Crystal Nucleation And Growth Of Diflufenican

Solution crystallization is a kind of purification method widely used in chemical industry,which products high purity solids through nucleation and growth process from solution driven by supersaturation.The nucleation and growth process directly or indirectly affects the purity of the crystals,the morphology,shape,size,particle size distribution and other characters,to control the process,therefore,is quite important.However,the theories related are not well developed due to the stochastic nature of nucleation and the individual interaction between solute and solvent molecules,and are not able to be used for engineering design and guiding production.In order to develop the production process of diflufenican and to promote fundamental research simultaneously,the nucleation and growth process of diflufenican was systematically studied under the framework of classical nucleation theory.Details are as follow.The solubility of diflufenican was measured using the laser-detection technology,and the data obtained were well correlated by Apelblat and Jouyban-Acree models for mono-solvent and binary solvent system respectively.From the result,it can be concluded that acetone,toluene,benzene and ethyl acetate can be used as good solvents for diflufenican,and the solvent systems of acetone-water and acetoneethanol are suitable for anti-solvent crystallization.The stochastic nature of nucleation was studied by one hundred parallel experiments of induction period measurement in the solvent of acetone under the same condition.The obtained data were analyzed by using poisson distribution from statistical mathematics,under the framework of classical nucleation theory,and nucleation rate was calculated.Then the parameters for nucleation were estimated from the result of orthogonal experiments,employing the expression form of Arrhenius equation,and the heterogeneous nucleation mechanism was determined from the data of interfacial energy.Further investigations of influencing factors on the nucleation process demonstrate that the increase of supersaturation,temperature and energy input from agitating accelerate the nucleation,and the effect of solvent was studied subsequently.Binding energy between solute and solvent(1:1)is ranked as isopropanol>acetone>benzene calculated by density functional theory,and together with the results of induction period measurement in different solvents,a conclusion can be made,the stronger binding between solvent and solute,the more difficult to nucleate.The relative growth rates of crystal planes in vacuum were predicted by means of attachment energy(AE)method based on the crystal structure of flunarizine,and the relative growth rates in different solvents were obtained by the modified AE method,which are verified by the experiments of crystal growth.The result shows that,{0 1 1} and {0 0 2} crystal planes have the fast growth which makes the crystals plate-like,and the slower-growing plane is dominated in the final morphology.Between the two fast-growing planes,the growth rate functions were established,the polar solvents are more likely to attach on the {0 1 1} plane,inhibiting its growth,and aspect ratio of the plates was modified therefore.For the slower-growing {1 0 0} plane,its microstructure shows it grows layer by layer,and the step stages are quite clear.The growth striations become disordered with the decrease of supersaturation and temperature,as stages shifting.In addition,a crystallization technology combining temperature oscillation and segmental aging was put forward to produce ellipsoidal crystals,which reduces the specific surface area effectively,contributing to the slow release of drug effect.