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一种新出现的多态体的固态评估,用于早期药物开发的早期药物开发

Wei Zhang¹, Antonio DiPasquale¹, Jerry Phan¹

¹Synthetic Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.

Molecular pharmaceutics

|June 10, 2025

概括

确定GDC-6599的一个新多态 (M型) 比A型更稳定. 尽管溶解度较低,但建议M型用于制造和开发,而A型支持早期临床研究.

科学领域:

制药固态化学制药固态化学
药物物质开发药物物质开发
结晶科学结晶科学

背景情况:

在GDC-6599的早期发展阶段,A型被确定为最稳定的多态.
晶体结构预测 (CSP) 表明存在更稳定的多态体.
在千克尺度的API批量结晶过程中发现了一种新的多态,M形式.

研究的目的:

描述和评估GDC-6599.9的新发现的多态 (M形式)
为了将Form M的稳定性和性能与已建立的Form A进行比较.
评估M表对药物产品性能和制造的影响.

主要方法:

多态选和结晶的发展.
粉末X射线衍射 (PXRD) 用于模式分析.
差分扫描热量计 (DSC) 用于热分析.
泥竞争 (SC) 用于稳定性评估.
为工艺控制开发定量PXRD方法.
内在溶解度和生物制药评估.

主要成果:

形式M的PXRD模式与排名最高的CSP预测相匹配.
DSC和SC证实了Form A和Form M之间的等离子关系,其中Form M更稳定.
开发了一种定量PXRD方法来控制结晶过程中的A型百分比.
形式M表现出56%的形式A的内在溶解度,与热力学预测保持一致.
生物制药评估表明,在相关剂量下,药物性能没有显著影响.

结论:

形式M是热力学上更稳定的多态,建议用于API制造和固体剂型开发.
形式A适用于悬浮配方和早期临床研究,在开发中提供灵活性.
这些发现为制药开发中明智选择固体形式提供了关键数据.

关键词:

生物制药生物制药生物制药它们是enantiotropic的多态体.药品制药公司药品制药公司多形态主义的多态主义.有关PXRDD的定量研究.

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