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Employment of Quality by Design Approach via Response Surface Methodology to Optimize and Develop modified-release Formulation of Hydrochlorothiazide


Vikas D Singhai, Rahul Maheshwari*, Swapnil Sharma and Sarvesh Paliwal   Pages 1 - 15 ( 15 )


Background: Heart attack predominantly occurs during the last phase of sleep and early morning hours, causing millions of death worldwide. Hydrochlorothiazide (HCTZ) is 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 extended-release formulation may have industrial significance. Regulatory agencies emphasize Quality by Design based approach for product development to entrust quality in the product.

Objective: Aim of the current research was to develop a quality product profile of HCTZ modified-release tablets (MRT; ~14 h) by applying Response Surface Methodology using computational QbD approach.

Methods: Three independent factors were identified by qualitative and quantitative risk assessment. Statistical terms like p-value, lack of fit, 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 model selection. Graphical relationship among the critical, independent variables was represented using the Contour plot and 3-D surface plot. Design space was identified by designing 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.

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


Quality by design, Modified release formulation, Quality target product profile, heart attack, Surface response method, Graphical Models


Department of Pharmacy, Banasthali Vidyapith, Banasthali-304022, Rajasthan, India and Alembic Research Center, Alembic pharmaceuticals limited, Alembic Road, Vadodara, Gujarat-390003, School of Pharmacy and Technology Management, SVKM’s NMIMS, Hyderabad, Telangana-509301, Department of Pharmacy, Banasthali Vidyapith, Banasthali-304022, Rajasthan, Department of Pharmacy, Banasthali Vidyapith, Banasthali-304022, Rajasthan

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