Nitazoxanide Cocrystals in Combination with Succinic, Glutaric, and 2,5-Dihydroxybenzoic Acid

Combination of nitazoxanide (NTZ)
with a total of 32 cocrystal
formers gave cocrystals with succinic acid (NTZ-SUC, 2:1) and glutaric
acid (NTZ-GLU, 1:1). Additionally, 2,5-dihydroxybenzoic acid provided
a cocrystal solvate with acetonitrile (NTZ-25DHBA-CH3CN,
1:1:1). All solid phases were characterized by X-ray powder diffraction
analysis, IR spectroscopy, thermogravimetric analysis, differential
scanning calorimetry, and single-crystal X-ray diffraction analysis.
Single-crystal X-ray crystallography revealed that NTZ and the carboxylic
acid cocrystal formers were linked in all three cocrystals through
the same supramolecular heterodimeric synthon, C­(N)­NH···HOOC.
Despite having different stoichiometries, the crystal structures of
NTZ-SUC and NTZ-GLU showed similarities in the supramolecular organization,
both containing two-dimensional layers formed by NTZ molecules, which
were further interconnected by single (NTZ-SUC) and homodimeric entities
(NTZ-GLU) of the cocrystal former. Basic physical stability tests
showed that cocrystals NTZ-SUC and NTZ-GLU are stable at least for
one month under standardized temperature/relative humidity stress
conditions but decompose within 1 h into the corresponding physical
phase mixtures, when exposed to aqueous solutions simulating physiological
gastrointestinal conditions. Measurement of the dissolution rates
gave small increases of the intrinsic dissolution rate constants when
compared with NTZ. Pressure stability tests showed that the cocrystals
support higher pressures (at least up to 60 kg/cm2) than
NTZ.