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: 8455581
• 负责人: GIRISH SRINIVAS
• 金额: $ 51.1万
• 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 2014-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455581
• 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. PUBLIC HEALTH RELEVANCE: Many pharmaceuticals prescribed to tens-of-millions of patients are contaminated with toxic impurities originating from metal catalysts used during drug synthesis. Chronic use of medications contaminated with toxic metals can cause cumulative neurological damage similar to that produced by mercury, lead and other neurotoxic substances. Catalytic metals, if not removed between synthesis steps, catalyze in later steps production of organic side products, similar to target drug molecules that are difficult to separat and which induce additional toxic side-effects or which interfere with action of the drug molecules.

描述：该项目的总体目标是开发脱除药物合成中使用的催化金属的吸附剂，如果在合成步骤之间和最终活性药物成分中没有充分去除这些金属，可能会导致毒副作用。正在设计吸着剂，以满足将于2013年9月实施的新的美国药典和国际标准。目标是将催化金属，特别是钯去除到5ppmw(口服药物)和0.5ppmw(非肠道药物)。虽然使用Pd和其他铂族金属的均相催化剂给药物开发带来了革命性的变化，但这些有机金属化合物具有极高的毒性，产生的神经效应类似于甲基汞和四乙基铅引起的影响。这种毒性的分子机制类似于抗癌药物顺铂、卡铂及其顺式钯类似物引起的副作用，顺铂和顺铂类似物与核和线粒体DNA强烈结合，阻止关键神经酶的转录，并结合对大脑能量代谢至关重要的酶的活性部位。均相有机金属催化剂很容易通过血脑屏障，特别是当设计有亲脂配体时，这种配体允许非常快速地通过神经系统的脂膜运输，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，在每一步之后以及从最终产品中都应该去除催化金属。如果在每一步后不移除催化剂，它们可能会在随后的步骤中催化形成细胞毒性有机副产物，这些副产物不易与靶药物分子分离。此外，均相催化剂可以降解，形成新的配位化合物、簇合物和纳米悬浮液，如果不去除这些化合物，还可能催化额外的副反应。这些有毒金属脱色产品也必须从最终药物产品中去除。为了去除各种各样的金属污染物，多孔炭正在被科学地设计成具有独特的孔分布，以捕获通过传统过滤、离心法或金属清除剂不易去除的笨重的配位化合物、簇合物和纳米颗粒。此外，碳还被功能化，以结合污染药物的钯化合物。第一阶段测试的吸附剂将铃木偶联反应的Pd浓度降低到0.20ppmw，Heck偶联反应的Pd浓度降低到0.90ppmw。在第二阶段，我们将致力于为制药行业创建一条新的碳吸附剂产品线。这些碳将被装在罐中出售；通过活性碳填充床洗脱溶液提纯的药物混合物。 与公共卫生相关：许多开给数千万患者的药物受到有毒杂质的污染，这些杂质来自药物合成过程中使用的金属催化剂。长期使用受有毒金属污染的药物会导致累积的神经损害，与汞、铅和其他神经毒性物质造成的损害类似。如果在合成步骤之间不去除催化金属，则在后面的步骤中催化产生有机副产物，类似于目标药物分子，这些分子很难分离，会引起额外的毒副作用或干扰药物分子的作用。