Effects of nucleation on solvate and polymorph control – evaporative crystallization of taltirelin

Abstract

This study focuses on the selective formation of taltirelin (TTL) solvates (hydrates) and polymorphs through evaporative crystallization. Factors influencing the nucleation of TTL polymorphs in evaporative crystallization, such as evaporation rate, supersaturation, solvent, temperature, and concentration, were investigated. In the evaporative crystallization of TTL in water, only the β-form was formed at an evaporation rate below 0.412 cm³ (min·m²)⁻¹, whereas a mixture of the α-form and β-form was obtained at evaporation rates of 0.44–0.71 cm³ (min·m²)⁻¹. At evaporation rates of 0.74–1.99 cm³ (min·m²)⁻¹, the α-form crystals were formed. Regarding the formation conditions of solvates influenced by degree of supersaturation, the β-form was obtained at supersaturation (S) < 1.68, while a mixture of the α-form and β-form appeared in the range of 1.86 < S < 3.75. The α-form was observed within the range of 2.68 < S < 8.80. The anhydrous γ-form was obtained from methanol, ethanol, 1-propanol, and isopropanol (IPA) solvents, regardless of the supersaturation in evaporative crystallization. From the plot of dimensionless supersaturation and dimensionless solubility, the α-form was obtained when the nucleation rate was 1 × 10²³ < B_het < 6 × 10²³ nuclei per m³ s, whereas the β-form was obtained when the nucleation rate was 2 × 10²² < B_het < 1 × 10²³ nuclei per m³ s. Therefore, this plotting method provides important information on nucleation rates for the selective formation of polymorphs/solvates and can also be applied to predict new polymorphs/solvates.