TEPZZ_8_97 

ZB_T
(19)

(11) EP 1 819 720 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.:

of the grant of the patent: C07H 23/00 (2006.01) A61P 7/06 (2006.01)
15.05.2013 Bulletin 2013/20 A61K 31/7135 (2006.01)

(21) Application number: 05817906.0 (86) International application number:

PCT/IB2005/003629
(22) Date of filing: 02.12.2005
(87) International publication number:
WO 2006/061685 (15.06.2006 Gazette 2006/24)

(54) A COST-EFFECTIVE PROCESS FOR PREPARATION OF MANUFACTURE OF IRON SUCROSE

KOSTENGÜNSTIGES VERFAHREN ZUR HERSTELLUNG VON EISENSACCHAROSE
PROCEDE ECONOMIQUE DE PREPARATION DE COMPLEXES SUCROSE/FER

(84) Designated Contracting States: • SUTAR, Rajiv Pandurag,

AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Emcure Pharmaceuticals Ltd.
HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI Pune,
SK TR Maharashtra 411 018 (IN)
• MEHTA, Satish Ramanlal,
(30) Priority: 06.12.2004 IN MU12982004 Emcure Pharmaceuticals Ltd
Pune,
(43) Date of publication of application: Maharashtra 411 018 (IN)
22.08.2007 Bulletin 2007/34
(74) Representative: Chantraine, Sylvie Hélène et al
(73) Proprietor: Emcure Pharmaceuticals Limited Cabinet Beau de Loménie
Pune 411 018 158, rue de l’Université
MAH (IN) 75340 Paris Cedex 07 (FR)

(72) Inventors: (56) References cited:

• GHARPURE, Milind Moreshwar, WO-A-2005/000210 WO-A-2005/094202
Emcure Pharmaceuticals IN-A1- 187 116 US-A- 3 821 192
Pune, US-A1- 2004 038 416 US-A1- 2005 123 504
Maharashtra 411 018 (IN) US-A1- 2005 209 187
• BHAWAL, Baburao Manikrao,
Emcure Pharmaceuticals • ’US Pharmacopeia 27 NF 2004’, pages 1025 - 1026
Pune,
Maharashtra 411 018 (IN) Remarks:
The file contains technical information submitted after
the application was filed and not included in this
specification
EP 1 819 720 B1

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent
Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the
Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been
paid. (Art. 99(1) European Patent Convention).

Printed by Jouve, 75001 PARIS (FR)

 EP 1 819 720 B1

Description

FIELD OF THE INVENTION

5 [0001] The present invention relates to a cost-effective process for manufacture of iron sucrose complex.

BACKGROUND OF THE INVENTION

[0002] Iron Sucrose, which belongs to the therapeutic class of haemitinic is a complex of polynuclear iron (III) hydroxide
10 in sucrose having molecular weight approximately between 34,000 and 60,000 daltons, and structural formula [Na2Fe5O8
(OH).3(H2O)]n. m(C12H22O11), where n is the degree of polymerization and m is the number of sucrose molecules
associated with the iron(III) hydroxide.
[0003] Iron sucrose containing 30% sucrose (w/v) is an injectable, which is administered intravenously for replenishing
body iron stores in patients with iron deficiency on chronic hemodialysis and receiving erythropoietin.
15 [0004] There are numerous references in prior art, which disclose methods for preparation of complexes of carbohy-
drates with various metals.
[0005] US 4 746 730 (assigned to Medinianum Farmaceutic) discloses a method for preparation of complexes of iron
and various carbohydrates like fructose and saccharose. The method comprises addition of an aqueous solution of ferric
chloride to a fructose solution followed by addition of aqueous potassium hydroxide solution to get pH between 7.8 and
20 8.5. The complex is obtained by a process of lyophilisation which is very expensive on an industrial scale.
[0006] US 4 994 283 (assigned to Procter and Gamble) discloses a method for preparing iron-sugar carbohydrate
complex, which comprises initial preparation of a complex of calcium and a sugar followed by preparation of the iron-sugar
complex by reaction with an iron source such as ferrous ammonium sulfate and treating the resultant iron-sugar complex
with malic acid to give the desired iron-sugar complex.
25 [0007] The method is quite lengthy as it does not involve the direct preparation of the iron-sugar complex and rather
involves the intermediary of a calcium-sugar complex from which the product is obtained. Further, there is no surety that
the iron-sugar complex obtained will be free from the calcium-sugar complex.
[0008] US2005/0209187 discloses a method for preparing an iron sucrose complex, substantially free of ex-
cipients, for example sucrose free. The method comprises the step of reacting ferric hydroxide and sucrose at
30 100-105°C without controlling pH.
[0009] CA 1 253 821 (assigned to Pfeifer & Langer) discloses a method for preparation of water soluble iron dextran
complex comprising formation of dextran utilizing enzyme and bacteria and subsequently reacting the same with freshly
prepared iron (III) hydroxide. The preparation of iron dextran utilizing enzyme and bacteria is very selective and not
convenient for commercial production.
35 [0010] US 2003/0216566A1 (assigned to Patel, et. al) discloses a method for preparation of a complex of sodium
ferric gluconate in sucrose comprising reaction of sodium gluconate with ferric oxyhydroxide to give sodium ferric glu-
conate which is freeze-dried. The complex thus obtained is added to sucrose solution to give sodium ferric gluconate
in sucrose. Also, the choice of the base selection is critical in the process.
[0011] IN 187116 (assigned to Alkem Laboratories) teaches a method for preparing saccharated iron oxide by reaction
40 of a ferric salt with an aqueous solution of an inorganic base to give ferric oxyhydroxide which on further treatment with
sucrose at pH 6.5 to 7.5 gives saccharin iron oxide.
[0012] Although, it is mentioned in IN 187116 that saccharin iron oxide is obtained at pH 6.5 to 7.5 but it is our finding
that preparation of saccharin iron oxide at pH 6.5 to 7.5 fails as there is no formation of saccharin iron oxide at the said pH.
[0013] WO 2005/094202 A2 (assigned to Navinta LLC) discloses another method for the preparation of Iron sucrose
45 comprising of addition of an inorganic base in a phased manner to an aqueous solution of ferric salts to obtain ferric
hydroxide followed by addition to an aqueous solution of sucrose and heating at a temperature of 100-105°C, followed
by freeze drying of the resulting product. The iron sucrose thus obtained has to be purified to obtain the product conforming
to desired specifications.
[0014] The method disclosed in this patent application utilizes freeze drying for isolating iron sucrose, which is however
50 not suitable for industrial purpose, since the isolation method is very expensive.
[0015] WO 2005/000210 A2 discloses a general method for the preparation of iron-saccharidic complexes, including
iron sucrose. The preparation of iron sucrose disclosed in this patent application involves mixing of the aqueous solution
of the ferric salt and sucrose followed by addition of sodium hydroxide solution to give ferric hydroxide sucrose complex.
This method has the disadvantage of the inability to monitor whether the ferric salt initially added has been completely
55 converted to ferric hydroxide for further reaction with sucrose solution. Therefore, there is every possibility of the iron
sucrose thus formed being contaminated with the ferric salts employed initially and secondly, due to the possible incom-
plete formation of ferric hydroxide, the yield of iron sucrose will be lower, rendering the process unsuitable for industrial
applications. Further, iron sucrose thus obtained has a molecular weight around 1,570,000 daltons (Example 2), which

2
 EP 1 819 720 B1

does not conform to the specification for molecular weight desired by the regulatory authorities (34,000 to 60,000 daltons)
for Iron sucrose.
[0016] Thus the prior art methods have several shortcomings such as

5 i) utilization of freeze drying, which is expensive on industrial scale,

ii) in one of the prior art methods iron sugar complex is prepared through the intermediary of the calcium complex
of the carbohydrate, which is lengthy and more expensive.
iii) glucose is required in conjunction with sucrose for preparation of the iron sucrose complex. Utilization of another
carbohydrate like glucose makes the process more costly.
10 iv) selection of an inorganic base for preparation of ferric oxyhydroxide is critical as inorganic bases like ammonium
hydroxide or sodium hydroxide utilized for preparation of ferric oxyhydroxide fails to give the sodium ferric gluconate
complex with sodium gluconate.

[0017] There is ample information about the iron complexes in the literature, however for the preparation of iron sucrose
15 the information available is scanty.
[0018] Therefore, in view of these shortcomings there is a need for an improved method, which is not only economical
and cost-effective but is also simple and overcomes the drawbacks of prior art methods to give iron sucrose complex
conforming to regulatory standards.
[0019] The present inventors have a simple cost-effective method for preparation of iron-sucrose complex, which
20 comprises reaction of a ferric salt solution with an aqueous solution of an inorganic base at pH between 3.5 and 7.0 to
give ferric oxyhydroxide, which is then treated with sucrose solution at a temperature of 20-100°C and pH 8.0 to 13.0
to give iron-sucrose complex conforming to regulatory specifications.

OBJECT OF THE INVENTION

25
[0020] An object of the present invention is to provide an improved method for preparation of iron sucrose complex,
conforming to regulatory specifications.
[0021] Another object of the invention is to provide an improved method for preparation of iron sucrose complex, which
is simple and cost-effective.
30
SUMMARY OF THE INVENTION

[0022] One aspect of the invention relates to an improved method for preparation of iron source complex in sucrose
by a simple cost-effective method.
35 [0023] Another aspect of the invention relates to an improved process for preparation of iron sucrose complex in
sucrose, which comprises reaction of ferric salts with an inorganic base at pH 3.5 to 7.0 to give ferric oxyhydroxide,
which is then added to a solution of sucrose followed by adjusting the pH of the mixture between 9.0 and 13.0 with an
inorganic base to give iron sucrose complex, which is then isolated by partial concentration of the aqueous mixture and
precipitation, by addition of an organic solvent or mixture thereof to give iron sucrose complex in sucrose conforming to
40 pharmacopoeial specification.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The invention deals with a process of preparing iron sucrose complex, comprising the steps of:
45
a) reacting a ferric salt with a base in a solvent, at a pH between 3.5 and 7.0 and isolating ferric oxyhydroxide,
b) reacting sucrose and ferric oxyhydroxide in an aqueous medium comprising of sodium ions, initially at a pH
between 11.3 and 12.0 at a temperature between 15°C and 40°C, followed by heating to a temperature between
85°C and 100°C and finally adjusting pH between 9.75 and 10.0, and
50 c) isolating iron sucrose complex from the reaction mixture by adjusting pH between 12.0 and 12.5, concentrating
the reaction mixture and adding to an organic solvent or reversely adding the organic solvent to the concentrated
reaction mixture and filtering.

[0025] The present invention describes the preparation of iron (III) sucrose complex in sucrose. Although, we do not
55 wish to be bound by theory, the following is proposed as the Scheme (i.e. Scheme - I) of formation of iron (III) sucrose
comprising the steps of:

3
 EP 1 819 720 B1

10

15

20

a) Preparation of ferric oxy hydroxide at a pH between 3.5 and 7.0, preferably by addition of an inorganic base to
25 a suspension of ferric salt in water at a temperature between 5.0°C and 35°C.

[0026] The ferric salts are selected from a group comprising of ferric chloride, ferric bromide, ferric iodide, ferric acetate,
ferric citrate, ferric nitrate, and ferric sulphate.
[0027] The preferred ferric (III) salt was ferric (III) chloride and ferric (III) nitrate either in anhydrous or hydrated form.
30 [0028] Ferric (III) nitrate or ferric (III) chloride was suspended in water and dissolved by stirring at room temperature.
[0029] An inorganic base or an organic base was added to the mixture. The preferred base was an inorganic base.
[0030] The inorganic base was selected from a group comprising of carbonates or hydroxides of alkali metals like
sodium, potassium or alkaline earth metals like calcium, barium etc or ammonia.
[0031] The preferred inorganic base was sodium carbonate, while the pH was between 3.5 and 7.0, and the preferred
35 pH selected was between 4.0 and 6.0.
[0032] The preferred pH range was between 4.1 and 5.2.
[0033] An aqueous solution of sodium carbonate was added to the mixture.
[0034] The mixture was stirred for 60-90 minutes for complete precipitation of ferric oxyhydroxide, which was then
filtered and washed with water.
40 [0035] The wet cake was utilized for preparing iron sucrose.

b) Addition of ferric oxyhydroxide to an aqueous solution of sucrose at 15-40°C and adjusting the pH of the resultant
mixture with an aqueous solution of an inorganic base between 11.3 and 12.0, followed by heating the reaction
mixture between 85 to 100°C, preferably between 90-95°C and adjusting the pH to 9.75 to 10.0, using an inorganic
45 acid, preferably HCl. Charcoal was optionally added to the mixture, stirred and filtered. The pH of the filtrate was
again adjusted between 12.0 and 12.5, preferably between 12.1 6 0.2 using an inorganic base.

The pH of step (b) is preferably initially adjusted between 11.4 and 11.9. The pH of step (b) can be preferably finally
adjusted between 9.85 and 9.95. The initial temperature of step (b) is advantageously chosen between 25°C and
50 30°C. The final temperature of step (b) is preferably between 90°C and 100°C.

[0036] The inorganic base utilized for adjusting pH of the reaction mixture was selected from hydroxides of alkali
metals like sodium, potassium etc or alkaline earth metals like calcium, barium etc.
[0037] The preferred inorganic base was either sodium hydroxide or potassium hydroxide.
55 [0038] It is pertinent to mention that without the gradual adjustment of pH at selected temperature, it was not possible
to obtain iron sucrose complex in sucrose conforming to pharmacopoeial specification.

c) Isolation of iron sucrose complex preferably by partial concentration of the aqueous solution at reduced pressure

4
 EP 1 819 720 B1

between 40°C and 60°C, followed by addition of a single or mixture of organic solvents to the partially concentrated
mixture or vice-versa to precipitate the iron sucrose complex, which is filtered and optionally washed with an organic
solvent.

5 The pH of step (c) is preferably adjusted between 12.20 and 12.30. The temperature of step (c) can be between
15°C and 40°C, preferably between 25°C and 30°C.

The reaction mixture is cooled to ambient temperature and concentrated.

10 [0039] The residue containing iron sucrose was added to an organic solvent.
[0040] The organic solvents employed for precipitation of the iron sucrose complex was selected from the group
comprising of alcohols, ketones, ethers, amides, and sulfoxides.
[0041] The alcohol was selected from the group comprising of methanol, ethanol, isopropanol, n-propanol, isobutanol,
n-butanol. The preferred alcohol was methanol.
15 [0042] The ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone.
The preferred ketonic solvent was acetone.
[0043] The ethers are selected from the group comprising of tetrahydrofuran, dioxane and diethyl ether. The preferred
ether was tetrahydrofuran.
[0044] The amides are selected from the group comprising of dimethyl formamide, dimethyl acetamide, N-methyl
20 pyrrolidone. The preferred amide was dimethyl formamide.
[0045] The sulfoxide was dimethyl sulfoxide.
[0046] These solvents are either employed alone or in combination thereof.
[0047] Iron sucrose thus obtained was further processed by adding iron sucrose complex to aqueous water-miscible
organic solvent.
25 [0048] The organic solvents employed for reprocessing of the iron sucrose complex was selected from the group
comprising of alcohols, ketones, ethers, amides, and sulfoxides.
[0049] The alcohol was selected from the group comprising of methanol, ethanol, isopropanol, n-propanol, isobutanol,
n-butanol. The preferred alcohol was methanol.
[0050] The amount of water in methanol was selected between 3.0% and 10%.
30 [0051] The mixture was stirred for time between 30 minutes and 300 minutes.
[0052] The mixture was filtered and dried.
[0053] The iron sucrose obtained by the above method has the desired molecular weight between 34,000 and 60,000
daltons and conforms to regulatory specifications.
[0054] The inventors during their investigations and studies found that the preparation of iron sucrose is pH sensitive
35 and heat sensitive. Hence, the inventors have vastly improved the process that the iron sucrose thus prepared is pure
and the conditions employed are such that the iron sucrose complex remains unaffected throughout and pH condi-
tions/heat does not affect it during production stage. Further and surprisingly, the inventors found that even though pH
is adjusted several times during the process, it does not affect the final product. In fact, changes in the pH at selected
temperature assists in preparation of an improved product. The iron sucrose prepared as per the process of the present
40 invention may be employed and used as an injectable or formulated in any pharmaceutically acceptable form including
syrup or suspension. It may also be formulated or used as supplemented in vitamin tablets; it may also be used as food
supplement.
[0055] The process of the invention can further comprise the steps of processing the isolated iron sucrose complex
in sucrose, and comprise the steps of:
45
a) adding the isolated iron sucrose complex in sucrose to aqueous water-miscible organic solvent,
b) stirring the mixture at ambient temperature for a time duration between 30 minutes and 300 minutes,
c) filtering the iron sucrose complex in sucrose and drying.

50 [0056] In this embodiment, the organic solvent used in step (c) is preferably an alcohol, for example an alcohol is
selected from the group comprising of methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, and preferably
methanol.
[0057] In this embodiment, the amount of water in the aqueous water-miscible organic solvent used in step (a) is
preferably between 3% and 10%.
55 [0058] According to another aspect, the invention deals with a process of preparing iron sucrose complex in sucrose,
comprising the steps of:

a) reacting sucrose and ferric oxyhydroxide in an aqueous medium comprising of sodium ions, initially at a pH

5
 EP 1 819 720 B1

between 11.3 and 12.0 at a temperature between 15°C and 40°C, followed by heating to a temperature between
85°C and 100°C and finally adjusting pH between 9.75 and 10.00, and
b) isolating iron sucrose complex in sucrose from the reaction mixture by adjusting pH between 12.0 and 12.5,
concentrating and adding to it an organic solvent or reversely adding the organic solvent to the concentrating reaction
5 mixture and filtering. The final temperature of step (a) is preferably between 90°C and 95°C.
This invention is illustrated by the following examples, but should not be construed to be limited thereto.

EXAMPLE

10 1. Preparation of Iron sucrose from ferric chloride.

[0059] Iron (III) Chloride anhydrous (100 gms, 0.6161 moles) was dissolved in distilled water (3000 ml). Added charcoal
(10.0 gms) to the mixture.. The reaction mass was stirred for 30 minutes, and filtered. A solution of 30% (w/v) Na2CO3
was gradually to the ferric chloride solution and the pH of the reaction mixture adjusted between 4.4 and 4.6 at 24-26°C.
15 Filtered the slurry and washed with water. Slurry of wet cake was made in water (500 ml).
[0060] Prepared a mixture of water (500 ml) & Sucrose (900 gms; 2.629moles). The slurry of ferric oxyhydroxide was
added at 25-30°C. NaOH solution (30%w/v) was then added and pH adjusted between 11.5-11.8. The mixture was
maintained for 10 min. at 25-30°C. The reaction mixture was heated to 90-95°C and the pH adjusted to 9.85-9.95 with
HCl (35%) The mixture was stirred for 2.0-3.0 hours. Added activated charcoal and stirred the mixture for about 30
20 minutes and filtered through 0.2 micron filter. Readjusted the pH to 12.2-12.3 with 30% NaOH solution at 25-30°C and
concentrated under reduced pressure. In another flask charged methanol (5000ml) and added concentrated mass to
obtain iron sucrose and filtered it, washed with methanol (1000 ml) and acetone (1000.0 ml).
[0061] Yield: 420 gms.

25 2. Purification of Iron sucrose

[0062] Iron sucrose complex (1700gms) was added to a mixture of methanol (6975ml) and water (525ml) at 25-30°C
and stirred for 120 minutes. The mixture was filtered, washed with acetone (1500ml) and dried.
[0063] Yield: 1300gms.
30

Claims

1. A process of preparing iron sucrose complex, comprising the steps of:

35
a) reacting a ferric salt with a base in a solvent, at a pH between 3.5 and 7.0 and isolating ferric oxyhydroxide,
b) reacting sucrose and ferric oxyhydroxide in an aqueous medium comprising of sodium ions, initially at a pH
between 11.3 and 12.0 at a temperature between 15°C and 40°C, followed by heating to a temperature between
85°C and 100°C and finally adjusting pH between 9.75 and 10.0, and
40 c) isolating iron sucrose complex from the reaction mixture by adjusting pH between 12.0 and 12.5, concentrating
the reaction mixture and adding to an organic solvent or reversely adding the organic solvent to the concentrated
reaction mixture and filtering.

2. A process according to claim 1, wherein the pH of step (b) is initially adjusted between 11.4 and 11.9.
45
3. A process according to claim 1 or 2, wherein the pH of step (b) is finally adjusted between 9.85 and 9.95.

4. A process according to any one of claims I to 3, wherein the pH of step (c) is adjusted between 12.20 and 12.30.

50 5. A process according to claims 1 to 4, wherein the initial temperature of step (b) is between 25°C and 30°C.

6. A process according to any one of claims I to 5, wherein the final temperature of step (b) is between 90°C and 100°C.

7. A process according to any one of claims 1 to 6, wherein the temperature of step (c) is between 15°C and 40°C.
55
8. A process according to claim 7, wherein the temperature of step (c) is between 25°C and 30°C.

9. A process according to any one of claims 1 to 8, further comprising of processing the isolated iron sucrose complex

6
 EP 1 819 720 B1

in sucrose, comprising the steps of:

a) adding the isolated iron sucrose complex in sucrose to aqueous water-miscible organic solvent,
b) stirring the mixture at ambient temperature for a time duration between 30 minutes and 300 minutes,
5 c) filtering the iron sucrose complex in sucrose and drying.

10. A process according to claim 1 and claim 9, wherein the organic solvent used in step (c) is an alcohol.

11. A process according to claim 10, wherein the alcohol is selected from the group comprising of methanol, ethanol,
10 isopropanol, n-propanol, isobutanol, n-butanol.

12. A process according to claim 11, wherein the preferred alcohol is methanol.

13. A process according to any one of claims 9 to 12, wherein the amount of water in the aqueous water-miscible organic
15 solvent used in step (a) is between 3% and 10%.

14. A process of preparing iron sucrose complex in sucrose, comprising the steps of:

a) reacting sucrose and ferric oxyhydroxide in an aqueous medium comprising of sodium ions, initially at a pH
20 between 11.3 and 12.0 at a temperature between 15°C and 40°C, followed by heating to a temperature between
85°C and 100°C and finally adjusting pH between 9.75 and 10.00, and
b) isolating iron sucrose complex in sucrose from the reaction mixture by adjusting pH between 12.0 and 12.5,
concentrating and adding to it an organic solvent or reversely adding the organic solvent to the concentrating
reaction mixture and filtering.
25
15. A process according to claim 14, wherein the final temperature of step (a) is between 90°C and 95°C.

Patentansprüche
30
1. Verfahren zum Herstellen eines Eisensaccharosekomplexes, umfassend die Schritte:

a) Reagieren eines Eisensalzes mit einer Base in einem Lösungsmittel bei einem pH-Wert von 3,5 bis 7,0 und
Isolieren des Eisenoxyhydroxids,
35 b) Reagieren der Saccharose und des Eisenoxyhydroxids in einem wäßrigen Medium umfassend Natriumionen
bei einem Anfangs-pH-Wert von 11,3 bis 12,0 bei einer Temperatur von 15°C bis 40°C, gefolgt von Erwärmen
auf eine Temperatur von 85°C bis 100°C und Einstellen des End-pH-Wertes von 9,75 bis 10,0, und
c) Isolieren des Eisensaccharosekomplexes aus der Reaktionsmischung durch Einstellen des pH-Wertes auf
12,0 bis 12,5, Konzentrieren der Reaktionsmischung und Hinzufügen eines organischen Lösungsmittels oder
40 umgekehrt Hinzufügen des organischen Lösungsmittels zur konzentrierten Reaktionsmischung und Filtern.

2. Verfahren nach Anspruch 1, wobei der Anfangs-pH-Wert des Schrittes (b) auf 11,4 bis 11,9 eingestellt wird.

3. Verfahren nach Anspruch 1 oder 2, wobei der End-pH-Wert des Schrittes (b) auf 9,85 bis 9,95 eingestellt wird.
45
4. Verfahren nach einem der Ansprüche 1 bis 3, wobei der pH-Wert des Schrittes (c) auf 12,20 bis 12,30 eingestellt wird.

5. Verfahren nach einem der Ansprüche 1 bis 4, wobei die Anfangstemperatur des Schrittes (b) zwischen 25°C und
30°C liegt.
50
6. Verfahren nach einem der Ansprüche 1 bis 5, wobei die Endtemperatur des Schrittes (b) zwischen 90°C und 100°C
liegt.

7. Verfahren nach einem der Ansprüche 1 bis 6, wobei die Temperatur des Schrittes (c) zwischen 15°C und 40°C liegt.
55
8. Verfahren nach Anspruch 7, wobei die Temperatur des Schrittes (c) zwischen 25°C und 30°C liegt.

9. Verfahren nach einem der Ansprüche 1 bis 8, ferner umfassend Verarbeiten des isolierten Eisensaccharosekom-

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 EP 1 819 720 B1

plexes in Saccharose, umfassend die Schritte:

a) Hinzufügen des isolierten Eisensaccharosekomplexes in Saccharose zu einem wäßrigen wassermischbaren

organischen Lösungsmittel,
5 b) Rühren der Mischung bei Umgebungstemperatur für eine Zeitdauer von 30 bis 300 Minuten,
c) Filtern des Eisensaccharosekomplexes in Saccharose und Trocknen.

10. Verfahren nach Anspruch 1 und Anspruch 9, wobei das in Schritt (c) verwendete organische Lösungsmittel Alkohol ist.

10 11. Verfahren nach Anspruch 10, wobei der Alkohol aus der aus Methanol, Ethanol, Isopropanol, n-Propanol, Isobutanol
und n-Butanol bestehenden Gruppe ausgewählt ist.

12. Verfahren nach Anspruch 11, wobei der bevorzugte Alkohol Methanol ist.

15 13. Verfahren nach einem der Ansprüche 9 bis 12, wobei der Wassergehalt in dem in Schritt (b) verwendeten wäßrigen
wassermischbaren organischen Lösungsmittels zwischen 3% und 10% beträgt.

14. Verfahren zum Herstellen eines Eisensaccharosekomplexes in Saccharose, umfassend die Schritte:

20 a) Reagieren von Saccharose und Eisenoxyhydroxyd in einem wäßrigen Medium umfassend Natriumionen,
bei einem Anfangs-pH-Wert von 11,3 bis 12,0 bei einer Temperatur von 15°C bis 40°C, gefolgt von Erwärmen
auf eine Temperatur von 85°C bis 100°C und Einstellen eines End-pH-Wertes von 9,75 bis 10,0, und
b) Isolieren des Eisensaccharosekomplexes in Saccharose aus der Reaktionsmischung durch Einstellen des
pH-Wertes auf 12,0 bis 12,5, Konzentrieren und Hinzufügen eines organischen Lösungsmittels oder umgekehrt
25 Hinzufügen des organischen Lösungsmittels zur konzentrierten Reaktionsmischung und Filtern.

15. Verfahren nach Anspruch 14, wobei die Endtemperatur des Schrittes (a) zwischen 90°C und 95°C liegt.

30 Revendications

1. Procédé de préparation d’un complexe fer-saccharose, comprenant les étapes consistant à :

a) faire réagir un sel ferrique avec une base dans un solvant, à un pH entre 3,5 et 7,0 et isoler l’oxyhydroxyde
35 ferrique,
b) faire réagir le saccharose et l’oxyhydroxyde ferrique dans un milieu aqueux comprenant des ions sodium,
initialement à un pH entre 11,3 et 12,0 à une température entre 15 et 40 °C, puis chauffer jusqu’à une température
entre 85 et 100 °C et ajuster finalement le pH entre 9,75 et 10,0, et
c) isoler le complexe fer-saccharose du mélange réactionnel par ajustement du pH entre 12,0 et 12,5, concentrer
40 le mélange réactionnel et l’ajouter à un solvant organique ou à l’inverse, ajouter le solvant organique au mélange
réactionnel concentré et filtrer.

2. Procédé selon la revendication 1, dans lequel le pH à l’étape (b) est initialement ajusté entre 11,4 et 11,9.

45 3. Procédé selon les revendications 1 ou 2, dans lequel le pH à l’étape (b) est finalement ajusté entre 9,85 et 9,95.

4. Procédé selon l’une quelconque des revendications 1 à 3, dans lequel le pH à l’étape (c) est ajusté entre 12,20 et
12,30.

50 5. Procédé selon les revendications 1 à 4, dans lequel la température initiale à l’étape (b) est entre 25 et 30 °C.

6. Procédé selon l’une quelconque des revendications 1 à 5, dans lequel la température finale à l’étape (b) est entre
90 et 100 °C.

55 7. Procédé selon l’une quelconque des revendications 1 à 6, dans lequel la température à l’étape (c) est entre 15 et 40 °C.

8. Procédé selon la revendication 7, dans lequel la température à l’étape (c) est entre 25 et 30 °C.

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 EP 1 819 720 B1

9. Procédé selon l’une quelconque des revendications 1 à 8, comprenant en outre le traitement du complexe fer-
saccharose isolé dans le saccharose, comprenant les étapes consistant à :

a) ajouter le complexe fer-saccharose isolé dans le saccharose à un solvant organique aqueux miscible à l’eau,
5 b) agiter le mélange à température ambiante pendant une durée comprise entre 30 et 300 minutes,
c) filtrer le complexe fer-saccharose dans le saccharose et sécher.

10. Procédé selon la revendication 1 et la revendication 9, dans lequel le solvant organique utilisé à l’étape (c) est un
alcool.
10
11. Procédé selon la revendication 10, dans lequel l’alcool est choisi dans le groupe comprenant le méthanol, l’éthanol,
l’isopropanol, le n-propanol, l’isobutanol, le n-butanol.

12. Procédé selon la revendication 11, dans lequel l’alcool préféré est le méthanol.
15
13. Procédé selon l’une quelconque des revendications 9 à 12, dans lequel la quantité d’eau dans le solvant organique
aqueux miscible à l’eau utilisé à l’étape (a) est entre 3 et 10 %.

14. Procédé de préparation d’un complexe fer-saccharose dans le saccharose, comprenant les étapes consistant à :
20
a) faire réagir le saccharose et l’oxyhydroxyde ferrique dans un milieu aqueux comprenant des ions sodium,
initialement à un pH entre 11,3 et 12,0 à une température entre 15 et 40 °C, puis chauffer jusqu’à une température
entre 85 et 100 °C et ajuster finalement le pH entre 9,75 et 10,0, et
b) isoler le complexe fer-saccharose dans le saccharose du mélange réactionnel par ajustement du pH entre
25 12,0 et 12,5, le concentrer et l’ajouter à un solvant organique ou à l’inverse, ajouter le solvant organique au
mélange réactionnel concentré et filtrer.

15. Procédé selon la revendication 14, dans lequel la température finale à l’étape (a) est entre 90 et 95 °C.

30

35

40

45

50

55

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 EP 1 819 720 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European
patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be
excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 4746730 A [0005] • US 20030216566 A1, Patel [0010]

• US 4994283 A [0006] • IN 187116 [0011] [0012]
• US 20050209187 A [0008] • WO 2005094202 A2 [0013]
• CA 1253821, Pfeifer & Langer [0009] • WO 2005000210 A2 [0015]

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