Clofazimine Mesylate: A High Solubility Stable Salt

Clofazimine (CFZ), an antibacterial and anti-inflammatory
drug,
is also recommended by the World Health Organization for the treatment
of leprosy in combination with dapsone and rifampicin. It is an iminophenazine
derivative and classified as a Biopharmaceutics Classification System
(BCS) class II drug because of poor aqueous solubility (10 mg L–1). Despite it being a very classical drug known for
more than five decades, there is no systematic study of CFZ salts
for solubility and stability enhancement. We report a solid form screen
of CFZ with pharmaceutically acceptable coformers/acids. Salts of
CFZ with methanesulfonic acid, maleic acid, isonicotinic acid, nicotinic
acid, malonic acid, and salicylic acid in an equimolar ratio as well
as an amorphous phase of CFZ are reported. All new solid phases were
characterized by FT-IR, powder X-ray diffraction, and differential
scanning calorimetry, and confirmed by single crystal X-ray diffraction.
The acid proton is transferred to the imine nitrogen of CFZ in a R21(7) ring motif. The driving force for facile salt
formation is the ionic N+–H···O– and N–H···O– bifurcated hydrogen bond synthon. Solubility and powder dissolution
experiments were carried out in 60% EtOH–water to compare the
higher solubility of salts compared to that of pure CFZ. CFZ-mesylate
(1:1) is 99 times more soluble than the pure drug in water. All salts
were stable for up to 24 h in 60% EtOH–water slurry medium.
CFZ–MSA is the best pharmaceutical salt with high solubility
and good stability.