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: 8200619
• 负责人: GIRISH SRINIVAS
• 金额: $ 15万
• 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 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8200619
• 关键词: Sorbents; Toxic; Metal; Removal; Pharmaceutical

DESCRIPTION (provided by applicant): Sorbents for Toxic-Metal Removal in Pharmaceutical Development and Manufacture SBIR Phase I Application P.I.: Girish Srinivas, TDA Research, Inc. The overall project goal is to minimize toxic impurities in pharmaceuticals that arise during drug synthesis. Toxic contaminants include the metals used as catalysts during drug synthesis and undesired organic side-products produced by metal catalysts remaining in solution between synthetic steps. Sorbents are being developed to lower concentrations of catalytic metals, Pd, Pt, Rh, Ru and Ir to below 500 parts per billion by mass, the recommended maximum for intravenous injection. Homogeneous catalysts using Pt-group metals, and especially Pd, have revolutionized drug development and synthesis. However, many coordination compounds of the Pt-group metals have been found to be extremely toxic, producing effects similar to mercury and lead. This is well established from the known neurotoxicity and cytotoxicity of the anti- cancer agents, cis-platinum, cis-palladium and their analogues, which bind strongly to DNA and block transcription of critical neural enzymes and also bind, for example, to sulfhydryl groups at active sites of enzymes that are critical for energy metabolism in the nervous system. Moreover, homogeneous catalysts used in drug synthesis are often designed with lipophilic ligands, which allow rapid transport through lipid membranes analogous to transport of methyl mercury and tetraethyl lead. Modern drug synthesis may involve three or more catalytic steps. If metal catalysts used in early steps are not removed, they may catalyze formation of toxic organic side- products, not easily separated from drug molecules. Homogeneous catalysts may degrade, forming cluster compounds and nano-suspensions, which, if not removed between synthesis steps, catalyze additional side-reactions. To remove the entire range of toxic-metal particles under 10 nm, which are not easily removed by filtration or by centrifugation, carbon sorbents are being developed. The porous carbons, specifically designed for the pharmaceutical industry, will remove the entire range of toxic metal species, without significantly adsorbing drug product. PUBLIC HEALTH RELEVANCE: Sorbents for Toxic-Metal Removal in Pharmaceutical Development and Manufacture SBIR Phase I Application P.I.: Girish Srinivas, TDA Research, Inc. Public Health Relevance Statement: Many pharmaceuticals prescribed to millions of patients are contaminated with toxic impurities originating from metal catalysts used during drug synthesis. The toxic metals accumulate in the nervous system causing damage similar to that of mercury and lead. Improved purification of medications will reduce many toxic side-effects.

描述（由申请人提供）：用于药物开发和制造SBIR I期应用程序P.I。：Girish Srinivas，TDA Research，Inc。的吸附剂。有毒污染物包括在药物合成过程中用作催化剂的金属以及由金属催化剂在合成步骤之间溶液中留在溶液中产生的不想要的有机副产物。正在开发吸附剂，以较低的催化金属（PD，PT，RH，RU和IR）的浓度，到质量为每十亿美元的500份，这是静脉注射的建议最大值。使用PT组金属，尤其是PD的均质催化剂已彻底改变了药物的开发和合成。但是，已经发现PT组金属的许多配位化合物具有极高的毒性，产生的作用类似于汞和铅。这是从抗癌剂的已知神经毒性和细胞毒性，顺式 - 铂，顺式 - - 甲基及其类似物的已知神经毒性和细胞毒性中确定的，它们与临界神经酶的DNA紧密结合并阻止了临界神经酶的转录，还结合了例如，在能量含量的硫酸含量的硫酸基团中，对硫酸基团的含量是含有含量的含量。此外，药物合成中使用的均质催化剂通常是用亲脂性配体设计的，可以通过脂质膜快速运输，类似于类似于甲基汞和四乙基铅的运输。现代药物合成可能涉及三个或更多的催化步骤。如果未去除早期措施中使用的金属催化剂，它们可能会催化有毒有机侧产物的形成，而不容易与药物分子分离。均匀的催化剂可能会降解，形成簇化合物和纳米悬浮液，如果在合成步骤之间未去除，则会催化其他副反应。为了去除10 nm以下的整个有毒金属颗粒，这不容易通过过滤或离心去除，正在开发碳吸附剂。专为制药行业设计的多孔碳将消除整个有毒金属物种，而无需大量吸附药品。 公共卫生相关性：药物开发和制造中有毒金属清除的吸附剂SBIR I期应用程序P.I。：Girish Srinivas，TDA Research，Inc。公共卫生相关性声明：许多对数百万患者处方的药物，这些药物被用于在药物中使用的金属催化剂中启发的有毒杂质污染。有毒金属在神经系统中积累，造成类似于汞和铅的损害。改善药物纯化将减少许多有毒的副作用。