Control strategy and quality by design (QbD) are widely used to develop pharmaceutical products and improve drug quality; however, studies on fixed-dose combination (FDC) bilayer tablets are limited. In this study, the bilayer tablet consisted of high-dose metformin HCl in a sustained-release layer and low-dose dapagliflozin l-proline in an immediate-release layer. The formulation and process of each layer were optimized using the QbD approach. A d-optimal mixture design and response surface design were applied to optimize critical material attributes and critical process parameters, respectively. The robust design space was developed using Monte Carlo simulations by evaluating the risk of uncertainty in the model predictions. Multivariate analysis showed that there were significant correlations among impeller speed, massing time, granule bulk density, and dissolution in the metformin HCl layer, and among roller pressure, ribbon density, and dissolution in the dapagliflozin l-proline layer. Process analytical technology (PAT) was used with in–line transmittance near-infrared spectroscopy to confirm the bulk and ribbon densities of the optimized bilayer tablet. Moreover, the in vitro drug release and in vivo pharmacokinetic studies showed that the optimized test drug was bioequivalent to the reference drug. This study suggested that integrated QbD, statistical, and PAT approaches can develop a robust control strategy for FDC bilayer tablets by implementing real-time release testing based on the relationships among various variables.

中文翻译：

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通过设计、统计和过程分析技术方法开发具有综合质量的固定剂量复方双层片的稳健控制策略

控制策略和质量源于设计 (QbD) 被广泛用于开发药品和提高药品质量；然而，对固定剂量复方 (FDC) 双层片的研究是有限的。在这项研究中，双层片剂由缓释层中的高剂量盐酸二甲双胍和速释层中的低剂量达格列净 l-脯氨酸组成。使用 QbD 方法优化每一层的配方和工艺。d 最优混合设计和响应面设计分别用于优化关键材料属性和关键工艺参数。通过评估模型预测中的不确定性风险，使用蒙特卡罗模拟开发了稳健设计空间。多因素分析表明，叶轮转速、质量时间、颗粒堆积密度和在盐酸二甲双胍层中的溶解度，以及滚筒压力、色带密度和在达格列净 l-脯氨酸层中的溶解度。过程分析技术 (PAT) 与在线透射近红外光谱一起使用，以确认优化的双层片剂的体积和带状密度。此外，体外药物释放和体内药代动力学研究表明，优化后的受试药物与参比药物具有生物等效性。该研究表明，综合 QbD、统计和 PAT 方法可以通过基于各种变量之间的关系实施实时释放测试，为 FDC 双层片制定稳健的控制策略。过程分析技术 (PAT) 与在线透射近红外光谱一起使用，以确认优化的双层片剂的体积和带状密度。此外，体外药物释放和体内药代动力学研究表明，优化后的受试药物与参比药物具有生物等效性。该研究表明，综合 QbD、统计和 PAT 方法可以通过基于各种变量之间的关系实施实时释放测试，为 FDC 双层片制定稳健的控制策略。过程分析技术 (PAT) 与在线透射近红外光谱一起使用，以确认优化的双层片剂的体积和带状密度。此外，体外药物释放和体内药代动力学研究表明，优化后的受试药物与参比药物具有生物等效性。该研究表明，综合 QbD、统计和 PAT 方法可以通过基于各种变量之间的关系实施实时释放测试，为 FDC 双层片制定稳健的控制策略。体外药物释放和体内药代动力学研究表明，优化后的受试药物与参比药物具有生物等效性。该研究表明，综合 QbD、统计和 PAT 方法可以通过基于各种变量之间的关系实施实时释放测试，为 FDC 双层片制定稳健的控制策略。体外药物释放和体内药代动力学研究表明，优化后的受试药物与参比药物具有生物等效性。该研究表明，综合 QbD、统计和 PAT 方法可以通过基于各种变量之间的关系实施实时释放测试，为 FDC 双层片制定稳健的控制策略。