Robustness testing, using experimental design, of a flow-through dissolution method for a product where the actives...

Area of Science:

• Pharmaceutical Sciences
• Analytical Chemistry
• Drug Development

Background:

• Atovaquone solubility is suppressed by proguanil hydrochloride in Malarone tablets.
• Coating material insolubility can cause imprecision in dissolution testing.
• Robust dissolution methods are crucial for quality control of multi-drug formulations.

Purpose of the Study:

• To evaluate the robustness of a flow-through dissolution method for atovaquone using experimental design.
• To identify critical method parameters affecting atovaquone dissolution testing.
• To ensure reliable dissolution profiles for Malarone tablets.

Main Methods:

• Application of a quarter fractional two-level factorial design for robustness testing.
• Utilized Ph. Eur./USP Apparatus 4 for flow-through dissolution.
• Assessed six factors across sixteen experiments with six center points.

Main Results:

• The dissolution method demonstrated robustness to minor variations in most factors at 30 minutes and beyond.
• At 15 minutes, sodium hydroxide concentration, pump speed, and flow rate significantly impacted results.
• Atovaquone release reached pharmacopoeial limits (Q=75%) by 45 minutes.

Conclusions:

• The developed flow-through dissolution method is robust for atovaquone, ensuring reliable quality control.
• Specific parameters (NaOH concentration, pump speed, flow rate) require strict control during early dissolution stages.
• This experimental design approach can be adapted for other dissolution testing procedures.