Salts and Cocrystal of Etodolac: Advantage of Solubility, Dissolution, and Permeability

Abstract

Etodolac (ETD) is a nonsteroidal anti-inflammatory drug (NSAID) approved by the United States Food and Drug Administration (US-FDA) in 1991 for the treatment of rheumatoid arthritis. Because of its poor aqueous solubility and high permeability, ETD falls under Biopharmaceutics Classification System (BCS) Class II drug. The present study was aimed to screen stable salts and cocrystals of ETD using Generally Recognized as Safe (GRAS) and a few non-GRAS coformers. Crystallization of five salts (i.e., isopropylamine = isoPA, n-hexylamine = nHA, cyclohexylamine = cycloHA, 2-phenylethylamine = phEA, piperazine = PPZ) and one cocrystal (isonicotinamide = INT) was successful. These products were characterized by single crystal X-ray and powder diffraction. Differential scanning calorimetry (DSC) showed a single endotherm for the salts, which confirmed their thermal stability and phase homogeneity, except for ETD-·phEA+ where a solid-solid transition at 152 °C was observed with an enthalpy of transition δH ≈ 16 J/g. Among the five salts, ETD-·isoPA+ showed the highest solubility of 267.50 mg/mL and ∼20 times faster intrinsic dissolution rate than ETD in pH 7.0 phosphate buffer medium. The salts are stable under solubility and dissolution conditions as confirmed by fitting the powder X-ray diffraction profile of each sample after the experiment with the calculated lines from the X-ray structure. Permeability and flux analysis of ETD salts showed that ETD-·isoPA+ exhibits a high flux rate across the semipermeable membrane due to a higher molecular mobility and greater concentration gradient.