Polymorphism And Solvate Of γ-Aminobutyric Acid And Crystallization Process Optimization

γ-Aminobutyric acid is an important inhibitory neurotransmitter in mammalian nervous system.With numerous physiological functions,it is widely used in pharmaceutical and food industry.At present,the domestic process to produceγ-aminobutyric acid is too tedious,leading to severe energy consumption,low purity and quality.In order to improve the process yield,product purity and quality,the existing production process was optimized with theoretical analysis and experimental research.Besides,a study on polymorphic and solvate behavior ofγ-aminobutyric acid was also performed in this thesis,which can not only provide theoretical basis for the screening of optimal polymorphs but also serve a lot for the polymorphic control and optimazition of the products.Firstly,additive-induced method was used to prepare a new kind of crystal form ofγ-aminobutyric acid and mixed suspension method a new kind of hemihydrate in water,respectively.And in order to characterize and analyze the obtained crystal forms and solvate ofγ-aminobutyric acid,several means including polarizing microscope,PXRD,TGA,DSC and solid-state Raman were applied.The single crystal of formⅠofγ-aminobutyric acid was achieved by slow evaporation method in water and determined as monoclinic system and P2₁/c space group by SXRD.With the method of in situ monitoring by Raman spectroscopy and off-line sampling,the solvent-mediated transformation between formⅠand hemihydrate has been investigated qualitatively.It turns out to be that the rate-determining step of transformation process is nucleation and growth of stable polymorph.Secondly,the solubility ofγ-aminobutyric acid crystalⅠin water,aqueous methanol and aqueous ethanol system were determined by using the dynamic method of laser detection.It turns out to be that solubility is positively correlated with temperature.Nevertheless,the change trend is not obvious.However,the solubility decreases sharply with the increase of methanol or ethanol content in two kinds of mixed solvent system.Besides,various thermodynamic models were employed to correlate the experimental solubility data.In water,Apelblat equation gave the best fitting results;while in two kinds of mixed solvent system,CNIBS/R-K equation gave the best fitting results.Through"state function method",dissolving process was assumed as four steps,including heating,melting,cooling and mixing precess.The solution mixing thermodynamics was also calculated.It turns out to be that the mixing process ofγ-aminobutyric acid in three kinds of system are all spontaneous,endothermal and entropy-driven.Lastly,the influence of additives on oiling out phenomenon during ethanol dilution crystallization process ofγ-aminobutyric acid was studied.Furthermore,the concentration range of main influencing factors monosodium glutamate was also limited.A new coupled crystallization process was established,including decompression evaporation,cooling and dilution.The influence of several factors on the crystallization process and product ofγ-aminobutyric acid was investigated,such as the way to crystallize,evaporation process,ethanol dilution process,cooling process,subsequent centrifugation,washing operations and so on.The optimized crystallization process conditions has been determined.By using the optimized crystallization process,once-through yield is more than 85%,product purity is more than 95%,agglomeration problem has been solved basically,product color is pale yellow or white,particle size is with 150²00mm and size distribution is concentrated,bulk density is 0.35 g/mL and tap density is 0.45 g/m L,angle of repose is about 35°and liquidity is better.No similar research to above study results has been reported in literature up to date.