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.

项目总体目标是开发吸附剂，去除药物合成中使用的催化金属，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，可能导致毒副作用。吸收剂的设计符合新的美国药典和国际标准，将于2013年9月实施。目标是将催化金属，特别是钯去除到口服药物的<5ppmw和非肠外药物的<0.5ppmw。虽然使用Pd和其他pt族金属的均相催化剂已经彻底改变了药物开发，但这些有机金属化合物具有剧毒，产生的神经系统影响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与抗癌药物、顺式铂、卡铂及其顺式钯类似物引起的副作用相似，它们与核和线粒体DNA紧密结合，阻断关键神经酶的转录，并结合对大脑能量代谢至关重要的酶的活性位点。均相有机金属催化剂很容易穿过血脑屏障，特别是当设计有亲脂配体时，可以非常快速地通过神经系统的脂质膜运输，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，并且在每个步骤之后以及从最终产品中去除催化金属。如果催化剂在每一步后没有被去除，它们可能在随后的步骤中催化形成细胞毒性有机副产物，不易与目标药物分子分离。此外，均相催化剂可以降解，形成新的配位化合物，簇化合物和纳米悬浮液，如果不去除，也可能催化额外的副反应。这些有毒金属降解产物也必须从最终药品中去除。为了去除各种各样的金属污染物，多孔碳被科学地设计成具有独特的孔隙分布，以捕获大块的配位复合物，簇状化合物和纳米颗粒，这些化合物不易被传统的过滤，离心或金属清除剂去除。此外，碳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0.20 ppmw， Heck偶联反应的Pd浓度降低到0.90 ppmw。在第二阶段，我们将致力于为制药行业创造新的碳吸附剂产品线。碳将装在罐子里出售；通过活性炭填充床的洗脱溶液纯化的药物混合物。