Research On The Polymorphs And Crystallization Process Of Lincomycin Hydrochloride

Lincomycin hydrochloride is a broad-spectrum antibiotic of linkamide.It is mainly used in the treatment of septicemia,respiratory tract infection,bone and joint infection and so on.It has been widely used because of its quick effect and few side effects.Lincomycin hydrochloride has been produced for a long time,but it lacks systematic research on crystallization and the final crystallization product has the problem of uncontrollable size.In this paper,the crystallization process of lincomycin hydrochloride is studied in order to provide a theoretical basis for industrial production.Firstly,the solubility of lincomycin hydrochloride polymorph II in pure solvent n-propanol,n-butanol,isobutanol,n-dimethylacetamide and mixed solvent water-n-butanol and water-acetone,along with the solubility of lincomycin hydrochloride polymorph Ⅰ in mixed solvent water-n-butanol was determined by dynamic method.The results showed that the solubility increases with the increase of temperature and water fraction in the solvent.The solubility data were fitted by van’t Hoff equation,Apelblat equation,(CNIBS)/Redlich-Kister equation and Jouyban-Acree equation.Then the thermodynamic data of the dissolution process were calculated.The change of metastable zone width of lincomycin hydrochloride due to the different rate of adding acid,initial concentration and reaction temperature in the process of reaction crystallization was determined by laser method.The results showed that the metastable zone width increased with the increase of temperature,initial concentration and the rate of acid addition.And at low temperature(≤ 333.15k)and low initial concentration(≤ 0.2482g/g),the polymorph I was precipitated.The solution-mediated transformation process of lincomycin hydrochloride was monitored by in situ Raman spectrometer.Combined with the concentration change(During the period of transformation induction,it gradually increased to a stable level and began to decrease after nucleation of stable crystal form,and then decreased to stable crystal form solubility at the end of transformation.)of the transformation process,the rate control step of solution-mediated transformation of lincomycin hydrochloride was determined to be nucleation-dissolution control.The effects of different solvent composition,solid loading,temperature and stirring rate on the transformation process of lincomycin hydrochloride were investigated.It was found that the effect of water fraction and temperature was the greatest.The rate of transformation increased with the increase of temperature and water fraction in the solvent.Aiming at the problem of uneven particle size of lincomycin hydrochloride produced in factory,the effect of different crystallization process parameters on the particle size of the product was investigated to determine the best parameters.For azeotropic crystallization,the faster the evaporation rate was,the more concentrated the particle size distribution of the product was,and the particle size could be smaller;for reactive crystallization,the product with uniform particle size could be obtained by adding crystal seeds.The effects of seed addition time,seed addition amount,seed size distribution,crystal culture time,and acid addition rate on the particle size of the product were investigated.The optimum process parameters were determined.