Nucleation And Polymorphic Transformation Mechanism Studies Of L-glutamic Acid

The po lymorphism has a certain impact on characterization, bioavailability a nd formulation o f drug, which therefore has been an import ant issue in t he c hemical industry for a few years, and the study of polymorph has become an essential part in the research and d evelopment of drugs. T he nucleation mechanism, crystallization control of polymorphic transformation and analys is methods of polymorph mixture have became the difficulties in polymorphic field. The in-depth study and discussion about nucleation and transformation process of polym orph were carried out in this work, and L-glutamic acid was chosen as the research system, the details were as followed.The solubility of both forms L-g lutamic acid in pure wat er was m easured by a gravimetric method, the data wer e correlated by experiential equation, and the enthalpy and entropy of dissolution of two forms estimated based on regression of the solubility dat a by ut ilizing the van’t Hoff equ ation. The e ffect of pH va lue on solubility was also studied. The solubility of both forms in solvent mixture of ethanol + water and 1-propanol + water and acetone + water was measured, and the effect of solution composition was investigated.In order to ex plore the nucleation mechanism of polymorphs, the metastable zone and induction time of -and -form L-glutamic acid were determined. The effect of initial temperature, cooling speed and soild impurity on metastable zone width and the effect of temperature and supersaturation on induction time were investigated. The effect mechanism of different crystallization conditions on nucleation was discussed. The nucleation kinetics parameters were estimated based on the induction time data.Powder X-ray diffraction, FT-IR and Raman spectrometer were used in the quantitative analysis of L -glutamic acid polymorphs an d the reliability o f t hree methods were co mpared. Then, the calibration models formed from binary mixtures of - and -form L-glutamic acid were built to quantify the amount of - or -form L-glutamic acid in powder mixture.The change o f solution concentration and po lymorphic co mposition in the so lid phase during the polymorphic transformtation of L-glutamic acid were investigated using the in situ Raman spectrometer. The e ffect of t emperature, supersatuation, seeding and agitation rate were systematically studied. The variety of particle size during polymorphic transformatin process was mon itored using FBRM. The crystal habit of L-glutamic acid was observed by microscope.The po lymorphic transformation o f L-glutamic acid in the presence o f different L-amino acid and the influence mechanism of thes e additives wer e investigated. L-tryptophan was then cho sen as a r epresentative case to evaluate t he effect of addition concentration on the morphology, nucleation and polymorphic transformation rate of L-glutamic acid. The resident additives in L-Glu crystals were determined by HPLC.