Solid Dispersions of Benidipine Hydrochloride. I. Preparations Using Different Solvent Systems and Dissolution Properties

The solid dispersion technique has been widely utilized to improve the dissolution profile and oral bioavailability of water insoluble drugs. Benidipine hydrochloride, a calcium-antagonist, is a slightly soluble compound in a weak acid, so that its bioavailability is liable to be influenced by the gastric acidity of patients. In the preparation of solid dispersions by the solvent removal process, organic solvents are used as agents to intimately mix a drug or drugs and carrier molecules. Benidipine hydrochloride is also poorly soluble in commonly used organic solvents. The application of the solvent removal prosess for preparing solid dispersions of the drug makes it necessary to enhance the organic solubility of the drug. Two kinds of solvent systems have been investigated : one in an organic solution of Eudragit[○!R] E-100 (OSE) and the other in binary solvent mixtures (BSM). In the OSE, the presence of Eudragit[○!R] E-100 in dichloromethane resulted in an appreciable increase in drug solubility. However, in ethanol, this solubilization effect of the polymer was completely inhibited. In the BSM, enhanced solubility of the drug was obtained in ethanol-dichloromethane mixtures. Further, the addition of polyvinylpyrrolidone (PVP) or hydroxypropylmethyl-cellulose (HPMC) to this system did not deposit the dissolved drug. In these two solvent systems, solubilization of benidipine hydrochloride was presumed to be caused by intermolecular interactions. It enabled the preparation of solid dispersions of benidipine hydrochloride with Eudragit[○!R] E-100, PVP or HPMC. Especially, when dispersed in PVP or HPMC, the dissolution rate of the drug improved remarkably in a weak acid (pH 6.0).