The effect of additives on the molecular mobility, physical stability and dissolution of amorphous solid dispersions

Abstract

Amorphization provides an avenue for improving the oral bioavailability of poorly water-soluble compounds. However, crystallization of the amorphous phase during storage or dissolution could negate the solubility advantage. The objectives were to (i) develop an accelerated testing method for predicting the solid-state physical stability of drugs in amorphous solid dispersions (ASD), (ii) gain a mechanistic understanding of the stabilization in the amorphous state brought about by small molecule excipients, and (iii) investigate the relationship between solid-state properties and dissolution performance of ASDs. Utilizing glycerol as a plasticizer, an accelerated physical stability testing method of ASD was developed. The acceleration in crystallization brought about by glycerol expedited the determination of the coupling between molecular mobility and crystallization. This approach is especially useful for ASDs with high polymer content where drug crystallization is extremely slow at relevant storage temperature. The ability of several organic acids to stabilize an amorphous API, ketoconazole (KTZ), was next investigated. Oxalic (OXA), citric (CIT), tartaric (TAR) and succinic (SUC) acids were chosen based on their relative strengths (pKa values). Coamorphous systems of KTZ with each acid exhibited ionic and/or hydrogen bonding interactions. An increase in the strength of KTZ-acid interactions translated to a reduction in molecular mobility. However, molecular mobility could not completely explain the crystallization propensity of the systems. When in contact with water, coamorphous KTZ-citric and KTZ-tartaric were exceptionally stable while KTZ-succinic and KTZ-oxalic systems crystallized more readily than KTZ. The dissolution performance of the coamorphous systems were compared using the areas under the curve (AUC) obtained from the concentration-time profiles. KTZ-OXA exhibited the highest AUC, while it was about the same for KTZ-TAR and KTZ-CIT and the lowest for KTZ-SUC. Coamorphization with acid caused at least a 2-fold increase in AUC when compared with amorphous KTZ. In ternary KTZ-acid-polyvinylpyrrolidone (PVP) ASDs, the interactions between drug and acid each acid influenced the solid-state stability as well as dissolution performance.