Solute crystallization in the frozen and freeze-dried systems: Inhibition of crystallization to enhance pharmaceutical stability.

摘要

Lyophilization is a commonly used drying technique for thermolabile pharmaceuticals. Crystallization of formulation components may occur during the various stages of the freeze-drying process. While crystallization of bulking agents is desirable, both from processing and product-elegance perspectives, buffer salt crystallization can cause a significant pH shift. The objectives of this work were: (i) to study the buffer component crystallization in pharmaceutical buffer systems and the consequent pH shift, (ii) to evaluate the phase behavior of lyoprotectant during all the stages of freeze-drying, and (iii) to explore various formulation approaches to inhibit both buffer and lyoprotectant crystallization in multi-component systems. When the succinate solutions were cooled, due to the sequential crystallization of buffer components, there was a swing in the freeze-concentrate pH. Other pharmaceutically relevant buffers were rank ordered based on the pH shift in the frozen solutions brought about by selective buffer component crystallization. Malate buffer showed the lowest crystallization tendency, followed by citrate buffer, but only when buffered to pH > pKa2. Crystallization of trehalose dihydrate was observed in frozen aqueous solutions. The dehydration of the trehalose dihydrate to a substantially amorphous anhydrate occurred during drying. Mannitol, by readily crystallizing as a hemihydrate, accelerated trehalose dihydrate crystallization in frozen solutions. Lyoprotectants, such as sucrose and trehalose, only when retained amorphous in a frozen solution, effectively inhibited the crystallization of succinate buffer components and prevented pH shifts. In addition to stabilizing the active pharmaceutical ingredient, lyoprotectants may prevent pH shift by inhibiting buffer salt crystallization.