School of Pharmacy and Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Ave, Pittsburgh, Pennsylvania 15282, United States.
Mol Pharm. 2022 Nov 7;19(11):3959-3972. doi: 10.1021/acs.molpharmaceut.2c00434. Epub 2022 Sep 1.
Specific noncovalent drug-polymer interactions were analytically identified using Raman and Fourier transform infrared spectroscopy for amorphous solid dispersions (ASD) formed between either chlorpropamide or tolbutamide and polyvinylpyrrolidone vinyl acetate random copolymer (PVPVA). Spectral changes in the C-Cl stretching vibrations due to changes in the electronic environment of the Cl atom confirmed halogen bond formation in chlorpropamide-PVPVA ASDs, the extent of which was established to be inversely related to the concentration of the drug using 2D correlation spectroscopy analysis. Hydrogen bonding between the secondary amide of each drug and the pyrrolidone carbonyl of the copolymer was also confirmed in all dispersions. Implications of coexistent interactions were investigated for drug-polymer solubility, mixing free energy, and molecular mobility relative to tolbutamide, which only formed hydrogen bonds with PVPVA. Chlorpropamide had a higher solubility, a larger negative mixing free energy, and lower mobility in PVPVA relative to tolbutamide. These thermodynamic and kinetic differences demonstrate the significance of halogen bond formation even when hydrogen bonding is present.
使用拉曼和傅里叶变换红外光谱分析鉴定了氯丙酰胺或甲苯磺丁脲与聚乙烯吡咯烷酮醋酸乙烯酯无规共聚物（PVPVA）形成的无定形固体分散体（ASD）中特定的非共价药物-聚合物相互作用。由于 Cl 原子的电子环境发生变化，C-Cl 伸缩振动的光谱发生变化，证实了氯丙酰胺-PVPVA ASD 中形成了卤键，其程度通过二维相关光谱分析确定与药物浓度成反比。在所有分散体中，还确认了每个药物的仲酰胺与共聚物的吡咯烷酮羰基之间的氢键。共存相互作用的影响对于药物-聚合物的溶解度、混合自由能以及相对于仅与 PVPVA 形成氢键的甲苯磺丁脲的分子迁移率进行了研究。与甲苯磺丁脲相比，氯丙酰胺在 PVPVA 中的溶解度更高，混合自由能的负值更大，分子迁移率更低。这些热力学和动力学差异表明，即使存在氢键，卤键的形成也具有重要意义。
