A Greener Creatine:
By Peter Kimball
pex24@wildcats.unh.edu
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A Creatine MoleculeImage held by public domain

What is Creatine?

Creatine is a nitrogenous organic acid that is synthesized naturally by the human body. The synthesis occurs in the liver, kidneys, and pancreas from the amino acids glycine, L-arginine, and S-adenosylmethionine. Creatine is mainly found in skeletal muscles and where it exists in equilibrium with phosphocreatine. When a phosphorus atom is added to creatine it becomes phosphocreatine. Phosphocreatine can then donate it phosphorous to ADP making it APT; the energy source used by muscles during anaerobic activity.
The Biological Pathway for the Synthesis of Creatine


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Biological Pathway for the Synthesis of Creatine
Reproduced with permission from Dr. Carl Lecher, clecher@marian.edu


Why supplement with Creatine?
The idea behind creatine supplementation is that increasing the amount of creatine in muscles will provide the muscles with more energy during exercise and decrease the amount of time needed for recovery, allowing the muscles to grow faster than normal. The effectiveness of creatine has been debated for many years but there are now many studies showing that creatine supplementation is effect in gaining muscle mass (2) .

How is Creatine made?The basic reaction for synthetic creatine is sarcosine, cyanamide, water and a catalyst, with some manufacturers choosing to use an acid catalyst and some use a base catalyst. In the reaction the
cyanamide will act as the electrophile (Lewis acid) and the sarcosinate will act as the nucleophile (Lewis base) .


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Reproduced with permission from Dr. Carl Lecher, clecher@marian.edu
Basic catalyst: The most common synthesis method uses sarcosine and cyanamide (used in excess) in the presence of concentrated ammonium hydroxide (NH4OH), which contains about 28-30 percent ammonia in solution and NaCl is added to aid in the formation of the product. The pros of this method are that the reaction takes place at room temperature and pressure and require no additional energy . The cons of this method are when cyanamide is used in excess the excess will react with the ammonium hydroxide and will produce dicyanamide which will result in a lower yield of creatine. Ammonium hydroxide can cause skin irritation and burns so it would be preferable to use a safer catalyst for this reaction.

Acid Catalyst: When speaking with a representative of Creapure ® I was told that the process starts with sodium sarcosinate, cyanamide and hydrochloride acid and produces only water and NaCl as byproducts. The pros this method is that very pure creatine is produced a minimum of 99.95% and has a yield which falls between 80% to 90% depending on batch. This method also contains very low levels of contaminants and the by products of the synthesis are very benign and can be easily disposed of. The cons of this method are the HCl used which could be replaced with a safer catalyst and HCL is heated to 90 C before being added to the sarcosinate cyanamide mixture and then the mixtures temperature stays at 80 C and is kept under pressure.


Common impurities: Creatine is a sport supplement and not classified as a food or drug meaning meaning it is not regulated by FDA. Therefore, companies do not have to reveal the materials used or specify the synthetic procedure that is used, causing a variety of possible contaminants, byproducts, and other impurities. The most common impurities that are found are the result of the chemical processes used, however this can be minimized by following the green chemistry principles of preventing waste, maximizing atom efficiency, and analyzing the reaction in real time as to prevent by products from forming. Two of these compounds cannot be avoided, only minimized, they are dicyanamide and creatinine.
Dicyanamide: Or 2-Cyanoguanidine is produced by combining cyanamide with a base, it is the dimer form of cyanamide. Dicyanamide usually is used as a fertilizer, a fire proofing agent or in explosives. Is not considered toxic in small doses and is listed as generally safe for consumption but the FDA (3) . While not toxic, dicyanamide has no positive effects on the human body and minimizing the amount produced would help to maximize atom efficiency. Dicyanamide forms in creatine when all sarcosinate has been used up but there is still cyanamide. The remaining cyanamide will continue to react and in the presence of a base, such as the one used to catalyze the reaction.

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Image held in public domain.
Creatinine: Is found naturally in the human body as it is one the products that occur as creatine. After the creatine has given away is phosphorus group it will begin to degrade into creatinine and water. It is most often looked for in a liver test as a marker healthy kidney function. Ingesting creatinine could interfere with healthy kidney function and will interfere with tests done to assess kidney function. Creatinine can form during the manufacturing process in the presence of an acidic pH. Creatine and Creatinine exist at equilibrium inside muscles cells when at a neutral pH, however in an acidic pH creatinine becomes much more favored, much like how creatine will break down within a muscle with an acidic pH caused due to lactic acid (1). The pH of the cyanamide and sarcosinate solution will naturally a pH between 9 and 10 depending on the amount of each
(2). This will allow an acid catalyst to not produce significant amounts of creatinine in the reaction as long as the solution's pH remains basic.

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Image held in public domain.

Ways to make a Greener Creatine:
There are several possible ways to reduce the environmental impact of synthetic creatine manufacturing, using some of the EPA's Principles of Green Chemistry. The first would be to maximize atomic efficiency, in doing so the creatine would contain less of its mostly likely impurities, making the reaction more green and making a creatine safer to consume. The reaction can also take place at room temperature and pressure, although in the case of Creapure ® creatine the use of heat and pressure lead to a creatine with fewer impurities (4). Also in the case of
Creapure ® they analyze in real time, which them to minimize byproducts and helps to prevent pollution. The use of safer solvents and reaction conditions is something that can be improved on, the solvents that are used are not the safest for humans. It is however possible to get high yields of highly pure creatine by using diluted ammonia that is use enough for people to handle without special precautions (2).
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References:

(1)Cannan, Robert Keith; Shore; Agnes. “The Creatine-Creatinine Equilibrium. The Apparent Dissociation Constants of Creatine and Creatinine.” Biochem. J., 1928, 22(4), 920-929.
(2) Leacher, C. and Bernhardt, R. (2008) "A Greener Synthesis of Creatine."
(3) OECD (2003). SIDS Initial Assessment Report: Cyanoguanidine
(4) Weiss, S., and Krommer, H. (1998) "Process for the preparation of a creatine or creatine monohydrate." US Patent: 5719319 A.