This section provides information on the pharmacopoeial dissolution test and guidance on its function and application in individual

monographs of the British Pharmacopoeia for tablets and capsules.

1. Apparatus

Four types of apparatus are now described in the British and European Pharmacopoeias; the basket, the paddle, the reciprocating cylinder and the flow-through cell. The descriptions are concordant with those published in the United States Pharmacopeia (USP). Of the two established apparatus (basket and paddle) the paddle is now the apparatus of choice for many preparations. However, where a published test uses the basket, work to validate a change to the paddle method is not contemplated. The flow-through cell may be more appropriate for preparations of poorly soluble active ingredients (see section 6).
2. Test conditions and acceptance criteria

2.1 Test conditions Pharmacopoeial tests using either the basket or the paddle are based on the principle of operating under 'sink conditions', that is, in a manner such that material already in solution does not exert a modifying effect on the rate of dissolution of the remainder. 'Sink conditions' normally occur in a volume of dissolution medium that is at least 5 to 10 times the saturation volume. The standardised conditions have been chosen to provide a gentle hydrodynamic regimen. 'Physiological' media are preferred to water/organic solvent mixtures or solutions incorporating surfactants. 2.2 In the interests of international harmonisation the British Pharmacopoeia Commission reviewed the testing conditions specified in the British Pharmacopoeia and adopted a dissolution medium volume of 900 ml instead of 1000 ml as the norm and now requires the analyst to test 6 individual tablets or capsules instead of 5. Following consultation of manufacturers, the published tests, wherever appropriate, were also amended to conform to the revised standardised conditions. However, changes to the volume of the dissolution medium were not made in cases such as Digoxin Tablets, where there was an indication of correlation between the results of in-vivo bioavailability and the established pharmacopoeial test and in other justified cases. 2.3 The revised standardised BP conditions for published tests using either the basket or the paddle are: rotation speed:100 rpm (basket), 50 rpm (paddle) dissolution medium volume: 900 ml dissolution medium composition: aqueous, commonly 0.1M hydrochloric acid or phosphate buffers of pH 6.8 to 7.6 number of units tested: 6 (plus 6, if retest). The number of units tested is specified in Appendix XII D; other conditions are specified in the relevant individual monographs. 2.4 Acceptance criteria The standardised BP criteria for published tests using either the basket or the paddle are that, for each unit tested, not less than 70% of the active ingredient or ingredients dissolves within 45 minutes. If one unit fails to meet this requirement, a retest may be carried out using the same number of units; all units in the retest must comply. These criteria are specified in Appendix XII D and apply unless otherwise stated in the individual monograph. It is intended to maintain these standardised criteria as the norm in published monographs. 2.5 It should be noted that the 70% dissolution requirement must be met by each of the tablets or capsules tested (or by all but one of the total number of units if a retest is performed) and that the

percentage is in terms of the stated amount (that is, the labelled claim). Taking account of permissible assay ranges and content uniformity, this pharmacopoeial (that is, shelf-life) dissolution requirement is considered to offer an acceptable degree of assurance of 'total dissolution'. The choice of a time is, of necessity, somewhat arbitrary but 45 minutes is considered satisfactory for the majority of conventional-release (non-modified-release) products. 2.6 Standardised conditions and limits are considered appropriate for a pharmacopoeial test that is intended for application to monographs covering products from different manufacturers. It might be argued that non-standardised conditions and limits would be more discriminatory but 'tailormade' test conditions and limits may introduce product bias and may discriminate unnecessarily between products that are equally acceptable from a clinical view-point. Similarly with sufficient manipulation of the test conditions dissolution of almost any product can be achieved. Ideally the test should reflect clinically significant differences in bioavailability arising from differences in dissolution in such a way that clinically acceptable formulations will pass whereas clinically unacceptable formulations will fail. 2.7 Another issue that has been considered in relation to test conditions and criteria is that of multiple-point dissolution profiles as opposed to single-point dissolution tests. It has been concluded that for conventional-release preparations such an extension of testing is not generally necessary or appropriate for pharmacopoeial purposes.

3. Function

3.1 The BP policy of selective application of dissolution testing is based on an assumption that such testing is relevant to the clinical situation and that, in general, a conventional-release preparation of already proven bioavailability, which consistently complies with the requirement, is unlikely to give rise to major problems of bioavailability. While the ultimate objective of dissolution testing might be described as ensuring adequate and reproducible bioavailability without recourse to routine in-vivo testing, this ideal goal is considered unrealistic in relation to the majority of pharmacopoeial applications. It may be achieved sometimes by a manufacturer's in-house dissolution testing of a particular product for which in vitro/in vivo correlation has been demonstrated. 3.2 The published standards of the British Pharmacopoeia are applied to products that have received a product licence in accordance with the relevant regulations. Such products will have met any necessary requirements for bioavailability and bioequivalence and dissolution testing will have been carried out as part of the development studies. Once a product is licensed, a dissolution test may be required routinely as part of quality control to demonstrate consistency of process before the release of each batch of the finished product or, when necessary, to provide evidence to support changes in manufacture such as minor changes in formulation or process, changes in site or changes in immediate packaging materials.
4. Application

4.1 In reviewing the future application of dissolution testing in the British Pharmacopoeia, the British Pharmacopoeia Commission decided that dissolution testing would be applied to a wider range of capsules and tablets than before. It did not, however, adopt a policy of universal application and a dissolution requirement will not be included automatically in every capsule and tablet monograph. 4.2 As a general guideline, it is expected that all new monographs for conventional-release capsules and tablets will contain a dissolution requirement except (i) where the solubility of the active ingredient is 10% or better in water or in dilute hydrochloric acid, at approximately 20; (ii) where the nature or intended use of the preparation renders a dissolution test inappropriate (for example, liquid-containing capsules, dispersible, effervescent, chewable or soluble tablets) or (iii) in other justified and authorised circumstances.

4.3 Tests have been added to a considerable number of monographs using this guideline. While the objective is to include a 'standard' pharmacopoeial test wherever appropriate, the circumstances for each preparation are considered individually in consultation with the manufacturers. It should be appreciated, however, that the retrospective addition of dissolution tests is not without its difficulties. The problems are most acute for those well-established preparations that are manufactured by a wide range of companies, each with its own dissolution specification. A pragmatic approach is being taken to developing compromise test procedures in these circumstances. It has sometimes been possible to harmonise with the test conditions specified in the corresponding monograph in the USP. Development of a test for preparations containing active substances of low aqueous solubility, for which application of the paddle method using standard aqueous media may not be technically feasible, has been deferred pending the outcome of further collaborative work (see section 6).

5. Bioavailability and Bioequivalence

Compliance with the standard British Pharmacopoeia requirement for dissolution provides an assurance that most of the active ingredient will be dissolved in a reasonable amount of time when the preparation is subjected to mild agitation. Compliance with the pharmacopoeial dissolution test does not by itself guarantee bioavailability and is not necessarily an adequate basis for judging bioequivalence between preparations. For example, tablets using micronised active ingredients may have different release characteristics and therefore bioavailability, compared to nonmicronised materials.
6. Low-solubility preparations

6.1 Certain BP monographs for tablets or capsules containing active substances of low solubility in aqueous media were originally identified as requiring a dissolution specification. Progress in developing suitable specifications for these preparations has been difficult. 6.2 One way of resolving the problem is use of media modified by the addition of an organic solvent, such as ethanol, or a surfactant. This approach has been adopted by the USP and as an interim measure in certain BP monographs. Dissolution tests based on those in the USP using modified media were published for Griseofulvin Tablets (1.5% sodium dodecyl sulphate) and Spironolactone Tablets (0.1% sodium dodecyl sulphate), following laboratory work to demonstrate applicability to products on the UK market and in the knowledge that, in the absence of a published BP test, the requirement in the USP was usually cited. 6.3 While such an approach may be validated by in vivo correlation on a product-specific basis, doubt has continued to be expressed as to its validity for pharmacopoeial purposes. Departure from the gentle hydrodynamic regimen represented by the aqueous media normally used in BP tests calls into question the relevance of the specification especially as an indicator of bioavailability and in relation to product comparisons. With respect to the modifiers, some have argued that the use of surfactants is more likely to give problems of product bias while others have suggested that water/organic solvent mixtures can adversely affect the initial disintegration of the tablet. A consensus has emerged, however, that in circumstances where use of a modified medium is unavoidable, a low concentration of sodium dodecyl sulphate is the modifier of choice. 6.4 Another approach to dealing with low-solubility preparations is to use a flow-through cell apparatus. This is described in the European Pharmacopoeia (Ph Eur, 2.9.3; BP, Appendix XII D) and this method has yet to be investigated as a possible method of choice for low-solubility preparations since it would overcome the objections to the use of 'non-physiological' media.
7. Modified-release preparations

7.1 Any consideration of the quality of modified-release preparations in relation to their safety and efficacy must include attention to the release characteristics of these products. A manufacturer must be able to provide the licensing authority with an assurance that the dissolution profile reflects in vivo performance, which in turn is compatible with the recommended dosage schedule for the specific product. 7.2 The general monographs for Capsules and Tablets include a Production requirement that a suitable test is carried out to demonstrate the appropriate release of the active ingredient or ingredients. With respect to providing tests in individual monographs, however, it has been concluded, following detailed discussion, that it is not possible to provide satisfactory pharmacopoeial control of the dissolution profile of the majority of modified-release preparations.