Pharmaceutical cocrystals of niclosamide

Abstract

Niclosamide (NCL) is an anthelmintic BCS class II drug of low solubility and high permeability. Pharmaceutical cocrystals of NCL were prepared with GRAS molecules, such as caffeine (CAF), urea (URE), p-aminobenzoic acid (PABA), theophylline (THPH), nicotinamide (NCT), and isonicotinamide (INA), to improve drug solubility. Neat grinding, wet granulation, and slow evaporation methods were successful to make niclosamide cocrystals. All new crystalline forms were characterized by X-ray diffraction, differential scanning calorimetry, and IR-Raman spectroscopy to confirm their purity and homogeneity. X-ray crystal structures provided details of hydrogen bonding, molecular packing, and drug•••coformer interactions. The intermolecular O-H•••O hydrogen bond from the hydroxyl donor to the carbonyl acceptor in the niclosamide crystal structure was replaced by an acceptor atom of the coformer in cocrystal structures. Cocrystals with nicotinamide and isonicotinamide were characterized by 13C ss-NMR spectroscopy because their single crystals could not be obtained. All cocrystals, except NCL-PABA, showed a faster powder dissolution rate than the reference active pharmaceutical ingredient (API). Niclosamide-theophylline acetonitrile solvate showed the highest solubility (6 times compared to the API) among all the crystalline forms. NCL-THPH cocrystals showed comparably good dissolution (5 times faster than the drug) up to 90 min. The solubility advantage of the cocrystal was diminished by transformation to insoluble niclosamide monohydrate within 1 h of the dissolution experiment in 40% i-PrOH-water. Equilibrium solubility experiments showed that all cocrystals as well as the pure API transformed to NCL monohydrate within 24 h in 40% i-PrOH-water slurry medium. Among the cocrystals studied, NCL-NCT and NCL-INA exhibited better stability under accelerated humidity conditions (75% RH, 40 °C), but they did not have the same solubility advantage as the fast dissolving species NCL-THPH. © 2012 American Chemical Society.