Mechanochemical Synthesis of Pharmaceutical Cocrystal Suspensions via Hot Melt Extrusion: Feasibility Studies and Physicochemical Characterisation

Engineered cocrystals offer an alternative solid drug form with tailored physicochemical properties. Interestingly, although cocrystals provide many new possibilities, they also present new challenges, particularly in regard to their design and large-scale manufacture. Current literature has primarily focused on the preparation and characterization of novel cocrystals typically containing only the drug and coformer, leaving the subsequent formulation less explored. In this paper we propose, for the first time, the use of hot melt extrusion for the mechanochemical synthesis of pharmaceutical cocrystals in the presence of a meltable binder. In this approach, we examine excipients that are amenable to hot melt extrusion, forming a suspension of cocrystal particulates embedded in a pharmaceutical matrix. Using ibuprofen and isonicotinamide as a model cocrystal reagent pair, formulations extruded with a small molecular matrix carrier (xylitol) were examined to be intimate mixtures wherein the newly formed cocrystal particulates were physically suspended in a matrix. With respect to formulations extruded using polymeric carriers (Soluplus and Eudragit EPO, respectively), however, there was no evidence within PXRD patterns of either crystalline ibuprofen or the cocrystal. Importantly, it was established in this study that an appropriate carrier for a cocrystal reagent pair during HME processing should satisfy certain criteria including limited interaction with parent reagents and cocrystal product, processing temperature sufficiently lower than the onset of cocrystal Tm, low melt viscosity, and rapid solidification upon cooling.

The use of binary polymeric networks in stabilising polyethylene oxide solid dispersions

The objective of this study was to determine if a high Tg polymer (Eudragit® S100) could be used to stabilize amorphous domains of polyethylene oxide (PEO) and hence improve the stability of binary polymer systems containing celecoxib (CX). We propose a novel method of stabilizing the amorphous PEO solid dispersion through inclusion of a miscible, high Tg polymer, namely, that can form strong inter-polymer interactions. The effects of inter-polymer interactions and miscibility between PEO and Eudragit S100 are considered. Polymer blends were first manufactured via hot-melt extrusion at different PEO/S100 ratios (70/30, 50/50, and 30/70 wt/wt). Differential scanning calorimetry and dynamic mechanical thermal analysis data suggested a good miscibility between PEO and S100 polymer blends, particularly at the 50/50 ratio. To further evaluate the system, CX/PEO/S100 ternary mixtures were extruded. Immediately after hot-melt extrusion, a single Tg that increased with increasing S100 content (anti-plasticization) was observed in all ternary systems. The absence of powder X-ray diffractometry crystalline Bragg’s peaks also suggested amorphization of CX. Upon storage (40°C/75% relative humidity), the formulation containing PEO/S100 at a ratio of 50:50 was shown to be most stable. Fourier transform infrared studies confirmed the presence of hydrogen bonding between Eudragit S100 and PEO suggesting this was the principle reason for stabilization of the amorphous CX/PEO solid dispersion system.