红霉素溶析结晶过程的介稳特性

The Metastable Characteristic of Erythromycin Solventing-out Crystallization Process

在工业生产中,红霉素采用溶析结晶的方法制备,红霉素溶析结晶过程的介稳特性直接影响红霉素晶体的粒径和粒度分布。本研究采用差重法测定丙酮水溶液中红霉素的溶解度,采用激光散射法测定红霉素的超溶解度,由此获得红霉素-丙酮-水结晶体系的介稳区宽度。红霉素在丙酮水溶液中的溶解度随着丙酮浓度的降低而减小,32℃以下的各溶解度曲线有逐渐趋于一点的趋势。50℃时,介稳区的宽度随着丙酮浓度的降低而变窄,并于质量比MWater/MAcetone约为1.7时趋于最小值;红霉素的超溶解度随着反溶剂水导入速率的增大而减小,导致介稳区宽度变窄;搅拌速率的增加使红霉素的超溶解度先减小再增大,介稳区宽度于转速约为340r.min·1时达最小值。基于以上研究结果形成的变温、变搅拌强度的红霉素动态溶析结晶方法制备的红霉素晶体的粒度增大且分布集中,其生物效价也有明显提高。

In industry, the erythromycin is usually produced by the method of solventing-out crystallization. The metastable characteristic of erythromycin solventing-out process directly influences the granularity and crystal size distribution of the product. In the present work, the metastable zone width of erythromycin was studied, where the gravimetric method was employed to measure the erythromycin solubility in water-acetone solution, and the laser scattering method was used to determine its supersolubility. The investigation indicates that the erythromycin solubility in water-acetone solution reduces with decreasing temperature, and all solubility curves with temperatures below 32℃ would tend to converge on a certain point. The metastable zone width of erythromycin narrows down with the decrease of the acetone concentration, and the minimum width will be reached when the mass ratio of Mwater/MAcetone is about 1.7 at 50℃. Supersolubility curves drop obviously when the water adding rate is increased. The metastable zone width at 50℃ changes with the variation of stirring speed and reaches its minimum when the stirring speed is 340 r·min^-1. Based on the above studies, a novel alternatively controlled crystallization process was proposed, in which the high temperature and high stirring intensity are taken for the beginning of the crystallization, and then a lower temperature and lower stirring intensity are used to extend the growth of the crystals. The alternatively controlled solventing-out crystallization process proposed can favor the formation of crystals with apparently larger crystal size and homogeneous size distribution, and the product with high specific activity can thus be obtained.