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Effect of Carrier Excipient and Processing on Stability of Indorenate Hydrochloride/Excipient Mixtures

The purpose of this investigation was to determine the solid-state chemical stability of a model drug, indorenate hydrochloride, as a function of carrier excipient and mixing process. Physical mixtures and granules were prepared by tumble mixing and alcoholic granulation with and without binder. Stability of the mixtures was estimated using differential scanning calorimetry and isothermal degradation studies at 40, 50, and 60°C. Average first-order degradation constants at 25°C, extrapolated from isothermal studies, were much lower for indorenate hydrochloride after tumbling mixing with microcrystalline cellulose (3.45 × 10− 5 day− 1) than those obtained after tumbling mixing with lactose (112.0 × 10− 5 day− 1). Distribution of the drug on the excipient's surface, through granulation with and without Povidone, increased the average drug degradation rates in granules with microcrystalline cellulose (36.2 × 10− 5 day− 1) as well as in granules with lactose (326 × 10− 5 day− 1). Partially amorphous lactose (spray-dried lactose) showed higher average degradation rates (310.5 × 10− 5 day− 1) than crystalline lactose (199.3 × 10− 5 day− 1). It appears that the amorphous portion of the drug as well as that of reacting excipients play a major role in affecting the reaction rate. The calorimetric studies showed a strong solid–solid interaction between indorenate hydrochloride and lactose, suggesting chemical incompatibility. This strong solid–solid interaction was characterized by disappearance of typical transition peaks of lactose at temperatures above 200°C and the development of new peaks at about 130–170°C. No major changes in transition peaks were observed in mixtures of microcrystalline cellulose and indorenate hydrochloride, suggesting chemical compatibility. Calorimetric results allow the prediction of the chemical incompatibility between indorenate hydrochloride and lactose observed in isothermal degradation studies.