HYDROSOLUBLE ORGANIC SALTS OF CREATINE

Abstract: Hydrosoluble organic salts of creatine are disclosed. The salts are useful in the dietetic and food industry.

Description: HYDROSOLUBLE ORGANIC SALTS OF CREATINE The present invention refers to hydrosoluble organic salts of creatine of general formula I: wherein fβ represents the anion of a mono, bi- or tricarboxylic acid. Preferred anions are the citrate, maleate, fu arate, tartrate or malate. Creatine or N-(aminoiminomethyl)-N-methylglycine is a sarcosine derivative present in the muscle tissue of many vertebrates, man included, mainly combined with phosphoric acid in form of phosphorylcreatine and it is involved in the energy transfer from mitochondria to the ATP utilization sites. Several studies indicate that there is a relationship between the creatine (phosphoryl creatine) concentration in the muscles having the function of keeping an high intracellular ATP/ADP ratio and maximum sustainable physical effort (Annu. Rev. Biochem. 54: 831-862, 1985; Science 24: 448-452, 1981; BESSMAN S.P., and F. SAVABI. The role of the phosphocreatine energy shuttle in exercise and muscle hypertrophy. In: Biochemistry of Exercise VII. A.W. Taylow, P.D. Gollnick, H.J. Green, CD. Ianuzzo, E.G. Noble, G. Metivier, and J.R. Sutton. , Intl. Series Sports Sciences 21: 167-178, 1990). The creatine increase in diets may therefore be useful to bring the plasma creatine concentrations at levels providing significant values of creatine itself in the muscle. The short creatine half-life in plasma (1-1.5 hours) makes however necessary to reach rapidly said levels and this, in view of the bioavailability degree of creatine, is obtainable only by the administration of high doses of 5-10 g (for mean body weights of 70 kg), amounts well tolerated because of the lack of toxicity of the compound. The low solubility of creatine in water (1 g in 75 ml) is therefore a practical limitation to the possibility of marking immediately available in the specific diet the necessary amounts of creatine. The present invention provides hydrosoluble stable organic salts of creatine of formula I characterized by high water solubility (from 3 to 15 times higher them that of creatine itself) and a process for their preparation. The salts of formula I are prepared by salifying creatine with the corresponding acids in aqueous or hydroalcoholic concentrated solution or in a water-immiscible solvent, at temperatures ranging from the room temperature to 50 * C, optionally concentrating the solutions and filtering the crystallized salts. According to a preferred embodiment the salts of formula I are prepared by reacting creatine with an excess organic acid in ethyl acetate until the salt is completely formed, detectable with the IR analysis, cooling and filtering. The filtrated solvent, containing the excess acid is recycled and, after filling up of the components, is used for a further reaction. The salts are characterized by IP., melting point, potentiometric and HPLC assay. Table 1 reports the solubility of the salts I of the invention. Table 1 Creatine salt Water solubility % (g/100 ml) Citrate 10 Maleate 19 Fu arate 3 Tartrate 8,5 Malate 4,5 Example 1 39.45 g (0.18 mol) of monohydrate citric acid are suspended in 100 ml of ethyl acetate. 20 g (0.134 mol) of monohydrate creatine are added to the stirred suspension at 20-25 * C and the mixture is stirred 4 hours at 25*C. After IR control, the product is filtered and washed with ethyl acetate, then dried in oven at 50-55'C, obtaining 90% of salts, m.p. 112- 114 # C, 99.2% titer. Example 2 14.9 g (0.1 mol) of monohydrate creatine are added to a solution of 11.6 g (0,1 mol) of maleic acid in 20 ml of water. The so obtained solution is concentrated, cooled to 5 * C and the product filtered and dried under vacuum at 50 * C, obtaining 87% of salt, m.p. 128-129'C, 99.8% titer.

Claims: CLAIMS Salts of creatine of general formula I wherein A® represents the anion of a mono, bi- or tricarboxylic acid. 2. Creatine salts of claim 1 wherein β is the anion of citric acid. 3. Creatine salts of claim 1 wherein A® is the anion of maleic acid. 4. Creatine salts of claim 1 wherein is the anion of offumaric acid. 5. Creatine salts of claim 1 wherein A© is the anion of tartaric acid. 6. Creatine salts of claim 1 wherein A© is the anion of malic acid. 7. A process for the preparation of salts of claims 1-6, comprising: a) contemporaneous dissolution of creatine and of the organic acid in water; b) concentration of the solution up to complete crystallization and drying of the obtained product. 8. A process for the preparation of salts of claims 1-6, comprising: a) reaction of creatine with the organic acid in a water-immiscible solvent at a temperature from the room temperature to 50*C; b) filtration and drying of the obtained product. 9. Use of salts of claims 1-6, as additive in dietetic and/or alimentary compositions.

Inventors: DEL CORONA LUCIO, NEGRISOLI GIAMPAOLO, DEL CORONA, LUCIO, NEGRISOLI, GIAMPAOLO
Applicants: DEL CORONA LUCIO, FLAMMA SPA, NEGRISOLI GIAMPAOLO, DEL CORONA, LUCIO, FLAMMA S.P.A., NEGRISOLI, GIAMPAOLO
Application year: 1995
Main classification: C07C279
IPC codes: A23L1, C07C57, C07C59, C07C279