在Tegoprazan中全面调查多态稳定性和相变动力学
Joo Ho Lee1, Ki Hyun Kim2, Se Ah Ryu1
1J2Hbiotech Inc., #210, B Dong, Suwon Venture Valley II, Suwon 16648, Republic of Korea.
Pharmaceutics
|July 30, 2025
概括
泰戈普拉桑 (TPZ) 固体形式的选择是由溶液相分子行为和溶剂相互作用驱动的. 了解这些因素可以合理控制药物结晶,并防止多态的损失.
科学领域:
- 固态化学 固态化学
- 制药科学 制药科学
- 物理化学 物理化学
背景情况:
- 泰戈普拉桑 (TPZ) 是一种与竞争的酸阻塞剂 (P-CAB),用于胃食道逆流症,胃潰瘍和H. pylori感染.
- TPZ表现出三种固体形式:无形,多态A和多态B.
- 多态体的选择和稳定性对于药物的有效性和制造至关重要.
研究的目的:
- 为了研究tegoprazan (TPZ) 多态选择的分子基础.
- 了解TPZ固体形式行为中构造偏差和溶剂介导相变 (SMPTs) 的作用.
- 开发一个框架,以合理的多态控制在 tautomeric 药物.
主要方法:
- 使用OPLS4力场计算了符合性能量景观,并通过NMR进行了验证.
- 用分散密度函数理论 (DFT-D) 来分析与结合的二次元.
- 用各种溶剂 (甲醇,乙,水) 进行粉末X射线衍射 (PXRD),DSC,溶解度和泥测试.
主要成果:
- 在所有测试条件下,多态A被确定为热力学稳定的形式.
- 无形TPZ和多态B以依赖溶剂的方式转化为多态A.
- 益基溶剂 (例如甲醇) 有利于多态A的直接结晶,而益基溶剂 (例如乙) 导致过渡性多态B的形成.
结论:
- 泰戈普拉桑 (TPZ) 的多态选择由溶液相形状偏好,复合体和溶剂介导的键决定.
- 溶剂类型显著影响结晶路径,指导稳定或转移稳定的多态体的形成.
- 这些发现提供了一个实际的,独立于晶体结构预测 (CSP) 的策略,用于控制多态过渡,并减轻与消失的多态相关的风险.
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