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Sorbents for Toxic-Metal Removal in Pharmaceutical Development and Manufacture

Award Information

Agency:
Department of Health and Human Services
Branch:
N/A
Award ID:
Program Year/Program:
2012 / SBIR
Agency Tracking Number:
R44FD004079
Solicitation Year:
2012
Solicitation Topic Code:
FDA
Solicitation Number:
PA12-088
Small Business Information
TDA Research, Inc.
12345 W. 52nd Ave. Wheat Ridge, CO 80033-
View profile »
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No
 
Phase 2
Fiscal Year: 2012
Title: Sorbents for Toxic-Metal Removal in Pharmaceutical Development and Manufacture
Agency: HHS
Contract: 2R44FD004079-02
Award Amount: $1,000,000.00
 

Abstract:

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 lt 5ppmw for oral medications and lt 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. PUBLIC HEALTH RELEVANCE: Many pharmaceuticals prescribed to tens-of-millions of patients are contaminated with toxic impurities originating from metal catalysts used during drug synthesis. Chronic use of medications contaminated with toxic metals can cause cumulative neurological damage similar to that produced by mercury, lead and other neurotoxic substances. Catalytic metals, if not removed between synthesis steps, catalyze in later steps production of organic side products, similar to target drug molecules that are difficult to separat and which induce additional toxic side-effects or which interfere with action of the drug molecules.

Principal Investigator:

Girish Srinivas
303-940-2321
gsrinivas@tda.com

Business Contact:

John D. Wright
303-940-2300
jdwright@tda.com
Small Business Information at Submission:

TDA RESEARCH, INC.
TDA RESEARCH, INC. 12345 W 52ND AVE WHEAT RIDGE, CO 80033-1916

EIN/Tax ID: 184104337
DUNS: N/A
Number of Employees: N/A
Woman-Owned: No
Minority-Owned: No
HUBZone-Owned: No