An investigation on the correlation between drug dissolution properties and the growth behaviour of granules in high shear mixer

Abstract

The aim of this study was to investigate the correlation between the growth behaviour and in-vitro dissolution rate of water-insoluble drugs prepared with high-shear wet granulation. Granules containing nimodipine, microcrystalline cellulose, low-substituted hydroxypropylcellulose and aqueous solution of hydroxypropylcellulose were prepared and the effects of independent process variables, including impeller speed and liquid-to-solid ratio were taken into consideration. The mean granule size, granule-size distribution (GSD), porosity and surface properties were monitored at different kneading times to identify the granule-growth mechanisms simultaneously. A computer-based method was applied to simulate the dissolution behaviour of polydisperse granules based on the GSD data. The in-vitro dissolution rate of drug was high for the early stages of granulation and sharply decreased when coalescence and consolidation of granules started, approaching a flat and low level when granules were sufficiently consolidated. The simulated dissolution results were in agreement with experimental observations and were significantly affected by the GSD, porosity and surface properties of granules during the granulation process. Moreover the GSD was directly related to the granule-growth behaviour and mechanisms. In general, it was concluded that the dissolution properties of nimodipine basically correlated with the growth behaviour of granules in a high-shear mixer. The simulation method based on GSD can be used as a convenient and rapid way to predict the dissolution properties for formulation development and granulation optimization.