Avanafil (AV) is the phosphodiesterase (PDE) type 5 inhibitor drug used in erectile dysfunction, having pyrrolidine, pyrimidine, carboxamide, and chlorine as functional groups which can easily break by environmental changes and cause toxicity. Henceforth, in detail, HPLC stability study with the Quality-by-Design (QbD) approach is presented which leads to recommended storage conditions. The stability of AV was analyzed in hydrolysis, photolysis, and thermal and oxidative conditions. The application of the QbD approach during the stability method development comprises steps as screening and optimization. Quality target product profile (QTPP) was defined, and critical quality attributes (CQAs) were assigned to meet the QTPP requirements. Primary parameters obtained from the Ishikawa diagram were studied via Placket–Burman, and four critical factors were optimized through the central composite design (CCD). The finalized method includes mobile phase [10 mM ammonium acetate, pH 4.5 adjusted by acetic acid:ACN (60:40, v/v)] at 0.9-mL/min flow rate and 239-nm wavelength. A control strategy was set up to ensure that the method repeatedly meets the acceptance criteria. Overall, 16 degradation product peaks of AV in all conditions (solid and solution state) were identified with optimized method and evaluated by HPLC-PDA study. A comprehensive systemic optimization of AV stability study is stated for the first time, which reveals that AV is prone to degrade in sunlight, moisture, and temperature. Global regulators and manufacturers should take care of the packaging, handling, and labeling of AV. A fully validated LC–MS compatible stability method can be successfully applied to monitor AV stability from its formulation which can be wisely extrapolated to assess the AV from biological samples. Graphical abstract

中文翻译：

---

使用先进的质量设计方法开发阿伐那非磷酸二酯酶 5 型抑制剂的综合稳定性指示方法

Avanafil (AV) 是一种用于勃起功能障碍的磷酸二酯酶 (PDE) 5 型抑制剂药物，具有吡咯烷、嘧啶、甲酰胺和氯作为官能团，容易被环境变化破坏并引起毒性。此后，详细介绍了使用质量源于设计 (QbD) 方法的 HPLC 稳定性研究，这会导致推荐的储存条件。在水解、光解、热和氧化条件下分析了 AV 的稳定性。QbD 方法在稳定性方法开发过程中的应用包括筛选和优化步骤。定义了质量目标产品概况 (QTPP)，并分配了关键质量属性 (CQA) 以满足 QTPP 要求。通过 Plaket-Burman 研究从 Ishikawa 图获得的主要参数，并通过中央复合设计（CCD）优化了四个关键因素。最终的方法包括流动相 [10 mM 醋酸铵，pH 4.5，由醋酸:乙腈 (60:40, v/v) 调节]，流速为 0.9 mL/min，波长为 239 nm。建立了控制策略以确保该方法反复满足验收标准。总体而言，在所有条件（固体和溶液状态）下，AV 的 16 个降解产物峰均采用优化方法进行鉴定，并通过 HPLC-PDA 研究进行评估。首次对 AV 稳定性研究进行了全面的系统优化，揭示了 AV 在阳光、潮湿和温度下容易降解。全球监管机构和制造商应注意 AV 的包装、处理和标签。完全验证的 LC-MS 兼容稳定性方法可以成功应用于从其配方监测 AV 稳定性，可以明智地外推以评估来自生物样品的 AV。图形概要