选择性稳定性指示液体染色法基于质量设计框架和In Silico毒性评估对infigratinib及其降解产品的选择性稳定性指示液体染色法
Awadh M Ali1, Mohammed M Alanazi1, Mohamed W Attwa1
1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Molecules (Basel, Switzerland)
|November 25, 2023
概括
这项研究详细介绍了在压力条件下降解 cholangiocarcinoma 药物 infigratinib 的情况. 一种新的分析方法确定了五种降解产物,其中两种被预测为变异原体,确保了药物安全.
科学领域:
- 制药化学 制药化学 制药化学
- 分析化学 分析化学
- 药物开发 药物开发
背景情况:
- 因菲格拉提尼布是胆管癌的关键治疗药物.
- 了解药物降解对于确保治疗疗效和患者安全至关重要.
- ICH的指导方针要求对制药化合物进行压力测试.
研究的目的:
- 开发和验证一种强大的分析方法,用于分离和识别因菲格拉提尼布降解产品.
- 在各种压力条件下描述infigratinib的降解概况.
- 评估infigratinib及其降解剂的潜在毒性和变异性.
主要方法:
- 按照ICH指导方针进行压力降解研究 (水解,氧化,光解,热).
- 设计质量 (QbD) 原则,用于开发快速和特定的分离方法.
- 逆相高性能液态色谱 (RP-HPLC) 使用C18列和梯度化.
- UPLC-四极双重质谱法 (UPLC-MS/MS) 用于结构的阐明.
- 在使用DEREK Nexus和SARAH Nexus软件的毒性和变异性预测中.
主要成果:
- 在不同的压力条件下确定了五种不同的因菲格拉提尼布降解产物.
- 一种经过验证的RP-HPLC方法证明了出色的线性 (5.0-200.0μg/mL),准确性,可重复性和选择性.
- UPLC-MS/MS成功地描述了降解产品的结构.
- 在分析预测了一些降解剂的潜在毒性,其中两个被确定为潜在的致变物质.
结论:
- 开发的分析方法适合用于infigratinib的常规质量控制.
- 这项研究为infigratinib的稳定性概况提供了关键的见解.
- 识别潜在的突变性降解产品强调了严格的安全评估的重要性.
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