Research On Formation Mechanism And Key Control Technology Of Vinpocetine Crystal Defects

Crystal defect research was an important branch of crystallography research,the formation of macroscopic crystal defects during the crystallization process would affect the chemical purity and crystal properties of the crystal products.In the industry,the method of optimizing the crystallization process parameters was usually used to eliminate unfavorable crystal defects,or through the adjustment of crystal defects to achieve the purpose of improving the characteristics of crystal particles,but the mechanism of defect formation was not yet clear.Therefore,vinpocetine was selected as a model drug to investigate the formation mechanism of crystal defects and the key control technology in the process of defect formation.The solid-liquid equilibrium data of vinpocetine in nine pure solvents and ethanol-water binary system at temperatures ranging from 283.15 K to 323.15 K was experimentally measured by gravimetric method under atmospheric pressure.For the different types of investigated solvent,the solid-liquid equilibrium solubility of vinpocetine increased with augmented temperature.Experimental solubility was fitted with several thermodynamic models including the modified Apelblat model,λh model,NRTL model,as well as CNIBS/R-K model.All the fitted values were in satisfactory agreement with the experimental results.The thermodynamic parameters were calculated by the activity coefficients of vinpocetine in different solvents,which were obtained by NRTL model.The results demonstrated that mixing process of vinpocetine with experimental solvents was spontaneous and entropy-driven.The crystal defects of vinpocetine were characterized by micro-Raman analysis,and the macroscopic defects were determined as liquid inclusions and cavity holes.By screening solvents,it was determined that vinpocetine has two common crystal morphologies(quadrilateral polyhedral crystal habit and hexagonal polyhedral crystal habit).The effects of solvent effect,temperature,initial supersaturation,stirring and ultrasound on crystal defects were studied specifically.The study determined that a mild crystallization environment was conducive to inhibiting the formation of vinpocetine crystal defects.The introduction of gentle ultrasonic treatment at the beginning of crystallization effectively promoted nucleation and eliminated crystal defects in the product.By observing the crystal growth of vinpocetine in ethanol solution online,it was found that the formation of defects occurred during the crystal growth process.Combined with molecular dynamics simulation,the interaction between the surface of vinpocetine crystal and pure solvent was studied.The modified attachment energy model was used to simulate the molecular arrangement of crystal planes and the crystal growth process,and it is clarified that the "starvation center" formed by {(1 0 0)}crystal plane during the growth of vinpocetine crystal was the main inducing factor for the formation of crystal defects.