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The Effect of Amino Acids on the Solubility of Zinc Citraconate Rhomesia Ramkellowan Mentor: Sabrina G. Sobel Hofstra University Abstract • Zinc salts are known to shorten the duration and severity of the common cold. • Increasing the percentage of free zinc ions as compared to chelated zinc increases the efficacy of this treatment. • A study of the influence that amino acids have on the solubility of zinc citraconate may be relevant to such zinc ion therapy. • It is hoped that this research may help aid future development of medical zinc salt treatments. Introduction • Zinc complexes are important in biological and industrial contexts • Treatment of common cold (treatment within 24 hrs: 4.8 days ill vs. 9.2 days ill) • Wound healing (promotes debridement and healing of burn wounds) • Plant nutrition (provides an essential nutrient) • Removal of zinc from coal fly ash (reduce environmental zinc overload = pollution) • What form of zinc is best for each situation? • Are free zinc ions (weakly complexed) or strongly complexed zinc ions more beneficial? • Strong complexes for the removal of zinc; weak complexes for the delivery of zinc Zinc and the Body • • • • • Zinc is essential for: Tissue/wound repair Resistance to infection Natural growth Manufacture & regulation of genetic material • • • • • Antioxidant enzymes Energy production Healthy immune & reproductive systems Hormone production and use in the body Antiviral properties Zinc Ion Therapy • • • • • For treating the common cold For treating minor burns, cuts, scrapes, abrasions and infections For treating mouth canker sores For treating bad breath For treating shingles Attack of the Cold Virus • Cold virus binds to positive projections on cell surface • Cold virus uses its negatively charged fivesided ‘canyons’ • 1/5th of a canyon can be used for zinc binding model • Related viruses: herpes, chicken pox Model of Zinc Binding to Cold Virus • Six binding sites found • Total Zn2+ ions needed for each virus: 360 • Comparison of viral loading to lozenge therapy: 23 mg Zn2+ from lozenge in 25 mL saliva = 13.1 mM 1% transfer to nose = 0.131 mM typical viral load = 108 virions/L excess Zn2+= 8 x 1011 Zn2+/virion Procedure • Zinc citraconate was combined with varying molar amounts of amino acids • Glycine, alanine and serine • Each solution was titrated with Na2EDTA • To determine the total zinc ion content in the solutions • To find the percent of zinc citraconate that dissolved and the percent zinc titrated Organic Molecules Used Alanine Citraconic acid Serine Glycine Zinc Citraconate and Glycine • Zinc titrated starts at • Added glycine gradually increases the solubility of [ZnO]0.47[Zn(citr)]0.53 • Increase in percent solubility from 3-4 molar excess may be due to experimental error in preparation of salt % Zinc Titrated ~22% in gylcine. Zinc Titrated with Glycine 90 80 70 60 50 40 30 20 10 0 y = -0.0697x2 + 3.6929x + 31.893 R2 = 0.839 0 5 10 15 20 Rel. Mol. Glycine • Maximum solubility of 79% was seen at a glycine to total zinc molar ratio of 20:1 25 Zinc Citraconate and Alanine Zinc Titrated with Alanine • Added alanine gradually 80 increases the solubility of 70 [ZnO]0.47[Zn(citr)]0.53 y = -0.0573x + 2.1244x + 66.548 60 R = 0.5127 • Maximum solubility of 81% was seen at a alanine 50 0 5 10 15 20 25 30 35 Rel. Mol. Alanine to mixed zinc salt molar • Alanine is less polar than glycine, and ratio of 20:1 • Composite Ksp of mixed serine is more polar that glycine salt is 1.47 x 10-4 • Order in solubilites is not clear – possibly due to impure starting material (mixed zinc salt instead of zinc citraconate) % Zn Titrated 90 2 2 Zinc Citraconate and Serine 100 % Zinc Tritrated • Added serine increases the solubility of the mixed zinc salt [ZnO]0.47[Zn(citr)]0.53 • Maximum solubility of 72% was seen at a serine to total zinc molar ratio of 1:1 Zinc Titrated with Serine 80 60 40 y = -0.0827x + 72.161 R2 = 0.9512 20 0 0 2 4 6 8 10 Rel. Mol. Serine • Lack of significant change in solubilities indicates a need to repeat experiment with better prepared zinc citraconate 12 Modeling the Zinc Citraconate:Glycine System Speciation Diagram of Citraconic Acid Glycine Speciation as a function of pH 1.2 1 1 0.8 alpha α 0.8 0.6 0.4 0.6 0.4 0.2 0.2 0 1 2 3 4 5 pH 6 7 8 0 0 1 2 3 4 5 6 7 8 9 10 11 pH • Standard plots of acid speciation as a function of pH based on acid ionization constants. Citraconic acid:blue = H2citr, red = Hcitr-, green = citr-2; Glycine: green = Hgly+, blue = gly zwitterion, red = gly- 12 13 14 Total Metal Ion and Ligand Concentrations •These equations provide a way to test if mixed ligand complexes are important. • If TM = calculated values from all measured concentrations, then mixed ligand complexes are not important. • The same analysis can be completed with ligand. • Determination of free [Zn] via ion specific electrode titration is essential to this analysis. Conclusion • Attempted synthesis of zinc citraconate was partially successful • It was concluded that while making zinc citraconate, a mixed zinc salt was made • Elemental analysis showed 46.4% Zn in the salt prepared, which is consistent with a mixed salt: [ZnO]0.47[Zn(citr)]0.53 (Theor: 46.44%, Exptl 46.4%) • Zinc titrated did show general trends seen in group previously • Percent zinc dissolved increased as amino acid ratio increased • Added amino acid dramatically enhances solubility of mixed zinc salt prepared • Enhancement of solubility cannot solely be due to protonation of salt anion by free amino acid as pK’s of anions and amino acids are comparable Future Work • Create new method to synthesize pure zinc citraconate • Analysis of salt will be done before titrations with amino acids • Expect percent zinc dissolved to increase as amino acid ratio increase • Expect to see an increase in free [Zn2+] as the amino acid : zinc salt ratio increases Bibliography Analytical Articles • Bobtelsky, M.; Jordan, J. J. Am. Chem. Soc. 1945, 67, 1824-31. • Campi, E.; Ostacoli, G. et al. J. Inorg. Nucl. Chem. 1964, 26, 55364. • Childs, C.W.; Perrin, D.D. J. Chem. Soc. A 1969, 1039 - 44. • Novick, S.G. J. Chem. Educ. 1997, 74, 1463. • Zarembo, J.E.; Godfrey, J.C.; Godfrey, N.J. J. Pharm. Sci. 1992, 81, 128-30. Medical/Agricultural Articles • Novick, S.G.; Godfrey, J.C. et al. Med. Hypoth. 1996, 46, 295-302. • Henzel, J.; DeWase, M. et al. Arch. Surg. 1970, 100, 349. • Cunningham, J.J.; Lydon, M.K.; et al. J. Am. Coll. Nutr. 1991, 10, 57-62. • Haertl, E. J. Agric. Food Chem. 1963, 11, 108-11. Acknowledgments • Tracy Concepcion, Allison Haigney: additional mentors, • Lois and Mike: helpful co-researchers, • Hofstra U. Chemistry Department: site sponsor,. Partially funded by Godfrey Science & Design, Inc., Huntingdon Valley, PA • Ms. Susan Fahrenholtz, Project Seed and the American Chemical Society, • Dr. Sat Bhattacharya and Harlem Children Society.