Compositions and methods for low malodor l-selenomethionine feed additive

Abstract

The present disclosure relates to compositions and methods for maintaining or improving the health of a human or animal. The present invention is broadly concerned with the invention of a low or no malodor L-selenomethionine (L-SeMet) that can be subsequently used in a palatable feed composition for animals such that the essential selenium element is more bioavailable, better tolerated, more efficiently stored and therefore more available for human or animal consumption. Animals may be livestock and include but are not limited to dairy cows, beef cows, swine and poultry. The invention provides for animal or livestock feeds and supplements and particularly to animal feeds and supplements containing a formulation of a low or no malodor L-selenomethionine (L-SeMet) produced by methods of the invention.

Description

COMPOSITIONS AND METHODS FOR LOW MALODOR L-SELENOMETHIONINEFEED ADDITIVECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 682,161, entitled “COMPOSITIONS AND METHODS FOR LOW MALODOR L- SELENOMETHIONINE FEED ADDITIVE,” filed on August 12, 2024, the entire contents of which are incorporated herein by reference.BACKGROUND1. Technical Field

[0002] The present invention relates to a process for producing pure L-selenomethionine having low to no malodor for the purpose of producing palatable animal feed compositions and method of producing animal feed comprising L-selenomethionine having low to no malodor. Animals may be livestock and include but are not limited to dairy cows, beef cows, swine and poultry.2. Description of the Related Art

[0003] The present invention is broadly concerned with the invention of a malodorous free L- selenomethionine (L-SeMet) that can be subsequently used in a palatable feed composition for animals such that the essential selenium element is more bioavailable, better tolerated, more efficiently stored and therefore more available for human consumption.

[0004] Like many trace nutrients, L-SeMet enters the animal feed supply chain through plants. Animals are incapable of synthesizing this molecule in vivo or distinguishing it from methionine, and as a result, it is nonspecifically incorporated into a wide range of Se-containing proteins (Daniels, 1996). It is thought that approximately 80% of total organic Se found in plants such as corn, soya, and wheat, comes in the form of L-SeMet and is directly correlated to the Se found inDocket No.: 1022.551WO1 the soil (Olson et al., 1970) and (Schrift, 1969). It follows that in regions of the world where Se is not inbounded to the animal from plant matter, then supplemental L-SeMet could be the natural / organic answer to the problems associated with Se deficiencies as it is considered to be the most appropriate and least toxic dietary source of Se (Schrauzer, 2001). Furthermore, M.C. Mony, 2000 determined that L-SeMet was more bioavailable and better tolerated relative to inorganic forms of Se like selenites and selenates.

[0005] The major Se supplements in use for the last twenty years are selenite and selenate — both inorganic forms of Se. The limitations of using inorganic Se were thought to be toxicity, interactions with other minerals, low efficiency of transfer to milk, meat, and eggs and an inability to build and maintain Se reserves in the body. As a result, a high proportion of the element consumed is simply excreted.

[0006] L-selenomethionine is intended to be used as a substitute for other selenium sources used as food additives in animal nutrition, such as sodium selenite, sodium selenate, and selenized yeast. Indeed, Rayman tabulated the main components in commercial yeast products in Europe and found that in all cases, L-SeMet was the largest single species accounting for 54-75% of the total Se (Rayman M. P., 2004). Later in 2006, Schrauzer suggested that improved methods of analysis revealed that Se-yeast contained 90+ % of its Se in the form of selenomethionine and it is the principal organic nutritional form of Se for higher animals and humans. Schrauzer concluded that concerns regarding the accumulation of L-SeMet (from yeast source) to toxic levels was unfounded since ingested L-SeMet is incorporated into proteins and continuously released by normal catabolic processes (Schrauzer, 2006). In fact, ingested selenomethionine is actively absorbed and is either metabolized directly or is incorporated into proteins. The metabolic breakdown of selenomethionine occurs in analogy to that of methionine, yielding selenocystine, which is metabolized further to selenide and either used for selenoprotein synthesis or methylated and excreted. Mammalian enzymes do not discriminate between selenomethionine and methionine, hence prolonged ingestion of selenomethionine at nutritional levels will not result in the gradual accumulation of Se in organs and tissues to toxic levels. At constant intakes of both, the ratio of selenomethionine to methionine in proteins will remain constant, i.e., a steady state will establish itself. This is one of the reasons that a linear relationship exists between the dietary Se intakes and the Se levels in whole blood. This linear relationship exists over several orders of magnitude of the SeMet to Met ratio. The daily supplementation of Se in the form of Se yeastDocket No.: 1022.551WO1 causes blood Se levels to increase for about 6 weeks. Thereafter, on continuing supplementation, blood Se levels begin to plateau, marking the beginning of the establishment of a steady-state condition. Similarly, plasma Se levels of study subjects receiving 200 pg of Se per day in the form of Se yeast increased during the first two months and then plateaus and remains constant for up to four years of supplementation. Direct linear relationships also exist between the dietary Se intakes and the Se contents of hair, toenails, and fingernails. While the rates at which steady-state conditions are reached in different organs may vary, there is evidently no uncontrolled accumulation of selenomethionine, even after prolonged supplementation at nutritional dosages. It can be stated that the ingestion of selenomethionine does not result in the accumulation of Se to potentially toxic levels in the organism, since ingested selenomethionine is not only incorporated into proteins but is also continuously released from them by normal catabolic processes (Schrauzer, 1998) (Schrauzer, 2006).

[0007] Historically, the element Se and its heretofore dietary sources, including L-SeMet entered that SeMet and Se-yeast are suitable for nutritional Se-supplementation (Power R. F., 1994) that children are more susceptible than adults to adverse effects from selenium. Hence, they concluded that it was appropriate to extrapolate the UL from adults to children on a body weight basis. This provided ULs ranging from 60 pg / day for children aged 1-3 years and 90 pg / day for children aged 4-6 years, to 250 pg / day for ages 15-17 years. Specific legislative provisions on nutrient sources apply to foods manufactured for infants and young children. The fate of the Se in humans inbound from animals is widely studied, and safety controls are in place. Sections [4.2 and 4.3] below contain reviews of the L-SeMet target animal and consumer safety.

[0008] Selenium primarily enters the human food chain through consumption of foodstuffs containing SelP. To the author’s knowledge, no human case of L-SeMet poisoning has been reported to date. In the European Union, L-SeMet as a source of dietary Se is authorized to be added to foods, including food supplements, by Commission Regulation (EC) No 1170 / 2009. According to the EFSA Scientific Opinion of the Panel on Food Additives and Nutrient Sources added to Food on L-SeMet as a source of selenium added for nutritional purposes to food supplements, following a request from the European Commission, L-SeMet was intended to be used in food supplements, e.g., in capsules, tablets, ampules, or powders at proposed levels of 100- 400 pg Se / day, typically 200 pg selenium / day. The latter intake is equivalent to 496 pg L- SeMet / day (EFSA, 2009). L-SeMet was approved by the FDA as a dietary supplement in manyDocket No.: 1022.551WO1 formulations and is listed in the United States Pharmacopoeia. A population reference intake (PRI) of 55 pg selenium per day for adults was established by the SCF in 1993 (Scientific Committee on Food, 1993). The SCF has also established a UL for Se of 300 pg / day [Ref, F-4], while the UK Expert Committee on Vitamins and Minerals (EVM) from the UK derived a Safe Upper Level (SUL) of 450 pg / day for total Se (Expert Group on Vitamins and Minerals, 2003).

[0009] The US Food and Nutrition Board (FNB) estimated a UL of 400 pg / day (Food and Nutrition Board, 2000). Both the SCF UL and that of the FNB UL also apply to pregnant and lactating women, and while the SCF commented that there were no specific data to support a derivation of a UL for children, they noted that there are no reports indicating that children are more susceptible than adults to adverse effects from Se. Hence, they concluded that it was appropriate to extrapolate the UL from adults to children on a body weight basis. This provided ULs ranging from 60 pg / day for children aged 1-3 years and 90 pg / day for children aged 4-6 years to 250 pg / day for ages 15-17 years (EFSA, 2009). Selenium is a natural component of the diet and is present in fish (0.32 mg / kg), offal (0.42 mg / kg), Brazil nuts (0.25 mg / kg), eggs (0.16 mg / kg), and cereals (0.02 mg / kg). In foods, Se is generally present as the amino acid derivates L-SeMet, Se- methyl selenocysteine, and selenocysteine, with lesser amounts of inorganic forms such as selenite and selenate. The L-SeMet molecule accounts for 50% to over 80% of total Se in plants such as cereals and legumes, including soybean grown on Se-rich soil (Rayman, Infante, & Sargent, 2008). Plants initially absorb Se from the soil and convert it to L-SeMet and other Se- containing amino acids such as selenocysteine. L-SeMet from plant crops has been estimated to account for at least half of the dietary Se. The amount of Se available in the soil for plant growth and corresponding variations in the intake of Se by humans varies considerably among regions and countries (Committee on Animal Nutrition, 1983). A synthetic source of L-SeMet alleviates this geographical imbalance.

[0010] Based on these data, the Se content of food products of animal origin from animals fed with an L-selenomethionine supplemented diet is expected to be in the same range as the Se content of products from animals fed a diet supplemented with selenized yeast (which is already authorized in the USA as a food additive for use in animal nutrition). It can be concluded that, if the legal maximum limits of total Se in the complete feeding stuff are respected, the UL of 400 pg / day set by the US FNB will not be exceeded (Food and Nutrition Board, 2000).Docket No.: 1022.551WO1

[0011] Considering the purity of the L-SeMet and the metabolic pathways of SeMet, L-SeMet should be considered as safe for all animal species, provided that the maximum total Se level authorized in feed is respected. The use of L-SeMet in animal nutrition is expected to result in a similar increase or better in Se deposition in animal tissues / products as that resulting from other sources of SeMet. To ensure consumer safety from consumption of food originating from animals fed L-SeMet, it is concluded that dietary Se supplementation from the additive should not exceed a maximum of 0.3 mg Se / kg complete feed. In the absence of specific data, the additive should be considered as an irritant to skin and eyes, as a skin sensitizer, and potentially harmful by inhalation. The use of L-SeMet in feed does not pose an additional risk to the environment compared to other sources of Se for which it will substitute, if the maximum authorized content in feeding stuffs is not exceeded. L-SeMet is an efficient source of Se for all species. This conclusion was derived from studies with laying hens and pigs for fattening and, in the case of ruminants, from literature describing the microbial incorporation of Se from organic sources in the rumen.

[0012] The incorporation of the additive into feed should be made via premixtures only. The maximum content for total Se in feed is set by the FDA. The conclusions of the FEEDAP Panel on the safety of L-SeMet for the target animals, the consumers, and the environment are valid only if these maximum contents are strictly considered in feed formulation and feeding practices. Since Se is routinely supplemented to feed, only a small amount, if any, could be administered additionally via water for drinking. Exact dosing in water for drinking can be achieved only if the total dietary Se content and its availability are known, which is normally not the case. It is therefore recommended not to introduce the use of L-SeMet via water for drinking. Exposure of users by inhalation should be avoided, and protective measures are recommended. Furthermore, it is strongly recommended that L-SeMet should only be made available on the market to premixture compounders only in a formulation with reduced Se content (i.e., <40000 mg Se / kg) and a reduced selenium dusting potential.

[0013] The production of dietary forms of L-SeMet was developed in response to improving strategies for dealing with nutritional deficiencies in both humans and animals. The FDA approved the use of inorganic selenates and selenites, whose efficacy had already been demonstrated to be lower than that of organic L-SeMet. In 2000, the FDA also approved yeast forms of Se, which have since been proven to deliver 90+% of the Se from L-SeMet (Schrauzer, 2006). The biochemistry of yeast (Saccharomyces cerevisiae) was reported as early as 1961 to take upDocket No.: 1022.551WO1 inorganic Se from the culture medium and to convert it into SeMet (Blau, 1961). The biosynthesis of SeMet was known to occur in analogy to that of methionine and to utilize the same enzymes (Schrauzer, 2003). The maximum amount of Se, a yeast cell can theoretically incorporate accordingly depends on its methionine content and is in the order of 6000 ppm. However, the full replacement of methionine by L-SeMet is not possible. The highest amount of Se in yeast achieved by 2006 was about 3000 ppm. The Se yeast is produced industrially by methods which may differ in important details and which in part, are proprietary and / or patented. To be marketable as a food, Se yeast must meet or exceed the standards laid down by IUPAC for dried food yeast. It is defined as “the whole organism of one individual yeast, or a mixture of several yeasts belonging to the family Saccharomycetaceae, obtained either as a by-product of fermentation processes or by special culture.” Dried Se yeast must not exceed the upper limits of moisture (10%), ash (10%), lead (5pg / g), arsenic (5pg / g), live bacteria count (7500 / g), and mold counts(50 / g). Minimum levels are set for nitrogen (7.2%, equivalent to 45% protein), thiamine, riboflavin, and niacin. Furthermore, it is required to be free of starch and bacteria of the genus Salmonella.

[0014] In 1984, L-SeMet was synthesized at a cost comparable to Se yeasts (i.e., on a Se content basis), which were the only available economical dietary L-SeMet sources prior to the ‘80s (Schrauzer, 2000). Of course, synthetic preparations of L-SeMet were known for some time before the economics were on par with Se yeasts but suffered from the formation of foul-smelling and poisonous methyl hydrogen selenide (Painter, 1947) (Plieninger, 1950). Later, Koch and Buchardt, in 1983 articulated a 3-pot novel synthesis of L-SeMet that could be done at scale with high yields, high optical activity, and with evil-smelling constituents. Suffice it to say, synthetic L-SeMet is commercially available today, stemming from bulk manufacturing around the world for markets where it has been approved for over a decade but remains a foul-smelling molecule with limited palatability.

[0015] Synthetic L-SeMet first became available in 1947 (Klosterman & Painter, 1947). L- SeMet is identified as (S) [2-amino-4-(methylseleno)-butanoic acid] or CHa-Se- CH2CH2CH(NH2)-COOH or C5HnNO2Se. It comprises 30.62% C, 5.65% H, 7.14% N, 16.32% O, and 40.26% Se, and has a molecular weight of 196.1 Ig / mol. L-SeMet is a colorless compound with a musty odor and crystallizes from aqueous acetone in the form of hexagonal crystals. SeMet can exist as a racemic mixture of the L-form, which occurs naturally, and the D-enantiomer or D,L-mixture which are obtained synthetically. Pure L-SeMet melts with decomposition at 274°C,Docket No.: 1022.551WO1DL-SeMet at 265°C, making it thermally somewhat less stable than its sulfur analog. SeMet is less soluble in water than Met due to the greater hydrophobicity of the CH3-Se- as compared to the CH3-S group, at 30°C and pH 7.0 (Shepherd & Huber, 1969). In 2N HC1 (c=0.02), L-SeMet has a [a]D of +21.28° (Koch & Buchardt, 1993). Its half-time of racemization of 19-20 days in aqueous solution at 100°C and pH 7.4 is similar to that of Met (Boehm & Bada, 1985). On acid hydrolysis, SeMet is significantly less stable than Met. In 6N HC1 at 110°C, hydrolysis of SeMet was complete after 7 hours, while the same treatment leaves the sulfur analog Met still essentially unchanged (Chiao & Peterson, 1953). SeMet is also more oxygen-sensitive than Met, although the rates of oxidation and the role of promoters and inhibitors in oxidation remain to be determined (Schrauzer, 2003). Methionine selenoxide, (CHs Se(O) CH2CH2CH(NH2) COOH), is formed upon the reaction of SeMet with hydrogen peroxide. The oxidation also occurs efficiently with peroxynitrite (Assmann, Briviba, & Sies, 1998). Whereas methionine sulfoxide is difficult to reduce to Met under physiological conditions, methionine selenoxide is easily converted back to SeMet upon reaction with reducing agents such as glutathione (GSH), leading to the suggestion that L-SeMet acts catalytically as a cellular antioxidant. Pure SeMet may be distinguished from Met by its infrared spectrum (Shepherd & Huber, 1969). Identification of SeMet in protein hydrolysates is possible by means of standard amino acid analyzers (Sliwkowski, 1984).

[0016] Therefore, there is a need for a process for producing pure L-selenomethionine having low to no malodor for the purpose of producing palatable animal feed compositions.Docket No.: 1022.551WO1

[0017] BRIEF SUMMARY OF THE INVENTION

[0018] In one aspect, the present disclosure provides a novel process for producing pure, malodorous L-selenomethionine molecule for the purpose of producing palatable low odor or malodor free animal feed compositions with minimal variation, superior bioavailability, and superior tissue storage of the essential element selenium.

[0019] The present invention relates to a novel manufacturing process that yields a pure L- selenomethionine product with low or no malodor. In another inventive embodiment, the malodor free composition is part of inventive compositions for animal feeds that are characterized by improved palatability.

[0020] In one embodiment, the low or no malodor L-selenomethionine supplemented animal feed compositions are appealing to the animal in such a way as to improve dry matter intake and subsequently animal performance and wellness.

[0021] In one embodiment, the method comprises (a) reacting L-methionine with methyl iodide to produce an intermediate reaction product and (b) reacting the intermediate reaction product with methylselenol or its salts to produce an L-selenomethionine reaction product.

[0022] The methods of the present invention produce L-selenomethionine according to the reaction shown in Equation 1 :

[0024] In another embodiment, the methods of the present invention produce L- selenomethionine according to the reaction shown in Equation 2:

[0025] Eq. (2)

[0026] In another embodiment, the method of the present invention is a method for synthesizing for L-selenomethionine comprised of the following steps for Equation 1 :Docket No.: 1022.551WO1(a) reacting L- methionine with methyl iodide at a temperature and for time sufficient for the reaction to produce an intermediate reaction product;(b) reacting the intermediate reaction product with methylselenol or its salts at a temperature and for time sufficient for the reaction to produce L-selenomethionine;(c) collecting the L-selenomethionine.

[0027] In one embodiment, the first step in the manufacturing process starts with suspending L-methionine in water by stirring until an aqueous solution is formed. After dissolving, methyl iodide is added at a proprietary rate at room temperature and subsequently heated to about 40°C for approximately 4-6 hours. The reaction is carried out according to the temperature. After the reaction is completed, it is filtered, and the filter cake is washed with water to obtain a white intermediate product. The yield is calculated after washing the filter cake, which is greater than 90, 92, 94, 95, 96, 97, or 98%. The purity of the intermediate is checked using a bespoke HPLC technique and the purity of the intermediate is greater than 90, 92, 94, 95, 96, 97, 98, 99% at this stage.

[0028] In one embodiment, the second step of the manufacturing process the intermediate is dissolved in a high purity grade ethanol under blanket nitrogen of a high purity grade. Sodium selenium methoxide, which is also dissolved in a high purity grade of methanol is added to the ethanolic solution of the intermediate at a proprietary rate and then reacted at 45°C + / - 3° for about 4-6 hours. The reaction mixture temperature is subsequently dropped to 20°C + / - 3°C. The reactant mixture is then quenched with glacial acetic acid. The system is adjusted to a pH value from about 5 to about 6. The final product is filtered and dried to obtain L-selenomethionine. The yield is calculated and is greater than 90, 92, 94, 95, 96, 97, 98, or 99%. The purity of the sample is checked using HPCL technique known to those well versed in the art and found to be greater than 90, 92, 94, 95, 96, 97, 98, or 97%. Residual alcoholic solvents are measured using bespoke HPLC techniques during the drying process to ensure the purity of the L-SeMet product.

[0029] In another inventive embodiment, the low or no malodor L-SeMet is determined by a) mass spectroscopy analysis and an olfactory panel.

[0030] In one embodiment, the present invention provides for methods of supplementing feed with the use of L-selenomethionine made by the methods of the present invention.Docket No.: 1022.551WO1

[0031] In another embodiment, the low or no malodor L-SeMet compounds described in this invention may be added to solid or liquid feed as a readily available source of selenium. The amount of the compound added will depend on the animal being supplemented. For swine and poultry, the diet will be supplemented by 0.05-2.00 ppm Se, preferably 0.1-0.3 ppm Se. For cattle, the feed will be supplemented by 0.05-10 mg Se per head per day, preferably 2-7 mg Se per head per day.

[0032] The above summary contains simplifications, generalizations and omissions of detail and is not intended as a comprehensive description of the claimed subject matter but, rather, is intended to provide a brief overview of some of the functionality associated therewith. Other systems, methods, functionality, features and advantages of the claimed subject matter will be or will become apparent to one with skill in the art upon examination of the following figures and detailed written description.Docket No.: 1022.551WO1

[0033] DETAILED DESCRIPTION

[0034] The present invention will now be described with reference to the following embodiments. As is apparent by these descriptions, this invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. For example, features illustrated with respect to one embodiment can be incorporated into other embodiments, and features illustrated with respect to a particular embodiment can be deleted from that embodiment. In addition, numerous variations and additions to the embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention. Hence, the following specification is intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations, and variations thereof.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0036] All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0037] It is to be understood that in instances where a range of values are provided that the range is intended to encompass not only the end point values of the range but also intermediate values of the range as explicitly being included within the range and varying by the last significant figure of the range. By way of example, a recited range from 1 to 4 is intended to include 1-2, 1- 3, 2-4, 3-4, and 1-4.

[0038] Definitions

[0039] As used herein the term "biologically active derivatives" means organic covalently bound compounds prepared from the basic structure (for example L-selenomethionine) that retains the bioavailability properties to provide selenium diet enrichment of animals.

[0040] As used herein, the term “feed” or “feed material” refers to the basic feed material to be consumed by an animal. It will be further understood that this may comprise, for example, at least one or more unprocessed grains, and / or processed plant and / or animal material such as com, soybean meal or bone meal. In some embodiments, the feed material will comprise one or more of the following components: a) cereals, such as small grains (e.g., wheat, barley, rye, oats andDocket No.: 1022.551WO1 combinations thereof) and / or large grains such as maize or sorghum; b) by products from cereals, such as corn gluten meal, Distillers Dried Grain Solubles (DDGS), wheat bran, wheat middlings, wheat shorts, rice bran, rice hulls, oat hulls, palm kernel, and citrus pulp; c) protein obtained from sources such as soya, sunflower, peanut, lupin, peas, fava beans, cotton, canola, fish meal, dried plasma protein, meat and bone meal, potato protein, whey, copra, sesame; d) oils and fats obtained from vegetable and animal sources; e) minerals and vitamins.

[0041] As used herein, the term “feedstuff’ refers to a feed material to which one or more feed supplements have been added. It will be understood by the skilled person that different animals require different feedstuffs, and even the same animal may require different feedstuffs, depending upon the purpose for which the animal is reared. It will be further understood that depending on the starting feed material, the feedstuff may be a high fiber feedstuff or a low fiber feedstuff. Preferably, the feedstuff may comprise feed materials comprising maize or corn, wheat, barley, triticale, rye, rice, tapioca, sorghum, and / or any of the by-products, as well as protein rich components like soybean mean, rape seed meal, canola meal, cotton seed meal, sunflower seed mean, animal-by-product meals and mixtures thereof. More preferably, the feedstuff may comprise animal fats and / or vegetable oils. Optionally, the feedstuff may also contain additional minerals such as, for example, calcium and / or additional vitamins.

[0042] As used herein, the terms “animals” and “livestock” includes warm-blooded animals kept or raised for use or pleasure. Typically, “livestock” refers to animals that are commonly kept or raised for some commercial use or purpose. These may be animals that are kept in confinement within a building or shelter, or within some partially or fully enclosed area of land. Alternatively, livestock may be allowed to roam freely over an open area of land. In one specific embodiment, “livestock” refers to animals selected from the group consisting of swine, ruminants, poultry, equines, and any combination thereof. In one or more embodiments, the livestock is poultry. In one or more embodiments, the poultry is a chicken, turkey, guinea fowl, duck, goose, pigeon or quail in all growth stages.

[0043] The terms “metal” and “mineral” may be used interchangeably. Each refers particularly to any divalent or trivalent metal that, when in ionic form, can form one or more coordinate bonds with a ligand, and is substantially non-toxic when administered in traditional amounts as known in the art. Metals can form alkali or alkali earth metal salts such as Na, K, Rb, Cs, Mg, Ca, Sr, Ba, La, Ce, Y, Li, Zn, or a combination thereof. The metal is preferably a metal selected from theDocket No.: 1022.551WO1 group consisting of Na, K, Mn, Mg, Fe, Zn, Cr, and Ca. In one embodiment, the metal is selected from the group consisting of Na, K, Cs, Mg, Ca, La, or a combination thereof. In one embodiment, the metal is sodium (Na).

[0044] When referring to “metal salts” or “salts,” it is recognized that oxides and hydroxides are not technically salts in the classic sense. However, in accordance with embodiments of the present invention, metal oxides and hydroxides are considered to be salts along with any other metal salts as more typically defined.

[0045] The term “supplement” as used herein shall mean any foodstuff, composition, or compound that contains a substance intended to benefit an animal, and is provided to the animal in order to increase the amount of that substance ingested by the animal above the amount it receives by its normal dietary behavior.

[0046] The term “quenching” refers to the introduction of chemical quencher (quenching agent), which is a material that combines with any unused or excess reactants and effectively stops a chemical reaction. Generally, the chemical quencher or quenching agent should not engage in the reaction in any way other than to react or combine with one or more reactants in order to slow or stop the reaction.Docket No.: 1022.551WO1

[0047] DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0048] The present disclosure relates to compositions and methods for maintaining or improving the health of an animal.

[0049] In one or more embodiments, the present invention provides for animal or livestock feeds and supplements and particularly to animal feeds and supplements containing a formulation of low odor or malodor free selenomethionine.

[0050] In one aspect, the present disclosure provides a novel process for producing pure, L- selenomethionine molecule for the purpose of producing palatable low odor or malodor free animal feed compositions with minimal variation, superior bioavailability, and superior tissue storage of the essential element selenium.

[0051] The present invention relates to a novel manufacturing process that yields a pure L- selenomethionine product with low or no malodor. In another inventive embodiment, the malodor free composition is part of inventive compositions for animal feeds that are characterized by improved palatability.

[0052] In one embodiment, the low or no malodor L-selenomethionine supplemented animal feed compositions are appealing to the animal in such a way as to improve dry matter intake and subsequently animal performance and wellness. In one embodiment, the L-selenomethionine supplemented animal feed compositions are substantially odor free.

[0053] The methods of the present invention utilize L-methionine, having the formula shown in Formula I:

[0054]

[0055] Methionine, also known as (S)-2-Amino-4-(methylthio)butanoic acid, is a sulfur containing essential amino acid in humans and animals. Methionine has the formula: C5H11NO2S.Docket No.: 1022.551WO1

[0056] In one embodiment, the method comprises reacting L-methionine with iodomethane (methyl iodide) to produce an iodo-thio complex intermediate reaction product, having the formula shown in Formula II:

[0057]

[0058] lodomethane (CAS Number: 74-88-4), also called methyl iodide, and commonly abbreviated "Mel", is the chemical compound with the formula CFFI It is a dense, colorless, volatile liquid. It can be prepared by reacting dimethyl sulfate with concentrated KI.

[0059] U.S. Patent Ser. No. 7,586,003 (Zinpro Corp.) discloses novel processes for preparing derivatives of seleno-amino acids that are effective dietary sources of supplemental selenium in humans and livestock.

[0060] In another embodiment, the method comprises reacting the intermediate reaction product with methylselenol or its salts to produce an L-selenomethionine, having the formula shown in Formula III:

[0061]

[0062] Methylselenol, also known as methaneselenol (MSe), is an organoselenium compound with the formula CHsSeH. It is the simplest selenol and is a colorless gas, notorious for its foul odor. In one embodiment, the methylselenol is a metal salt. In one embodiment, the metal salt is sodium methylsel enolate. The sodium salt of methaneselenol (CAS No.: 37773-10-7) has a molecular formula: CF Se.Na and is also known as sodium selenium methoxide or sodium methylselenolate or sodium methanesulphonate. Sodium methylselenolate is a white crystalline powder soluble in water, alcohol, ether, hexane, benzene, methyl cyclopentane, toluene, o- chlorotoluene and ethyl disulfide.Docket No.: 1022.551WO1

[0063] In one embodiment, the method comprises (a) reacting L-methionine with methyl iodide to produce an intermediate reaction product and (b) reacting the intermediate reaction product with methylselenol or its salts to produce an L-selenomethionine reaction product.

[0064] The methods of the present invention produce L-selenomethionine according to the reaction shown in Equation 1 :

[0066] In another embodiment, the methods of the present invention produce L- selenomethionine according to the reaction shown in Equation 2:

[0067] Eq. (2)

[0068] In another embodiment, the method of the present invention is a method for synthesizing for L-selenomethionine comprised of the following steps for Equation 1 :(a) reacting L- methionine with methyl iodide at a temperature and for time sufficient for the reaction to produce an intermediate reaction product;(b) reacting the intermediate reaction product with methylselenol or its salts at a temperature and for time sufficient for the reaction to produce L-selenomethionine;(c) collecting the L-selenomethionine.

[0069] Step (a): Reaction of L-Methionine with Methyl Iodide

[0070] In one embodiment, the reacting of L-methionine with methyl iodide in step (a) is performed in a solvent. In one embodiment, the solvent is water, ethanol, methanol, or mixtures thereof. In another embodiment, the solvent is selected from the group consisting of water, absolute ethyl alcohol, 90-95% ethyl alcohol, methanol or isopropanol. In another embodiment, the solvent is substantially water. In another embodiment, the methyl iodide is added in equal molar amounts with the L-methionine. In another embodiment, the methyl iodide is added in excess amounts toDocket No.: 1022.551WO1L-methionine. In another embodiment, the methyl iodide is added in an amount of from about 2: 1 to about 1 : 1 ratio to L-methionine. In another embodiment, the methyl iodide is added in an amount of from about 1.5 : 1 to about 1.1: 1 ratio to L-methionine. In another embodiment, the methyl iodide is added in an amount of 1.2: 1 ratio to L-methionine.

[0071] In another embodiment, the L-methionine is suspended in water and heated prior to the addition of the methyl iodide. In another embodiment, the L-methionine is suspended in water and heated to a temperature above 10, 11, 12, 13, 14, 15, 16, 17, 19, 19, 20, 21, 22°C or more prior to the addition of the methyl iodide. In another embodiment, the L-methionine is suspended in water and heated to a temperature above 22°C prior to the addition of the methyl iodide.

[0072] In one embodiment, the reaction of step (a) is at a temperature from about 0°C to about 100°C. In another embodiment, the reaction temperature is from about 15°C to about 100°C. In another embodiment, the reaction temperature is from about 22°C to about 100°C. In another embodiment, the reaction temperature is from about 20°C to about 60°C. In another embodiment, the reaction temperature is from about 22°C to about 45°C. In another embodiment, the minimum reaction temperature is at least about 10, 11, 12, 13, 14, 15, 16, 17, 19, 19, 20 °C or more. In another embodiment, the maximum reaction temperature is at most about 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40 °C or less.

[0073] In one embodiment, the reaction of step (a) is for a time from about 1 hour to about 18 hours. In another embodiment, the reaction time is from about 1 hour to about 12 hours. In another embodiment, the reaction time is from about 2 hour to about 10 hours. In another embodiment, the reaction time is from about 3 hour to about 8 hours. In another embodiment, the reaction time is from about 5 hour to about 7 hours. In another embodiment, the minimum reaction time is at least about 0.1, 0.5, 1, 2, 3, 4, 5 hours or more.

[0074] In one embodiment, the reaction of step (a) is by addition of methyl iodide to L- methionine at a controlled rate. In another embodiment, the reaction of step (a) is by addition of methyl iodide to L-methionine at a rate of from about 0.01 to about 1 moles methyl iodide / minute / moles L-methionine. In another embodiment, the reaction of step (a) is by addition of methyl iodide to L-methionine at a rate of from about 0.02 to about 0.5 moles methyl iodide / minute / moles L-methionine. In another embodiment, the reaction of step (a) is by addition of methyl iodide to L-methionine at a rate of from about 0.05 to about 0.2 moles methyl iodide / minute / moles L-methionine.Docket No.: 1022.551WO1

[0075] In one embodiment, the reaction of step (a) is reacting methyl iodide with L-methionine in a solvent; wherein the solvent is water, ethanol, methanol, or mixtures thereof; wherein the reaction temperature is 0-60°C, and the reaction time is 3-12 hours. In one embodiment, the reaction of step (a) is reacting methyl iodide with L-methionine in a solvent; wherein the solvent is water, ethanol, methanol, or mixtures thereof; wherein the reaction temperature is 20-45 °C), and the reaction time is 5-7 hours.

[0076] In one embodiment, the intermediate reaction product (Formula II) that is created from reacting of L-methionine with methyl iodide is collected by filtration. In another embodiment, the intermediate reaction product (Formula II) that is created from reacting of L-methionine with methyl iodide is washed with one or more polar organic solvents. In another embodiment, the one or more polar organic solvents is selected from the group consisting of acetic acid, acetone, acetonitrile, dimelthylsulfoxide (DMSO), dimethylformamide (DMF), ethanol, ethyl acetate, formic acid, isopropanol, methanol, n-butanol, n-propanol, nitromethane, propylene carbonate, tetrahydrofuran, water, and combinations thereof. In another embodiment, the one or more polar organic solvents comprises acetic acid.

[0077] Step (b): Reaction of Intermediate Reaction Product with Methylselenol

[0078] In one embodiment, the method comprises reacting the intermediate reaction product (Formula II) that is created from step (a) with methylselenol or its salts to produce an L- selenomethionine (Formula III).

[0079] In one embodiment, the intermediate reaction product (Formula II) that is created from step (a) is collected and washed with one or more polar organic solvents. In one embodiment, the intermediate reaction product (Formula II) is collected by filtering. In one embodiment, the intermediate reaction product (Formula II) that is created from step (a) is a slurry suspended in one or more polar organic solvents. In another embodiment, the one or more polar organic solvents is selected from the group consisting of acetic acid, acetone, acetonitrile, dimelthylsulfoxide (DMSO), dimethylformamide (DMF), ethanol, ethyl acetate, formic acid, isopropanol, methanol, n-butanol, n-propanol, nitromethane, propylene carbonate, tetrahydrofuran, water, and combinations thereof. In another embodiment, the one or more polar organic solvents is substantially methanol or ethanol.Docket No.: 1022.551WO1

[0080] In one embodiment, the intermediate reaction product (Formula II) that is created from step (a) has a purity of at least 80, 85, 90, 95, 96, 97, 98, 99% or greater. In one embodiment, the intermediate reaction product (Formula II) that is created from step (a) is methylselenol or its salts.

[0081] In one embodiment, the intermediate reaction product (Formula II) that is created from step (a) is sodium methylselenolate.

[0082] In one embodiment, the intermediate reaction product (Formula II) that is created from step (a) is dissolved in one or more polar organic solvents. In another embodiment, the one or more polar organic solvents is selected from the group consisting of acetic acid, acetone, acetonitrile, dimelthylsulfoxide (DMSO), dimethylformamide (DMF), ethanol, ethyl acetate, formic acid, isopropanol, methanol, n-butanol, n-propanol, nitromethane, propylene carbonate, tetrahydrofuran, water, and combinations thereof. In another embodiment, the one or more polar organic solvents is substantially methanol or ethanol.

[0083] In one embodiment, the intermediate reaction product (Formula II) is reacted with methylselenol. In another embodiment, the intermediate reaction product (Formula II) is reacted with a methylselenolate salt. In another embodiment, the intermediate reaction product (Formula II) is reacted with sodium methylselenolate. In another embodiment, the methylselenolate salt is dissolved in a polar organic solvent. In another embodiment, the one or more polar organic solvents is selected from the group consisting of acetic acid, acetone, acetonitrile, dimelthylsulfoxide (DMSO), dimethylformamide (DMF), ethanol, ethyl acetate, formic acid, isopropanol, methanol, n-butanol, n-propanol, nitromethane, propylene carbonate, tetrahydrofuran, water, and combinations thereof. In another embodiment, the one or more polar organic solvents is substantially methanol or ethanol.

[0084] In another embodiment, the methylselenolate salt is dissolved in a polar organic solvent and added to the intermediate reaction product (Formula II), which is dissolved in a polar organic solvent. In another embodiment, the solvent is selected from the group consisting of water, absolute ethyl alcohol, 90-99% ethyl alcohol, methanol or isopropanol. In another embodiment, the methylselenolate salt is dissolved in solvent comprising methanol and added to the intermediate reaction product (Formula II), which is suspended in solvent comprising ethanol.

[0085] In one embodiment, the intermediate reaction product (Formula II) is reacted with methylselenol at a temperature and time sufficient for the reaction to produce an L- selenom ethionine (Formula III) product. In one embodiment, the intermediate reaction productDocket No.: 1022.551WO1(Formula II) is reacted with methylselenol under an inert atmosphere. In another embodiment, the inert atmosphere comprises a gas selected from nitrogen and argon.

[0086] In one embodiment, the reaction of step (b) is at a temperature from about 0°C to about 100°C. In another embodiment, the reaction temperature is from about 20°C to about 100°C. In another embodiment, the reaction temperature is from about 25°C to about 80°C. In another embodiment, the reaction temperature is from about 30°C to about 60°C. In another embodiment, the reaction temperature is from about 40°C to about 50°C. In another embodiment, the minimum reaction temperature is at least about 20, 25, 30, 35, 40°C or more. In another embodiment, the maximum reaction temperature is at most about 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45°C or less.

[0087] In one embodiment, the reaction of step (b) is performed wherein the methylselenol is added in equal molar amounts with the intermediate reaction product (Formula II). In another embodiment, a methylselenolate salt is added in excess amounts to intermediate reaction product (Formula II). In another embodiment, the methylselenolate salt is added in an amount of from about 2: 1 to about 1 : 1 ratio to intermediate reaction product (Formula II). In another embodiment, the methylselenolate salt is added in an amount of from about 1.5:1 to about 1.1 : 1 ratio to intermediate reaction product (Formula II). In another embodiment, the methylselenolate salt is added in an amount of 1.2: 1 ratio to intermediate reaction product (Formula II).

[0088] In one embodiment, the reaction of step (b) is for a time from about 1 hour to about 18 hours. In another embodiment, the reaction time is from about 1 hour to about 12 hours. In another embodiment, the reaction time is from about 2 hour to about 10 hours. In another embodiment, the reaction time is from about 3 hour to about 8 hours. In another embodiment, the reaction time is from about 5 hour to about 7 hours. In another embodiment, the minimum reaction time is at least about 0.1, 0.5, 1, 2, 3, 4, 5 hours or more.

[0089] In one embodiment, the reaction of step (b) is by addition of methylselenol to the intermediate reaction product (Formula II) at a controlled rate. In another embodiment, the reaction of step (a) is by addition of methylselenolate salt to intermediate reaction product (Formula II) at a rate of from about 0.01 to about 0.5 moles methylselenolate salt / minute / moles intermediate reaction product (Formula II). In another embodiment, the reaction of step (a) is by addition of methylselenolate salt to intermediate reaction product (Formula II) at a rate of from about 0.02 to about 0.2 moles methylselenolate salt / minute / moles intermediate reaction product (Formula II). InDocket No.: 1022.551WO1 another embodiment, the reaction of step (a) is by addition of methylselenolate salt to intermediate reaction product (Formula II) at a rate of from about 0.05 to about 0.2 moles methylselenolate salt / minute / moles intermediate reaction product (Formula II).

[0090] In one embodiment, after the reaction of step (b) by addition of methylselenol to the intermediate reaction product (Formula II) at a controlled rate and at a temperature and time sufficient for the reaction to produce an L-sel enomethionine (Formula III) product, the temperature of the reaction mixture produced is lowered. In one embodiment, the reaction mixture produced is lowered to a temperature of 30, 29, 28, 27, 26, 25, 24, 23, 22°C or less. In another embodiment, the reaction mixture produced is lowered to a temperature of 22°C or less. In another embodiment, the reaction mixture produced is lowered to a temperature of less than 25°C and greater than 15°C. In another embodiment, the reaction mixture produced is lowered to a temperature of less than 22°C and greater than 15°C. In another embodiment, the reaction mixture produced is lowered to a temperature wherein side reactions are minimized. In another embodiment, the reaction mixture produced is lowered to a temperature of about 20°C to about 25°C.

[0091] In one embodiment, after the reaction of step (b) by addition of methylselenol to the intermediate reaction product (Formula II) at a controlled rate and at a temperature and time sufficient for the reaction to produce an L-selenomethionine (Formula III) product, the reaction mixture is quenched. In one embodiment, the reaction mixture is quenched by the addition of a chemical quencher. In one embodiment, the chemical quencher or quenching agent is one or more compounds selected from a group consisting of nitro groups, sulfides, halides, amines, ketones, aldehydes, polar organic acids, esters, water, alcohols, ethers, and other hydrocarbons. In another embodiment, the chemical quencher or quenching agent is one or more compounds selected from a group consisting of nitromethane, diethyl sulfide, chloroform, 2-methoxyethylamine, acetone, acetaldehyde, acetic acid, ethyl acetate, water, ethanol, isopropanol, diethyl ether, and hexane. In another embodiment, the chemical quencher is an organic acid. In another embodiment, the chemical quencher is acetic acid. In another embodiment, the chemical quencher is glacial acetic acid.

[0092] In one embodiment, after the reaction of step (b) by addition of methylselenol to the intermediate reaction product (Formula II) at a controlled rate and at a temperature and time sufficient for the reaction to produce an L-selenomethionine (Formula III) product, the pH of the reaction mixture is adjusted. In one embodiment, the pH is adjusted to a pH value from about 4 toDocket No.: 1022.551WO1 about 7. In another embodiment, the pH value is adjusted to a pH value from about 5 to about 6. In another embodiment, the pH is adjusted to a pH value at least 4.5, 4.6, 4.7, 4.8, 4.9, 5 or more. In another embodiment, the pH is adjusted to a pH value at most 7, 6.9, 6.8, 6.7, 6.6, 6.5, 6.4, 6.3, 6.2, 6.1, 6 or less.

[0093] In one embodiment, after the reaction of step (b) by addition of methylselenol to the intermediate reaction product (Formula II) at a controlled rate and at a temperature and time sufficient for the reaction to produce an L-selenom ethionine (Formula III) product, the L- selenomethionine (Formula III) is collected. In one embodiment, the L-selenomethionine (Formula III) is collected by filtering. In one embodiment, the L-selenomethionine (Formula III) is dried acter collecting.

[0094] In one embodiment, the method of the present invention is a method for synthesizing for L-selenomethionine comprised of the following steps: a. reacting L- methionine with methyl iodide in a solvent at a temperature and for time sufficient for the reaction to produce an intermediate reaction product, wherein the solvent is water, ethanol, methanol, or mixtures thereof; b. collecting the intermediate reaction product and washing with one or more polar organic solvents; c. reacting the collected intermediate reaction product with methylselenol or its salts under an inert atmosphere at a temperature and for time sufficient for the reaction to produce an L-selenomethionine reaction product; d. lowering the temperature of the L-selenomethionine product mixture to a temperature from about 15°C to about 25°C; e. quenching the L-selenomethionine reaction product with a chemical quencher; f. adjusting the solution to a pH from about 5 to about 6; and g. collecting the L-selenomethionine.

[0095] In one embodiment, the one or more polar organic solvents is selected from the group consisting of acetic acid, acetone, acetonitrile, dimel thy 1 sulfoxide (DMSO), dimethylformamide (DMF), ethanol, ethyl acetate, formic acid, isopropanol, methanol, n-butanol, n-propanol, nitromethane, propylene carbonate, tetrahydrofuran, water, and combinations thereof.

[0096] In one embodiment, the chemical quencher or quenching agent is one or more compounds selected from a group consisting of nitro groups (nitromethane), sulfides (diethylDocket No.: 1022.551WO1 sulfide), halides (chloroform), amines (2-methoxyethylamine), ketones (acetone), aldehydes (acetaldehyde), organic acids (acetic acid), esters (ethyl acetate), water, alcohols (ethanol), ethers (diethyl ether), and other hydrocarbons (hexane). In another embodiment, the chemical quencher is an organic acid. In one embodiment, the chemical quencher is acetic acid.

[0097] Examples

[0098] In one example embodiment, the first step in the manufacturing process starts with suspending L-methionine in water by stirring until an aqueous solution is formed. After dissolving, methyl iodide is added at a proprietary rate at room temperature and subsequently heated to about 40°C for approximately 4 hours. The reaction is carried out according to the temperature. After the reaction is completed, it is filtered, and the filter cake is washed with water to obtain a white intermediate product. The yield is calculated after washing the filter cake, which is greater than 90, 92, 94, 95, 96, 97, or 98%. The purity of the intermediate is checked using a bespoke HPLC technique and the purity of the intermediate is greater than 90, 92, 94, 95, 96, 97, 98, 99% at this stage.

[0099] In one example embodiment, the second step of the manufacturing process the intermediate is dissolved in a high purity grade ethanol under blanket nitrogen of a high purity grade. Sodium selenium methoxide, which is also dissolved in a high purity grade of methanol is added to the ethanolic solution of the intermediate at a proprietary rate and then reacted at 45°C + / - 3° for 6 hours. The reaction mixture temperature is subsequently dropped to 20°C + / - 3°C. The reactant mixture is then quenched with glacial acetic acid. The pH value of the system is adjusted to 5-6. The final product is filtered and dried to obtain L-selenomethionine. The yield is calculated and is greater than 90, 92, 94, 95, 96, 97, 98, or 99%. The purity of the sample is checked using HPCL technique known to those well versed in the art and found to be greater than 90, 92, 94, 95, 96, 97, 98, or 97%. Residual alcoholic solvents are measured using bespoke HPLC techniques during the drying process to ensure the purity of the L-SeMet product.

[0100] In another inventive embodiment, the low or no malodor L-SeMet is determined by a) mass spectroscopy analysis and an olfactory panel.

[0101] In one or more embodiments, the present invention provides for animal feeds and supplements and particularly to animal feeds and supplements containing a formulation of the resulting L-selenomethionine compound created by the methods of the present invention aboveDocket No.: 1022.551WO1 and a carrier. Methods of making supplemented animal feed are described in, for example, U.S. Pat Publ. Nos. 20220409644, 20190262381, and 20180014557.

[0102] In one or more embodiments, the carrier is selected from the group consisting of amylose, amylopectin, corn starch, potato starch, Tapioca starch, rice starch, wheat starch, arrowroot starch, cassava starch, sweet potato starch, barley starch, oat starch, rye starch, sorghum starch, millet starch, glucose, fructose, galactose, sucrose, lactose, maltose, dextrose, ribose, xylose, mannose, arabinose, trehalose, sorbital, maltitol, lignosulfonates,, maltodextrin, cyclodextrin, amylodextrin, achrodextrin, limit dextrin, white dextrin, British gum 1-7, and mixtures thereof.

[0103] In one or more embodiments, the feed additive admixture is present such that the L- selenomethionine compound is no more than 0.3 mg per kg in the total feed composition.

[0104] REFERENCES

[0105] Assmann, A., Briviba, K., & Sies, H. (1998). Arch. Biochemistry Biophysics, 349, 201- 203.

[0106] Blau, M. (1961). Biochim. Biophys. Acta , 49, 389 .

[0107] Boehm, M. F., & Bada, J. L. (1985). The racemization rate of selenomethionine and methionine in yeast at 100 C and neutral pH. Anal. Biochem. , 145, 273-276.

[0108] Chiao, J. S., & Peterson, W. H. (1953). Yeasts: methionine and cystine contents. Agric. Food Chem. Agric. Food Chem., 1(15), 1005-1008.

[0109] Committee on Animal Nutrition. (1983). Selenium in Nutrition. Washington DC: National Academies Press.

[0110] EFSA. (2009). L-sel enomethionine: A source of Selenium added for nutritional purposes. European Journal of Feed Safety, 1082, 1-39.

[0111] Expert Group on Vitamins and Minerals. (2003). UK: http: / / www.food.gov / multimedia / pdfs / vitamin2003.pdg.

[0112] Food and Nutrition Board. (2000). Dietary reference Intakes for Vitamin C, E, Selenium and Carotenoids. Washington, DC: National Academy Press.

[0113] Klosterman, H. J., & Painter, E. P. (1947). An improved synthesis of the selenium analog of methionine and homocystine. J. Am. Chem. Soc. , 69, 2009-2010.

[0114] Koch, T., & Buchardt, O. (1993). Synthesis of L(+)-Selenomethionine. Synthesis, November, 1065-1067.Docket No.: 1022.551WO1

[0115] Mony, M. C. (2000). Journal of Trace Elements in Experimental Medicine, 13, 367- 380.

[0116] Painter, E. P. (1947). Journal of the American Chemical Society, 69, 232.

[0117] Plieninger, H. (1950). Chem. Ber., 83, 265.

[0118] Power, R. (1994). Selenium enriched yeast: form and applications. . Proc. STDA 5th IntematL Symp. (pp. pp. 89-94156). May 8-10. Brussels: STDA.

[0119] Rayman, M. P. (2004). The Use of High Selenium Yeast to Raise the Selenium Status: How does it measure up? British Journal of Nutrition, 92, 557-573.

[0120] Rayman, M. P., Infante, H. G., & Sargent, M. (2008). Food-chain selenium and human health: spotlight on speciation. British Journal of Nutrition, 100„ 238-253.

[0121] Schrauzer, G. N. (1998). Characterization of selenium yeasts for nutritional selenium supplementation. Proc. Sixth Internatl. Symp. on the Uses of Selenium and Tellurium” (Y. Palmieri, ed.), May, 77-79.

[0122] Schrauzer, G. N. (2000). Selenomethionine: A Review of Its Nutritional Significance, Metabolism and Toxicity. Journal of Nutrition, 130, 7, 1653-1656.

[0123] Schrauzer, G. N. (2001). Nutritional Selenium Supplements: Product Types, Quality, and Safety. J. Am. Coll. Nutrit.,, 1-4.

[0124] Schrauzer, G. N. (2003). The nutritional significance, metabolism and toxicology of selenomethione. Adv Food Nutr Res., 47, 73-112.

[0125] Schrauzer, G. N. (2006). Selenium yeast: Composition, quality, analysis, and safety. Journal of Pure Appl. Chemistry, 78, 1, 105-109.

[0126] Schrift, A. (1969). Aspects of Selenium Metabolism in Higher Plants. Annual Review of Plant Physiology, 20: 475-494.

[0127] Scientific Committee on Food. (1993). Nutrient and Energy Intakes for European Community . Luxembourg: Reports for the Scientific Committee on Food.

[0128] Shepherd, L., & Huber, R. E. (1969). Some chemical and biochemical properties of selenomethionine. Can. J. Biochem., 47, 877-881.

[0129] Sliwkowski, M. X. (1984). 1984. Characterization of selenomethionine in proteins. . Methods Enzymol., 107, 620-623.

[0130] While the disclosure has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made, and equivalentsDocket No.: 1022.551WO1 may be substituted for elements thereof without departing from the scope of the disclosure. In addition, many modifications may be made to adapt a particular system, device or component thereof to the teachings of the disclosure without departing from the essential scope thereof. Therefore, it is intended that the disclosure is not limited to the particular embodiments disclosed for carrying out this disclosure, but that the disclosure will include all embodiments falling within the scope of the appended claims. Moreover, the use of the terms first, second, etc. do not denote any order or importance, but rather the terms first, second, etc. are used to distinguish one element from another.

[0131] The description of the present disclosure has been presented for purposes of illustration and description but is not intended to be exhaustive or limited to the disclosure in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope of the disclosure. The described embodiments were chosen and described in order to best explain the principles of the disclosure and the practical application, and to enable others of ordinary skill in the art to understand the disclosure for various embodiments with various modifications as are suited to the particular use contemplated.

Claims

1. Docket No.: 1022.551WO1CLAIMSWhat is claimed is:

1. A synthetic method for L-selenomethionine comprised of the following steps: a. reacting L- methionine with methyl iodide in a solvent at a temperature and for time sufficient for the reaction to produce an intermediate reaction product (Formula II), wherein the solvent is water, ethanol, methanol, or mixtures thereof; b. collecting the intermediate reaction product and washing with one or more polar organic solvents; c. reacting the collected intermediate reaction product with methylselenol or its salts under an inert atmosphere at a temperature and for time sufficient for the reaction to produce an L-selenomethionine reaction product; d. lowering the temperature of the L-selenomethionine product mixture to a temperature from about 15°C to about 25°C; e. quenching the L-selenomethionine reaction product with a chemical quencher; f. adjusting the solution to a pH from about 5 to about 6; and g. collecting the L-selenomethionine.

2. The method of claim 1, wherein the resulting L-selenomethionine has low malodor or is substantially free of malodor.

3. The method of claim 1, wherein the temperature of step (a) is between 22°C and 100°C.

4. The method of claim 1, wherein addition of methyl iodide to L-methionine is at a rate of between 10 mls / hour and 100 mls / hour.

5. The method of claim 1, wherein addition of methylselenol or its salts to the intermediate reaction product is at a rate of between 10 mls / hour and 100 mis per hour.

6. The method of claim 1, wherein the one or more polar organic solvents is selected from the group consisting of acetic acid, acetone, acetonitrile, dimelthylsulfoxide (DMSO), dimethylformamide (DMF), ethanol, ethyl acetate, formic acid, isopropanol, methanol, n- butanol, n-propanol, nitromethane, propylene carbonate, tetrahydrofuran, water, and combinations thereof.Docket No.: 1022.551WO17. The method of claim 1, wherein the reaction temperature of step (c) is greater than about 40°C and less than about 45°C.

8. The method of claim 1, wherein the reaction time of step (c) is from about 5 to about 7 hours.

9. The method of claim 1, wherein the inert atmosphere comprises a gas selected from nitrogen and argon.

10. The method of claim 1, wherein the chemical quencher is a polar organic acid.

11. The method of claim 1, wherein the chemical quencher is acetic acid.

12. A composition comprising low malodor or substantially free of malodor L- selenomethionine produced by a process comprising: a) reacting L-methionine with methyl iodide in a solvent selected from the group consisting of water, ethanol, methanol, and mixtures thereof, at a temperature and for a time sufficient to form an intermediate reaction product of Formula II; b) collecting the intermediate reaction product and washing it with one or more polar organic solvents; c) reacting the collected intermediate reaction product with methylselenol or a salt thereof under an inert atmosphere at a temperature and for a time sufficient to form an L- selenomethionine reaction product; d) lowering the temperature of the L-selenomethionine reaction product mixture to a temperature from about 15°C to about 25°C; e) quenching the L-selenomethionine reaction product with a chemical quencher; f) adjusting the solution to a pH from about 5 to about 6; and g) collecting the L-selenomethionine.

13. A feed additive admixture comprising a mixture of the composition of Claim 12 and a carrier.Docket No.: 1022.551WO114. The feed additive admixture of claim 13, wherein the carrier is selected from the group consisting of amylose, amylopectin, corn starch, potato starch, Tapioca starch, rice starch, wheat starch, arrowroot starch, cassava starch, sweet potato starch, barley starch, oat starch, rye starch, sorghum starch, millet starch, glucose, fructose, galactose, sucrose, lactose, maltose, dextrose, ribose, xylose, mannose, arabinose, trehalose, sorbital, maltitol, lignosulfonates,, maltodextrin, cyclodextrin, amylodextrin, achrodextrin, limit dextrin, white dextrin, British gum 1-7, and mixtures thereof.

15. The feed additive admixture of claim 13, further comprising silage.

16. The feed additive admixture of claim 15, further comprising premix.

17. The feed additive admixture of claim 15, wherein the feed additive is present such that no more than 0.3 mg of Selenium per kg is present in the total feed composition.

18. The feed additive admixture of claim 15, wherein the feed additive admixture is present from such that no more than 0.3 mg per kg in the total feed composition.

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