Pharmaceutical Sciences, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
School of Pharmacy and Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States.
Mol Pharm. 2020 Jul 6;17(7):2585-2598. doi: 10.1021/acs.molpharmaceut.0c00268. Epub 2020 May 28.
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 F magic angle spinning (MAS) nuclear magnetic resonance (NMR) techniques. A variant of the F-C 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) H-F 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 F-C REDOR technique, revealed the close proximity of C-F 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 F MAS NMR techniques, including 2D F-H heteronuclear correlation and F-C 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.
尽管无定形固体分散体（ASD）被广泛用于制备水溶性差的药物，但对其稳定性和溶解行为的结构基础的基本理解是有限的。这主要是由于缺乏用于研究固态多组分和无定形系统的高分辨率结构工具。在这项研究中，我们首次利用 F 魔角旋转（MAS）核磁共振（NMR）技术，通过量化 ASD 中药物和聚合物之间的分子相互作用，在埃级水平上量化 ASD 中药物和聚合物之间的分子相互作用，这可能是首次发表的。通过实施超循环对称重聚方案和同步检测，开发了一种 F-C 旋转回波和双共振（REDOR）技术的变体，以量化原子间距离。我们成功地部署了这项技术来识别结晶泊沙康唑（POSA）的“头对头”和“头到尾”包装。作为本研究的主要目标之一，为了探测 POSA 和醋酸羟丙甲纤维素琥珀酸酯（HPMCAS）之间的分子相互作用，我们进行了二维（2D）H-F 相关实验。该方法促进了观察聚合物的羟基和药物物质的二氟苯基之间的分子间氢键接触。利用开发的 F-C REDOR 技术进行的原子距离测量表明，C-F 非常接近 4.3 Å。数值建模分析表明，聚合物 O-H 基团作为受体和 POSA 氟（O-H···F）或二氟苯基环（O-H···Ph）作为供体之间可能存在氢键相互作用。这些 F MAS NMR 技术，包括 2D F-H 异核相关和 F-C 原子距离测量，可能揭示 ASD 中药物-聚合物相互作用的性质（即类型和强度），并为探测无定形药物材料的微观结构提供新的高分辨率分析方案。
