Temperature dependence of bimolecular reactions associated with molecular mobility in lyophilized formulations

Purpose. We studied the temperature dependence of acetyl transfer between a spirin and sulfadiazine, a bimolecular reaction, in lyophilized formulation s at temperatures near the glass transition temperature (T-g) and NMR relax ation-based critical mobility temperature (T-mc), to further understand the effect of molecular mobility on chemical degradation rates in solid pharma ceutical formulations. The temperature dependence of the hydrolysis rates o f 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 conta ining dextran and various amounts of water at temperatures ranging from 1 d egrees C to 80 degrees C was analyzed by HPLC. The degradation of cephaloth in in lyophilized formulations containing dextran and methylcellulose was a lso analyzed at temperatures ranging from 10 degrees C to 70 degrees C. Results. Acetyl transfer in lyophilized asprin-sulfadiazine formulations co ntaining dextran exhibited a temperature dependence with a distinct break a round T-mc, which may be ascribed to a change in the translational mobility of aspirin and sulfadiazine molecules. The hydrolysis of aspirin and cepha lothin in lyophilized formulations, which is also a bimolecular reaction, d id not show a distinct break, suggesting that water diffusion is not rate-l imiting. Conclusions. The diffusion barrier of water molecules in lyophilized formul ations appears to be smaller than the activational barrier of the hydrolysi s of aspirin and cephalothin based on the results of this study that the te mperature dependence of the hydrolysis rate is almost linear regardless of T-mc and T-g. On the other hand, the diffusion barrier of aspirin and sulfa diazine molecules appears to be comparable to the activational barrier of t he acetyl transfer reaction between these compounds, resulting in nonlinear temperature dependence.