Clofazimine mesylate: A high solubility stable salt

Abstract

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. © 2012 American Chemical Society.