When Size Matters

When Size matters

Well, Miss Jones, it seems our scale up procedure worked. Question now, is, do we blister pack or bottle? Performance Testing in Quality Control and Product Development, Where are We? • Disintegration comparison 701 vs. 2040 • Beaker specifications and Harmonization • Rupture test • Disintegration vs. Dissolution • BCS sub classification • Buffer capacity and dissolution Factor for oral drug absorption

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transit time gastric emptying

motility

Peff

Solubility (pH)

food effect Tablet disintegration <701/2040> • Disintegration – USP specifies for drugs and Dietary Supplements in vitro disintegration test a dosage form must pass

• 6 units are tested • if one or two fail 12 additional units are tested… Dissolution testing / Rapture test

100

SIF Generic 60 FaSSIF Generic SIF Reference FaSSIF Referenc

0 0 5 10 15 20 25 30 Pharmaceutical vs. Dietary Supplement Chapters

2040 Disintegration

701 Disintegration Disintegration

2040 Rupture App 2 Disintegration, Dissolution and Rupture

• Disintegration = Dosage form is dispersed

• Dissolution = rate and extend of release

• Rupture = non-aqueous content is exposed Oral IR Dosage Forms

Solid Dosage Forms Liquid filled BCS I-IV Dosage Forms

Dose/Solubility ≥ 250 ml Dissolution Test API remains in (pH 1.2 - 6.8) no no Solution yes

Fast Dissolution no yes @ lowest solubility (85%, 15 min)

yes Rupture Test Disintegration Test Disintegration study: Minerals and Vitamins on the Canadian Market

Conditions: 20 minutes pH 6.8 No disk Disintegration Disintegration in USP 28

<701> <701> <2040> <2040> Dosage Form APP Medium APP Medium

Uncoated Tablets DIS Water DIS Water Film Coated DIS Water

Plain Coated Tablets DIS Water PCT Water (other than Film Coated)

Sublingual Tablets DIS Water L - DIS = Disintegration Test Apparatus A or B Buccal Tablets DIS Water L - PCT = Plain Coated Tablets Test RUP = Rupture test Chewable Tablets J J J - DRT = Delayed Release Tablets Test WM = Wire Mesh to cover top of Modified Release Tablets - - - - apparatus A L = not listed Delayed Release Tablets DRT SGF / SIF DRT SGF / SIF J = scientifically justified to be considered for disintegration tests Hard Shell Capsules DIS + Water DIS + Buffer WM WM 4.5 Soft Shell Capsules DIS + Water RUP Water WM Disintegration

A number of changes made to the disintegration test since the USP 23 need to be evaluated as to whether they will have any impact on the measured disintegration time of dosage forms. Disintegration will continue to be a valuable quality control procedure, but clearly further work is required to strengthen its place among the tools that assess the performance of dosage forms. Disintegration test

>25 mm

>15 mm

>25 mm Problems with current Specifications

• USP: The moving range of the basket-rack assembly should be between 53 and 57 mm • USP: the height of the basket from the bottom should be at least 25 mm and 15 mm from the top. • Math: This is a total height of 93 to 97 mm. – Taking the current beaker diameter specifications into account this adds up to a volume of between 687 and 1007 mL depending on the beaker diameter. • For 900 mL the medium height in a beaker with 115 mm diameter will only be 87 mm. • 900 mL will be too much in a 97 mm diameter beaker if the basket assembly should not be submerged. Disintegration Times Influence of the Changed USP Specifications on the Disintegration

Test Performance e-mail: [email protected]

Katja Schmid1 and Raimar Löbenberg2* 1Department of Pharmacy - Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilians-University Munich, 81377 Munich, Germany 2Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2N8, Canada

ABSTRACT The aim of this study was to investigate if the changes made in the specifications of the disintegration procedure impact the performance of the disintegration test described in USP chapters <701> and <2040>. Different tablets and capsules were produced, and their disintegration times were determined. The following disintegration time parameters were analyzed: volume of the immersion fluid, type of apparatus (Apparatus A for method <701>; Apparatus B for method <2040>), and attachment of a wire cloth to the basket assembly. By adjusting the compaction force and lubricant level, the disintegration time of the tablets was standardized to 15 min. The disintegration time change was statistically significant when varying the volume of the immersion fluid. The type of apparatus and the attachment of a wire cloth resulted in no significant difference in the disintegration time of capsules. The USP requirements for immersion medium volume should be strictly followed to obtain correct and reproducible test results. The disintegration test is a suitable performance test for certain pharmaceutical and dietary dosage forms.

INTRODUCTION <701> describes Apparatus A consisting of a basket isintegration was the first performance test for assembly with six observation cylinders. Chapter solid oral dosage forms required by the Swiss <2040> describes Apparatus B, which uses observation DPharmacopoeia back in 1935 (1). The rationale for cylinders with a larger diameter. Both apparatus are disintegration testing is given by the fact that most oral well-established, and their designs have hardly changed dosage forms need to fragment into powder particles over the past decade. Donauer et al. (5) reviewed the before drug particles are released and dissolved. Yet, current specification changes for the disintegration disintegration is no direct measure for drug dissolution apparatus and test conditions. USP 32 general chapter and cannot be used as a universal in vivo bioavailability <2040> lists a third method for the disintegration predictor (2). The disintegration test simply determines if of soft-shell capsules. In the “rupture test,” the opening of the solid oral dosage form under investigation disinte- soft-shell capsules is the performance test criterion. grates in a given time frame. However, for BCS class I drugs, Scientific data describing the disintegration test is disintegration rather than dissolution was lately discussed limited (6–9). In recent years, USP changed the procedure as a possible performance test (3). The dissolution of class I of the disintegration test and harmonized the chapter and class III drugs is not limited within the physiological <701> with the European and Japanese Pharmacopoeia pH range (4), and here, disintegration can be seen as the (10). The test conditions prior to USP 28 only specified that critical step for bioavailability (5). Using a Quality by the bottom wire mesh of the observation cylinder should Design (QbD) approach, a correlation between drug have a distance of at least 25 mm from the bottom of the particle size and dissolution rate might be established, and beaker on the downward stroke and at least 25 mm from subsequently, dissolution testing might be substituted by the fluid level on the upward stroke. Now, USP states the disintegration testing (3). Due to the establishment of same downward stroke specification but specifies that the QbD, disintegration might again become an important basket assembly should not be totally submerged and the performance test. distance of the wire mesh should be at least 15 mm from According to the USP, disintegration of a pharmaceutical the fluid level on the upward stroke (Figure 1). In the or dietary dosage form is a performance test that is previous specifications, a wire mesh was applied to keep intended to ensure the batch-to-batch consistency of a the dosage forms from floating out of the observation product. USP 32 describes three different apparatus that cylinders on the downward stroke, while the new specifi- can be used to perform a disintegration test. Chapter cation makes the upper wire cloth obsolete. However, it is still part of the USP text (11). To the best of our knowledge, the impact of these changes on the performance of the *Corresponding author. disintegration test has not been investigated. 6 Dissolution |

  Influence of the Changed USP Specifications on the Disintegration

Test Performance e-mail: [email protected]

ABSTRACT The aim of this study was to investigate if the changes made in the specifications of the disintegration procedure impact the performance of the disintegration test described in USP chapters <701> and <2040>. Different tablets and capsulesThe were produced,USP andrequirements their disintegration times were for determined. immersion The following disintegration medium time parameters were analyzed: volume of the immersion fluid, type of apparatus (Apparatus A for method <701>; Apparatus B for method <2040>), and attachment of a wire cloth to the basket assembly. By adjusting the compaction force and lubricant level, the disintegrationvolume time of theshould tablets was standardized be strictly to 15 min. The followed disintegration time change to obtainwas statistically significant when varying the volume of the immersion fluid. The type of apparatus and the attachment of a wire cloth resulted in correctno significant difference and in thereproducible disintegration time of capsules. test The USP results. requirements for immersionThe medium volume should be strictly followed to obtain correct and reproducible test results. The disintegration test is a suitable performancedisintegration test for certain pharmaceutical test and is dietary a suitabledosage forms. performance test

INTRODUCTIONfor certain pharmaceutical<701> anddescribes Apparatusdietary A consisting dosage of a basket isintegration was the first performance test for assembly with six observation cylinders. Chapter solid oral dosage forms required by the Swiss forms.<2040> describes Apparatus B, which uses observation DPharmacopoeia back in 1935 (1). The rationale for cylinders with a larger diameter. Both apparatus are disintegration testing is given by the fact that most oral well-established, and their designs have hardly changed dosage forms need to fragment into powder particles over the past decade. Donauer et al. (5) reviewed the before drug particles are released and dissolved. Yet, current specification changes for the disintegration disintegration is no direct measure for drug dissolution apparatus and test conditions. USP 32 general chapter and cannot be used as a universal in vivo bioavailability <2040> lists a third method for the disintegration predictor (2). The disintegration test simply determines if of soft-shell capsules. In the “rupture test,” the opening of the solid oral dosage form under investigation disinte- soft-shell capsules is the performance test criterion. grates in a given time frame. However, for BCS class I drugs, Scientific data describing the disintegration test is disintegration rather than dissolution was lately discussed limited (6–9). In recent years, USP changed the procedure as a possible performance test (3). The dissolution of class I of the disintegration test and harmonized the chapter and class III drugs is not limited within the physiological <701> with the European and Japanese Pharmacopoeia pH range (4), and here, disintegration can be seen as the (10). The test conditions prior to USP 28 only specified that critical step for bioavailability (5). Using a Quality by the bottom wire mesh of the observation cylinder should Design (QbD) approach, a correlation between drug have a distance of at least 25 mm from the bottom of the particle size and dissolution rate might be established, and beaker on the downward stroke and at least 25 mm from subsequently, dissolution testing might be substituted by the fluid level on the upward stroke. Now, USP states the disintegration testing (3). Due to the establishment of same downward stroke specification but specifies that the QbD, disintegration might again become an important basket assembly should not be totally submerged and the performance test. distance of the wire mesh should be at least 15 mm from According to the USP, disintegration of a pharmaceutical the fluid level on the upward stroke (Figure 1). In the or dietary dosage form is a performance test that is previous specifications, a wire mesh was applied to keep intended to ensure the batch-to-batch consistency of a the dosage forms from floating out of the observation product. USP 32 describes three different apparatus that cylinders on the downward stroke, while the new specifi- can be used to perform a disintegration test. Chapter cation makes the upper wire cloth obsolete. However, it is still part of the USP text (11). To the best of our knowledge, the impact of these changes on the performance of the *Corresponding author. disintegration test has not been investigated. 6 Dissolution |

  ICH Harmonization

European Medicines Agency

June 2008 EMEA/CHMP/ICH/308895/2008

ICH Topic Q4B Annex 5 Disintegration Test General Chapter

Step 3

ANNEX 5 TO NOTE FOR EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON DISINTEGRATION TEST GENERAL CHAPTER (EMEA/CHMP/ICH/308895/2008)

TRANSMISSION TO CHMP June 2008

TRANSMISSION TO INTERESTED PARTIES June 2008

DEADLINE FOR COMMENTS September 2008

Please forward your comments to the following email address: [email protected]

7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 85 75 Fax (44-20) 75 23 70 40 E-mail: [email protected] http://www.emea.europa.eu European Medicines Agency, 2008. Reproduction is authorised provided the source is acknowledged Draft Supplement II to the JP15

6.09 Disintegration Test

This test is harmonized with the European Pharmacopoeia and the U. S. Pharmacopeia. The parts of the text that are not harmonized are marked with symbols ( ).

Disintegration Test is provided to determine whether tablets, capsules, granules or pills disintegrate within the prescribed time when placed in a liquid medium at the experimental conditions presented below.

For the purposes of this test, disintegration does not imply complete solution of the unit or even of its active constituent. ICH Q4B Annex 5

Apparatus The apparatus consists of a basket-rack assembly, a 1000-mL, low-form beaker, 138 to 160 mm in height and having an inside diameter of 97 to 115 mm for the immersion fluid, a thermostatic arrangement for heating the fluid between 35 º and 39 º, and a device for raising and lowering the basket in the immersion fluid at a constant frequency rate between 29 and 32 cycles per minute through a distance of not less than 53 mm and not more than 57 mm. The volume of the fluid in the vessel is such that at the highest point of the upward stroke the wire mesh remains at least 15 mm below the surface of the fluid and descends to not less than 25 mm from the bottom of the vessel on the downward stroke. At no time should the top of the basket-rack assembly become submerged. The time required for the upward stroke is equal to the time required for the downward stroke, and the change in stroke direction is a smooth transition, rather than an abrupt reversal of motion. The basket-rack assembly moves vertically along its axis. There is no appreciable horizontal motion or movement of the axis from the vertical.

Basket-rack assembly - The basket-rack assembly consists of six open-ended transparent tubes, each 77.5 ± 2.5 mm long and having an inside diameter of 20.7 to 23 mm and a wall 1.0 to 2.8 mm thick; the tubes are held in a vertical

Fig. 6.09-1 Disintegration apparatus Fig. 6.09-2 Auxilary tube position by two plates, each 88 to 92 mm in diameter and 5 to 8.5 mm in thickness, with six holes, each 22 to 26 mm in diameter, equidistant from the center of the plate and equally spaced

Pharmacopeia and Japanese Pharmacopeia.

Apparatus A USP 23 (701) USP 26 USP 30 European Japanese Ph. (701/2040) (701/2040) Pharm. (14) 2007 (5.8) Volume of beaker (mL) 1000 1000 1000 1000 -

Height of beaker (mm) 142-148 138-155 138-160 149+/-11 about 155 (USP 23, suppl.9)

Diameter 103-10 97-110 97-115 106+/-9 about 110 (USP 23, (inside, suppl. mm) 9) Upward stroke: ≥25 ≥25 ≥15 ≥15 - distance wire mesh/ surface (mm) Downward stroke: ≥25 ≥25 ≥25 ≥25 25 distance wire mesh/ bottom (mm) Disintegration test Study Design

Two Beakers (diameter) 1) narrow USP specification 2) 1.5 L larger than new USP specification 3) With and without disk 4) Immersion medium 5) App A and B 1.5 L Beaker vs. Small Beaker

• 1.5 L Beaker Small Beaker

Observation: sediment Observation: No sediment Result (Tables) Result (Capsules) The AAPS Journal, Vol. 12, No. 4, December 2010 ( # 2010) DOI: 10.1208/s12248-010-9221-1The AAPS Journal, Vol. 12, No. 4, December 2010 ( # 2010) DOI: 10.1208/s12248-010-9221-1

Research Article Theme: Role of Dissolution in QbD and Drug Product Life Cycle Research Article Guest Editor: SusanTheme: D'Souza Role of Dissolution in QbD and Drug Product Life Cycle Guest Editor: Susan D'Souza

InvestigationInvestigation of the Performance of the Performance of the Disintegration of the Disintegration Test Test for Dietaryfor Supplements Dietary Supplements The AAPS Journal, Vol. 12, No. 4, December 2010 ( # 2010) DOI: 10.1208/s12248-010-9221-1

1 1 2 1,3 May Almukainzi,MayMahnor Almukainzi, Salehi,1 MahnorNadia Salehi, Araci1 Bou-Chacra,Nadia Araci Bou-Chacra,and Raimar2 and Löbenberg Raimar Löbenberg1,3 Research Article Theme: Role of Dissolution in QbD and Drug Product Life Cycle Guest Editor: Susan D'Souza Received 11 May 2010;Received accepted 11 May 28 2010; June 2010;accepted published 28 June online 2010; published 24 July 2010 online 24 July 2010

Abstract. The aimAbstract. of this studyThe aim was of to this investigate study was how to investigatebeaker size, how basket beaker assembly, size, basket use ofassembly, disk, and use of disk, and immersion mediumimmersion impact the medium disintegration impact the time disintegration ofInvestigation dietary supplements. time of dietary of The supplements. the disintegration Performance The times disintegration were of times the were Disintegration Test determined for fivedetermined tablet and for twofive capsule tablet products.and two capsule A two-station products. disintegration A two-station tester disintegration was used tester with was used with Apparatus A or ApparatusApparatus B A as or described Apparatus in Bthe as United describedfor States Dietary in the Pharmacopeia United Supplements States (USP) Pharmacopeia chapters, (USP) <701> chapters, and <701> and <2040>. Two beakers<2040>. complying Two beakers with the complying harmonized with thespeci harmonizedfications were speci used,fications one were with used, a volume one with of a volume of 1,000 mL and one with1,000 a mL 1,500-mL and one volume. with a 1,500-mL The disintegration volume. The data disintegration were analyzed data using were analyzed ANOVA using for the ANOVA for the following factors: beakerfollowing size, factors: equipment beaker (App size, equipment A andMay B) Almukainzi, (Appand condition A and1 B)Mahnor (with/without and condition Salehi, disk). (with/without1 Nadia Two Araci tablet disk). Bou-Chacra, Two tablet 2 and Raimar Löbenberg1,3 products were notproducts sensitive were to any not changes sensitive in to the any test changes conditions in the testor equipment conditions conor equipmentfigurations. con Onefigurations. One product was only partiallyproduct was sensitive only partially to the test sensitive conditions. to the Thetest conditions. other products The other showed products impact showed on the impact on the disintegration time for all test conditions. The results revealed that these tablet products might pass or disintegration time for all test conditions. The results revealed thatReceived these tablet 11 May products 2010; accepted might 28 pass June or 2010; published online 24 July 2010 fi fail current USP disintegrationfail current USP requirements disintegration depending requirements on the depending equipment on con thefi equipmentguration. Similarcon guration. results Similar results were obtained for the two investigated capsule formulations.Abstract. The One aim of product this study might was to fail investigate current how USP beaker size, basket assembly, use of disk, and were obtained for the two investigated capsule formulations. One product might fail current USP disintegration requirements if the large beaker was used,immersion but might medium pass impact the disintegration the disintegration requirements time of dietary supplements. The disintegration times were disintegration requirements if the large beaker was used, but might pass the disintegration requirements when the small beaker was used. Hydroxy propyl methyldetermined cellulose for five capsules tablet and were two mostly capsule in products.fluenced A if two-station disintegration tester was used with when the small beaker was used. Hydroxy propyl methyl cellulose capsules were mostly influenced if sodium instead of a potassium buffer was used as theApparatus immersion A or medium. Apparatus The B as results described demonstrate in the United that States Pharmacopeia (USP) chapters, <701> and fi sodium instead of athe potassium current harmonized buffer was used ICH as speci thefi immersioncations for medium. the<2040>. disintegration The Two results beakers test demonstrate complying are insuf withficient that the to harmonized make the speci cations were used, one with a volume of 1,000 mL and one with a 1,500-mL volume. The disintegration data were analyzed using ANOVA for the the current harmonizeddisintegration ICH speci test intofications reliable for test the for disintegration dietary supplements. test are insufficient to make the disintegration test into reliable test for dietary supplements. following factors: beaker size, equipment (App A and B) and condition (with/without disk). Two tablet KEY WORDS: dietary supplements; disintegration;products ICH; quality were by not design; sensitive USP. to any changes in the test conditions or equipment configurations. One KEY WORDS: dietary supplements; disintegration; ICH; quality byproduct design; was USP. only partially sensitive to the test conditions. The other products showed impact on the disintegration time for all test conditions. The results revealed that these tablet products might pass or fail current USP disintegration requirements depending on the equipment configuration. Similar results INTRODUCTION weresize obtained ensures for a suf thefi twocient investigated rate of dissolution capsule formulations. and disintegration One product might fail current USP INTRODUCTION size ensures adisintegrationis suf theficient rate-limiting requirements rate of dissolution step if the for large drug beaker and release disintegration was used, (6). but However, might pass to the be disintegration requirements The disintegration test as a performance testis for the imme- rate-limitingwhenable the to step small use for beaker the drug disintegration was release used. Hydroxy (6). test However, propyl as a methyl performance to cellulose be capsules test in were mostly influenced if sodium instead of a potassium buffer was used as the immersion medium. The results demonstrate that The disintegrationdiate release test as oral a performance dosage forms test is for receiving imme- moreable attention to use theQbD, current disintegration its harmonized suitability test ICH as as speci a a performancefi performancecations for the test disintegration test must in be test inves- are insufficient to make the diate release oral(1 dosage). This forms is due is to receiving dosage form more speci attentionfications forQbD, which its a suitabilitydisintegrationtigated. as Today test a into performance there reliable is testonly for test very dietary must limited supplements. be data inves- available that dissolution test might not be the best fit, as shown by Han et describe the performance of the disintegration test. (1). This is due to dosage form specifications for which a tigated. TodayKEY there WORDS: is onlydietary very supplements; limited disintegration; data available ICH; quality that by design; USP. dissolution test mightal. for not dosage be the forms best fi liket, as liquid- shownfilled by Han capsuleset describe (2) or fast- the performanceUSP (32) of currently the disintegration listed two test. chapters, which describe al. for dosage formsdissolving like liquid-tabletsfi (lled3,4). capsules (2) or fast- USP (32)the currently disintegration listed two test chapters, for dosage which forms. describe Chapter <701> dissolving tablets (3,4).Similarly, approaches like quality by designINTRODUCTION (QbD)the disintegration might describes test the for general dosage set-up forms. with Chapter beakersize speci<701> ensuresfications a suf andficient rate of dissolution and disintegration Similarly, approachesconsider like a disintegration quality by design test (QbD) as the might most appropriatedescribes thebasket general assembly set-up with A (Apparatus beaker speci A)fications (7).is the Chapter and rate-limiting <2040> step for drug release (6). However, to be consider a disintegrationperformance test test as for the fast dissolvingmost appropriate biopharmaceuticsbasketThe classi- disintegration assemblydescribes A test (Apparatus as basket a performance assembly A) test (7 B). for (Apparatus Chapter imme- able <2040> B) to and use test the con-disintegration test as a performance test in diate release oral dosage forms is receiving more attention QbD, its suitability as a performance test must be inves- performance testfi forcation fast system dissolving (BCS) biopharmaceutics class 1 drugs. classi- In QbD,describes scientific basketditions assembly and acceptance B (Apparatus criteria B) for and dietary test supplements con- (8). (1). This is due to dosage form specifications for which a tigated.fi Today there is only very limited data available that fication system (BCS)approaches class and 1 drugs. appropriateness In QbD, decide scienti whichfic ditions compendial and acceptanceOver the criteriayears the for disintegration dietary supplements test speci (8cations). were standard will be included into the overalldissolution quality and test mightchanged. not be Donauer the best fi andt, as Löbenbergshown by Han reviewedet describe these the changes performance in of the disintegration test. approaches and appropriateness decide which compendial Over the years the disintegrationfi test specifications were monitoring system of a product (1,5) al. for dosage formsdetail like (9). liquid- Bothlled United capsules States (2) Pharmacopeia or fast- (USP)USP (32) chapters currently listed two chapters, which describe standard will be included into the overall quality and dissolvingchanged. tablets Donauer (3,4). and Löbenberg reviewed these changesthe disintegration in test for dosage forms. Chapter <701> In QbD, a disintegration test might be justified to list test conditions for different dosage forms, but there are Similarly, approaches like quality by design (QbD) might describes the general set-up with beaker specifications and monitoring systemsubstitute of a product a single-point (1,5) dissolution test if the drugdetail particle (9). Bothsome United differences States Pharmacopeia between the chapters. (USP) chapters USP <701> uses fi consider a disintegration test as the most appropriate basket assembly A (Apparatus A) (7). Chapter <2040> In QbD, a disintegration test might be justi ed to list test conditionswater for as different the immersion dosage medium forms, forbuthard there gelatin are capsules substitute a single-point dissolution test if the drug particle performancesome differences test for fast between dissolving the biopharmaceutics chapters. USP classi- <701>describes uses basket assembly B (Apparatus B) and test con- fication system (BCS)while USP class <2040> 1 drugs. uses In a QbD, pH 4.5-acetate scientific bufferditions for andhard acceptance shell criteria for dietary supplements (8). 1 Faculty of Pharmacy and Pharmaceutical Science, University of approacheswater as and the appropriatenesscapsules immersion. The medium next decide difference which for hard compendial between gelatin both capsulesOver chapters the years is that the disintegration test specifications were Alberta, 1123A Dentistry/Pharmacy Centre (780), 492-1255, 1 standardwhile USP will <2040> besoft included gelatin uses intoa capsules pH the 4.5-acetate overallare tested quality buffer like and for uncoatedhardchanged. shell tablets Donauer in USP and Löbenberg reviewed these changes in Faculty of PharmacyEdmonton, and Pharmaceutical AB, Canada. Science, University of monitoringcapsules. system The next of a product difference (1,5) between both chaptersdetail is that (9). Both United States Pharmacopeia (USP) chapters Alberta, 1123A2 Dentistry/PharmacyFaculty of Pharmaceutical Centre Science, (780), University 492-1255, of Sao Paulo, Sao <701> while <2040> uses a rupture test for soft shell capsules. In QbD, a disintegration test might be justified to list test conditions for different dosage forms, but there are Paulo, Brazil. soft gelatin capsulesNon-gelatinare tested shell like capsules uncoated are tablets gaining in importance USP in the Edmonton, AB, Canada. substitute a single-point dissolution test if the drug particle some differences between the chapters. USP <701> uses 2 3 To whom correspondence should be addressed. (e-mail:<701> rloeben while <2040>pharmaceutical uses a rupture and dietary test for supplementsoft shell capsules industry.. Literature Faculty of Pharmaceutical Science, University of Sao Paulo, Sao water as the immersion medium for hard gelatin capsules [email protected]) Non-gelatinreports shell some capsules evidence are gaining that non-gelatin importance capsules in the made out of Paulo, Brazil. while USP <2040> uses a pH 4.5-acetate buffer for hard shell 3 1 To whom correspondence should be addressed. (e-mail: rloeben Facultypharmaceutical of Pharmacy and and Pharmaceuticaldietary supplement Science, University industry. of Literaturecapsules. The next difference between both chapters is that Alberta, 1123A Dentistry/Pharmacy Centre (780), 492-1255, [email protected])1550-7416/10/0400-0602/0 # 2010 American Association of Pharmaceuticalreports Scientists some602 evidence that non-gelatin capsules madesoft out gelatin of capsules are tested like uncoated tablets in USP Edmonton, AB, Canada. 2 Faculty of Pharmaceutical Science, University of Sao Paulo, Sao <701> while <2040> uses a rupture test for soft shell capsules. 1550-7416/10/0400-0602/0 # 2010 American Association of Pharmaceutical Scientists 602Paulo, Brazil. Non-gelatin shell capsules are gaining importance in the 3 To whom correspondence should be addressed. (e-mail: rloeben pharmaceutical and dietary supplement industry. Literature [email protected]) reports some evidence that non-gelatin capsules made out of

1550-7416/10/0400-0602/0 # 2010 American Association of Pharmaceutical Scientists 602 The AAPS Journal, Vol. 12, No. 4, December 2010 ( # 2010) DOI: 10.1208/s12248-010-9221-1The AAPS Journal, Vol. 12, No. 4, December 2010 ( # 2010) DOI: 10.1208/s12248-010-9221-1

Abstract. The aimAbstract. of this studyThe aim was of to this investigate study was how to investigatebeaker size, how basket beaker assembly, size, basket use ofassembly, disk, and use of disk, and immersion mediumimmersion impact the medium disintegration impact the time disintegration ofInvestigation dietary supplements. time of dietary of The supplements. the disintegration Performance The times disintegration were of times the were Disintegration Test determined for fivedetermined tablet and for twofive capsule tablet products.and two capsule A two-station products. disintegration A two-station tester disintegration was used tester with was used with Apparatus A or ApparatusApparatus B A as or described Apparatus in Bthe as United describedfor States Dietary in the Pharmacopeia United Supplements States (USP) Pharmacopeia chapters, (USP) <701> chapters, and <701> and <2040>.The Two beakers results<2040>. complying Two beakersdemonstrate with the complying harmonized with thespeci harmonized fithatcations werethe speci used,fications current one were with used, a volume one with of a volume of 1,000 mL and one with1,000 a mL 1,500-mL and one volume. with a 1,500-mL The disintegration volume. The data disintegration were analyzed data using were analyzed ANOVA using for the ANOVA for the following factors:harmonized beakerfollowing size, factors: equipment beaker ICH (App size, specifications equipment A andMay B) Almukainzi, (Appand condition A and1 B)Mahnor (with/without and for condition Salehi, the disk). (with/without1 Nadia Two Araci tablet disk). Bou-Chacra, Two tablet 2 and Raimar Löbenberg1,3 products were notproducts sensitive were to any not changes sensitive in to the any test changes conditions in the testor equipment conditions conor equipmentfigurations. con Onefigurations. One product was only partiallyproduct was sensitive only partially to the test sensitive conditions. to the Thetest conditions. other products The other showed products impact showed on the impact on the disintegrationdisintegration timetest for all are test conditions. insufficient The results revealed to that make these tablet the products might pass or disintegration time for all test conditions. The results revealed thatReceived these tablet 11 May products 2010; accepted might 28 pass June or 2010; published online 24 July 2010 fi fail current USP disintegrationfail current USP requirements disintegration depending requirements on the depending equipment on con thefi equipmentguration. Similarcon guration. results Similar results were obtained for the two investigated capsule formulations.Abstract. The One aim of product this study might was to fail investigate current how USP beaker size, basket assembly, use of disk, and weredisintegration obtained for the two investigated test capsuleinto formulations.reliable One test product for might dietary fail current USP disintegration requirements if the large beaker was used,immersion but might medium pass impact the disintegration the disintegration requirements time of dietary supplements. The disintegration times were disintegration requirements if the large beaker was used, but might pass the disintegration requirements when the small beaker was used. Hydroxy propyl methyldetermined cellulose for five capsules tablet and were two mostly capsule in products.fluenced A if two-station disintegration tester was used with when the small beaker was used. Hydroxysupplements. propyl methyl cellulose capsules were mostly influenced if sodium instead of a potassium buffer was used as theApparatus immersion A or medium. Apparatus The B as results described demonstrate in the United that States Pharmacopeia (USP) chapters, <701> and fi sodium instead of athe potassium current harmonized buffer was used ICH as speci thefi immersioncations for medium. the<2040>. disintegration The Two results beakers test demonstrate complying are insuf withficient that the to harmonized make the speci cations were used, one with a volume of 1,000 mL and one with a 1,500-mL volume. The disintegration data were analyzed using ANOVA for the the current harmonizeddisintegration ICH speci test intofications reliable for test the for disintegration dietary supplements. test are insufficient to make the disintegration test into reliable test for dietary supplements. following factors: beaker size, equipment (App A and B) and condition (with/without disk). Two tablet KEY WORDS: dietary supplements; disintegration;products ICH; quality were by not design; sensitive USP. to any changes in the test conditions or equipment configurations. One KEY WORDS: dietary supplements; disintegration; ICH; quality byproduct design; was USP. only partially sensitive to the test conditions. The other products showed impact on the disintegration time for all test conditions. The results revealed that these tablet products might pass or fail current USP disintegration requirements depending on the equipment configuration. Similar results INTRODUCTION weresize obtained ensures for a suf thefi twocient investigated rate of dissolution capsule formulations. and disintegration One product might fail current USP INTRODUCTION size ensures adisintegrationis suf theficient rate-limiting requirements rate of dissolution step if the for large drug beaker and release disintegration was used, (6). but However, might pass to the be disintegration requirements The disintegration test as a performance testis for the imme- rate-limitingwhenable the to step small use for beaker the drug disintegration was release used. Hydroxy (6). test However, propyl as a methyl performance to cellulose be capsules test in were mostly influenced if sodium instead of a potassium buffer was used as the immersion medium. The results demonstrate that The disintegrationdiate release test as oral a performance dosage forms test is for receiving imme- moreable attention to use theQbD, current disintegration its harmonized suitability test ICH as as speci a a performancefi performancecations for the test disintegration test must in be test inves- are insufficient to make the diate release oral(1 dosage). This forms is due is to receiving dosage form more speci attentionfications forQbD, which its a suitabilitydisintegrationtigated. as Today test a into performance there reliable is testonly for test very dietary must limited supplements. be data inves- available that dissolution test might not be the best fit, as shown by Han et describe the performance of the disintegration test. (1). This is due to dosage form specifications for which a tigated. TodayKEY there WORDS: is onlydietary very supplements; limited disintegration; data available ICH; quality that by design; USP. dissolution test mightal. for not dosage be the forms best fi liket, as liquid- shownfilled by Han capsuleset describe (2) or fast- the performanceUSP (32) of currently the disintegration listed two test. chapters, which describe al. for dosage formsdissolving like liquid-tabletsfi (lled3,4). capsules (2) or fast- USP (32)the currently disintegration listed two test chapters, for dosage which forms. describe Chapter <701> dissolving tablets (3,4).Similarly, approaches like quality by designINTRODUCTION (QbD)the disintegration might describes test the for general dosage set-up forms. with Chapter beakersize speci<701> ensuresfications a suf andficient rate of dissolution and disintegration Similarly, approachesconsider like a disintegration quality by design test (QbD) as the might most appropriatedescribes thebasket general assembly set-up with A (Apparatus beaker speci A)fications (7).is the Chapter and rate-limiting <2040> step for drug release (6). However, to be consider a disintegrationperformance test test as for the fast dissolvingmost appropriate biopharmaceuticsbasketThe classi- disintegration assemblydescribes A test (Apparatus as basket a performance assembly A) test (7 B). for (Apparatus Chapter imme- able <2040> B) to and use test the con-disintegration test as a performance test in diate release oral dosage forms is receiving more attention QbD, its suitability as a performance test must be inves- performance testfi forcation fast system dissolving (BCS) biopharmaceutics class 1 drugs. classi- In QbD,describes scientific basketditions assembly and acceptance B (Apparatus criteria B) for and dietary test supplements con- (8). (1). This is due to dosage form specifications for which a tigated.fi Today there is only very limited data available that fication system (BCS)approaches class and 1 drugs. appropriateness In QbD, decide scienti whichfic ditions compendial and acceptanceOver the criteriayears the for disintegration dietary supplements test speci (8cations). were standard will be included into the overalldissolution quality and test mightchanged. not be Donauer the best fi andt, as Löbenbergshown by Han reviewedet describe these the changes performance in of the disintegration test. approaches and appropriateness decide which compendial Over the years the disintegrationfi test specifications were monitoring system of a product (1,5) al. for dosage formsdetail like (9). liquid- Bothlled United capsules States (2) Pharmacopeia or fast- (USP)USP (32) chapters currently listed two chapters, which describe standard will be included into the overall quality and dissolvingchanged. tablets Donauer (3,4). and Löbenberg reviewed these changesthe disintegration in test for dosage forms. Chapter <701> In QbD, a disintegration test might be justified to list test conditions for different dosage forms, but there are Similarly, approaches like quality by design (QbD) might describes the general set-up with beaker specifications and monitoring systemsubstitute of a product a single-point (1,5) dissolution test if the drugdetail particle (9). Bothsome United differences States Pharmacopeia between the chapters. (USP) chapters USP <701> uses fi consider a disintegration test as the most appropriate basket assembly A (Apparatus A) (7). Chapter <2040> In QbD, a disintegration test might be justi ed to list test conditionswater for as different the immersion dosage medium forms, forbuthard there gelatin are capsules substitute a single-point dissolution test if the drug particle performancesome differences test for fast between dissolving the biopharmaceutics chapters. USP classi- <701>describes uses basket assembly B (Apparatus B) and test con- fication system (BCS)while USP class <2040> 1 drugs. uses In a QbD, pH 4.5-acetate scientific bufferditions for andhard acceptance shell criteria for dietary supplements (8). 1 Faculty of Pharmacy and Pharmaceutical Science, University of approacheswater as and the appropriatenesscapsules immersion. The medium next decide difference which for hard compendial between gelatin both capsulesOver chapters the years is that the disintegration test specifications were Alberta, 1123A Dentistry/Pharmacy Centre (780), 492-1255, 1 standardwhile USP will <2040> besoft included gelatin uses intoa capsules pH the 4.5-acetate overallare tested quality buffer like and for uncoatedhardchanged. shell tablets Donauer in USP and Löbenberg reviewed these changes in Faculty of PharmacyEdmonton, and Pharmaceutical AB, Canada. Science, University of monitoringcapsules. system The next of a product difference (1,5) between both chaptersdetail is that (9). Both United States Pharmacopeia (USP) chapters Alberta, 1123A2 Dentistry/PharmacyFaculty of Pharmaceutical Centre Science, (780), University 492-1255, of Sao Paulo, Sao <701> while <2040> uses a rupture test for soft shell capsules. In QbD, a disintegration test might be justified to list test conditions for different dosage forms, but there are Paulo, Brazil. soft gelatin capsulesNon-gelatinare tested shell like capsules uncoated are tablets gaining in importance USP in the Edmonton, AB, Canada. substitute a single-point dissolution test if the drug particle some differences between the chapters. USP <701> uses 2 3 To whom correspondence should be addressed. (e-mail:<701> rloeben while <2040>pharmaceutical uses a rupture and dietary test for supplementsoft shell capsules industry.. Literature Faculty of Pharmaceutical Science, University of Sao Paulo, Sao water as the immersion medium for hard gelatin capsules [email protected]) Non-gelatinreports shell some capsules evidence are gaining that non-gelatin importance capsules in the made out of Paulo, Brazil. while USP <2040> uses a pH 4.5-acetate buffer for hard shell 3 1 To whom correspondence should be addressed. (e-mail: rloeben Facultypharmaceutical of Pharmacy and and Pharmaceuticaldietary supplement Science, University industry. of Literaturecapsules. The next difference between both chapters is that Alberta, 1123A Dentistry/Pharmacy Centre (780), 492-1255, [email protected])1550-7416/10/0400-0602/0 # 2010 American Association of Pharmaceuticalreports Scientists some602 evidence that non-gelatin capsules madesoft out gelatin of capsules are tested like uncoated tablets in USP Edmonton, AB, Canada. 2 Faculty of Pharmaceutical Science, University of Sao Paulo, Sao <701> while <2040> uses a rupture test for soft shell capsules. 1550-7416/10/0400-0602/0 # 2010 American Association of Pharmaceutical Scientists 602Paulo, Brazil. Non-gelatin shell capsules are gaining importance in the 3 To whom correspondence should be addressed. (e-mail: rloeben pharmaceutical and dietary supplement industry. Literature [email protected]) reports some evidence that non-gelatin capsules made out of

1550-7416/10/0400-0602/0 # 2010 American Association of Pharmaceutical Scientists 602 Change in USP Standard Soft Gelatine Capsules

http://www.sixthseal.com/archive/June2006/normison_capsules_gel.jpg http://www.jsppharma.com/Liquid-capsule-softgel.html Method

5 different products, in form of soft gelatine capsules, were Received:

1. Amantadine HCL Suspension 2. Pseudoephedrine HCl Solution 3. Flaxseed Oil 4. Ginseng 100mg Oil base 5. Soybean Oil Method

Each Product

12 Capsules 12 Capsules ( Disintegration test ) ( Rupture test )

6 Capsules 6 Capsules 6 Capsules 6 Capsules (Coated) (intact) (Coated) (intact) Result

Interval Plot of Time (minutes): test, condition and storage for Amadantine capsule 95% CI for the Mean

) 12 s e

t 11 u

n 10 i

m 9 (

e 8 m i

T 7

Storage T ks ks T ks ks T ks ks T ks ks R e e R e e R e e R e e e e e e e e e e w w w w w w w w 2 2 2 2 2 2 2 2 T C T C T C T C o o o o R 0 R 0 R 0 R 0 4 4 4 4 T T T T R R R R

Condition d d d d te te te te a a a a co co co co n n u u

Test n e o r ti tu a p r u g R te in is D Result

Interval plot for Time (minutes): test; condition and storage for Flaxseed oil capsule 95% CI for the Mean

9 )

s 8 e

t 7

u 6 n i 5 m

( 4

e 3

m 2 i Interval plot for Time (minutes): test; condition and storage for Flaxseed oil capsule 95% CI for the Mean T 1 9 )

s 8 e

t 7 0 u 6 n i 5 m

( 4

e 3

m 2 i

T 1 Storage s s s s 0 s s s s T T Storage s s s s T s s s s T T k k T k k T k k T k k k k k k R e e R e e R e e R ke e k k k e e e e e e e e R R w w w w R w w w w R e e e e 2 2 2 2 2 2 e 2 2 e e e T 40 T 40 T 40 T 40 e e e e R T R T R T e R T e e e Condition d d d d te te te te a a a a w w w w co co co w co w w w n n u u Test n e 2 2 2 2 io 2 r 2 2 2 t tu a p r u g R te n T 0 T 0 si T 0 T 0 i 4 4 D 4 4 R T R T R T R T

Condition d d d d te te te te a a a a co co co co n n u u Test on re ti tu a p r u g R te in is D Result

Interval Plot for Time (minutes): test; condition; storage for Pseudoephedrine capsule 95% CI for the Mean

8 )

s 7 e t 6 u n

i 5 m

( 4

e 3 m i 2 T 1 Storage T ks ks T ks ks T ks ks T ks ks R e e R e e R e e R e e e e e e e e e e w w w w w w w w 2 2 2 2 2 2 2 2 T 0 T 0 T 0 T 0 4 4 4 4 R T R T R T R T

Condition d d d d te te te te a a a a co co co co n n u u

Test n e o r ti tu a p r u g R te in is D ComparisonComparison of the Rupture of the and Rupture and DisintegrationDisintegration Tests for Soft-Shell Tests for Soft-Shell Capsules e-mail: [email protected] Capsules e-mail: [email protected]

ABSTRACT The USP GeneralABSTRACT Chapter <2040> Disintegration and Dissolution of Dietary Supplements introduced a rupture test as a performance test of soft-shellThe USP capsules. General Traditionally, Chapter <2040> the disintegration Disintegration test was and used Dissolution for determining of Dietar the ydisintegration Supplements introduced a rupture test as a time of all solid oralperformance dosage forms. test The ofaim soft-shell of this investigation capsules. Traditionally,was to investigate the differencesdisintegration between test the was rupture used testfor determining the disintegration and the disintegrationtime test of allusing solid soft-shell oral dosage capsules. forms. The aim of this investigation was to investigate differences between the rupture test Five different soft-shelland the capsule disintegration products were test chosenusing soft-shell based on theircapsules. filling contents and treated to simulate a production deficiency.Five The different study design soft-shell compared capsule capsules products as received were with chosen capsules based that onwere their treated filling by contentscoating them and treated to simulate a with the liquid contentsproduction of another deficiency. capsule. TheThe capsules study design were incubated compared at roomcapsules temperature as received and at with 40 °C. capsules The tests that were treated by coating them were repeated after two weeks, and at each time point, twelve capsules of each product were tested using the rupture and the disintegrationwith tests. the Sixliquid capsules contents were oftested another untreated, capsule. while The the capsules other six capsuleswere incubated were treated at room. Rupture temperature and and at 40 °C. The tests disintegration timeswere were repeated recorded afteras dependent two weeks, variables and atin eacheach experiment. time point, The twelve data werecapsules analyzed of each using product ANOVA. were tested using the rupture According to theand USP the definition disintegration for disintegration, tests. Six the capsules rupture ofwere a soft-shell tested capsuleuntreated, can bewhile seen the as fulfillingother six the capsules were treated. Rupture and disintegration criteriondisintegration if the capsule times contents were is recorded a semisolid as or dependent liquid. Statistical variables analysis in showedeach experiment. no advantage The of thedata were analyzed using ANOVA. rupture test over the Accordingdisintegration to test. the OnUSP a product-by-productdefinition for disintegration, basis, both tests the rupturewere sensitive of a soft-shell to certain investigatedcapsule can be seen as fulfilling the parameters. A noticeabledisintegration difference criterion between ifboth the tests capsule was thatcontents in most is cases, a sem theisolid rupture or liquid. test reached Statistical the defined analysis showed no advantage of the endpoint faster thanrupture the disintegration test over the test. disintegration test. On a product-by-product basis, both tests were sensitive to certain investigated Soft-shell capsules that are subject to a Quality by Design approach should be tested with both methods to determine which performanceparameters. test is the most A noticeable appropriate difference test for a specific between product. both tests was that in most cases, the rupture test reached the defined endpoint faster than the disintegration test. Soft-shell capsules that are subject to a Quality by Design approach should be tested with both methods to determine INTRODUCTION which performance test is the most appropriaterupture test test was for first a specificpublished product. in Pharmacopeial Previews uality by Design (QbD) is a scientific approach that (7), then forwarded to USP’s In-Process Revision (8), and in uses statistical methods for product design, quality 2007 it was finally published in USP 30–NF 25. USP 32 lists Qtesting (1), andINTRODUCTION predicting product performance 14 monographs that use therupture rupture test test wasperformed first published in in Pharmacopeial Previews from early product developmentuality toby final Design product (QbD) release is a scientificdissolution approach Apparatus that 2 (paddle)(7), then operated forwarded at 50 rpm to USP’s with In-Process Revision (8), and in (2). QbD is highly dependent on the appropriateness of 500 mL of water as the immersion medium. The test uses statistical methods for product design, quality 2007 it was finally published in USP 30–NF 25. USP 32 lists test methods used and can only be successfully applied if requirements are met if all capsules rupture within 15 min testing (1), and predicting product performance a test is sensitive toQ the parameter that is tested. or if not more than 2 of the14 total monographs of 18 capsules that tested use the rupture test performed in The performancefrom testing early of soft-shellproduct capsulesdevelopment is rather to finalrupture product in more release than 15 butdissolution not more than Apparatus 30 min. For 2 (paddle) any operated at 50 rpm with a challenge because(2 ).the QbD contents is highly of soft-shell dependent capsules on the appropriatenessother oral dietary of supplement500 dosage mL of form,water disintegration as the immersion medium. The test can vary from solidstest to liquidsmethods (3). Dissolutionused and canmethods only be successfullytest Apparatus applied A or if B is usedrequirements if the monograph are metrequires if all capsules rupture within 15 min used for solid oral dosagea test is forms sensitive might to not the be parameter appropriate that isdisintegration. tested. or if not more than 2 of the total of 18 capsules tested for soft-shell capsulesThe that performance have liquid or semisolidtesting of soft-shell capsulesAnother isdifference rather is that for hard-shell capsules, contents (4). rupture in more than 15 but not more than 30 min. For any a challenge because the contents of soft-shellChapter capsules <2040> lists USP pHother 4.5 buffer oral dietary as the immersion supplement dosage form, disintegration USP General Chapter <701> Disintegration describes medium while Chapter <701> lists water as the default the procedure to evaluatecan vary disintegration from solids ofto oral liquids dosage (3). Dissolution methods medium if a monograph doestest not Apparatus specify any A otheror B is used if the monograph requires forms (5). The requirementsused for ofsolid disintegration oral dosage are forms met might not be appropriate medium (Figure 1) (9). USP Chapterdisintegration. <2040> also lists if all test units disintegratefor soft-shell or if not capsules more than that two have units liquid or semisolid Apparatus B, which is intendedAnother for dosage difference forms greater is that for hard-shell capsules, out of a total of 18 contentsunits fail to (4 disintegrate). within a than 18 mm in diameter. CurrentlyChapter there <2040> are no lists scientific USP pH 4.5 buffer as the immersion predetermined time period. USP General Chapter <701> Disintegrationdata available describes that comparemedium the performance while Chapter of the <701> lists water as the default USP General Chapterthe procedure <2040> Disintegration to evaluate and disintegration of oral dosage rupture test with that of themedium disintegration if a monograph test. The aim does of not specify any other Dissolution of Dietaryforms Supplements (5). The requirements uses a rupture of test disintegration as are met performance test of soft-shell capsules (6). In 2002 the this study was to evaluate ifmedium there are (Figure advantages 1) (9 in). usingUSP Chapter <2040> also lists if all test units disintegrate or if not more than two units the rupture test over the disintegrationApparatus B,test. which A series is intended of for dosage forms greater out of a total of 18 units fail to disintegrateexperiments within a was performed and statistical analysis was than 18 mm in diameter. Currently there are no scientific *Corresponding author.predetermined time period. used to determine differences between the tests. data available that compare the performance of the USP General Chapter <2040> Disintegration and Dissolution !"#$%&'&()"*+|!"#$%&'%(!)*++ Dissolution of Dietary Supplements uses a rupture test as rupture test with that of the disintegration21 test. The aim of performance test of soft-shell capsules (6). In 2002 the this study was to evaluate if there are advantages in using the rupture test over the disintegration test. A series of experiments was performed and statistical analysis was *Corresponding author. used to determine differences between the tests. !!"##$%&$'%$%()"*!!+++,%"##$%&$'%$%()"*!!+++,% ,,-,.-,'%%+++./0&/00+12-,.-,'%%+++./0&/00+12 Dissolution !"#$%&'&()"*+|!"#$%&'%(!)*++ 21

!!"##$%&$'%$%()"*!!+++,%"##$%&$'%$%()"*!!+++,% ,,-,.-,'%%+++./0&/00+12-,.-,'%%+++./0&/00+12 ComparisonComparison of the Rupture of the and Rupture and DisintegrationDisintegration Tests for Soft-Shell Tests for Soft-Shell Capsules e-mail: [email protected] Capsules e-mail: [email protected]

May Almukainzi1, MahnorMay Almukainzi Salehi1, Nadia1, Mahnor A. B. Chacra Salehi2, 1, Nadia A. B. Chacra2, and Raimar Löbenbergand1, Raimar* Löbenberg1,* 1Faculty of Pharmacy & Pharmaceutical1Faculty of Pharmacy Science, University & Pharmaceutical of Alberta, Science, University of Alberta, 1123A Dentistry/Pharmacy1123A Centre, Dentistry/Pharmacy Edmonton, Alberta, Canada Centre, Edmonton, Alberta, Canada 2 On Departmenta product-by-product of Pharmaceutical2Department Science, University of Pharmaceutical of Sao Paulo, Science, Brazilbasis, University bothof Sao Paulo, tests Brazil were ABSTRACT The USP GeneralsensitiveABSTRACT Chapter <2040> to Disintegration certain and investigatedDissolution of Dietary Supplements parameters. introduced a rupture test as a performance test of soft-shellThe USP capsules. General Traditionally, Chapter <2040> the disintegration Disintegration test was and used Dissolution for determining of Dietar the ydisintegration Supplements introduced a rupture test as a timeA of noticeableall solid oralperformance dosage forms. difference test The ofaim soft-shell of this investigation capsules. between Traditionally,was to investigate both the differencesdisintegration tests between testwas the was rupture used that testfor determining the disintegration and the disintegrationtime test of allusing solid soft-shell oral dosage capsules. forms. The aim of this investigation was to investigate differences between the rupture test Fivein different most soft-shelland cases, the capsule disintegration products the were test rupture chosenusing soft-shell based ontest theircapsules. filling reached contents and treated the to definedsimulate a production deficiency.Five The different study design soft-shell compared capsule capsules products as received were with chosen capsules based that onwere their treated filling by contentscoating them and treated to simulate a with the liquidendpoint contentsproduction of another deficiency. faster capsule. TheThe capsulesthan study design were the incubated compared disintegration at roomcapsules temperature as received and at test.with 40 °C. capsules The tests that were treated by coating them were repeated after two weeks, and at each time point, twelve capsules of each product were tested using the rupture and the disintegrationwith tests. the Sixliquid capsules contents were oftested another untreated, capsule. while The the capsules other six capsuleswere incubated were treated at room. Rupture temperature and and at 40 °C. The tests disintegrationSoft-shell timeswere were repeated recordedcapsules afteras dependent two weeks, that variables and are atin eacheach experiment.subject time point, The twelve datato werecapsules a analyzedQuality of each using product ANOVA. by were tested using the rupture According to theand USP the definition disintegration for disintegration, tests. Six the capsules rupture ofwere a soft-shell tested capsuleuntreated, can bewhile seen the as fulfillingother six the capsules were treated. Rupture and disintegrationDesign criteriondisintegration if the approachcapsule times contents were is recorded a semshouldisolid as or dependent liquid. be Statistical testedvariables analysis in showedeach with experiment. no advantageboth The of thedata were analyzed using ANOVA. rupture test over the Accordingdisintegration to test. the OnUSP a product-by-productdefinition for disintegration, basis, both tests the rupturewere sensitive of a soft-shell to certain investigatedcapsule can be seen as fulfilling the parameters.methods A noticeabledisintegration difference to determine criterion between ifboth the tests capsule was which thatcontents in most isperformance cases, a sem theisolid rupture or liquid. test reached Statistical test the defined analysis is showed no advantage of the endpoint faster thanrupture the disintegration test over the test. disintegration test. On a product-by-product basis, both tests were sensitive to certain investigated Soft-shellthe capsules most that are appropriate subject to a Quality by Design test approach for should a specificbe tested with both product. methods to determine which performanceparameters. test is the most A noticeable appropriate difference test for a specific between product. both tests was that in most cases, the rupture test reached the defined endpoint faster than the disintegration test. Soft-shell capsules that are subject to a Quality by Design approach should be tested with both methods to determine INTRODUCTION which performance test is the most appropriaterupture test test was for first a specificpublished product. in Pharmacopeial Previews uality by Design (QbD) is a scientific approach that (7), then forwarded to USP’s In-Process Revision (8), and in uses statistical methods for product design, quality 2007 it was finally published in USP 30–NF 25. USP 32 lists Qtesting (1), andINTRODUCTION predicting product performance 14 monographs that use therupture rupture test test wasperformed first published in in Pharmacopeial Previews from early product developmentuality toby final Design product (QbD) release is a scientificdissolution approach Apparatus that 2 (paddle)(7), then operated forwarded at 50 rpm to USP’s with In-Process Revision (8), and in (2). QbD is highly dependent on the appropriateness of 500 mL of water as the immersion medium. The test uses statistical methods for product design, quality 2007 it was finally published in USP 30–NF 25. USP 32 lists test methods used and can only be successfully applied if requirements are met if all capsules rupture within 15 min testing (1), and predicting product performance a test is sensitive toQ the parameter that is tested. or if not more than 2 of the14 total monographs of 18 capsules that tested use the rupture test performed in The performancefrom testing early of soft-shellproduct capsulesdevelopment is rather to finalrupture product in more release than 15 butdissolution not more than Apparatus 30 min. For 2 (paddle) any operated at 50 rpm with a challenge because(2 ).the QbD contents is highly of soft-shell dependent capsules on the appropriatenessother oral dietary of supplement500 dosage mL of form,water disintegration as the immersion medium. The test can vary from solidstest to liquidsmethods (3). Dissolutionused and canmethods only be successfullytest Apparatus applied A or if B is usedrequirements if the monograph are metrequires if all capsules rupture within 15 min used for solid oral dosagea test is forms sensitive might to not the be parameter appropriate that isdisintegration. tested. or if not more than 2 of the total of 18 capsules tested for soft-shell capsulesThe that performance have liquid or semisolidtesting of soft-shell capsulesAnother isdifference rather is that for hard-shell capsules, contents (4). rupture in more than 15 but not more than 30 min. For any a challenge because the contents of soft-shellChapter capsules <2040> lists USP pHother 4.5 buffer oral dietary as the immersion supplement dosage form, disintegration USP General Chapter <701> Disintegration describes medium while Chapter <701> lists water as the default the procedure to evaluatecan vary disintegration from solids ofto oral liquids dosage (3). Dissolution methods medium if a monograph doestest not Apparatus specify any A otheror B is used if the monograph requires forms (5). The requirementsused for ofsolid disintegration oral dosage are forms met might not be appropriate medium (Figure 1) (9). USP Chapterdisintegration. <2040> also lists if all test units disintegratefor soft-shell or if not capsules more than that two have units liquid or semisolid Apparatus B, which is intendedAnother for dosage difference forms greater is that for hard-shell capsules, out of a total of 18 contentsunits fail to (4 disintegrate). within a than 18 mm in diameter. CurrentlyChapter there <2040> are no lists scientific USP pH 4.5 buffer as the immersion predetermined time period. USP General Chapter <701> Disintegrationdata available describes that comparemedium the performance while Chapter of the <701> lists water as the default USP General Chapterthe procedure <2040> Disintegration to evaluate and disintegration of oral dosage rupture test with that of themedium disintegration if a monograph test. The aim does of not specify any other Dissolution of Dietaryforms Supplements (5). The requirements uses a rupture of test disintegration as are met performance test of soft-shell capsules (6). In 2002 the this study was to evaluate ifmedium there are (Figure advantages 1) (9 in). usingUSP Chapter <2040> also lists if all test units disintegrate or if not more than two units the rupture test over the disintegrationApparatus B,test. which A series is intended of for dosage forms greater out of a total of 18 units fail to disintegrateexperiments within a was performed and statistical analysis was than 18 mm in diameter. Currently there are no scientific *Corresponding author.predetermined time period. used to determine differences between the tests. data available that compare the performance of the USP General Chapter <2040> Disintegration and Dissolution !"#$%&'&()"*+|!"#$%&'%(!)*++ Dissolution of Dietary Supplements uses a rupture test as rupture test with that of the disintegration21 test. The aim of performance test of soft-shell capsules (6). In 2002 the this study was to evaluate if there are advantages in using the rupture test over the disintegration test. A series of experiments was performed and statistical analysis was *Corresponding author. used to determine differences between the tests. !!"##$%&$'%$%()"*!!+++,%"##$%&$'%$%()"*!!+++,% ,,-,.-,'%%+++./0&/00+12-,.-,'%%+++./0&/00+12 Dissolution !"#$%&'&()"*+|!"#$%&'%(!)*++ 21

!!"##$%&$'%$%()"*!!+++,%"##$%&$'%$%()"*!!+++,% ,,-,.-,'%%+++./0&/00+12-,.-,'%%+++./0&/00+12 Dissolution or Disintegration?

Cs ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈≈ ≈≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈≈ ≈ ≈ API ≈ ? ≈ ≈ ≈ ≈ dl ≈≈ ≈ ≈ ≈ ≈ ≈ ≈

≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈≈ ≈≈ ≈ ≈ ≈ ≈ ≈ When to use which test? The FDA draft guidance on “Dissolution Testing and Specification Criteria for Immediate-Release Solid Oral Dosage Forms Containing Biopharmaceutics Classification System Class 1 and 3 Drugs” U.S. Department of Health and Human Services, 2015 allows the use of disintegration testing as a surrogate for routine release and stability dissolution testing for certain BCS class 1 & 3 drug products. The acceptance criteria is a 5 min disintegration time for drug products which passed a dissolution Q=80% within 15 min. Dissolution Controlled Dosage Forms

• immediate release oral drug products, such as tablets and capsules, are formulated to release the active drug immediately after oral administration. • In the formulation no deliberate effort is made to modify the drug release rate.

Direct compression Granulation: Wet Dry Sinter Immediate release a mechanistic view

Two cases: ≈ Cs ≈ ≈ ≈ •1) API driven Dissolution (drug particle ≈ ≈ ≈ ≈ ≈ properties) ≈ API ≈ ≈ ≈ ≈ dl – Example: direct compression ≈≈ ≈ ≈ ≈ ≈ ≈

•2) Formulation impacted or controlled ≈ ≈ ≈ dissolution (excipient API interaction – drug ≈ particles properties can not be liked to ≈ dissolution behavior) ≈ ≈ – Example: wet granulation ≈ ≈ ≈ ≈ Flushing a Toilet vs. opening a Faucet

• The rate depends only on the hydrostatic pressure and diameter of the pipe • Opening a faucet you can control the amount and rate of water Two manufacturing methods Direct compression Granulation

Drug Drug MCC MCC CaPO4 X 2H2O CaPO4 X 2H2O Croscarmellose Na Water Mg Stearate Croscarmellose Na Mg Stearate

FDT SET

Model Fitting using Excel-Add-In Common release Models for IR and ER dosage forms • Zero Order • First Order • Gompertz • Hixson Cromwel

• Hopfenberg • Weibull Drug release mechanism Korsmeyer Peppas equation:

Exponent n of the power law and drug release mechanism from polymeric controlled delivery systems of different geometry

n values Drug release mechanism Thin Film Cylinder Sphere 0.5 0.45 0.43 Fickian Diffusion 0.5

25 rpm observed 25 rpm observed 120 50 rpm observed 120 75 rpm observed 50 rpm observed 100 100 75 rpm observed 80 80 60 60 40 40 20 20 % Dissolution % Dissolution 0 0 0 20 40 60 0 20 40 60 Time Time Korsmeyer-Peppas n values Korsmeyer-Peppas n values Sphere 75 0.111 <0.43 75 1.11 50 0.293 0.430.85 25 0.924

Fickian Diffusion Controlled Release How to show that disintegration is the most important step?

ICH Guideline Q6A “Specifications: Test procedures and acceptance criteria for new drug substances and new drug products” outlines acceptance criteria for different dosage forms and routes of administration. The guidance document contains decision tree #7.1, which allows disintegration testing to be used as a performance/quality control test if a relationship between dissolution and disintegration has been established

U.S. Department of Health and Human Services, 1999 FDA Study 2009 FDA Study 2009

However, no direct correlation was observed between the disintegration and the dissolution New method: Impact of immersion media on disintegration

Effect of dissolution medium on disintegration Test formulation #1 (direct compression) 400

350 conventional disintegration 300 media impacting media

250

200 Disintegration Time [s] Disintegration 150

100

0 SGF Buffer 4.5 Syrup 10% Syrup 20% Syrup 30%

Test formulation #1 (direct compression)

100

80 f2-test comparison to SGF-profile 60 USP pH 4.5 75 Syrup 10% 83 40 Syrup 20% 65

amount dissolved [mg] dissolved amount Syrup 30% 45 20

0 0 10 20 30 40 50 60 time [min]

SGF Buffer 4.5 Sugar 10% Sugar 20% Sugar 30%

DPD Technology Governance Semi-Annual Review | Company Confidential © 2015 51 For certain Formulations Disintegration and Dissolution are Sequential Processes No correlation other than the Sequence should be found if API controls Dissolution

Cs ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ API ≈ ? ≈ ≈ dl ≈≈ ≈ ≈ ≈ ≈ ≈ ≈

≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈≈ ≈≈ ≈ ≈ ≈ ≈ ≈

§ It was found that dis integration and dissolution can be sequential or parallel processes, or both. § If disintegration occurs first, API dependent dissolution can happen and disintegration can be used as performance test of rapidly disintegrating tablets beyond the current FDA criteria. § The scientific data needed for this justification being, that dissolution is API dependent and formulation factors have to be negligible for the dissolution process. § This approach will enable globally operating pharmaceutical companies to scientifically justify their product specifications for disintegration independent from national – sometimes contradicting – regulatory guidance documents. PHASE 1/2 R&D DEVELOPMENT Capsule Tablet or ODT/FDT Dosage form Direct compression Fluid bed granulation Manufacturing Dry granulation Sinter granulation Powder blend Melt extrusion process Wet granulation

R&D Dissolution Test Development Formulation API controls Release Proposed New dissolution significantly mechanism controls Formulation excipients have no Modeling dissolution Classification: significant API vs. impact Formulation Controlled Dissolution

QC Method Disintegration Test Dissolution Test In Vitro vs. In Vivo Dissolution Mechanistic considerations At this time point, there is no universal medium available which can be used to predict every drug substance’s solubility or a drug product’s in vivo dissolution behavior. anatomy & in vitro model Gastric secretions Slow mixing Stomach space transfer

Intense mixing

Pancreatic secretions transfer Organic Sink Duodenum

Jejunum Organic Sink Solubility vs. pH Profile for Acids and Bases and their potential Solubility Gap

Solubility Solubility Log S Log S Gap pKa pKa Gap

pH pH R&D Consideration for Dissolution Test Development BCS Sub-Classification

Acids Acids BCS 1/3 Base BCS 2/4 Base Neutral Neutral

Low dose / Fast Abs Low dose / Slow Abs High Dose / Fast Abs High dose / Slow Abs High dose R&D investigations Possible dissolution requirements

Acids transfer model Biphasic High dose / Fast Abs BCS 1 Base transfer model Biphasic Neutral Single vessel dissolution Biphasic Acids transfer model Biphasic High dose / Fast Abs BCS 2 Base transfer model Biphasic Neutral Single vessel dissolution Biphasic Acids Single vessel dissolution Biphasic? High dose / Slow Abs BCS 3 Base transfer model Biphasic? Neutral Single vessel dissolution Biphasic? Acids transfer model Biphasic? High dose / Slow Abs BCS 4 Base transfer model Biphasic? Neutral Single vessel dissolution Biphasic? BIPHASIC – Dissolution Ibuprofen

Octanol

buffer Ibuprofen

Direct compression Granulation

Ibuprofen Ibuprofen MCC MCC CaPO4 X 2H2O CaPO4 X 2H2O Croscarmellose Na Water Mg Stearate Croscarmellose Na Mg Stearate Excipients characteristics (Handbook of Pharmaceutical Excipients)

MCC (Avicel Dextrose CaHPO4 PH102) Monohydrate Solubility - - + + - - - pH 5.0 - 7.0 3.5 – 5.5 7.4 Uses Adsorbent; Tablet and Tablet and suspending capsule diluent; capsule diluent. agent; tablet and therapeutic capsule diluent agent; tonicity (20-90%); tablet agent; Disintegrant sweetening agent. Binder as well Wet Direct granulation compression Different excipient Different excipient composition composition

≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈≈ ≈ ≈ ≈≈ ≈ ≈ ≈ ≈ ≈≈ ≈≈ ≈ ≈ ≈≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈ ≈

200mL 900mL 200mL 900mL 200mL 900mL

BIPHASIC DISSOLUTION Phosphate buffer 5mM Phosphate buffer USP Phosphate buffer 5mM strength + Octanol Microcrystalline Cellulose formulations

Direct Wet Compression Granulation D formulation G formulation Ibuprofen – 400mg Ibuprofen – 400mg Avicel PH102 – 800mg Avicel PH102 – 800mg Intragranular Croscarmellose Na – 3% Croscarmellose Na – 5% Mg Stearate – 1% Starch 1500* – 210mg Mg Stearate – 1% Extragranular

Granulation liquid: EtOH 70% *Added as powder Overview G and D tablets in 900mL

MCC G USP MCC D USP MCC G 5mM MCC D 5mM

MCC G BP aqueous

MCC D BP aqueous Neutral excipient MCC D BP octanol USP buffer: MCC G BP octanol No difference

Low buffer capacity: Process differentiation MCC G tablets – 900ml vs 200ml

MCC G total BP 900ml MCC G total BP 200ml MCC G BP octanol 200ml

MCC G BP aqueous 900ml

MCC G BP octanol 900ml

MCC G BP aqueous 900mL - Zero order 200ml Additional sink assisted on medium pH maintenance MCC G BP – 200mL

MCC G BP – 900mL

MCC D BP – 900mL

MCC D 5mM – 900mL

MCC G 5mM – 900mL CaHPO4 FORMULATIONS

Direct Compression Wet Granulation

Ibuprofen – 400mg Ibuprofen – 400mg Avicel PH102 – 400mg Avicel PH102 – 400mg CaHPO4 – 400mg CaHPO4 - 400mg Croscarmellose Na – Croscarmellose Na – 5% 3% Starch 1500* – 210mg Mg Stearate – 1% Mg Stearate – 1%

+ Granulation liquid: EtOH 70% • Extragranular • Intragranular Overview G and D tablets in 900mL CaHPO4 D USP CaHPO4 G USP CaHPO4 G 5mM CaHPO4 D 5mM

CaHPO4 G BP aqueous

CaHPO4 D BP aqueous CaHPO4 G BP octanol USP buffer: CaHPO4 D BP No difference octanol

Low buffer capacity: Process differentiation Overview G and D tablets in 200mL

CaHPO4 G USP CaHPO4 D USP CaHPO4 G BP octanol CaHPO4 D BP octanol

CaHPO4 D 5mM CaHPO4 G 5mM

CaHPO4 G BP aqueous

CaHPO4 D BP aqueous Dextrose monohydrate formulations

Direct Compression Wet Granulation

Ibuprofen – 400mg Ibuprofen – 400mg Avicel PH102 – 400mg Avicel PH102 – 400mg Dextrose – 400mg Dextrose - 400mg Croscarmellose Na – 5% Croscarmellose Na – Starch 1500* – 210mg 3% Mg Stearate – 1% Mg Stearate – 1% Granulation liquid: EtOH 70% *Added as powder • Intragranular • Extragranular Dextrose G USP Dextrose D USP 900mL Dextrose G 5mM Dextrose D 5mM

Dextrose G BP aqueous f2: Dextrose D BP aqueous USP buffer: 48 No difference Dextrose D BP octanol Low buffer capacity: Dextrose G BP octanol Process differentiation

Dextrose D USP 200mL Dextrose G BP octanol f2: Dextrose D BP octanol 30

Octanol layer – 200mL set up Process differentiation Dextrose D 5mM and excipient effect Dextrose G BP aqueous Dextrose D BP aqueous Study summary

• USP buffer (50mM) did not differentiate between excipients nor manufacturing process. • Low buffer capacity (monophasic) differentiated between processes in 900mL but not in 200mL due to medium saturation. (Also seen in the aqueous phase of biphasic dissolution – 900ml) • For minor excipient changes within the same dosage form, biphasic dissolution (200mL) was much more discriminative in the octanol phase. • More pronounced excipient effect on the G formulations was captured in the aqueous phase of the biphasic dissolution 900mL, whereas in the 200mL set up it was captured in the octanol phase. • The additional sink helped maintaining the medium pH. In the 200mL set up the medium pH recovery was much faster. Conclusions • Pharmacopeial tests have their limitations • More basic mechanistic questions need to be asked in drug development • A BCS sub-classification helps to decide on the in vitro performance testing set-up • Disintegration might be used for API driven dissolution • Immediate release needs to be better defined. • Biphasic dissolution needs to be more studied to find suitable conditions to differentiate between excipient and process variables.

10/23/18 76 Any Questions