Solubility Advantage of Tenoxicam Phenolic Cocrystals Compared to Salts

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.