Study On The Solid-liquid Equilibrium And Crystallization Process Of Etodolac

Etodolac belongs to the indole acetic acid class of non-steroidal anti-inflammatory drugs,which are widely used clinically for analgesia,treatment of osteoarthritis and rheumatoid arthritis.Compared with other anti-inflammatory drugs,etodolac has the advantage of exerting its efficacy while protecting the gastrointestinal mucosa,so it has been widely used clinically.At present,the research on etodolac is only focused on synthesis,and there are almost no reports on its crystallization.However,the domestic synthesis of etodolac has some problems,such as small particle size,uneven products,incomplete crystal form,etc.Therefore,it is important to study the crystallization process of etodolac.Based on the above,this article has carried out a systematic study on the solid-liquid equilibrium and crystallization process of etodolac.The contents are as follows:The laser dynamic monitoring method was used to determine the solubility of etodolac in 12 pure organic solvents,including methyl acetate,n-butyl acetate,n-amyl acetate,isobutyl acetate,isoamyl acetate,toluene,n-propanol,n-butanol,isopropanol,isobutanol,acetone(278.15 K-323.15 K)and dichloromethane(278.15 K-303.15 K).Five models(modified Apelblat model,van’t Hoff model,NRTL model,λh model and Uniquac model)were used to fit and analyze the solubility data of etodolac in pure solvents.And by comparing the values of ARD and RMSD obtained from various models,a better correlation equation suitable for pure solvent fitting was determined.Based on the solubility data of etodolac in pure solvents,the solubility data of etodolac in the mixed systems of n-propanol + n-hexane,methyl acetate + n-hexane,nbutyl acetate + n-hexane and acetone + n-hexane were determined at 278.15 K to323.15 K.Five models(modified Apelblat model,λh model,Wilson model,ThreeSuffifix Margules model and Uniquac model)were used to fit the solubility data of etodolac in the mixed system.And by comparing the values of ARD and RMSD obtained from various models,a better correlation equation suitable for the mixed solvent system was determined.According to the dissolution law of etodolac,the crystallization method was determined as the crystallization method,and the solvent system was determined as methyl acetate + n-hexane.The single factor method was used to study the crystallization process of etodolac.The influence of factors such as initial mother liquor concentration,stirring rate,addition amount of eluent,seed crystal addition,addition rate of eluent,aging time and crystallization temperature on the crystal size and crystal yield of etodolac was investigated,and a suitable result was obtained.The process conditions are: the initial mother liquor concentration is 0.32 g/m L,the stirring rate is300 r/min,the aging time is 4 h,the seed crystal addition amount is 2%,the eluent addition amount is 3 m L/m L,the eluent addition rate is 1.5 m L/min,and the temperature is 30 ℃.The yield of crystals obtained under this condition reached 64%,which was larger than the average particle size of the bulk drug,and the distribution was more uniform,and the crystal habits were more complete.