Search:sink conditions

E. Dissolution testing of solid oral dosage forms

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
Three types of apparatus are now described in the British and European Pharmacopoeias; the
basket, the paddle 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 5).
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 1993 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. The latter change was made by means of an amendment
to Appendix XII D included in the Addendum 1995 to the British Pharmacopoeia 1993. Following
consultation of manufacturers, the published tests, wherever appropriate, were also amended by
means of this Addendum 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 HCl 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.

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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 Compliance with the standard BP requirement provides an assurance that most of the active
ingredient will be dissolved in a reasonable time when the preparation is subjected to mild agitation
in an aqueous environment. While such an assurance does not, of course, guarantee bioavailability,
it significantly reduces the likelihood of unsatisfactory bioavailability due to inadequate dissolution.
2.7 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 'tailor-made'
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.
2.8 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 assurance 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.
3.3 Compliance with a pharmacopoeial dissolution test does not by itself guarantee bioavailability
and is not necessarily an adequate basis for judging bioequivalence between preparations.
However, such a pharmacopoeial test contributes to an overall assurance of the consistency of the
quality of a preparation with respect to its drug release properties.
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.

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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 or soluble tablets) or (iii) in other justified
circumstances.
4.3 The same guideline is being applied to a review of those capsule and tablet monographs that
were published in the British Pharmacopoeia 1993. Each case is being judged on its merits and
departures from the norm accepted where appropriate. Addition of tests to the relevant monographs
is being carried out under the Commission's revision programme in accordance with defined
priorities and available resources.
4.4 Tests were added to a considerable number of monographs by means of the Addendum 1997 to
the British Pharmacopoeia 1993 and more have been added in subsequent editions. It is
emphasised that, 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.
4.5 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 5).
5. Low-solubility preparations
5.1 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.
5.2 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 in the Addendum 1992 to the British Pharmacopoeia 1988 for Cortisone
Tablets (30% propanol), 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, that in
the USP was usually cited.
5.3 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 two types of modifier, 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.
5.4 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 it was proposed that this method should now 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. In view of the lack of wide experience of the use of this method in the United Kingdom, it was
recognised that collaborative practical work would be necessary to standardise the technique and
explore its potential for pharmacopoeial applications. A working party was established under the

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explore its potential for pharmacopoeial applications. A working party was established under the
auspices of BP Committee P: Pharmacy to carry out this work with participation from industry,
control laboratories and licensing assessors. The study would focus on preparations of two or three
poorly soluble active substances. In addition to investigating the use of the flow-through apparatus,
the study would look at the use of sodium dodecyl sulphate in conjunction with the paddle
apparatus. Based on the preliminary findings from the first phase of the trial, this latter approach has
been adopted for Cortisone Tablets and it has been suggested that it might usefully be explored for
other formulations. Further work will be carried out when resources permit.
6. Modified-release preparations
6.1 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.
6.2 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 reluctantly, following detailed discussion and practical investigation, that it is not possible
to provide satisfactory pharmacopoeial control of the dissolution profile of the majority of
modified-release preparations. Data obtained in a study of theophylline formulations, for example,
indicated that it was not possible even to devise simplified dissolution criteria for such preparations
to ensure that dose-dumping did not occur and that an acceptable amount of the active ingredient
was eventually released. Between-product differences are such as to preclude the setting of
meaningful pharmacopoeial limits even for these more limited objectives.

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