Dissolution testing intrinsic

One approach to the study of solubility is to evaluate the time dependence of the solubilization process, such as is conducted in the dissolution testing of dosage forms [70], In this work, the amount of drug substance that becomes dissolved per unit time under standard conditions is followed. Within the accepted model for pharmaceutical dissolution, the rate-limiting step is the transport of solute away from the interfacial layer at the dissolving solid into the bulk solution. To measure the intrinsic dissolution rate of a drug, the compound is normally compressed into a special die to a condition of zero porosity. The system is immersed into the solvent reservoir, and the concentration monitored as a function of time. Use of this procedure yields a dissolution rate parameter that is intrinsic to the compound under study and that is considered an important parameter in the preformulation process. A critical evaluation of the intrinsic dissolution methodology and interpretation is available [71]. 

Figure 12.1 Six configurations of simple dissolution test apparatus (a) the Wruble method in which the dose form is rotated in a container of solvent (b) a simple beaker method (c) an apparatus in which the dosage form is in a cradle which oscillates vertically (d) the rotating disc method to determine the intrinsic dissolution characteristics of a compressed powder (e) method in which the dosage form is placed in a medium which is shaken and (f) a method in which the decreasing size of suspensions is measured on dissolution.

Studies involving instrumented compaction equipment can be extremely useful in the development of dosage forms, especially when the amount of drug substance is limited in quantity. Marshall has described a program in which dynamic studies of powder compaction can be used at all stages of the development process to acquire formulation information [63]. The initial experiments include a determination of the intrinsic compactability of the compound. In subsequent work, simple tablets are prepared, and tested for dissolution, potency, and content uniformity. Through studies of the compaction mechanism, it becomes possible to deduce means to improve the formulation under study. 

Usually salt formation is carried out to increase the solubility of the base, however, salts with lower solubilities are sometimes prepared to, e.g., mask taste, provide slower dissolution and increase chemical stability. An example of salt formation to decrease dissolution rate is described by Benjamin and Lin (1985), who prepared a range of salts of an experimental antihypertensive as shown in Table 3.10. The solubilities and intrinsic dissolution rates (IDR) of the prepared salts of this compound are also shown in Table 3.10. These in vitro tests showed that there were significant differences in the dissolution rate when the experiments were performed in water and buffer. However, the difference in the IDRs of the salts was similar in 0.1 M HC1. Hence, it was recommended that ebonate, 3-hydroxynaphthoate or napsylate salts should be formulated as enteric-coated dosage forms. This would avoid dissolution in the stomach acid, which could cause local GI irritation, and would still provide release of the compound. 

The main merits of the rotating disc apparatus are the well-defined hydrodynamic conditions and constant surface area. These reduce the risk of artefacts in dissolution rate determinations caused by non-ideal test conditions. Furthermore, it is possible to determine an intrinsic dissolution rate and to perform other mechanistic evaluations of the dissolution process. The main limitation of the method is that it is not suitable for drugs that form fragile or porous discs, since it is not possible to maintain a constant surface area. 

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