Preparation, physical characterization, mechanisms of drug/polymer interactions, and stability studies of controlled-release solid dispersion granules containing weak base as active substance

Verapamil hydrochloride solid dispersion granules were prepared using solvent evaporation technique. Ethyl cellulose, hydroxypropyl cellulose, Eudragit L or Eudragit S were used as polymers for controlling the dissolution rate of the drug substance, and to avoid the continuous decrease of drug dissolution rate at higher pH values. By incorporating Eudragit L in ethyl cellulose network it is possible to prepare controlled-release formulation with increased release rate of active substance (weak base) at higher pH values without causing abrupt drug release at lower pH values. The release rate at low pH values was not highly influenced by Eudragit L content. The behavior of Eudragit L and Eudragit S in coprecipitates was different relating to the solubilization effect and the release of active substance. In order to understand the drug release mechanism better, the release data were tested assuming Higuchi model and first-order kinetic model. Since the calculated correlation coefficients were very close for both kinetics, to distinguish between the mechanisms the differential forms of first-order and square root of time equation were used. The differential test showed that diffusion-controlled release was operative in solid dispersions, except for series with higher content of Eudragit S. X-ray powder diffraction method, IR spectroscopy studies, and differential thermal analysis were used for physical characterization of coprecipitates and drug-polymer interaction evaluation. After 24 months of real time stability studies, the prepared coprecipitates were still x-ray amorphous, with no changes in their IR spectra and DTA studies. The dissolution rates of the tested formulations showed no significant changes during the stability studies, reflecting the stability of x-ray amorphous drug phase.