Study On The Solid-liquid Phase Equilibrium And Crystal Habit Of Lidocaine And Its Hydrochloride

The solid-liquid phase equilibrium is an important component in crystallization thermodynamics research,and the data of solid-liquid phase equilibrium determines the production capacity of industrial crystallization,involving the yield of crystalline materials,the rational use of crystallization solvents,and the choice of crystallization methods and equipment,The data of solid-liquid phase equilibrium provides theoretical guidance for industrial crystallization technology.Crystallization is the means of separation and purification in the pharmaceutical and chemical industries to obtain high purity,high quality products.Especially in the process of medicine production,the particle size distribution,particle size and morphology of the medicine crystals affect the solubility,stability,safety and bioavailability of the medicine,further affecting the final clinical efficacy.In the crystallization process,it is necessary not only to master the basic data of thermodynamics,but also to obtain crystal structure data,making a reasonable judgment for selecting appropriate process conditions.At present,domestic research about lidocaine focuses on the fields of pharmacodynamics,pharmacokinetics,formulation,and its synthesis and development.The research on its crystallization process has not been involved.Based on this phenomenon,the subject studies the lidocaine cooling crystallization process based on solid-liquid phase equilibrium theory.The main content of this paper includes,(1)In the solubility determination experiment,lidocaine and lidocaine hydrochloride were determined by gravimetric analysis in various pure solvents(ethanol,n-propanol,isopropanol,n-butanol,isobutanol,acetone,methyl acetate,ethyl acetate)and binary mixed solvent systems,and the solubility curve was drawn to more clearly understand its solubility law in each system.(2)In the characterization experiment,the thermal analysis characterization experiment(DSC)and X-ray diffraction experiment(XRD)were used to obtain the melting point value,melting enthalpy value and corresponding diffraction pattern of the thermodynamic parameters of the substance during the dissolution process,and to determine whether the molecular structure of the substance changed before and after the experiment was dissolved.(3)In the thermodynamic model correlation experiment,five models of Apelblat equation,van't Hoff equation,?h equation,Wilson model and NRTL model were used to correlate the experimental data of lidocaine and lidocaine hydrochloride solubility.(4)In the crystal habit prediction experiment,the lidocaine single crystal is produced by volatilization of solvent.The single crystal structure data was found from the CCDC database,and the structural data was imported into the Material Studio software.Finally,the BFDH model and the AE model were used to predict the crystal habit of lidocaine.(5)In the crystallization process experiment,Optimization experiments on the crystallization process of lidocaine based on thermodynamic studies and crystal morphology studies by cooling method,and the effects of supersaturation,final temperature,stirring rate,crystal growing time and cooling rate were investigated on the final properties of the product.The solubility determination experiment found that the solubility of lidocaine and lidocaine hydrochloride in pure solvent and binary system increased with the increase of temperature.The maximum solubility of lidocaine is in acetone solvent,which provides theoretical support for the choice of rational reagents for the preparation of lidocaine single crystals,and the maximum solubility of lidocaine is in n-propanol solvent.Combined with thermodynamic analysis,the solubility enthalpy,solubility entropy and Gibbs free energy of lidocaine and lidocaine hydrochloride were calculated by the Van't Hoff equation.The enthalpy contribution value and the entropy contribution value were used to determine the dissolution process of the non-spontaneous and entropy increase.In the model correlation experiment,the Apelblat equation model showed a very good correlation effect in all experiments.Under each solvent system,the RAD value was below 1%,showing good correlation.In the crystallization process experiment,the appearance and particle size distribution of the crystal were taken as reference index to determine the optimal process condition as follows:supersaturation is 1.08,final temperature is 10? stirring rate is 160 rmp/min,crystal growing time is 1 h,and cooling rate is 0.1 ?/min.