CA2195283C - Process for manufacturing iron dextran using ultrafiltration - Google Patents
Process for manufacturing iron dextran using ultrafiltration Download PDFInfo
- Publication number
- CA2195283C CA2195283C CA002195283A CA2195283A CA2195283C CA 2195283 C CA2195283 C CA 2195283C CA 002195283 A CA002195283 A CA 002195283A CA 2195283 A CA2195283 A CA 2195283A CA 2195283 C CA2195283 C CA 2195283C
- Authority
- CA
- Canada
- Prior art keywords
- dextran
- solution
- iron dextran
- ultrafiltration
- product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/16—Feed pretreatment
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
- B01D61/14—Ultrafiltration; Microfiltration
- B01D61/145—Ultrafiltration
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
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- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Water Supply & Treatment (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
A process for manufacturing Iron Dextran comprising, forming a direct complex of dextran with ferric chloride, and using an ultrafiltration membrane having a molecular weight cut off between 5,000 to 50,000 to purify the product.
Description
90030-23 RDF:bw PROCESS FOR MANUFACTURING IRON DEXTRAN
USING ULTRAFILTRATION
It is well known that the so called "IRON DEXTRAN"
preparation has been developed and utilized as a satisfactory product for therapeutic use, as intramuscular injection in animals and intravenous injection in humans for correcting iron deficiencies.
A wide variety of preparations have been utilised for the above purpose. Most preparations of iron dextran are made, using degraded dextran complex with ferric hydroxide and purified alcohol, e.g. isopropyl alcohol, ethyl alcohol, methyl alcohol etc.
The raw dextran is obtained according to known methods by growing organisms, especially leuconostoc mesenteroldes, under carefully controlled conditions in a suitable nutrient medium with high concentration of sugar. Crude dextran is partially hydrolysed by dilute mineral acid. Fractions of different average molecular weight can be precipitated with organic liquid such as isopropyl alcohol, methyl alcohol, ethyl alcohol. This degraded product consists of polymerized glucose in which the anhydroglucose units are linked predominantly by oo-1:6 and to a lesser extent by o0-1:4 linkage.
The dextrans used for most Iron Dextran preparations have molecular weight less than 10,000. After fractionation, dextran is converted to heptonic acid with an alkali metal such as cyanide, or hydrogenated with sodium borohydride as described in US Patent No. 3,234,209.
Further, experience with manufacturing Iron Dextran complex using the above method has indicated loss of dextran and Iron Dextran during precipitation with alcohol and consequent loss of stability of final product. Again due to purification with alcohol. The product from this standard method has pronounced variation such as pH, Dextran content, colour and chemical variation from batch to batch.
We have now discovered a process for manufacturing Iron Dextran, using dextran produced with a known process, which by a direct complex with ferric chloride and, with modified purification method, produces a stable complex with minimum variation from batch to batch.
Purification is done using tightly controlled molecular weight ultrafiltration membranes instead of alcohol precipitation. Ultrafiltration membranes remove all other impurities e.g. chloride, heavy metal, free acid etc. without loss of dextran or Iron Dextran. Using such ultrafiltration membranes also reduces free ferric ions and free ferrous ions in the final product. This increases the stability, reduces the toxicity, and increase the yield of Iron Dextran.
In addition to the above advantages, the new process, reduces the chances of explosion or environmental risk due to lack of alcohol in the process.
Accordingly, we have discovered a process for manufacturing Iron Dextran comprising, forming a direct complex of dextran with ferric chloride, and using an ultrafiltration membrane to purify the product. The ultrafiltration membrane may have a molecular weight cut off between 5,000-50,000. The Fe content of the final product may be between 5-20%. The invention extends to Iron Dextran made by the novel processes described herein which is substantially free of impurities.
Example: 1 A solution of ferric chloride having Fe content of 8.0% is added into a plastic tank.
Separately a 20.0% solution of sodium carbonate is made, and with agitation added to the ferric chloride solution, until the pH of the solution is 1.6.
A solution of dextran having a concentration of about 16.0% is added to the above mixture in a ratio of 1:1.4 (Fe:Dextran), continuously adding the solution of sodium carbonate until the pH of the mixture is 5.5.
USING ULTRAFILTRATION
It is well known that the so called "IRON DEXTRAN"
preparation has been developed and utilized as a satisfactory product for therapeutic use, as intramuscular injection in animals and intravenous injection in humans for correcting iron deficiencies.
A wide variety of preparations have been utilised for the above purpose. Most preparations of iron dextran are made, using degraded dextran complex with ferric hydroxide and purified alcohol, e.g. isopropyl alcohol, ethyl alcohol, methyl alcohol etc.
The raw dextran is obtained according to known methods by growing organisms, especially leuconostoc mesenteroldes, under carefully controlled conditions in a suitable nutrient medium with high concentration of sugar. Crude dextran is partially hydrolysed by dilute mineral acid. Fractions of different average molecular weight can be precipitated with organic liquid such as isopropyl alcohol, methyl alcohol, ethyl alcohol. This degraded product consists of polymerized glucose in which the anhydroglucose units are linked predominantly by oo-1:6 and to a lesser extent by o0-1:4 linkage.
The dextrans used for most Iron Dextran preparations have molecular weight less than 10,000. After fractionation, dextran is converted to heptonic acid with an alkali metal such as cyanide, or hydrogenated with sodium borohydride as described in US Patent No. 3,234,209.
Further, experience with manufacturing Iron Dextran complex using the above method has indicated loss of dextran and Iron Dextran during precipitation with alcohol and consequent loss of stability of final product. Again due to purification with alcohol. The product from this standard method has pronounced variation such as pH, Dextran content, colour and chemical variation from batch to batch.
We have now discovered a process for manufacturing Iron Dextran, using dextran produced with a known process, which by a direct complex with ferric chloride and, with modified purification method, produces a stable complex with minimum variation from batch to batch.
Purification is done using tightly controlled molecular weight ultrafiltration membranes instead of alcohol precipitation. Ultrafiltration membranes remove all other impurities e.g. chloride, heavy metal, free acid etc. without loss of dextran or Iron Dextran. Using such ultrafiltration membranes also reduces free ferric ions and free ferrous ions in the final product. This increases the stability, reduces the toxicity, and increase the yield of Iron Dextran.
In addition to the above advantages, the new process, reduces the chances of explosion or environmental risk due to lack of alcohol in the process.
Accordingly, we have discovered a process for manufacturing Iron Dextran comprising, forming a direct complex of dextran with ferric chloride, and using an ultrafiltration membrane to purify the product. The ultrafiltration membrane may have a molecular weight cut off between 5,000-50,000. The Fe content of the final product may be between 5-20%. The invention extends to Iron Dextran made by the novel processes described herein which is substantially free of impurities.
Example: 1 A solution of ferric chloride having Fe content of 8.0% is added into a plastic tank.
Separately a 20.0% solution of sodium carbonate is made, and with agitation added to the ferric chloride solution, until the pH of the solution is 1.6.
A solution of dextran having a concentration of about 16.0% is added to the above mixture in a ratio of 1:1.4 (Fe:Dextran), continuously adding the solution of sodium carbonate until the pH of the mixture is 5.5.
Transfer the resulting solution into a glass lined reactor and heat at 80 C until the concentration of Fe in the solution is 4.0%. Cool and purify with ult raf ilt rat ion membrane, having the Molecular Weight cutoff 5,000-50,000.
Purification is continued until the Fe concentration is raised to 10.0%, and other impurities are removed, pH:of solution adJusted to 6.5, adding required amount of phenol as preservative. The solution is then filtered and stabilized by heating the solution at 105 C for 3 hours.
Example: 2 A solution of ferric chloride having Fe content of 8.0%
is added into a plastic tank.
Separately a 20.0% of sodium carbonate is made, and with agitation added to the ferric chloride solution, unt i l the pH
of the solution is 1.6.
A solution of dextran having a concentration of about 16.0% is added to the above mixture in a ratio of 1:4 (Fe : Dext ran ), with continuous adding of the so lut ion of sodium carbonate until the pH of the mixture is 6Ø
Transfer the resulting solution into a glass lined reactor and heat at 80 C until the concentration of Fe in the solution is 4.0%. Cool and purify with ultrafiltration membrane (Molecular Weight cutoff 5,000-50,000).
Purif icat ion is continued unt i 1 the Fe concent rat ion is raised to 5.0%, and other impurities are removed. The pH of the solution is adJusted to 6.5, adding the required amount of phenol. The solution is filtered and stabilized by heating the solution at 105 C for 3 hours.
Example: 3 A solution of ferric chloride having Fe content of 8.0%
is added into a plastic tank.
Separately 20.0% solution of sodium carbonate is made, and with agitation added to the ferric chloride solution, until the pH of the solution is 1.6.
A solution of dextran having a concentration of about 16.0% is added to the above mixture in a ratio of 1:1.1 ( Fe : Dext ran ), with cont inuous adding of the solut ion of sodium carbonate until the pH of the mixture is 5.5.
Transfer the resulting solution into a glass lined reactor and heat at 80 C until the concentration of Fe in the solution is 4.0%. cool and purify with ult raf ilt rat ion membrane.
Purification is continued until the Fe concentration is raised to 10.0%, and other impurities are removed, pH:of solution adJusted to 6.5, adding required amount of phenol as preservative. The solution is then filtered and stabilized by heating the solution at 105 C for 3 hours.
Example: 2 A solution of ferric chloride having Fe content of 8.0%
is added into a plastic tank.
Separately a 20.0% of sodium carbonate is made, and with agitation added to the ferric chloride solution, unt i l the pH
of the solution is 1.6.
A solution of dextran having a concentration of about 16.0% is added to the above mixture in a ratio of 1:4 (Fe : Dext ran ), with continuous adding of the so lut ion of sodium carbonate until the pH of the mixture is 6Ø
Transfer the resulting solution into a glass lined reactor and heat at 80 C until the concentration of Fe in the solution is 4.0%. Cool and purify with ultrafiltration membrane (Molecular Weight cutoff 5,000-50,000).
Purif icat ion is continued unt i 1 the Fe concent rat ion is raised to 5.0%, and other impurities are removed. The pH of the solution is adJusted to 6.5, adding the required amount of phenol. The solution is filtered and stabilized by heating the solution at 105 C for 3 hours.
Example: 3 A solution of ferric chloride having Fe content of 8.0%
is added into a plastic tank.
Separately 20.0% solution of sodium carbonate is made, and with agitation added to the ferric chloride solution, until the pH of the solution is 1.6.
A solution of dextran having a concentration of about 16.0% is added to the above mixture in a ratio of 1:1.1 ( Fe : Dext ran ), with cont inuous adding of the solut ion of sodium carbonate until the pH of the mixture is 5.5.
Transfer the resulting solution into a glass lined reactor and heat at 80 C until the concentration of Fe in the solution is 4.0%. cool and purify with ult raf ilt rat ion membrane.
Purification is continued until the Fe concentration is raised to 20.0%, and other impurities are removed. The pH of the solution is adJusted to 6.5, adding the required amount of phenol as preservative. The solution is filtered and stabilized by heating solution at 105 C for 3 hours.
The aforesaid examples are for i llust rat ive purposes and do not limit the scope of the invention. Those skilled in the art will appreciate modifications which may be made to the aforedescribed processes which fall within the scope of the invention.
The aforesaid examples are for i llust rat ive purposes and do not limit the scope of the invention. Those skilled in the art will appreciate modifications which may be made to the aforedescribed processes which fall within the scope of the invention.
Claims (5)
1. A process for manufacturing Iron Dextran comprising, forming a direct complex of dextran with ferric chloride, and using an ultrafiltration membrane to purify the product.
2. The process of claim 1 wherein the ultrafiltration membrane has a molecular weight cutoff between 5,000 to 50,000.
3. The process of claim 1 wherein the Fe content of the product is between 5 to 20%.
4. The process of claim 2 wherein the Fe content of the product is between 5 to 20%.
5. An Iron Dextran product made by the process of claim 1, 2, 3 or 4 which is substantially free of impurities.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002195283A CA2195283C (en) | 1997-01-16 | 1997-01-16 | Process for manufacturing iron dextran using ultrafiltration |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002195283A CA2195283C (en) | 1997-01-16 | 1997-01-16 | Process for manufacturing iron dextran using ultrafiltration |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2195283A1 CA2195283A1 (en) | 1998-07-16 |
| CA2195283C true CA2195283C (en) | 2008-07-22 |
Family
ID=4159676
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002195283A Expired - Fee Related CA2195283C (en) | 1997-01-16 | 1997-01-16 | Process for manufacturing iron dextran using ultrafiltration |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2195283C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101585887B (en) * | 2008-05-22 | 2011-12-14 | 中国科学院过程工程研究所 | Method for desalting and concentrating dextriferron complex compound aqueous solution by nanofiltration technology |
| CN104829745A (en) * | 2015-04-29 | 2015-08-12 | 江西华太药业有限公司 | Iron dextran and preparation method thereof |
| CN110183548A (en) * | 2019-06-28 | 2019-08-30 | 瑞普（天津）生物药业有限公司 | A kind of preparation method and applications of low molecular weight dextran iron |
| US11590097B2 (en) | 2002-10-23 | 2023-02-28 | Vifor (International) Ag | Aqueous iron carbohydrate complexes, their production and medicaments containing them |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMO20050056A1 (en) | 2005-03-15 | 2006-09-16 | Biofer Spa | PROCESS FOR THE PREPARATION OF TRIVALENT IRON COMPLEXES WITH MONO-, DI- AND POLISACCARIDI SUGARS. |
| WO2007081744A2 (en) | 2006-01-06 | 2007-07-19 | Luitpold Pharmaceuticals, Inc. | Methods and compositions for administration of iron |
| CN103224571B (en) * | 2013-04-08 | 2015-04-29 | 江苏久吾高科技股份有限公司 | Method for purifying polysaccharide iron complex based on ultrafiltration membrane method |
| CN106526050B (en) * | 2015-09-15 | 2018-06-19 | 河北远征药业有限公司 | The content assaying method of phenol in a kind of iron dextran injection |
| CN113480678B (en) * | 2021-08-06 | 2022-03-25 | 江西华太药业有限公司 | Iron dextran synthesizing method and its dispersing tablet |
-
1997
- 1997-01-16 CA CA002195283A patent/CA2195283C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11590097B2 (en) | 2002-10-23 | 2023-02-28 | Vifor (International) Ag | Aqueous iron carbohydrate complexes, their production and medicaments containing them |
| CN101585887B (en) * | 2008-05-22 | 2011-12-14 | 中国科学院过程工程研究所 | Method for desalting and concentrating dextriferron complex compound aqueous solution by nanofiltration technology |
| CN104829745A (en) * | 2015-04-29 | 2015-08-12 | 江西华太药业有限公司 | Iron dextran and preparation method thereof |
| CN110183548A (en) * | 2019-06-28 | 2019-08-30 | 瑞普（天津）生物药业有限公司 | A kind of preparation method and applications of low molecular weight dextran iron |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2195283A1 (en) | 1998-07-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20150116 |