Study On Solid State Forms Of AHMP And Its Molecular Mechanism

2-amino-4-hydroxy-6-methylpyrimidine(AHMP),which is an intermediate of Antrycide,can exist in three different tautomer forms in theory(tautomer A,B,C).However,only two tautomeric forms in solid state have been found and included(tautomer A and AB)in Cambridge Crystal Database(CSD).Unfortunately,till now no one has ever proposed a reasonable explanation of this phenomenon yet.In order to rationalize the phenomenon as well as to further explore the way to control polymorph and morphology of crystals,a systematic research was done to study the controlling of tautomer polymorph and morphology,as well as the mechanism behind this control.Based on the fact that thermodynamic data is of significantly importance in the crystallization process,the solubility of AHMP in different solvents and at different temperatures was measured using static method.Models such as Wilson,NRTL,Apelblat etc.were used to fit the solubility data.A hydrogen bond calculation between AHMP and solvent molecules was done to explain the solubility diversity in different solvents.Various of method were applied to screen the tautomeric polymorphs of AHMP,in which tautomer A and AB were crystallized.Measurements such as PXRD and thermoanalysis were done to compare the differences between these two polymorphs.To further explore the principle in this crystallization process as well as rationalize this result,relative stability of AHMP tautomer molecules in solvents of different polarities were calculated using Gaussian 09.It is indicated that tautomer C2 molecule is most stable in less polar solvents,while AHMP tends to stay in tautomer B in extremely polar solvents.Optimized molecules were put in Crystal Structure Predictor to generate thousands of potential crystal structures of AHMP tautomers,and lattice energies of “best predicted” structures were compared.The result that,tautomer A is the most stable solid state,with tautomer AB ranking second,is in consistent with the data in CSD.In order to crystallize other tautomer state of AHMP,different kinds of coformers were used to cocrystalize with AHMP,in which 15 new crystals were crystallized and 11 were successfully crystallized as single crystals.Crystal structures were analyzed,and AHMP performed various of tautomeric forms with coformers,and the results were confirmed by following X-ray Photoelectron Spectroscopy(XPS)data.Simulation on different AHMP molecules and dimers was done to rationalize the different states of AHMP in multicompounds.Influence of additives on morphology variation of AHMP crystals was investigated.The results illustrated that additives could inhibit the growth of some specific faces of AHMP crystal according to some specific functional groups,and this effect varied with the concentration and polymerization degree of the additives.