AGGREGATION DURING THE DISSOLUTION OF DIAZEPAM IN INTERACTIVE MIXTURES

ABSTRACT

The dissolution of micronized diazepam (1.0-10.0%) in interactive mixtures with lactose-povidone, Emdex®, TabBase® and Compactrol® as carriers was investigated using the USP paddle method and distilled water as the dissolution medium. Dissolution rate of the binary diazepam-carrier mixtures increased using more soluble carriers such as lactose-povidone and decreased as the diazepam concentration of the mixtures increased. The data were interpreted by considering dissolution from both dispersed and aggregated particles and modelled using monoexponential and biexponential equations allowing the estimation of reciprocal dissolution rate constants for dispersed and aggregated particles (k_d and k_a and initial aggregate concentrations (C_a). The estimated k_d parameters were independent of carrier and diazepam concentration while the ka. parameters varied and were dependent on the aggregate size distribution in the interactive mixtures studied. The degree of aggregation increased markedly with increasing diazepam concentration and was greatest for the less soluble carrier, Compactrol®. Ternary surfactant interactive mixtures containing diazepam and sodium lauryl sulphate (100:2) adhered to the carrier surface were developed and demonstrated improved dissolution rates which were attributed to the deaggregation effect of the surfactant in the aggregate microenvironment. The effect was most noticeable at 10 percent drug loadings where the surfactant concentration was greatest and where both the k_a and C_a parameters were minimized.