Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Mol Pharm. 2024 Nov 4;21(11):5880-5891. doi: 10.1021/acs.molpharmaceut.4c00935. Epub 2024 Oct 3.
Using the time-temperature-transformation diagrams, we demonstrated a correlation between molecular mobility and crystallization in amorphous solid dispersions of nifedipine (NIF) with each polyvinylpyrrolidone vinyl acetate (PVPVA64) and polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus). The behavior was compared with the NIF dispersions prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) [Lalge et al., 2023, (3), 1806-1817]. Each system was characterized by a unique temperature at which the crystallization onset time was the shortest. Below this temperature, a coupling was observed between the α-relaxation time determined by dielectric spectroscopy and crystallization onset time. Above this temperature, the activation barrier for crystallization had a more significant role than molecular mobility. In the solid state, PVP and PVPVA64 dispersion exhibited higher resistance to crystallization than HPMCAS and Soluplus. The role of polymers in inhibiting crystal growth in nucleated systems was discerned by monitoring crystallization following wetting of the amorphous dispersion with the dissolution medium. PVPVA64 and Soluplus dispersions exhibited higher resistance to crystal growth than PVP and HPMCAS.
利用时-温-转变图，我们展示了硝苯地平（NIF）与每一种聚乙烯吡咯烷酮醋酸乙烯酯（PVPVA64）和聚乙烯己内酰胺聚醋酸乙烯酯-聚乙二醇接枝共聚物（Soluplus）无定形固体分散体中的分子迁移率与结晶之间的相关性。该行为与用每一种聚乙烯吡咯烷酮（PVP）和羟丙基甲基纤维素醋酸琥珀酸酯（HPMCAS）[Lalge 等人，2023 年，（3），1806-1817]制备的 NIF 分散体进行了比较。每个系统的特点是存在一个独特的温度，在此温度下结晶起始时间最短。在此温度以下，介电光谱法测定的α弛豫时间与结晶起始时间之间观察到耦合。在此温度以上，结晶的活化能垒比分子迁移率具有更重要的作用。在固态下，PVP 和 PVPVA64 分散体比 HPMCAS 和 Soluplus 对结晶的抵抗力更高。通过监测无定形分散体在溶解介质中润湿后的结晶情况，可以辨别聚合物在成核体系中抑制晶体生长的作用。PVPVA64 和 Soluplus 分散体比 PVP 和 HPMCAS 对晶体生长的抵抗力更高。
