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Quality by Design (QbD)-Based Numerical and Graphical Optimization Technique for the Development of Osmotic Pump Controlled-Release Metoclopramide HCl Tablets
Drug Design, Development and Therapy ( IF 4.7 ) Pub Date : 2020-11-26 , DOI: 10.2147/dddt.s278918 Sadaf Farooqi 1 , Rabia Ismail Yousuf 1 , Muhammad Harris Shoaib 1 , Kamran Ahmed 1 , Sabah Ansar 2 , Tazeen Husain 1
Drug Design, Development and Therapy ( IF 4.7 ) Pub Date : 2020-11-26 , DOI: 10.2147/dddt.s278918 Sadaf Farooqi 1 , Rabia Ismail Yousuf 1 , Muhammad Harris Shoaib 1 , Kamran Ahmed 1 , Sabah Ansar 2 , Tazeen Husain 1
Affiliation
Purpose: To develop the osmotically controlled-release gastroprokinetic metoclopramide HCl tablets, using quality by design (QbD)-numerical and graphical optimization technique for the treatment of gastroparesis and prophylaxis of delayed nausea and vomiting induced by low-high emetogenic chemotherapy.
Methods: Formulations were designed by central composite design using Design Expert version 11.0.0, with osmogen concentration (X1), orifice size (X2), and tablet weight gain after coating (X3) as input and in-vitro drug release at 1hr. (Y1), 6 hrs. (Y2), and 12 hrs. (Y3), and the regression coefficient of drug release data fitted to zero-order, RSQ zero (Y4) as output variables. Core tablets prepared by direct compression were coated with Opadry® CA. The experimental design was validated by the polynomial equation. A correlation between predicted and observed values was evaluated by random checkpoint analysis. The optimized formulations were characterized for drug release, pH effect, osmolarity, agitation intensity, surface morphology, and stability study, and were subjected to accelerated studies according to ICH guidelines.
Results: The interaction charts and response surface plots deduced a significant simultaneous effect of X variables on in vitro drug release and RSQ zero. The numerical optimization model predicted > 90% drug release with X1 (13.30%), X2 (0.6 mm), and X3 (7.96%). Random checkpoint analysis showed a good correlation between predicted and observed values. The optimized formulation followed zero-order kinetics (r2=0.9703) drug release. Shelf life calculated was 2.8 years as per ICH guidelines.
Conclusion: The QbD-based approach was found successful in developing controlled release osmotic tablets of metoclopramide HCl, for reducing the dosage frequency, better emetic control, and improve patient compliance.
Keywords: metoclopramide, elementary osmotic tablet, EOP, central composite design, controlled release, quality by design, QbD, numerical optimization
中文翻译：
基于质量源于设计 (QbD) 的数值和图形优化技术，用于开发渗透泵控释甲氧氯普胺盐酸盐片剂
目的：采用质量源于设计（QbD）数字和图形优化技术开发渗透控释促胃动力盐酸甲氧氯普胺片，用于治疗胃轻瘫和预防低-高致吐化疗引起的迟发性恶心和呕吐。
方法：使用 Design Expert 11.0.0 版通过中心复合设计设计制剂，以渗透原浓度 (X 1 )、孔口尺寸 (X 2 ) 和包衣后片剂重量增加 (X 3 ) 作为输入和体外药物释放在 1 小时。(Y 1 )，6小时。(Y 2 )和12小时。(Y 3 )，以及拟合零阶、RSQ 零的药物释放数据的回归系数(Y 4 )作为输出变量。通过直接压片制备的片芯采用 Opadry ® CA包衣。通过多项式方程验证了实验设计。通过随机检查点分析评估预测值和观测值之间的相关性。对优化的制剂进行了药物释放、pH 效应、渗透压、搅拌强度、表面形态和稳定性研究的表征，并根据 ICH 指南进行了加速研究。
结果：交互作用图和响应面图推断出 X 变量对体外药物释放和 RSQ 零的显着同时影响。数值优化模型预测 X 1 (13.30%)、X 2 (0.6 mm) 和 X 3 (7.96%) 的药物释放率 > 90%。随机检查点分析显示预测值和观测值之间具有良好的相关性。优化的制剂遵循零级动力学（r 2 =0.9703）药物释放。根据 ICH 指南计算的保质期为 2.8 年。
结论：基于 QbD 的方法成功开发了盐酸甲氧氯普胺控释渗透片，可减少给药频率，更好地控制呕吐，并提高患者的依从性。
关键词：甲氧氯普胺，基本渗透片，EOP，中心复合设计，控释，质量源于设计，QbD，数值优化
更新日期：2020-11-25
Methods: Formulations were designed by central composite design using Design Expert version 11.0.0, with osmogen concentration (X1), orifice size (X2), and tablet weight gain after coating (X3) as input and in-vitro drug release at 1hr. (Y1), 6 hrs. (Y2), and 12 hrs. (Y3), and the regression coefficient of drug release data fitted to zero-order, RSQ zero (Y4) as output variables. Core tablets prepared by direct compression were coated with Opadry® CA. The experimental design was validated by the polynomial equation. A correlation between predicted and observed values was evaluated by random checkpoint analysis. The optimized formulations were characterized for drug release, pH effect, osmolarity, agitation intensity, surface morphology, and stability study, and were subjected to accelerated studies according to ICH guidelines.
Results: The interaction charts and response surface plots deduced a significant simultaneous effect of X variables on in vitro drug release and RSQ zero. The numerical optimization model predicted > 90% drug release with X1 (13.30%), X2 (0.6 mm), and X3 (7.96%). Random checkpoint analysis showed a good correlation between predicted and observed values. The optimized formulation followed zero-order kinetics (r2=0.9703) drug release. Shelf life calculated was 2.8 years as per ICH guidelines.
Conclusion: The QbD-based approach was found successful in developing controlled release osmotic tablets of metoclopramide HCl, for reducing the dosage frequency, better emetic control, and improve patient compliance.
Keywords: metoclopramide, elementary osmotic tablet, EOP, central composite design, controlled release, quality by design, QbD, numerical optimization
中文翻译：
基于质量源于设计 (QbD) 的数值和图形优化技术，用于开发渗透泵控释甲氧氯普胺盐酸盐片剂
目的：采用质量源于设计（QbD）数字和图形优化技术开发渗透控释促胃动力盐酸甲氧氯普胺片，用于治疗胃轻瘫和预防低-高致吐化疗引起的迟发性恶心和呕吐。
方法：使用 Design Expert 11.0.0 版通过中心复合设计设计制剂，以渗透原浓度 (X 1 )、孔口尺寸 (X 2 ) 和包衣后片剂重量增加 (X 3 ) 作为输入和体外药物释放在 1 小时。(Y 1 )，6小时。(Y 2 )和12小时。(Y 3 )，以及拟合零阶、RSQ 零的药物释放数据的回归系数(Y 4 )作为输出变量。通过直接压片制备的片芯采用 Opadry ® CA包衣。通过多项式方程验证了实验设计。通过随机检查点分析评估预测值和观测值之间的相关性。对优化的制剂进行了药物释放、pH 效应、渗透压、搅拌强度、表面形态和稳定性研究的表征，并根据 ICH 指南进行了加速研究。
结果：交互作用图和响应面图推断出 X 变量对体外药物释放和 RSQ 零的显着同时影响。数值优化模型预测 X 1 (13.30%)、X 2 (0.6 mm) 和 X 3 (7.96%) 的药物释放率 > 90%。随机检查点分析显示预测值和观测值之间具有良好的相关性。优化的制剂遵循零级动力学（r 2 =0.9703）药物释放。根据 ICH 指南计算的保质期为 2.8 年。
结论：基于 QbD 的方法成功开发了盐酸甲氧氯普胺控释渗透片，可减少给药频率，更好地控制呕吐，并提高患者的依从性。
关键词：甲氧氯普胺，基本渗透片，EOP，中心复合设计，控释，质量源于设计，QbD，数值优化
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