Salt formation of two BCS II drugs (indomethacin and naproxen) with (1R, 2R)-1,2-diphenylethylenediamine: Crystal structures, solubility and thermodynamics analysis

Abstract

Indomethacin (Indo) and naproxen (Nap) belong to Biopharmaceutical Classification System (BCS) class II drugs, which permeate membranes well but are poorly soluble. Two pharmaceutical salts hydrate of Indo and Nap with (1R,2R)-1,2-diphenylethylenediamine (DPEN) were obtained using solution crystallization. Both salts, (DPEN)2·(Indo)2·(H2O)2 and (DPEN)1·(Nap)1·(H2O)0.5, were characterised using various solid-state characterisation techniques such as single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and Raman spectra. The structure analysis shows that DPEN is monocation as only one amine is protonated into ammonium. The Indo, DPEN and water molecules form one-dimensional hydrogen bond chains through extensive NH⋯O, NH⋯N and OH⋯N interactions. The solubility study shows that the two salts are more soluble in pH 1.2, 4.5 and 6.8 buffer mediums compared with pure raw materials. Solubility thermodynamics calculation was carried out to further understand the solubility properties of two salts.