Separation, Identification And Control Of Specific Impurities In Milbe

Milbemycin Oxime is a semi-synthetic sixteen-membered ring macrolides product derived from the fermentation product Milbemectin. It displays notable anthelmintic and antiparasitic activities.As pharmaceutical active ingredient, it is very critical and important that how the industry controls inactive ingredients, especially those related substances with high content level, which cannot be removed completely during purification steps.By now, most studies focused on the structure modification of Milbemectin, or its derivatives. There is no report of further study on the related substances exists in Milbemycin Oxime. U.S. Pharmacopoeia Forum published a draft monograph of Milbemycin Oxime for comments in 2010, which listed a known impurity named 11-desmethyl-mibemycin oxime A4, this draft is still under discussion. European Pharmacopoeia published a draft monograph for this active substance in January 2013, in which nine impurities are displayed as known related substances, additional tests are necessary to be conducted to evaluate whether they are present in the active substance, and the suitability of the test procedures should also be evaluated. Therefore, further studies on impurity profiles of Milbemycin Oxime and the test procedures are considered to be more important. This study is to design separation approach, and obtain individual component sample with high purity level for each research target. NMR spectra and EI-MS are utilized to determine the chemical structure of each target. Furthermore, this study also compare the obtained component structures with those impurities listed in U.S. pharmacopoeia draft monograph and European Pharmacopoeia draft monograph, it was confirmed that these four components are included neither in USP draft monograph nor EP draft monograph. Additional comments and feedback will be sent to pharmacopoeia committee.