Molecular interactions between the active pharmaceutical ingredient and polymer have potentially substantial impacts on the physical stability of amorphous solid dispersions (ASDs), presumably by manipulating molecular mobility and miscibility. However, structural details for understanding the nature of the molecular contacts and mechanistic roles in various physicochemical and thermodynamic events often remain unclear. This study provides a spectroscopic characterization of posaconazole (POSA) formulations, a second-generation triazole antifungal drug (Noxafil, Merck & Co., Inc., Kenilworth, NJ, USA), at molecular resolution. One- and two-dimensional (2D) solid-state NMR (ssNMR) techniques including spectral editing, heteronuclear 1H–13C, 19F–13C, 15N–13C, and 19F–1H polarization transfer, and spin correlation and ultrafast magic angle spinning, together with the isotopic labeling strategy, were utilized to uncover molecular details in POSA ASDs in a site-specific manner. Active groups in triazole and difluorophenyl rings exhibited rich but distinct categories of interactions with two polymers, hypromellose acetate succinate and hypromellose phthalate, including intermolecular O–H···OC and O–H···F–C hydrogen bonding, π–π aromatic packing, and electrostatic interaction. Interestingly, the chlorine-to-fluorine substituent in POSA, one of the major structural differences from itraconazole that could facilitate binding to the biological target, offers an additional contact with the polymer. These findings exhibit 2D ssNMR as a sensitive technique for probing sub-nanometer structures of pharmaceutical materials and provide a structural basis for optimizing the type and strength of drug–polymer interactions in the design of amorphous formulations.

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.

Bile salts are natural surfactants present in the human gastrointestinal tract. Therefore, it is essential to consider their effect on the dissolution and crystallization tendency of oral drug formulations. Although a recent study showed that sodium taurocholate delayed nucleation for 11 structurally diverse compounds, there is limited information about the crystallization inhibition properties of other bile salts and whether they are interchangeable in this context. In this study, we evaluated the ability of 13 bile salts to maintain supersaturated aqueous solutions of three compounds: celecoxib, nevirapine, and fibanserin. Most bile salts extended nucleation induction times. However, their inhibitory effects varied depending on the structure and concentration of the bile salt and the drug. The R5 group and hydrophobicity of the bile salt appeared to be essential. Molecular dynamics simulations indicated that van der Waals and hydrogen bonding interactions occurred between nevirapine and bile salts, with variations in different systems. These results are important to better understand the crystallization tendency of orally delivered poorly water-soluble compounds in vivo.

Despite the wide utilization of amorphous solid dispersions (ASDs) for formulating poorly water-soluble drugs, fundamental understanding of the structural basis behind their stability and dissolution behavior is limited. This is largely due to the lack of high-resolution structural tools for investigating multicomponent and amorphous systems in the solid state. In this study, we present what is likely the first publication quantifying the molecular interaction between the drug and polymer in ASDs at an angstrom level by utilizing 19F magic angle spinning (MAS) nuclear magnetic resonance (NMR) techniques. A variant of the 19F–13C rotational-echo and double-resonance (REDOR) technique was developed to quantify interatomic distances by implementing a supercycled symmetry-based recoupling schedule and synchronized simultaneous detection. We successfully deployed the technique to identify “head-to-head” and “head-to-tail” packing of crystalline posaconazole (POSA). To probe molecular interactions between POSA and hypromellose acetate succinate (HPMCAS) in the dispersion, as a major goal of this study, two-dimensional (2D) 1H–19F correlation experiments were performed. The approach facilitated observation of intermolecular hydrogen-to-fluorine contacts between the hydroxyl group of the polymer and the difluorophenyl group of the drug substance. Atomic distance measurement, utilizing the developed 19F–13C REDOR technique, revealed the close proximity of 13COH–19F at 4.3 Å. Numerical modeling analysis suggested a possible hydrogen bonding interaction between the polymer O–H group as an acceptor and POSA fluorine (O–H···F) or difluorophenyl ring (O–H···Ph) as a donor. These 19F MAS NMR techniques, including 2D 19F–1H heteronuclear correlation and 19F–13C atomic distance measurement, may shed light on the nature (i.e., type and strength) of drug–polymer interactions in ASDs and offer a new high-resolution analytical protocol for probing the microstructure of amorphous pharmaceutical materials.

A variety of formulation strategies have been developed to mitigate the inadequate aqueous solubility of certain therapeutic agents. Amongst these, achieving supersaturation in vivo is a promising approach to improve the extent of oral absorption. Due to the thermodynamic instability of supersaturated solutions, inhibitors are needed to kinetically hinder crystallization. In addition to commonly used polymeric additives, bile salts, naturally present in the gastrointestinal tract, have been shown to exhibit crystallization inhibition properties. However, the impact of bile salts on solution thermodynamics is not well understood, although this knowledge is essential in order to explore the mechanism of crystallization inhibition.To better describe solution thermodynamics in the presence of bile salts, a side-by-side diffusion cell was used to evaluate solute flux for solutions of telaprevir in the absence and presence of the six most abundant bile salts in human intestinal fluid at various solute concentrations; flux measurements provide information about the solute thermodynamic activity and hence can provide an improved measurement of supersaturation in complex solutions. Trihydroxy bile salts had minimal impact on solution phase boundaries as well as solute flux, while micellar dihydroxy bile salts solubilized telaprevir leading to reduced solute flux across the membrane. An inconsistency between the concentration-based supersaturation ratio and that based on solute thermodynamic activity (the fundamental driving force for crystallization) was noted, suggesting that the activity-based supersaturation should be determined to better interpret any modification in crystallization kinetics in the presence of these additives. These findings indicate that bile salts are not interchangeable from a thermodynamic perspective, and provide a foundation for further studies evaluating the mechanism of crystallization inhibition.3