(523a) Understanding the Impact of Bile Salts on Crystallization Kinetics of Supersaturated Solutions of a Poorly Water Soluble Compound

Lu, J. - Presenter, Purdue University
Ormes, J. D., Merck & Co., Inc.
Lowinger, M., Merck & Co., Inc.
Xu, W., Merck & Co., Inc.
Litster, J. D., The University of Sheffield
Taylor, L. S., Purdue University
Amorphous solid dispersions (ASD) have been one of the most popular formulation strategies to address the issue of inadequate aqueous solubility for small molecules. Although ASD greatly improves oral drug absorption by creating a highly supersaturated solution upon dissolution, addition of a crystallization inhibitor is often required to maintain the supersaturation advantage. In addition to commonly employed polymeric additives, bile salts, which are endogenous surfactants, have attracted the interest of researchers since they show potential as crystallization inhibitors. While the commercial recipe for simulated intestinal fluid contains only one bile salt, sodium taurocholate, there are at least six different bile salts found in human intestinal fluids, and the composition varies from person to person and amongst species. To better understand and maximize oral drug absorption, it is imperative to evaluate the impact of bile salts on key attributes of supersaturated drug solutions.

In this study, a systematic experimental design was carried out to investigate the potential of six biologically relevant bile salts (sodium taurocholate (STC), sodium glycocholate (SGC), sodium taurodeoxycholate (STDC), sodium glycodeoxycholate (SGDC), sodium taurochenodeoxycholate (STCDC), sodium glycochenodeoxycholate (SGCDC)) as crystallization inhibitors for telaprevir, a poorly soluble drug commercialized as an ASD formulation. A side-by-side diffusion cell was used to evaluate solute flux for solutions of telaprevir in the absence and presence of bile salts at various solute concentrations, and to provide an improved estimate of the crystallization driving force in a complex medium. Telaprevir nucleation induction time experiments were performed at the same activity-based supersaturation in the absence and presence of six different bile salts, at monomeric and micellar levels. To decouple crystal growth and nucleation, telaprevir crystal growth experiments with an in-situ common history seeding method were designed and performed at the same activity-based supersaturation. The potential roles of both monomeric and micellar bile salt as crystallization inhibitors were then evaluated.

All bile salts investigated in this study slow down crystallization of highly supersaturated telaprevir solutions. However, the extent and kinetics of crystallization inhibition varies with structural difference amongst the bile salts and their aggregation level. The tri-hydroxyl bile salts (STC and SGC) do not impact solution thermodynamics, and are good nucleation and crystal growth inhibitors at both aggregation level. Di-hydroxyl bile salts solubilize telaprevir at micellar level. In addition, monomeric STDC and SGDC are strong nucleation inhibitors while monomeric STCDC and SGCDC are strong crystal growth inhibitor for telaprevir. Lastly, bile salts are not interchangeable from either a thermodynamic or crystallization inhibition standpoint.