Co-Crystals of Active Pharmaceutical Ingredients - Acetazolamide

A total of 20 co-crystal formers have been combined with acetazolamide (ACZ) via solvent drop grinding in acetone, acetonitrile, and water. The screening experiments provided co-crystals with 4-hydroxybenzoic acid (4HBA) and nicotinamide (NA) (ACZ-4HBA and ACZ-NA-H 2 O), which were identified by X-ray powder diffraction (XRPD) and further characterized by IR spectroscopy and differential scanning calorimetry-thermogravimetric analysis (DSC-TGA). Both co-crystals could be prepared also by neat grinding (NG) and reaction crystallization (RC). Single-crystal X-ray diffraction analyses allowed for an examination of the dominant hydrogen bonding patterns in the co-crystals, showing that 4HBA binds to the thiadiazole acetamide fragment of ACZ via C(N)NH···HOOC and O−H···N interactions, while NA is linked through N−H···N and N−H···O contacts. In ACZ-NA-H 2 O, the components are connected further by crystal lattice water molecules through N−H···Ow and Ow−H···N hydrogen bonds. Phase stability assays in water at physiological pH values ranging from 1.2 to 6.8 showed that for ACZ-4HBA the crystalline solid phase did not transform to ACZ within 72 h, while for ACZ-NA-H 2 O a gradual transformation occurred. Thermal treatment of ACZ-NA-H 2 O and reaction crystallization experiments in methanol and anhydrous ethanol gave the dehydrated crystalline phase ACZ-NA, which is stable at ambient conditions for at least four months but transforms to the corresponding co-crystal monohydrate when stirred with deionized water.