Study On The Process Of Anti-solvent Crystallization Of Cefathiamidine

Cefathiamidine,which belongs to a kind of first generation ?-lactam antibiotics,is the first independently developed antibiotic drug in China.Due to the characteristics of a broad antibacterial spectrum,strong antibacterial effect,high blood concentration,definite clinical efficacy,and few adverse reactions,it has a broad application market in China.Aimed at solving the problems existing in the production of cefathiamidine,such as the difficulty in controlling the crystal form and particle size distribution,the anti-solvent crystallization process of cefathiamidine was researched in this paper.It provides a theoretical basis and basic data for the crystallization purification and industrial production of cefathiamidine.Single crystal of cefathiamidine and solvates were prepared.The cell parameters and the spatial groups of cefathiamidine were obtained by single crystal analysis.Depending on the data of single crystal,the Materials Studio(MS)software was utilized to do the molecules simulation.Morphology of cefathiamidine in different mixed solvents was predicted according to the modified adsorption energy model.Cefathiamidine crystals were prepared in different kinds of solvents,the crystal products were characterized by IR,XRD,DSC,TG,and SEM.Simulated crystal morphology was verified by the crystal morphology obtained from experiment.The thermodynamic properties of crystallization of cefathiamidine were studied by the experimental method.The solubility of cefathiamidine in acetone-water,acetonitrile-water,tetrahydrofuran-water,and other mixed solvents,and the solubility of cefathiamidine acetone solvate monohydrate in acetone-water mixed system was measured by the gravimetric method.The solubility data were fitted with the van't Hoff equation,Apelblat equation,and CNIBS/R-K equation.The thermodynamic parameters of the dissolution of cefathiamidine in different solvents systems were obtained.Acetone-water was selected as a suitable solvent system for the crystallization of cefathiamidine.The metastable stable zone width(MSZW)of cefathiamidine in acetone-water system was determined by the turbidity method.It provides a data base for the operation range of seeded method in the future experiments.The induction period of cefathiamidine in acetone-water system was determined by the turbidity method.The Gibbs free energy,interfacial tension,and surface entropy factors of cefathiamidine crystallization were estimated by the classical primary nucleation theory.It is inferred that the crystal growth mechanism of cefathiamidine was continuous growth mode.The kinetic parameters of the cefathiamidine crystallization process were determined.The growth rate equation and the nucleation rate equation of the cefathiamidine crystallization process in acetone-water system were obtained.It provides theoretical support for the design of optimization experiment and the data basis for the simulation of cefathiamidine crystallization process.Process analytical technology(PAT)was utilized in this study.2D imaging system,ATR-FTIR,and other process analysis tools were used.The transformation between cefathiamidine and cefathiamidine acetone solvate monohydrate in the acetone-water system was studied and the preparation methods were summarized.The properties of cefathiamidine anhydrate and cefathiamidine acetone solvate monohydrate were compared in terms of morphology,fluidity,and particle size distribution(PSD).The thermal analysis kinetics and thermal instability of cefathiamidine and cefathiamidine acetone solvate monohydrate were investigated by thermal analysis method.Thermal degradation kinetic factors and theoretical storage period of the products of the anhydrate and solvate were calculated.The reason of solvate occurred during the production process was explained.The seeding method is the effective method to control the crystal form of the final product.It provides direction for process optimization experiment.Based on the thermodynamic and kinetic data,the crystallization process of cefathiamidine anti-solvent crystallization was simulated based on the equations of population balance and mass balance.The effects of crystallization temperature and stirring speed on the average particle size and coefficient variation(C.V.)of particle size distribution were simulated.A single factor experiment was designed to investigate the effects of initial concentration of solute,crystallization temperature,stirring speed,anti-solvent addition rate,amount of crystal,and the breeding time of crystallization on the PSD of the product.Based on the results of the single factor experiment,a response surface optimization experiment was designed.The interaction between different factors was investigated with the variation coefficient of particle size distribution as the response value,and the optimized crystallization process parameters were obtained.The results show that,the seeding method is an effective method to control the crystal form,and the amount of seed is an important factor to control the average particle size.The optimized conditions for obtaining 1 L scale crystallization are as follows: initial concentration of cefathiamidine was 0.004 mol(solute)/mol(solution),crystallization temperature was 16?,stirring speed 141 rpm,anti-solvent addition rate was 2.13 mL/min,the initial concentration of anti-solvent was 0.30 mol(anti-solvent)/mol(solvent),the final concentration of anti-solvent was 0.65 mol(anti-solvent)/mol(solvent),the addition of crystal seeds were 1.0-4.0 wt%,the length of the crystal breeding time of both after the seeding point and the final crystallization were all 30 min.According to the optimized process parameters,the process was successfully magnified from 1 L laboratory pilot scale to 4000 L industrial production scale.The optimized crystallization process can be used to produce cefathiamidine with uniform crystal of anhydrate form,controllable average particle size between 30 ?m to 70 ?m,and the variation coefficient of particle size distribution less than 50%.