Background: Heart attack predominantly occurs during the last phase of sleep and early morning hours, causing millions of death worldwide. Hydrochlorothiazide (HCTZ) is a recommended drug for the prevention of heart disease, but its long action (>4 h) dosage form is lacking in the commercial market and development of modified-release formulation may have industrial significance. Regulatory agencies emphasize Quality by Design based approach for product development to entrust quality in the product.

Objective: The current research aimed to develop a quality product profile of HCTZ modifiedrelease tablets (MRT; ~14 h) by applying Response Surface Methodology using the computational QbD approach.

Methods: Three independent factors were identified by qualitative and quantitative risk assessment. Statistical terms like p-value, lack of fit, the sum of square, R-squared value, model F value, and linear equations were determined. Graphical tools like normal plot of residual, residual vs predicted plot and box cox plot were used to verify the model selection. The graphical relationship among the critical, independent variables was represented using the Contour plot and 3-D surface plot. Design space was identified by designing an overlay plot using response surface design.

Results: Excellent correlation was observed between actual and predicted values. Similarity Factor (F2) of reproducible trials was 78 and 79, and content uniformity was 100.9% and 100.4%. Average weight, hardness, thickness, diameter, and friability were within acceptable limits.

Conclusion: QbD approach, along with a quality risk management tool, provided an efficient and effective paradigm to build quality MRT of HCTZ.

背景：心脏病发作主要发生在睡眠的最后阶段和清晨，导致全球数百万人死亡。氢氯噻嗪（HCTZ）是预防心脏病的推荐药物，但其长效（>4 h）剂型在商业市场上缺乏，开发缓释制剂可能具有工业意义。监管机构强调基于设计质量的产品开发方法，以确保产品质量。

目标：当前的研究旨在通过使用计算 QbD 方法应用响应面方法学来开发 HCTZ 缓释片 (MRT；~14 小时) 的质量产品概况。

方法：通过定性和定量风险评估确定三个独立因素。确定了诸如 p 值、失拟、平方和、R 平方值、模型 F 值和线性方程等统计项。使用残差正态图、残差与预测图和箱形考克斯图等图形工具来验证模型选择。使用等值线图和 3-D 曲面图表示关键的自变量之间的图形关系。通过使用响应面设计设计叠加图来确定设计空间。

结果：在实际值和预测值之间观察到极好的相关性。可重复试验的相似因子 (F2) 为 78 和 79，含量均匀度为 100.9% 和 100.4%。平均重量、硬度、厚度、直径和脆碎度均在可接受的范围内。

结论：QbD 方法以及质量风险管理工具为构建 HCTZ 的质量 MRT 提供了高效和有效的范例。