Predicting the Thermodynamic Solubility and Stability of Co-crystals and Eutectics of Febuxostat by using a Thermodynamic Model involving Flory Huggins Interaction Parameter.

Abstract

A method is presented for determining the thermodynamic (equilibrium) solubility of a drug in coformer for the non-covalent derivative (NCD) systems i.e. eutectics/co-crystals. The method is based on a thermodynamic model to calculate the Gibbs energy change ∆GCC associated with forming a drug-coformer NCD system. This model includes contributions from heat capacity differences between the mixed and unmixed components, breaking up of the solid drug and coformer lattice structure, and drug ─ coformer mixing. Calculation of ∆GCC from thermal analysis data is demonstrated, and the equilibrium drug solubility in coformer is represented by minima of plots of ∆GCC versus the dissolved drug fraction(f1). Eight (8) coformer molecules, namely, 1-hydroxy 2-naphthoic acid (1H-2NPH), 4-hydroxy benzoic acid (4-HBA), salicylic acid (SLC), 4-amino salicylic acid (4-ASA), 5-nitro isophthalic acid (5N-IPH), pyrazinamide (PZD), isonicotinamide (ISNCT), and picolinamide (PICO) were used for the formation of NCDs of a highly water insoluble drug febuxostat (FXT). The importance of heat capacity and interaction parameter in determining the solubility behavior of drug-coformer in the formed NCDs was discussed. Further, ∆GCC for FXT in selected NCDs were plotted as a function of composition and temperature to determine the thermodynamic stability over the range of room temperature to formulation melting. It was concluded that the thermodynamic model can reasonably predict the maximum stable drug loading in a multi-crystalline system at a particular temperature, and serve as a complementary screening tool in determining the best stoichiometric ratio of the drug and coformer in terms of solubility and thermodynamic stability.