Solid State Characterization and Miscibility of Raltegravir in Soluplus Using Solid Dispersion Technology

Abstract:

Background: Raltegravir Potassium (RTGP), a BCS class II drug used in the treatment of HIV, has minimal solubility in the aqueous medium, resulting in poor bioavailability; Further, RTGP poor dissolution and limited solubility are also major factors responsible for the significant inter- and intra-patient variability in absorption following oral administration. Objectives: To enhance the solubility of Raltegravir potassium and its free acid using Soluplus® by solid dispersion technology. Materials and Methods: In the current study, Amorphous Solid Dispersions (ASDs) of RTGP and Raltegravir free acid (RTG) of 20:80% w/w with Soluplus® (SLP) were prepared using quench cooling. The prepared ASDs analyzed for homogenous single-phase formation and intermolecular interactions employing DSC, XRD, and FT-IR. The drug-polymer miscibility was calculated theoretically as well as experimentally with the aid of Hansen solubility parameter and melting point depression methods. The solubility of the ASDs was evaluated by the shake flask method. Results: Quench cooling yielded an RTGP-SLP and RTG-SLP homogeneous amorphous systems. DSC and XRPD results showed the complete transformation of crystalline to the amorphous phase for ASDs. Intermolecular interactions in specific hydrogen bonding were observed between the carbonyl (-C=O) group of Soluplus® and the Raltegravir -N-H moiety. RTG solubility in salt solid dispersion increases by 10.7 and 17.4 folds, respectively, compared to pure forms. Furthermore, free acid ASDs improved solubility by 8.7 and 14.1 folds, respectively, compared to their pure compounds. Conclusion: Salt solid dispersion showed a greater extent of miscibility and improved solubility of RTG compared to free acid solid dispersion.

Keywords: Raltegravir, Amorphous salt solid dispersion, Amorphous solid dispersion, Quench
cooling, Solubility.