Continuous Countercurrent Distribution In Edulcoration Of Bitespiramycin Purification Process And Solution Crystallization Process Control

Bitespiramycin, macro cyclic lactone antibiotic drugs which contain a variety of effective components of acylated Spiramycin, are the first national 1.1 antibiotic drugs in China. Bitespiramycin have strict requirements on not only the content and constituent of the effective components, but also non acylated Spiramycin and other impurities content. In the refining process ionic strength, pH and temperature will cause the variation of the components. Therefore, in the process of separation, it is not only to ensure the removal of impurities, but also to give consideration to the impact of the content fluctuation caused by component change on the quality of the product. It is difficult to purify Bitespiramycin. To make component content up to the pharmacopoeia standard, synergistic purification of multiple separation means needs be adopted. In the paper multistage countercurrent liquid phase distribution technology was applied in scrubbing process, and the operational conditions of scrubbing, stripping, crystallization process were optimized.In this study, the impurities were classified according to the polarity of the components. The separation processes was optimized by aiming at the separation of a class of impurities rather than a single impurity. Considering the effect of growth and decline of the composition by the separation process on the product quality, the process conditions were established. The separation ability of different impurities in the scrubbing, stripping and crystallization was studied. Then the influence on removal of impurities in all processes of purification with alcohol, which changed the composition of the solvent system, was also probed and that is a new purification process. Research shows that:(1) in the scrubbing process the removal effect of strong polar impurity is better, and the optimum conditions of the scrubbing process by three stage countercurrent were attained and show as follows:the ratio of ester and aqueous phase is 1:1.5(V/V), the scrubbing temperature is 20℃, the concentration of NaH2PO4 is 1 (wt)%. (2) it is found that when the stripping end point pH is between 3.75 and 3.80 the strong polar impurities can be remained in the ester phase, that can improve the purity of Bitespiramycin in stripping solution-phosphate solution; it is more beneficial to obtain high purity crystal products by controlling the crystallization final pH between 7.5-7.75, making impurities tend to dissolve in the crystallization mother liquor; and in fractional crystallization process control the fractional pH to 7.00 can abate the loss of the effective components and reduce the weak polar impurities in product. (3) by analysis the impurities of off-test product, it is found that there are three reasons for the difficulty of obtaining the qualified product: among the strong polar impurities, impurity z (the impurity that is out of peak in 12 minutes on liquid chromatography) has a huge content and is difficult to remove; there is no effective means of separation for removing the medium impurities which have high content in the process; weak polar impurities is difficult to separate from the effective components (Isovaleryspiramycin Ⅲ), and the fractional pH of fractional crystallization is hard to control, leading to the low feasibility of application in production. Based on the distribution feature of impurities in the off-test product, this paper first postulated that change the polarity of the solution by adding alcohol to form a mixed solvent in the stripping and crystallization process to improve the removal efficiency of impurities. The result showed that it could reduce the content of medium and strong polar impurities ulteriorly, and have the best removal effect when adding amount of 6 (wt)%.The study improved and optimized original purification process of Bitespiramycin, meanwhile proposed a new process that using the compound solvent, alcohol-water system, for washing, stripping, crystallization. The medium impurities which were difficult to deal with by the traditional process had good removal effect by the new process. The result of this study is expected to provide guidelines on industrial production and quality control of Bitespiramycin.