MXPA03006215A - An improved process for preparing pure ondansetron hydrochloride dihydrate. - Google Patents
An improved process for preparing pure ondansetron hydrochloride dihydrate.Info
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Abstract
An improved method for preparing dimethylamino-methyl-carbazolone and ondansetron base. A recrystallization process for preparing pure ondansetron hydrochloride dihydrate with a purity of at least 99.0% is also disclosed.
Description
AN IMPROVED PROCESS FOR PREPARING PURE DIHYDRATE ONDANSETRON HYDROCHLORIDE
FIELD OF THE INVENTION
The present invention relates to an improved process for preparing dimethylamino-methylcarbazolone. The present invention relates to an improved process for preparing an ondansetron base. The present invention also relates to an improved process for preparing ondansetron dihydrate hydrochloride to obtain pure ondansetron dihydrate hydrochloride.
BACKGROUND OF THE INVENTION
Ondansetron, also called 1,2,3,9-tetrahydro-9-methyl-3- [(2-methyl-lH-imidazol-1-yl) methyl] -4H-carbazol-4-one is a potent serotonin antagonist and highly selective (5-HT3, 3 receptor of 5-hydroxytryptamine) and has the following formula:
Ondansetron is currently available as an antiemetic agent, particularly in chemotherapy for cancer, and in some other uses such as antidepressant, antimigraine and antipsychotic. It is commonly used in the relief of cognitive disorders such as Alzheimer's disease, in the treatment of rhinitis, in psychiatric disorders and for increased surveillance and for the control of narcotic dependence.
U.S. Patent No. 4,695,578, assigned to Glaxo Group
Limited, describes a process for preparing ondansetron and its uses. However, ondansetron prepared according to said process contains impurities and by-products such as 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one.
There is a constant need to improve the method of preparation of ondansetron with high purity that meets the standards for clinical uses.
OBJECTIVES AND EXTRACT OF THE INVENTION
The known methods of preparation of ondansetron fail to describe a high purity and color pharmaceutically. An object of the present invention is to satisfy a need for high purity (ie at least 99.0%) and improved color.
Another objective of the present invention is to prepare pure ondansetron dihydrate hydrochloride substantially free of any impurities and by-products such as 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazole-4-one (ex. the exo-methylene byproduct).
Another objective of the present invention is to prepare ondansetron hydrochloride dihydrate having a purity of at least 99.0%. Preferably, the ondansetron hydrochloride dihydrate has a purity of at least 99.5%. More preferably, the ondansetron hydrochloride dihydrate has a purity of at least 99.9%.
Another object of the present invention is to provide a means to prepare dimethylamino-methyl-carbazolone, the process comprises the steps of: a) preparing a methyl-carbazolone solution, b) heating the solution in the presence of dimethyl hydrochloride and paraformaldehyde , c) basify the solution to form a precipitate, d) separate the precipitate from the solution to obtain dimethylamino-methyl carbazolone and e) dry the dimethylamino-methylcarbazolone.
Another objective of the present invention is a process for preparing ondansetron base, the process comprises the steps of: a) preparing a solution of methylimidazole and dimethylamino-methylcarbazolone, b) heating the solution, c) removing a precipitate that contains ondansetron base, d) wash the precipitate, and e) dry the precipitate to obtain the pure ondansetron base.
Preferably, step e) is followed by recrystallization of the ondansetron base in the presence of activated carbon and methanol. Another object of the present invention is a process for preparing ondansetron dihydrate chlorhydrate, the process comprises the steps of: a) preparing a base solution of ondansetron, b) acidifying the solution with hydrogen chloride to form a precipitate, c) wash the precipitate, and d) crystallize dihydrated ondansetron hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
As used in the present invention, the term "exo-methylene by-product" refers to 1, 2, 3, 9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one. It represents one of the main impurities in the preparation of ondansetron. Another impurity in the preparation of ondansetron is the dimer exo-methylene byproduct.
Unless otherwise specified, it refers to% by weight.
As used in the present invention, the term "pure ondansetron" refers to ondansetron which is substantially free of the exo-methylene by-product and which has a high purity of at least 99.0%. As used in the present invention, the term "hydrogen chloride" refers to a gaseous hydrogen chloride or a gaseous hydrogen chloride solution in water.
As used in the present invention, the term "equivalent" refers to the molar equivalent.
As used in the present invention, the term "vacuum distillation" refers to the separation of liquid solids by passing the mixture through a vacuum filter.
As used in the present invention, the term "reflux" refers to the fact that during a chemical process, part of the product stream can be returned to the process to help give an increased conversion or recovery, as in distillation or liquid-liquid extraction.
As used in the present invention, the term "filter cake" refers to a solid or semi-solid material that is separated from a liquid and remains on the filter after pressure filtration.
The present invention is an improved method for preparing a pure ondansetron hydrochloride dihydrate with a purity of at least 99.0%. More preferably, the purity of ondansetron hydrochloride dihydrate is at least 99.5%. More preferably, the purity of ondansetron hydrochloride dihydrate is at least 99.9%.
The present invention provides an improved method for preparing dimethylamino-methylcarbazolone. The present invention also provides an improved method for preparing ondansetron base. The present invention also provides an improved method for preparing pure ondansetron dihydrate hydrochloride.
Preparation of Dimethylamino-Methyl-Carbazolone
The present invention provides a process for preparing dimethylamino-methyl carbazolone comprising the steps of: a) preparing a solution of methylcarbazoline having the formula:
(where R = Ci_4 alkyl) b) heating the solution in the presence of dimethylamine and paraformaldehyde hydrochloride; c) basify the solution to form a precipitate; d) separating the precipitate from the solution to obtain dimethylaminomethylcarbazolone; and e) drying the dimethylamino-methylcarbazolone.
During the heating step, the solution is heated in the presence of dimethylamine hydrochloride and organic solvent paraformaldehyde. Preferably, the organic solvent is acetic acid.
Preferably, one equivalent of methylcarbazolone is refluxed with 1.1 to 1.5 equivalent of dimethylamine hydrochloride and paraformaldehyde. More preferably, one equivalent of methyl carbazolone is refluxed with 1.2 equivalent of dimethylamine hydrochloride and paraformaldehyde. During the heating step, formaldehyde can be used to replace the paraformaldehyde in the reflux reaction.
Preferably, an equivalent of methylcarbazolone is refluxed with 4 to 16 volumes of acetic acid. More preferably, one equivalent of methylcarbazolone is refluxed with 4 volumes of acetic acid.
Preferably, the heating step is carried out at a temperature of 70 ° C to 100 ° C. More preferably, the heating step is carried out at a temperature of 80 ° C to 90 ° C.
Preferably, the heating step is carried out for 6 to 24 hours. More preferably, the heating step is carried out for 6 to 12 hours.
Preferably, the step of separating is performed using filtration.
Preferably, the step of heating is performed without using distillation or vacuum extraction. The step of heating performed in the absence of distillation or vacuum extraction consistently gives a better pure dimethylamino-methyl carbazolone.
The present invention also provides a process for the preparation of pure dimethylamino-methyl carbazolone which further comprises dissolving the filter cake in acetone and treating it with activated carbon and hydrogen chloride.
Preferably, water is added to the basification step which then gives the basic solution to 45% sodium hydroxide (NaOH) at a pH in the range of 13 to 14. Preferentially, the basification step is performed in the presence of celite (10%), it is filtered and dried.
Preferably, the dried cake is dissolved in acetone. Preferably, the dissolved cake is treated with activated carbon and hydrogen chloride to precipitate di methylamino-methylcarbazolone.
Preparation of the Ondansetron Base
The present invention provides a process for the synthesis of the ondansetron base comprising the steps of: a) preparing a solution of methylimidazole and dimethylaminomethylcarbazolone of the formula
alkyl of Ca_4) b) heat the solution; c) removing a precipitate containing ondansetron base from the solution; d) washing the precipitate; e) Dry the precipitate to obtain the ondansetron base.
The present invention also provides a process for the synthesis of a substantially pure ondansetron base, which further comprises the steps of: recrystallizing in the presence of activated carbon and methanol.
During the preparation step of the methylimidazole and dimethylamino-methylcarbazolone solution, preferably from 4 to 6 equivalents of methylimidazole are added to one equivalent of dimethylamino-methylcarbazolone. More preferably, 5 equivalents of methylimidazole are added to 1 equivalent of dimethylaminomethylcarbazolone.
Preferably, the preparation step is carried out in the presence of 10% of celite.
Preferably, the present invention provides a process for preparing ondansetron base which further comprises (after step e) a step of recrystallizing the ondansetron base in the presence of activated carbon and methanol.
Crystallization to Prepare Ondansetron Hydrochloride Pure Dihydrate
The present invention provides an improved method for precuring a pure ondansetron dihydrate hydrochloride. Specifically, the preparation consists of the crystallization of ondansetron hydrochloride dihydrate from the base of ondansetron with water and activated carbon and in the absence of an organic solvent.
The crystallization process of the present invention greatly increases the purity of ondansetron dihydrate hydrochloride and dramatically decreases the content of the exo-methylene byproduct impurity. Preferably, the crystallization step is performed 1 to 3 times. More preferably, the crystallization step is carried out twice.
The present invention provides a crystallization method of ondansetron dihydrate hydrochloride comprising the steps of: a) preparing a base solution of ondansetron; b) acidifying the solution with hydrogen chloride to form a precipitate; c) washing the precipitate; and d) crystallize pure ondansetron dihydrate hydrochloride.
Preferably, the step of preparing the solution is achieved by adding 3 to 7 volumes of water to the base of ondansetron. More preferably, the step of preparing the solution is achieved by adding 5 volumes of water to the base of ondansetron.
Preferably, the step of acidifying is achieved by adding hydrochloric acid. Preferably, 1.0 -1.4 equivalents of 32% (v: v) hydrochloric acid are added to induce precipitation. More preferably, 1.1 equivalent of 32% (v: v) of hydrochloric acid is added to induce precipitation. More preferably, the step of acidifying is achieved at a pH of 1 to 4. More preferably, the step of acidifying is achieved at a pH of 3.
Preferably, the washing step is accomplished using isopropanol. Preferably, 5 ml to 15 ml of isopropanol are used to wash the precipitates. More preferably, 10 ml of isopropanol is used to wash the precipitates.
Preferably, the step of crystallizing is achieved by adding 3 to 5 volumes of water to induce crystallization. More preferably, 4 volumes of water are added to induce crystallization.
Preferably, the step of crystallizing is carried out in the presence of activated carbon. Preferably, the activated carbon is selected from the group consisting of SX -2, CA-1, CXV and SX-1.
Preferably, the step of crystallizing is carried out in the presence of 5% to 15% of activated carbon SX-1. More preferably, the step of crystallizing is carried out in the presence of 10% activated carbon SX-1.
The present invention is also explained by the following examples. The present invention is by no means restricted by these specific examples. An ordinary art connoisseur will understand how to vary the preparations and procedures to obtain the desired results.
EXAMPLES
Example 1: Preparation of Pintethylamino Salt -Methyl-Carbazolone Pure
In 180 ml of glacial acetic acid, 45 grams (0.266 mol, 1.0 equivalent) of methylcarbazolone, 22.4 grams (0.275 mol, 1.22 equivalent) of dimethylamine hydrochloride and 9 grams (0.3) were added. mol, 1.33 equivalent) of paraformaldehyde.
The reaction was maintained at 80 ° C ± 2 ° C for 12 hours, then 540 ml of water and 4.5 grams of high flow were introduced into the reactor, the batch was cooled to 10 ° C and made basic with 45 ° C. % NaOH at pH 13 to 14 while the batch temperature did not exceed 25 ° C. Then the batch was stirred from 5 ° C to 10 ° C for 1 more hour, the precipitate that formed together with the high flow was collected and dried in a vacuum oven at 60 ° C to a constant weight to obtain a product crude that contained high flow.
The crude product reacted with 3.3 grams of SX-1 type activated carbon (NORIT) in 990 ml of acetone, filtered, cooled to 25 ° C and hydrochloric acid was bubbled through the acetone solution to the pH was 3, the batch was cooled from 0 ° C to 5 ° C, kept at this temperature for half an hour, filtered, washed with 20 ml of acetone and dried in a 50 ° C oven until a constant weight to give 49.6 grams of dimethylamino methylcarbazolone-HCl.
Example 2: Preparation of Pure Ondansetrort Base
In 330 ml of water, 33 grams (0.112 mol, 1 equivalent) of dimethylamino-methylcarbazolone-HCl, 3.3 grams of high flow, 46.3 grams (0.563 mol, 5 equivalents) of methyl imidazole were added.
The reaction was heated to reflux for 12 hours and cooled from 5 ° C to 10 ° C, the precipitate was filtered, washed with 3 x 300 ml of water and dried in a vacuum oven at 60 ° C to a weight constant to give the crude compound containing high flow.
The crude compound was treated with 1.5 grams of activated carbon of SX-1 type (NORIT) in 930 ml of methanol, filtered (hot filtration) from the high flow and activated carbon and crystallized from 0 ° C to 5 ° C for one hour. The hot filtration was at 60 ° C and was done with methanol close to its boiling point (ie at 65 ° C). The precipitate was collected by filtration, washed with 2 x 20 ml of cold methanol and dried in a vacuum oven at 60 ° C to a constant weight to give 21.3 grams of ondansetron base.
Example 3: Preparation of Ondansetron Hydrochloride Pure Dihydrate
In 100 ml of water, 20 grams of ondansetron base were introduced. To the stirred suspension was added 7.5 ml (1, equivalent) of 32% hydrochloric acid (HC1). A slightly exothermic reaction occurred, the suspension became almost transparent and a precipitate began to form.
The reaction was cooled and maintained at 3 ° C -5 ° C for an additional 1 hour, filtered, washed with 10 ml of cold isopropanol and dried at 50 ° C under vacuum.
Example 4: Recrystallization of Ondansetron Hydrochloride Dihydrate
Ondansetron-HCl-2H20 was crystallized twice from water at 1: 4 w / v and 10% w / w activated carbon of type SX-1 (from NORIT) at 95 ° C for half an hour, filtered (hot filtration) , it was washed with 1 volume of hot water, cooled to 5 ° C and kept at this temperature for 1 hour. The crystals were collected, washed with 10 mL of cold isopropanol and dried to give pure ondansetron-HCl-2¾0. It was determined by HPLC that the pure ondansetron dihydrate hydrochloride obtained was at least more than 99.0%. Ondansetron hydrochloride pure dihydrate contained less than 0.01% exo-methylene byproduct or it was undetectable.
Claims (47)
- i CLAIMS 1. Ondansetron dihydrate hydrochloride having a purity of at least 99.0%. 5. Ondansetron dihydrate hydrochloride having a purity of at least 99.5%. 3. Ondansetron dihydrate hydrochloride having a purity of 0 at least 99.9%. 4. A process for preparing dimethylamino-methyl carbazolone comprising the steps of: a) preparing a solution of methylcarbazolone having the formula (where R = C 1 - alkyl) b) heating the solution in the presence of dimethylamine hydrochloride and paraformaldehyde; c) basify the solution to form a precipitate; 0 d) separating the precipitate from the solution; e) drying the precipitate. 2 5. The process according to claim 4, wherein R is methyl. 6. The process according to claim 4, wherein the step of heating is carried out at a temperature of 70 ° C to 100 ° C. 7. The process according to claim 4, wherein the step of heating is carried out at a temperature of 80 ° C to 90 ° C. 8. The process according to claim 4, wherein the step of heating is performed for 6 to 24 hours. 9. The process according to claim 4, wherein the step of heating is performed for 6 to 12 hours. 10. The process according to claim 4, wherein the step of heating is performed in acetic acid. 11. The process according to claim 4, wherein an equivalent of methylcarbazolone is heated in the presence of 1.1 to 1.5 equivalent of dimethylamine hydrochloride and paraformaldehyde. 3 12. The process according to claim 4, wherein an equivalent of methylcarbazolone is heated in the presence of 1.2 equivalent of diraethylamide hydrochloride and formaldehyde. 13. The process according to claim 4, wherein an equivalent of methylcarbazolone is heated in the presence of 1. 1 to 1.5 equivalent of dimethylamine hydrochloride and formaldehyde. 14. The process according to claim 4, wherein an equivalent of methylcarbazolone is heated in the presence of 1. 2 equivalent of dimethylamine hydrochloride and formaldehyde. 15. The process according to claim 4, wherein an equivalent of methylcarbazolone is heated in the presence of 4 to 6 volumes of acetic acid. 16. The process according to claim 4, wherein an equivalent of methylcarbazolone is heated in the presence of 4 volumes of acetic acid. 17. The process according to claim 4, wherein the methylcarbazolone solution is basified by 45% sodium hydroxide. 4 I I 18. The process of claim 17, wherein the solution is basified to a pH of 13 to 14. 19. The process of claim 17 or 18, wherein the basifying process is performed in the presence of 10% of celite. 20. A process for preparing an ondansetron base, comprising the steps of: a) preparing a solution of methylimidazole and dimethylaminomethylcarbazolone of the formula Ci-4 alkyl) b) heat the solution; c) removing a precipitate containing bas ondansetron from the solution; d) washing the precipitate; e) Dry the precipitate to obtain the ondansetron base. 5 21. The process according to claim 20, wherein the solution is prepared by adding from 4 to 6 equivalents of methyl imidazole to one equivalent of dimethylamino-methylcarbazole. 22. The process according to claim 20, wherein the solution is prepared by adding 5 equivalents of methylimidazole to one equivalent of dimethylamino-methylcarbazolone. 23. The process according to claim 20, wherein the solution is prepared in the presence of 10% celite. 24. The process according to claim 20, further comprising the step of recrystallizing the ondansetron base. 25. The process according to claim 24, wherein the recrystallization step is carried out in the presence of activated carbon and methanol. 26. A process for preparing ondansetron dihydrate hydrochloride comprising the steps of: a) preparing an ondansetron base solution; b) acidifying the solution with hydrogen chloride to form a precipitate; c) washing the precipitate; and 6 d) crystallize pure ondansetron dihydrate hydrochloride. 27. The process according to claim 26, wherein 3 to 7 volume is added is water to prepare a base solution of ondansetron. 28. The process according to claim 26, wherein 5 volumes of water are added to the ondansetron base to prepare a solution of the ondansetron base. 29. The process according to claim 26, wherein from 1.0 to 1.4 equivalents of 32% (v: v) of hydrochloric acid are added to acidify the solution to induce precipitation. 30. The process according to claim 26, wherein 1.1 equivalent of 32% (v: v) of hydrochloric acid is added to acidify the solution to induce precipitation. 31. The process according to claim 29 or 30, wherein the solution is acidified to a pH of 1 to 4. 32. The process according to claim 29 or 30, wherein the solution is acidified to a pH of 3. 33. The process according to claim 26, wherein the precipitate is washed with 5 ml to 15 ml of isopropanol. 34. The process according to claim 26, wherein the precipitate is washed with 10 ml of isopropanol. 35. The process according to claim 26, wherein the crystallization step is achieved by adding 3 to 5 volumes of water to induce crystallization. 36. The process according to claim 26, wherein the step of crystallizing is achieved by adding 4 volumes of water to induce crystallization. 37. The process according to claim 26, wherein the crystallization step is repeated twice. 38. The process according to claim 26, wherein the crystallization step is achieved in the presence of activated carbon. 39. The process according to claim 36, wherein the activated carbon is selected from the group consisting of SX -2, CA-1, cxv and sx-i. 8 i 4 40. The process according to claim 39, wherein the activated carbon is from 5% to 15% of SX-1. 41. The process according to claim 39, wherein the activated carbon is from 5% to 10% of SX-1. 42. Ondansetron dihydrate hydrochloride prepared according to a process of claim 26, wherein the ondansetron hydrochloride 0 dihydrate has a purity of at least 99.0%. 43. Ondansetron dihydrate hydrochloride prepared according to a process of claim 26, wherein the ondansetron hydrochloride dihydrate has a purity of at least 5 99.5%. 44. Ondansetron dihydrate hydrochloride prepared according to a process of claim 26, wherein the ondansetron hydrochloride dihydrate has a purity of at least 0 99.9%. 45. A pharmaceutical formulation comprising ondansetron dihydrate hydrochloride prepared according to a claim 26 process, wherein the ondansetron hydrochloride dihydrate has a purity of at least 99.0%. 46. A pharmaceutical formulation comprising ondansetron dihydrate hydrochloride prepared according to a process of claim 26, wherein the ondansetron hydrochloride dihydrate has a purity of at least 99.5%. 47. A pharmaceutical formulation comprising ondansetron dihydrate hydrochloride prepared according to a process of claim 26, wherein the ondansetron hydrochloride dihydrate has a purity of at least 99.9%. , * fr BESUMEN OF THE INVENTION An improved method for preparing dimethylamino-methyl-carbazole an ondansetron base. A recrystallization process for preparing ondansetron dihydrate hydrochloride with a purity of at least 99.0% is also disclosed.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US26105201P | 2001-01-11 | 2001-01-11 | |
PCT/US2002/000853 WO2002055492A2 (en) | 2001-01-11 | 2002-01-11 | An improved process for preparing pure ondansetron hydrochloride dihydrate |
Publications (1)
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---|---|
MXPA03006215A true MXPA03006215A (en) | 2005-02-17 |
Family
ID=22991757
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
MXPA03006215A MXPA03006215A (en) | 2001-01-11 | 2002-01-11 | An improved process for preparing pure ondansetron hydrochloride dihydrate. |
Country Status (21)
Country | Link |
---|---|
EP (1) | EP1355881A4 (en) |
JP (1) | JP2004526692A (en) |
KR (3) | KR20030068583A (en) |
CN (2) | CN1496350A (en) |
AU (1) | AU2002236753B2 (en) |
CA (1) | CA2433720A1 (en) |
CZ (1) | CZ20032090A3 (en) |
DE (1) | DE02703115T1 (en) |
ES (1) | ES2219201T1 (en) |
HR (1) | HRP20030631A2 (en) |
HU (1) | HUP0400767A2 (en) |
IL (1) | IL156835A0 (en) |
IS (1) | IS6869A (en) |
MX (1) | MXPA03006215A (en) |
NO (1) | NO20033147L (en) |
PL (1) | PL368837A1 (en) |
SK (1) | SK9892003A3 (en) |
TR (1) | TR200401460T3 (en) |
WO (1) | WO2002055492A2 (en) |
YU (1) | YU56103A (en) |
ZA (1) | ZA200305338B (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005529142A (en) | 2002-04-29 | 2005-09-29 | テバ ジョジセルジャール レースベニュタールシャシャーグ | Process for producing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one |
HU225885B1 (en) * | 2002-10-17 | 2007-11-28 | Richter Gedeon Nyrt | Process for producing ondansetron hydrochlorid dihydrate of high purity |
FI6164U1 (en) * | 2003-01-09 | 2004-03-15 | Synthon Bv | Ondansetronformer |
GB2398071B (en) * | 2003-01-24 | 2006-06-07 | Synthon Bv | Process for making ondansetron and intermediate thereof |
US7696356B2 (en) | 2004-08-17 | 2010-04-13 | Taro Pharmaceutical Industries Limited | Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one and ondansetron therefrom |
US7547791B2 (en) * | 2004-10-26 | 2009-06-16 | Ipca Laboratories Ltd. | One-pot process for the preparation of antiemetic agent, 1,2,3,9-tetrahydro-9-methyl-3[(2-methyl)-1H-imidazole-1-yl)methyl]-4H-carbazol-4-O |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4695578A (en) * | 1984-01-25 | 1987-09-22 | Glaxo Group Limited | 1,2,3,9-tetrahydro-3-imidazol-1-ylmethyl-4H-carbazol-4-ones, composition containing them, and method of using them to treat neuronal 5HT function disturbances |
GB8630071D0 (en) * | 1986-12-17 | 1987-01-28 | Glaxo Group Ltd | Medicaments |
KR20030042038A (en) * | 2000-10-30 | 2003-05-27 | 테바 파마슈티컬 인더스트리즈 리미티드 | Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation |
-
2002
- 2002-01-11 KR KR10-2003-7009221A patent/KR20030068583A/en active IP Right Grant
- 2002-01-11 AU AU2002236753A patent/AU2002236753B2/en not_active Expired - Fee Related
- 2002-01-11 CA CA002433720A patent/CA2433720A1/en not_active Abandoned
- 2002-01-11 IL IL15683502A patent/IL156835A0/en unknown
- 2002-01-11 MX MXPA03006215A patent/MXPA03006215A/en unknown
- 2002-01-11 CN CNA028062019A patent/CN1496350A/en active Pending
- 2002-01-11 DE DE02703115T patent/DE02703115T1/en active Pending
- 2002-01-11 CZ CZ20032090A patent/CZ20032090A3/en unknown
- 2002-01-11 EP EP02703115A patent/EP1355881A4/en not_active Withdrawn
- 2002-01-11 SK SK989-2003A patent/SK9892003A3/en not_active Application Discontinuation
- 2002-01-11 KR KR1020067020069A patent/KR20060113792A/en not_active Application Discontinuation
- 2002-01-11 CN CNA2006101667179A patent/CN101045704A/en active Pending
- 2002-01-11 KR KR1020077010146A patent/KR20070054749A/en not_active Application Discontinuation
- 2002-01-11 PL PL02368837A patent/PL368837A1/en not_active Application Discontinuation
- 2002-01-11 JP JP2002556165A patent/JP2004526692A/en active Pending
- 2002-01-11 YU YU56103A patent/YU56103A/en unknown
- 2002-01-11 TR TR2004/01460T patent/TR200401460T3/xx unknown
- 2002-01-11 WO PCT/US2002/000853 patent/WO2002055492A2/en active Application Filing
- 2002-01-11 ZA ZA200305338A patent/ZA200305338B/en unknown
- 2002-01-11 HU HU0400767A patent/HUP0400767A2/en unknown
- 2002-01-11 ES ES02703115T patent/ES2219201T1/en active Pending
-
2003
- 2003-07-08 IS IS6869A patent/IS6869A/en unknown
- 2003-07-09 NO NO20033147A patent/NO20033147L/en not_active Application Discontinuation
- 2003-08-06 HR HR20030631A patent/HRP20030631A2/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
YU56103A (en) | 2006-05-25 |
TR200401460T3 (en) | 2004-08-23 |
EP1355881A2 (en) | 2003-10-29 |
ES2219201T1 (en) | 2004-12-01 |
KR20030068583A (en) | 2003-08-21 |
HRP20030631A2 (en) | 2005-06-30 |
IS6869A (en) | 2003-07-08 |
JP2004526692A (en) | 2004-09-02 |
NO20033147D0 (en) | 2003-07-09 |
SK9892003A3 (en) | 2004-05-04 |
KR20060113792A (en) | 2006-11-02 |
CA2433720A1 (en) | 2002-07-18 |
EP1355881A4 (en) | 2004-03-31 |
ZA200305338B (en) | 2004-07-12 |
PL368837A1 (en) | 2005-04-04 |
CN101045704A (en) | 2007-10-03 |
WO2002055492A2 (en) | 2002-07-18 |
IL156835A0 (en) | 2004-02-08 |
AU2002236753B2 (en) | 2007-06-28 |
CZ20032090A3 (en) | 2004-08-18 |
DE02703115T1 (en) | 2004-10-21 |
WO2002055492A3 (en) | 2003-02-13 |
KR20070054749A (en) | 2007-05-29 |
NO20033147L (en) | 2003-09-02 |
HUP0400767A2 (en) | 2004-07-28 |
CN1496350A (en) | 2004-05-12 |
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