On the use of linear model-based optimization to obtain optimum solubility permeability balance (OSPB) in cinnarizine-hydrotropic blends

The objectives of this work are (1) To scrutinize the various hydrotropes for acting as cinnarizine solubility augmenting excipient, (2) To show the existence of solubility-permeability interplay phenomenon on cinnarizine-hydrotrope blend through an in vitro experimental set up and (3) To apply linear model-based optimization (by using Design Expert (R) software) for finding out optimum solubility permeability balance on cinnarizine-hydrotrope blend. Among the tested six-different hydrotropic molecules such as nicotinamide, sodium acetate, sodium benzoate, sodium citrate, sodium salicylate and urea, the cinnarizine solubility values were found to increase from 2.39 +/- 0.00 to 57.98 +/- 0.02 and 150.42 +/- 0.02 mu g/ml, respectively, for sodium benzoate and sodium salicylate at 40 % w/v concentration levels. However, the solubility enhancement effect produced by these two hydrotropic molecules was occurred at the expense of cinnarizine permeability value (from 44.00 x 10-5 to 35.00 +/- 12.00 (x10- 5) cm/sec) indicating the presence of solubility-permeability interplay/tradeoff phenomenon. Indeed, the Box-Behnken design yielded the optimized formula for preparing cinnarizinehydrotrope blends possessing the maximum drug solubility value without significant reduction of drug permeability value. Hence, the quality by design approach plays a crucial role in optimizing the cinnarizinehydrotropic formulations.