Analytical Quality by Design-Driven RP-HPLC Method Conditions to Concomitantly Determine Cinnarizine and Morin Hydrate in Combined Drug Solution and Dual Drug-Loaded Formulations.

Abstract

The replacement of traditional oils with a camphor and menthol-based eutectic mixture is done to prepare oil-less emulsion-like dispersions for co-delivery of cinnarizine (CNZ) and morin hydrate (MH) for managing Meniére's disease (MD). Since two drugs are loaded into the dispersions, the development of a suitable reverse phase-high performance liquid chromatography (RP-HPLC) method for their simultaneous analysis becomes inevitable. By applying the analytical quality by design (AQbD) approach, the RP-HPLC method conditions were optimized for the concomitant determination of two drugs. The systematic AQbD started with identifying critical method attributes (CMA) through an Ishikawa fishbone diagram, risk estimation matrix, and risk priority number-based failure mode effect analysis followed by screening using fractional factorial design and optimization by face-centered central composite design. The concomitant determination of two drugs by the optimized RP-HPLC method condition was substantiated via specificity checking using combined drug solution, drug entrapment efficiency, and in vitro release of the two drugs from emulsion-like dispersions. The AQbD optimized RP-HPLC method conditions revealed the retention time for CNZ and MH at 5.017 and 5.323, respectively. The studied validation parameters were found within the ICH-prescribed limits. Exposing the individual drug solutions to acidic and basic hydrolytic conditions yielded extra chromatographic peaks for MH, probably due to the degradation of MH. The DEE % values of 87.40 ± 4.70 and 74.79 ± 2.94, respectively, were noticed for CNZ and MH in emulsion-like dispersions. More than 98% CNZ and MH release was occurred from emulsion-like dispersions within 30 min post-dissolution in artificial perilymph. Overall, the AQbD approach could be helpful for systematic optimization of RP-HPLC method conditions to estimate concomitantly other therapeutic moieties. The proposed article shows the successful application of AQbD for the optimization of RP-HPLC method conditions to concomitantly estimate CNZ and MH in combined drug solution and dual-drug-loaded emulsion-like dispersions.