The objective of the study was to evaluate the possible pH-dependent interaction of ribociclib succinate with acid-reducing agents, which are concomitantly administered as supportive care medicines in cancer. Quality by Design-based analytical method development for a weakly basic drug ribociclib succinate supposedly having the characteristic ability of pH-dependent solubility was carried out for analyzing micro-dissolution experiment samples in biorelevant media to study pH-dependent interaction. An accurate and robust analytical method was developed using a three-level three-factorial box–behnken design for quantification of ribociclib succinate in micro-dissolution samples by the implementation of the Analytical Quality by Design approach. Here, pH of aqueous mobile phase and flow rate proved to be critical process parameters. The gastric compartment solubility was found to be 814.05 μg/mL, which dropped down to 494.71 μg/mL after a pH shift from pH 1.2–6.5. In the intestinal compartment, initial solubility was 717.58 μg/mL, which reduced to 463.20 μg/mL after a pH shift from 6.5 to 6.8. Concluded results state that pH shift does not impact the solubility or the absorption of the drug to a significant extent in the presence of acid-reducing agents. However, the study would prove to be a practical approach for examination of the behavior of the drugs at the initial stages.

中文翻译：

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是否应该避免酸还原剂与 Ribociclib 联合使用？用于评估 pH 介导的相互作用的综合 QbD 方法


该研究的目的是评估 ribociclib 琥珀酸盐与酸还原剂之间可能存在的 pH 依赖性相互作用，这两种药物同时作为癌症支持治疗药物使用。针对据称具有 pH 依赖性溶解度特性的弱碱性药物瑞博西尼琥珀酸盐进行了基于设计质量的分析方法开发，用于分析生物相关介质中的微溶出实验样品，以研究 pH 依赖性相互作用。通过实施“分析质量源于设计”方法，使用三水平三因子盒本肯设计开发了一种准确而稳健的分析方法，用于定量微溶出样品中的 ribociclib 琥珀酸盐。在此，水性流动相的 pH 值和流速被证明是关键的工艺参数。胃室溶解度为 814.05 μg/mL，pH 从 1.2-6.5 变化后降至 494.71 μg/mL。在肠室中，初始溶解度为 717.58 μg/mL，pH 从 6.5 变为 6.8 后降低至 463.20 μg/mL。结论结果表明，在酸还原剂存在的情况下，pH 值变化不会在很大程度上影响药物的溶解度或吸收。然而，该研究将被证明是一种在初始阶段检查药物行为的实用方法。