Research On Crystallization Technology Of Pidotimod And S-acetyl-L-glutathione

Pidotimod is a chemically synthesized dipeptide modulator with immunological activity,which is widely used in medicine and health care industry.At present,the products of Pdotimod have problems such as poor stability,unclear crystal structure and uneven particle size.S-acetyl-L-glutathione with high efficiency and no toxic side effects is the precursor of glutathione,the basic component of cells.S-acetyl-L-glutathione is becoming an important material for health care in medicine and food with great market potential.So far,S-acetyl-L-glutathione products have some problems,such as low purity,unclear crystal habit,poor stability and aggregation.In this paper,the crystallization process of pidotimod and S-acetyl-L-Glutathione were systematically studied,and the crystallization processes of the two drugs were designed and developed,purity,stability and crystal habit morphology have been significantly improved.Firstly,the thermodynamic properties of Pidotimod and S-acetyl-L-glutathione were studied.The solubility of pidomod in pure solvent systems（water,methanol,benzyl alcohol,ethanol,isopropanol,n-butanol,acetone,acetonitrile,DMF）and binary mixed solvent systems（methanol+acetone,methanol+butyl acetate,methanol+water,water+acetonitrile,water+isopropanol）were determined by dynamic method.The preparation process of S-acetyl-L-Glutathione was optimized,and the product was 99.3%purity and had a yield of80%,prepared under the best conditions On the basis of optimization of synthesis,the solubility of S-acetyl-L-glutathione in water+methanol binary solvent systems were determined.Wilson model,NRTL model,Apelblat empirical model,The Redlich-Kister（CNIBS/R-K）equation and KAT-LSER model were used to fit the experimental data,and the relevant model parameters were calculated.The mearsured solubility data provide basic data for process optimization.Then the kinetic data of Pidotimod degradation in pure water and water+acetonitrile(w_acetonitrile=0.5)binary solvent were measured by HPLC,order of reaction were determined by the kinetic data fitting.The degradation rate and the expiration date in two solvent system were compared,and the effect of temperature on the degradation of Pidotimod in aqueous solvent was also investigated in the range of 278.15K-328.15K.Moreover,the effects of temperature and p H on the degradation of S-acetyl-L-Glutathione in aqueous solution were studied.Order of reaction of S-acetyl-L-Glutathione in aqueous solution was determined by measured data fitting,and the degradation rate and expiration date were analyzed.Degradation analysis provided a theoretical basis for later crystallization process optimization.Finally,the crystallization process conditions of Pidotimod and S-acetyl-L-glutathione were optimized.Based on the experimental data of Pidotimod thermodynamic study and degradation stability,the crystallization process of Pidotimod was optimized including the chosen of crystallization method and crystallization temperature,anti-solvent selection,the amount and rate of addition of anti-solvent,stirring speed and other conditions.And then the optimum crystallization process of Pidotimod was determined.The yield of Pidotimod is97.2%and the purity is 99.7%,the analysis data of 7 days accelerated experiment show that the Pidotimod product is more stable and has complete crystal morphology and uniform particle size.Base on thermodynamic study and degradation stability,the crystallization process of S-acetyl-L-glutathione was designed and optimized,including the selection of the solvent system,the amount of the solvent,the adding method,the adding rate,the cooling temperature and the stirring rate.And then two kinds of S-acetyl-L-glutathione products with stable crystal shape（flake,needle crystal）were prepared,characterized by XRD,DSC.The analysis data of 7 days accelerated experiment show that the flake crystal product is more stable and has uniform particle size.The yield of S-acetyl-L-glutathione is 92.3%and the purity is 99.5%,...