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

Abstract

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 homogenous supersaturated telaprevir solutions and highly supersaturated telaprevir solutions containing a second phase. The ability to retard telaprevir nucleation, however, varied amongst 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.

Compositional effect of complex biorelevant media on the crystallization kinetics of an active pharmaceutical ingredient

“…Most studies to date have focused on the crystallization inhibitory ability of individual bile salts. These studies revealed the potential of monomeric bile salts as nucleation [11][12][13] and/or crystal growth, 14 inhibitors. Furthermore, it was noted that bile salts showed a comparable inhibition ability to polymers for poorly water soluble drugs.…”

“…Recently, it has been noted that bile salts, which are endogenous surfactants, are, in many instances, effective crystallization inhibitors. [10][11][12][13] These observations are of particular interest due to the inevitable encounter of oral formulations with bile salts in biorelevant dissolution media and in vivo. Most studies to date have focused on the crystallization inhibitory ability of individual bile salts.…”

“…Furthermore, it was noted that bile salts showed a comparable inhibition ability to polymers for poorly water soluble drugs. 13 Bile salts exist in the upper intestinal tract as mixed micelles that also contain phospholipids and cholesterol. 15 Consequently, it is also important to understand the impact of multicomponent bile salt micelles on drug crystallization kinetics.…”

“…However, it has been recently demonstrated that biologically relevant bile salts are not interchangeable from either a thermodynamic 16 or crystallization standpoint. 12,13 Therefore, it is of interest to investigate whether the current biorelevant medium used for in vitro testing might be oversimplified in the context of supersaturating dosage forms. The goal of this study was to evaluate the impact of biorelevant testing media composition on drug crystallization kinetics from supersaturated solutions.…”

“…The goal of this study was to evaluate the impact of biorelevant testing media composition on drug crystallization kinetics from supersaturated solutions. Telaprevir was chosen as the model compound since the influence of individual biorelevant bile salts on this compound has been thoroughly studied from both a thermodynamic 16 and crystallization inhibition stand point 13,14 . In addition, the effects of binary and ternary bile salt combinations, as well as bile salt-polymer systems on telaprevir crystallization, were investigated in order to systematically evaluate the impact of multiple additives on crystallization kinetics.…”