Chemical and physical stability of hydroxypropylmethylcellulose matrices containing diltiazem hydrochloride after gamma irradiation.

In recent years, the exposure to gamma-radiation is an increasingly used method to sterilize or to reduce bacterial charge in drug-delivery devices. The aim of this study was to investigate whether the ionizing radiation may be responsible for drug inactivation or for the alteration of the functional excipient used to modulate drug release from a controlled-release delivery system. In this work, we investigated the physical and dissolution stability of prolonged release matrix tablets containing diltiazem hydrochloride, as a model drug, and hydroxypropylmethylcellulose (HPMC) of two different viscosity grades, as the retarding polymer, before and after exposure to increasing doses of gamma-rays. The results show that gamma-irradiation induces chemical modifications in the structure of the active agent, and also of the hydrophilic polymer. The electronic paramagnetic resonance analysis of gamma-irradiated diltiazem has afforded evidence of carbon radicals stemming from C-H bond ruptures and sulphur radicals, the latter being formed mainly after admission of air at room temperature. The major radical products in the HPMC polymer radiolysis have been reckoned with chain scission events in agreement with the results of viscosity measurements that show a progressive decrease of the average molecular weight with increasing the radiation dose. The elaboration of the viscosity data has led to linear relationships between the eta(o)/eta ratio and the radiation dose D which were rationalized with the following equation under the assumption of a Mark-Houwink Sakurada coefficient a approximately equal 1: eta(o)/eta = (1 + uy(o) D)(a). In this equation, D is gamma-radiation dose, eta(o) and eta are the reduced viscosities before and after the irradiation respectively, u is the number average degree of polymerization, and y(o) is the chain scission radiolytic yield. From the linear relationships G(chain scissions) = 1.2 x 10(-6) and 1.4 x 10(-6) moles/J have been obtained for the two HPMC polymer samples M100 and M4 of different molecular weight used in the experiments. These changes could be responsible for the alteration of the drug-release mechanism and reduced polymer efficacy in controlling drug release. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association