AU4001700A - Low odor choline salts - Google Patents

Description

WO 00/48986 PCT/US0O/04016 TITLE LOW ODOR CHOLINE SALTS 5 FIELD OF THE INVENTION The invention is directed to a low odor choline salt product. More particularly, the invention is directed to a choline salt product which does not release an amine or "fishy-like" odor, due to a reduction in the content of total trimethylamine in the choline salt by purification. 10 BACKGROUND OF THE INVENTION Choline is a dietary component that is important for the structural integrity of cell membranes, methyl metabolism, cholinergic neurotransmission, transmembrane signaling, and lipid-cholesterol transport and metabolism. Choline accelerates the 15 synthesis and release of acetylcholine, an important neurotransmitter involved in memory storage, muscle control, and many other functions. Choline is also a precursor for the synthesis of (1) phospholipids including phosphatidylcholine, a membrane constituent important for the structure and function of membranes, for intracellular signaling, and for hepatic support of very low-density lipoproteins; 20 (2) sphingomyelin, another membrane constituent that has structural and signaling functions; and (3) platelet activating factor, a potent messenger molecule. Finally, choline is a precursor for the formation of the methyl donor betaine. Choline has been used widely in a number of applications for many years. Its 25 predominant use is in the animal nutrition field, and, in the form of chloride salt, it is used as a direct dietary supplement for production animals such as poultry, swine and the like. Choline also has application in the human nutrition field, where several salts of choline are used to convey this nutrient into the diet. In 1998, the U.S. Institute of Medicine published a recommendation for adequate 30 intake of choline in the human diet. It is recognized as an essential nutrient in both humans and animals, and has been used commercially for nearly 50 years. The primary functions of choline are (1) nerve transmission; (2) as a component of cell membranes; (3) as a lipotropic (fat metabolizing) agent where it helps to prevent liver damage; and (4) as a methyl group donor in the production of DNA WO 00/48986 PCT/USOO/04016 and other body compounds. In addition, some studies have shown that intake of choline can (1) diminish the severity of memory deficits in aged animals; (2) be used as a treatment to lower cholesterol concentrations and (3) reduce the risk of liver cancer and decrease sensitivity to carcinogenic chemicals. 5 One noted concern regarding choline is that it has a characteristic fishy odor which is deemed offensive to most humans. In addition, this odor reduces the initial palatability of the product, and can be conferred to the consumer, such that, if consumed in sufficient quantity, the consumer acquires a similar odor. Studies 10 suggest that the production of methylamines from ingested choline causes the fishy body odor in that the produced methylamines are excreted. In order to improve the initial palatability of these types of products and further, to reduce the undesired cholinergic side-effects, it is desired to obtain a new 15 composition of choline salts which no longer carry, or cause the "characteristic" fishy-odor. SUMMARY OF THE INVENTION In its primary aspect, the invention is directed to a low odor choline salt product 20 purified to an extent wherein the equilibrium concentration of trimethylamine in the atmosphere above the choline salt is less than 0.2 parts per billion. In another aspect, the invention is directed to a low odor choline salt product selected from the group consisting of choline bitartrate, choline dihydrogen citrate 25 and choline chloride, wherein the choline salt comprises less than approximately 10 parts per million of trimethylamine. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to low-odor choline salts and methods for making 30 the same. Choline salts, such as choline chloride, choline bitartrate and choline dihydrogen citrate are generally described as having a slight amine or fishh" odor. This is especially noticeable when the choline salt is provided as a product to be ingested, 2 WO 00/48986 PCT/USOO/04016 and the odor is often offensive enough to cause people to avoid such choline containing products. The source of this odor can actually be traced to trimethylamine (TMA) salt impurities remaining in the product after its manufacture. It is Applicants' discovery that the TMA salt impurities in a choline 5 salt can be reduced to a low enough level that the choline salt does not emit a detectable amine or "fishy" odor. Choline salts are produced by reaction of TMA with ethylene oxide or ethylene chlorohydrin and an acid, such as hydrochloric, tartaric, citric, etc. As with any 10 synthesis, natural or otherwise, the final product is rarely of such purity as to exclude all other ingredients or byproducts. TMA salt is often found as an impurity in choline salts., resulting from incomplete raw material conversion. The TMA salt in the choline salt is in equilibrium with free TMA, releasing into the atmosphere a very low level of volatile (free) TMA, but enough to exceed the 15 odor threshold for humans. TMA is widely recognized as having a strong amine like, fishy odor, detectable by humans at levels as low as 0.2 parts per billion (ppb) in air. It is a primary objective of this invention to provide a choline salt product which 20 does not emit this characteristic amine-like odor. In particular, when a choline salt product is packaged in container for sale to a customer, it is preferred that the packaged choline does not emit the amine-like odor when the container is opened. Therefore, it is preferred that the choline salt product of the invention be purified to an extent wherein the equilibrium concentration of TMA in the atmosphere 25 above the choline salt is less than 0.2 parts per billion. The concentration of volatile (free) TMA in equilibrium with the salts in the choline salt product is dependent on a number of factors, including temperature, humidity, and most importantly, the acidity of the TMA salt. In particular. the 30 free amine concentration will depend on the ratio of TMA groups to acid. Therefore, in the case of a polycarboxylic acid, such as tartaric acid, wherein the acid salt is TMA tartrate (which contains 2 moles of amine per mole of tartaric acid), it can be expected that the product will release orders of magnitude more free TMA than would TMA bitartrate, the amine and acid components of which 3 WO 00/48986 PCT/USOO/04016 are equimolar. Along these lines, the equilibrium vapor concentration of free TMA can be further reduced if excess tartaric acid is present in the product. Similar situations exist for each acid that is used to form the choline salt as acids vary in terms of strength of acidity. 5 In order that a choline salt does not release an odor-detectable level of free TMA (i.e. less than 0.2 ppb) it is critical that the level of total TMA within the choline salt be reduced to a very low level. As described above, the required level of total TMA needed to not release a detectable amine odor will vary depending upon the 10 acidity of the TMA salt in the choline salt. In the case of choline bitartrate, choline dihydrogen citrate and choline chloride, in which all of the TMA salts therein (trimethylammonium bitartrate, trimethylammonium dihydrogen citrate, and trimethylammonium chloride respectively) are roughly equal in acidity, it is preferred that the level of total TMA be less than approximately 10 ppm, and 15 more preferably, less than 5 ppm. In the case of a more weakly acidic salt, such as the TMA salt in choline acetate (trimethylammonium acetate), the total TMA would preferably be even less. The total TMA content within a choline salt is reduced to the desired low level by 20 various modes of purification. A preferred purification method is set forth in Example 1. This preferred method is basically a form of crystallization. Example 2 sets forth a method of further purification by recrystallization. Other purification techniques include vacuum stripping (see Example 3), ion exchange and any other purification technique that will remove TMA known to those 25 having skill in the art. In an alternative embodiment, many applications of choline salts include providing the choline salt in a formulation containing an alkaline ingredient such as, among others, calcium carbonate or magnesium oxide. When the alkaline 30 ingredients contact the choline salt, e.g. choline bitartrate, they can react to form the alkaline salt of the bitartrate, as follows: 4 WO 00/48986 PCT/US0O/04016 CaCO 3 - Ch~ TartH~ -> CaTart + Ch' HC0 3 If a TMA salt is present, even at relatively low levels, an analogous reaction will occur, yielding free TMA: CaCO 3 + Me 3 N-' TartH' -> CaTart + NIe 3 NH HCOj Me 3 N + CO 2 + H 2 0 This reaction is a non-equilibrium process, which will rapidly release into the 10 atmosphere much of the TMA content of the salt. Thus, if the application involves use of choline salts in the presence of an alkaline ingredient, it is even more critical that the level of TMA salt impurities be as low as possible. This is perhaps one of the most important advantages of our low-TMA choline salts. 15 The advantageous properties of this invention can be observed by reference to the following examples which illustrate the invention. EXAMPLES EXAMPLE 1 20 Purification by Crystallization A 250 g. sample of choline bitartrate containing 45 ppm of TMA (as the bitartrate salt) was charged to 375 mL of water and heated with stirring until completely dissolved. Water was then removed in vacuo using a rotary evaporator, until crystals appeared and became heavy, at which point 250 mL of methanol was 25 charged to the slurry. The mixture was cooled to -3 'C and held for one hour. The crystalline product was then filtered, washed on the funnel with -50 mL of cold methanol and dried, to yield a product containing 5 ppm of trimethylamine (as the bitartrate salt). This resulting product having 5 ppm of total trimethylamine did not emit a detectable level of characteristic amine or "fishy" 30 odor normally associated with choline bitartrate. 5 WO 00/48986 PCT/USOO/04016 EXAMPLE 2 Recrystallization In a similar procedure used to further remove TMA from a choline salt, a sample of choline bitartrate containing 2 ppm of trimethylamine (this sample did not emit 5 an odor) was doubly recrystallized. After the first recrystallization the choline bitartrate, recovered in 84% yield, was found to contain I ppm of trimethylamine. After the second recrystallization, no trimethylamine could be detected in the product (estimated detection level <0.5 ppm). This product still did not emit a detectable level of the characteristic amine odor. 10 EXAMPLE 3 Purification by Vacuum Stripping A sample of 45% aqueous choline hydroxide (prepared by the reaction of ethylene oxide with TMA) was found to contain 3,800 ppm of trimethylamine, and emitted 15 the expected strong amine-like odor. The solution was purified by distilling in vacuo with a nitrogen sweep at a pressure of 20 mm of Hg and a pot temperature of-38 'C. Water was added to the still pot as needed to maintain the initial volume. Distillation was continued until the TMA level in the pot liquid was reduced below 15 ppm. 20 The purified choline hydroxide was now converted to choline bitartrate by the addition of an equimolar quantity of tartaric acid, resulting in a choline bitartrate product, which did not emit a detectable amine-like odor. 25 6

Claims (9)

1. A low odor choline salt product purified to an extent wherein the equilibrium concentration of trimethylamine in the atmosphere above the choline 10 salt is less than 0.2 parts per billion.

2. The choline salt product of claim I wherein the choline salt product is disposed within a sealable container. 15

3. The choline salt product of claim I wherein the choline salt is selected from the group consisting of choline bitartrate, choline dihydrogen citrate and choline chloride.

4. The choline salt product of claim I further comprising an alkaline 20 ingredient.

5. The choline salt product of claim 4 wherein the choline salt is selected from the group consisting of choline bitartrate, choline dihydrogen citrate and choline chloride. 25

6. The choline salt product of claim 5 further comprising less than 10 parts per million of trimethylamine.

7. The choline salt product of claim 6 further comprising less than 5 parts per 30 million of trimethylamine.

8. A low odor choline salt product selected from the group consisting of choline bitartrate, choline dihydrogen citrate and choline chloride. wherein the 7 WO 00/48986 PCT/USOO/04016 choline salt comprises less than approximately 10 parts per million of trimethylamine.

9. The choline salt product of claim 8 further comprising less than 5 parts per 5 million of trimethylamine. 8