多组分酰化螺旋霉素的球形结晶工艺

Spherical Crystallization Process of Multicomponent Acylated Spiramycin

螺旋霉素及其酰化产品为多组分的大环内酯类抗生素,易吸潮、团聚,不利于储存和后续加工。研究了酰化螺旋霉素的类乳浊液溶剂扩散法球形结晶技术,以有效提升产品的晶体性能,并实现有效成分的富集。通过对关键影响因素的考察,得到最优化的工艺条件:温度30℃、溶剂与水的体积比为0.030、停留时间5 h以及搅拌转速500 r/min。该条件下,酰化螺旋霉素球形结晶产品平均粒径365μm,粒径分布均匀。与原料相比,产品有效成分质量分数提高5%以上。使用质量分数高于2%的K_2HPO_4溶液作为不良溶剂可有效提高产品收率,但同时也促使酰化螺旋霉素的水解,使产品纯度下降。

Spiramycin and its acylated derivative,multicomponent macrolide antibiotic,have high lipotropy and excellent antibacterial effect in clinical medicine.However,most of acylated spiramycin products are powder crystal prepared by reaction crystallization which absorb moisture and agglomerate easily,compromising their storage and subsequent processing in industry.This paper focuses on using the spherical crystal preparation technology,the quasi emulsion solvent diffusion method,to improve the crystal morphology and enrich the active ingredients of acylated spiramycin.An oil in water emulsion system of solvent and water under high shear and emulsification of polymer excipient (HPMC E50) was generated in a jacket crystallizer.During this process,acylated spiramycin precipitated and agglomerated into spherical crystal with solvents diffusing in emulsion droplets.Finally,based on the study of the key effects of the spherical crystallization process,the optimal parameters were obtained: system temperature is 30 ℃,volume ratio of solvent to water is 0.030,resident time is 5 h,stirring rate is 500 r/min.Both the average diameter and unity of spherical crystal product are increased significantly (D43 is 365 μm,consistency index is 0.213) compared with raw material (D43 is 10.97 μm,consistency index is 0.897).Moreover,the content of main effective component was increased by 5%with the mass yield no less than 75%.The product yield can be improved when using K2HPO4 solution with a mass concentration greater than 2%,but the standing time needs to be strictly controlled to avoid reduction of production purity caused by the hydrolysis of acylated spiramycin.