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.