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（由申请方提供）：药物开发和生产中用于去除有毒金属的吸附剂SBIR I期申请P.I.：Girish Srinivas，TDA Research，Inc.项目的总体目标是最大限度地减少药物合成过程中产生的有毒杂质。有毒污染物包括在药物合成过程中用作催化剂的金属和由金属催化剂在合成步骤之间残留在溶液中产生的不期望的有机副产物。目前正在开发吸附剂，以降低催化金属、Pd、Pt、Rh、Ru和Ir的浓度，使其低于静脉注射的推荐最大浓度-十亿分之500。使用Pt族金属，特别是Pd的均相催化剂已经彻底改变了药物开发和合成。然而，许多铂族金属的配位化合物被发现具有极强的毒性，产生类似于汞和铅的影响。这是从抗癌剂、顺铂、顺式钯及其类似物的已知神经毒性和细胞毒性充分确立的，所述抗癌剂强烈结合DNA并阻断关键神经酶的转录，并且还结合例如在对神经系统中的能量代谢至关重要的酶的活性位点处的巯基。此外，用于药物合成的均相催化剂通常设计有亲脂性配体，其允许通过脂质膜的快速转运，类似于甲基汞和四乙基铅的转运。现代药物合成可能涉及三个或更多个催化步骤。如果在早期步骤中使用的金属催化剂没有被去除，它们可能会催化形成有毒的有机副产物，这些副产物不容易与药物分子分离。均相催化剂可能会降解，形成簇合物和纳米悬浮液，如果在合成步骤之间不去除，则会催化额外的副反应。为了去除10 nm以下的所有有毒金属颗粒，这些颗粒不容易通过过滤或离心去除，正在开发碳吸附剂。专门为制药行业设计的多孔碳将去除所有有毒金属物质，而不会显著吸附药物产品。 公共卫生相关性：药物开发和生产中用于去除有毒金属的吸附剂SBIR第I阶段应用P.I.：Girish Srinivas，TDA Research，Inc.公共卫生相关性声明：数百万患者服用的许多药物都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。有毒金属在神经系统中积累，造成类似汞和铅的损害。改善药物的净化将减少许多毒副作用。