Sorbents for Toxic-Metal Removal in Pharmaceutical Development and Manufacture

描述（由申请人提供）：用于药物开发和制造中有毒金属去除的吸附剂SBIR I期申请P.I: Girish Srinivas, TDA Research, Inc。整个项目的目标是尽量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在合成步骤之间由金属催化剂产生的不需要的有机副产物留在溶液中。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，按质量计低于500亿分之一，这是静脉注射的建议最大值。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的开发和合成。然而，pt族金属的许多配位化合物已被发现是剧毒的，产生类似于汞和铅的作用。这一点已经从已知的抗癌药物顺式铂、顺式钯及其类似物的神经毒性和细胞毒性中得到了很好的证实，这些药物与DNA紧密结合，阻断关键神经酶的转录，也与酶活性位点的巯基结合，这些酶对神经系统的能量代谢至关重要。此外，用于药物合成的均相催化剂通常采用亲脂配体设计，可以通过脂质膜进行快速运输，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。如果在早期步骤中使用的金属催化剂不去除，它们可能催化形成有毒的有机副产物，不易从药物分子中分离出来。均相催化剂可能降解，形成簇状化合物和纳米悬浮液，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，碳吸附剂正在开发中，这些颗粒很难通过过滤或离心去除。专门为制药工业设计的多孔碳将去除整个范围的有毒金属物种，而不会明显吸附药物产品。

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.