Dehydration without Heating: Use of Polymer-Assisted Grinding for Understanding the Stability of Hydrates in the Presence of Polymeric Excipients

Abstract

Hydrates are ubiquitous multicomponent solids of particular interest in the pharmaceutical field. As such, there is a practical need of monitoring the stability of this class of solids, especially when formulated with one or more excipients. In this paper, we propose an innovative solid state method, namely, polymer-assisted grinding (POLAG), for exploring the stability of carbamazepine dihydrate under the simultaneous effects of manufacturing-induced stress (milling) and the presence of polymeric excipients. We demonstrate that, while milling alone did not cause any dehydration, the presence of specific polymers induced partial or total dehydration of the selected model drug carbamazepine dihydrate. Through detailed experimental evidence, it is concluded that the polymer chain length plays a main role in the kinetics of the solid state reaction, while a combination of the amount of polymer and the milling time allowed the isolation of different polymorphic forms of the resulting dehydrated carbamazepine ...