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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 pharmaceutical industry, 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 imply complete dissolution, much more research has been focused on dissolution rather than on disintegration testing. Nevertheless, owing to its simplicity, disintegration testing seems to be an attractive replacement to dissolution testing as recognized by the International Conference on Harmonization guidelines, in some cases. Therefore, with proper research being carried out to overcome the associated challenges, the full potential of disintegration testing could be tapped saving considerable efforts allocated to QC testing and quality assurance. C 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2664–2675, 2015 Keywords: bioavailability; biopharmaceutics classification system (BCS); dissolution; excipients; formulation; gastrointestinal; in vitro models; intestinal absorption

INTRODUCTION

It is a well-known fact that an immediate-release dosage form should disintegrate in order to efficiently liberate its active ingredient(s) and make it available for absorption. Therefore, disintegration testing methods were developed. The first mention of a test for disintegration was in the 1907 Edition of Pharmacopoeia Helvetica, in the compressed pastilles 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 same pharmacopoeia. 2 It stated that a tablet should be placed in a 100-mL Erlenmeyer flask containing 50 mL of water, at a tem- perature of 37 C, and the flask was to be gently swirled from time to time. 2 It was stated that the tablet had to disintegrate into 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 disintegration behavior in test tubes. 3 However, by that time, a specific disin- tegration testing apparatus had been used for 8 years by the laboratories of US Army Medical Department (Fig. 1), 4 and this apparatus formed the basis for the basket-rack assembly apparatus, 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 for orally 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 complete dissolution of the active ingredient. This has contributed to the 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: langguth@uni-mainz.de) Journal of Pharmaceutical Sciences, Vol. 104, 2664–2675 (2015)

C

2014 Wiley Periodicals, Inc. and the American Pharmacists Association

greater amount of publications dealing with dissolution testing methodologies compared with those dealing with disintegration testing methodologies (as shown in Fig. 2). Nevertheless, the greater simplicity of disintegration com- pared with dissolution testing (e.g., no analytics needed, lesser volume of fluids required, less time-consuming) makes the idea of putting more focus on disintegration attractive. This has been recognized by the International Conference on Harmo- nization (ICH) that allowed the use of disintegration testing as a surrogate for dissolution testing if certain conditions are met. 6 Therefore, focusing more interest and research on disin- tegration testing could, because of the test’s simplicity, enable the 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 and possible means of enhancing its potential as a QC method in the pharmaceutical industry are introduced. Particular focus will be given to its potential use as a surrogate for dissolution testing.

DISINTEGRATION APPARATUS

A disintegration apparatus is composed of a 1-L low-form cylin- drical beaker, a heating system that keeps the temperature at 37 ± 2 C, a basket-rack assembly, and a device to move the basket-rack assembly vertically. 710 Two types of basket-rack assembly 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 Japanese Pharmacopoeia (JP), whereas apparatus B is described only in the Ph Eur, BP, and the Dietary Supplements chapter of the USP, where it is required for testing tablets and capsules more than 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 tubes maintained in a vertical position by two plates containing the corresponding number of openings arranged in a circle

  • 2664 Al-Gousous and Langguth, JOURNAL OF PHARMACEUTICAL SCIENCES 104:2664–2675, 2015

COMMENTARY

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COMMENTARY 2665 Figure 1. Disintegration apparatus from the 1940’s before becoming official in the USP. 4
Figure 1. Disintegration apparatus from the 1940’s before becoming official in the USP. 4 Figure 2.
Figure 1.
Disintegration apparatus from the 1940’s 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.

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2666 COMMENTARY Figure 3. Disintegration apparatus A with dimensions in millimeter. equidistantly from the center of

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

equidistantly from the center of the plate as well as from each other. 710 The two plates are fastened to each other by three bolts passing through them. 710 A stainless steel wire cloth with square apertures (size 2.0 ± 0.2 mm) is attached to the bot- tom plate. 710 The thickness of the wire is specified to be 0.57– 0.66 mm for apparatus A, whereas for apparatus B, it is set at 0.60–0.66 mm by Ph Eur and BP and 1/4 inch by the Dietary Supplements chapter of the USP. 710 Apparatus A contains six tubes, while apparatus B contains three larger tubes. 710 The exact design of the device can be varied as long as the specifi- cations for the tubes and the wire cloth are adhered to. 710 The JP also provides specifications for a perforated metal plate that can be used to secure the tubes and the plates. 10 Both types are supplied with transparent plastic cylindrical disks specified to have a relative density of 1.18–1.20, but those of apparatus A are smaller and, unlike those of apparatus B, have trapezoidal-shaped planes cut into the lateral surface of the cylinder. 710 Unique to the JP is an accessory called the “auxiliary tube” (Fig. 5) made up of an open-ended plastic tube and two plastic rings, each containing an acid-resistant wire gauze, to be attached to the tube’s ends. 10 A handle made of acid-resistant wire is fitted to the tube. This auxiliary tube is used 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 vertical movement is specified to occur at a rate of 29–32 cycles per

minute through a 53–57 mm distance in a smooth manner with the speed being the same for both the upward and the downward strokes. 710 The volume of the immersion fluid in the vessel is specified to be 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.” 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, capsule shells are a soft mass with no firm palpable core. In addition, disks that can provide automatic detection for disintegration time, and are recognized by the pharmacopoeias, 710 are com- mercially available, and can be used when the use of disks is proscribed. These disks give a signal that disintegration is complete when they come into contact with the stainless steel mesh and can be particularly useful when doing the test in turbid media. A striking aspect is lack of harmonization for certain fea- tures like the use of apparatus B. This apparatus is specified in the Ph Eur, BP, and the Dietary Supplements chapter of the USP, but not by the General Tests chapter of the USP and the JP. This may lead to same dosage forms (tablets and cap- sules longer than 18 mm) being tested differently in different

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COMMENTARY 2667 Figure 4. Disintegration apparatus B with dimensions in millimeter. Figure 5. Auxiliary tube for

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

COMMENTARY 2667 Figure 4. Disintegration apparatus B with dimensions in millimeter. Figure 5. Auxiliary tube for

Figure 5. Auxiliary tube for the disintegration testing of granules according 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 required by the Ph Eur, BP, USP, and JP. The BP has its general dis- integration tests harmonized with Ph Eur so the BP and Ph Eur occupy the same column of the table. Otherwise, harmo- nization among pharmacopoeias concerning the disintegration tests 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 on disintegration testing and in the dietary supplements chapter, and these two sets of tests are not identical, as is seen in the table.

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Generally, the usage of disks is more common in the Ph Eur and the BP. These two pharmacopoeias also often state that if the test fails because of sticking to disks, it should be repeated omitting them. 7,8 Generally, for tests performed with the basket-rack assembly, if one or two units fail to disinte- grate (according the Ph Eur, BP, and JP) or to disintegrate completely (USP), the test should be repeated with 12 more units, 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 when 1 or 2 units fail the acid-resistance stage of the disintegration test for enteric-coated tablets and capsules. 10 Another excep- tional feature is that, for the type B apparatus, the Ph Eur and BP state that only a total of 6 units are to be tested without

Table 1. Compendial Disintegration Tests for Different Dosage Forms

stating the allowance of testing 12 more units in case 1 or 2 of the first 6 units fail to disintegrate. 7,8 Concerning hard capsules, the USP specifies water as the immersion medium in its general chapter on disintegration, but pH 4.5 acetate buffer for dietary supplements. 9 And these two media may sometimes lead to different disintegration performance for the same product, as shown by Almukainzi et al. 11 Another USP-specific feature is the use of a remov- able wire cloth attached to the upper surface of the basket-rack assembly. 9 This is a relic of the older USP editions that did not forbid the basket-rack assembly becoming submerged, and can be considered redundant now. The testing methods for enteric-coated dosage forms show some striking differences between the different

Dosage Form

USP General Chapter 9

USP Dietary Supplements Chapter a 9

Ph Eur and BP 7,8

JP 10

Uncoated tablets

Using water or specified medium. Disks used if proscribed by the individual monograph.

Using water or specified medium with a 30-min time limit. Disks used if proscribed by the individual monograph.

Using water as the medium. Fifteen minute time limit. Disks are used.

Using water or specified medium and a 30-min time limit unless otherwise specified. Disks used if

Plain-coated

Same as uncoated.

Same as uncoated, but

For tablets other than

proscribed by the individual monograph. Using water or specified

tablets

sugar-coated tablets

film-coated tablets, use

medium and a 30-min

Pills

should be immersed in water for 5 min at room temperature before the start of the test.

water with disks for 60 min unless otherwise justified or authorized. If any of the tablets fails to disintegrate, repeat with six more tablets using 0.1 M HCl. For film-coated tablets, use the same procedure but for 30 min unless otherwise justified or authorized.

time limit unless otherwise specified. Disks are used if proscribed by the individual monograph.

Delayed release

Using water or specified medium and a 60-min time limit. Disks are used if proscribed by the individual monograph. If they contain a crude drug, use the first fluid for disintegration. b If any residue remains, a successive 60-min test with the second fluid b for disintegration is carried out. Two-hour stage in first

tablets

One-hour acid stage with SGF, followed by 1-h SIF stage without disks. In case a sugar coating is present, immerse in water for 5 min at room temperature.

One-hour acid stage with SGF, followed by 1-h SIF stage without disks. In case a sugar coating is present, immerse in water for 5 min at room temperature.

Two-hour acid stage (or other time duration if justified or authorized but not less than 1 h) with 0.1 M HCl without disks followed by an 1-h stage in phosphate buffer pH 6.8 R with disks.

fluid for disintegration followed by 1-h stage in the second fluid for disintegration. b

 

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Table 1. Continued

 

USP General

USP Dietary

Dosage Form

Chapter 9

Supplements Chapter a 9

Ph Eur and BP 7,8

JP 10

Effervescent

Six tablets, one at a time,

tablets

are tested in a beaker

Soluble tablets

containing 200 mL of water at 15 C–25 C. When the evolution of gas ceases, the tablet has disintegrated, being either dissolved or dispersed in the water so that no agglomerates of particles remain. A 5-min time limit is specified. Using water at 15 C–25 C

Dispersible

for 3 min. Using water at 15 C–25 C

tablets

for 3 min.

Orodispersible

Should disintegrate within

tablets

3 min. No other features specified.

Hard capsules

Same as uncoated tablets, but with a removable wire cloth attached to the surface of the upper plate of the basket.

Similar to the General Chapter but using 0.05 M acetate buffer at a pH of 4.5 as the immersion medium, and with a 30-min time limit.

Using water as the medium. When justified and authorized, 0.1 M HCl or artificial gastric juice may be used. If the capsules float on the surface of the water, a disk may be

Using water or specified medium and a 20-min time limit unless otherwise specified. Disks used if proscribed by the individual monograph.

Uncoated soft

added. A 30-min time limit, unless otherwise justified and authorized. Similar to hard capsules but

Same as hard capsules

shell capsules

Same as hard capsules

A rupture test is performed in water using USP type II dissolution apparatus.

disks are to be used even if the capsules do not float. In case the fill liquid attacks the disks, they may be omitted.

Delayed release

Only soft shell capsules

Covers both hard and soft

Same as tablets

capsules

are mentioned.

capsules. Same as delayed

Granules and

Similar to delayed release tablets but with disks during the SIF stage.

release tablets, with an additional statement allowing the use of pancreatin when justified or authorized during the buffer stage.

dried syrups

Shake on a 500-: m sieve, and transfer 100 mg of the residue

Delayed release

to each of the auxiliary tubes. Use water as immersion medium unless otherwise specified. A 30-min time limit for plain and a 60-min one for coated granules unless otherwise specified. Similar to immediate release,

granules

but a two-stage approach (1 h in the first fluid for disintegration and 30 min in the second fluid for disintegration b ). In the first stage, not more than 15 particles should fall from the gauze.

Continued

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Table 1. Continued

Dosage Form

USP General Chapter 9

USP Dietary Supplements Chapter a 9

Ph Eur and BP 7,8

JP 10

Buccal tablets

Same as for uncoated tablets but with a 4-h time limit.

Same as in the General Chapter.

Sublingual tablets

Same as for uncoated tablets with

Same as in the General Chapter.

Oral lyophilizates

the time limit being specified in the individual monograph.

Using a beaker containing 200 mL of water at 15 C–25 C. Six units tested, 1 at a time. It should disintegrate within 3 min.

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

2670 COMMENTARY Table 1. Continued Dosage Form USP General Chapter USP Dietary Supplements Chapter Ph Eur

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

pharmacopoeias. The buffer used by the Ph Eur and the BP contains much higher phosphate concentration than those spec- ified by the USP and the JP leading to faster disintegration in the Ph Eur/BP buffer by virtue of its higher buffer capacity and ionic strength (Fig. 6). 12 On the basis of what is known about GI fluid composition, the USP and JP media can be considered less bioirrelevant than the Ph Eur/BP medium. 12 In addition, for delayed-release tablets, the USP, contrary to the Ph Eur and the 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 not necessarily imply complete dissolution, making dissolution testing necessary even when disintegration testing is success- ful. However, in some cases, a disintegration test may act as a surrogate 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 test if the following conditions are met 6 :

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

  • 2. The drug has a dose/solubility ratio not less than 250 mL over a pH range of 1.2–6.8.

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

  • 4. A relation has been determined between dissolution and disintegration.

This means that disintegration testing may replace dissolu- tion testing as a routine QC test for some formulations of BCS class I and III drugs, which carries the advantage of making routine QC testing easier because of reasons mentioned before. However, fulfilling the above-listed conditions, the fourth one in particular, may be not an easy task as the dissolution rate of solid oral dosage forms is often not determined by their dis- integration (in particular when the disintegration is rapid) as shown by Radwan et al. 13 (Fig. 8). For instance, among 12 tablet formulations of Verapamil hydrochloride prepared by Gupta et al., 14 only one was identified as being suitable for having the dissolution test replaced by a disintegration test showcas- ing the need of a thorough investigation to ascertain that the formulation meets the required criteria.

Liquid-Filled Capsules

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

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COMMENTARY 2671 Figure 7. ICH Q6A decision tree 7. dissolution test for routine QC, in case

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. This may save time and costs associated with the elaborate sample preparation steps/equipment that are often needed for the dis- solution testing of such products, particularly when the liquid fill is a lipid-based formulation—with self-emulsifying systems providing a particular challenge as it is difficult to distinguish the drug within the emulsion droplets from the released drug. For enteric-coated liquid-filled capsules, however, there is a risk of the active ingredient diffusing undetected across the cap- sule shell and the coat into the immersion medium during the acid stage of a disintegration test, making its use as a dis- solution test surrogate for enteric-coated liquid-filled capsules questionable.

An interesting case study for liquid-filled capsules is de- scribed by Han and Gallery, 15 where the FDA approved the use of disintegration testing instead of dissolution testing for an encapsulated oily solution product of a poorly soluble drug not exhibiting rapid release on the grounds of complicated analytics resulting in too much variability leading to a strong potential for overdiscrimination. A thoughtful point of argument made in the new drug application was that if the product was dosed in a spoon instead of a capsule, no dissolution test would have been required. 15 This case study shows that some ICH criteria can be, sometimes, waived to allow the use of disintegration test- ing as a surrogate for dissolution testing, when an appropriate scientific reasoning is presented, and it is another example on the value of disintegration testing for QC testing of liquid-filled capsules.

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Figure 8. Relationship between disintegration time and percent drug dissolved at 30 min for different trospium chloride tablet products. 13 Zone A shows that, for rapidly disintegrating products, disintegration time has little impact on dissolution rate, whereas in zone B, as disinte- gration becomes slower, dissolution rate is slowed down. In zone C, the disintegration time is greater than 30 min, so, naturally, no relation can be determined with the parameter percent dissolved at 30 min.

Challenges of the Pharmacopoeial Disintegration Test

Using disintegration testing as a dissolution testing surrogate offers clear benefits but also various challenges that need to be addressed. A particular aspect of the hydrodynamics in a disintegra- tion tester is problematic, as far as determining a relationship between 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 is theoretically conceivable that situations may arise where the disintegration may determine the dissolution rate in a paddle apparatus, but it will not exhibit such a relation with the disso- lution results when performed in a disintegration tester owing to its being faster there. However, many other challenges need to be addressed too for the proper use of disintegration testing as a dissolution test surrogate. 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 resulting in significantly different test results. For example, in a study by 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 the media 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 expected in vivo release behavior of the batch may not be detected by in vitro testing. This problem is present in dissolution testing too and so is not disintegration testing-specific, but still needs to be addressed. For example, Radwan et al., 17 showed that the fluid velocity around the tablets in a disintegration tester is much higher than the estimated fluid velocity in the stomach, and they sug-

gested decreasing the speed of the vertical movement of the basket-rack assembly as a way to overcome this problem. On the other hand, Kamba et al., 18 showed that the mechanical destructive force within the disintegration apparatus is prob- ably lower than in the GI tract, which may be of particular concern 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 test provides even milder hydrodynamic conditions, making it even more unlikely for a dissolution test to detect this phenomenon. This shows the importance of conducting disintegration testing despite the presence of dissolution testing. As for how do the results of pharmacopoeial in vitro disin- tegration testing, indeed, correlate with in vivo performance in humans, a study by Bhagavan and Wolkoff, 19 for example, provided disintegration time data and pharmacokinetic data obtained from human volunteers for four different vitamin C tablet formulations. We did correlate the disintegration times and the in vivo time to peak plasma vitamin C concentrations (T max ) (Fig. 9). The disintegration data showed an apprecia- ble degree of correlation with the in vivo T max for the first three products (R 2 value of 0.9375 when only those three products are included); however, they overdiscriminated between the slow- est and the second slowest formulations worsening the overall correlation. 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 (with the hardness being similar). 19 Therefore, a possible (at least partial) explanation could be that pure water overdiscriminated between the two formulations as it could not penetrate through- out the lipophilic structure of the slowest formulation’s tablet as 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 was not the case with pure water. And, furthermore, as there is the possibility that the disintegration of the slowest formulation’s tablet was completed in the intestine, intestinal fluid, by virtue of its pH, could have partially solubilized the stearic acid, thus aiding disintegration and dissolution. This shows the need for considering the use of media of better biorelevance. In addition, in the same study, higher values of vitamin C bioavailability extent were achieved with the slower disintegrating tablets, 19 which the authors explained by higher saturation degree of the transporters involved in vitamin C transport with the faster-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 their properties. In another study, both disintegration and dissolution testing failed to predict the rank order of the speed of absorption of paracetamol from three different solid oral formulations. 20 And yet in another study, performed by Whiting and Pluhator, 21 disintegration testing exhibited a higher degree of correlation than dissolution testing with urinary calcium excretion rate increase during the interval of 2–4 h after administration of calcium carbonate tablets. These examples, indicate that, though far from being perfect, the use of disintegration test- ing as dissolution surrogate, could prove useful provided that further work is performed to enhance the biorelevance of both dissolution and disintegration testing methodologies. This will

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COMMENTARY 2673 Figure 9. Relationship between the in vivo T values and the disintegration times of

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

make it more possible to obtain disintegration test methods that correlate well with both dissolution testing and in vivo product performance. In addition to biorelevance issues, another potential chal- lenge is the definition of a protocol that shows a relationship between dissolution and disintegration. For tablets, this can be performed by compressing the tablet formulation to differ- ent hardness levels using different compression forces (similar to what was performed by Gupta et al. 14 ), and establishing a relationship 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 release values. Further research to characterize the nature of the dis- solution versus disintegration correlation would be helpful in this regard. For capsules, the picture is a bit more complicated. If the capsule was filled with a powder or a liquid, the opening of the shell will be the critical step for disintegration, unless powder clumping occurs. But in case the capsule is filled with a plug, or powder clumping occurs, plug/clump disintegration may be the critical step for capsule disintegration. When the shell opening is the critical disintegration step, the disintegration behavior of the product can be varied by shell cross-linking (an example using formaldehyde vapor is described by Han and Gallery 15 ), and in case plug disin- tegration is the critical step, then compressing the plug to different hardness levels may be the procedure to be ap- plied. However, first of all, it needs to be ascertained whether plug 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 comparing the resulting effects on disintegration times. If it is diffi- cult to make a judgment, then it will be better to perform the dissolution–disintegration correlation protocol using both procedures.

Combining Disintegration with Pooled Dissolution

A disintegration tester can be potentially used for pooled disso- lution testing provided that the active ingredient has sufficient solubility to maintain sink conditions. It may be argued, how- ever, that similar advantages may be obtained by performing a pooled dissolution for six tablets in one dissolution vessel instead of pooling the samples, but, in some cases, a pooled dissolution test result might be combined with a disintegration test result to give a surrogate for a normal dissolution test and thus saving some analytics-associated effort. This may work, in particular, for some enteric-coated products. A combined disintegration-pooled dissolution testing scheme for enteric-coated products may be proposed as follows:

  • 1. At the end of the acid resistance stage, observe for any visible signs of leakage, cracking and the like. In case they are not observed, take a sample of the immersion fluid and then move on to the buffer stage and observe the disintegration.

  • 2. In case the units successfully disintegrate in the buffer within the set time limit, and the amount released into the acid at the end of the acid resistance stage is below the set tolerance level, the batch is considered to have passed the test.

Such an approach may be allowed when:

  • 1. The active ingredient is sufficiently soluble in the buffer so 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.

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Table 2. Alternative Disintegration Test Methods for ODTs

Apparatus

Methodology

Modified USP dissolution apparatus 2 Wire cloth method

Operated at 100 rev/min, 900 mL dissolution medium. Time required by the ODT to pass through sinker screen is determined. Water dropped at a rate of 4 mL/min over the

Charged couple

ODT placed in wire cloth no. 10. Time taken for the ODT to pass through the wire cloth considered as disintegration time Disintegration of ODT placed on a grid placed

device camera

over a stirring element contained in a

(CCD) method

dissolution medium. Disintegration time

Shaking water

monitored by a CCD camera ODT placed in glass cylinder with a 10 mesh.

bath method

The unit is immersed in a shaking water

Rotary shaft

bath at 150 rev/min. Time for the ODT to pass through the 10-mesh screen considered as disintegration time Mouth dissolving tablet placed on a wire

method

gauze immersed in the medium is

Texture analyzer

compressed by a rotary shaft. Rotation speed and mechanical stress control the disintegration time Constant penetration force using flat-ended

ElectroForce 3100

probe is applied to the mouth dissolving tablet concomitantly while immersing in the aqueous medium. Time for the probe to penetrate into the ODT is measured Application of very low force (10 mN) to the ODT placed on holder followed by an addition of 5 mL of aqueous medium. Small displacements of the piston and disintegration rate are measured

Such a testing scheme can be particularly useful for liquid- filled enteric-coated capsules, especially if the filling liquid is a solution that does not exhibit precipitation upon contact with release media. This would allow us to save the costs and times associated with analyzing dissolution samples of the buffer into which 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 could be performed in a dissolution apparatus, with the buffer stage being performed in a disintegration device.

ALTERNATIVE APPARATUSES

The design of the disintegration testing apparatus has basically remained 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 disintegrating force developing within the tablet as well as the water uptake kinetics, helping to provide insights into disintegrant–water in- teractions and to compare the action and efficiency of different disintegrants. This apparatus was further adapted to also mea- sure the mass of the disintegrated tablet’s debris alongside the disintegrating force versus time profile. 23 This test was found promising for optimizing tablet disintegrant levels, 23 and it ex- hibited the ability to discriminate between the effects of tablet structure changes that could not be discriminated by conven- tional pharmacopoeial disintegration and dissolution tests. 24

However, as it is carried out in a static mode, such a test, though being potentially highly useful in the context of understanding the work and effects of different formulation and/or processing variables and designing the formulation and/or the manufac- turing process accordingly, may not reflect the situation in the human stomach and/or intestine where the tablet is far from being static, thus potentially limiting its effectiveness as an in vivo performance predictor. But, in this regard, it could fit into the framework of testing the disintegration of orally disinte- grating tablets (ODTs), where static disintegration testing has found its place among the disintegration testing methods pro- posed as alternatives to the pharmacopoeial test. Actually, the bulk of the proposed alternative disintegration testing designs are centered on disintegration testing of ODTs as the large fluid volumes and the agitation intensity used do not reflect the con- ditions the tablet is subjected to in the oral cavity. 25 Kraemer et al., in their review on dissolution testing for ODTs, have listed 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 of the USP specifies a rupture test using a type II dissolution apparatus 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 compared with a disintegration test.

CONCLUSION

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

ACKNOWLEDGMENTS

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

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