Raina Shweta A, Alonzo David E, Zhang Geoff G Z, Gao Yi, Taylor Lynne S
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University , West Lafayette, Indiana 47907, United States.
Mol Pharm. 2014 Oct 6;11(10):3565-76. doi: 10.1021/mp500333v. Epub 2014 Sep 18.
The commercial and clinical success of amorphous solid dispersions (ASD) in overcoming the low bioavailability of poorly soluble molecules has generated momentum among pharmaceutical scientists to advance the fundamental understanding of these complex systems. A major limitation of these formulations stems from the propensity of amorphous solids to crystallize upon exposure to aqueous media. This study was specifically focused on developing analytical techniques to evaluate the impact of polymers on the crystallization behavior during dissolution, which is critical in designing effective amorphous formulations. In the study, the crystallization and polymorphic conversions of a model compound, nifedipine, were explored in the absence and presence of polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), and HPMC-acetate succinate (HPMC-AS). A combination of analytical approaches including Raman spectroscopy, polarized light microscopy, and chemometric techniques such as multivariate curve resolution (MCR) were used to evaluate the kinetics of crystallization and polymorphic transitions as well as to identify the primary route of crystallization, i.e., whether crystallization took place in the dissolving solid matrix or from the supersaturated solutions generated during dissolution. Pure amorphous nifedipine, when exposed to aqueous media, was found to crystallize rapidly from the amorphous matrix, even when polymers were present in the dissolution medium. Matrix crystallization was avoided when amorphous solid dispersions were prepared, however, crystallization from the solution phase was rapid. MCR was found to be an excellent data processing technique to deconvolute the complex phase transition behavior of nifedipine.
无定形固体分散体（ASD）在克服难溶性分子低生物利用度方面取得的商业和临床成功，促使药物科学家们进一步深入了解这些复杂体系。这些制剂的一个主要局限性在于无定形固体在接触水性介质时易于结晶。本研究特别专注于开发分析技术，以评估聚合物对溶解过程中结晶行为的影响，这对于设计有效的无定形制剂至关重要。在该研究中，在不存在和存在聚乙烯吡咯烷酮（PVP）、羟丙基甲基纤维素（HPMC）和醋酸琥珀酸羟丙基甲基纤维素（HPMC-AS）的情况下，探究了模型化合物硝苯地平的结晶和多晶型转变。采用包括拉曼光谱、偏光显微镜等分析方法以及多变量曲线分辨（MCR）等化学计量技术，来评估结晶动力学和多晶型转变，以及确定结晶的主要途径，即结晶是在溶解的固体基质中发生，还是在溶解过程中产生的过饱和溶液中发生。发现纯无定形硝苯地平在接触水性介质时，即使溶解介质中存在聚合物，也会从无定形基质中迅速结晶。然而，制备无定形固体分散体时可避免基质结晶，但溶液相的结晶很快。发现MCR是一种出色的数据处理技术，可对硝苯地平复杂的相变行为进行解卷积。
