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

Abstract

Bile salts are endogenous surfactants present in the human gastrointestinal tract in the form of mixed micelles that also contain phospholipids. Due to the inevitable encounter of oral drug formulations with bile salts, it is important to understand the impact of bile salts on the crystallization tendency of poorly soluble compounds that form supersaturated solutions in vivo in order to maximize oral drug absorption. Although there has been an increasing number of studies focusing on the role of individual bile salts on drug crystallization, the effects of mixed micelles and biorelevant media composition on crystallization kinetics have only been studied to a limited extent. In this study, we evaluated the ability of binary and ternary bile salt combinations to maintain supersaturated aqueous solutions of telaprevir. Crystallization kinetics were also compared in more complex media that also contained the phospholipid, lecithin. These included fasted state simulated intestinal fluid (FaSSIF) (a widely used medium for formulation testing which contains a single bile salt, sodium taurocholate), and media that contained several endogenous bile salts. Finally, the combined effects of a polymer, hydroxypropylmethyl cellulose acetate succinate, and the testing media on crystallization kinetics were evaluated to provide insights into supersaturation formulation design. Solution bile salt composition was found to significantly influence crystallization kinetics. However, the presence of the polymer increased induction times sufficiently that differences between media were minimized. This study suggests that when evaluating the crystallization kinetics of systems with a propensity to undergo supersaturation in vivo, attention should be paid to selecting biorelevant media.

Overcoming the Common Ion Effect for Weakly Basic Drugs: Inhibiting the Crystallization of Clofazimine Hydrochloride in Simulated Gastrointestinal Media

“…The observation that NaTc and porcine bile extract (a mixture of bile salts) can prolong the supersaturation of CFZH + , also correlates well with previous studies conducted by Chen et al,Li et al and Lu et al [3], [18]- [21], which showed how the crystallization of hydrophobic drugs can be slowed and in some cases prevented by the presence of NaTc and other bile acids [3], [18]- Highlighted by a red border in Figure 5 is a region of the CFZB crystal, where circular arrangements of CFZ hydrochloride crystals have nucleated onto the surface of the free base. As CFZB dissolved in 25 mM HCl, the surface of the dissolving crystals appears to provide a template onto which the HCl salt can nucleate and grow.…”

“…The driving force for the common ion effect for weakly basic ionisable APIs is an increase in counterion concentration, which shifts the solubility equilibrium of the dissociated reaction to favour crystallization of the solid salt form of the API. The use of synthetic polymers, and recently of bile salts, to inhibit the crystallization of hydrophobic APIs is well described in the literature [3], [14]- [17], [21], [37], [38] This complements our previous study which shows how solution concentration and stability of CFZH + at pH 1.6 (in 25 mM HCl) depends on the presence and concentration of NaTc, lecithin, and pepsin in the system [22]. These results explain that the underlying mechanism for this manipulation of solution behaviour was through interference with the crystallization kinetics of CFZ hydrochloride from these solutions, with the exception of pepsin.…”

“…Most previous studies have focused on using polymeric additives, such as cellulose derivatives, to prolong supersaturation by inhibiting nucleation [14]- [17]. However, recently several studies have demonstrated that bile salts can also act as crystallization inhibitors for hydrophobic APIs [3], [18]- [21]. A recent systemic study of the effects of bile salts, phospholipids, and digestive peptides, on the solution concentration of the antibiotic agent clofazimine (CFZ), showed that the presence of these amphipathic compounds has a strong influence on solution behaviour i.e.…”

Increasing the Robustness of Biopharmaceutical Precipitation Assays – Part II: Recommendations on the use of FaSSIF

“…Mixed micelles obtained from a mixture of several bile salts and lecithin were shown to inhibit the precipitation of supersaturated telaprevir solutions. 23 By contrast, no effect was observed for sodium taurocholate and lecithin (FaSSIF) compared to buffer. 23 With respect to the solubilizing capacity, the chain length and saturation number of phospholipids were found to be related to their drug solubilizing capacity.…”

“…23 By contrast, no effect was observed for sodium taurocholate and lecithin (FaSSIF) compared to buffer. 23 With respect to the solubilizing capacity, the chain length and saturation number of phospholipids were found to be related to their drug solubilizing capacity. 24 In the current study, the thermodynamic solubility of ketoconazole was not affected by aged FaSSIF, which is in line with the thermodynamic equilibrium after the transfer experiments.…”