Soluble Salts and Cocrystals of Clotrimazole

Novel
crystalline adducts of clotrimazole with pharmaceutically acceptable
coformers were prepared. Five salts and two cocrystals of the antimycotic
drug clotrimazole (CLT) were crystallized with carboxylic acid coformers
adipic acid (ADA), 2,5-dihydroxybenzoic acid (25DHBA), 2,4,6-trihydroxybenzoic
acid (246THBA), p-coumaric acid (PCA), caffeic acid
(CFA), maleic acid (MA), and suberic acid (SBA). Molecular overlay
diagram of clotrimazole in the four salts (CLT–25DHBA, 1:1;
CLT–246THBA, 1:1; CLT–PCA, 1:1; CLT–CFA–ANI,
1:1:1) and CLT–ADA (1:0.5) cocrystal showed conformational
flexibility of the phenyl rings in the triaryl methane molecule. The
X-ray crystal structures are sustained by N+–H···O–/ N–H···O hydrogen bonds. The
solid-state forms were well characterized and analyzed by PXRD, FT-IR,
and DSC and confirmed by single crystal X-ray diffraction (except
for CLT–MA and CLT–SBA adducts). 15N ss-NMR
indicated intermolecular proton transfer in CLT–MA, and the
chemical shifts are consistent with salt formation. The acidic coformers
for CLT base were selected based on the ΔpKa rule of 3. Solubility measurements showed improved solubility
by a factor of 2.9 (CLT–25DHBA), 14.0 (CLT–246THBA),
1.3 (CLT–PCA), 2.8 (CLT–CFA), and 22.4 (CLT–MA)
for salts and 5.0 in cocrystals (CLT–ADA and CLT–SBA)
compared to CLT in 65% EtOH–water.