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.