Antisolvent Crystallization Using Ionic Liquids As Solvent and Antisolvent for Polymorphic Design of Active Pharmaceutical Ingredient

The applicability of ionic liquids to the polymorphic design of the active pharmaceutical ingredient adefovir dipivoxil (AD) was investigated in the case of antisolvent crystallization. When using 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF 4 ) as the solvent and 1-butyl-2,3dimethylimidazolium tetrafluoroborate (BDMImBF 4 ) as the antisolvent (AEImBF 4 /BDMImBF 4 ), a new form (NF) of AD crystal was obtained at a crystallization temperature below 50 °C and initial solute concentration of 25.6 mg/mL. However, when using 1-allyl-3-ethylimidazolium tetrafluoroborate/1,3-diallylimidazolium tetrafluoroborate (AEImBF 4 /AAImBF 4 ) and 1-allyl-3-ethylimidazolium tetrafluoroborate/1-ethyl-3-methylimidazolium ethylsulfate (AEImBF 4 /EMImEtSO 4 ), the conventional form-I polymorph was directly crystallized. No crystallization occurred in the ionic solutions of 1-allyl-3-ethylimidazolium tetrafluoroborate/1-allyl-3-ethylimidazolium bromide (AEImBF 4 /AEImBr) and 1-allyl-3-ethylimidazolium tetrafluoroborate/1,3-diallylimidazolium bromide (AEImBF 4 /AAImBr). According to a spectroscopic analysis, the polymorphs were predominantly determined by the preorientation of the solute molecules in the ionic liquid solution (AEImBF 4 /BDMImBF 4 ), and this preorientation varied according to the crystallization temperature. Thus, the pure form-X polymorph was nucleated at a crystallization temperature above 80 °C. Plus, the polymorphic nucleation depending on the crystallization temperature was also combined with the crystallization concentration. Thus, the minimum crystallization temperature for the nucleation of the pure form-X polymorph was reduced to 40 °C when decreasing the crystallization concentration to 15 mg/mL. The relationship between the polymorphic nucleation and the crystallization conditions was effectively predicted by a polymorphic supersaturation level diagram ( S NF – S form-X diagram), where the formation of the metastable polymorph (NF crystals) was favored at a high supersaturation level ( S NF > 2.1), while the stable polymorph (form-X crystals) was preferentially nucleated at a low supersaturation level ( S NF < 1.6). Differental scanning calorimetry thermal analysis confirmed that the NF polymorph was the metastable phase and the form-X polymorph was the stable phase, and there was a monotropic relationship between the two polymorphs.