Sorbents for Toxic-Metal Removal in Pharmaceutical Development and Manufacture

用于药物开发和制造中有毒金属去除的吸附剂

• 批准号: 8544399
• 负责人: GIRISH SRINIVAS
• 金额: $ 48.9万
• 依托单位: TDA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544399
• 关键词: Sorbents; Toxic; Metal; Removal; Pharmaceutical

DESCRIPTION: The overall project goal is to develop sorbents that remove catalytic metals used in drug synthesis, which if not adequately removed between synthetic steps and from the final active pharmaceutical ingredients, can lead to toxic side-effects. Sorbents are being designed to meet new U.S. Pharmacopeia and international standards to be implemented in September, 2013. Goals are to remove catalytic metals and especially palladium to <5ppmw for oral medications and <0.5ppmw for parenteral medications. While homogeneous catalysts using Pd and other Pt-group metals have revolutionized drug development, these organo-metallic compounds are extremely toxic, producing neurological effects similar to those induced by methyl mercury and tetraethyl lead. The molecular mechanisms of this toxicity are similar to the side-effects induced by the anti-cancer agents, cis- platin, carboplatin and their cis-palladium analogues which bind strongly to both nuclear and mitochondrial DNA, block transcription of critical neural enzymes and bind to active sites of enzymes that are critical for energy metabolism in the brain. Homogeneous organo-metallic catalysts readily cross the blood-brain barrier especially when designed with lipophilic ligands that allow very rapid transport through lipid membranes of the nervous system analogous to transport of methyl mercury and tetraethyl lead. Drug synthesis may involve numerous catalytic steps, and the catalytic metals should be removed after each step, as well as from the final product. If catalysts are not removed after each step, they may catalyze in subsequent steps formation of cytotoxic organic side-products, not easily separated from the target drug molecules. In addition, homogeneous catalysts can degrade, forming new coordination compounds, cluster compounds and nano- suspensions, which if not removed, may also catalyze additional side-reactions. These toxic-metal degredation products must also be removed from the final drug product. To remove a wide variety of metal contaminants, porous carbons are being scientifically designed with a unique pore distribution to trap bulky coordination complexes, cluster compounds and nanoparticles that are not easily removed by conventional filtration, centrifugation or metal scavengers. In addition, the carbons are functionalized to bind palladium compounds contaminating pharmaceuticals. Sorbents tested in Phase I lowered Pd concentrations to 0.20 ppmw for a Suzuki Coupling Reaction and 0.90 ppmw for a Heck Coupling Reaction. In Phase II we will work towards creation of a product line of new carbon sorbents for the pharmaceutical industry. The carbons will be sold in canisters; pharmaceutical mixtures purified by eluting solutions through packed beds of the activated carbons.

描述：总体项目目标是开发吸附剂，以去除药物合成中使用的催化金属，即使在合成步骤之间以及从最终的活性药物成分之间进行充分去除，可能会导致有毒的副作用。吸引人的目的是满足2013年9月实施的新美国药房和国际标准。目标是去除催化金属，尤其是钯的口服药物<5ppmw，用于口服药物，<0.5ppmw用于肠胃外药。虽然使用PD和其他PT组金属的均质催化剂彻底改变了药物开发，但这些有机金属化合物具有极高的毒性，产生的神经系统作用类似于甲基汞和四乙基铅诱导的效应。这种毒性的分子机制类似于抗癌剂，顺丁蛋白，卡铂及其顺式 - 甲基 - - 甲基类似物，它们与核和线粒体DNA强烈结合，封闭了关键的神经酶的转移，并与enzemes的活性位点结合，而brain的活性部位是至关重要的。同质有机金属催化剂很容易穿越血脑屏障，尤其是在使用亲脂性配体设计时，可以非常快速地通过神经系统的脂质膜运输，类似于类似于甲基汞和四乙基铅的运输。药物合成可能涉及许多催化步骤，并且在每一步之后以及最终产物中应除去催化金属。如果在每个步骤之后未去除催化剂，则它们可能在随后的细胞毒性有机副产品的后续步骤中催化，而不容易与目标药物分子分离。此外，均匀的催化剂会降解，形成新的配位化合物，簇化合物和纳米悬浮液（如果未去除）也可能会催化其他副反应。这些有毒金属降解产物也必须从最终药物中去除。为了去除各种金属污染物，正在科学设计多孔碳，具有独特的孔隙分布，可捕获笨重的配位络合物，簇化合物和纳米颗粒，这些孔通过常规过滤，偏心或金属清除剂轻易去除。此外，将碳官功能化以结合钯化合物污染药物。在I期中测试的吸附剂将PD浓度降低至0.20 ppmw，用于铃木偶联反应，0.90 ppmw降低了heck偶联反应的0.90 ppmw。在第二阶段，我们将致力于为制药行业创建新的碳吸附剂产品系列。碳将在罐子中出售；药物混合物通过通过活性碳的包装床洗脱溶液来纯化。