Solubility Advantage of Tenoxicam Phenolic Cocrystals Compared to Salts

Abstract

Tenoxicam (TNX) belongs to the oxicam family of drugs popularly known as nonsteroidal anti-inflammatory drugs (NSAIDs). Its therapeutic action as a drug is limited by poor aqueous solubility (14 mg/L). Here, we report cocrystals of TNX with benzoic acid, salicylic acid, catechol, resorcinol, pyrogallol, and salts with piperazine, HCl, and methanesulfonic acid and solvates with formic acid, acetic acid, propionic acid, and nitromethane. All the new solid phases (cocrystals and salts) were characterized by infrared spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and confirmed by single crystal X-ray diffraction. Tenoxicam exists in the zwitterionic form in its stable crystalline form, as well as all the novel adducts reported in this study. The crystal structures are assembled via O–H···O– hydrogen bonds further assisted by weaker C–H···O interactions. This is the first report of oxicam cocrystals with phenols to our knowledge. Solubility and intrinsic dissolution rate of TNX cocrystals/salts were carried out to optimize the solid form with the best physicochemical properties. Tenoxicam–resorcinol (1:1) cocrystal exhibited the highest solubility (10-fold compared to the API), and moreover it was stable for up to 24 h in the slurry crystallization conditions of pH 7 phosphate buffer (neutral) and pH 1.2 medium (acidic). Tenoxicam–piperazine (1:0.5) salt is stable for 24 h in the slurry medium of the pH 7 buffer and exhibited 5.5 times higher solubility than tenoxicam. The other cocrystals dissociated slowly while the HCl and mesylate salts dissociated completely to tenoxicam within the same duration. TNX–benzoic acid and TNX–salicylic acid cocrystals were stable for up to 24 h in slurry conditions of pH 1.2 but in pH 7 medium they slowly converted to TNX after 24 h.