Impact of optimum annealing on chemical stabilization of model amorphous pharmaceuticals

Date of Completion

January 2007


Chemistry, Pharmaceutical




Amorphous pharmaceuticals are becoming increasingly important because different drying procedures such as freeze-drying and spray-drying used for biotechnology based products like proteins produce amorphous solids, or glasses. In amorphous solids, the translational and rotational motions occur much more slowly than in the solution state, but the mobility is sufficient to allow degradation on the time scale of normal pharmaceutical storage. The physical and chemical properties of formulations in the solid state depend on the dynamics in the amorphous state. Different types of motions, i.e., global α motions, secondary β motions, and fast dynamics are suspected to play a key role in determining the overall stability of glasses and their relative contributions are affected by formulation and processing conditions. For any type of degradation reaction, physical (e.g., crystallization) or chemical (e.g., cyclization) molecular motion is necessary, and there is sufficient mobility in the glass below room temperature to allow these reactions, which makes stabilization a challenging subject for pharmaceutical scientists. The nature and consequences of molecular motions in amorphous pharmaceuticals is reviewed. Glassy systems experience an increase in relaxation time, i.e., decrease in overall molecular mobility, upon aging at temperatures below the glass transition temperature (Tg). By experimental studies (Differential Scanning Calorimetery-DSC) and theoretical analysis (Tool-Narayanaswamy-Moynihan phenomenology-TNM), the optimum annealing conditions to obtain maximum structural relaxation in lyophilized glasses, composed of a saccharide excipient and a small concentration of aspartame as a model "drug" were determined. The optimum aging temperature was found to be about 15-20° below Tg which resulted in maximum structural relaxation. The fast dynamics measured using NMR T1 and T spin-lattice relaxation times indicated that a maximal relaxed state can be obtained by annealing at the optimum temperature, where a minimum in global mobility estimated by τβ measured using Isothermal Microcalorimetry (IMC) and DSC and modeled using TNM occurs. Chemical stability results showed that thermal conditioning of samples under protocols that were predicted and shown to produce optimum annealing for "mobility" were close to those conditions that produce optimum chemical stability as measured by degradation rate. The comparison between chemical stability in sucrose and trehalose formulation suggest that mobility measured by structural relaxation is not a perfect surrogate for the mobility critical to chemical decomposition. That is, it is possible that the "fast motions" rather than the α-relaxations are critical to stability under some circumstances. ^