Study On The Preparation,Characterization And Property Of Pharmaceutical Multicomponent Crystals Of Dapsone

Synthesizing the new multicomponent crystals is an effective way to improve the solubility and bioavailability of a drug.However,there are some problems making it a challenge,such as the blindness of ligand screening,the complexity of the interaction between components and the unknown molecular assembly mechanism.Dapsone（DAP）is a special drug for treating leprosy and different skin diseases,but it has low water solubility.In this paper,the solubility of DAP was first studied,which can provide basic data for solvent screening in the subsequent research.Then,from the perspective of crystal engineering,supramolecular synthon strategy was used to design ligands and synthesize new multi-component crystals of DAP.It provides new cases for solving the poor water solubility of DAP and investigating the molecular assembly mechanism.The solubility of DAP in different solvents is the basial parameter of crystallization research.Thus,the static method was selected to determine the solubility of it in twelve mono solvents at the temperature from 10 to 50℃.The solubility of DAP increases with the rise of temperature and solvent polarity.Also,the modified Apelblat model,λh equation and NRTL model fitted well with ARD%<5%.The solubility data help to predict the thermodynamic properties and screen the solvent for the crystallization of DAP.Hydroxybenzoic acid coformers were selected to synthesize multicomponent crystals with DAP to improve its solubility.PXRD,DSC,FTIR and Raman studies showed the formation of 1:1 salt and eutectics.To determine the composition of the eutectics,the binary phase diagrams were constructed by DSC analysis.Moreover,the electrostatic potential of the molecular surface was analyzed to explain the formation of salt or eutectic of DAP with different coformers.Further,the dissolution experiment in p H=1.2,4.5 and 6.8 showed that salt and eutectics of DAP display faster dissolution rate and higher equilibrium concentration than that of pure DAP.Meanwhile,it was found that the coformers affected the solubility of DAP by affecting the p H of the solution.This work can provide a direction for future coformer screening of multicomponent solids with improved pharmaceutical properties.Based on the supramolecular synthon strategy,1-（4pyridyl）piperazine（PYR）was selected as a coformer according to"-NH₂···N_pyridine"synthon.PXRD,FTIR and Raman studies show that DAP-PYR（1:1）and（2:1）were two new cocrystals,and their single crystal structure were also obtained.The formation of two cocrystals are mainly dependent on the ratio of DAP and PYR.They can transform to each other by adding a certain amount of DAP or PYR and by grinding.Furthermore,the molecular electrostatic potential and binding energy were calculated,which can identify the hydrogen bonding formation sites.It also revealed that the"-NH₂···N_pyridine"motif promoted the formation of DAP-PYR cocrystal.