Sorbents for Toxic-Metal Removal in Pharmaceutical Development and Manufacture

描述(由申请人提供)：用于制药开发和制造中有毒金属去除的吸着剂SBIR第一阶段应用P.I.：TDA Research，Inc.的Girish Srinivas。该项目的总体目标是将药物合成过程中出现的有毒杂质降至最低。有毒污染物包括在药物合成过程中用作催化剂的金属，以及在合成步骤之间留在溶液中的金属催化剂产生的不受欢迎的有机副产品。正在开发吸着剂，以将催化金属Pd、铂、Rh、Ru和Ir的浓度降低到万分之500以下，这是推荐的静脉注射最高浓度。使用铂族金属的均相催化剂，特别是钯，已经彻底改变了药物的开发和合成。然而，许多铂族金属的配位化合物被发现具有极高的毒性，产生类似于汞和铅的效果。这是从已知的抗癌药物顺铂、顺铂及其类似物的神经毒性和细胞毒性出发的，它们与DNA强烈结合，阻止关键神经酶的转录，还与例如对神经系统能量代谢至关重要的酶活性部位的巯基结合。此外，用于药物合成的均相催化剂通常设计有亲脂配体，允许快速通过脂膜传输，类似于甲基汞和四乙基铅的传输。现代药物合成可能涉及三个或三个以上的催化步骤。如果不去除早期步骤中使用的金属催化剂，它们可能会催化形成有毒的有机副产物，这些副产物不易从药物分子中分离出来。均相催化剂可能会降解，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它们，就会催化额外的副反应。为了去除10纳米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法去除，碳吸附剂正在开发中。这种专门为制药行业设计的多孔炭将去除所有有毒金属物种，而不会显著吸附药物产品。 公共卫生相关性：药品开发和制造中用于去除有毒金属的吸着剂SBIR第一阶段应用P.I.：吉里什·斯里尼瓦斯，TDA研究公司。公共卫生相关性声明：开给数百万患者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。有毒金属聚集在神经系统中，造成类似于汞和铅的损害。改进药物的提纯将减少许多毒副作用。

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.