S Yoshioka1, Y Aso, S Kojima. 1. National Institute of Health Sciences, Tokyo, Japan. yoshioka@nihs.go.jp
Abstract
PURPOSE: We studied the temperature dependence of acetyl transfer between aspirin and sulfadiazine, a bimolecular reaction, in lyophilized formulations at temperatures near the glass transition temperature (Tg) and NMR relaxation-based critical mobility temperature (Tmc), to further understand the effect of molecular mobility on chemical degradation rates in solid pharmaceutical formulations. The temperature dependence of the hydrolysis rates of aspirin and cephalothin in lyophilized formulations was also studied as a model of bimolecular reactions in which water is a reactant. METHODS: Degradation of lyophilized aspirin-sulfadiazine formulations containing dextran and various amounts of water at temperatures ranging from 1 degrees C to 80 degrees C was analyzed by HPLC. The degradation of cephalothin in lyophilized formulations containing dextran and methylcellulose was also analyzed at temperatures ranging from 10 degrees C to 70 degrees C. RESULTS: Acetyl transfer in lyophilized aspirin--sulfadiazine formulations containing dextran exhibited a temperature dependence with a distinct break around Tmc, which may be ascribed to a change in the translational mobility of aspirin and sulfadiazine molecules. The hydrolysis of aspirin and cephalothin in lyophilized formulations, which is also a bimolecular reaction, did not show a distinct break, suggesting that water diffusion is not rate-limiting. CONCLUSIONS: The diffusion barrier of water molecules in lyophilized formulations appears to be smaller than the activational barrier of the hydrolysis of aspirin and cephalothin based on the results of this study that the temperature dependence of the hydrolysis rate is almost linear regardless of Tmc and Tg. On the other hand, the diffusion barrier of aspirin and sulfadiazine molecules appears to be comparable to the activational barrier of the acetyl transfer reaction between these compounds, resulting in nonlinear temperature dependence.
PURPOSE: We studied the temperature dependence of acetyl transfer between aspirin and sulfadiazine, a bimolecular reaction, in lyophilized formulations at temperatures near the glass transition temperature (Tg) and NMR relaxation-based critical mobility temperature (Tmc), to further understand the effect of molecular mobility on chemical degradation rates in solid pharmaceutical formulations. The temperature dependence of the hydrolysis rates of aspirin and cephalothin in lyophilized formulations was also studied as a model of bimolecular reactions in which water is a reactant. METHODS: Degradation of lyophilized aspirin-sulfadiazine formulations containing dextran and various amounts of water at temperatures ranging from 1 degrees C to 80 degrees C was analyzed by HPLC. The degradation of cephalothin in lyophilized formulations containing dextran and methylcellulose was also analyzed at temperatures ranging from 10 degrees C to 70 degrees C. RESULTS: Acetyl transfer in lyophilized aspirin--sulfadiazine formulations containing dextran exhibited a temperature dependence with a distinct break around Tmc, which may be ascribed to a change in the translational mobility of aspirin and sulfadiazine molecules. The hydrolysis of aspirin and cephalothin in lyophilized formulations, which is also a bimolecular reaction, did not show a distinct break, suggesting that water diffusion is not rate-limiting. CONCLUSIONS: The diffusion barrier of water molecules in lyophilized formulations appears to be smaller than the activational barrier of the hydrolysis of aspirin and cephalothin based on the results of this study that the temperature dependence of the hydrolysis rate is almost linear regardless of Tmc and Tg. On the other hand, the diffusion barrier of aspirin and sulfadiazine molecules appears to be comparable to the activational barrier of the acetyl transfer reaction between these compounds, resulting in nonlinear temperature dependence.