Investigation of Permeability Trend in Primary Alkyl Ammonium Salts of Diclofenac

This is the authors' abstract. We don't add key points for this paper.

The preparation of salts of diclofenac (DCF) with alkyl amines is an important pharmaceutical formulation in terms of improving its skin permeability. However, no trend in permeability changes has been reported in the case of primary alkyl ammonium salts of DCF. Herein, we have prepared four salts of DCF with primary alkyl amines of the carbon chain length, that is, n -butylamine ( n BA), isoamylamine (isoAA), n -hexylamine ( n HA), and 2-phenylethylamine (phEA). Salts were prepared by dissolving DCF in acetonitrile, followed by stoichiometric addition of primary amines. Crystals were grown from an acetonitrile–methanol mixture of solvents using slow evaporation technique under ambient conditions. Structural characterization of salt forms DCF – · n BA +, DCF – ·isoAA +, DCF – · n HA +, and DCF – ·phEA + was carried out by single-crystal X-ray diffraction. All salt forms were crystallized in the anhydrate form and are phase stable under ambient conditions. Differential scanning calorimetry thermograms showed that alkyl ammonium salts of DCF had good thermal stability except DCF – ·phEA + which showed a solid–solid phase transition at ∼114 °C with Δ H ≈ 12 J/g. All salt forms showed a lower melting endotherm than that of the DCF free acid. The thermodynamic stability of salt forms was analyzed by the slurry method under acidic pH 1.2 and in a pH 7 aqueous buffer solution. All salts disproportionated to DCF free acid at pH 1.2 but were stable under a pH 7 buffer solution. Solubility, dissolution, and permeability experiments were performed in a pH 7 buffer solution. Solubility, dissolution, and flux through the semipermeable membrane were the highest for DCF – · n BA + and lowest for DCF free acid. There was a solubility and dissolution trend with the alkyl amine chain length, but no trend was observed for permeability in terms of lipophilicity of the alkyl amine. It is interesting to note a relation between molecular volume/molecular weight of the salt forms with permeability trend. Due to tight ion-pairing of ammonium counterions with DCF carboxylate, the salts behave as a neutral species during membrane permeation, and the rate of transport was determined by molecular mobility of the salt. Therefore, an inverse relation was observed between molecular volume/molecular weight of salts and their permeability and hence their bioavailability. In previous studies, no such correlation between the permeability trend and lipophilicity of primary amines was reported. This study establishes a relation between molecular volume/molecular weight of tight ion pairs and membrane permeability. Among the prepared salt forms, the bioavailability of DCF – · n BA + was ∼1000 times higher than that of DCF free acid.