唑来膦酸含量测定及有关物质的研究
发布时间：2018-11-28 18:33
【摘要】：研究背景:唑来膦酸为第三代二膦酸盐类药物,唑来膦酸可以用于恶性肿瘤引起的骨转移、高钙血症、骨质疏松症等的治疗,其治疗具有给药剂量小,给药方便,依从性好等优点。基于实验室的前期工作,以咪唑为原料,生成咪唑-1-乙酸中间体,之后进行两步磷酸化后,生成唑来膦酸。前期中试工艺中,对咪唑乙酸(中间体)中试工艺放大到870.40g(咪唑的投药量),对唑来膦酸的工艺放大到1kg(咪唑乙酸的投药量),结果比较稳定,而且纯度较好。根据本实验的前期工作,本文对唑来膦酸的中试工艺做了进一步研究:(1)对中间体咪唑乙酸,我们制定了咪唑投料量为2kg、5kg、8kg、10kg时的中试工艺,收率较高,纯度较好。(2)对目标产物唑来膦酸一水合物,我们制定了中间体咪唑乙酸投料量在2kg、5kg、8kg时的中试工艺,并对其重要参数进行了系统优化,获得了较好的收率及纯度。并参考文献及我们的合成经验,制备了重要杂质A和B,并鉴定了其结构,为下一步的质量研究提供了条件。在实验室前期工作的基础上,我们利用高效液相色谱法对唑来膦酸含量测定方法学进行了系统研究,制定了其含量测定条件:苯基柱4.6*250mm 5μm(汉邦);流动相:取2m L三乙胺加到800m L去离子水中,加磷酸调p H为3.0,加水定容至1L,取950m L加50m L甲醇为流动相。检测波长:220nm,流速:0.7m L/min,柱温:40℃,进样浓度:0.1mg/m L,进样量:10μL。并对自制的唑来膦酸三批样品进行测定,含量为:99.91%、100.2%、99.78%。该结果表明,本工艺制备的唑来膦酸中试样品含量稳定,结果较好。此外我们尚对中间体咪唑乙酸中起始原料咪唑及杂质B的残留以及终产品唑来膦酸中起始原料咪唑及中间体咪唑乙酸的残留进行了初步探讨。上述结果表明:(1)经本工艺制备的中间体咪唑乙酸中未发现咪唑及杂质B的残留;(2)经本工艺制备的终产物唑来膦酸中也未发现起始原料咪唑及中间体咪唑乙酸的残留。该部分工作为唑来膦酸原料药及其中间体咪唑乙酸最终质量标准的确定奠定基础。
[Abstract]:Background: zoledronic acid is a third-generation diphosphonic acid drug. Zoledronic acid can be used in the treatment of bone metastasis, hypercalcemia, osteoporosis and so on. Good compliance and other advantages. Based on the laboratory work, imidazole-1-acetic acid intermediate was synthesized from imidazole, and then phosphorylated to zoledronic acid. In the earlier pilot-scale process, imidazole acetic acid (intermediate) was amplified to 870.40 g (dosage of imidazole), and zoledronic acid was amplified to 1kg (dosage of imidazolyl acetic acid). The results were stable and the purity was good. According to the previous work of this experiment, the pilot-scale process of zoledronic acid was studied in this paper. (1) for imidazolyl acetic acid, the pilot-scale process of imidazole was developed when the dosage of imidazole was 2 kg / L, 5 kg / kg ~ (8 kg) ~ (10 kg), and the yield was high. (2) for the target product, Zoledronic acid monohydrate, a pilot-scale process of imidazolium acetic acid at the dosage of 2 kg ~ 5kg ~ (-1) was established, and its important parameters were systematically optimized, and a good yield and purity were obtained. With reference to literature and our synthetic experience, important impurities A and B were prepared, and their structures were identified, which provided conditions for further quality study. On the basis of the previous work in laboratory, we systematically studied the method of determination of zoledronic acid by high performance liquid chromatography (HPLC). The determination conditions of zoledronic acid content were determined as follows: phenyl column 4.6*250mm 5 渭 m (Hanbang); Mobile phase: 2m L triethylamine was added to 800 mL deionized water, pH was adjusted by phosphoric acid 3.0, water volume was fixed to 1L, and 950ml + 50ml methanol was used as mobile phase. The detection wavelength was 220 nm, the flow rate was 0.7 mL / min, the column temperature was 40 鈩，
本文编号：2363885
[Abstract]:Background: zoledronic acid is a third-generation diphosphonic acid drug. Zoledronic acid can be used in the treatment of bone metastasis, hypercalcemia, osteoporosis and so on. Good compliance and other advantages. Based on the laboratory work, imidazole-1-acetic acid intermediate was synthesized from imidazole, and then phosphorylated to zoledronic acid. In the earlier pilot-scale process, imidazole acetic acid (intermediate) was amplified to 870.40 g (dosage of imidazole), and zoledronic acid was amplified to 1kg (dosage of imidazolyl acetic acid). The results were stable and the purity was good. According to the previous work of this experiment, the pilot-scale process of zoledronic acid was studied in this paper. (1) for imidazolyl acetic acid, the pilot-scale process of imidazole was developed when the dosage of imidazole was 2 kg / L, 5 kg / kg ~ (8 kg) ~ (10 kg), and the yield was high. (2) for the target product, Zoledronic acid monohydrate, a pilot-scale process of imidazolium acetic acid at the dosage of 2 kg ~ 5kg ~ (-1) was established, and its important parameters were systematically optimized, and a good yield and purity were obtained. With reference to literature and our synthetic experience, important impurities A and B were prepared, and their structures were identified, which provided conditions for further quality study. On the basis of the previous work in laboratory, we systematically studied the method of determination of zoledronic acid by high performance liquid chromatography (HPLC). The determination conditions of zoledronic acid content were determined as follows: phenyl column 4.6*250mm 5 渭 m (Hanbang); Mobile phase: 2m L triethylamine was added to 800 mL deionized water, pH was adjusted by phosphoric acid 3.0, water volume was fixed to 1L, and 950ml + 50ml methanol was used as mobile phase. The detection wavelength was 220 nm, the flow rate was 0.7 mL / min, the column temperature was 40 鈩，
本文编号：2363885
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