Abstract
Creatine, a small molecule present in muscular tissue of many vertebrates, evolves to one of the most widely used and successful dietary supplements of recent decades (Graham and Hatton, 1999). Importantly, in the industrial manufacturing process, a high quality standard must be maintained. Validated analytical methods capable of providing reliable and consistent analysis of the main substance, side products and potentially harmful impurities must be employed. The principles of those determinations and the nature of possible by-products will be elucidated in this chapter. In addition, the pure creatine produced may be unstable under certain conditions, e.g. within special formulations or galenical forms. Some hints how to deal with this fact and how to avoid instability will also be discussed. Thus, this chapter will serve as a survey of the paths of chemical synthesis of creatine, its chemistry, properties, stability, analytical determination methods and legal status
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References
Abraham, S., and Jiang, S., 2005, Process for preparing a creatine heterocyclic acid salt and method of use. US patent no. 6,838,562.
An, L., Zheng, Y., and Zhang, G., 1999, Process for producing creatine or creatine monohydrate. Chinese patent no. 99118985.
Baker, T.J., Rew, Y., and Goodman, M., 2000, Novel reagents and reactions for drug design. Pure Appl. Chem. 72: 347–354.
Benedict, S.R., 1914, Studies in creatine and creatinine metabolism. I. The preparation of creatine and creatinine from urine. J. Biol. Chem. 18: 183–190.
Berlinck, R.G.S., 2002, Natural guanidine derivatives. Nat. Prod. Rep. 19: 617–649.
Bernt, E., Bergmeyer, H.U., and Möllering, H., 1970, Creatin. In: Bergmeyer, H.U., Methoden der Enzymatischen Analyse, 2. Aufl., Verlag Chemie, Weinheim, Germany, pp. 1724–1728.
Beyer, C., 1993, Creatine measurement in serum and urine with an automated enzymatic method. Clin. Chem. 39: 1613–1619.
Blick, K.E., and Liles, S.M., 1985, Principles of Clinical Chemistry, John Wiley & Sons, New York, p. 598.
Cannan, R.K., and Shore, A., 1928, The creatine-creatinine equilibrium: The apparent dissociation constants of creatine and creatinine. Biochemistry 22: 920–929.
Carnazzo, J.W., 1999, Method for enhancing delivery and uniformity of concentration of cellular Creatine. US patent no. 5,925,378.
Chevreul, M.E., 1834, Creatin, eine neue im Muskelfleisch enthaltene Substanz. Liebigs Ann. Chem. 4: 293–294.
Dash, A.K., and Sawhney, A., 2002, A simple LC method with UV detection for the analysis of creatine and creatinine and its application to several creatine formulations. J. Pharm. Biomed. Anal. 29: 939–945.
Davidsohn, I., and Henry, J.B., 1969, Clinical Diagnosis by Laboratory Methods, W.B. Saunders Company, Philadelphia, pp. 544–546.
Dessaignes, M., 1857, In: Jber. Fortschr. Chem., p. 543.
Edgar, G., and Shiver, H.E., 1925, The equilibrium between creatine and creatinine, in aqueous solution: the effect of hydrogen ion. J. Am. Chem. Soc. 47: 1179–1188.
Fang, S., 1999, Carnitine creatinate. US patent no. 5,994,581.
Folin, O., 1904, Beitrag zur Chemie des Kreatinins und Kreatins im Harne. Z. physiol. Chem. 41: 223–242.
Folin, O., 1914, On the preparation of creatine, creatinine and standard creatinine solutions. J. Biol. Chem. 17: 463–468.
Gardiner, P., Heuer, M.A., and Molino, M., 2006, Creatine hydroxycitric acids salts and methods for their production and use in individuals. US patent application no. 20060194877 A1.
Gastner, T., 2002, Amidination reagents for the synthesis of guanidines. Cyanamide Newsletter, Degussa AG, http://www.finechemicals.de/Service/PDF/cyanamide_newsletter_1_2002.pdf.
Graham, A.S., and Hatton, R.C., 1999, Creatine: a review of efficacy and safety. J. Am. Pharm. Assoc. 39: 803–810.
Grambow, C., Weiss, S., Youngman, R., Antelmann, B., Mertschenk, B., Stengele, K.P., 2003, Guanidine and Derivatives. In: Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH-Verlag, Weinheim, Germany, 6th ed., Vol. 16, pp. 73–86.
Greindl, T., Scherr, G., Schneider, R., and Mundinger, K., 1999, Preparation of substituted guanidine derivative. US patent no. 5,994,582.
Greindl, T., and Scherr, G., 1999, Verfahren zur Herstellung von substituierten Guanidinderivaten. German patent no. 19748696.
Hartmann, F., and Zieke, K., 1954, Calciumcyanamid. In: Foerst, W. (ed.), Ullmanns Encyklopädie der technischen Chemie, Vol. 5, pp. 43–68.
Howard, A.N., and Harris, R.C., 1999, Compositions containing creatine. US patent no. 5,968,544.
Iwai, T., and Tsunoda, T., 1980, Preparation of creatine. Japanese patent no. 55004349.
Jaffé, M., 1886, Über den Niederschlag, welchen Pikrinsäure in normalem Harn erzeugt und über eine neue Reaktion des Kreatinins. Z. physiol. Chem. 10: 391–400.
Kapfhammer, J., and Müller, H., 1934, Guanidinosäuren und Guanidinopeptide. Z. physiol. Chem. 225: 1–12.
Kessel, K., and Kluge, M., 1998, Synthesis of guanidines from O-alkylisoureas using a crystal seed. German patent no. 19860048.
Kessel, K., Kluge, M., Bogenstatter, T., and Scherr, G., 2003, Process for preparing guanidine derivatives. US patent no. 6,509,497.
Kessel, K., Scherr, G., Bogenstatter, T., Orsten, S., and Franke, D., 2002, Process for purifying creatine. US patent no. 6,399,819.
Kessel, K., Scherr, G., Kluge, M., Biedermann, N., Greindl, T., Bogenstatter, T., and Hahnlein, W., 2004, Process for the preparation of creatine or creatine monohydrate. US patent no. 6,759,553.
Lawler, J.M., Barnes, W.S., Wu, G., Song, W., and Demaree, S., 2002, Direct antioxidant properties of creatine. Biochem. Biophys. Res. Commun. 290: 47–52.
Liebig, J.v., 1847, Ueber die Bestandtheile der Flüssigkeiten des Fleisches. Liebigs Ann. Chem. 62: 257–369.
Liebig, J.v., 1858, Ueber Kreatin und Kynurensäure im Hundeharn, Liebigs Ann. Chem. 108: 354–356.
Merck, E., 1974, Klinisches Labor. E. Merck, Darmstadt, pp. 125–127.
Merck, E., 1987, Arbeitsanleitung Diagnostika Merck, Darmstadt, pp. 46–47.
Mulder, E., and Mouthaan, N., 1869, Kreatin und Aldehyde. Z. Chem., p. 341.
Negrisoli, G., and Del Corona, L., 1997, Hydrosoluble organic salts of creatine. Italian patent no. 1271687.
Persky, A.M., Brazeau, G.A., and Hochhaus, G., 2003, Pharmacokinetics of the dietary supplement creatine. Clin. Pharmacokinet. 42: 557–574.
Pischel, I., and Weiss, S., 1996, New creatine pyruvate derivatives from crystallisation in polar solvents. German patent no. 19653225.
Pischel, I., Weiss, S., Gloxhuber, C., and Mertschenk, B., 1999, Creatine ascorbates and a method of producing them. US patent no. 5,863,939.
Purpura, M., Pischel, I., Jaeger, R., and Ortenburger, G., 2005, Solid and stable creatine/citric acid composition(s) and compositions carbohydrate(s) or hydrates thereof, method for the production and use thereof. US patent application no. 20050037069 A1.
Schütte, E., 1943, Preparation of guanido acids and guanido peptides. Z. physiol. Chem. 279: 52–59.
Steudel, H., 1921, A simple method for the preparation of creatinine from meat extract. Z. physiol. Chem. 112: 53–54.
Strecker, A., 1868, In: Jber. Fortschr. Chem., p. 686.
Tanzer, M.L., and Gilvarg, C., 1959, Creatine and creatine kinase measurement. J. Biol. Chem. 234: 3201–3204.
Vassel, B., and Garst, R., 1953, Method of preparation of guanidino fatty acids. US patent no. 2,654,779.
Volhard, J., 1868, In: Jber. Fortschr. Chem., p. 685.
Weiss, S., and Krommer, H., 1995, Process for the preparation of creatine or creatine-monohydrate. European patent application no. 0754679.
Wheeler, H.I., and Merriam, H.F., 1903, On the condensation-products of the pseudothioureas: synthesis of uracil, thymine, and similar compounds. Am. Chem. J. 29: 478–492.
Yet, L., 1999, Recent developments in guanylation chemistry. Albany Molecular Research, Inc., Technical Reports, Vol. 3, No. 6, http://www.albmolecular.com/chemlinks/vol3.html.
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Pischel, I., Gastner, T. (2007). Creatine – its Chemical Synthesis, Chemistry, and Legal Status. In: Salomons, G.S., Wyss, M. (eds) Creatine and Creatine Kinase in Health and Disease. Subcellular Biochemistry, vol 46. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6486-9_15
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