CIESC Journal ›› 2021, Vol. 72 ›› Issue (1): 508-520.DOI: 10.11949/0438-1157.20201192

• Thermodynamics • Previous Articles     Next Articles

Nonequilibrium thermodynamic modeling and prediction of the effect of polymer excipients on aspirin crystallization kinetics

JI Yuanhui(),CHEN Qiao,WENG Jingyun   

  1. Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211100, Jiangsu, China
  • Received:2020-08-20 Revised:2020-12-02 Online:2021-01-05 Published:2021-01-05
  • Contact: JI Yuanhui

聚合物辅料对阿司匹林结晶动力学影响机制的非平衡热力学建模及预测

吉远辉(),陈俏,翁靖云   

  1. 东南大学化学化工学院,江苏省生物药物高技术研究重点实验室,江苏 南京 211100
  • 通讯作者: 吉远辉
  • 作者简介:吉远辉(1982—),女,博士,教授,yuanhui.ji@seu.edu.cnyuanhuijinj@163.com
  • 基金资助:
    国家自然科学基金面上项目(21776046);中央高校基本科研业务费专项资金(2242020K40033)

Abstract:

Exploring the mechanism of the influence of polymer excipients on the crystallization of insoluble drugs is the key to guide the design of amorphous solid dispersion formulations and the selection of excipients in the preparation. The effects of different factors (temperature, stirring rate, polymer concentration, molecular weight and polymer type) on the growth kinetics of aspirin crystal were studied. Firstly, the chemical potential gradient model based on three different crystal growth mechanisms and the UNIQUAC activity coefficient model were used to describe and predict the crystallization kinetics of aspirin under different conditions. The effects of different factors on the growth constant kt and crystallization driving force ?μ of aspirin were studied. The results showed that the crystal growth rate of aspirin decreased with the increase of crystallization temperature and polymer concentration, but increased with the increase of stirring rate. Polyvinylpyrrolidone (PVP K25) and hydroxypropyl methyl cellulose (HPMC E3) significantly inhibited the crystal growth of aspirin. The crystal growth of aspirin in HPMC E3 aqueous solution belongs to two-dimensional nucleation mechanism, while the crystal growth in pure water and PEGs aqueous solution belongs to adhesion growth mechanism. The chemical potential gradient model used in this paper can well predict the crystallization kinetics of aspirin at different temperatures and stirring speeds, which can effectively reduce the manpower, material and financial resources required for the experiment. This study can provide theoretical basis for the selection of polymers in the preparation of solid dispersions.

Key words: solid liquid equilibrium, activity coefficient, crystal inhibition, polymer excipients, dynamic model, nonequilibrium thermodynamics

摘要:

探究聚合物辅料对难溶性药物结晶的影响机制,是指导无定形固体分散体制剂设计和制备中辅料筛选的关键。研究了不同因素(温度、搅拌速率、聚合物浓度、聚合物分子量和聚合物种类等)对阿司匹林晶体生长动力学的影响。首先,采用基于三种不同晶体生长机制的化学势梯度模型结合UNIQUAC活度系数模型,描述和预测了阿司匹林在不同条件下的结晶动力学。进一步分析了不同因素对晶体生长速率常数kt和结晶热力学推动力?μ的影响以及对阿司匹林结晶动力学的影响机制。结果表明,阿司匹林晶体生长速率随着结晶温度、聚合物浓度的增加而降低,随搅拌速率的增加而升高;聚乙烯吡咯烷酮(PVP K25)和羟丙基甲基纤维素(HPMC E3)显著抑制了阿司匹林的晶体生长,在PVP K25和HPMC E3水溶液体系下阿司匹林的晶体生长属于二维成核机制,在纯水和PEGs水溶液体系下晶体生长属于粗糙生长机制。所采用的化学势梯度模型能很好预测不同温度和搅拌速率下阿司匹林的结晶动力学,可有效减少实验所需的人力、物力和财力。研究可为固体分散体制剂制备中聚合物的筛选提供理论研究基础。

关键词: 固液相平衡, 活度系数, 结晶抑制, 聚合物辅料, 动力学模型, 非平衡热力学

CLC Number: