Laboratory of Drug Analysis, Faculty of Pharmacy, University of Costa Rica, San Jose, Costa Rica.
Research and Development, Laboratorio Raven S.A, San Jose, Costa Rica.
Drug Dev Ind Pharm. 2024 Jul;50(7):646-657. doi: 10.1080/03639045.2024.2383932. Epub 2024 Jul 31.
This work aims to present a Quality-by-Design (QbD) step-by-step methodology to formulate anti-ulcer and gastro-protective oral suspensions.
Sucralfate was used as a drug model. The Quality Target Product Profile was established early during preformulation. Viscosity, resuspendability, pH, and density were assessed through the screening of several suspension platforms based on different prototype compositions. A compatibility study between the active pharmaceutical ingredient and the excipients was performed by thermal analysis and infrared spectroscopy. An Ishikawa fishbone diagram and Failure Mode and Effect Analysis were employed to identify the Critical Material Attributes (CMAs), Critical Process Parameters (CPPs), and Critical Quality Attributes (CQAs). CMAs' and CPPs' impact on identified CQAs was further assessed through a 2 full factorial experimental design at normal conditions after manufacture and one month at super-accelerated stress conditions. The lead prototype exhibited no physicochemical incompatibilities. The risk assessment tools revealed that the concentration of the wetting agent and the total concentration of thickening agents represented critical factors for the quality profile of the preparation in terms of viscosity. The optimized formulation comprising 1.125 w/v% total concentration of Natrosol 250 HX and Avicel RC 591 exhibited an enhanced performance according to the established profile.
The analytical and physicochemical tests showed the robustness and compliance of the final preparation with the quality profile. The proposed step-by-step methodology based on QbD, Design of Experiments, and Quality Risk Management presented in our research holds practical implications for local industries and formulation scientists involved in the development of oral suspensions.
本工作旨在提出质量源于设计（QbD）的逐步方法，以配制抗溃疡和胃保护口服混悬剂。
使用蔗糖铁作为药物模型。在配方前阶段尽早建立质量目标产品概况。通过基于不同原型组成的几种混悬液平台的筛选，评估了混悬液的黏度、再悬浮性、pH 值和密度。通过热分析和红外光谱对活性药物成分与赋形剂之间的相容性进行研究。采用石川鱼骨图和失效模式与影响分析（FMEA）来识别关键物料属性（CMA）、关键工艺参数（CPP）和关键质量属性（CQA）。在正常条件下制造后和在超加速应力条件下一个月后，通过 2 全因子实验设计进一步评估 CMA 和 CPP 对已识别 CQA 的影响。主要原型无物理化学不相容性。风险评估工具表明，润湿剂的浓度和增稠剂的总浓度在黏度方面代表了制剂质量特性的关键因素。包含 1.125 w/v%Natrosol 250 HX 和 Avicel RC 591 的总浓度的优化配方表现出根据所建立的特性的增强性能。
分析和物理化学测试表明最终制剂具有与质量特性相符的稳健性和合规性。本研究中提出的基于 QbD、实验设计和质量风险管理的逐步方法对当地工业和参与口服混悬剂开发的制剂科学家具有实际意义。
