WO2004035567A1 - High purity ondansetron hydrochloride dihydrate and process for its synthesis - Google Patents
High purity ondansetron hydrochloride dihydrate and process for its synthesis Download PDFInfo
- Publication number
- WO2004035567A1 WO2004035567A1 PCT/HU2003/000081 HU0300081W WO2004035567A1 WO 2004035567 A1 WO2004035567 A1 WO 2004035567A1 HU 0300081 W HU0300081 W HU 0300081W WO 2004035567 A1 WO2004035567 A1 WO 2004035567A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydrochloride dihydrate
- synthesis
- solution
- ondansetron
- ondansetron hydrochloride
- Prior art date
Links
- 229960005343 ondansetron Drugs 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 18
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 8
- 239000012535 impurity Substances 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- -1 2-methyl- 1 H-imidazol- 1 -yl Chemical group 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 5
- 239000003610 charcoal Substances 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- MKBLHFILKIKSQM-UHFFFAOYSA-N 9-methyl-3-[(2-methyl-1h-imidazol-3-ium-3-yl)methyl]-2,3-dihydro-1h-carbazol-4-one;chloride Chemical compound Cl.CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 MKBLHFILKIKSQM-UHFFFAOYSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- AMLYRCOEFHJSFS-UHFFFAOYSA-N carbazol-1-one Chemical class C1=CC=C2C3=CC=CC(=O)C3=NC2=C1 AMLYRCOEFHJSFS-UHFFFAOYSA-N 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 229960000770 ondansetron hydrochloride Drugs 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000005029 sieve analysis Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the invention relates to high purity ondansetron hydrochloride dihydrate as well as to the process for its synthesis.
- Ondansetron (chemical name: l,2,3,9-tetrahydro-9-methyl-3-/(2-methyl-lH- imidazol-l-yl)-methyl/-4H-carbazol-4-one) is the active ingredient of pharmaceutical compositions with highly efficient antiemetic activity. These compositions are especially important for chemotherapeutically treated patients.
- ondansetron base is transformed into ondansetron hydrochloride dihydrate with hydrochloric acid in aqueous isopropanol in the final step.
- the aim of our invention is to elaborate a process for the synthesis of high purity, white (or almost white) coloured active pharmaceutical ingredient, which has the appropriate crystal size.
- the crystal size of the obtained crystalline product can also be determined by the appropriate rate of cooling of the crystallization from water. Namely, fast cooling results in very fine crystal size ( ⁇ 63 ⁇ m min. 95 %), while with slow cooling crystal size above 250 ⁇ m can safely be obtained.
- the invention relates to such ondansetron hydrochloride dihydrate (chemical name: l,2,3,9-tetrahydro-9- methyl-3-/(2-methyl-lH-imidazol-l-yl)-methyl/-4H-carbazol-4-one hydrochloride dihydrate), which contains not more than 0.10 w/w % of chemical impurity.
- the invention also relates to the process for the synthesis of the above product, which is the following: the ondansetron base obtained by known chemical synthesis (impurity content: 0.5-10 w/w %; colour: from gray to dark brown) is treated with hydrochloric acid solution in water at 95-100 °C, the pH is adjusted to 5.8-6.2, then the solution is clarified at this temperature, the impurities are removed by filtration, the pH of the obtained filtrate is adjusted to 1-2 by addition of aqueous hydrochloric acid solution, and the so obtained solution is cooled at a rate of 0.1-1 °C/min to 20-25 °C to give the desired product, which is isolated.
- the ondansetron base obtained by known chemical synthesis impurity content: 0.5-10 w/w %; colour: from gray to dark brown
- the pH is adjusted to 5.8-6.2
- the solution is clarified at this temperature
- the impurities are removed by filtration
- the pH of the obtained filtrate is adjusted to 1-2
- compositions which contain the above defined and prepared product as active ingredient, as well as known auxiliaries.
- the main advantage of the invention is that high purity ondansetron hydrochloride dihydrate - which fulfils the colour requirements and can be used as active ingredient in pharmaceutical compositions as well - can be obtained in good yield - in aqueous solution without liberation of the free base - from such ondansetron hydrochloride dihydrate, which does not fulfil the colour requirements and is prepared by known method (for example EP-Pat. 595 111) from isopropanol solution.
- Example 1 The invention is illustrated by the following not limiting examples: Example 1
- the purity of the product is 99.90 w/w % according to HPLC after system peak correction, the total amount of the impurities is 0.10 w/w %, they are 0.03 w/w % (RT 6.76), 0.02 w/w % (RT 7.10) and 0.05 w/w % (RT 8.65), respectively.
- Type of the apparatus Spectra System/TSP (manufacturer: Thermo Separation Products, USA) Column: LICHROCART 250-4, LICHROSPHER 100 CN (5 ⁇ m)
- the amount of the impurities in the product is:
- the purity of the product is 99.92 w/w % according to HPLC after system peak correction, the total amount of the impurities is 0.08 w/w %, they are
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to high purity ondansetron hydrochloride dihydrate containing not more than 0.10 w/w % chemical impurities as well as to the process for its synthesis.
Description
High purity ondansetron hydrochloride dihydrate and process for its synthesis
The invention relates to high purity ondansetron hydrochloride dihydrate as well as to the process for its synthesis.
Ondansetron (chemical name: l,2,3,9-tetrahydro-9-methyl-3-/(2-methyl-lH- imidazol-l-yl)-methyl/-4H-carbazol-4-one) is the active ingredient of pharmaceutical compositions with highly efficient antiemetic activity. These compositions are especially important for chemotherapeutically treated patients.
Several chemical processes are known from the literature for the synthesis of ondansetron. GB-Pat. 2 153 821 and 2 192 885 describe syntheses starting from carbazolone derivative, and EP-Pat. 595 111 as well as a Hungarian patent application ( P 00-01287 ) give detailed information about some different chemical procedures.
According to the above literature the ondansetron base is transformed into ondansetron hydrochloride dihydrate with hydrochloric acid in aqueous isopropanol in the final step.
Furthermore, there is a known procedure described in the EP-Pat. Specification 415 522, in which the ondansetron hydrochloride dihydrate is prepared from dried anhydrous ondansetron hydrochloride by rehydration. According to this description the main advantage of the above procedure is that the average size of the granules of the active ingredient can be kept at considerably low value (< 63 μm min. 80 %; < 250 μm 100 %).
After reproduction of the above procedures we found that the obtained products do not fulfill the high colour requirements measured by objective experiments, they rather belong to the beige colour category. The more rigorous colour requirements, which are prescribed since then (for example the white or almost white colour; see European Pharmacopoeia, shortly Ph.
Eur. Vol. 4.3, page 3101) can not be fulfilled by using these above mentioned, known technological processes, even after repeated application.
The aim of our invention is to elaborate a process for the synthesis of high purity, white (or almost white) coloured active pharmaceutical ingredient, which has the appropriate crystal size.
The basis of our invention is the following: if the crude ondansetron base is dissolved in water in the presence of equivalent amount of hydrochloric acid (pH=5-6.5), the so obtained solution is clarified with charcoal, the charcoal is filtered off, then a colourless, transparent aqueous filtrate is obtained, from which after adjusting the pH to maximum 1 with further addition of hydrochloric acid, the high purity ondansetron hydrochloride dihydrate, which fulfils the highest colour requirements as well, can be prepared in good yield.
Surprisingly it was found, that the product prepared by the above process contains maximum 0.1 % individual impurity, this very high chemical purity was not to be expected at all.
According to the process of our invention, which is carried out in the knowledge of this observation, the crystal size of the obtained crystalline product can also be determined by the appropriate rate of cooling of the crystallization from water. Namely, fast cooling results in very fine crystal size (< 63 μm min. 95 %), while with slow cooling crystal size above 250 μm can safely be obtained.
According to the above mentioned facts, the invention relates to such ondansetron hydrochloride dihydrate (chemical name: l,2,3,9-tetrahydro-9- methyl-3-/(2-methyl-lH-imidazol-l-yl)-methyl/-4H-carbazol-4-one hydrochloride dihydrate), which contains not more than 0.10 w/w % of chemical impurity.
The invention also relates to the process for the synthesis of the above product, which is the following: the ondansetron base obtained by known chemical synthesis (impurity content: 0.5-10 w/w %; colour: from gray to dark brown) is treated with hydrochloric acid solution in water at 95-100 °C, the pH is adjusted to 5.8-6.2, then the solution is clarified at this temperature, the impurities are removed by filtration, the pH of the obtained filtrate is adjusted to 1-2 by addition of aqueous hydrochloric acid solution, and the so obtained solution is cooled at a rate of 0.1-1 °C/min to 20-25 °C to give the desired product, which is isolated.
Furthermore the invention relates to pharmaceutical compositions, which contain the above defined and prepared product as active ingredient, as well as known auxiliaries.
The main advantage of the invention is that high purity ondansetron hydrochloride dihydrate - which fulfils the colour requirements and can be used as active ingredient in pharmaceutical compositions as well - can be obtained in good yield - in aqueous solution without liberation of the free base - from such ondansetron hydrochloride dihydrate, which does not fulfil the colour requirements and is prepared by known method (for example EP-Pat. 595 111) from isopropanol solution.
The invention is illustrated by the following not limiting examples:
Example 1
Preparation of ondansetron hydrochloride dihydrate from crude ondansetron base
Under nitrogen, 10 g of crude ondansetron base (prepared according to the method described in example 3b of the HU-Pat. 212 785, and in example 3 of the Hungarian patent application Number of P-00-01287; impurity content measured by HPLC: 3.8 %, colour brownish red) is suspended in 150 ml of desalinated water, the pH is adjusted to 6 with concentrated hydrochloric acid at 95-100 °C, 2 g of charcoal is added to the solution, and the mixture is stirred at this temperature for 1 h. The charcoal is filtered off at 95-100 °C, the pH of the filtrate is adjusted to 1-2 with concentrated hydrochloric acid and the solution is cooled slowly, at a rate of not more, than 0.3 °C/min to 20-
25 °C, then after cooling to 0-5 °C the product is filtered off, washed with cooled (0-5 °C) desalinated water (2x5 ml), and dried below 35 °C. The obtained dried ondansetron hydrochloride dihydrate is 10.8 g (87 %)
(water content: 9.5 %, which is equivalent to 2 mol of water).
Additional measured data: the purity of the product is 99.90 w/w % according to HPLC after system peak correction, the total amount of the impurities is 0.10 w/w %, they are 0.03 w/w % (RT 6.76), 0.02 w/w % (RT 7.10) and 0.05 w/w % (RT 8.65), respectively.
Colour: white, ΔE = 0.5 on the range of colours Granule size results:
<63 μm 36 %
<150 μm 72 % <250 μm 95 %
The above results were obtained by the following analytical methods:
A. HPLC measurements:
Type of the apparatus: Spectra System/TSP (manufacturer: Thermo Separation Products, USA) Column: LICHROCART 250-4, LICHROSPHER 100 CN (5 μm)
Eluent: 70 % of 0.02 M KH2PO4
30 % of acetonitrile Flow rate: 1.00 ml/min Wavelength: 216 nm Temperature: 25 °C
Dissolution of samples: in the eluent
B. Colour measurement: Type of the apparatus: Minolta chromometer with CR-200 measuring head.
Before measuring the sample the apparatus is calibrated to standard white CR-
A43.
Measured parameters:
L lightness factor
Y chromaparameter
ΔE, the colour deviation from the standard, is calculated from the measured data according to the following equation:
ΔEab = [(dL)2 + (da)2 + (db)2] Vi
If ΔEab value is between 0-0.5, the deviation from the white colour is not visible; if ΔE value is between 0.5-1.5, in some cases the deviation can be visible to good eyes, this value fulfils a very good colour requirement.
C. Granule size: the granule size was determined by sieve analysis, using Alpine airjet sieve.
Example 2
Preparation of ondansetron hydrochloride dihydrate from hydrochloride salt by purification
Under nitrogen, 10 g of ondansetron hydrochloride dihydrate of beige colour (ΔE = 4.2 on the range of colours) is dissolved in 150 ml of ion- exchanged water at 75-80 °C. 2 g of charcoal is added to the homogeneous solution. After 1 h stirring the mixture is filtered and the pH of the filtrate is adjusted to 1-2. The solution is cooled slowly (at a rate of not more, than 0.3 °C/min) to 5-10 °C, stirred at this temperature for 1 h, the product is filtered off, washed 2x5 ml of desalinated water at 5-10 °C, and dried below 35 °C.
Dried weight: 9.6 g (96 %)
The colour of the product is white, ΔE = 0.55 on the range of colours The amount of the impurities in the product:
The purity of the product is 99.92 w/w % according to HPLC after system peak correction, the total amount of the impurities is 0.08 w/w %, they are
0.01 w/w % (RT 2.08), 0.01 w/w % (RT 2.43), 0.02 w/w % (RT 6.51), 0.01 w/w % (RT 6.83) and 0.03 w/w % (RT 7.74), respectively. Granule size results:
<63 μm 31 % <150 μm 71 %
<250 μm 97 % These results were obtained according to the methods described in example 1.
Claims
1. Ondansetron hydrochloride dihydrate (chemical name: 1,2,3,9- tetrahydro-9-methyl-3 -/(2-methyl- 1 H-imidazol- 1 -yl)-methyl/-4H- carbazol-4-on hydrochloride dihydrate), characterized by containing not more than 0.10 w/w % chemical impurities.
2. Process for the synthesis of the product according to claim 1, - characterized by treating the ondansetron base obtained by known chemical methods (impurity content: 0.5-10 w/w %; colour: from gray to dark brown) with hydrochloric acid solution in water at 95-100 °C, adjusting the pH of the solution to 5.8-6.2 and clarifying the so obtained solution at this temperature, filtering the mixture and adjusting the pH of the filtrate to 1-2 with aqueous hydrochloric acid solution, then cooling the so obtained solution at a rate of 0.1-1 °C/min to 20-25 °C to crystallize the desired product, which is isolated.
3. Pharmaceutical composition, characterized by containing the product according to claim 1 as active ingredient, together with known auxiliaries.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003276488A AU2003276488A1 (en) | 2002-10-17 | 2003-10-16 | High purity ondansetron hydrochloride dihydrate and process for its synthesis |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP0203547 | 2002-10-17 | ||
| HU0203547A HU225885B1 (en) | 2002-10-17 | 2002-10-17 | Process for producing ondansetron hydrochlorid dihydrate of high purity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2004035567A1 true WO2004035567A1 (en) | 2004-04-29 |
Family
ID=89980861
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2003/000081 WO2004035567A1 (en) | 2002-10-17 | 2003-10-16 | High purity ondansetron hydrochloride dihydrate and process for its synthesis |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2003276488A1 (en) |
| HU (1) | HU225885B1 (en) |
| WO (1) | WO2004035567A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7288660B2 (en) | 2004-05-07 | 2007-10-30 | Taro Pharmaceutical Industries Limited | Process for preparing ondansetron hydrochloride dihydrate having a defined particle size |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0276559A2 (en) * | 1986-12-17 | 1988-08-03 | Glaxo Group Limited | Use of ketone derivatives in the treatment of depression |
| WO2002055492A2 (en) * | 2001-01-11 | 2002-07-18 | Teva Pharmaceutical Industries Ltd. | An improved process for preparing pure ondansetron hydrochloride dihydrate |
-
2002
- 2002-10-17 HU HU0203547A patent/HU225885B1/en unknown
-
2003
- 2003-10-16 AU AU2003276488A patent/AU2003276488A1/en not_active Abandoned
- 2003-10-16 WO PCT/HU2003/000081 patent/WO2004035567A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0276559A2 (en) * | 1986-12-17 | 1988-08-03 | Glaxo Group Limited | Use of ketone derivatives in the treatment of depression |
| WO2002055492A2 (en) * | 2001-01-11 | 2002-07-18 | Teva Pharmaceutical Industries Ltd. | An improved process for preparing pure ondansetron hydrochloride dihydrate |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7288660B2 (en) | 2004-05-07 | 2007-10-30 | Taro Pharmaceutical Industries Limited | Process for preparing ondansetron hydrochloride dihydrate having a defined particle size |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0203547A2 (en) | 2004-06-28 |
| AU2003276488A1 (en) | 2004-05-04 |
| HUP0203547A3 (en) | 2004-10-28 |
| HU0203547D0 (en) | 2002-12-28 |
| HU225885B1 (en) | 2007-11-28 |
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