WO2000048986A2

WO2000048986A2 - Low odor choline salts

Info

Publication number: WO2000048986A2
Application number: PCT/US2000/004016
Authority: WO
Inventors: Thomas A. Jerrell; Mark H. Krackov
Original assignee: Dcv, Inc.
Priority date: 1999-02-19
Filing date: 2000-02-17
Publication date: 2000-08-24
Also published as: JP2002537281A; CA2363680A1; MXPA01008354A; WO2000048986A3; WO2000048986A8; BR0008337A

Abstract

A low-odor choline salt 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.

Description

TITLE

LOW ODOR CHOLINE SALTS

FIELD OF THE INVENTION

The inv ention is directed to a low odor choline salt product More particularly, the inv ention is directed to a choline salt product which does not release an amine or "fishv-Iike" odor, due to a reduction in the content of total tπmethvlamine in the choline salt by purification

BACKGROUND OF THE INVENTION

Choline is a dietarv component that is important for the structural integrity of cell membranes methyl metabolism cho nergic neurotransmission, transmembrane signaling, and hpid-cholesterol transport and metabolism Choline accelerates the 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) phosphohpids including phosphatidylchohne, a membrane constituent important for the structure and function of membranes, for intracellular signaling, and for hepatic support of very low-density hpoproteins, (2) sphingomyelm, 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 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 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 pπmarv functions of choline are ( 1 ) nerve transmission, (2) as a component of cell membranes, (3) as a hpotropic (fat metabolizing) agent where it helps to prevent liver damage, and (4) as a methyl group donor in the production of DNA 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

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 palatabihty of the product, and can be conferred to the consumer, such that, if consumed in sufficient quantity, the consumer acquires a similar odor Studies 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 palatabihty of these types of products and further, to reduce the undesired chohnergic side-effects, it is desired to obtain a new 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 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 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 the same

Choline salts, such as choline chloride, choline bitartrate and choline dihydrogen citrate are generally described as having a slight amine or "fishy' odor This is especially noticeable when the choline salt is provided as a product to be ingested, 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 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 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 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 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 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 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 are equimolar A.long 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

In order that a choline salt does not release an odor-detectable level of free TMA (1 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 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 (tπmethvlammonium bitartrate, tπmethylammonium dihydrogen citrate, and tπmethvlammonium chloride respectively) are roughly equal in acidity, it is preferred that the level of total TMA be less than approximately 10 ppm, and more preferably, less than 5 ppm In the case of a more weakly acidic salt, such as the TMA salt in choline acetate (tπmethylammonium 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 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 recrystalhzation Other purification techniques include vacuum stripping (see Example 3), ion exchange and any other purification technique that will remove TMA known to those 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 ingredients contact the choline salt, e g choline bitartrate, thev can react to form the alkaline salt of the bitartrate, as follows CaCO., + Ch^" TartH^" → CaTart + Ch^" HCO.-T

If a TMA salt is present, even at relatively low levels, an analogous reaction will occur, yielding free TMA:

CaCO₃ + Me NTT TartH^' → CaTart + Me-»NH^' HCO₃ ^"

I

Me₃N + CO₂ + H₂O This reaction is a non-equilibrium process, which will rapidly release into the 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-T A choline salts.

The advantageous properties of this invention can be observed by reference to the following examples which illustrate the invention.

EXAMPLES EXAMPLE 1 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 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^" odor normally associated with choline bitartrate. 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 an odor) was doubly recry stall ized After the first recrystallization the choline bitartrate, recovered in 84% yield, was found to contain 1 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

EXAMPLE 3

Purification hv Vacuum Strinning 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 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

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

Claims

TITLELOW ODOR CHOLINE SALTSCLAIMS

We Claim

1 A low odor choline salt product 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

2 The choline salt product of claim 1 wherein the choline salt product is disposed within a sealable container

3 The choline salt product of claim 1 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 1 further comprising an alkaline 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

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 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 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 million of trimethylamine.