Hybridized nanoamorphous micellar dispersion using a QbD-DM 3 linked rational product design strategy for ritonavir: A BCS IV drug.

A QbD-DM linked rational product design strategy was adopted to create a hybridized ritonavir (RTV, BCS Class IV) nanoamorphous micellar dispersion (RTV-NAD). A DM research strategy was employed in conjunction with the quality-by-design spaces, and quality target product profile to link the critical material attributes and critical process parameters to the quality target product profile's critical product attributes QbD elements. A Box-Behnken design and multivariate analysis using multiple linear regression and partial least squares provided data analysis. The hybridized strategy leveraged three different mechanisms to increase RTV's solubility and four mechanisms to increase its dissolution rate. Statistically significant models were generated for critical product attributes: particle size (p = 0.0000, R adjusted = 0.9513), polydispersity index (p = 0.0002, R adjusted = 0.6398), zeta potential (p = 0.0000, R adjusted = 0.9744), and drug loading on a dry basis (p = 0.0000, R adjusted = 0.9951). The impact of drug concentration, Soluplus® concentration, and solvent:antisolvent ratio, their interactions and square effects on the critical product attributes were assessed by multivariate analysis. The QbD optimal formulation was determined for RTV-NAD. Multiple linear regression and partial least squares computational predictability was evaluated using three verification batches. The prediction error for critical product attributes was <5%. RTV-NAD and ritonavir microsuspension were characterized by x-ray diffraction and in-vitro dissolution studies. X-ray diffraction confirmed the amorphous nature of the RTV-NAD. RTV-NAD exhibited a 'spring-hover' dissolution profile at pH 4.5. At pH 6.8, a classic 'spring-parachute' dissolution behavior was observed.