Enhancing Ketoprofen Solubility: A Strategic Approach Using Solid Dispersion and Response Surface Methodology

Abstract

Background: In the pharmaceutical sciences, the solubility profile of therapeutic molecules is crucial for identifying and formulating drugs and evaluating their quality across the drug discovery pipeline based on factors like oral bioavailability, metabolic transformation, biodistribution kinetics, and potential toxicological implications. The investigation aims to enhance the solubility parameters of ketoprofen (BCS-II class), which exhibits low solubility and high permeability.

Methods: In this method, hydrotrope blends of aromatic sodium benzoate and electrolyte sodium acetate were employed to enhance the solubility parameter of ketoprofen. Several batches of solid dispersion of ketoprofen were made using a solvent evaporation method, and the response surface method 3² factorial design was used to find the best one. The optimised formulation, KSD9, underwent in-vitro drug dissolution, DSC, pXRD, and SEM studies.

Results: The optimized batch demonstrated substantial improvement in ketoprofen solubility, attributed to mixed hydrotropy. The results indicated that both solubility and %CDR improved when hydrotropes were employed, suggesting a direct proportionality between the rise in solubility and % CDR. Formulations KSD1-KSD9 exhibited solubility enhancements ranging from 2.23 to 5.77-fold, along with an elevation in % CDR from 72.28% to 94.76%. This implies that the % CDR was modulated by the hydrotropes, specifically influenced by the concentration levels of the independent variables. An increase in hydrotrope levels corresponded to an increase in % CDR. The positive coefficients in the quadratic equation for % CDR underscored the significant role of these independent variables in augmenting the in-vitro release of Ketoprofen. Similarly, during a comparative dissolution investigation, the optimized KSD9 formulation exhibited remarkable solubility and drug content compared to conventional Ketoprofen dispersible tablets.

Conclusion: The synergistic effect of combining two hydrotropic agents significantly increased the solubility of ketoprofen by up to 58 times. The results indicated that the independent variables exerted a positive influence on solubility and % CDR. Furthermore, the responses were contingent on the specific hydrotropes selected, which functioned as the independent variables. Analyzing the r² and ANOVA results suggested that the dependent variables aligned well with the chosen model. Visual representations, such as the 3D response surface plot and contour plot, demonstrated the impact of each hydrotrope individually and when combined. Overall, employing hydrotropes led to improved solubility and % CDR, highlighting a direct proportionality between the rise in solubility and % CDR. Mixed hydrotropic lessens the toxicity associated with individual hydrotrope concentrations while also offering a sustainable and eco-friendly alternative. This study paves the way for future research aiming to improve the solubility of low- solubility drugs, broadening their clinical applications.

Keywords: Hydrotropy; mixed hydrotropes; optimization; solid dispersion; solubilization; surface response methodology..