Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven , Campus Gasthuisberg O&N2, Herestraat 49 b921, 3000 Leuven, Belgium.
Department of Pharmaceutics, Hanoi University of Pharmacy , 13-15 Le Thanh Tong, Hoan Kiem, Ha Noi, Vietnam.
Mol Pharm. 2018 Feb 5;15(2):629-641. doi: 10.1021/acs.molpharmaceut.7b01007. Epub 2018 Jan 24.
The microstructure of pharmaceutical semicrystalline solid dispersions has attracted extensive attention due to its complexity that might result in the diversity in physical stability, dissolution behavior, and pharmaceutical performance of the systems. Numerous factors have been reported that dictate the microstructure of semicrystalline dispersions. Nevertheless, the importance of the complicated conformation of the polymer has never been elucidated. In this study, we investigate the microstructure of dispersions of polyethylene glycol and active pharmaceutical ingredients by small-angle X-ray scattering and high performance differential scanning calorimetry. Polyethylene glycol with molecular weight of 2000 g/mol (PEG2000) and 6000 g/mol (PEG6000) exhibited remarkable discrepancy in the lamellar periodicity in dispersions with APIs which was attributed to the differences in their folding behavior. The long period of PEG2000 always decreased upon aging-induced exclusion of APIs from the interlamellar region of extended chain crystals whereas the periodicity of PEG6000 may decrease or increase during storage as a consequence of the competition between the drug segregation and the lamellar thickening from nonintegral-folded into integral-folded chain crystals. These processes were in turn significantly influenced by the crystallization tendency of the pharmaceutical compounds, drug-polymer interactions, as well as the dispersion composition and crystallization temperature. This study highlights the significance of the polymer conformation on the microstructure of semicrystalline systems that is critical for the preparation of solid dispersions with consistent and reproducible quality.
由于药物半结晶固体分散体的微观结构可能导致系统物理稳定性、溶解行为和药物性能的多样性，因此引起了广泛关注。已经报道了许多决定半结晶分散体微观结构的因素。然而，聚合物复杂构象的重要性从未得到阐明。在这项研究中，我们通过小角 X 射线散射和高性能差示扫描量热法研究了聚乙二醇和活性药物成分分散体的微观结构。分子量为 2000 克/摩尔（PEG2000）和 6000 克/摩尔（PEG6000）的聚乙二醇在与 API 分散时表现出明显不同的层状周期性，这归因于它们折叠行为的差异。长周期的 PEG2000 在老化诱导 API 从伸展链晶体的层间区域排除时总是减小，而 PEG6000 的周期性在储存过程中可能减小或增加，这是由于药物隔离和从非整折叠链晶体到整折叠链晶体的层增厚之间的竞争。这些过程反过来又受到药物化合物的结晶趋势、药物-聚合物相互作用以及分散体组成和结晶温度的显著影响。本研究强调了聚合物构象对半结晶体系微观结构的重要性，这对于制备具有一致和可重复质量的固体分散体至关重要。
