Dissolution testing sink conditions

Dissolution test data will be required in all cases (and for all strengths of product) for development and routine control and should be based on the most suitable discriminatory conditions. The method should discriminate between acceptable and unacceptable batches based on in vivo performance. Wherever possible Ph Eur test methods should be used (or alternatives justified). Test media and other conditions (e.g., flow through rate or rate of rotation) should be stated and justified. Aqueous media should be used where possible and sink conditions should be maintained. A small amount of surfactant may be added where necessary to control surface tension or for active ingredients of very low solubility. Buffer solutions should be used to span the physiologically relevant range—the current advice is over pH 1 6.8 or perhaps up to pH 8 if necessary. Ionic strength of media should be reported. The test procedure should employ six dosage forms (individually) with the mean data and a measure of variability reported. 

The second situation when IVIVC is not likely for class II drugs is where the absorption is limited by the saturation solubility in the gastrointestinal tract rather than the dissolution rate, as discussed in more detail above. In this situation, the drug concentration in the gastrointestinal tract will be close to the saturation solubility, and changes of the dissolution rate will not affect the plasma concentrationtime profile and in vivo bioavailability. Standard in vitro dissolution tests are carried out under sink conditions , i.e., at concentrations well below the saturation solubility. Thus, only effects related to dissolution rate can be predicted in vitro. If more physiologically relevant dissolution media are used, which do not necessarily provide sink conditions , the possibility for IVIVC could be improved, as has been indicated by the results of recent studies using simulated intestinal medium [76],... 

The choice of dissolution medium will depend on the purpose of the dissolution test. For batch-to-batch quality control testing, selection of the dissolution medium is based, in part, on the solubility data and the dose range of a drug product to ensure that sink conditions are met. However, under certain circumstances, a medium that fails to provide sink conditions may be justiLable [8], If the... 

As discussed in detail above, the intestinal absorption of Class II drug substances may be limited by dissolution rate or solubility rate. In the latter case, when the absorption is limited by the drug equilibrium solubility, an IVIVC is not likely to be obtained. The GI tract drug concentrations in this case will be close to the saturation concentration, and since standard dissolution tests are carried out under sink conditions, they can predict only processes occurring well below the saturation concentration [85], Hence, at this point, Class II solubility rate limited drugs are probably poor candidates for BA/BE waiver. 

Figure 7.3 In vitro dissolution-time profiles of a poorly soluble compound, felodipine, for three different hydrophilic matrix extended release tablets CA-C) when three different surfactants CSLS, CTAB, Tween) were used in the dissolution test medium at levels providing sink conditions .

Generally, the objective is to select a medium in which sink conditions are maintained so that the drug already in solution does not exert a modifying effect on the dissolution of the remaining drug. For low solubility drugs it may not be possible to achieve sink conditions, and so it may be preferable to test formulations of these drugs under nonsink conditions that accurately reflect the in vivo situation. 

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