Sorbents for Toxic-Metal Removal in Pharmaceutical Development and Manufacture

产品说明：该项目的总体目标是开发吸附剂，以去除药物合成中使用的催化金属，如果在合成步骤之间和从最终活性药物成分中没有充分去除，可能会导致有毒副作用。吸附剂的设计符合将于2013年9月实施的新的美国药典和国际标准。目标是去除催化金属，特别是钯，以<5 ppmw用于口服药物和<0.5ppmw用于肠胃外药物。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极强的毒性，产生类似于甲基汞和四乙基铅诱导的神经效应。这种毒性的分子机制与抗癌剂顺铂、卡铂及其顺式钯类似物诱导的副作用相似，这些药物与细胞核和线粒体DNA强烈结合，阻断关键神经酶的转录，并与脑中能量代谢关键酶的活性位点结合。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性配体时，其允许非常快速地通过神经系统的脂质膜转运，类似于甲基汞和四乙基铅的转运。药物合成可能涉及许多催化步骤，并且催化金属应该在每个步骤之后以及从最终产品中去除。如果催化剂在每个步骤后不被去除，则它们可能在后续步骤中催化形成细胞毒性有机副产物，这些副产物不容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，如果不除去，也可以催化另外的副反应。这些有毒金属降解产物也必须从最终制剂中除去。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分布，以捕获不容易通过常规过滤、离心或金属清除剂去除的大体积配位络合物、簇合物和纳米颗粒。此外，碳被官能化以结合污染药物的钯化合物。在阶段I中测试的吸附剂将Pd浓度降低到对于Suzuki偶联反应为0.20ppmw和对于Heck偶联反应为0.90ppmw。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线。碳将以罐出售;药物混合物通过活性炭填充床的洗脱溶液纯化。

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.