Investigations on the Desolvation Reaction of Pseudopolymorphic Forms of Hydrocortisone

The crystal structures of two pseudopolymorphic modifications of the glucocorticoid hydrocortisone were determined, in addition to the known structures of the 2-propanol (1), methanol (2) and pyridine (3) solvate reported recently. The chloroform solvate (4) and the N,N′-dimethylformamide solvate (5) crystallize in the monoclinic space group P2₁, with a = 12.5947 (8) Å, b = 12.4413 (5) Å, c = 14.9884 (11) Å, β =90.571 (9)°, V = 2348.5(2) ų for (4) and a = 13.4186 (10) Å, b = 6.0878 (3) Å, c = 14.6595 (11) Å, β = 104.711 (10)°, V = 1158.27(14) ų for 5. The crystal structures of 1, 3, and 5 are isotypic and are very similar to that of the thermodynamically metastable solvent free modification III of hydrocortisone. The removal of solvents from the pseudopolymorphic forms at elevated temperatures results in the formation of the thermodynamically most stable form I or the metastable form II of hydrocortisone. For the methanol solvate, the desolvation reaction indicates the formation of a new modification of this drug. In contrast, the removal of the solvent from the N,N′-dimethylformamide solvate (5) at room-temperature leads to the formation of the metastable form III of hydrocortisone. These results indicate a smooth reaction pathway for the desolvation reactions of the solvates into the solvent free modifications of hydrocortisone.