Study On Crystallization Thermodynamics And Polymer-regulated Crystal Morphology Based On Ropivacaine

The crystal morphology of crystal material has obvious influence on its production,process optimization and specific application.Ropivacaine（ROP）,as a small molecule crystal,is generally in the shape of a long needle,which is easy to break,easy to generate static electricity,low density and poor liquidity,which is very unfavorable to its processing,storage and transportation process.In order to solve this problem,this paper has carried out detailed studies from the perspectives of dissolution thermodynamics,cooling crystallization process,crystal morphology regulation and single crystal growth mechanism.In this paper,the solid-liquid equilibrium solubility of ROP in 14 common solvents was determined by static weighing method from the perspective of dissolution thermodynamics.The results were well correlated with several thermodynamic models（Apelblat,λH and NRTL）.The results show that the high solubility of ropivacaine is related to the low solvent polarity,cohesive energy density and dielectric constant.Molecular dynamics simulations show that strong intermolecular interactions between solute and solvent lead to higher solubility.ROP can interact with organic solvents through van der Waals forces and electrostatic interactions,in which van der Waals forces play a dominant role.The main hydrogen bonds between solute and solvent are O-H _solvent···O_ROP and N-HROP···O solvent.Secondly,the cooling crystallization process of ROP and the effects of polyvinylpyrrolidone（PVP）with different molecular weight and different additive concentration on ROP crystal morphology were studied.The results show that the width of the metastable zone of ROP crystals increases and widens with the increase of susaturation solution temperature,decreases and narrates with the increase of agitation rate,and widens with the increase of cooling rate.The induction period decreased with the increase of supersaturation,and PVP inhibited the nucleation and crystallization.High concentration of PVP can cause the crystal forming delay,particle size decrease and obvious coalescence of ropivacaine products,while low concentration of PVP ketone can cause the particle size increase of ropivacaine products,morphology change from long rod shape to short sheet shape,and aspect ratio decrease obviously.PVP with low molecular weight will make ROP products tend to be short film or even granular,while PVP with high molecular weight will make ROP crystals tend to be long sheet,and the aspect ratio increases significantly.The physical property test results also show that PVP can effectively improve the particle size distribution,bulk density and fluidity of ROP crystal products.Finally,the inhibition mechanism of PVP on ROP single crystal growth was discussed by combining the effects of PVP on single crystal growth rate,crystal surface prediction results and molecular surface analysis.The results showed that PVP inhibited the growth of ropivacaine single crystal mainly due to the hydrogen bond formed by C=O_PVP and N-H_ROP,which weakened the adhesion ability of molecules on the crystal plane and slowed down the growth rate of single crystal.In this study,the interaction force between ropivacaine and different solvents was revealed,and the morphology of ropivacaine crystal was effectively regulated and the physical properties were significantly improved.The mechanism of inhibiting the growth of ropivacaine single crystal was analyzed.This paper not only provides guidance for the production,purification and crystallization process optimization of ropivacaine products,but also provides basic reference for the morphology control of other crystal materials.