动力障碍 弱基本药物的盐不成比例的动力障碍
Tu Van Duong1, Samir Diab2, Neil S Hodnett3
1Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana47907, United States.
Molecular pharmaceutics
|July 26, 2023
概括
药物盐不成比例是一个挑战. 这项研究表明,盐转基的转化速度取决于动力障碍,如自由基核化,而不仅仅是pH. 考虑这些动力学可以改善配方稳定性的预测.
科学领域:
- 制药科学 制药科学
- 物理化学 物理化学
- 材料科学 材料科学 材料科学
背景情况:
- 弱基药盐的不成比例是一个关键的配方问题.
- 预测盐基转化和评估配方风险仍然具有挑战性.
- 仅仅热力学因素是不够的;动力学障碍也影响盐不成比例.
研究的目的:
- 为了研究水性泥中盐不成比例的动力学.
- 评估自由基核化动力学在盐基转换中的作用.
- 开发一个改进的模型来预测盐配方的固态稳定性.
主要方法:
- 同时应用现场拉曼光谱和pH监测.
- 对三种模型盐的研究:皮奥格利塔化,索拉菲尼布托西拉酸和阿塔扎纳维尔硫酸盐.
- 开发一个修改后的热力学模型,包括动力学效应.
主要成果:
- 不成比例的动力学在盐之间有显著的差异,即使在有利的热力学条件下 (pH>pHmax).
- 盐的转化时间与自由基核化诱导时间直接相关.
- 皮奥格利塔松化显示出快速转化 (<1分钟),而阿塔萨纳维尔硫酸盐转化需要几个小时.
结论:
- 盐不成比例受到热力学驱动力和动力学障碍的控制,特别是自由基核.
- 必须将动力学因素整合到模型中,以准确预测药物配方中的固态稳定性.
- 考虑动力学的一种修改后的热力学模型提供了一种机械学上适当的方法来预测盐不成比例.
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