Development of a Robust Control Strategy for Fixed-Dose Combination Bilayer Tablets with Integrated Quality by...

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Process Engineering

Background:

• Fixed-dose combination (FDC) bilayer tablets present unique development challenges.
• Quality by Design (QbD) principles are crucial for optimizing complex pharmaceutical formulations.
• Limited studies exist on applying QbD to FDC bilayer tablet development.

Purpose of the Study:

• To optimize the formulation and manufacturing process of an FDC bilayer tablet containing metformin HCl and dapagliflozin l-proline.
• To establish a robust control strategy for FDC bilayer tablets using QbD and Process Analytical Technology (PAT).
• To demonstrate bioequivalence of the developed FDC bilayer tablet with a reference product.

Main Methods:

• Utilized a Quality by Design (QbD) approach for formulation and process optimization.
• Employed d-optimal mixture and response surface designs to optimize critical material attributes and process parameters.
• Applied Monte Carlo simulations for robust design space development and multivariate analysis to identify key variable correlations.
• Integrated Process Analytical Technology (PAT) with in-line near-infrared spectroscopy for real-time monitoring.

Main Results:

• Optimized critical material attributes and process parameters for both sustained-release (metformin HCl) and immediate-release (dapagliflozin l-proline) layers.
• Established significant correlations between process variables (e.g., impeller speed, roller pressure) and critical quality attributes (e.g., dissolution).
• Confirmed critical tablet attributes using PAT, demonstrating successful process control.
• Achieved bioequivalence between the optimized FDC bilayer tablet and the reference drug through in vitro and in vivo studies.

Conclusions:

• Integrated QbD, statistical methods, and PAT enable the development of a robust control strategy for FDC bilayer tablets.
• Real-time release testing can be implemented for FDC bilayer tablets based on established variable relationships.
• This approach enhances drug quality and facilitates efficient manufacturing of complex dosage forms.