Basic Research On Dilution Crystallization Of Levamisole Hydrochloride

Levamisole Hydrochloride?LH?,as a broad-spectrum,high-activity,low-toxicity,fast metabolic rate,and immune-regulating anthelmintic agent,remains the focus of research.In the production and application of LH,the necessary basic physical property data and systematic research to control its product quality are still lacking.Dilution crystallization can be used as a classic method to control the basic data of crystal size distribution,crystal structure,thermal stability,solubility,etc.to evaluate drug efficacy indicators.Based on this,the basic research on the dilution crystallization of LH is carried out in this work.The p Ka and the solid-liquid phase equilibrium data and its thermodynamic properties of levamisole hydrochloride in pure solvents and mixed solvents are measured.The dilution crystallization kinetics was studied,the dilution crystallization process was proposed and studied,and the thermal stability and crystal structure simulation of the crystal were investigated.A laser dynamic method was used to measure the dissolution behavior of LH in solvents such as alcohols,esters,alkanes,and water.Finally,the solid-liquid phase equilibrium data in twelve pure solvents and three mixed solvents were determined.Seven related thermodynamic models including NRTL model,UNIQUAC model,Wilson model,van't Hoff model,and GSM model et.al were used to correlate the 218data points of the 24 groups of systems.Based on Wilson Equation,the mixing thermodynamic parameters of levamisole hydrochloride in the pure solvent dissolution process,such as the mixing enthalpy(?_mixH),the mixing Gibbs free energy(?_mixG)and the mixing entropy(?_mixS)were analyzed.The apparent thermodynamic properties of levamisole hydrochloride in the selected solvents,such as the dissolution Gibbs free energy(?_solG⁰),enthalpy of dissolution(?_solH⁰),entropy of dissolution(?_solS⁰),were calculated by van't Hoff method.The infinite dilution activity coefficient?ln?₁^??and dilution activity coefficient?ln?₁?of solute in dissolution process were also studied.The results show that the dissolution process of LH in the binary solvent is an entropy driven endothermic process,and the contribution of enthalpy change to Gibbs energy change is greater than that of entropy change.The dissolution rule of levamisole hydrochloride in the solvents was analyzed by using the Dmol³ and Forcite model of Material Studio.Based on the data of phase equilibrium,the crystallization process of levamisole hydrochloride was determined.Based on the dissolution phase equilibrium data and thermodynamic properties,the dilution crystallization process of levamisole hydrochloride with methanol-isopropanol was studied.The appropriate conditions is as follows:the mole fraction of methanol is 0.7377,the temperature is 308.15 K,the aging time is 4 h,the dripping rate of the eluent is 1.31 m L?min^-1,the amount of seed added is 1.0%of the mass of the added solute,the stirring rate is 400 rpm,and the initial concentration is 0.24 g?g^-1,the mass ratio of the solvent and anti-solvent is 1:2,the crystalline yield of LH is 80%,the average crystal size is 16.37?m,and the coefficient of variation is 0.6823.The laser dynamic method was used to determine the metastable zone and induction period of LH in a methanol+isopropanol mixed solvent.The homogeneous and heterogeneous processes of dissolution of LH in a methanol-isopropanol mixed solvent were calculated.The surface entropy factor f,the solid-liquid surface tension?,and the characteristic factor?of the heterogeneous process indicate that the crystal of LH is in a continuous growth mode.The kinetics of the dilution crystallization of LH was studied by the intermittent dynamic method.The growth model of levamisole crystalline growth and particle size was established.The crystallization kinetics model was obtained by using the MJ3 model.The nucleation activation energy is 105.9k J·mol^-1;the crystal growth activation energy is 144.3 k J·mol^-1.The LH product were characterized by SEM,PXRD,FTIR,DSC,TG-DSC analysis,and the PXRD data of the LH crystal was analyzed using simulation software?Materials Studio 2017?,and the unit cell parameters of LH crystal:a=14.7105?;b=12.9425?;c=5.9348?;?=90°;?=90°;?=90°;unit cell volume V=1129.93?³;belongs to orthorhombic system,and the space group belongs to P2₁2₁2₁;there are4 molecules in the unit cell.The crystal habit of LH was simulated by using the BFDH model of Materials Studio software,which is consistent with the actual SEM,are needle like.The dissolution crystallization process does not affect the physicochemical properties and crystal habit of LH,but it can change the particle size distribution,coefficient of variation and other indicators.TG-DSC method was used to study the thermal decomposition kinetics of LH crystal.The Kissinger maximum rate method,?atava-?esták integration method and Flynn–Wall–Ozawa integration method were used to analyze the measured experimental data.The average thermal decomposition activation energy of LH crystal was 94.25 k J·mol^-1and the average value of preexponential factor was 4.479×10⁷ s^-1,the result indicate that the stability of LH is not good,so it needs to be stored at low temperature.The experimental and analysis results indicate that the thermal decomposition mechanism of LH crystal was a chemical reaction,and the differential form of the thermal decomposition mechanism function was obtained:f???=?1-??²;integral form G???=?1-??^-1-1.The thermodynamic parameters of the first-stage thermal decomposition process of LH:Gibbs free energy change?G^?,enthalpy change?H^?,and entropy change?S^?are 153.19 k J·mol^-1,89.53 k J·mol^-1,-112.11 J·mol-1·K^-1,respectively.The density and viscosity of the LH solution at atmospheric pressure between283.15 and 323.15K were investigated.The Vogel-Tamman-Fulcher equation was used to correlate the data.The ARD and SD values of the experimental and calculated values were 2.49%and 0.039,respectively.The above research results provide basic data for the crystallization process and industrial design and production of levamisole hydrochloride,which has important practical significance and application value.