Title of Invention	A PROCESS FOR PREPARATION OF A METASTABLE MAGNESIUM CITRATE MALATE COMPLEX
Abstract	The present invention discloses a process for the preparation of a metastable magnesium citrate mala te complex by preparing a solution of citric acid and malic acid in water and to this solution adding a magnesium source at a temperature in the range of 30 to 80°C to obtain a neutralized solution of magnesium citrate malate, adding a suitable adsorbent to thke neutralized solution of magnesium citrate malate to obtain a colourless solution of magnesium citrate malate, isolating metastable magnesium citrate malate from said colourless solution to obtain a metastable magnesium citrate malate complex. The metastable magnesium citrate malate complex is used for tabletting, filling in capsules, gels, solutions and for fortification of food and beverages without imparting off flavours.

Title of Invention

A PROCESS FOR PREPARATION OF A METASTABLE MAGNESIUM CITRATE MALATE COMPLEX

Abstract

The present invention discloses a process for the preparation of a metastable magnesium citrate mala te complex by preparing a solution of citric acid and malic acid in water and to this solution adding a magnesium source at a temperature in the range of 30 to 80°C to obtain a neutralized solution of magnesium citrate malate, adding a suitable adsorbent to thke neutralized solution of magnesium citrate malate to obtain a colourless solution of magnesium citrate malate, isolating metastable magnesium citrate malate from said colourless solution to obtain a metastable magnesium citrate malate complex. The metastable magnesium citrate malate complex is used for tabletting, filling in capsules, gels, solutions and for fortification of food and beverages without imparting off flavours.

Full Text	Field of the Invention The present invention relates to pro cess for preparation of a metastable magnesium citrate malate complex having better solubility and bioavailability. Background and Prior Art Magnesium is a mineral that is neede d in humans and other warm-blooded animals for bone, protein, and fatty acid fonnatiom. Magnesium is also involved in the formation of new cells, activating certain vitamins, relaxing muscles, clotting blood, and forming ATP. People with diabetes often have magnesium levels that are lower than normal compared with those who have normal glucose tolerance. Supplementation of magnesium can help maintain healtli, as well as help in overcoming some of the problems in clotting blood, relaxing muscles, etc. Typically, many people do not consume enough magnesium in their diet. Choosing a form of magnesium for supplementation has been a source of some confusion in the industry. Magnesium is an extremely important and valuable mineral, whose value for good health is just being recognized by conventional physicians. Virtually, all chemical reactions in the body require an enzyme system to promote the biochemical reactions that take place. An enzyme system generally consists of three parts. They are a specific protein molecule, another smaller organic compound, vwhich is often a vitamin, such as pyridoxine or vitamin B6, and finally a charged mineral, such as zinc, copper, manganese or magnesium. Magnesium is an important co-factor in more than 300 enzymatic reactions in the human body. The recommended daily allowance (RDA) for magnesium is 350 milligrams of elemental magnesium. Usually the elemental content in existing magnesium salts is low and there is a need for a product having high elemental content. Therefore a magnesium salt/complex vwhich is readily bioavailable and which is highly soluble in neutral solutions as well as acidic solutions is highly desirable. This would allow the magnesium salt/complex to be added to neutral as well as acid foods in a soluble form and to be an effective supplement. Although known inorganic salts of magnesium have excellent solubility but none of them are absorbed in the body via passive diffusion and require an active transport mechanism. Thus organic mineral salts are proved efficacious over the inorganic salts. It is therefore an object of this invention to produce a magnesium citrate malate complex which is readily soluble in water. The preferred acids are chosen from the group of edible acids like malic acid and citric acid. iviain; atiu vnyoroxysiiccmic acia> is an alpha-hydroxy organic acid that is sometimes referred to as a fruit acid. Malic acid is a tart-tasting organic dicarboxylic acid that plays a role in many sour or tart foods. In its ionised form it is malate, an intermediate of the TCA cycle along with fumarate. It can also be formed from pyruvate as one of the anaplerotic reactions. Apples contain malic acid, which contributes to the sourness of a green apple. Malic acid is a key intermediate in the major biochemical energy-producing cycle in cells known as the citric acid or Krebs cycle located that takes place in the cells' mitochondria in most living organisms. Citric acid (2-Hydroxy-l,2,3-propanetricarboxylic acid) is a weak organic acid found in citrus fruits. It is a natural preservative and is also used to add an acidic (sour) taste to foods and soft drinks. In biochemistry, it is important as an intermediate in the citric acid cycle and therefore occurs in the metabolism of almost all living things. It also serves as an antioxidant. Citric acid exists in a variety of fruits and vegetables, but it is most concentrated in lemons, where it can comprise as much as 8% of the dry weight of the fruit. Citric acid is recognized as safe for use in food by all major national and international food regulatory agencies. It is naturally present in almost all forms of life, and excess citric acid is readily metabolized and eliminated from the body .Citrate is a naturally occurring substance in the body, a metabolic product formed at the beginning of the energy cycle. During the tricarboxylic acid cycle, carbohydrates, fatty acids and proteins are broken down to provide energy. Citrate being an "energy rich" moiety, helps to deliver the associated "mineral" nutrients and ensures its ready availability for absorption in the system. Inorganic magnesium salts taken up from the soil by the plants are converted into complex organic compounds, which contain citrate in particular. Nothing can be more natural than to select a magnesium source of food fortification which is ingested naturally with plant -based foods, thus only the part which nature can no longer provide, under the circumstances, is supplemented as magnesium citrate malate. Various patents describe fonnation of metastable complexes. US 4599152 discloses electrolytic methods for preparing anion free amino acid chelates. US 6706904 describes a procedure for making Dimetalhydroxy malate compositions. Many of the proceduies that have been described appear to be concerned with the formation of stable chelates, and metastable complexes of calcium citrate malate have also been described in US 5186965. US6569477 explains methods of making highly soluble and stable mineral supplements containing calcium and magnesium. In US6616955 beverage compositions comprising palatable calcium and magnesium sources and formation of in situ calcium and magnesium salts are described. This patent discloses many magnesium salts but none of them is isolated. Moreover, the above patent application discloses the insitu formation of a magnesium citrate malate complex in the beverage composition, where many components are also present. Also, the product claimed is not isolated in solid form and its physico-chemical properties are not studied. While US4551342 describes beverages containing specific cation-edible acid mixtures for improved flavor impression. Another US6261610 discloses calcium-magnesium fortified water, juices beverages and other liquid food products and process of making. US 5939394, US5922765, US5871769 and US5843996 relate to methods and compositions for prevention and treatment of immunological disorders, improving muscular strength, diabetes mellitus and oxidative stress conditions respectively using magnesium gluconate. Various methods disclosed focus mainly on calcium salts and whereas there is a need for further improvements in methods of making magnesium metastable complexes which are soluble and are cost effective. Objects of the Invention Accordingly, the primai-y object of the present invention is to provide a process for preparation of a metastable magnesium citrate malate complex wherein magnesium source is completely reacted with citric acid and malic acid. An object of the piesent invention is to provide a process wherein a metastable magnesium citrate malate complex is obtained at a temperature from 60 to 70°C. Another object of the process is to provide a process wherein the metastable magnesium citrate malate complex obtained is free firom magnesium citrate, magnesium malate and other inorganic impurities. Summary of the Invention The present invention provides a process for preparation of a metastable magnesium citrate malate complex by preparing a solution of citric acid and malic acid in water and to this solution adding a magnesium source at a temperature in the range of 30 to 80°C to obtain a neutralized solution of magnesium citrate malate, adding a suitable adsorbent to the neuiralized solution of magnesium citrate malate to obtain a colourless solution of magnesium citrate malate, isolating metastable magnesium citrate malate from said colourless solution to obtain a metastable magnesium citrate malate complex. Detailed Description of tlie Invention Accordingly, the present invention provides a process for the preparation of a metastable magnesium citrate malate complex, said process comprising the steps of: preparing a solution of citric acid and malic acid in water; adding a magnesium source to the said solution at a temperature in the range of 30 to 80°C to obtain a neutralized solution of magnesium citrate malate; adding an adsorbent to the neutralized solution of magnesium citrate malate to obtain a colourless solution of magnesium citrate malate; and isolating metastable magnesium citrate malate from said colourless solution to obtain a metastable magnesium citrate malate complex. The process steps for the preparation of metastable magnesium citrate malate complex of the present invention are depicted in the following Scheme I. The magnesium citrate malate refers to a metastable mineral complex of magnesium carbonate, citric acid and malic acid. Magnesium citrate malate is isolated at a metastable stage delicately maintaining the balance between temperature, pressure and other reaction conditions. Thus soluble magnesium citrate malate is obtained only at a particular stage in the process. Magnesium citrate malate is highly soluble and therefore is better absorbed in the system and thus has high efficacy. As used herein, the temi "malic acid" refers to the mixture of the D and the L isomers, i.e. malic acid is optically active and the racemic mixture is used herein. D-malic acid and L-malic acid can be used. As used herein the term "metastable" means that the material is not at equilibrium, and is a mixture of various fomis with longer shelf life. While the reaction kinetics would indicate that the magnesium neutralizes all of the acid groups of citric and malic acid and equilibrium is established between the salts and, when prepared by the proc ess herein, a complex salt is formed. This complex salt is distinct from pure magnesium citrate or pure magnesium malate or simple mixtures thereof The magnesium citiate malate of present invention can exist in several states of hydration with from 1 to 5 water molecules. This complex is thermodynamically an intermediate complex formed in the preparation of a dry fonn. The physical and chemical data of these salts are consistent with the theory that there are non-crystalline regions within the powdered material which can hydrate to the point of behaving like a solution. It is important for the solubility characteristics of the magnesium citrate malate that the apparent metastable structure be achieved. Magnesium malate has a solubility of 10% on boiling and magnesium citrate is nearly insoluble even at boiling conditions. Magnesium citrate malate of the present invention has a solubility of 30% at room temperature. Thus it is a soluble and highly acceptable form. The magnesium citrate malate is prepared by dissolving malic acid and citric acid in purified water and adding a magnesium source selected from magnesium oxide, magnesium hydroxide and mag;nesium carbonate, as a powder or as aqueous slurry, to the aqueous solution of citric acid and malic acid in the molar ratio necessary to make the desired magnesium citrate malate material. When magnesium carbonate is used, carbon dioxide evolves and the magnesium carbonate is neutralized by the citric and malic acid. The magnesium citrate malate is free from magnesium citrate, magnesium malate and other inorganic impurities such as inorganic salts of magnesium. It is preferable that tiie magnesium source is added to the solution of citric acid and malic acid. A solid is fonned during the mixing of magnesium oxide or magnesium hydroxide with the citric acid and malic acid. When these magnesium sources are used, it is necessary to mix the solution until all of the magnesium appears to have dissolved. The preferred method of preparation is to prepare a highly concentrated aqueous solution of the magnesium citrate malate which quickly and efficiently forces metastable magnesium citrate malate out of solution. Concentrations of from 20% to 75% (weight of reactants) in water are preferred. More preferably the concentration is from 40% to 65%. Activated charcoal is added to get a clear solution. The subsequent mixture is filtered to remove the activated charcoal. The reaction temperature can be ambient (20°C) or higher. Preferably the temperature of the reaction is in the range of 30 to 80°C. Most preferably it is from 60 to 70°C. This mixture is further dried preferably by spray or vacuum drying. Drying is carried out below 90°C in order to prevent decomposition of the formed metastable magnesium citrate malate. Preferably, when using vacuum air drying, the drying is accomplished on a thin layer of product between 60 and 90°C. In spray drying, the solution mixture is sprayed into a hot air column at 60 to 90°C. The material is preferably dried until the amount of free or unbound water is less than 10%. When vacuum air drying is used, the dried material is ground using any conventional grinding equipment and then sieved to a variable particle size which is useful for food and beverage fortification and for tabletting or filling in capsules. The ratio of magnesium to citric acid to malic acid in the final product will depend upon the reactants used. Generally, the preparation of this material starting with pure magnesium carbonate, citric acid and malic acid and drying the entire solution will produce a magnesium citrate malate complex of the same ratio of the materials mixed. Molar ratios of magnesium, citric acid and malic acid used are 5:2:2, 4:2:1 and 6:2:3. The exact formula lor the complex can be derived by measuring the percent of magnesium in the said complex. The metastable magnesium citrate malate complex represents a soluble form of magnesium which is more soluble than inorganic magnesium salts and magnesium citrate and magnesium malate. The process can be used to make a variety of magnesium citrate malate complexes which have higher solubilities and neutral taste. The enhanced solub ility of these salts is unexpected since one would not expect the anions and the ratio of magnesium to anions to play such a key role in solubility. An embodiment of tlie process of the present invention wherein the molar ratio of citric acid is from I to 2, the molar ratio of malic acid is from 1 to 3, and the molar ratio of magnesium is from 4 to 6. It is an embodiment of the process of the present invention wherein the magnesium source is selected from the group consisting of magnesium carbonate, magnesium oxide or magnesium hydro xide. It is also an embodiment of the process of the present invention wherein the magnesium source is magnesium carbonate. Another embodiment of the process of the present invention wherein the citric acid is added simultaneously with the magnesium source to malic acid in water. Yet another embodi ment of the process of the present invention wherein the molar ratios of the magnesium, citric acid and malic acid are 4:2:1, 5:2:2, and 6:2:3. Still another embodiment of the process of the present invention wherein the addition of magnesium source to the solution of citric acid and malic acid is carried out at a temperature in the range of 60 to 70°C. It is also an embodiuient of the process of the present invention wherein the adsorbent used to remove colour impurities is an activated charcoal. It is an embodimen t of the process of the present invention wherein the metastable magnesium citrate malate has a neutral taste. From the description, one skilled in the art can easily ascertain that the invention may be performed within a wide and equivalent range of conditions, without departing from the spirit or scope o f invention and embodiments thereof. It is intended that all matter contained in the description above shall be interpreted as illustrative and not in a limiting sense. Moreover, other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. Meta stable Magnesium Citrate Malate Further, the following examples are illustrative caf the present invention and should not be construed as limiting the scope of the inventioni in any manner. Example L 850 g of citric acid and 298 g of malic acid are dissolved in 2 L of purified water at ambient temperature and 885 g of magnesium c arbonate are added in small quantities to the reaction mass at 30-95°C, most preferably at 60-80°C, followed by the addition of activated charcoal to remove impurities. The reaction mixture is filtered to remove activated charcoal. The filtrate is spray dried at appropriate conditions to obtain about 1445.0 g of white crystalHne powder of nxetastable magnesium citrate malate, containing about 12.4% magnesium content on dried basis. The product has melting point of above 350"C and is freely soluble in water and the product obtained is highly stable at ambient conditions. Further, the product is characterized by XRD and FTIR studies. The resultant spectra are attached herewi th. The MCM product is usually made with varied ratios of citric acid and malic acid, so as to get the product with desired solubility, stability and magnesium contents, which is usually based on the end-user requirements. Example-2 gives one such composition. Example 2 192 g of citric acid and 202.5 g of malic acid are dissolved in 1 L of purified water at ambient temperature and 300 g of magnesium carbonate are added to the solution followed by activated charcoal to remove impurities. The reaction mixture is filtered to remove activated charcoal. The Tiltrate is spray dried at 85°C to obtain metastable magnesium citrate malate. Example 3 The metastable magnesium citrate malate is prepared by dissolving 8.5 kg of citric acid and 6kg of malic acid to purified water around 45 L at ambient temperature and 12.0 kg of magnesium carbonate are added in small quantities to the reaction mass at 30-95°C, most preferably at 60-80°C, under vigorous agitation, followed by the addition of activated charcoal to remove impurities. The reaction mixture is filtered to remove activated charcoal. The filtrate is spray dried at 85-90'C inlet temperature to get 13.5 kg of white crystalline powder of metastable magnesium citrate malate, containing about 12.6% magnesium content 03 dried basis. The product has melting point of above 350*'C and is freely soluble in water and the product obtained is highly stable at ambient conditions. Example 4 The metastable magnesium citrate malate is prepared by dissolving 4.25 kg of citric acid and 4.5 kg of malic acid to purified water around 25 L and adding 7.1 kg of magnesium carbonate. The output of magnesium citrate malate is 7.5 kg. As nutrient composition: Example 5 50 mg of citric acid and 30 mg of malic acid are subjected to grinding and blended. Then blended with 2.1g of magnesium citrate malate in parts 30mg of sucralose is added as sweetener, colour and orange flavour for taste. The composition produced is added to a glass of water and is a ready to drink beverage. Each dose is given in a sachet. It provides 350 mg of elemental magnesium per serving which is 100% of RDA in a single dosage. Thus composition is suitable as a supplement in magnesium deficiency. As nutrient additive: Example 6 Fortification of juice with magnesium citrate malate is suitable as it has high solubility, thus a clear solution is obtained. Apple juice 200ml fortified with 2g of magnesium citrate malate provides in one serving of 200 ml of juice 300mg of elemental magnesium. The apple juice is neutral in taste with no off flavours. It provides approximately 100% RDA of magnesium in a single serving. Example 7 2g of magnesium citrate malate added to 1 litre of milk is neutral in taste and stable after pasteurization when a sequestering agent like tripotassium citrate is added at 0.2% concentration. Determination of Magnesium Content is performed by Complexometric Titration: ASSAY 0.3g of magnesium citrate malate is dissolved in water (or in dil.HCl) and diluted to 100 ml with the same solvent. 10 ml of ammonia-ammonium chloride buffer and 50mg of Eriochrome Black T indicator are added and titrated against 0.05M Disodium salt of EDTA. The end point is indicated by a colour change of the solution from pink to blue. 1 ml of 0.051VI Disodium salt of EDTA is equivalent to 0.01215g of Mg^"". Determination of citric acid and malic acid Citric acid and malic acid are determined by HPLC using the following conditions: Column CI8 reversed phase (4.6 x 100mm) Detection UV at 206nm Mobile Phase acetonitrile: 0.1 m diammonium hydrogen phosphate (3:97) Flow rate 1.0 ml/min Injection 10 microL Run time 10 min Retention time For Citric acid 3 min For Malic acid 3.5 min Method: Equal amounts of the sample solution and the calibration solution are separately injected into the chromatograph. The chromatograms are recorded and the responses of citric acid and malic acid peak are measured. The metastable magnesium citrate malate complex produced by the process of the present invention is an isolated solid powder, whose physico-chemical properties are well established from its melting range, XRD pattern, and IR spectrum. Therefore the product exliibits the following features- and finds uses in various applications. Advantages of the invented process and product: 1. The magnesium citrate malate complex of the present invention has increased solubility and hence increased bioavailability as compared to other magnesium salts like magnesium citrate, magnesium malate or a physical admixture of magnesium citrate and magnesium malate. 2. Since tlic magnesium citrate malate complex is highly soluble in water and hence it finds application in various beveiages and other liquid formulations whereas the magnesium citrate and magnesium malate are not suitable because of their insoluble nature. 3. The magnesium citrate malate complex has a neutral taste and thus is suitable for food fortification. 4. Magnesium citrate malate being highly soluble in water can provide 90% RDA in approximately 2 grams of a single dose. 5. The present invention provides a magnesium citrate malate complex with high magnesium content. 6. The present invention provides a pharmaceutical and food grade magnesium citrate malate complex. 7. The present invention provides a method for treating magnesium deficiency comprising administration to a patient in need of such treatment an effective amount of the metastable magnesLum citrate malate complex. 8. We claim: 1. A process for the preparation of a metastable magnesium citrate malate complex, said process comprising the steps of: a) preparing a solution of citric acid and malic acid in water; b) adding a magnesium source to the said solution at a temperature in the range of 30 to 80°C to obtain a neutralized solution of magnesium citrate malate; c) adding an adsorbent to the neutralized solution of magnesium citrate malate to obtain a colourless solution of magnesium citrate malate; and d) isolating metastable magnesium citrate malate from said colourless solution to obtain a metastable magnesium citrate malate complex. 2. The process as claimed in claim 1, wherein the molar ratio of citric acid is from 1 to 2, malic acid is from I to 3, and magnesium is from 4 to 6. 3. The process as claimed in claim 1, wherein the magnesium source is selected from the group consisting of magnesium carbonate, magnesium oxide or magnesium hydroxide. 4. The process as claimed in claim I, wherein the magnesium source is magnesium carbonate. 5. The process as claimed in claim 1, wherein the citric acid is added simultaneously with the magnesium source to malic acid in water. 6. The process as claimed in claim 1, wherein the molar ratios of the magnesium, citric acid and malic acid are 4:2:1, 5:2:2, and 6:2:3. 7. The process as claimed in claim 1, wherein the addition of magnesium source to the solution of citric acid and malic acid is carried out at a temperature in the range of 60 to 70°C. 8. The process as claimed in claim 1, wherein the adsorbent is an activated charcoal.

Full Text

Field of the Invention
The present invention relates to pro cess for preparation of a metastable magnesium citrate malate complex having better solubility and bioavailability. Background and Prior Art
Magnesium is a mineral that is neede d in humans and other warm-blooded animals for bone, protein, and fatty acid fonnatiom. Magnesium is also involved in the formation of new cells, activating certain vitamins, relaxing muscles, clotting blood, and forming ATP. People with diabetes often have magnesium levels that are lower than normal compared with those who have normal glucose tolerance. Supplementation of magnesium can help maintain healtli, as well as help in overcoming some of the problems in clotting blood, relaxing muscles, etc. Typically, many people do not consume enough magnesium in their diet. Choosing a form of magnesium for supplementation has been a source of some confusion in the industry. Magnesium is an extremely important and valuable mineral, whose value for good health is just being recognized by conventional physicians. Virtually, all chemical reactions in the body require an enzyme system to promote the biochemical reactions that take place. An enzyme system generally consists of three parts. They are a specific protein molecule, another smaller organic compound, vwhich is often a vitamin, such as pyridoxine or vitamin B6, and finally a charged mineral, such as zinc, copper, manganese or magnesium. Magnesium is an important co-factor in more than 300 enzymatic reactions in the human body.
The recommended daily allowance (RDA) for magnesium is 350 milligrams of elemental magnesium. Usually the elemental content in existing magnesium salts is low and there is a need for a product having high elemental content.
Therefore a magnesium salt/complex vwhich is readily bioavailable and which is highly soluble in neutral solutions as well as acidic solutions is highly desirable. This would allow the magnesium salt/complex to be added to neutral as well as acid foods in a soluble form and to be an effective supplement. Although known inorganic salts of magnesium have excellent solubility but none of them are absorbed in the body via passive diffusion and require an active transport mechanism. Thus organic mineral salts are proved efficacious over the inorganic salts. It is therefore an object of this invention to produce a magnesium citrate malate complex which is readily soluble in water. The preferred acids are chosen from the group of edible acids like malic acid and citric acid.

iviain; atiu vnyoroxysiiccmic acia> is an alpha-hydroxy organic acid that is sometimes referred to as a fruit acid. Malic acid is a tart-tasting organic dicarboxylic acid that plays a role in many sour or tart foods. In its ionised form it is malate, an intermediate of the TCA cycle along with fumarate. It can also be formed from pyruvate as one of the anaplerotic reactions. Apples contain malic acid, which contributes to the sourness of a green apple. Malic acid is a key intermediate in the major biochemical energy-producing cycle in cells known as the citric acid or Krebs cycle located that takes place in the cells' mitochondria in most living organisms.
Citric acid (2-Hydroxy-l,2,3-propanetricarboxylic acid) is a weak organic acid found in citrus fruits. It is a natural preservative and is also used to add an acidic (sour) taste to foods and soft drinks. In biochemistry, it is important as an intermediate in the citric acid cycle and therefore occurs in the metabolism of almost all living things. It also serves as an antioxidant. Citric acid exists in a variety of fruits and vegetables, but it is most concentrated in lemons, where it can comprise as much as 8% of the dry weight of the fruit. Citric acid is recognized as safe for use in food by all major national and international food regulatory agencies. It is naturally present in almost all forms of life, and excess citric acid is readily metabolized and eliminated from the body .Citrate is a naturally occurring substance in the body, a metabolic product formed at the beginning of the energy cycle. During the tricarboxylic acid cycle, carbohydrates, fatty acids and proteins are broken down to provide energy. Citrate being an "energy rich" moiety, helps to deliver the associated "mineral" nutrients and ensures its ready availability for absorption in the system.
Inorganic magnesium salts taken up from the soil by the plants are converted into complex organic compounds, which contain citrate in particular. Nothing can be more natural than to select a magnesium source of food fortification which is ingested naturally with plant -based foods, thus only the part which nature can no longer provide, under the circumstances, is supplemented as magnesium citrate malate. Various patents describe fonnation of metastable complexes.
US 4599152 discloses electrolytic methods for preparing anion free amino acid chelates.
US 6706904 describes a procedure for making Dimetalhydroxy malate compositions. Many of the proceduies that have been described appear to be concerned with the formation of stable chelates, and metastable complexes of calcium citrate malate have also been described in US 5186965.

US6569477 explains methods of making highly soluble and stable mineral supplements
containing calcium and magnesium.
In US6616955 beverage compositions comprising palatable calcium and magnesium
sources and formation of in situ calcium and magnesium salts are described. This patent
discloses many magnesium salts but none of them is isolated. Moreover, the above
patent application discloses the insitu formation of a magnesium citrate malate complex
in the beverage composition, where many components are also present. Also, the
product claimed is not isolated in solid form and its physico-chemical properties are not
studied.
While US4551342 describes beverages containing specific cation-edible acid mixtures
for improved flavor impression.
Another US6261610 discloses calcium-magnesium fortified water, juices beverages
and other liquid food products and process of making.
US 5939394, US5922765, US5871769 and US5843996 relate to methods and
compositions for prevention and treatment of immunological disorders, improving
muscular strength, diabetes mellitus and oxidative stress conditions respectively using
magnesium gluconate.
Various methods disclosed focus mainly on calcium salts and whereas there is a need
for further improvements in methods of making magnesium metastable complexes
which are soluble and are cost effective.
Objects of the Invention
Accordingly, the primai-y object of the present invention is to provide a process for
preparation of a metastable magnesium citrate malate complex wherein magnesium
source is completely reacted with citric acid and malic acid.
An object of the piesent invention is to provide a process wherein a metastable
magnesium citrate malate complex is obtained at a temperature from 60 to 70°C.
Another object of the process is to provide a process wherein the metastable
magnesium citrate malate complex obtained is free firom magnesium citrate,
magnesium malate and other inorganic impurities.
Summary of the Invention
The present invention provides a process for preparation of a metastable magnesium
citrate malate complex by preparing a solution of citric acid and malic acid in water and
to this solution adding a magnesium source at a temperature in the range of 30 to 80°C
to obtain a neutralized solution of magnesium citrate malate, adding a suitable

adsorbent to the neuiralized solution of magnesium citrate malate to obtain a colourless solution of magnesium citrate malate, isolating metastable magnesium citrate malate from said colourless solution to obtain a metastable magnesium citrate malate complex. Detailed Description of tlie Invention
Accordingly, the present invention provides a process for the preparation of a metastable magnesium citrate malate complex, said process comprising the steps of: preparing a solution of citric acid and malic acid in water; adding a magnesium source to the said solution at a temperature in the range of 30 to 80°C to obtain a neutralized solution of magnesium citrate malate; adding an adsorbent to the neutralized solution of magnesium citrate malate to obtain a colourless solution of magnesium citrate malate; and isolating metastable magnesium citrate malate from said colourless solution to obtain a metastable magnesium citrate malate complex.
The process steps for the preparation of metastable magnesium citrate malate complex of the present invention are depicted in the following Scheme I.

The magnesium citrate malate refers to a metastable mineral complex of magnesium
carbonate, citric acid and malic acid. Magnesium citrate malate is isolated at a
metastable stage delicately maintaining the balance between temperature, pressure and
other reaction conditions. Thus soluble magnesium citrate malate is obtained only at a
particular stage in the process. Magnesium citrate malate is highly soluble and therefore
is better absorbed in the system and thus has high efficacy.
As used herein, the temi "malic acid" refers to the mixture of the D and the L isomers,
i.e. malic acid is optically active and the racemic mixture is used herein. D-malic acid
and L-malic acid can be used.
As used herein the term "metastable" means that the material is not at equilibrium, and
is a mixture of various fomis with longer shelf life.
While the reaction kinetics would indicate that the magnesium neutralizes all of the
acid groups of citric and malic acid and equilibrium is established between the salts
and, when prepared by the proc ess herein, a complex salt is formed.
This complex salt is distinct from pure magnesium citrate or pure magnesium malate or
simple mixtures thereof
The magnesium citiate malate of present invention can exist in several states of
hydration with from 1 to 5 water molecules.
This complex is thermodynamically an intermediate complex formed in the preparation
of a dry fonn. The physical and chemical data of these salts are consistent with the
theory that there are non-crystalline regions within the powdered material which can
hydrate to the point of behaving like a solution. It is important for the solubility
characteristics of the magnesium citrate malate that the apparent metastable structure be
achieved. Magnesium malate has a solubility of 10% on boiling and magnesium citrate
is nearly insoluble even at boiling conditions. Magnesium citrate malate of the present
invention has a solubility of 30% at room temperature. Thus it is a soluble and highly
acceptable form.
The magnesium citrate malate is prepared by dissolving malic acid and citric acid in
purified water and adding a magnesium source selected from magnesium oxide,
magnesium hydroxide and mag;nesium carbonate, as a powder or as aqueous slurry, to
the aqueous solution of citric acid and malic acid in the molar ratio necessary to make
the desired magnesium citrate malate material. When magnesium carbonate is used,
carbon dioxide evolves and the magnesium carbonate is neutralized by the citric and

malic acid. The magnesium citrate malate is free from magnesium citrate, magnesium malate and other inorganic impurities such as inorganic salts of magnesium. It is preferable that tiie magnesium source is added to the solution of citric acid and malic acid.
A solid is fonned during the mixing of magnesium oxide or magnesium hydroxide with the citric acid and malic acid. When these magnesium sources are used, it is necessary to mix the solution until all of the magnesium appears to have dissolved. The preferred method of preparation is to prepare a highly concentrated aqueous solution of the magnesium citrate malate which quickly and efficiently forces metastable magnesium citrate malate out of solution. Concentrations of from 20% to 75% (weight of reactants) in water are preferred. More preferably the concentration is from 40% to 65%.
Activated charcoal is added to get a clear solution. The subsequent mixture is filtered to remove the activated charcoal. The reaction temperature can be ambient (20°C) or higher. Preferably the temperature of the reaction is in the range of 30 to 80°C. Most preferably it is from 60 to 70°C.
This mixture is further dried preferably by spray or vacuum drying. Drying is carried out below 90°C in order to prevent decomposition of the formed metastable magnesium citrate malate. Preferably, when using vacuum air drying, the drying is accomplished on a thin layer of product between 60 and 90°C. In spray drying, the solution mixture is sprayed into a hot air column at 60 to 90°C.
The material is preferably dried until the amount of free or unbound water is less than 10%. When vacuum air drying is used, the dried material is ground using any conventional grinding equipment and then sieved to a variable particle size which is useful for food and beverage fortification and for tabletting or filling in capsules. The ratio of magnesium to citric acid to malic acid in the final product will depend upon the reactants used. Generally, the preparation of this material starting with pure magnesium carbonate, citric acid and malic acid and drying the entire solution will produce a magnesium citrate malate complex of the same ratio of the materials mixed. Molar ratios of magnesium, citric acid and malic acid used are 5:2:2, 4:2:1 and 6:2:3. The exact formula lor the complex can be derived by measuring the percent of magnesium in the said complex.
The metastable magnesium citrate malate complex represents a soluble form of magnesium which is more soluble than inorganic magnesium salts and magnesium

citrate and magnesium malate. The process can be used to make a variety of
magnesium citrate malate complexes which have higher solubilities and neutral taste.
The enhanced solub ility of these salts is unexpected since one would not expect the
anions and the ratio of magnesium to anions to play such a key role in solubility.
An embodiment of tlie process of the present invention wherein the molar ratio of citric
acid is from I to 2, the molar ratio of malic acid is from 1 to 3, and the molar ratio of
magnesium is from 4 to 6.
It is an embodiment of the process of the present invention wherein the magnesium
source is selected from the group consisting of magnesium carbonate, magnesium oxide
or magnesium hydro xide.
It is also an embodiment of the process of the present invention wherein the magnesium
source is magnesium carbonate.
Another embodiment of the process of the present invention wherein the citric acid is
added simultaneously with the magnesium source to malic acid in water.
Yet another embodi ment of the process of the present invention wherein the molar
ratios of the magnesium, citric acid and malic acid are 4:2:1, 5:2:2, and 6:2:3.
Still another embodiment of the process of the present invention wherein the addition
of magnesium source to the solution of citric acid and malic acid is carried out at a
temperature in the range of 60 to 70°C.
It is also an embodiuient of the process of the present invention wherein the adsorbent
used to remove colour impurities is an activated charcoal.
It is an embodimen t of the process of the present invention wherein the metastable
magnesium citrate malate has a neutral taste.
From the description, one skilled in the art can easily ascertain that the invention may
be performed within a wide and equivalent range of conditions, without departing from
the spirit or scope o f invention and embodiments thereof. It is intended that all matter
contained in the description above shall be interpreted as illustrative and not in a
limiting sense. Moreover, other embodiments of the invention will be apparent to those
skilled in the art from consideration of the specification and practice of the invention
disclosed herein.

Meta stable Magnesium Citrate Malate
Further, the following examples are illustrative caf the present invention and should not be construed as limiting the scope of the inventioni in any manner.
Example L 850 g of citric acid and 298 g of malic acid are dissolved in 2 L of purified water at ambient temperature and 885 g of magnesium c arbonate are added in small quantities to the reaction mass at 30-95°C, most preferably at 60-80°C, followed by the addition of activated charcoal to remove impurities. The reaction mixture is filtered to remove activated charcoal. The filtrate is spray dried at appropriate conditions to obtain about 1445.0 g of white crystalHne powder of nxetastable magnesium citrate malate, containing about 12.4% magnesium content on dried basis. The product has melting point of above 350"C and is freely soluble in water and the product obtained is highly stable at ambient conditions. Further, the product is characterized by XRD and FTIR studies. The resultant spectra are attached herewi th.

The MCM product is usually made with varied ratios of citric acid and malic acid, so as to get the product with desired solubility, stability and magnesium contents, which is usually based on the end-user requirements. Example-2 gives one such composition.
Example 2 192 g of citric acid and 202.5 g of malic acid are dissolved in 1 L of purified water at ambient temperature and 300 g of magnesium carbonate are added to the solution followed by activated charcoal to remove impurities. The reaction mixture is filtered to remove activated charcoal. The Tiltrate is spray dried at 85°C to obtain metastable magnesium citrate malate.
Example 3 The metastable magnesium citrate malate is prepared by dissolving 8.5 kg of citric acid and 6kg of malic acid to purified water around 45 L at ambient temperature and 12.0 kg of magnesium carbonate are added in small quantities to the reaction mass at 30-95°C, most preferably at 60-80°C, under vigorous agitation, followed by the addition of activated charcoal to remove impurities. The reaction mixture is filtered to remove activated charcoal. The filtrate is spray dried at 85-90'C inlet temperature to get 13.5 kg of white crystalline powder of metastable magnesium citrate malate, containing about 12.6% magnesium content 03 dried basis. The product has melting point of above 350*'C and is freely soluble in water and the product obtained is highly stable at ambient conditions.
Example 4 The metastable magnesium citrate malate is prepared by dissolving 4.25 kg of citric acid and 4.5 kg of malic acid to purified water around 25 L and adding 7.1 kg of magnesium carbonate. The output of magnesium citrate malate is 7.5 kg. As nutrient composition:
Example 5 50 mg of citric acid and 30 mg of malic acid are subjected to grinding and blended. Then blended with 2.1g of magnesium citrate malate in parts 30mg of sucralose is added as sweetener, colour and orange flavour for taste. The composition produced is added to a glass of water and is a ready to drink beverage. Each dose is given in a sachet. It provides 350 mg of elemental magnesium per serving which is 100% of RDA in a single dosage. Thus composition is suitable as a supplement in magnesium deficiency.

As nutrient additive:
Example 6
Fortification of juice with magnesium citrate malate is suitable as it has high solubility,
thus a clear solution is obtained. Apple juice 200ml fortified with 2g of magnesium
citrate malate provides in one serving of 200 ml of juice 300mg of elemental
magnesium. The apple juice is neutral in taste with no off flavours. It provides
approximately 100% RDA of magnesium in a single serving.
Example 7
2g of magnesium citrate malate added to 1 litre of milk is neutral in taste and stable
after pasteurization when a sequestering agent like tripotassium citrate is added at 0.2%
concentration.
Determination of Magnesium Content is performed by Complexometric Titration: ASSAY
0.3g of magnesium citrate malate is dissolved in water (or in dil.HCl) and diluted to 100 ml with the same solvent. 10 ml of ammonia-ammonium chloride buffer and 50mg of Eriochrome Black T indicator are added and titrated against 0.05M Disodium salt of EDTA. The end point is indicated by a colour change of the solution from pink to blue. 1 ml of 0.051VI Disodium salt of EDTA is equivalent to 0.01215g of Mg^"".
Determination of citric acid and malic acid
Citric acid and malic acid are determined by HPLC using the following conditions:

Column CI8 reversed phase (4.6 x 100mm)
Detection UV at 206nm
Mobile Phase acetonitrile: 0.1 m diammonium hydrogen phosphate (3:97)
Flow rate 1.0 ml/min
Injection 10 microL
Run time 10 min
Retention time
For Citric acid 3 min
For Malic acid 3.5 min
Method: Equal amounts of the sample solution and the calibration solution are separately injected into the chromatograph. The chromatograms are recorded and the responses of citric acid and malic acid peak are measured.
The metastable magnesium citrate malate complex produced by the process of the present invention is an isolated solid powder, whose physico-chemical properties are

well established from its melting range, XRD pattern, and IR spectrum. Therefore the product exliibits the following features- and finds uses in various applications.
Advantages of the invented process and product:
1. The magnesium citrate malate complex of the present invention has increased solubility and hence increased bioavailability as compared to other magnesium salts like magnesium citrate, magnesium malate or a physical admixture of magnesium citrate and magnesium malate.
2. Since tlic magnesium citrate malate complex is highly soluble in water and hence it finds application in various beveiages and other liquid formulations whereas the magnesium citrate and magnesium malate are not suitable because of their insoluble nature.
3. The magnesium citrate malate complex has a neutral taste and thus is suitable for food fortification.
4. Magnesium citrate malate being highly soluble in water can provide 90% RDA in approximately 2 grams of a single dose.
5. The present invention provides a magnesium citrate malate complex with high magnesium content.
6. The present invention provides a pharmaceutical and food grade magnesium citrate malate complex.
7. The present invention provides a method for treating magnesium deficiency comprising administration to a patient in need of such treatment an effective amount of the metastable magnesLum citrate malate complex.
8.

We claim:
1. A process for the preparation of a metastable magnesium citrate malate complex,
said process comprising the steps of:
a) preparing a solution of citric acid and malic acid in water;
b) adding a magnesium source to the said solution at a temperature in the range of 30 to 80°C to obtain a neutralized solution of magnesium citrate malate;
c) adding an adsorbent to the neutralized solution of magnesium citrate malate to
obtain a colourless solution of magnesium citrate malate; and
d) isolating metastable magnesium citrate malate from said colourless solution to
obtain a metastable magnesium citrate malate complex.
2. The process as claimed in claim 1, wherein the molar ratio of citric acid is from 1 to
2, malic acid is from I to 3, and magnesium is from 4 to 6.
3. The process as claimed in claim 1, wherein the magnesium source is selected from
the group consisting of magnesium carbonate, magnesium oxide or magnesium
hydroxide.
4. The process as claimed in claim I, wherein the magnesium source is magnesium
carbonate.
5. The process as claimed in claim 1, wherein the citric acid is added simultaneously
with the magnesium source to malic acid in water.
6. The process as claimed in claim 1, wherein the molar ratios of the magnesium,
citric acid and malic acid are 4:2:1, 5:2:2, and 6:2:3.
7. The process as claimed in claim 1, wherein the addition of magnesium source to the
solution of citric acid and malic acid is carried out at a temperature in the range of
60 to 70°C.
8. The process as claimed in claim 1, wherein the adsorbent is an activated charcoal.

Documents:

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Patent Number

269844

Indian Patent Application Number

1605/CHE/2006

PG Journal Number

46/2015

Publication Date

13-Nov-2015

Grant Date

11-Nov-2015

Date of Filing

05-Sep-2006

Name of Patentee

GLOBAL CALCIUM PVT. LTD

Applicant Address

Registered Office: 125 & 126 Sipcot Industrial Complex Hosur-635126.

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. KURUSAMY ALAGESAN	GLOBAL CALCIUM PVT LTD 125 & 126 sipcot Industrial Complex Hosur-635126.
2	MUTHURAMAN CHANDRASEKAR	GLOBAL CALCIUM PVT LTD, 125 & 126 sipcot Industrial Complex, Hosur-635126.
3	SAHIL VAZIRALLY	GLOBAL CALCIUM PVT LTD, 125 & 126 sipcot Industrial Complex, Hosur-635126.
4	TARU SHARMA	GLOBAL CALCIUM PVT LTD, 125 & 126 sipcot Industrial Complex, Hosur-635126.

PCT International Classification Number

A23L2/02

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA