Study On The Pharmaceutical Salt Formation Of Dapsone And Sulfonate Molecules And Their Relationship Between Structure And Solubility

Improving the solubility of poorly soluble drugs has always been a challenging subject in the field of medicine.In this regard,a pharmaceutical cocrystal strategy has been considered to be an effective way.Dapsone(DAP)is a BCS class IV drug and is nowadays a first-line drug for the treatment of leprosy and is also effective in the treatment of dermatoses,malaria and other AIDS-related diseases.However,because of its low aqueous solubility,the high oral doses required and associated side effects limit the tolerability and efficacy of a dapsone free base.In this paper,selected dapsone(DAP)and containing sulfonic acid groups as coformates,such as 2-Naphthalenesulfonic acid(NSA),2-Naphthylamine-1-sulfonic acid(ASA),p-Nitrotoluene o-sulfonic acid(NTSA),to form pharmaceutical salts DAP-NSA-H,DAP-ASA-H and DAP-NTSA-Me OH,using mechanical grinding method and solution evaporation method.The structure was characterized by X-ray powder diffraction(PXRD),single crystal X-ray powder diffraction(SC-XRD),proton nuclear magnetic resonance spectroscopy(~1H NMR)and infrared spectroscopy(FT-IR).The thermal stability of three cocrystals salts was investigated by differential scanning calorimetry(DSC)and thermogravimetric experiment(TGA).The solubility of DAP-NSA-H,DAP-ASA-H and DAP-NTSA-Me OH was determined.Compared with DAP,the solubility of DAP was improved.A comprehensive analysis of DAP eutectic salts from the Cambridge database,the focus was also directed to understand the supramolecular synthons present in these salts and establish a structure-property relationship among them.Qualitative(XPac analysis)and quantitative(Hirshfeld surface analyses)approaches were also employed to analyse related the single crystal structures of DAP salts to gain an insight regarding the supramolecular assemblies formed and to establish the relationship between N-H···O=S interaction and solubility.The results showed that the strategy of preventing the formation of hydrogen bonds between drug molecules by introducing eutectic crystals be an effective way to improve the low solubility of drug molecules.