A Sduty On Crystallization Process And Crystal Morphology Control Of L-carnosine

L-carnosine,as a kind of bioactive peptide,is widely used in areas of medical,cosmetics and food industries.However,there are still problems such as the needle-like morphology with great length-diameter ratio,small particle size and broad size distribution,which result in difficulty in filtration,washing,drying as well as storage.What's more,its bulk density,fluidity and compressibility also can not meet the requirements of formulation process.In this study,crystallization process and crystal morphology control of L-carnosine were investigated in detail.Thermodynamic properties are the basis of crystallization process and crystal morphology control study.In this work,solubility of L-carnosine in different solvent mixtures,including water +(methanol,ethanol,isoproponal or acetone),was determined by static method.To extend the applicability of the solubility data,the experimental solubility data was fitted using modified Apelblat equation,the CNIBS/R-K model and the Jouyban–Acree model,respectively.In addition,the dissolution thermodynamic properties,such as Gibbs free energy,entropy and enthalpy were calculated.Based on the thermodynamic data of L-carnosine,the effect of antisolvent as well as temperature on the width of metastable zone and nucleation induction period were measured by online turbidimeter.Based on the classical nucleation theory,the relationship between induction period and supersaturation was analyzed to configure the mechanism of nucleation,and the surface tension of nucleation process was calculated.In addition,the change trend of induction period with supersaturation was also analyzed by different crystal growth theories.Based on this,growth mechanism of L-carnosine crystals was discussed.According to the thermodynamic and kinetic properties of L-carnosine crystallization process,new polymorph of L-carnosine was successfully developed by solution crystallization method,and it was characterized by PXRD,thermal analysis,microscope analysis and spectrum analysis.Moreover,it was further compared with the existing polymorph by powder properties and dissolution characteristics.It could be suggested that the new polymorph has an advantage over the existing one.Furthermore,the solvent-mediated polymorph transformation from Form II to Form I was investigated by online Raman,in which the influence of solvent was further discussed.The rate determining step in the transformation process was determined using the method of offline sampling,and the kinetics of crystal dissolution,nucleation and growth were simulated and analyzed according to dissolution-precipitation model.Finally,on the basis of the theoretical research metioned above,spherical crystals of L-carnosine were first observed by antisolvent crystallization process without bridging agent.Monodispersed spherical crystals were successfully prepared by optimizing crystallization process using single-factor experiments,which improves the powder properties of Form I.The self-assembling process of spherical crystals was analyzed by online PVM,based on which the spherical crystallization mechanism was proposed.In conclusion,aimed at the problem of needle-like morphology and poor powder properties,the crystallization process of L-carnosine was studied and analyzed systematically.Thermodynamic and kinetic data were confirmed in this study,and crystal morphology control of L-carnosine was carried out considering the selection and evaluation of crystal form,the solvent-mediated polymorph transformation,and the development of spherical crystals technology.Finally,the bulk density and fluidity of L-carnosine were improved greatly by preparation short rod-like crystals of new polymorph or spherical crystals of Form I.