Dissolution of an HIV Protease Inhibitor : Dissociation Versus Diffusion as the Rate-Limiting Step
Alexander, Marjorie Guenevear
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U-96988, a non-peptidic protease inhibitor, is poorly absorbed from suspension or solid oral dosage forms. This indicates that absorption from a suspension will be limited by particle dissolution. The goal of this work was as follows: 1) To determine if dissociation or diffusion limited the rate of U-96988 particle dissolution. 2) To determine if particle size influenced dissolution rate. 3) To elucidate a dissolution mechanism from the observed dependency on driving force. During dissolution a molecule is transported from the solid phase to the solution phase. This process is the result of a sequence of steps. At the dissolving crystal surface, solid-solid interactions between molecules are replaced by solid-solvent interactions. This step is called dissociation. Diffusion from the crystal surface across a concentration gradient to the bulk solution then completes the process. Either of these steps may be rate limiting. The dissolution of U-96988 particles was measured by monitoring their change in diameter with time. Concurrently, the bulk solution concentration of U-96988 was also measured. No change in the dissolution rate was observed when agitation rate was increased. This implies that diffusion across the boundary layer surrounding the particles was not rate limiting and that a surface dissociation mechanism controls the rate of dissolution. The Kelvin Equation implies that smaller particles may dissociate more rapidly than larger ones due to bond strain at extreme angles. Dissolution rates were calculated for small, medium and large U-96988 particles. These dissolution rates showed no significant variance, establishing that dissolution is not size dependent. By plotting the measured dissolution rate versus a representation of driving force, an indication of the surface dissociation mechanism can be obtained. An experimental plot of several dissolution experiments performed at various U-96988 concentrations exhibited a curved shape, which indicated a slow surface dissociation mechanism was limiting U-96988 dissolution.