Preformulation, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Mol Pharm. 2021 Dec 6;18(12):4299-4309. doi: 10.1021/acs.molpharmaceut.1c00372. Epub 2021 Nov 5.
Polymers play an important role in amorphous solid dispersions (ASDs), enhancing stability in the solid state and maintaining supersaturation in aqueous solutions of intrinsically low-water-soluble drug candidates. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is widely used in ASDs due to its hydrophobic/hydrophilic balance and ionizability of the substituent functionalities. While colloid formation of HPMCAS in solution due to this hydrophobic/hydrophilic balance has been studied, the impact of the polymer conformation (random coil vs aggregated) on drug supersaturation of ASDs is not well understood. To our knowledge, this is the first report where the critical aggregation concentration for three grades of HPMCAS (HF/MF/LF) has been determined via fluorescence spectroscopy using the environment-sensitive probe pyrene. The specific impact of polymer conformation (random coil vs aggregate) on the model drug celecoxib (CLX) has been elucidated with fluorescence quenching and nuclear magnetic resonance (NMR) spectroscopy. A negative deviation of the Stern-Volmer plot indicated that aggregated HPMCAS effectively blocked the quencher's access to CLX. This is further supported by NMR observations, where NMR spectra indicate a larger change of chemical shift of the -NH group of CLX when HPMCAS is above its aggregated concentration, suggesting strong H-bonding interactions between aggregated HPMCAS and CLX. Finally, the supersaturation-precipitation study shows that all three grades of HPMCAS in the aggregated state significantly enhanced CLX supersaturation compared to the nonaggregated state, indicating that polymer aggregation plays a critical role in maintaining drug supersaturation.
聚合物在无定形固体分散体（ASD）中起着重要作用，可提高固体状态的稳定性并保持内在低水溶性药物候选物在水溶液中的过饱和度。由于其疏水/亲水平衡和取代基功能团的可离子化性，羟丙基甲基纤维素醋酸琥珀酸酯（HPMCAS）在 ASD 中被广泛使用。虽然已经研究了 HPMCAS 在溶液中由于这种疏水/亲水平衡而形成胶体，但聚合物构象（无规卷曲与聚集）对 ASD 中药物过饱和度的影响尚未得到很好的理解。据我们所知，这是首次使用环境敏感探针芘通过荧光光谱法确定三种 HPMCAS（HF/MF/LF）的临界聚集浓度的报告。通过荧光猝灭和核磁共振（NMR）光谱法阐明了聚合物构象（无规卷曲与聚集）对模型药物塞来昔布（CLX）的具体影响。Stern-Volmer 图的负偏离表明聚集的 HPMCAS 有效地阻止了猝灭剂接近 CLX。这进一步得到了 NMR 观察的支持，其中 NMR 谱表明当 HPMCAS 高于其聚集浓度时，CLX 的-NH 基团的化学位移发生较大变化，表明聚集的 HPMCAS 与 CLX 之间存在强氢键相互作用。最后，过饱和度-沉淀研究表明，与非聚集状态相比，所有三种 HPMCAS 在聚集状态下均显著提高了 CLX 的过饱和度，表明聚合物聚集在维持药物过饱和度方面起着关键作用。
