Study On The Anti-solvent Crystallization Process Of (R)-(-)-Phenylephrine Hydrochloride

(R)-(-)-Phenylephrine hydrochloride(R-PEHC),an a receptor agonists,is a primary ingredient of the newly generated anti-cold medicine which has broad applications at home and abroad as it’s not a precursor chemical of narcotics like ephedrine but with much more benign nature than that of latter one.However,there are still some production issues such as small average particle size and uneven distribution of particle size which limits its availability for industrial field.Thus,this thesis has comprehensively investigated the process of anti-solvent crystallization to provide basic data and basis for preparation of crystal products of R-PEHC in the industrial process.The crystallization thermodynamic properties of R-PEHC were studied.The solidliquid equilibrium solubility of R-PEHC in 11 mono-solvents and 4 binary solvents was determined by laser monitoring method from 278.15 K to 323.15 K.The miscibility between R-PEHC and selected solvents was analyzed by using Hansen solubility parameter.Through the Material studio(MS)software,the solute-solvent interaction in binary solution was investigated via the corresponding interaction energies.And the solvent-solvent and solute-solvent interaction were analyzed by the radial distribution function and solvation free energy respectively in ternary system.The solubility differences of R-PEHC in different solvents were evaluated by using solute-solvent and solvent-solvent interactions.Further,solubility of R-PEHC in mono-solvents was correlated through six thermodynamic models including Margules model,Wilson model,UNIQUAC model,NRTL model,NRTL-SAC model and Apelblat equation,while Margules model,Wilson model,UNIQUAC model,NRTL model,Jouyban Acree model and Ma model were applied in correlation of R-PEHC solubility in binary solvents.Also,thermodynamic properties of mixing process and dissolution process RPEHC in selected solvents were interpreted by UNIQUAC model and van’t Hoff equation respectively.According to the solid-liquid equilibrium solubility regular pattern of R-PEHC,the anti-solvent crystallization was selected as the crystallization method.The effects of different binary solvents on the crystal habit of R-PEHC were investigated.The crystal samples of R-PEHC prepared from different solvents by antisolvent crystallization were characterized by multi-techniques such as differential scanning calorimetry(DSC),thermogravimetric differential scanning calorimetry(TGDSC),X-ray diffraction(XRD),flourier transform infrared spectrum(FT-IR),laser Raman spectroscopy(Raman),scanning electron microscope(SEM),high performance liquid chromatography(HPLC)and so forth.The modified adsorption energies of crystal faces influenced by different solvents were calculated by MS software based on the single crystal data of R-PEHC,which further used in the reconstruction of crystal habits for each system.The morphology for each crystal sample was also simulated according to XRD data by MS software.Depending on crystal yield,experimental and simulated morphologies of R-PEHC crystals,methanol+ethyl acetate was selected as the solvent system for the anti-solvent crystallization process of R-PEHC.Basic transport properties of R-PEHC solutions were experimentally measured.The density and viscosity of "R-PEHC+methanol+ethyl acetate" solution were determined at(278.15～323.15)K by pycnometer method and ubbelohde viscometer method respectively.Density values were further fitted by VTF model,LE model and NLE model while viscosity values were correlated by VTF model,GAE model and LGAE model.The obtained data could provide meaningful support for further crystallizer design especially for its pipeline part as well as subsequent enlargement.Kinetics of R-PEHC anti-solvent crystallization process was experimentally investigated.The metastable zone and induction period of R-PEHC in methanol+ethyl acetate were determined by laser monitoring method.The interfacial tension,surface entropy factor,critical nucleus radius,Gibbs free energy change and molecular number of critical nucleus were calculated based on classical primary nucleation theory.It was inferred that the crystal growth mechanism of R-PEHC was continuous growth mode.Meanwhile,the kinetic parameters of anti-solvent crystallization were investigated by batch dynamic method with further calculation of nucleation rate equation as well as growth rate equation.Above results could provide basic data for the design of optimization experiment R-PEHC anti-solvent crystallization process.The optimization of the technological conditions for R-PEHC anti-solvent crystallization process was studied.The parameter of crystallization temperature,relative supersaturation of initial solution,stirring rate,anti-solvent addition speed,dosage of anti-solvent,dosage of seed crystal and aging time of anti-solvent crystallization were investigated to evaluate the average particle size,coefficient of variation and crystal yield in different condition.According to the results of the single factor experiment,the response surface methodology was further applied to research the interaction between different factors including anti-solvent addition speed,dosage of anti-solvent,stirring rate as well as aging time on above indexes.The optimized crystallization conditions for 0.25 L scale were as follows:crystallization temperature was 40℃,relative supersaturation of initial solution was 1.02,stirring rate was 389 rpm,anti-solvent addition speed was 7.6 rev·min-1(0.3642 g·min-1),ratio of antisolvent was 4.95,ratio of seed crystal was 1.0%,breeding time was 1.13 h.Under optimized conditions,the average particle size of the crystal product increased by 35.68%,the coefficient of variation reduced by 45.25%,and the crystallization yield reached 92.58%.Furthermore,the crystal cell parameters were analyzed by MS software based on XRD data of the optimized crystal,and the crystal morphology as well as main crystal face information were also obtained.