Title of Invention	A PROCESS FOR THE PREPARATION OF A SOLUBLE DOUBLE METAL SALT OF GROUP IA AND IIA OF (-) HYDROXYCITRIC ACID (HCA)
Abstract	ABSTRACT This invention relates to a process for the preparation of a soluble calcium salt of (-) hydroxycitric acid (HCA) comprising of following steps: step 1- obtaining water extract of salted or salt free garcinia rind containing free hydroxycitric acid, step 2- neutralizing the said free hydroxycitric acid with group IA metal hydroxides to obtain soluble sodium salt of hydroxycitric acid, step 3- displacing completely the group IA metal oil in the said salt solution by adding group IIA metal chlorides to precipitate insoluble calcium salt of hydroxycitric acid, step 4- collecting the said precipitate of insoluble calcium salt of hydroxycitric acid and purifying it by washing with water, step 5 -obtaining a free hydroxycitric acid of solution from the said insoluble calcium salt of hydroxycitric acid by adding an organic acid as herein described to form a stronger salt of calcium, step 6- removing the traces of organic acid present by adding excess of calcium hydroxycitrate to precipitate calcium salt of the organic acid, step 7- neutralizing the free hydroxycitric acid solution of step 5 with group IA metal hydroxide step 8- displacing partially the group TA metal ions present in the above salt solution by addition of group IIA metal chlorides, step 9- precipitating completely solublized calcium salt of hydroxycitric acid by the addition of water mixable organic solvent.

Title of Invention

A PROCESS FOR THE PREPARATION OF A SOLUBLE DOUBLE METAL SALT OF GROUP IA AND IIA OF (-) HYDROXYCITRIC ACID (HCA)

Abstract

ABSTRACT This invention relates to a process for the preparation of a soluble calcium salt of (-) hydroxycitric acid (HCA) comprising of following steps: step 1- obtaining water extract of salted or salt free garcinia rind containing free hydroxycitric acid, step 2- neutralizing the said free hydroxycitric acid with group IA metal hydroxides to obtain soluble sodium salt of hydroxycitric acid, step 3- displacing completely the group IA metal oil in the said salt solution by adding group IIA metal chlorides to precipitate insoluble calcium salt of hydroxycitric acid, step 4- collecting the said precipitate of insoluble calcium salt of hydroxycitric acid and purifying it by washing with water, step 5 -obtaining a free hydroxycitric acid of solution from the said insoluble calcium salt of hydroxycitric acid by adding an organic acid as herein described to form a stronger salt of calcium, step 6- removing the traces of organic acid present by adding excess of calcium hydroxycitrate to precipitate calcium salt of the organic acid, step 7- neutralizing the free hydroxycitric acid solution of step 5 with group IA metal hydroxide step 8- displacing partially the group TA metal ions present in the above salt solution by addition of group IIA metal chlorides, step 9- precipitating completely solublized calcium salt of hydroxycitric acid by the addition of water mixable organic solvent.

Full Text	This i'nvention relates to a new process for the preparation of a soluble double metal salt of group lA and UA of (-) hydroxycitric acid (HCA). This process involves hot water extraction of HCA from the fruit rind of Garcinia species {G. cambogia, G. indica), precipitation of hydroxycitric acid as an insoluble calcium salt, release of free acid with oxalic acid and conversion of the free acid into its soluble calcium salt. This product with >98% purity can be used safely as food supplement in various nutriteutical formulations and beverages. BACKGROUND (-) Hydroxycitric acid occurs in the fruit rind of Garcinia species (e.g., G. cambogia, G. indica and G. atroviridis). The first two species grow abundantly in India and the third occurs mostly in the south east Asian countries. (-) hydroxycitric acid received worldwide attention because of its unique property of competitively inhibiting ATP-dependent citrate-lyase, a key enzyme in diverting carbohydrate to fatty acid and cholesterol synthesis in rats (Sullivan et al. Lipids, 9:121 and 129 (1973), Sergio, W., medical Hypothesis 27:39 (1988)). The age old practice of the Indian peninsula has established the safety and non-toxic nature of (-) hydroxycitric acid from Garcinia rind are described in the publications of Lewis Y.S., et al (Methods in Enzymology, 13:613 (1967) and in the patents (Indian patent no. 160753 and US patent No. 5536516) and Indian patent application no. 814/Mas/94 (178298) In our earlier patent application no. 178298 which describes preparation of a concentrate of hydroxycitric acid and its lactone in liquid form, comprising of several steps like water extraction of Garcinia rind containing (-)-hydroxycitric acid and its concentration, acetone refinement of this concentrated water extract, evaporation of acetone, loading thus obtained refined extract on ion-exchange columns containing an anion exchange resin followed by a cation exchange resin, and finally evaporation of the free acid liberated from the ion-exchange process to said concentration. This liquid form of hydroxycitric acid has problems of stability and half life. Being highly acidic, it poses problems in formulations prepared from liquid formulations of hydroxycitric acid . The object of this invention is to overcome the above drawbacks by developing a new process circumventing the use of ion-exchange column and the heating steps of concentrating and producing a calcium salt of hydroxycitric acid which is completely soluble at room temperature unlike the insoluble calcium salt of hydroxycitric acid . To achieve the said objective this invention provides a process for the preparation of a soluble double metal salt of group lA and IIA of (-) hydroxycitric acid (HCA) of formula I, particularly formula II as given below step 1-obtaining water extract of salted or salt free garcinia rind containing free hydroxycitric acid, step 2-neutralizing the said free hydroxycitric acid with group lA metal hydroxides to obtain soluble metal salt of group LA of hydroxycitric acid, step 3- displacing completely the group lA metal ion in the said salt solution by adding group IIA metal chlorides to precipitate insoluble group IIA metal salt of hydroxycitric acid, step 4-collecting the said precipitate of insoluble group IIA metal salt of hydroxycitric acid and purifying it by washing with water, step 5 -treating the said precipitate of insoluble group HA metal salt of hydroxycitric acid with organic acid as herein described to form metal ion organic acid complex and free hydroxycitric acid, step 6- removing the traces of organic acid present in the above solution by adding excess of calcium hydroxycitrate to precipitate group IIA metal salt of the organic acid and filtering to get the free hydroxycitric acid solution step 7- neutralizing the free hydroxycitric acid solution of step 6 with group lA metal hydroxide step 8- displacing partially the group lA metal ions present in the above salt solution by addition of group IIA metal chlorides, as herein described, step 9- precipitating completely solublized double metal salt of group lA and IIA of hydroxycitric acid by the addition of water mixable organic solvent, as herein described. The free hydroxycitric acid present in step 2 is neutralized by three equivalents of group lA metal hydroxides. Group LA metal hydroxides are NaOH, KOH and group IIA metal chlorides are MgC2, CaCl2. The organic acid is an oxalic acid. The free hydroxycitric acid solution is decolourised by heating with 2-5% activated charcoal, if desired. The partial displacement of group lA metal ion in step 8 is carried out with one equivalent of group IIA metal chloride. The said water mixable organic solvent are water mixable alcohols such as methanol, ethanol, propanol and isopropanol, preferably ethanol 3Description of preferred embodiment: The concentrated 40 brix Garcinia water extract can be prepared from salted or salt free Garcinia rind by extracting with water in several steps by counter current method. The extract thus obtained is neutralized by adding three equivalents of sodium hydroxide. Then the sodium salt is displaced by calcium chloride to obtain an insoluble calcium salt of hydroxycitric acid. This is washed thoroughly with water to remove non-acidic impurities such as pectins, gums and color. Then the precipitate is treated with three equivalents of oxalic acid to convert calcium hydroxycitrate to calcium oxalate and hydroxycitric acid. Calcium oxalate is separated by centrifugation and the supernatant collected is again added to calcium hydroxycitrate to enrich the hydroxycitric acid. The traces of oxalic acid are removed by adding excess calcium hydroxycitrate and by centrifugation. This is monitored by high performance liquid chromatography, which confirms the absence of any traces of oxalic acid. The free acid enriched solution is then neutralized with sodium hydroxide and one equivalent of calcium chloride solution is added with stirring. Finally this solution is precipitated by addition of ethanol. The precipitate is dried at room temperature to obtain a white powder of soluble calcium salt of hydroxycitric acid. Example: Water extract of Garcinia rind is obtained by counter current extraction, this is carried out in three vessels more specifically each time fresh Garcinia rind is loaded into vessel 3 and treated with 1.5 litres of water, the rind is moved from V3 to V2 then to Vj. On the other hand the extract moved from V1 to V2 then to V3. The extract obtained from V3 was 1.2 liters containing 198 gm of acid along with the other water soluble substances, the percentage of the total soluble constituents in the extract i.e. brix was found to be 43 degrees. The extraction efficiency is found to be 90%. This 40 brix extract containing 560 gms of acid in 3.6 liters is transferred to a vessel and neutralized by addition of 323 gm of sodium hydroxide. After cooling this solution to room temperature, 500 ml of solution containing 442 gm of calcium chloride is added to it and resultant insoluble calcium salt was centrifuged and washed thoroughly to remove the color and water soluble impurities. The salt obtained was dried and weight is found to be 693 gm. One hundred grams of this insoluble salt is taken in a one liter vessel to and 71.32 gm oxalic acid dihydrate dissolved in 350 ml of water is added and stirred at 150 RPM on a shaker for 30 min. and the supernatant 210 ml was collected. To this supernatant 71.32 gm of oxalic acid dihydrate is added and another 100 gm of calcium hydroxycitrate added and this procedure is followed until the hydroxycitric acid content in the extract reaches -45% detected by high performance liquid chromatography (HPLC). The traces of oxalic acid are also removed by finally adding excess calcium hydroxycitrate, this is monitored by HPLC by observing the total absence of oxalic acid peak. The solution of hydroxycitric acid thus obtained is found to contain 202 gm of acid in 450 ml of extract. This is neutralized by 117 gm of sodium hydroxide and the solution is cooled to room temperature. To this sodium salt solution of hydroxycitric acid, 200 ml of solution containing 81 gm of calcium chloride is added drop wise with vigorous stirring. The soluble calcium salt of hydroxycitric acid is then precipitated by addition of ethanol. The precipitated salt is filtered, washed with ethanol and dried to obtain 234 gm of the soluble calcium salt of hydroxycitric acid (yield: 91.2%). Reference is made to our co-pending application nos. 1985/Mas/97, 1986/Mas/97 and ]987/Mas/97. We claim: 1. A process for the preparation of a soluble double metal salt of group lA and HA of (-) hydroxycitric acid (HCA) of formula I, particularly formula II as given below step 1- obtaining water extract of salted or salt free garcinia rind containing free hydroxycitric acid, step 2- neutralizing the said free hydroxycitric acid with group lA metal hydroxides to obtain soluble metal salt of group LA of hydroxycitric acid, step 3- displacing completely the group lA metal ion in the said salt solution by adding group IIA metal chlorides to precipitate insoluble group IIA metal salt of hydroxycitric acid, step 4- collecting the said precipitate of insoluble group IIA metal salt of hydroxycitric acid and purifying it by washing with water, step 5 -treating the said precipitate of insoluble group IIA metal salt of hydroxycitric acid with organic acid as herein described to form metal ion organic acid complex and free hydroxycitric acid, step 6- removing the traces of organic acid present in the above solution by adding excess of calcium hydroxycitrate to precipitate group IIA metal salt of the organic acid and filtering to get the free hydroxycitric acid solution step 7- neutralizing the free hydroxycitric acid solution of step 6 with group lA metal hydroxide step 8- displacing partially the group lA metal ions present in the above salt solution by addition of group IIA metal chlorides, as herein described, step 9- precipitating completely solublized double metal salt of group lA and IIA of hydroxycitric acid by the addition of water mixable organic solvent, as herein described. 2. A process as claimed in claim 1 wherein the free hydroxycitric acid present in step 2 is neutralized by three equivalents of group lA metal hydroxides. 3. A process as claimed in claims 1 & 2 wherein group lA metal hydroxides are NaOH and KOH. 4. A process as claimed in claim 1 wherein group IIA metal chlorides are MgCl2 and CaCl2. 5. A process as claimed in claim 1 wherein the organic acid is an oxalic acid. 6. A process as claimed in claim 1 wherein the free hydroxycitric acid solution is decolourised by heating with 2-5% activated charcoal, if desired. 7. A process as claimed in claim 1 wherein partial displacement of group LA metal ion in step 8 is carried out with one equivalent of group IIA metal chloride. 8. A process as claimed in claim 1 wherein said water mixable organic solvent are water mixable alcohols such as methanol, ethanol, propanol and isopropanol, preferably ethanol 9. A process for the preparation of a soluble double metal salt of group lA and IIA of (-) hydroxycitric acid (HCA) substantially as herein described with reference to the foregoing examples.

Full Text

This i'nvention relates to a new process for the preparation of a soluble double metal salt of group lA and UA of (-) hydroxycitric acid (HCA). This process involves hot water extraction of HCA from the fruit rind of Garcinia species {G. cambogia, G. indica), precipitation of hydroxycitric acid as an insoluble calcium salt, release of free acid with oxalic acid and conversion of the free acid into its soluble calcium salt. This product with >98% purity can be used safely as food supplement in various nutriteutical formulations and beverages.
BACKGROUND
(-) Hydroxycitric acid occurs in the fruit rind of Garcinia species (e.g., G. cambogia, G. indica and G. atroviridis). The first two species grow abundantly in India and the third occurs mostly in the south east Asian countries.
(-) hydroxycitric acid received worldwide attention because of its unique property of competitively inhibiting ATP-dependent citrate-lyase, a key enzyme in diverting carbohydrate to fatty acid and cholesterol synthesis in rats (Sullivan et al. Lipids, 9:121 and 129 (1973), Sergio, W., medical Hypothesis 27:39 (1988)). The age old practice of the Indian peninsula has established the safety and non-toxic nature of (-) hydroxycitric acid from Garcinia rind are described in the publications of Lewis Y.S., et al (Methods in Enzymology, 13:613 (1967) and in the patents (Indian patent no. 160753 and US patent No. 5536516) and Indian patent application no. 814/Mas/94 (178298)
In our earlier patent application no. 178298 which describes preparation of a concentrate of hydroxycitric acid and its lactone in liquid form, comprising of several steps like water extraction of Garcinia rind containing (-)-hydroxycitric acid and its concentration, acetone refinement of this concentrated water extract, evaporation of acetone, loading thus obtained refined extract on ion-exchange columns containing an anion exchange resin followed by a cation exchange resin, and finally evaporation of the free acid liberated from the ion-exchange process to said concentration. This liquid form

of hydroxycitric acid has problems of stability and half life. Being highly acidic, it poses problems in formulations prepared from liquid formulations of hydroxycitric acid .
The object of this invention is to overcome the above drawbacks by developing a new process circumventing the use of ion-exchange column and the heating steps of concentrating and producing a calcium salt of hydroxycitric acid which is completely soluble at room temperature unlike the insoluble calcium salt of hydroxycitric acid .
To achieve the said objective this invention provides a process for the preparation of a soluble double metal salt of group lA and IIA of (-) hydroxycitric acid (HCA) of formula I, particularly formula II as given below

step 1-obtaining water extract of salted or salt free garcinia rind containing free hydroxycitric acid,
step 2-neutralizing the said free hydroxycitric acid with group lA metal hydroxides to obtain soluble metal salt of group LA of hydroxycitric acid,
step 3- displacing completely the group lA metal ion in the said salt solution by adding group IIA metal chlorides to precipitate insoluble group IIA metal salt of hydroxycitric acid,
step 4-collecting the said precipitate of insoluble group IIA metal salt of
hydroxycitric acid and purifying it by washing with water,

step 5 -treating the said precipitate of insoluble group HA metal salt of hydroxycitric acid with organic acid as herein described to form metal ion organic acid complex and free hydroxycitric acid,
step 6- removing the traces of organic acid present in the above solution by adding excess of calcium hydroxycitrate to precipitate group IIA metal salt of the organic acid and filtering to get the free hydroxycitric acid solution
step 7- neutralizing the free hydroxycitric acid solution of step 6 with group lA metal hydroxide
step 8- displacing partially the group lA metal ions present in the above salt solution by addition of group IIA metal chlorides, as herein described,
step 9- precipitating completely solublized double metal salt of group lA and IIA of hydroxycitric acid by the addition of water mixable organic solvent, as herein described.
The free hydroxycitric acid present in step 2 is neutralized by three equivalents of group lA metal hydroxides.
Group LA metal hydroxides are NaOH, KOH and group IIA metal chlorides are MgC2, CaCl2.

The organic acid is an oxalic acid. The free hydroxycitric acid solution is decolourised by heating with 2-5% activated charcoal, if desired.
The partial displacement of group lA metal ion in step 8 is carried out with one equivalent of group IIA metal chloride.
The said water mixable organic solvent are water mixable alcohols such as methanol, ethanol, propanol and isopropanol, preferably ethanol
3Description of preferred embodiment:
The concentrated 40 brix Garcinia water extract can be prepared from salted or salt free Garcinia rind by extracting with water in several steps by counter current method. The extract thus obtained is neutralized by adding three equivalents of sodium hydroxide. Then the sodium salt is displaced by calcium chloride to obtain an insoluble calcium salt of hydroxycitric acid. This is washed thoroughly with water to remove non-acidic impurities such as pectins, gums and color. Then the precipitate is treated with three equivalents of oxalic acid to convert calcium hydroxycitrate to calcium oxalate and hydroxycitric acid. Calcium oxalate is separated by centrifugation and the supernatant collected is again added to calcium hydroxycitrate to enrich the hydroxycitric acid. The traces of oxalic acid are removed by adding excess calcium hydroxycitrate and by centrifugation. This is monitored by high performance liquid chromatography, which confirms the absence of any traces of oxalic acid. The free acid enriched solution is then neutralized with sodium hydroxide and one equivalent of calcium chloride solution is added with stirring. Finally this solution is precipitated by addition of ethanol. The precipitate is dried at room temperature to obtain a white powder of soluble calcium salt of hydroxycitric acid.
Example:
Water extract of Garcinia rind is obtained by counter current extraction, this is carried out in three vessels more specifically each time fresh Garcinia rind is loaded into vessel 3 and treated with 1.5 litres of water, the rind is moved from V3 to V2 then to Vj. On the other hand the extract moved from V1 to V2 then to V3.

The extract obtained from V3 was 1.2 liters containing 198 gm of acid along with the other water soluble substances, the percentage of the total soluble constituents in the extract i.e. brix was found to be 43 degrees. The extraction efficiency is found to be 90%. This 40 brix extract containing 560 gms of acid in 3.6 liters is transferred to a vessel and neutralized by addition of 323 gm of sodium hydroxide. After cooling this solution to room temperature, 500 ml of solution containing 442 gm of calcium chloride is added to it and resultant insoluble calcium salt was centrifuged and washed thoroughly to remove the color and water soluble impurities. The salt obtained was dried and weight is found to be 693 gm.
One hundred grams of this insoluble salt is taken in a one liter vessel to and 71.32 gm oxalic acid dihydrate dissolved in 350 ml of water is added and stirred at 150 RPM on a shaker for 30 min. and the supernatant 210 ml was collected. To this supernatant 71.32 gm of oxalic acid dihydrate is added and another 100 gm of calcium hydroxycitrate added and this procedure is followed until the hydroxycitric acid content in the extract reaches -45% detected by high performance liquid chromatography (HPLC). The traces of oxalic acid are also removed by finally adding excess calcium hydroxycitrate, this is monitored by HPLC by observing the total absence of oxalic acid peak. The solution of hydroxycitric acid thus obtained is found to contain 202 gm of acid in 450 ml of extract. This is neutralized by 117 gm of sodium hydroxide and the solution is cooled to room temperature. To this sodium salt solution of hydroxycitric acid, 200 ml of solution containing 81 gm of calcium chloride is added drop wise with vigorous stirring. The soluble calcium salt of hydroxycitric acid is then precipitated by addition of ethanol. The precipitated salt is filtered, washed with ethanol and dried to obtain 234 gm of the soluble calcium salt of hydroxycitric acid (yield: 91.2%).
Reference is made to our co-pending application nos. 1985/Mas/97, 1986/Mas/97 and ]987/Mas/97.

We claim:
1. A process for the preparation of a soluble double metal salt of group lA and HA of (-) hydroxycitric acid (HCA) of formula I, particularly formula II as given below

step 1- obtaining water extract of salted or salt free garcinia rind containing free hydroxycitric acid,
step 2- neutralizing the said free hydroxycitric acid with group lA metal hydroxides to obtain soluble metal salt of group LA of hydroxycitric acid,
step 3- displacing completely the group lA metal ion in the said salt solution by adding group IIA metal chlorides to precipitate insoluble group IIA metal salt of hydroxycitric acid,
step 4- collecting the said precipitate of insoluble group IIA metal salt of hydroxycitric acid and purifying it by washing with water,
step 5 -treating the said precipitate of insoluble group IIA metal salt of hydroxycitric acid with organic acid as herein described to form metal ion organic acid complex and free hydroxycitric acid,
step 6- removing the traces of organic acid present in the above solution by adding excess of calcium hydroxycitrate to precipitate group IIA metal salt of the organic acid and filtering to get the free hydroxycitric acid solution
step 7- neutralizing the free hydroxycitric acid solution of step 6 with group lA metal hydroxide
step 8- displacing partially the group lA metal ions present in the above salt solution by addition of group IIA metal chlorides, as herein described,
step 9- precipitating completely solublized double metal salt of group lA and IIA of hydroxycitric acid by the addition of water mixable organic solvent, as herein described.

2. A process as claimed in claim 1 wherein the free hydroxycitric acid present in step 2 is neutralized by three equivalents of group lA metal hydroxides.
3. A process as claimed in claims 1 & 2 wherein group lA metal hydroxides are NaOH
and KOH.
4. A process as claimed in claim 1 wherein group IIA metal chlorides are MgCl2 and
CaCl2.
5. A process as claimed in claim 1 wherein the organic acid is an oxalic acid.
6. A process as claimed in claim 1 wherein the free hydroxycitric acid solution is
decolourised by heating with 2-5% activated charcoal, if desired.
7. A process as claimed in claim 1 wherein partial displacement of group LA metal ion
in step 8 is carried out with one equivalent of group IIA metal chloride.
8. A process as claimed in claim 1 wherein said water mixable organic solvent are water
mixable alcohols such as methanol, ethanol, propanol and isopropanol, preferably
ethanol
9. A process for the preparation of a soluble double metal salt of group lA and IIA of (-)
hydroxycitric acid (HCA) substantially as herein described with reference to the
foregoing examples.

Documents:

1880-chenp-2005 abstract-duplicate.pdf

1880-chenp-2005 claims-duplicate.pdf

1880-chenp-2005 description(complete)-duplicate.pdf

1880-mas-1997 abstract.pdf

1880-mas-1997 claims.pdf

1880-mas-1997 correspondence others.pdf

1880-mas-1997 correspondence po.pdf

1880-mas-1997 description (complete).pdf

1880-mas-1997 form-1.pdf

1880-mas-1997 form-26.pdf

1880-mas-1997 form-4.pdf

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Patent Number

182487

Indian Patent Application Number

1880/MAS/1997

PG Journal Number

30/2009

Publication Date

24-Jul-2009

Grant Date

27-Aug-1997

Date of Filing

27-Aug-1997

Name of Patentee

M/S. VITTAL MALLYA SCIENTIFIC RESEARCH FOUNDATION

Applicant Address

POST BOX NO. 406, K.R. ROAD, BANGALORE 560 004,

Inventors:

#	Inventor's Name	Inventor's Address
1	KARANAM BALASUBRAMANYAM	POST BOX NO. 406, K.R. ROAD, BANGALORE 560 004,
2	BHASKARAN CHANDRASEKHAR	POST BOX NO. 406, K.R. ROAD, BANGALORE 560 004,
3	CANDADAI S RAMADOSS	POST BOX NO. 406, K.R. ROAD, BANGALORE 560 004,
4	PILLARISETTI V.SUBBA RAO	POST BOX NO. 406, K.R. ROAD, BANGALORE 560 004,

PCT International Classification Number

C07C 59/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA