. Pharm. Sci. 56:1108-1111
`(1%7).
`4. S. Symchowicz and B. Katchen. J. Pharm. Sci. 57:1383-1386
`(1%8).
`5. W. L. Chiou and S. Riegelman. J. Pharm. Sci. 59:937-942
`(1970).
`6. W. D. Walkling, R. K. Nayak, J. Plostnieks, and W. A. Cress(cid:173)
`man. Drug Dev. Indust. Pharm. 5(1):17-27 (1979).
`7. T. J. Goehl, G. M. Sundaresan, and V. K. Prasad. Int. J.
`Pharm. 11:181-186 (1982).
`8. G. Levy. J. Pharm. Sci. 50:388-392 (1%1).
`9. J. G. Wagner, P. D. Holmes, P. K. Wilkinson, D. C. Blair, and
`R. G. Stoll. Am. Rev. Resp. Dis. 108:536-546 (1973).
`
`10. FDA. FDA Division of Bioequivalence Guidance for in vivo
`Bioequivalence Study in vitro Dissolution Testing for Carbam(cid:173)
`azepine Tablets (Sept. 30, 1987).
`11. H. Schott, L. C. Kwan, and S. Feldman. J. Pharm. Sci.
`71:1038-1045 (1982).
`12. T. R. Bates, M. Gibaldi, and J. L. Kanig. Int. J. Pharm. 55:191-
`199 (1%6).
`13. B. Gander, K. Ventouras, R. Gumy, and E. Doelker. Int. J.
`Pharm. 27:117-124 (1985).
`14. USP. Pharmacop. Forum 14(3):3893 (1988).
`15. P. Burl and J. Humbert-Droz. 3rd Int. Cong. Pharm. Techn.
`Paris 4:136-143 (1983).
`16. G. E. Amidon, W. I. Higuichi, and N. F. Ho. J. Pharm. Sci.
`71:77-84 (1982).
`17. H. M. Abdou. Remington's Pharmaceutical Sciences, 17th ed.
`Mack Publishing, Easton, Pennsylvania, 1985, pp. 653-666.
`
`0007
`
`