A

Speed (rpm) as specified in monograph 25-150 rpm (± 4% USP/NF; ± 5% BP)

Shaft

USP/NF: 6-10.5 mm diameter BP: approximately 6 mm diameter 2 mm vent in drive disc

Eccentricity

USP/NF: no significant wobble BP: no perceptible wobble

Sampling point

USP/NF: midway from top of basket to top of fluid and no closer than 1 cm to side of flask BP: halfway between basket and side at middle of basket

Flask

USP/NF: cylindrical with spherical bottom, 16-17.5 cm high, inside diameter 10-10.5 cm, plastic or glass BP: cylindrical, flat bottomed, glass

Basket

Basket position

Figure 12.2 The rotating basket and rotating paddle versions of the official method for dissolution testing of solid oral dosage forms. (a) The rotating basket - method 1, USP/NF. This method is official for USP/NF and BP. Current specifications describing geometry and positions for each compendium are shown. (b) The rotating paddle - method 2, USP/NF.

Reproduced from reference 1 with permission.

Figure 12.2 The rotating basket and rotating paddle versions of the official method for dissolution testing of solid oral dosage forms. (a) The rotating basket - method 1, USP/NF. This method is official for USP/NF and BP. Current specifications describing geometry and positions for each compendium are shown. (b) The rotating paddle - method 2, USP/NF.

Reproduced from reference 1 with permission.

agitation in vivo. In natural-convection methods in which, for example, a pellet of material is suspended from a balance arm in the dissolution medium, the conditions are unnatural. In forced-convection methods a degree of agitation is introduced. These can, in turn, be divided into those that employ nonsink conditions and those that achieve sink conditions in the dissolution medium. Figure 12.1 illustrates methods involving forced convection and nonsink conditions, that is where there is no mechanism for replenishing the solvent, so that for most drugs the concentration in solution will increase rapidly to approach Q,. Most methods rely on the assay of the dissolution medium for drug content, although particle sizing techniques (such as the Coulter Counter method) can directly measure the change in particle size as dissolution (and disintegration of granules) occurs.

12.1.1 Pharmacopoeial and compendial dissolution tests

The dissolution method now widely used and adopted by the British Pharmacopoeia is a variant of the rotating basket method (Fig. 12.2a). Tablets or capsules are placed in a basket of wire mesh, the mesh being small enough to retain broken pieces of tablet but large enough to allow entry of solvent without wetting problems. The basket may be rotated at any suitable speed but most USP monographs specify 50, 100 or 1500 rpm. In all the methods the appropriate pH for the dissolution medium must be chosen, and a reasonable degree of agitation in those techniques which allow it. The considerable effect of rotation speed on the dissolution profile of a sulfamethizole formulation is shown in Fig. 12.3, an effect which would be predicted from our understanding of particle dissolution. 2

With drugs of very low solubility it is sometimes necessary to consider the use of in vitro tests which allow sink conditions to be maintained. This generally involves the use of a lipid phase into which the drug can partition; alternatively, it may involve dialysis or physical replacement of the solvent phase. Mixed-solvent systems such as ethanol-water or surfactant systems may be used to enhance the solubility of sparingly soluble drugs, but some prefer the use of flow-through systems in these cases.

12.1.2 Flow-through systems

A variant on the dissolution methods discussed uses neither basket nor paddle. Convection is achieved by solvent flow through a chamber such as that drawn in Fig. 12.4. Dissolution data obtained from such a system where continuous monitoring of drug concentration is achieved must be interpreted with care as the concentration-time profile will be dependent on the volume of solvent, its flow rate and the distance of the detection device from the flow cell, or rather the void volume of solvent.

This emphasises that there is no absolute method of dissolution testing. With whatever form of test is adopted, results are really only useful on a comparative basis - batch vs batch, brand vs brand, or formulation vs formulation.

Time (min)

Figure 12.3 Single-tablet dissolution profiles for sulfa-methizole formulation in dilute HCl with USP XVIII method at three stirring rates.

Reproduced from reference 2.

Time (min)

Figure 12.3 Single-tablet dissolution profiles for sulfa-methizole formulation in dilute HCl with USP XVIII method at three stirring rates.

Reproduced from reference 2.

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