Chen Zhen, Liu Zhengsheng, Qian Feng
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University , Beijing 100084, P. R. China.
Mol Pharm. 2015 Feb 2;12(2):590-9. doi: 10.1021/mp500661v. Epub 2015 Jan 21.
The morphology and microstructure of crystalline drug/polymer solid dispersions could influence their physical stability and dissolution performance. In this study, the drug crystallization mechanism within PEG, PPG, and poloxamer matrix was investigated, and the resultant microstructure of various solid dispersions of acetaminophen (ACM) and bifonazole (BFZ) in the aforementioned polymers was characterized by differential scanning calorimetry (DSC), polarized optical microscopy (POM), and wide/small-angle X-ray diffraction (WAXD/SAXS). With a stronger molecular interaction with the PEG segments, ACM decreased the crystallization onset temperature and crystallinity of PEG and poloxamers much more than BFZ. The stronger molecular interaction and better miscibility between ACM and PEG also induced a more defective lamellar structure in the ACM solid dispersions compared with that in the BFZ systems, as revealed by DSC and SAXS investigation. Observed under polarized optical microscopy, PEG, PPG, and poloxamer could all significantly improve the crystallization rate of ACM and BFZ, because of the largely reduced Tg of the solid dispersions by these low Tg polymers. Moreover, when the drug loading was below 60%, crystallization of BFZ in PEG or poloxamer occurred preferably along the radial direction of PEG spherulite, rather than the perpendicular direction, which was attributed to the geometric restriction of well-ordered polymer lamellar structure in the BFZ solid dispersions. Similar phenomena were not observed in the ACM solid dispersions regardless of the drug loading, presumably because ACM could diffuse freely across the perpendicular direction of the PEG spherulite, through the well-connected interlamellar or interfibrillar spaces produced by the defective PEG lamellar structure. The different drug-polymer interaction also caused a difference in the microstructure of polymer crystal, as well as a difference in drug distribution within the polymer matrix, which then synergistically facilitated a "confined crystallization" process to reduce the drug crystallite size below 100 nm.
结晶药物/聚合物固体分散体的形态和微观结构会影响其物理稳定性和溶解性能。本研究考察了对乙酰氨基酚（ACM）和联苯苄唑（BFZ）在聚乙二醇（PEG）、聚丙二醇（PPG）和泊洛沙姆基质中的药物结晶机制，并通过差示扫描量热法（DSC）、偏光显微镜（POM）和广角/小角X射线衍射（WAXD/SAXS）对上述聚合物中各种乙酰氨基酚和联苯苄唑固体分散体的微观结构进行了表征。由于与PEG链段的分子相互作用更强，ACM比BFZ更能降低PEG和泊洛沙姆的结晶起始温度和结晶度。DSC和SAXS研究表明，ACM与PEG之间更强的分子相互作用和更好的混溶性，也使得ACM固体分散体中的片层结构比BFZ体系中的更有缺陷。在偏光显微镜下观察发现，由于这些低玻璃化转变温度（Tg）聚合物使固体分散体的Tg大幅降低，PEG、PPG和泊洛沙姆都能显著提高ACM和BFZ的结晶速率。此外，当药物载量低于60%时，BFZ在PEG或泊洛沙姆中的结晶优先沿PEG球晶的径向发生，而不是垂直方向，这归因于BFZ固体分散体中有序聚合物片层结构的几何限制。无论药物载量如何，在ACM固体分散体中均未观察到类似现象，可能是因为ACM可以通过有缺陷的PEG片层结构产生的连通层间或原纤维间空间，在PEG球晶的垂直方向上自由扩散。不同的药物 - 聚合物相互作用也导致了聚合物晶体微观结构的差异，以及药物在聚合物基质中的分布差异，进而协同促进了“受限结晶”过程，将药物微晶尺寸减小到100 nm以下。
