Study On Polymorphic Control Of Pharmaceutical

The pharmaceutical crystal chemical and physical properties of different polymorphs can be very different.In the pharmaceutical production and processing process,we often encounter difficulties such as poor stability,poor crystal morphology,difficult filtration,and poor tablet compression performance of certain polymorph.Therefore,the study of drug crystal properties and the screening and control of polymorphs are of great academic significance and application value.In the present work,the structure-mechanical properties relationship of organic polymorphs is elucidated,and different methods and their influence mechanisms of screening and control of drug polymorphs are investigated.Different polymorphs of drugs have different mechanical properties,which can have important effects on the production process such as tablet pressing and filtration.Therefore,in this paper,the elastic and plastic properties of two polymorphs of coumarin were investigated.The crystal structures of different forms were analyzed to find the origins of their diverse mechanical behaviors and to establish a set of structuremechanical property relationships.In this work,three crystallization methods were chosen to screen and control the polymorphic systems.Firstly,two new metastable polymorphs of the tuberculosis drug isoniazid,considered monomorphic for sixty years,were discovered using melt crystallization.The two new forms are readily distinguished from the known form by optical microscopy,Raman spectroscopy and X-ray powder diffraction.A single crystal structure was obtained for one of the new polymorphs.Secondly,template-induced crystallization was used to induce the nucleation of pyrazinamide γ form directionally.In this work,the heterosynthon design method was used to screen the effective templates,and sulfonamides and purines were selected as templates to obtain pure γ forms stably.It was found that the effectiveness of template regulation on the nucleation selectivity of pyrazinamide γ form was greatly influenced by the amount of template and solvent systems,where the weak solute-solvent interaction facilitates template regulation.It was also found that the nucleation of γ form pyrazinamide can be directed by the ordering and specific orientation of functional groups on the surface of hydrochlorothiazide or sulfathiazole templates.Finally,the effect of nanoconfinement crystallization on the nucleation of flufenamic acid polymorphs was investigated.The results show that crystals of the formation of the extremely unstable flufenamic acid form VIII was favored in nanopores.Under confinement,form VIII was sufficiently stable to allow the measurement of its melting point,which decreased with decreasing pore size in accord with the Gibbs-Thomson relationship,enabling determination of the otherwise elusive melting point of the bulk form.Moreover,the transformation pathways among the various polymorphs depended on pore size,proceeding as form VIII form II form I for nanocrystals embedded in 30-50 nm diameter pores,and form VIII form IV form III in 100-200 nm pores.In contrast,form VIII converts directly to form III in the bulk.Whereas previous reports have demonstrated that nanoconfinement can alter(thermodynamic)polymorph stability rankings,these results illustrate that nanoscale confinement can arrest and alter phase transformations kinetics such that otherwise hidden pathways can be observed.In this paper,the structure-mechanism relationship of pharmaceutical polymorphs is elucidated in detail,and the screening and regulation mechanisms of polymorphs by different crystallization methods are investigated,which provide guidance for drug design and drug product stability and subsequent processing.