Solid state stability of amorphous pharmaceuticals: Effects of process variations

Multiple ways are employed in the pharmaceutical industry to prepare active pharmaceutical ingredients (API) such as proteins, vaccines and antibiotics in the glassy state. Of these methods, solvent removal is the most widely applied technique e.g. lyophilization, spray drying, spray freeze drying, vacuum drying, film drying, drying from a foam, etc. The stability of API in different glasses after their preparation is of prime importance to the pharmaceutical industry. In our studies, we will investigate the influence of different processing conditions and drying methods on the storage stability of API in amorphous matrices. We will mainly address two important points: the impact of heating glasses on storage stability and on some of physicochemical properties, and the impact of drying method on the storage stability and physicochemical properties of amorphous formulations containing proteins and vaccines as active ingredients. ^ First, we will address structural relaxation and its relationship to the solid state stability of amorphous pharmaceuticals. Because thermal history of an amorphous material affects its properties, one can theoretically alter the stability profile of a pharmaceutical glass even by a modification in processing conditions during drying e.g. performing secondary drying at a higher temperature during freeze drying cycle (i.e. annealing). There is growing evidence for a correlation between chemical degradation rate in amorphous pharmaceuticals and the glassy state dynamics of the glass formed by the excipient and the active ingredient. This has been attributed to the fact that degradation must require some degree of molecular motion for molecules to move into and through the transition state. Movement of neighboring molecules in the glassy state to generate the volume required for motion may be very slow, and therefore rate-limiting. The circumstances under which the mobility required for the degradation process is similar to the mobility required for structural relaxation are unknown, and therefore how well coupled the degradation dynamics and glassy state structural dynamics are is not well understood. It is also known that a glassy system experiences an increase in global relaxation time during aging, but the stability consequences of such an increase are unknown. ^ Second, we address the impact of drying method on the solid state properties of amorphous pharmaceuticals (e.g. specific surface area, particle morphology, particle size, thermal properties, and storage stability). One important effect we investigate in our studies is composition heterogeneity. (Abstract shortened by UMI.)