Maintaining Supersaturation of Active Pharmaceutical Ingredient Solutions with Biologically Relevant Bile Salts

Currently, it is of interest to improve the oral absorption of poorly water-soluble therapeutic agents using supersaturating formulations. Understanding crystallization kinetics of supersaturated drug solutions is central to the design and evaluation of such formulations. Bile salts have drawn increasing attention in this context as they serve important roles in biorelevant dissolution media, in vivo, and have been shown to slow down the crystallization of active pharmaceutical ingredients. The goal of this study was to evaluate the impact of bile salt monomers and micelles on the crystallization of telaprevir, a poorly water-soluble drug, from aqueous solution. To better describe the crystallization driving force in the presence of the bile salts, a side-by-side diffusion cell was used to evaluate telaprevir mass flow rate, and hence solute activity, in the absence and presence of different bile salts. The effectiveness of monomeric and miceller bile salts as crystallization inhibitors was then evaluated by performing crystallization induction time experiments at constant, activity-based supersaturation. The six most abundant biologically relevant bile salts were investigated (sodium taurocholate, sodium taurodeoxycholate, sodium taurochenodeoxycholate, sodium glycocholate, sodium glycodeoxycholate, and sodium glycochenodeoxycholate). All six bile salts exhibited nucleation inhibition properties in both homogeneous supersaturated telaprevir solutions and highly supersaturated telaprevir solutions containing a second phase. The ability to retard telaprevir nucleation, however, varied among the bile salts and also depended on the aggregation state. Monomeric bile salts were found to be effective crystallization inhibitors. At higher bile salt concentrations, trihydroxy bile salts showed better inhibition compared to dihydroxy bile salts. These results highlight the importance of considering the composition of the test medium used to evaluate product performance, in particular in the context of evaluating crystallization kinetics.