DEVELOPMENT AND CHARACTERIZATION OF NOVEL CO-AMORPHOUS SYSTEM OF RITONAVIR WITH FUMARIC ACID: IMPROVED SOLUBILITY AND DISSOLUTION

Abstract

Ritonavir is highly lipophilic molecule that is practically insoluble in water, is widely used in
low-dose fixed combinations, as a pharmacokinetic booster in antiretroviral regimens. Although
it has favourable lipophilicity, ritonavir is reported to be a substrate of P-glycoprotein. Thus, the
oral absorption of ritonavir could be limited by both dissolution and permeability, and is
therefore considered a Class IV compound in the Biopharmaceutics Classification System. As
the permeability is least impacted due to formulation strategies, hence the attempts were made
to improve the solubility and dissolution rate. A novel coamorphous system of ritonavir was
prepared with fumaric acid as low molecular weight coformer. Developed coamorphous system
was meticulously characterized by advanced solid state characterization techniques such as
DSC, modulated DSC, PXRD and PLM. Fit-to-purpose HPLC method was developed and
validated with limited quantification parameters. Intermolecular interaction between ritonavir
and fumaric acid was carefully studied by FTIR analysis. Developed coamorphous system
showed ~6 fold improvement in the water solubility over crystalline ritonavir. Due to enhanced
solubility, coamorphous system showed complete release in water as compared to crystalline
ritonavir.