Equilibrium solubility determination, Hansen solubility parameters and solution thermodynamics of cabozantinib malate in different monosolvents of pharmaceutical importance

Abstract

Abstract This research work reports new equilibrium solubility data for a novel weakly soluble tyrosine kinase inhibitor cabozantinib malate (CBZM) (a novel antitumor drug) in twelve different monosolvents (MS) of pharmaceutical importance including “water, methanol (MeOH), ethanol (EtOH), isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), ethylene glycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), ethyl acetate (EA), Transcutol-HP (THP) and dimethyl sulfoxide (DMSO)” within the temperature range “T = 298.2-318.2 K under p = 101.1\u202fkPa. The experimental equilibrium solubility values of CBZM were correlated well with “van t Hoff and the modified Apelblat models” with an error values of less than 3.0%. Different Hansen solubility parameters (HSPs) for CBZM and different MS of pharmaceutical importance were also predicted using HSPiP software and various mathematical equations. The maximum value of CBZM solubility was 4.35\u202f×\u202f10−2 in mole fraction in DMSO at T = 318.2\u202fK, but the least data was found in water. The equilibrium solubility of CBZM increased with the rising temperature and the order followed in the twelve MS of pharmaceutical importance was DMSO (4.35\u202f×\u202f10−2) > PEG-400 (1.42\u202f×\u202f10−2) > THP (5.45\u202f×\u202f10−3) > PG (2.38\u202f×\u202f10−3) > 2-BuOH (2.21\u202f×\u202f10−3) > 1-BuOH (2.15\u202f×\u202f10−3) > IPA (1.69\u202f×\u202f10−3) > EG (1.38\u202f×\u202f10−3) > EtOH (1.27\u202f×\u202f10−3) > MeOH (7.05\u202f×\u202f10−4) > EA (4.15\u202f×\u202f10−4) > water (8.50\u202f×\u202f10−7) at T = 318.2\u202fK. Similar trends were also found in other temperatures investigated. Most of the solubility parameters of CBZM were found to be closed with that of DMSO. Thermal analysis showed no existence of processes such as solvation, hydration or polymorphic transformation of CBZM during the entire experiment. The maximum solute-solvent interactions were recorded in CBZM-DMSO, CBZM-PEG-400 and CBZM-THP compared to other combination of drug and MS. “Apparent thermodynamic analysis” suggested an “endothermic and entropy-driven dissolution” of CBZM in all studies MS of pharmaceutical importance. Based on these results, DMSO has been considered as the best co-solvent for the solubilization of CBZM.