Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-12-12
2002-06-04
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S560000, C562S561000, C564S230000
Reexamination Certificate
active
06399819
ABSTRACT:
The amino acid derivative creatine occurs in nature in particular as creatine phosphate in vertebrate muscles. Creatine phosphate acts here as cellular energy source for muscular contraction energy. Creatine is used as a food supplement in the therapy of neuromuscular disorders (for example muscular dystrophy) and in endocrinopathies where there is deficient creatine storage and increased creatine excretion via the urine. In addition to use in culture media and as a flavor intensifier in seasonings, creatine is being used to an increasing extent as a food supplement in sport for increasing the body's performance and in particular in bodybuilding.
Creatine prepared by chemical synthesis or isolated from natural sources generally has impurities which can originate from the isolation process and synthetic process or from the starting materials of creatine synthesis. In view of the high amounts consumed per day, of up to 30 g of creatine, for example by competitive sportspersons, strict requirements must be made as to the purity of the creatine consumed in order to prevent accumulation of impurities. There is therefore a requirement for processes which permit creatine to be provided in a simple manner in very high purity. In addition, in the known preparation processes, the creatine is generally produced in a small particle size which is impractical for further processors and end users. A coarser product would therefore be desirable, since this is less dust-forming and has a reduced tendency toward electrostatic charging and caking.
EP 0 754 679 describes a process for preparing creatine in which cyanamide is reacted with sodium sarcosinate or potassium sarcosinate in water at from 20 to 150° C. and a pH of from 7.0 to 14.0. The resultant creatine precipitates from the aqueous solution as sparingly soluble creatine monohydrate, which is separated off and is then washed with cold or hot water for purification. In addition, the possibility of subsequent recrystallization is indicated.
JP 59-000 500 describes creatine synthesis by continuously introducing O-alkylisourea into an aqueous sarcosine solution at a constantly maintained pH of from 10 to 12 and at from 5 to 25° C. The resultant creatine monohydrate crystals are purified via a sequence of two washing operations using water and methanol. Disadvantageously, during the synthesis spontaneous crystal seed formation occurs and as a result there is high variability of the crystal size and an undesirably high fines content.
DE 197 48 696 describes a process for preparing creatine by O-methylation of urea and reaction of the resultant O-methylisourea salt with sodium sarcosinate. The resultant creatine monohydrate crystals are washed with water or ice-water.
In the preparation process of DE-A-198 60 048.8, an aqueous solution of O-alkylisourea and an aqueous solution of sarcosinate are reacted in the presence of previously introduced creatine monohydrate crystals. The resultant creatine monohydrate crystals are also washed with cold or warm water here.
The subsequent wash operations common to these preparation processes have the disadvantage that only superficially adherent impurities are removed, whereas the impurities incorporated into the crystals at a molecular level or included in the crystals in the form of droplets of the mother liquor remain substantially unaffected.
Recrystallization does offer the opportunity of achieving a higher degree of purity and, in addition, setting the crystal size more precisely. In this process the substance to be purified is dissolved with heating in a solvent, for example water, and crystallizes out from the solution in a purer form on cooling. The saturated solution obtained after separating off the crystals in which the dissolved impurities remain is generally termed “mother liquor”. However, the recrystallization of creatine from water is difficult in that not only the absolute solubility but also the temperature dependence of the solubility of creatine in water are low. The solubility of creatine in water is, for example, only about 1% at 0° C. and about 9% at 80° C. In addition, the temperature difference between the dissolution process and crystallization process cannot be increased as desired, since above a temperature of about 80° C., the decomposition of creatine to form breakdown products such as creatinine and N-methylhydantoin, increases to a level which is no longer acceptable. In conclusion, for the recrystallization of creatine from water, generally at least 12 parts by weight of water are required per part by weight of creatine. Therefore, a large volume of mother liquor is produced which must be worked up or disposed of. To obtain larger crystals, typically slow cooling is required during the recrystallization.
Recrystallization from solvents other than water in which creatine is more soluble and the solubility is more dependent on temperature is not described in the literature. When organic solvents are used, in addition, the problem of residue-free disposal of the solvent would occur.
It is an object of the present invention, therefore, to specify a process for purifying creatine, which process does not have said disadvantages.
We have found that this object is achieved, surprisingly, by a purification process which can be carried out economically on an industrial scale and which simultaneously also permits targeted influencing of the crystal size, which process exploits the thermodynamically favored conversion of creatine free of water of crystallization to form creatine monohydrate.
The invention therefore relates to a process for purifying creatine in which the creatine to be purified (also termed “crude creatine” hereinafter) in the form free of water of crystallization is introduced into a saturated aqueous solution of creatine monohydrate, in which the creatine free of water of crystallization is dissolved with hydration, crystals of creatine monohydrate precipitate from the aqueous solution and these are separated off from the aqueous solution.
Creatine free of water of crystallization is in the present case any form of creatine which is deficient in water of crystallization compared with creatine monohydrate, in particular forms which contain, per mol of creatine, less than 0.3 mol, preferably less than 0.05 mol, of water of crystallization.
Crude creatine generally has—without taking into account the content of water of crystallization—a purity of greater than 95%, preferably greater than 98%, for example up to 99.5%. The difference from 100% is formed by impurities which can be of inorganic nature, such as salts, for example sodium chloride or sodium sulfate, or of organic nature, such as urea, dicyandiamide, creatinine, guanidine, N-methylhydantoin, N-methylhydantoic acid, methyliminodiacetic acid, sarcosine or salts thereof. The impurities are generally water soluble. The crude creatine free of water of crystallization is preferably used in finely divided form, for example having a mean particle size of less than 10 &mgr;m, in particular less than 5 &mgr;m, which may be present in agglomerated form. The small particle size ensures complete dissolution of the particles. If the particles are larger, under some circumstances there is the risk that a skin of sparingly soluble creatine monohydrate rapidly forms which will delay or prevent further dissolution of the particles.
The crude creatine free of water of crystallization is generally produced from the creatine monohydrate (crude creatine monohydrate), which is primarily obtained, for example, as a chemical synthesis product, by drying, for example in a shelf drier, belt drier or by pneumatic transport in a hot-air stream at temperatures of preferably up to 80° C. The drying can be performed at atmospheric pressure or under reduced pressure. During the drying the water of crystallization escapes from the layers of the crystal structure of the creatine monohydrate, the crystals develop cracks in the course of this which are parallel to the layers and finally disintegrate completely to form an amorphous powder
Bogenstätter Thomas
Franke Dirk
Kessel Knut
Orsten Stefan
Scherr Günter
BASF - Aktiengesellschaft
Forohar Farhad
Keil & Weinkauf
Killos Paul J.
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