The polymorphic drug substances of the European pharmacopoeia. Part 9. Physicochemical properties and crystal structure of acetazolamide crystal forms.

The crystal structure of acetazolamide modification I (mod. I) was determined, and its differences compared with the already known crystal structure of the triclinic modification II (mod. II) are discussed. The monoclinic mod. I crystallizes in space group P2(1)/n with four molecules in the unit cell: a = 4.7674, b = 21.956, and c = 8.186 A, beta = 104.23 degrees. In both modifications, the molecules form hydrogen-bonded centrosymmetric dimers. The two modifications differ distinctly in the spatial arrangement of these pairs and in the hydrogen bonds formed between them. The thermodynamic relationship between the two modifications is demonstrated by a semischematic energy/temperature diagram, based on the results of thermal analysis and solubility experiments. Mod. II is the thermodynamically stable modification at 20 degrees C and enantiotropically related to mod. I. The thermodynamic transition point lies between 120 and 148 degrees C. The solid-state properties of acetazolamide are mainly directed by the strong intermolecular hydrogen bond forces. Thus, the metastable mod. I exhibits a higher density than mod. II and a very high kinetic stability at 20 degrees C. Both modifications can be crystallized from water and the solubility differences are very small, so, in addition to mod. II, the metastable but extremely resistant mod. I is suggested to be suitable for use in solid pharmaceutical formulations.