Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 9-177 WDH, 308 Harvard Street S.E., Minneapolis, Minnesota 55455, United States.
Mol Pharm. 2023 Aug 7;20(8):4196-4209. doi: 10.1021/acs.molpharmaceut.3c00313. Epub 2023 Jun 26.
In an earlier investigation, the critical cooling rate to prevent drug crystallization (CR) during the preparation of nifedipine (NIF) amorphous solid dispersions (ASDs) was determined through a time-temperature transformation (TTT) diagram (Lalge et al. Mol. Pharmaceutics 2023, 20 (3), 1806-1817). The current study aims to use the TTT diagram to determine the critical cooling rate to prevent drug nucleation (CR) during the preparation of ASDs. ASDs were prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The dispersions were first stored under conditions promoting nucleation and then heated to the temperature that favors crystallization. The crystallization onset time () was determined by differential scanning calorimetry and synchrotron X-ray diffractometry. TTT diagrams for nucleation were generated, which provided the critical nucleation temperature (50 °C) and the critical cooling rate to avoid nucleation (CR). The strength of the drug-polymer interactions as well as the polymer concentration affected the CR, with PVP having a stronger interaction than HPMCAS. The CR of amorphous NIF was ∼17.5 °C/min. The addition of a 20% w/w polymer resulted in CR of ∼0.05 and 0.2 °C/min and CR of ∼4.1 and 8.1 °C/min for the dispersions prepared with PVP and HPMCAS, respectively.
在之前的一项研究中，通过时间-温度转变 (TTT) 图确定了硝苯地平 (NIF) 无定形固体分散体 (ASD) 制备过程中防止药物结晶 (CR) 的临界冷却速率（ Lalge 等人，《分子药剂学》，2023 年，20 (3)，1806-1817）。本研究旨在使用 TTT 图确定制备 ASD 时防止药物成核 (CR) 的临界冷却速率。使用聚乙烯吡咯烷酮 (PVP) 和醋酸羟丙甲纤维素琥珀酸酯 (HPMCAS) 制备 ASD。首先将分散体在促进成核的条件下储存，然后加热至有利于结晶的温度。通过差示扫描量热法和同步加速器 X 射线衍射法确定结晶起始时间 (t0)。生成了成核 TTT 图，提供了临界成核温度 (50°C) 和避免成核的临界冷却速率 (CR)。药物-聚合物相互作用的强度以及聚合物浓度影响 CR，PVP 的相互作用比 HPMCAS 更强。无定形 NIF 的 CR 约为 17.5°C/min。添加 20% w/w 聚合物会导致 PVP 和 HPMCAS 制备的分散体的 CR 分别约为 0.05 和 0.2°C/min 和 CR 分别约为 4.1 和 8.1°C/min。
