Solid Form Selection of Highly Solvating TAK-441 Exhibiting Solvate-Trapping Polymorphism

Solid form selection of active pharmaceutical ingredients is essential for pharmaceutical development. Solvates, except for hydrates, are rarely selected because of their physical instability and the potential toxicity of solvent. Here, the solid form selection of TAK-441, a highly solvating compound, was conducted. Anhydrate form I and 12 solvates were obtained from solution. The solvates showed isomorphism and could be placed into three categories. Anhydrate forms II, III, and IV were obtained via the desolvation of different type solvates, and anhydrate form V crystallized following thermal conversion of solvates. Equilibrium solubility analysis suggested that certain thermodynamic relationships between anhydrates were enantiotropic in nature. Moreover, form I was more stable than other polymorphs at ambient temperature, and was thus selected for further development. Finally, crystal structure analyses revealed that form I was an isomorphic desolvate of another solvate type (type 4), which immediately desolvated upon harvesting, and that TAK-441 crystallized only via solvate formation. Notably, types 2 and 3 solvates possessed unique channel structures, and pores of type 4 solvate were much larger than those of other types. This large pore size may cause extreme instability of type 4 solvate.