Solubility and thermodynamics of polymorphic indomethacin in binary solvent mixtures

The significant effect of solvent mixtures on the dissolution behavior of indomethacin (IMC) was systematically studied. Experimental measurements were carried out using an in-situ attenuated total reflection Fourier transform infrared (ATR-FTIR) spectrometer. Three thermodynamic models were used to correlate the experimental data to determine the solubilities of α- and γ-form IMC in three representative systems, including acetone–heptane, acetone–water and ethanol–water at temperatures ranging from 293 K to 318 K under atmospheric pressure. The acetone–water mixture has the largest dissolving capacity for IMC among the three studied solvent mixtures, and generates “cosolvent effect”. This effect is associated with the strong hydrogen-bond interaction between acetone and water. Notably, it is found that solvent–cosolvent mixtures with solubility parameters of 21 MPa 0.5 –24 MPa 0.5 are suitable for solubility improvement in the design of pharmaceutical formulations of IMC. The solvent and antisolvent can be chosen in this order: δ antisolvent  <  δ solvent  < 21 MPa 0.5 or δ antisolvent  >  δ solvent  > 24 MPa 0.5 for the antisolvent crystallization of IMC. Our analysis strongly demonstrates that the solubility parameter can be a simple and efficient tool in preliminary solvent screening. However, the relationship between the solubility parameter and the resulting polymorphic form in antisolvent crystallization requires further study to achieve its potential applicability in polymorphic control.