JPS commentary.pdf

COMMENTARY

Oral Solid Dosage Form Disintegration Testing The Forgotten Test

JOZEF AL-GOUSOUS, PETER LANGGUTH

Pharmaceutical Technology and Biopharmaceutics, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University Mainz,Mainz D-55128, Germany

Received 18 August 2014; revised 16 November 2014; accepted 18 November 2014

Published online 24 December 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24303

ABSTRACT: Since its inception in the 1930s, disintegration testing has become an important quality control (QC) test in pharmaceuticalindustry, and disintegration test procedures for various dosage forms have been described by the different pharmacopoeias, with har-monization among them still not quite complete. However, because of the fact that complete disintegration does not necessarily implycomplete dissolution, much more research has been focused on dissolution rather than on disintegration testing. Nevertheless, owingto its simplicity, disintegration testing seems to be an attractive replacement to dissolution testing as recognized by the InternationalConference on Harmonization guidelines, in some cases. Therefore, with proper research being carried out to overcome the associatedchallenges, the full potential of disintegration testing could be tapped saving considerable efforts allocated to QC testing and qualityassurance. C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:26642675, 2015Keywords: bioavailability; biopharmaceutics classification system (BCS); dissolution; excipients; formulation; gastrointestinal; in vitromodels; intestinal absorption

INTRODUCTION

It is a well-known fact that an immediate-release dosage formshould disintegrate in order to efficiently liberate its activeingredient(s) and make it available for absorption. Therefore,disintegration testing methods were developed.

The first mention of a test for disintegration was in the1907 Edition of Pharmacopoeia Helvetica, in the compressedpastilles monograph, stating that they should dissolve or disin-tegrate after a short time of them being placed in cold water.1

In 1933, a disintegration test for tablets appeared in the samepharmacopoeia.2 It stated that a tablet should be placed in a100-mL Erlenmeyer flask containing 50 mL of water, at a tem-perature of 37C, and the flask was to be gently swirled fromtime to time.2 It was stated that the tablet had to disintegrateinto a powder or dissolve within 15 min.2

In 1948, the British Pharmacopoeia (BP) adopted a disinte-gration test for tablets based on observing the disintegrationbehavior in test tubes.3 However, by that time, a specific disin-tegration testing apparatus had been used for 8 years by thelaboratories of US Army Medical Department (Fig. 1),4 andthis apparatus formed the basis for the basket-rack assemblyapparatus, first adopted by the United States Pharmacopoeia(USP) in 1950,5 which is the apparatus currently used to per-form the vast majority of disintegration testing procedures fororally administered dosage forms.

Since then, the disintegration test has been a major qual-ity control (QC) test in pharmaceutical development and QC.However, it has been well understood that, despite disintegra-tion being a prerequisite for acceptably rapid drug dissolution,complete disintegration does not necessarily imply completedissolution of the active ingredient. This has contributed tothe much greater focus on dissolution testing methods in phar-maceutical research, which can be easily noticed by the much

Correspondence to: Peter Langguth (Telephone: +49-6131-392-5746;Fax: +49-6131-392-5021; E-mail: [email protected])Journal of Pharmaceutical Sciences, Vol. 104, 26642675 (2015)C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

greater amount of publications dealing with dissolution testingmethodologies comparedwith those dealingwith disintegrationtesting methodologies (as shown in Fig. 2).

Nevertheless, the greater simplicity of disintegration com-pared with dissolution testing (e.g., no analytics needed, lesservolume of fluids required, less time-consuming) makes the ideaof putting more focus on disintegration attractive. This hasbeen recognized by the International Conference on Harmo-nization (ICH) that allowed the use of disintegration testingas a surrogate for dissolution testing if certain conditions aremet.6 Therefore, focusing more interest and research on disin-tegration testing could, because of the tests simplicity, enablethe QC departments of pharmaceutical companies to save ap-preciable expenses in terms of time, efforts, and even money.

In this commentary, disintegration testing is discussed andpossible means of enhancing its potential as a QC method inthe pharmaceutical industry are introduced. Particular focuswill be given to its potential use as a surrogate for dissolutiontesting.

DISINTEGRATION APPARATUS

A disintegration apparatus is composed of a 1-L low-form cylin-drical beaker, a heating system that keeps the temperature at37 2C, a basket-rack assembly, and a device to move thebasket-rack assembly vertically.710 Two types of basket-rackassembly are described: apparatus A (Fig. 3) and apparatus B(Fig. 4). Apparatus A is described in all major pharmacopoeias:European Pharmacopoeia (Ph Eur), BP, USP, and JapanesePharmacopoeia (JP), whereas apparatus B is described only inthe Ph Eur, BP, and the Dietary Supplements chapter of theUSP, where it is required for testing tablets and capsules morethan 18 mm in length.710 The chapters on disintegration test-ing are harmonized between Ph Eur and BP.

Both types consist of a set of open-ended transparent tubesmaintained in a vertical position by two plates containingthe corresponding number of openings arranged in a circle

2664 Al-Gousous and Langguth, JOURNAL OF PHARMACEUTICAL SCIENCES 104:26642675, 2015

COMMENTARY 2665

Figure 1. Disintegration apparatus from the 1940s before becoming official in the USP.4

Figure 2. Hits when searching for the terms Disintegration Test and Dissolution test within the date ranges shown on the x-axis in PubMed.Accessed June 23, 2014.

DOI 10.1002/jps.24303 Al-Gousous and Langguth, JOURNAL OF PHARMACEUTICAL SCIENCES 104:26642675, 2015

2666 COMMENTARY

Figure 3. Disintegration apparatus A with dimensions in millimeter.9

equidistantly from the center of the plate as well as from eachother.710 The two plates are fastened to each other by threebolts passing through them.710 A stainless steel wire cloth withsquare apertures (size 2.0 0.2 mm) is attached to the bot-tom plate.710 The thickness of the wire is specified to be 0.570.66 mm for apparatus A, whereas for apparatus B, it is set at0.600.66 mm by Ph Eur and BP and 1/4 inch by the DietarySupplements chapter of the USP.710 Apparatus A contains sixtubes, while apparatus B contains three larger tubes.710 Theexact design of the device can be varied as long as the specifi-cations for the tubes and the wire cloth are adhered to.710 TheJP also provides specifications for a perforated metal plate thatcan be used to secure the tubes and the plates.10

Both types are supplied with transparent plastic cylindricaldisks specified to have a relative density of 1.181.20, but thoseof apparatus A are smaller and, unlike those of apparatus B,have trapezoidal-shaped planes cut into the lateral surface ofthe cylinder.710 Unique to the JP is an accessory called theauxiliary tube (Fig. 5) made up of an open-ended plastic tubeand two plastic rings, each containing an acid-resistant wiregauze, to be attached to the tubes ends.10 A handle made ofacid-resistant wire is fitted to the tube. This auxiliary tube isused for the disintegration testing of granules.10

The disintegration tester also includes a device for the ver-tical movement of the basket rack assembly.710 This verticalmovement is specified to occur at a rate of 2932 cycles per

minute through a 5357 mm distance in a smooth mannerwith the speed being the same for both the upward and thedownward strokes.710 The volume of the immersion fluid inthe vessel is specified to be such that at the highest point ofthe upward stroke the wire mesh remains at least 15 mm belowthe surface of the fluid, and descends to not less than 25 mmfrom the bottom of the vessel on the downward stroke. Atno time should the top of the basket-rack assembly becomesubmerged.710

The detection of the disintegration time is usually deter-mined visually, when all of the dosage forms except insolu-ble fragments of coating and/or, in case of capsules, capsuleshells are a soft mass with no firm palpable core. In addition,disks that can provide automatic detection for disintegrationtime, and are recognized by the pharmacopoeias,710 are com-mercially available, and can be used when the use of disksis proscribed. These disks give a signal that disintegration iscomplete when they come into contact with the stainless steelmesh and can be particularly useful when doing the test inturbid media.

A striking aspect is lack of harmonization for certain fea-tures like the use of apparatus B. This apparatus is specifiedin the Ph Eur, BP, and the Dietary Supplements chapter ofthe USP, but not by the General Tests chapter of the USP andthe JP. This may lead to same dosage forms (tablets and cap-sules longer than 18 mm) being tested differently in different

Al-Gousous and Langguth, JOURNAL OF PHARMACEUTICAL SCIENCES 104:26642675, 2015 DOI 10.1002/jps.24303

COMMENTARY 2667

Figure 4. Disintegration apparatus B with dimensions in millimeter.9

Figure 5. Auxiliary tube for the disintegration testing of granulesaccording to JP.10

laboratories, and using different apparatuses can lead to dif-ferent disintegration times.11

COMPENDIAL TESTS

Table 1 gives a preview of the disintegration tests requiredby the Ph Eur, BP, USP, and JP. The BP has its general dis-integration tests harmonized with Ph Eur so the BP and PhEur occupy the same column of the table. Otherwise, harmo-nization among pharmacopoeias concerning the disintegrationtests required for different dosage forms is clearly not com-plete, and many dosage forms are not mentioned in all phar-macopoeias. Moreover, in the USP, disintegration tests for dif-ferent dosage forms are specified in both the general chapter ondisintegration testing and in the dietary supplements chapter,and these two sets of tests are not identical, as is seen in thetable.


2668 COMMENTARY

Generally, the usage of disks is more common in the PhEur and the BP. These two pharmacopoeias also often statethat if the test fails because of sticking to disks, it should berepeated omitting them.7,8 Generally, for tests performed withthe basket-rack assembly, if one or two units fail to disinte-grate (according the Ph Eur, BP, and JP) or to disintegratecompletely (USP), the test should be repeated with 12 moreunits, and at least 16 out of the 18 tested units should com-pletely disintegrate.710 A unique feature of the JP in this re-gard is that it allows the repetition on further 12 units when1 or 2 units fail the acid-resistance stage of the disintegrationtest for enteric-coated tablets and capsules.10 Another excep-tional feature is that, for the type B apparatus, the Ph Eur andBP state that only a total of 6 units are to be tested without

stating the allowance of testing 12 more units in case 1 or 2 ofthe first 6 units fail to disintegrate.7,8

Concerning hard capsules, the USP specifies water as theimmersion medium in its general chapter on disintegration,but pH 4.5 acetate buffer for dietary supplements.9 And thesetwo media may sometimes lead to different disintegrationperformance for the same product, as shown by Almukainziet al.11 Another USP-specific feature is the use of a remov-able wire cloth attached to the upper surface of the basket-rackassembly.9 This is a relic of the older USP editions that did notforbid the basket-rack assembly becoming submerged, and canbe considered redundant now.

The testing methods for enteric-coated dosage formsshow some striking differences between the different

Table 1. Compendial Disintegration Tests for Different Dosage Forms

Dosage Form USP General Chapter9USP Dietary

Supplements Chaptera9 Ph Eur and BP7,8 JP10

Uncoated tablets Using water or specifiedmedium. Disks used ifproscribed by theindividual monograph.

Using water or specifiedmedium with a 30-mintime limit. Disks usedif proscribed by theindividual monograph.

Using water as themedium. Fifteenminute time limit.Disks are used.

Using water or specifiedmedium and a 30-mintime limit unlessotherwise specified.Disks used ifproscribed by theindividual monograph.

Plain-coatedtablets

Same as uncoated. Same as uncoated, butsugar-coated tabletsshould be immersed inwater for 5 min atroom temperaturebefore the start of thetest.

For tablets other thanfilm-coated tablets, usewater with disks for60 min unlessotherwise justified orauthorized. If any ofthe tablets fails todisintegrate, repeatwith six more tabletsusing 0.1 M HCl. Forfilm-coated tablets, usethe same procedurebut for 30 minunless otherwisejustified or authorized.

Using water or specifiedmedium and a 30-mintime limit unlessotherwise specified.Disks are used ifproscribed by theindividual monograph.

Pills Using water or specifiedmedium and a 60-mintime limit. Disks areused if proscribed bythe individualmonograph. If theycontain a crude drug,use the first fluid fordisintegration.b If anyresidue remains, asuccessive 60-min testwith the second fluidb

for disintegration iscarried out.

Delayed releasetablets

One-hour acid stage withSGF, followed by 1-hSIF stage withoutdisks. In case a sugarcoating is present,immerse in water for5 min at roomtemperature.

One-hour acid stage withSGF, followed by 1-hSIF stage withoutdisks. In case a sugarcoating is present,immerse in water for5 min at roomtemperature.

Two-hour acid stage (orother time duration ifjustified or authorizedbut not less than 1 h)with 0.1 M HClwithout disks followedby an 1-h stage inphosphate buffer pH6.8 R with disks.

Two-hour stage in firstfluid for disintegrationfollowed by 1-h stagein the second fluid fordisintegration.b

Continued


COMMENTARY 2669

Table 1. Continued

Dosage FormUSP General

Chapter9USP Dietary

Supplements Chaptera9 Ph Eur and BP7,8 JP10

Effervescenttablets

Six tablets, one at a time,are tested in a beakercontaining 200 mL ofwater at 15C25C.When the evolution of gasceases, the tablet hasdisintegrated, beingeither dissolved ordispersed in the water sothat no agglomerates ofparticles remain. A 5-mintime limit is specified.

Soluble tablets Using water at 15C25Cfor 3 min.

Dispersibletablets

Using water at 15C25Cfor 3 min.

Orodispersibletablets

Should disintegrate within3 min. No other featuresspecified.

Hard capsules Same as uncoatedtablets, but witha removable wirecloth attached tothe surface of theupper plate of thebasket.

Similar to the GeneralChapter but using0.05 M acetate bufferat a pH of 4.5 as theimmersion medium,and with a 30-mintime limit.

Using water as the medium.When justified andauthorized, 0.1 M HCl orartificial gastric juice maybe used. If the capsulesfloat on the surface of thewater, a disk may beadded. A 30-min timelimit, unless otherwisejustified and authorized.

Using water or specifiedmedium and a 20-min timelimit unless otherwisespecified. Disks used ifproscribed by the individualmonograph.

Uncoated softshell capsules

Same as hardcapsules

A rupture test isperformed in waterusing USP type IIdissolutionapparatus.

Similar to hard capsules butdisks are to be used evenif the capsules do notfloat. In case the fill liquidattacks the disks, theymay be omitted.

Same as hard capsules

Delayed releasecapsules

Only soft shell capsulesare mentioned.Similar to delayedrelease tablets butwith disks during theSIF stage.

Covers both hard and softcapsules. Same as delayedrelease tablets, with anadditional statementallowing the use ofpancreatin when justifiedor authorized during thebuffer stage.

Same as tablets

Granules anddried syrups

Shake on a 500-:m sieve, andtransfer 100 mg of the residueto each of the auxiliary tubes.Use water as immersionmedium unless otherwisespecified. A 30-min time limitfor plain and a 60-min one forcoated granules unlessotherwise specified.

Delayed releasegranules

Similar to immediate release,but a two-stage approach (1 hin the first fluid fordisintegration and 30 min inthe second fluid fordisintegrationb). In the firststage, not more than 15particles should fall from thegauze.

Continued


2670 COMMENTARY

Table 1. Continued

Dosage Form USP General Chapter9USP Dietary Supplements

Chaptera9 Ph Eur and BP7,8 JP10

Buccal tablets Same as for uncoated tablets butwith a 4-h time limit.

Same as in the General Chapter.

Sublingual tablets Same as for uncoated tablets withthe time limit being specified inthe individual monograph.

Same as in the General Chapter.

Oral lyophilizates Using a beaker containing200 mL of water at15C25C. Six units tested,1 at a time. It shoulddisintegrate within 3 min.

aUnder dietary supplements in USP, disks are generally proscribed for vitamin-mineral dosage forms (unless otherwise proscribed in the individual monograph),whereas in botanical and other dosage forms, disks are generally omitted unless otherwise proscribed in the individual monograph.

bFirst and second fluids for disintegration of JP are the same as the SGF and SIF of the USP, respectively, but without enzymes.

Figure 6. Difference between the disintegration times of placebo soft gelatin capsules coated to different levels with shellac enteric coat whenusing the Ph Eur and the USP disintegration tests.12

pharmacopoeias. The buffer used by the Ph Eur and the BPcontainsmuch higher phosphate concentration than those spec-ified by the USP and the JP leading to faster disintegration inthe Ph Eur/BP buffer by virtue of its higher buffer capacity andionic strength (Fig. 6).12 On the basis of what is known aboutGI fluid composition, the USP and JP media can be consideredless bioirrelevant than the Ph Eur/BP medium.12 In addition,for delayed-release tablets, the USP, contrary to the Ph Eur andthe BP, states that disks should be omitted.79

DISINTEGRATION AS A DISSOLUTION SURROGATE

ICH Q6A Decision Tree 7

It is a well-known fact that complete disintegration does notnecessarily imply complete dissolution, making dissolutiontesting necessary even when disintegration testing is success-ful. However, in some cases, a disintegration test may act as asurrogate for dissolution testing.

According to the ICH Q6A Decision Tree 7 (Fig. 7), a disin-tegration test can be used as a surrogate for a dissolution testif the following conditions are met6:

1. The dosage form does not exhibit modified release char-acteristics.

2. The drug has a dose/solubility ratio not less than 250 mLover a pH range of 1.26.8.

3. More than 80% of the dose is dissolved within 15 min atpH values of 1.2, 4.0, and 6.8.

4. A relation has been determined between dissolution anddisintegration.

This means that disintegration testing may replace dissolu-tion testing as a routine QC test for some formulations of BCSclass I and III drugs, which carries the advantage of makingroutine QC testing easier because of reasons mentioned before.

However, fulfilling the above-listed conditions, the fourth onein particular, may be not an easy task as the dissolution rateof solid oral dosage forms is often not determined by their dis-integration (in particular when the disintegration is rapid) asshown by Radwan et al.13 (Fig. 8). For instance, among 12 tabletformulations of Verapamil hydrochloride prepared by Guptaet al.,14 only one was identified as being suitable for havingthe dissolution test replaced by a disintegration test showcas-ing the need of a thorough investigation to ascertain that theformulation meets the required criteria.

Liquid-Filled Capsules

Liquid-filled capsules may be a dosage form for which adisintegration test provides an appropriate surrogate for a


COMMENTARY 2671

Figure 7. ICH Q6A decision tree 7.6

dissolution test for routine QC, in case the liquid fill is a so-lution from which no precipitation of drug occurs after dis-integration and contact with appropriate release media. Thismay save time and costs associated with the elaborate samplepreparation steps/equipment that are often needed for the dis-solution testing of such products, particularly when the liquidfill is a lipid-based formulationwith self-emulsifying systemsproviding a particular challenge as it is difficult to distinguishthe drug within the emulsion droplets from the released drug.For enteric-coated liquid-filled capsules, however, there is a riskof the active ingredient diffusing undetected across the cap-sule shell and the coat into the immersion medium during theacid stage of a disintegration test, making its use as a dis-solution test surrogate for enteric-coated liquid-filled capsulesquestionable.

An interesting case study for liquid-filled capsules is de-scribed by Han and Gallery,15 where the FDA approved the useof disintegration testing instead of dissolution testing for anencapsulated oily solution product of a poorly soluble drug notexhibiting rapid release on the grounds of complicated analyticsresulting in too much variability leading to a strong potentialfor overdiscrimination. A thoughtful point of argument made inthe new drug application was that if the product was dosed in aspoon instead of a capsule, no dissolution test would have beenrequired.15 This case study shows that some ICH criteria canbe, sometimes, waived to allow the use of disintegration test-ing as a surrogate for dissolution testing, when an appropriatescientific reasoning is presented, and it is another example onthe value of disintegration testing for QC testing of liquid-filledcapsules.


2672 COMMENTARY

Figure 8. Relationship between disintegration time and percent drugdissolved at 30 min for different trospium chloride tablet products.13

Zone A shows that, for rapidly disintegrating products, disintegrationtime has little impact on dissolution rate, whereas in zone B, as disinte-gration becomes slower, dissolution rate is slowed down. In zone C, thedisintegration time is greater than 30 min, so, naturally, no relationcan be determined with the parameter percent dissolved at 30 min.

Challenges of the Pharmacopoeial Disintegration Test

Using disintegration testing as a dissolution testing surrogateoffers clear benefits but also various challenges that need to beaddressed.

A particular aspect of the hydrodynamics in a disintegra-tion tester is problematic, as far as determining a relationshipbetween dissolution and disintegration results is concerned.As the hydrodynamic conditions are milder in a typical pad-dle dissolution apparatus than in a disintegration tester,16 it istheoretically conceivable that situations may arise where thedisintegration may determine the dissolution rate in a paddleapparatus, but it will not exhibit such a relation with the disso-lution results when performed in a disintegration tester owingto its being faster there.

However, many other challenges need to be addressed toofor the proper use of disintegration testing as a dissolution testsurrogate. First of all, the specifications outlined for the dis-integration tester are not sufficiently narrow to prevent vari-ations, which still fall within the specifications, from resultingin significantly different test results. For example, in a studyby Almukainzi et al.,11 the use of two different beaker sizes,which both fall within the USP specifications, resulted in sig-nificantly different disintegration times for some dietary sup-plement products.

Moreover, the biorelevance of the hydrodynamics and themedia used for disintegration testing, in addition to the me-chanical stresses involved, is questionable. This may poten-tially lead to scenarios in which deviations from the expectedin vivo release behavior of the batch may not be detected by invitro testing. This problem is present in dissolution testing tooand so is not disintegration testing-specific, but still needs tobe addressed.

For example, Radwan et al.,17 showed that the fluid velocityaround the tablets in a disintegration tester is much higherthan the estimated fluid velocity in the stomach, and they sug-

gested decreasing the speed of the vertical movement of thebasket-rack assembly as a way to overcome this problem. Onthe other hand, Kamba et al.,18 showed that the mechanicaldestructive force within the disintegration apparatus is prob-ably lower than in the GI tract, which may be of particularconcern for enteric-coated products as, at least in theory, po-tential in vivo disintegration in the stomach may not be neces-sarily detected in vitro, and the typical paddle dissolution testprovides even milder hydrodynamic conditions, making it evenmore unlikely for a dissolution test to detect this phenomenon.This shows the importance of conducting disintegration testingdespite the presence of dissolution testing.

As for how do the results of pharmacopoeial in vitro disin-tegration testing, indeed, correlate with in vivo performancein humans, a study by Bhagavan and Wolkoff,19 for example,provided disintegration time data and pharmacokinetic dataobtained from human volunteers for four different vitamin Ctablet formulations. We did correlate the disintegration timesand the in vivo time to peak plasma vitamin C concentrations(Tmax) (Fig. 9). The disintegration data showed an apprecia-ble degree of correlation with the in vivo Tmax for the first threeproducts (R2 value of 0.9375 when only those three products areincluded); however, they overdiscriminated between the slow-est and the second slowest formulations worsening the overallcorrelation.

The disintegration test, in that study, was performed in dis-tilled water, and the difference between the slowest and the sec-ond slowest formulations was that the slowest formulation con-tained much more stearic acid and magnesium stearate (withthe hardness being similar).19 Therefore, a possible (at leastpartial) explanation could be that purewater overdiscriminatedbetween the two formulations as it could not penetrate through-out the lipophilic structure of the slowest formulations tabletas fast as GI fluids, which contain surface-active substances,could. Moreover, the surface-active materials in human GI flu-ids could help in partially dispersing the stearic acid, which wasnot the case with pure water. And, furthermore, as there is thepossibility that the disintegration of the slowest formulationstablet was completed in the intestine, intestinal fluid, by virtueof its pH, could have partially solubilized the stearic acid, thusaiding disintegration and dissolution. This shows the need forconsidering the use of media of better biorelevance. In addition,in the same study, higher values of vitamin C bioavailabilityextent were achieved with the slower disintegrating tablets,19

which the authors explained by higher saturation degree ofthe transporters involved in vitamin C transport with thefaster-releasing formulations, thus showcasing the need for fur-ther research in order to better tailor the compendial require-ments for the formulations of certain active ingredients to theirproperties.

In another study, both disintegration and dissolution testingfailed to predict the rank order of the speed of absorption ofparacetamol from three different solid oral formulations.20 Andyet in another study, performed by Whiting and Pluhator,21

disintegration testing exhibited a higher degree of correlationthan dissolution testing with urinary calcium excretion rateincrease during the interval of 24 h after administration ofcalcium carbonate tablets. These examples, indicate that,though far from being perfect, the use of disintegration test-ing as dissolution surrogate, could prove useful provided thatfurther work is performed to enhance the biorelevance of bothdissolution and disintegration testing methodologies. This will


COMMENTARY 2673

Figure 9. Relationship between the in vivo Tmax values and the disintegration times of four tablet formulations studied by Bhagavan andWolkoff.19

make it more possible to obtain disintegration test methodsthat correlate well with both dissolution testing and in vivoproduct performance.

In addition to biorelevance issues, another potential chal-lenge is the definition of a protocol that shows a relationshipbetween dissolution and disintegration. For tablets, this canbe performed by compressing the tablet formulation to differ-ent hardness levels using different compression forces (similarto what was performed by Gupta et al.14), and establishing arelationship between disintegration time and a dissolution pa-rameter, such as percent of dose released at suitable time inter-vals or times required to achieve certain percent of dose releasevalues. Further research to characterize the nature of the dis-solution versus disintegration correlation would be helpful inthis regard.

For capsules, the picture is a bit more complicated. If thecapsule was filled with a powder or a liquid, the opening of theshell will be the critical step for disintegration, unless powderclumping occurs. But in case the capsule is filled with a plug,or powder clumping occurs, plug/clump disintegration may bethe critical step for capsule disintegration.

When the shell opening is the critical disintegration step,the disintegration behavior of the product can be varied byshell cross-linking (an example using formaldehyde vapor isdescribed by Han and Gallery15), and in case plug disin-tegration is the critical step, then compressing the plug todifferent hardness levels may be the procedure to be ap-plied. However, first of all, it needs to be ascertained whetherplug or shell disintegration is the critical disintegration step.This can be carried out by performing both the plug hard-ening and the shell hardening procedures and comparingthe resulting effects on disintegration times. If it is diffi-cult to make a judgment, then it will be better to performthe dissolutiondisintegration correlation protocol using bothprocedures.

Combining Disintegration with Pooled Dissolution

A disintegration tester can be potentially used for pooled disso-lution testing provided that the active ingredient has sufficientsolubility to maintain sink conditions. It may be argued, how-ever, that similar advantages may be obtained by performinga pooled dissolution for six tablets in one dissolution vesselinstead of pooling the samples, but, in some cases, a pooleddissolution test result might be combined with a disintegrationtest result to give a surrogate for a normal dissolution test andthus saving some analytics-associated effort. This may work,in particular, for some enteric-coated products.

A combined disintegration-pooled dissolution testing schemefor enteric-coated products may be proposed as follows:

1. At the end of the acid resistance stage, observe for anyvisible signs of leakage, cracking and the like. In casethey are not observed, take a sample of the immersionfluid and then move on to the buffer stage and observethe disintegration.

2. In case the units successfully disintegrate in the bufferwithin the set time limit, and the amount released intothe acid at the end of the acid resistance stage is belowthe set tolerance level, the batch is considered to havepassed the test.

Such an approach may be allowed when:

1. The active ingredient is sufficiently soluble in the bufferso that sink conditions could be maintained.

2. The dissolution in the buffer is known to be fast.3. A relation has been determined between disintegration

and dissolution in the buffer.4. The intra-batch variability has been repeatedly shown to

be low.


2674 COMMENTARY

Table 2. Alternative Disintegration Test Methods for ODTs

Apparatus Methodology

Modified USPdissolutionapparatus 2

Operated at 100 rev/min, 900 mL dissolutionmedium. Time required by the ODT to passthrough sinker screen is determined.

Wire cloth method Water dropped at a rate of 4 mL/min over theODT placed in wire cloth no. 10. Timetaken for the ODT to pass through the wirecloth considered as disintegration time

Charged coupledevice camera(CCD) method

Disintegration of ODT placed on a grid placedover a stirring element contained in adissolution medium. Disintegration timemonitored by a CCD camera

Shaking waterbath method

ODT placed in glass cylinder with a 10 mesh.The unit is immersed in a shaking waterbath at 150 rev/min. Time for the ODT topass through the 10-mesh screenconsidered as disintegration time

Rotary shaftmethod

Mouth dissolving tablet placed on a wiregauze immersed in the medium iscompressed by a rotary shaft. Rotationspeed and mechanical stress control thedisintegration time

Texture analyzer Constant penetration force using flat-endedprobe is applied to the mouth dissolvingtablet concomitantly while immersing inthe aqueous medium. Time for the probe topenetrate into the ODT is measured

ElectroForce 3100 Application of very low force (10 mN) to theODT placed on holder followed by anaddition of 5 mL of aqueous medium. Smalldisplacements of the piston anddisintegration rate are measured

Such a testing scheme can be particularly useful for liquid-filled enteric-coated capsules, especially if the filling liquid is asolution that does not exhibit precipitation upon contact withrelease media. This would allow us to save the costs and timesassociated with analyzing dissolution samples of the buffer intowhich the liquid fill has been released.

In case concerns about intra-batch variability and/or main-taining sink conditions in the acid stage arise, this stage couldbe performed in a dissolution apparatus, with the buffer stagebeing performed in a disintegration device.

ALTERNATIVE APPARATUSES

The design of the disintegration testing apparatus has basicallyremained unaltered for several decades. Twenty-five years ago,Catellani et al.22 published an interesting article about a dis-integration device that could measure both the disintegratingforce developing within the tablet as well as the water uptakekinetics, helping to provide insights into disintegrantwater in-teractions and to compare the action and efficiency of differentdisintegrants. This apparatus was further adapted to also mea-sure the mass of the disintegrated tablets debris alongside thedisintegrating force versus time profile.23 This test was foundpromising for optimizing tablet disintegrant levels,23 and it ex-hibited the ability to discriminate between the effects of tabletstructure changes that could not be discriminated by conven-tional pharmacopoeial disintegration and dissolution tests.24

However, as it is carried out in a staticmode, such a test, thoughbeing potentially highly useful in the context of understandingthe work and effects of different formulation and/or processingvariables and designing the formulation and/or the manufac-turing process accordingly, may not reflect the situation in thehuman stomach and/or intestine where the tablet is far frombeing static, thus potentially limiting its effectiveness as an invivo performance predictor. But, in this regard, it could fit intothe framework of testing the disintegration of orally disinte-grating tablets (ODTs), where static disintegration testing hasfound its place among the disintegration testing methods pro-posed as alternatives to the pharmacopoeial test. Actually, thebulk of the proposed alternative disintegration testing designsare centered on disintegration testing of ODTs as the large fluidvolumes and the agitation intensity used do not reflect the con-ditions the tablet is subjected to in the oral cavity.25 Kraemeret al., in their review on dissolution testing for ODTs, havelisted a few examples on alternative apparatuses for disinte-gration testing of these dosage forms (Table 2).25

For soft shell capsules, the Dietary Supplements chapter ofthe USP specifies a rupture test using a type II dissolutionapparatus instead of a typical disintegration test (USP). Al-mukainzi et al.26 compared this rupture test with a disintegra-tion test and found no advantage for a rupture test comparedwith a disintegration test.

CONCLUSION

Despite its limitations, owing to its simplicity, disintegrationtesting remains an important QC tool in the pharmaceuticalindustry. And, with proper research performed, its use can beexpanded allowing it to serve as a release test surrogate insome instances, thus saving the QC departments of the phar-maceutical industry significant costs. But, in order to enhancethis aspect, clear guidance should be established and additionalresearch should be performed to make the test more biopredic-tive. In addition, more harmonization among pharmacopoeiasis still desirable with regard to disintegration testing.

ACKNOWLEDGMENTS

We would like to thank Dr. Simone Wengner for thehelpful discussion. The German Academic Exchange Ser-vice (DAAD) is acknowledged for providing a stipend toJ.A-G. This work was contributed to the OrBiTo project(http://www.imi.europa.eu/content/) as sideground.

REFERENCES

1. Pharmacopoeia Helvetica. 1907. Bern, Switzerland: The Swiss Phar-macopoeia Commission.2. Pharmacopoeia Helvetica. 1933. Bern, Switzerland: The Swiss Phar-macopoeia Commission.3. British Pharmacopoeia (BP). 1948. London, United Kingdom: TheGeneral Council of Medical education and Registration of the UnitedKingdom.4. Gershberg S, Stoll FD. 1948. Apparatus for tablet disintegration,and for shaking-out extractions. J Am Pharm Assoc Am Pharm Assoc35:284287.5. United States Pharmacopoeia (USP). 1950. Rockville, Maryland: TheUnited States Pharmacopoeial Convention.


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6. International Conference on Harmonization. 1999. ICH Q6A guide-line: Specifications: Test procedures and acceptance criteria for newdrug substances and new drug products: Chemical substances.7. European Pharmacopoeia (Ph Eur). 2014. Strasbourg, France: Euro-pean Directorate for the Quality of Medicines, Council of Europe.8. British Pharmacopoeia (BP). 2014. London, United Kingdom: TheStationery Office on behalf of the Medicines and Healthcare productsRegulatory Agency (MHRA).9. United States Pharmacopoeia (USP). 2014. Rockville, Maryland: TheUnited States Pharmacopoeial Convention.10. Japanese Pharmacopoeia (JP). 2011. Tokyo, Japan: Ministry ofHealth, Labour and Welfare.11. Almukainzi M, Salehi M, Chacra NAB, Loebenberg R. 2010. In-vestigation of the performance of the disintegration test for dietarysupplements. AAPS J 12:602607.12. Al-Gousous J, Langguth P. 2013. European versus United Statespharmacopoeia-specified disintegration testing for enteric-coated softgelatin capsules. Poster presented at the German Pharmaceutical So-ciety Annual Meeting, October 2013, Freiburg, Germany.13. Radwan A, Wagner M, Amidon GL, Langguth P. 2013. Bio-predictive tablet disintegration: Effect of water diffusivity, fluid flow,food composition and test conditions. Eur J Pharm Sci 16:273279.14. Gupta A, Hunt RL, Shah RB, Sayeed VA, Khan MA. 2009. Disin-tegration of highly soluble immediate release tablets: A surrogate fordissolution. AAPS Pharm Sci Tech 10:495499.15. Han JH, Gallery J. 2006. A risk-based approach to in vitro per-formance testing: A case study on the use of dissolution vs. disin-tegration for liquid-filled gelatin capsules. Am Pharm Rev 9:152157.16. Morihara M, Aoyagi N, Kaniwa N, Katori N, Kojim S. 2002. Hydro-dynamic flows around tablets in different pharmacopoeial dissolutiontests. Drug Dev Ind Pharm 28:655662.

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