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.