Hansen Solubility Parameters, Computational, and Thermodynamic Models for Tofacitinib Citrate Solubility in Neat Mono Solvents, and GastroPlus Based Predicted In Vivo Performance of Subcutaneous Solution in Humans

Abstract

We investigated the experimental solubility of tofacitinib citrate (TNF) in HSPiP predicted mono solvents at varied temperature points, followed by validation with various models (computational and thermodynamic) and GastroPlus based predicted in-vivo performance in individuals (adult humans). HSPiP (Hansen software) predicted five mono solvents (N-methyl-2-pyrrolidone as NMP, ethanol, polyethylene glycol 400 as PEG400, chloroform, and water). The thermally stable drug was solubilized in these solvents. Computational (Van't Hoff and Apelblat) models were applied to validate the experimental solubility data (mole fraction solubility, X_e). The selected solvent (NMP) was used as a vehicle for subcutaneous (sub-Q) formulation development and compared against conventional tablet for high effectiveness in terms of pharmacokinetic parameters (PK) in humans. Results showed that the drug solubility in NMP was “endothermic and entropy” driven as evidenced with the applied models (computational and thermodynamic). The optimized components for sub-Q delivery were NMP (21.5% v/v), PEG400 (10.0% v/v), and PBS (phosphate buffer solution at pH 7.4). GastroPlus predicted 0.036 µg/mL and 0.042 µg/mL values of C_max (maximum drug reached in the blood) in the blood after sub-Q and oral delivery, respectively. In vivo access of the drug was maximally extended in sub-Q delivery as compared to tablets as predicted in GastroPlus considering humans (fast condition). Conclusively, the sub-Q administration of TNF can be a promising alternative to the conventional tablets.

Graphical Abstract