Pharmaceutical Cocrystals of Niclosamide

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.