Mitigating unwanted amorphisation: A screening method for the selection of suitable excipients

Abstract

Co-processing an active pharmaceutical ingredient (API) with a low Tg excipient has been previously reported to be an effective strategy for preventing drug amorphisation on milling. This technique relies on the ability of the excipient to form a molecular dispersion with the amorphous API during the milling process. The presence of the excipient within the amorphous phase induces a reduction of the Tg. Hence, the molecular dispersion becomes less stable than the amorphous API alone and recrystallises upon milling. The objective of this study was to develop a screening method for the selection of suitable excipients to prevent amorphisation, based on two criteria: the Tg of the excipient and the solubility of the excipient in the amorphous API. The ability of the excipients to induce Tg reduction was first assessed by measuring the Tg of the amorphous composite by thermal analysis and comparing it with that of the pure API (griseofulvin). A predicted ability for mitigation of amorphisation upon milling was then deduced from these observations for each excipient and assessed against experimental results. The same excipients were then studied with regard to their expected solubility in another amorphous API (budesonide) by Hildebrand solubility parameter calculations in order to 2 evaluate their capacity to form an amorphous composite with the drug. The predicted effects of the excipients on comilling were compared with the amorphous content of the processed API. The screening method as applied to both APIs showed good agreement with the experimental results and were shown to be efficient for the selection of the most appropriate excipient. This approach revealed that the two key parameters involved are the Tg of the excipient and the ability of the API to form an amorphous molecular dispersion with the excipients. This work confirms and completes our previously published results on the mitigation of the amorphisation by comilling with low Tg excipients and constitutes the first report of the use of a polymeric additive for this purpose.