Ketoconazole Salt and Co-crystals with Enhanced Aqueous Solubility

Crystal
structures of ketoconazole oxalate salt (1) and three
co-crystals with fumaric (2), succinic (3), and adipic (4) acids in 1:1 stoichiometry
were determined by single-crystal X-ray diffraction in which 1 forms oxalate dimers involved in ionic interaction with
the imidazole ring of ketoconazole molecules, while 2–4 display 4-member circuit networks between
hydrogen-bonded ketoconazole and coformer molecules. The salt and
co-crystal nature of 1–4 was confirmed
by combining single-crystal X-ray diffraction, ss-NMR, and lattice
energy calculations. Ketoconazole molecules show highly similar conformations
and crystal packing in co-crystals 2 and 3, while different conformers are present in the 1, 2, and 4 structures. For all salt and co-crystals,
powder dissolution measurements revealed a significant solubility
improvement compared to ketoconazole, and the solubility of 1–4 is contrary to the solubility values
of the corresponding acids. A 100-fold solubility increase in water
was obtained by ketoconazole co-crystallization with fumaric and adipic
acids. Additionally, 1–4 are stable
in suspensions for at least 1 week and on storage at 40 °C/75%
RH for at least 4 months. The melting points of 1, 3, and 4 are in line to their solubility, while
the solubility difference between the highly similar co-crystals 2 and 3 is reflected in their different lattice
energy. Our study emphasizes the benefit of crystal engineering in
the landscape of the formulation techniques used to enhance the dissolution
rate of poorly water-soluble drugs such as ketoconazole.