| 1 Purpose of this paperBoth bupivacaine hydrochloride and ropivacaine hydrochloride are piperidine carboxamide comounds with N-substituted side chains.These two local anesthetics have precise analgesic effects,fast metabolism,low side effects,cardiovascular system and central nervous system They have the advantages of low system toxicity,more obvious separation of sensory block and motor block,etc.They are widely used in many fields such as gynecology,surgery,stomatology,orthopedics and so on.However,the current researches on bupivacaine hydrochloride and ropivacaine hydrochloride mostly focus on the synthetic route,dosage form design,clinical combined application of the drug,and adverse reactions.There are no relevant reports on the study of their crystallization process and thermodynamic properties.The crystal form,crystal size,morphology and particle distribution of the drug will directly affect the mechanical stress,bulk density,fluidity and other properties of the product.These characteristics are closely related to the design and development of the dosage form of the drug subsequently.In addition,it also affects the solubility and vivo dissolution of the drug,the safety,stability,bioavailability and clinical efficacy of the drug.The study of solid-liquid equilibrium around the solubility measurement and thermodynamic analysis can provide basic data for the related research of crystallization technology,which is indispensable in the research of drug crystallization.Therefore,this paper made a preliminary study on the so lid-liquid phase equilibrium and crystallization process of bupivacaine hydrochloride and ropivacaine hydrochloride,and provided a reference for the development and design of new dosage forms of two drugs.2 Experimental methods(1)In this experiment,bupivacaine hydrochloride and ropivacaine hydrochloride were selected as the research objects.Differential scanning calorimetry(DSC)was used to determine the melting point(Tm)and melting enthalpy(△fusH)of the two drugs;X-ray diffraction(XRD)was used to characterize the molecular structures of the two drugs before and after dissolution.(2)The molar solubility of analgin in methanol was determined at different temperatures to verify the reliability of the experimental method and device for solubility determination based on the relative deviation(RD)between the experimental value and the literature value.(3)The static weighing method was used to determine the molar solubility of bupivacaine hydrochloride and ropivacaine hydrochloride in 11 common pure solvents and ethanol+wate mixed solvents with nine concentration ratios.(4)Van’t Hoff equation was used to calculate the dissolution entropy,dissolution enthalpy,dissolution Gibbs free energy,relative entropy contribution and relative enthalpy contribution of bupivacaine hydrochloride and ropivacaine hydrochloride,and the dissolution thermodynamic analysis of the two drugs were performed.(5)Three empirical equations(Van’t Hoff equation,Apelblat equation,λh equation)and two local activity coefficient models(Wilson model,NRTL model)were used to correlate the measured solubility of bupivacaine hydrochloride and ropivacaine hydrochloride.The fitting effect of the thermodynamic model was evaluated based on the average relative deviation(RAD)between the exp erimental value and the model fitting value.(6)The single crystal structure data of ropivacaine hydrochloride recorded in the Cambridge Crystal Data Center was imported into the Material Studio.The BFDH model and AE model were used to predict the crystal morphology of ropivacaine hydrochloride in vacuum.And the MAE model was used to predict the crystal morphology of ropivacaine hydrochloride in ethanol solvent.(7)Based on the study of solid-liquid equilibrium and the prediction of crystal morphology,a preliminary study on the crystallization process of ropivacaine hydrochloride was carried out by control variable method.3 Experimental results(1)The melting points of bupivacaine hydrochloride and ropivacaine hydrochloride measured by DSC were 532.32 K and 540.60 K,respectively,and the melting enthalpies were 21.52 kJ/mol and 17.20 kJ/mol;The XRD pattern showed that the peak positions were neat,indicated that the molecular structures before and after dissolution were consistent.(2)At different temperatures,the RD values between the measured values of the solubility of analgin in methanol and the literature values were all within 1.5%,and most of them were below 1%,indicated that the experimental method and device for solubility determination were reliable.(3)The molar solubility of bupivacaine hydrochloride and ropivacaine hydrochloride in 11 common pure solvents and ethanol+ water mixed solvents of different concentration ratios all showed upward trends with the rising temperature.At the same temperature,the solubility of bupivacaine hydrochloride in 11 pure solvents from low to high was:methyl acetate≈acetone<acetonitrile<water<isopropanol<N,N-dimethylformamide<ethanol<methanol<isobutanol≈n-butanol<n-propanol.In different concentrations of ethanol+water mixed solvents,when the mass fraction of ethanol was 0.8,the solubility of bupivacaine hydrochloride was the largest.At the same temperature,the solubility of ropivacaine hydrochloride in 11 pure solvents from low to high was:methyl acetate<acetone≈acetonitrile<water<isopropanol≈N,N-dimethylformamide<isobutanol<n-propanol<n-butanol<ethanol<methanol.In different concentrations of ethanol+water mixed solvents,when the mass fraction of ethanol was 0.9,the solubility of ropivacaine hydrochloride was the largest.(4)When bupivacaine hydrochloride and ropivacaine hydrochloride were dissolved in all selected solvents,the dissolution enthalpy,dissolution entropy,and dissolution Gibbs free energy were all positive,and the relative enthalpy contribution was greater than the relative entropy contribution,indicated that the dissolution processes of the two drugs in all selected solvents were non-spontaneous endothermic and entropy increase processes,and the dissolution process were enthalpy-driven processes.(5)In the bupivacaine hydrochloride-pure solvent system,the average values of RAD of five thermodynamic models were 0.61(Van’t Hoff equation),0.49(Apelblat equation),0.61{λh equation),1.02(Wilson model),1.57(NRTL model).In the bupivacaine hydrochloride-mixed solvent system,the average values of RAD of the five thermodynamic models were 0.64(Van’t Hoff equation),0.58(Apelblat equation),0.76(λh equation),3.49(Wilson model),3.07(NRTL model),5 thermodynamic models had good correlation fitting effect on the measured solubility of bupivacaine hydrochloride in pure solvents and mixed solvents.Whether in pure solvents or mixed solvents,the Apelblat equation gave the best fitting effect.In the ropivacaine hydrochloride-pure solvent system,the average values of RAD of five thermodynamic models were 0.47(Van’t Hoff equation),0.69(Apelblat equation),0.45(λh equation),1.26(Wilson model),1.30(NRTL model).In the ropivacaine hydrochloride-mixed solvent system,the average values of RAD of the five thermodynamic models were 0.98(Van’t Hoff equation),0.65(Apelblat equation),1.28(λh equation),2.32(Wilson model),2.96(NRTL model).The five thermodynamic models had good correlation fitting effects on the measured solubility of ropivacaine hydrochloride in pure solvents and mixed solvents.The fitting effect of the λh equation was the best in pure solvents,and in mixed solvents,the Apelblat equation was the best.(6)The ropivacaine hydrochloride in vacuum predicted by the BFDH model was mainly composed of 9 faces,namely(0 0 1),(1 0 0),(0 1 1),(0-1 1),(1 0-1),(1 1 0),(1-1 0),(1 1-1),(1-1-1).Among them,(0 0 1)and(1 0 0)two crystal planes had large exposed area,which determined the morphology of the crystal.The ropivacaine hydrochloride in vacuum predicted by the AE model was mainly composed of 7 faces,namely(0 0 1),(1 0 0),(l 0-1),(0 1 1),(0-1 1),(1 1 0),(1-1 0).Among them,(0 0 1)and(1 0 0)contain a large proportion in the crystal plane,which determined the morphology of the crystal together.The order of the interaction strength between ethanol solvent molecules and different crystal faces of ropivacaine hydrochloride predicted was:(1 1 0)>(1-1 0)>(0 11)>(0-11)>(1 0 0)>(1 0-1)>(0 0 1).The interaction force between ethanol and(1 1 0),(1-1 0),(01 1)and(0-1 1)crystal planes were relatively large,crystal plane(0 1 1),(0-1 1)gradually disappeared in the process of competing with the crystal plane(1 1 0)and(1-1 0).(7)In the research of the crystallization process of ropivacaine hydrochloride,according to the morphology and particle size distribution of the crystalline product,the optimal process conditions were finally determined as follows:seed crystals were added,the supersaturation was S=1.05,the stirring rate was 150 rpm/min,cooling rate was 0.6℃/min,end temperature was 10℃,crystal growth time was 90 min.4 Conclusion of this article(1)The solubility of bupivacaine hydrochloride and ropivacaine hydrochloride in 11 different pure solvents and different ratios of ethanol+water mixed solvents all increased with the rising temperature,and the dissolution processes were enthalpy driven,endothermic,entropy increasing and nonspontaneous processes.(2)Van’t Hoff equation,Apelblat equation,λh equation,Wilson model and NRTL model had good correlation fitting effects on the solubility of bupivacaine hydrochloride and ropivacaine hydrochloride in the selected solvents.(3)The predicted results of BFDH model and AE model for the crystal morphology of ropivacaine hydrochloride in vacuum were similar to the real crystal morphology,but there were still some differences.The crystal morphology of ropivacaine hydrochloride in ethanol solvent predicted by MAE model was consistent with the experimental result,which provided a reference for obtaining the ideal crystal shape in the study of crystallization process.(4)After the optimization of crystallization process,the transparency and average particle size of ropivacaine hydrochloride crystal were improved.The morphology was complete,and the particle size distribution was more uniform. |
