Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF FERROUS ASCORBATE

Abstract The present invention provides an improved and industrially feasible earth metal salts or its hydroxides are reacted with ferrous sulfate to get corresponding ferrous salts, which are reacted with ascorbic acid in an aqueous medium at slightly acidic or neutral condition followed by filtration to get ferrous ascorbate in mother liquor. Alternatively, ascorbic acid salt can be treated with ferrous salt followed by the filtration of the same to get ferrous ascorbate in mother liquor. The said mother liquor, obtained by any means can be used for spray drying to get ferrous ascorbate. Optionally, ferrous salts are isolated by filtration then subjected to reaction with ascorbic acid in an aqueous medium at slightly acidic or neutral medium followed by spray drying to get ferrous ascorbate.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATIION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
"IMPROVED PROCESS FOR THE PREPARATION OF FERROUS ASCORBATE'
APPLICANT (S)
(a) NAME : EMCURE PHARMACEUTICALS LTD.
(b) NATIONALITY : India
(c) ADDRESS : R&D Centre T-184, MIDC, Bhosari, Pune - 411 046,
Maharashtra, India,

FIELD OF THE INVENTION
This invention relates to an improved and industrially feasible process for the preparation of ferrous ascorbate.
INTRODUCTION
Ferrous ascorbate (CAS Reg. No. 24808-52-4) is a reaction product of ferrous salts and ascorbic acid as disclosed in US Food and Drug Administration
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?fr=l 84.1307a. It is a blue-violet product containing 16 percent iron. The U.S. Food and Drug Administration is developing food-grade specifications for ferrous ascorbate in cooperation with the National Academy of Sciences. This ingredient must be of purity suitable for its intended use as a pharmaceutical product. Further more, the ingredient is used in food as a nutrient supplement, with no limitation other than current good manufacturing practice. The ingredient may also be used in infant formula.
Martindale drug reference discloses Ferrous ascorbate is used as a source of iron for iron-deficiency anaemia. It is given as oral dosage as the anhydrous form in usual dose units of 245 mg and as a hydrated form in usual dose units of 275 mg; both forms provide about 33 mg of iron per dose unit; wherein the total dose is generelly up to the equivalent of 200 mg of iron daily.
In the body, the iron content is normally kept constant by regulation of the amount absorbed and the amount lost. If loss is increased, and/or intake inadequate, a negative iron-balance may lead by degrees to depletion of body iron stores, iron deficiency, and eventually to anaemia. Generally, the Iron requirements are increased during infancy, puberty, pregnancy, and during menstruation, and iron-deficiency anaemias, which are most common in women and children. Further the most common cause in adult males and postmenopausal women is blood loss, usually from the gastrointestinal tract. Iron deficiency usually results in a microcytic, hypochromic anaemia, but the diagnosis of iron deficiency should be confirmed, if there is any doubt, by measurement of serum ferritin, erythrocyte protoporphyrin, or total iron binding capacity (transferrin). According to the
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prescription of the doctor Iron therapy can begin once deficiency is confirmed, but the underlying cause of the deficiency should still be sought and treated.
Reviews have been carried out or the prevention and control of iron-deficiency anaemias. Almost all iron-deficiency anaemias respond readily to treatment with iron. The treatment of choice is oral administration of a ferrous salt (ferrous iron is better absorbed than ferric iron). Many iron compounds have been used for this purpose, but do not offer any real advantage over the simple ferrous fumarate, gluconate, or sulfate salts. The usual adult dose is sufficient of these salts to supply about 100 to 200 mg of elemental iron daily (for the elemental iron content of various iron salts, like ferrous ascorbate, ferrous aspartate tetrahydrate, ferrous chloride, ferrous fumarate, ferrous gluconate dihydrate, ferrous succinate anhydrous, ferrous sulfate dried and ferrous sulfate heptahydrate).
A rise in haemoglobin concentration of about 0.1 g daily is considered a positive response. Haemoglobin response is greatest in the first few weeks of therapy and is proportional to the severity of the original anaemia. Once haemoglobin concentrations have risen to the normal range, iron therapy should be continued for a further 3 months to aid replenishment of iron stores.
Effectively, oral iron has been given with agents, such as ascorbic acid, that enhance iron absorption significantly if given in large enough doses, but such combinations may increase the incidence of adverse effects. Also, modified-release preparations have been used in patients intolerant of ordinary formulations of iron but some consider them therapeutically ineffective. Failure to respond to oral iron after about 3 weeks of therapy may be indicative of non-compliance, continued blood loss with inadequate replacement of iron, malabsorption, wrong diagnosis, or other complicating factors, and the treatment should be reassessed.
Parenteral iron therapy is rarely indicated, may produce severe adverse effects, and should be reserved for patients who are genuinely intolerant of oral iron, persistently non-compliant, who have gastrointestinal disorders exacerbated by oral iron therapy, continuing blood loss too severe for oral treatment to provide sufficient iron, or for those
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unable to absorb iron adequately from the gastrointestinal tract. The most common parenteral forms are iron sorbitol (given intramuscularly), iron sucrose (given intravenously), and iron dextran (given intravenously, in which case the complete iron requirement may be given as a single infusion, or intramuscularly).
Exceptionally, in patients with profound anaemia, blood transfusion may be necessary to restore dangerously low concentrations of haemoglobin. This may be the case, for example, in elderly patients with long-standing iron deficiency leading to heart failure. Hence, there is a need to provide appropriate iron therapy to the patients such as by iron ascorbate.
BACKGROUND OF THE INVENTION
GB 486,757 patent is issued to Fabrik Promonta G.m.b.H on June 09, 1938, entitled "Method of manufacturing a stable organic ferro-compound". This patent discloses process for the preparation of ferrous ascorbate, wherein ascorbic acid is reacted with freshly prepared solution containing ferrous chloride. The hydrochloric acid set free is then partly neutralized by gradual addition of sodium bicarbonate to adjust the reaction mass pH to 6.0. The resulting solution is evaporated under reduced pressure on water bath temperature to get the ferrous ascorbate, which contains sodium chloride salt. It needs one more purification step to get desire quality of ferrous ascorbate .
In GB 486,757 patent discloses another process for the preparation of the ferrous ascorbate, wherein ferrous sulphate is reacted with barium salt of ascorbic acid in water under nitrogen atmosphere. After completion of the reaction, the separated solids are filtered. The aqueous solution is evaporated under reduced pressure to get the ferrous ascorbate.
GB 488,784 patent discloses process for the preparation of ferrous ascorbate, wherein ascorbic acid is dissolved in water then N/10 solution of sodium hydroxide is added. To this solution of sodium ascorbate, which is reacted with ferric chloride solution to get clear violet solution. It is subjected to evaporation under reduced pressure in a CO2 to get
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ferrous ascorbate. The ferrous ascorbate contains sodium chloride. The sodium chloride can be removed by fraction crystallization
The major disadvantageous for making ferrous ascorbate according to the prior art as follows are as follows:
1) Repeated purifications steps are needed to get the desired quality of ferrous ascorbate.
2) The ferrous ascorbate process involved water distillation under vacuum. The water distillation under vacuum in the plant level is difficult, time consuming, costly, requires more utilities and laborious. The product is continuously under heating, it leads to decomposition, inturn gives lower yield of the ferrous ascorbate. Even if the isolation method can be slightly improved by precipitating the solid by use of other cosolvents such as water miscible organic solvent like alcohol / ketones / ether, the quantities of the said co-solvent and costs of the same can be prohibitative.
3) The solid ferrous ascorbate is isolated from the water by filtration. The part of final product is also present in the mother liquor. The second crop isolation and purification steps are necessary to get the desired yield and quality of the product.
OBJECT OF THE INVENTION
An object of the invention is to provide improved and industrially feasible process for the preparation of ferrous ascorbate.
Still next object of the present invention relates manufacture of ferrous ascorbate convenient for industrial process.
SUMMARY OF THE INVENTION
One aspect of the present invention provides improved and industrially feasible process for the preparation of ferrous ascorbate.
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Another aspect of the invention is a process for the preparation of ferrous ascorbate comprising the steps of:
(a) reacting alkali or alkaline earth metal salt or its hydroxide in an aqueous medium with ferrous or ferric salt, followed by treatment with ascorbic acid to obtain ferrous ascorbate in solution, wherein the addition of ferrous or ferric salt and ascorbic acid is in any order;
(b) filtering the solution of step (a); and
(c) subjecting the solution of step (b) to spray drying to obtain solid ferrous ascorbate.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the improved and industrially feasible process for the preparation of ferrous ascorbate, wherein ferrous salts are isolated and reacted with ascorbic acid followed by spray drying technique to get the ferrous ascorbate with improved yield.
Particularly, the invention provides a process for the preparation of ferrous ascorbate comprising the steps of:
(a) reacting alkali or alkaline earth metal salt or its hydroxide in an aqueous medium with ferrous or ferric salt, followed by treatment with ascorbic acid to obtain ferrous ascorbate in solution, wherein the addition of ferrous or ferric salt and ascorbic acid is in any order;
(b) filtering the solution of step (a) ; and
(c) subjecting the solution of step (b) to spray drying to obtain solid ferrous ascorbate.
The ferrous ascorbate obtained by the above process is of desired and acceptable quality, particle size, bulk density and moisture content.
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The alkali or alkaline earth metal is selected from the group comprising of sodium, potassium, barium and calcium. The preferred alkali metal is sodium. The cationic part is selected from the group comprising of carbonate, bicarbonate. The preferred one is carbonate. The preferred alkali metal salt is sodium carbonate.
In another aspect of the present invention, in place of alkali or alkaline earth metal salts, the alkali or alkaline earth metal hydroxide is used and the preferred alkali hydroxide is sodium hydroxide and barium hydroxide.
Sodium carbonate is reacted with ferrous sulphate / ferric chloride in an aqueous medium while maintaining the reaction mass pH between 6-9 at ambient temperature followed by filtration to get ferrous salt. The preferred reaction mass has pH between 7-8. The ferrous salt is separated by filtration, followed by optional washing with water to remove the unwanted salts.
The above isolated ferrous salt is suspended in water and reacted with ascorbic acid, maintaining the reaction mass with pH between 4.0-7.0 at ambient temperature. The preferred reaction pH is between 4.5-6.5. After completion of the reaction, reaction mass is optionally filtered through highflow bed. The clear filtrate is subjected to spray drying to get the desired quality, particle size, bulk density, moisture content and improved yield of ferrous ascorbate.
Particle size distribution is very critical parameter in pharmaceutical composition as it dictates the dissolution pattern. Bulk density is also an important feature as it governs the suitability of the bulk drug during the preparation of pharmaceutical composition, apart from processing and handling of the bulk drug.
In the alternative method, ascorbic acid is reacted with alkali or alkaline earth metal hydroxide as described above.
The ascorbic acid is reacted with barium hydroxide /calcium carbonate in an aqueous medium, while maintaining the reaction mass pH between 7.5- 9.5 at ambient temperature. The preferred reaction mass has pH between 8.0-9.0. Ferrous sulphate /
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A ferric chloride is added at an ambient temperature and maintained the reaction mass pH between 4.5-6.5. The preferred reaction mass pH is 5.0-6.5. After completion of the reaction, reaction mass is filtered through highflow bed. The clear filtrate is subjected to spray drying to get the desired quality, particle size, bulk density, moisture content and improved yield of ferrous ascorbate.
The alkali or alkaline earth metal salts or it's hydroxides are reacted with ferrous sulfate to get corresponding ferrous salts, which are reacted with ascorbic acid in an aqueous medium at slightly acidic or neutral condition followed by filtration to get ferrous ascorbate in mother liquor. Alternatively, ascorbic acid salt can be treated with ferrous salt followed by the filtration to get ferrous ascorbate in mother liquor.
The above obtained ferrous ascorbate in mother liquor is concentrated under reduced pressure to get residue. It needs 2-3 days to form the solid, which can be separated by filtration to get ferrous ascorbate. Isolation of the ferrous ascorbate by this methods involved high vacuum distillation as well as keeping the residue for such a long time.
Another method disclosed herein, to over come the isolation of ferrous ascorbate by using above method. Ferrous ascorbate mother liquor is concentrated under reduced pressure to get the residue containing small quantity of water, which is treated with a water miscible organic solvent such as methanol, ethanol, isopropyl alcohol and acetone and stirred the reaction mass at ambient temperature and cooled the reaction mass to ice bath temperature. The separated solid is filtered and washed with a mixture of water and water miscible organic solvent to get ferrous ascorbate. The major drawback of this process is lower yield of ferrous ascorbate due to the solubility of the ferrous ascorbate in a solvent medium. The solvent used is also required in high volumes and which adds on to the cost of the product. Thus, this method, though devoid of spray drying, is time consuming and costly, wherein the yields are low compared to the yields obtained by spray drying method. The recovery and reuse of the solvent form water involves higher utilities and in-turn the higher cost.
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According to the instant invention, the simple and industrially feasible method for the preparation of ferrous ascorbate is provided herein. Ferrous ascorbate mother liquor obtained by any mean is subjected to spray drying to get ferrous ascorbate with improved yield having desired particle size, bulk density, moisture content and solubility. According to this invention water distillation or use of water miscible solvents are avoided.
The major advantages according to the present invention are as follows:
i) Improved process and industrially feasible manufacturing process of ferrous
ascorbate ii) Obtained better quality of the final product iii) Obtained particle size distribution and bulk density suitable for
pharmaceutical composition iv) Avoided the problems with respect to moisture content v) Avoided the repeated crystallization to get the desired quality of the product, vi) Avoided high vacuum distillation in the manufacturing level, vii) Obtained the product in better yield (according to the procedure analogious to
the prior art (GB 486757) process provides ferrous ascorbate in about 60-65%
(weight / weight), whereas the yield of ferrous ascorbate as obtained by the
invented process is 40% more.
The invention can be further illustrated by the following examples, which however, should not be construed as limiting the scope of the invention.
Examples: 1
Process for the preparation of ferrous ascorbate (by using sodium carbonate') with spray drying:
Ferrous sulphate ( 500 gm; 1.798moles) was charged in to the flask containing water (1200 ml) and stirred for half an hour. 30% Na2C03 solution (187.0 gm, 1.76 moles + water 550 ml) was added and maintained the reaction mass pH between 7.0-8.0. The
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reaction mass was stirred for half an hour, the separated ferrous carbonate was filtered and washed with (500 ml) water to get solid ferrous carbonate. Ascorbic acid (538gm, 3.056 moles) and water 1.5 L was charged in to the flask. Ferrous carbonate slurry (in 500 ml water) was charged at 25-30°C and stirred the reaction mass for two hours. The reaction mass pH is maintained between 4.5 -4.8. After completion of the reaction, the reaction mass was filtered through hyflow bed. Washed the hyflow bed with (500 ml) water. The clear filtrate is subjected to spray drying to get ferrous ascorbate.
(Dry Weight = 550 gm.)
Example: 2
Process for the preparation of ferrous ascorbate (by using sodium hydroxide) without spray drying:
The ferrous sulphate (560 gm; 2.014 moles) was charged in to the flask containing water (1200 ml) and stirred for half an hour. 30% NaOH solution (183.0 gm, 4.5 moles + water 500 ml) was added and maintained the reaction mass pH between 11.0 - 11.5. The reaction mass was stirred for half an hour, the separated solid was filtered and washed with (500 ml) water to get solid ferrous hydroxide. Ascorbic acid (354.8gm, 2.01 moles) and water (1.5L) was charged in to the flask. Ferrous hydroxide slurry (in 500 ml water) was charged at 25-30°C and stirred the reaction mass for two hours. The reaction mass pH was maintained between 6.0 -7.0. Filter the reaction mass through hyflow bed. Concentrate the reaction mass under vacuum to its half volume. Quench the concentrated mass in (2.0 L) isopropanol. Wash the solid material with (200 ml) Acetone, and dry the solid material in Vacuum Tray Drier at 60°C.
(Dry Weight = 367 gm)
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Example:3
Process for the preparation of ferrous ascorbate (by using barium hydroxide-) with spray drying:
The barium hydroxide ( 567.3 gm; 1.83 moles) was charged in to the flask containing (2500 ml) water. Ascorbic acid (537.9 gm; 3.05 moles was added and maintained the reaction mass pH between 8.5-9.0. The ferrous sulphate (500 gm; 1.798 moles ) was added and the reaction mass was stirred for 3 hours under nitrogen atmosphere. After completion of the reaction, the reaction mass was filtered through hyflow bed, washed the hyflow bed with (500 ml) water. The clear filtrate is subjected to spray drying to get ferrous ascorbate. (Dry Weight = 560.0 gm)
Example: 4
Process for the preparation of ferrous ascorbate (by using calcium carbonate) with spray drying:
Ascorbic acid (53.6 gm 0.304 moles) was added in to the flask containing (120 ml) water. The calcium carbonate (21.57 gm; 0.21moles) was added at ambient temperature. The ferrous sulphate (50 gm ; 0.17 moles)was added and the reaction mass pH is maintained between 5.0-6.0, stirred for 2 hours under nitrogen atmosphere. After completion of the reaction, the reaction mass was filtered through hyflow bed, washed the hyflow bed with (50 ml) water. The clear filtrate is subjected to spray drying to get ferrous ascorbate. (Dry Weight = 54.0 gm)
Example: 5
Process for the preparation of ferrous Ascorbate (by using sodium hydroxide) with spray drying:
The ferrous sulphate (456 gm) was charged in to the flask containing water (977 ml) and stirred for half an hour. 30% NaOH solution (149.0gm, + water 407.0 ml) was added and
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maintained the reaction mass pH between 11.0 - 11.5. The reaction mass was stirred for half an hour, the separated solid was filtered and washed with (407.0ml) water to get solid ferrous hydroxide. Ascorbic acid (538.5gm ) and water (1.5L) was charged in to the flask. Ferrous hydroxide slurry (in 500 ml water) was charged at 25-30°C and stirred the reaction mass for two hours. The reaction mass pH was maintained between 6.0 -7.0. Filter the reaction mass through hyflow bed. The clear filtrate is subjected to spray drying to get ferrous Ascorbate.
RAJESHWARI H.]
OF K&S PARTNERS
ATTORNEY FOR THE APPLICANT
(Dry Weight =501.0 gm)
Dated this 24th day of April, 2006

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Documents:

650-MUM-2006-ABSTRACT(10-6-2009).pdf

650-MUM-2006-ABSTRACT(11-4-2007).pdf

650-MUM-2006-ABSTRACT(AMENDED)-(10-6-2009).pdf

650-mum-2006-abstract(granted)-(26-8-2009).pdf

650-MUM-2006-CANCELLED PAGES(10-6-2009).pdf

650-MUM-2006-CLAIMS(10-6-2009).pdf

650-MUM-2006-CLAIMS(11-4-2007).pdf

650-mum-2006-claims(granted)-(26-8-2009).pdf

650-mum-2006-correspondance-received.pdf

650-MUM-2006-CORRESPONDENCE(10-6-2009).pdf

650-MUM-2006-CORRESPONDENCE(13-4-2007).pdf

650-MUM-2006-CORRESPONDENCE(IPO)-(28-8-2009).pdf

650-mum-2006-description (provisional).pdf

650-MUM-2006-DESCRIPTION(COMPLETE)-(10-6-2009).pdf

650-MUM-2006-DESCRIPTION(COMPLETE)-(11-4-2007).pdf

650-mum-2006-description(granted)-(26-8-2009).pdf

650-MUM-2006-FORM 1(10-6-2009).pdf

650-MUM-2006-FORM 1(17-5-2006).pdf

650-MUM-2006-FORM 1(26-4-2006).pdf

650-mum-2006-form 13(10-6-2009).pdf

650-MUM-2006-FORM 18(16-4-2007).pdf

650-MUM-2006-FORM 2(COMPLETE)-(11-4-2007).pdf

650-mum-2006-form 2(granted)-(26-8-2009).pdf

650-MUM-2006-FORM 2(TITLE PAGE)-(10-6-2009).pdf

650-MUM-2006-FORM 2(TITLE PAGE)-(COMPLETE)-(11-4-2007).pdf

650-mum-2006-form 2(title page)-(granted)-(26-8-2009).pdf

650-MUM-2006-FORM 2(TITLE PAGE)-(PROVISIONAL)-(25-4-2006).pdf

650-MUM-2006-FORM 26(10-6-2009).pdf

650-MUM-2006-FORM 3(11-4-2007).pdf

650-MUM-2006-FORM 5(11-4-2007).pdf

650-mum-2006-form-1.pdf

650-mum-2006-form-2.doc

650-mum-2006-form-2.pdf

650-mum-2006-form-3.pdf

650-mum-2006-form-5.pdf

650-MUM-2006-SPECIFICATION(AMENDED)-(10-6-2009).pdf


Patent Number 235783
Indian Patent Application Number 650/MUM/2006
PG Journal Number 36/2009
Publication Date 04-Sep-2009
Grant Date 26-Aug-2009
Date of Filing 26-Apr-2006
Name of Patentee EMCURE PHARMACEUTICALS LTD
Applicant Address R & D CENTRE, T-184, MIDC, BHOSARI, PUNE 411026,
Inventors:
# Inventor's Name Inventor's Address
1 MILIND MORESHWAR GHARPURE Plot No 12/2, F II Block, M.I.D.C. Pimpri, Pune - 411018, Maharashtra, India
2 BABURAO MANIKRAO BHAWAL Plot No 12/2, F II Block, M.I.D.C. Pimpri, Pune - 411018, Maharashtra, India
3 RAJIV PANDURANG SUTAR Plot No 12/2, F II Block, M.I.D.C. Pimpri, Pune - 411018, Maharashtra, India
4 VILAS NATHU DHAKE Plot No 12/2, F II Block, M.I.D.C. Pimpri, Pune - 411018, Maharashtra, India
5 SATISH RAMANLAL MEHTA Plot No 12/2, F II Block, M.I.D.C. Pimpri, Pune - 411018, Maharashtra, India
PCT International Classification Number A61K31/375
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA