CA2630413A1 - Process for recovery of iopromide, suitable for pharmaceutical purposes, from mother liquors - Google Patents
Process for recovery of iopromide, suitable for pharmaceutical purposes, from mother liquors Download PDFInfo
- Publication number
- CA2630413A1 CA2630413A1 CA002630413A CA2630413A CA2630413A1 CA 2630413 A1 CA2630413 A1 CA 2630413A1 CA 002630413 A CA002630413 A CA 002630413A CA 2630413 A CA2630413 A CA 2630413A CA 2630413 A1 CA2630413 A1 CA 2630413A1
- Authority
- CA
- Canada
- Prior art keywords
- iopromide
- pharmaceutical purposes
- process according
- crystallization
- recovery
- 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.)
- Granted
Links
- DGAIEPBNLOQYER-UHFFFAOYSA-N iopromide Chemical compound COCC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I DGAIEPBNLOQYER-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 229960002603 iopromide Drugs 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000011084 recovery Methods 0.000 title claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 239000012452 mother liquor Substances 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- -1 dihydroxypropyl-methylamino group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B63/00—Purification; Separation; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention relates to a method for recovering iopromide that is suitable for pharmaceutical purposes by thermally treating the mother liquors or the second crystallizate in a reactor and then crystallizing the same.
Description
Process for Recovery of lopromide, Suitable for Pharmaceutical Purposes, from Mother Liquors.
The invention relates to a process for recovery of iopromide, suitable for pharmaceutical purposes, by heat treatment of mother liquors or dissolved secondary crystallizate in a reactor and subsequent crystallization.
lopromide, 5-methoxyacetylamino-2,4,6-tTiiodo-isophthalic acid-[(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl)]-diamide, (DE 196 41 178 C and EP 0 015 B), is an iodine-containing x-ray contrast med9um with the following chemical structure:
H
O N
OH
Fi O
(opromid [Iopromide]
The bulky iodine atoms prevent, to a great extent, the free rotation of the bond, identified by 1 in the structural fonnu]a, between the aromatic ring and the amide group with the dihydroxypropyl-methylamino group by the presence of the N-methyl group, so that two atropisomers that are thermally quite stable occur. Such atropisomers are described in, i.a., "Recent Advances in Atropisomerism" by M. Oki in the journal "Topics in Stereochemistry," 1983, Volume 14, pages 1-81, and Tetrahedron Letters No.
38, pages 4593-4598, 1966. In the case of one of the atropisomers, the substituted nitrogen atom lies above the ring plane; with other isomers, it lies below the ring plane.
The two atropisomeric compounds (isomer 1 and isomer 2) are different in their physical properties, especially in their solubilities in water and organic solvents.
Only iopromide of a certain composition relative to these atropisomers is allowed as an x-ray contrast medium (40-51% isomer I and 49-60% isomer 2).
Iopromide for pharmaceutical purposes is obtained by crystallization from ethanol. In this connection, a mixture that consists of about 48% isomer 1 and about 52%
isomer 2 accumulates regularly. The mother liquor contains the isomer I at about 60%
and the isomer 2 at only up to about 40%. For this reason, only a secondary crystallizate with a false composition relative to the atropisomers can be recovered from the mother liquor (contains too much isomer 1).
In the production of iopromide, a final crystallization that consists of alcohol is performed herein. In this connection, a proportion of about 10% of iopromide remains in dissolved form in the mother liquor, which becomes apparent as a loss of yield.
Earlier tests -- to crystallize out additionai iopromide from the accumulating mother liquors by secondary crystallization and thus to increase the yield --failed, since the iopromide K2 recovered from the mother liquors is not in accordance with specifications with respect to the atropisomeric ratio. This behavior can be attributed to the fact that certain atropisomers preferably accumulate in the mother liquor.
Object of the Invention:
The production processes for iopromide that are known from the prior art herein exhibit the drawback that a higher loss in yield must be tolerated and no technical process exists that allows iopromide, which is in accordance with specifications with respect to the atropisomeric ratio and thus can be used for pharmaceutical purposes, to be recovered from the mother liquors.
Resolution of the Invention:
The above-described drawbacks could be resolved, surprisingly enough, in that first a K2 is recovered from the iopromide, pure mother liquor, by a suitable secondary crystallization, which then is isomerized in a continuous tubutar-flow reactor in accordance with specifications by a suitable beat treatment, without significant decomposition of the substance occurring. The invention thus contains a process for recovery of iopromide and iopromide mother liquors, suitable for pharmaceutical purposes, or solutions of the secondary and subsequent crystallizates by heat treatment of the solution, preferably in a tubular-flow reactor at 100-300 C1 advantageously at 200-220 C, and then quick cooling to room temperature and crystallization. The heat treatment in a flow reactor is advantageously carried out in aqueous solution at hydrodynarnic dwell times of I to 60 minutes. The special embodiments are cited in the claims. The total yield of iopromide can be increased quite significantly by this process according to the invention, such that the economic efficiency increases. In addition, less halogen-containing waste accumulates.
Description of the Process in Detail:
First, a secondary crystallizate is recovered from the iopromide, pure mother liquors, by the ethanolic mother liquors being concentrated by evaporation by the factor 2-16 and being dissolved in an alcohol at elevated temperature. Examples of suitable alcohols are alkanols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol. Ethanol, 1-propanol and 2-propanol are preferably used, especially preferably 1-propanol, since the crystallization from this solvent takes place especially quickly and completely and thus is economical. To achieve the crystallization, it can be completely inoculated with iopromide. The K2 crystallizate is then isolated, washed and dried according to known methods.
Example 1:
Production of the K2 Crystallizate 12,000 g of iopromide, pure mother liquor (solid content about 6.2%), is concentrated by evaporation in a vacuum to form viscous oil of 892 g. 877 g of this residue is mixed in a suitable reaction vessel at a bath temperature of 65 C
with 439 ml of ]-propanol while being stirred. After inoculation with 0.73 g of iopromide, it is fully stirred for another 48 hours at a bath temperature of 65 C, The crystal suspension is then cooled to 20 C, stirred for l hour at this temperature and suctioned off via a suction filter.
After washing with 4 portions of 110 ml of ethanol, the secondary crystal lizate is dried at 40 C in a vacuum-drying oven.
Yield; 363.8 g (about 52% of the experiment) The secondary crystallizate that is obtained from the mother liquor has the following atropisomeric ratio:
HPLC Specification Result Isomer 1 40.0 - 51.0% 62.2 %
Isomer 2 49,0 - 60.0% 37.8%
The recovered secondary crystallizate is then brought into solution, i.e., dissolved in water and heat-isomerized in a pressure-resistant, suitably designed, continuously-operating tube reactor. In this connection, hydrodynamic dwell times of I to 60 minutes, preferably 1-30 minutes, especially preferably 1 to 10 minutes, are set at temperatures of between 100 to 300 C, preferably 150 C to 250 C, preferably 180 C to 230 C, especially preferably 200 C to 220 C. In a downstream heat exchanger, the heat-treated iopromide K2 solution is then quickly cooled to room temperature.
Example 2:
Heat-Isomerization of the Iopromide Secondary Crystallizate 280 g of iopromide-K2 from Example I is dissolved in 520 g of water. The solution is then pumped at a volumetric flow rate of 3 ml/minute through a flow pipe that is provided with a pressurization valve of 20 bar at 208-209 C. The flow pipe that is used has an inside diameter of 1.7526 mm and a heated length of 5.5 m (see Figure 1).
A solution of the isomerized iopromide secondary crystallizate is then purified via ion-exchange columns and crystallized from ethanol.
The yield of the iopromide that is crystallized from ethanol is approximately 80%
of the experiment relative to the secondary crystallizate that is used in the isomerization.
The crystal]izate shows a content after HPLC (standard method) of greater than 97.5% relative to the extemal standard and has the following atropisomeric ratio:
HPLC Specification Result Isomer 1 40.0 - 51.0% 49.4%
Isomer 2 49.0 - 60.0% 50.6%
The invention relates to a process for recovery of iopromide, suitable for pharmaceutical purposes, by heat treatment of mother liquors or dissolved secondary crystallizate in a reactor and subsequent crystallization.
lopromide, 5-methoxyacetylamino-2,4,6-tTiiodo-isophthalic acid-[(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl)]-diamide, (DE 196 41 178 C and EP 0 015 B), is an iodine-containing x-ray contrast med9um with the following chemical structure:
H
O N
OH
Fi O
(opromid [Iopromide]
The bulky iodine atoms prevent, to a great extent, the free rotation of the bond, identified by 1 in the structural fonnu]a, between the aromatic ring and the amide group with the dihydroxypropyl-methylamino group by the presence of the N-methyl group, so that two atropisomers that are thermally quite stable occur. Such atropisomers are described in, i.a., "Recent Advances in Atropisomerism" by M. Oki in the journal "Topics in Stereochemistry," 1983, Volume 14, pages 1-81, and Tetrahedron Letters No.
38, pages 4593-4598, 1966. In the case of one of the atropisomers, the substituted nitrogen atom lies above the ring plane; with other isomers, it lies below the ring plane.
The two atropisomeric compounds (isomer 1 and isomer 2) are different in their physical properties, especially in their solubilities in water and organic solvents.
Only iopromide of a certain composition relative to these atropisomers is allowed as an x-ray contrast medium (40-51% isomer I and 49-60% isomer 2).
Iopromide for pharmaceutical purposes is obtained by crystallization from ethanol. In this connection, a mixture that consists of about 48% isomer 1 and about 52%
isomer 2 accumulates regularly. The mother liquor contains the isomer I at about 60%
and the isomer 2 at only up to about 40%. For this reason, only a secondary crystallizate with a false composition relative to the atropisomers can be recovered from the mother liquor (contains too much isomer 1).
In the production of iopromide, a final crystallization that consists of alcohol is performed herein. In this connection, a proportion of about 10% of iopromide remains in dissolved form in the mother liquor, which becomes apparent as a loss of yield.
Earlier tests -- to crystallize out additionai iopromide from the accumulating mother liquors by secondary crystallization and thus to increase the yield --failed, since the iopromide K2 recovered from the mother liquors is not in accordance with specifications with respect to the atropisomeric ratio. This behavior can be attributed to the fact that certain atropisomers preferably accumulate in the mother liquor.
Object of the Invention:
The production processes for iopromide that are known from the prior art herein exhibit the drawback that a higher loss in yield must be tolerated and no technical process exists that allows iopromide, which is in accordance with specifications with respect to the atropisomeric ratio and thus can be used for pharmaceutical purposes, to be recovered from the mother liquors.
Resolution of the Invention:
The above-described drawbacks could be resolved, surprisingly enough, in that first a K2 is recovered from the iopromide, pure mother liquor, by a suitable secondary crystallization, which then is isomerized in a continuous tubutar-flow reactor in accordance with specifications by a suitable beat treatment, without significant decomposition of the substance occurring. The invention thus contains a process for recovery of iopromide and iopromide mother liquors, suitable for pharmaceutical purposes, or solutions of the secondary and subsequent crystallizates by heat treatment of the solution, preferably in a tubular-flow reactor at 100-300 C1 advantageously at 200-220 C, and then quick cooling to room temperature and crystallization. The heat treatment in a flow reactor is advantageously carried out in aqueous solution at hydrodynarnic dwell times of I to 60 minutes. The special embodiments are cited in the claims. The total yield of iopromide can be increased quite significantly by this process according to the invention, such that the economic efficiency increases. In addition, less halogen-containing waste accumulates.
Description of the Process in Detail:
First, a secondary crystallizate is recovered from the iopromide, pure mother liquors, by the ethanolic mother liquors being concentrated by evaporation by the factor 2-16 and being dissolved in an alcohol at elevated temperature. Examples of suitable alcohols are alkanols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol. Ethanol, 1-propanol and 2-propanol are preferably used, especially preferably 1-propanol, since the crystallization from this solvent takes place especially quickly and completely and thus is economical. To achieve the crystallization, it can be completely inoculated with iopromide. The K2 crystallizate is then isolated, washed and dried according to known methods.
Example 1:
Production of the K2 Crystallizate 12,000 g of iopromide, pure mother liquor (solid content about 6.2%), is concentrated by evaporation in a vacuum to form viscous oil of 892 g. 877 g of this residue is mixed in a suitable reaction vessel at a bath temperature of 65 C
with 439 ml of ]-propanol while being stirred. After inoculation with 0.73 g of iopromide, it is fully stirred for another 48 hours at a bath temperature of 65 C, The crystal suspension is then cooled to 20 C, stirred for l hour at this temperature and suctioned off via a suction filter.
After washing with 4 portions of 110 ml of ethanol, the secondary crystal lizate is dried at 40 C in a vacuum-drying oven.
Yield; 363.8 g (about 52% of the experiment) The secondary crystallizate that is obtained from the mother liquor has the following atropisomeric ratio:
HPLC Specification Result Isomer 1 40.0 - 51.0% 62.2 %
Isomer 2 49,0 - 60.0% 37.8%
The recovered secondary crystallizate is then brought into solution, i.e., dissolved in water and heat-isomerized in a pressure-resistant, suitably designed, continuously-operating tube reactor. In this connection, hydrodynamic dwell times of I to 60 minutes, preferably 1-30 minutes, especially preferably 1 to 10 minutes, are set at temperatures of between 100 to 300 C, preferably 150 C to 250 C, preferably 180 C to 230 C, especially preferably 200 C to 220 C. In a downstream heat exchanger, the heat-treated iopromide K2 solution is then quickly cooled to room temperature.
Example 2:
Heat-Isomerization of the Iopromide Secondary Crystallizate 280 g of iopromide-K2 from Example I is dissolved in 520 g of water. The solution is then pumped at a volumetric flow rate of 3 ml/minute through a flow pipe that is provided with a pressurization valve of 20 bar at 208-209 C. The flow pipe that is used has an inside diameter of 1.7526 mm and a heated length of 5.5 m (see Figure 1).
A solution of the isomerized iopromide secondary crystallizate is then purified via ion-exchange columns and crystallized from ethanol.
The yield of the iopromide that is crystallized from ethanol is approximately 80%
of the experiment relative to the secondary crystallizate that is used in the isomerization.
The crystal]izate shows a content after HPLC (standard method) of greater than 97.5% relative to the extemal standard and has the following atropisomeric ratio:
HPLC Specification Result Isomer 1 40.0 - 51.0% 49.4%
Isomer 2 49.0 - 60.0% 50.6%
Claims (8)
1. Process for recovery of iopromide, suitable for pharmaceutical purposes, from iopromide mother liquor by heat treatment of the mother liquor in a reactor and subsequent crystallization.
2. Process for recovery of iopromide, suitable for pharmaceutical purposes, by heat treatment of the secondary or subsequent crystallizate, dissolved in a solvent in a reactor and subsequent crystallization.
3. Process according to claim 1 or 2, in which iopromide that is contained in the mother liquor or the secondary or subsequent crystallizate has an isomeric ratio that is unsuitable for pharmaceutical purposes and is obtained by heat treatment in a tubular-flow reactor, subsequent cooling to room temperature and crystallization.
4. Process according to claim 1, 2 or 3, in which the heat treatment in a tubular-flow reactor is carried out at 100-300°C.
5. Process according to at least one of claims 1-3, in which the crystallization is carried out from an alcohol.
6. Process according to at least one of the processes 1-5, whereby the iopromide amounts that are suitable for pharmaceutical purposes and that are in accordance with specifications are obtained by temperature treatment of the atropisomers that are dissolved in a solvent.
7. Process according to at least one of claims 1-6, whereby the hydrodynamic dwell times of the atropisomers that are dissolved in a solvent are in the tubular-flow reactor for 1 to 60 minutes.
8. Process according to claim 7, in which water is used as a solvent.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE200510059191 DE102005059191B4 (en) | 2005-12-05 | 2005-12-05 | Process for the recovery of pharmaceutically acceptable iopromide from mother liquors |
| DE102005059191.4 | 2005-12-05 | ||
| US74817505P | 2005-12-08 | 2005-12-08 | |
| US60/748,175 | 2005-12-08 | ||
| PCT/EP2006/010943 WO2007065534A1 (en) | 2005-12-05 | 2006-11-10 | Method for recovering iopromide suitable for pharmaceutical purposes from mother liquors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2630413A1 true CA2630413A1 (en) | 2007-06-14 |
| CA2630413C CA2630413C (en) | 2013-06-25 |
Family
ID=37773154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2630413A Expired - Fee Related CA2630413C (en) | 2005-12-05 | 2006-11-10 | Process for recovery of iopromide, suitable for pharmaceutical purposes, from mother liquors |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1960348A1 (en) |
| JP (1) | JP2009518325A (en) |
| KR (1) | KR20080073369A (en) |
| CA (1) | CA2630413C (en) |
| WO (1) | WO2007065534A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100976097B1 (en) * | 2008-12-05 | 2010-08-16 | 주식회사 대웅제약 | Method for selective crystallization of iopromide z isomer |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2909439A1 (en) * | 1979-03-08 | 1980-09-18 | Schering Ag | NEW NON-ionic x-ray contrast agents |
| GB9720969D0 (en) * | 1997-10-02 | 1997-12-03 | Nycomed Imaging As | Process |
-
2006
- 2006-11-10 WO PCT/EP2006/010943 patent/WO2007065534A1/en active Application Filing
- 2006-11-10 JP JP2008543678A patent/JP2009518325A/en active Pending
- 2006-11-10 EP EP06818545A patent/EP1960348A1/en not_active Withdrawn
- 2006-11-10 KR KR1020087016311A patent/KR20080073369A/en not_active Application Discontinuation
- 2006-11-10 CA CA2630413A patent/CA2630413C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP1960348A1 (en) | 2008-08-27 |
| JP2009518325A (en) | 2009-05-07 |
| WO2007065534A1 (en) | 2007-06-14 |
| CA2630413C (en) | 2013-06-25 |
| KR20080073369A (en) | 2008-08-08 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20141110 |