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), <i>p</i>-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<sup>+</sup>–H···O<sup>–</sup>/ 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). <sup>15</sup>N 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 Δp<i>K</i><sub>a</sub> 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.