Study On The Anti-solvent Crystallization Process Of Doxifluridine

Doxifluridine is the derivative of antitumor drug fluorouracil（5-FU）,and it has become the first-choice drugs for the treatment of gastrointestinal tumors,breast cancer and other malignant tumors owing to its advantage of targeted release,selective inhibitory effect on tumor cells and less toxic to normal cells.The particle size as well as the crystal habits of the products are the main physical property indexes that affect the efficacy of the drugs,and the control of the crystal size and habits of the products could be realized by employing the solution crystallization.Currently,few literatures about the research on the crystallization process of doxifluridine has been reported.In addition,the problems such as poor particle size,uneven particle size distribution,and unstable crystal habits are existed in the production of doxifluridine.Therefore,conducting the research on the process of the solution crystallization of doxifluridine has the great significance and application value.Based on the above,the crystallization process of doxifluridine was systematically investigated in this paper and this research could provide data and theoretical basis for the production of doxifluridine in the industrial crystallization process.The solid-liquid phase equilibrium of doxifluridine was studied.The solubility of doxifluridine in fifteen pure solvents and four binary solvents was determined by using the laser monitoring method.The solubility data of doxifluridine in different solvents was correlated by employing several models includingλh model,Apelblat model,Van’t Hoff model,NRTL model,UNIQUAC model and Margules model.The miscibility between doxifluridine and selected solvents was analyzed by using the Hansen solubility parameter.By employing the Materials studio software（MS）,the solute-solvent interaction of different solvent systems was calculated and the dissolution behavior of doxifluridine in different solvents was explained.The thermodynamic properties of the mixing and dissolution process of doxifluridine in selected solvents were calculated and analyzed.According to the regularity of the solubility of doxifluridine in different solvents and the crystal morphologies of the products obtained through the cooling crystallization,the anti-solvent crystallization was selected for the production of doxifluridine and the appropriate binary solvent system was determined.The crystal morphology of doxifluridine was studied.The doxifluridine crystals obtained from different binary solvent systems were characterized by using XRD、FT-IR、Raman、DSC,and the results indicate that there is no formation of the new crystal form or solvates of doxifluridine during the crystallization process.On the basis of the single crystal data of doxifluridine,the crystal morphology of doxifluridine in the vacuum was predicted by using the AE model through MS software.In addition,the crystal morphologies of doxifluridine in different solvent systems were calculated by employing the MAE model.The results show that the doxifluridine products obtained from methanol+（±）-2-ethyl-1-hexanol have the best crystal morphology.Therefore,the solvent system of methanol+（±）-2-ethyl-1-hexanol was selected for the anti-solvent crystallization process.Besides,the affinity degree model was established and the relationship between the solvent molecules and the crystal faces was quantitatively analyzed,and the growth law of different crystal faces was explained in depth.The kinetics of the anti-solvent crystallization process of doxifluridine was investigated.The metastable zone and induction period of doxifluridine in methanol+（±）-2-ethyl-1-hexanol were determined by employing the laser monitoring method.The interfacial tension and surface entropy factors of the crystallization process were estimated based on the induction period data,and then the nucleation mechanism of the crystals was deduced.In addition,the relationship between induction period and supersaturation was analyzed by using four different crystal growth mechanisms,and the results show that the crystal growth of doxifluridine is controlled by two-dimensional nucleation.The kinetic parameters of the anti-solvent crystallization process of doxifluridine were determined,and the nucleation rate equation as well as the growth rate equation were established.Accoring to the above results,the research about optimizing the anti-solvent crystallization process of doxifluridine was carried out.The average particle size,the coefficient of variation and the yield were selected as the inspection indexes.The single factor experiment was conducted to investigate the effects of different factors on the inspection indexes including initial concentration,stirring rate,addition rate of the anti-solvent,experimental temperature,ratio of solvent to anti-solvent,amount of seed crystals and breeding time.On the basis of the single factor experiment,the response surface optimization experiment was designed.The average particle size,coefficient of variation and yield were set as the inspection indexes and the effects of temperature,stirring rate,addition rate of the anti-solvent and amount of seed crystals on the inspection indexes were explored.The optimized conditions for the crystallization process of doxifluridine are as follows:crystallization temperature22.11℃,stirring speed 251.16 rpm,addition rate of the anti-solvent 10.58 rev·min^-1,amount of the seed crystals 2.16%,supersaturation of the initial solution 1.1,ratio of solvent to anti-solvent 1:3.5,breeding time 4 h.Under the above condition,the yield of the crystallization process of doxifluridine can reach 84.63%.The average particle size and the variation coefficient was about 12.75μm and around 1.0536,respectively.In addition,the average particle size of the products upgraded by 38.43%and the coefficient of variation reduced by 19.97%compared with the raw materials.