| 77% |
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6 Example 6
The product was suspended in 30 ml of acetone and 3.0 ml of 6N HCl was slowly added thereto at 10°C or below, stirred at the same temperature for 3 hrs, and filtered, to obtain 4.24 g of the title compound (yield: 77%). The melting point and 1H-NMR data obtained were the same as those of Example 1. Purity (HPLC): 99% |
| 75% |
|
2 Preparation of 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one Hydrochloride Dihydrate
The resulting crystals were filtered to obtain 4.12 g of the title compound (yield: 75%). The melting point and 1H-NMR data obtained were the same as those of Example 1. Purity (HPLC): 99%. |
| 75% |
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1 Example 1
The reaction mixture was cooled, and 30 ml of acetone and 2.8 ml of 6N hydrochloric acid were added thereto to induce crystallization of the product. The resulting crystals were filtered to obtain 4.12 g of the title compound (yield: 75%). m.p.: 178-179°C 1H-NMR (DMSO-d6) δ: 1.88~2.06(m, 1H), 2.10~2.23(m, 1H), 2.65(s, 3H), 2.95~3.23(m, 3H), 3.74(s, 3H), 4.27(dd, 1H), 4.65(dd, 1H), 7.20(m, 2H), 7.56(m, 2H), 7.67(d, 1H), 8.00(d, 1H) Elementary Analysis (as C18H19N3O· HCl· 2H2O) Measured value (%) - C:59.4, H:6.5, N:11.4 Calculated value (%) - C:59.1, H:6.6, N:11.5 Moisture (Calfisher): 10.1% (Calculated value: 9.85%) Purity (HPLC): 99% |
| 75% |
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2 Example 2
The resulting crystals were filtered to obtain 4.12 g of the title compound (yield: 75%). The melting point and 1H-NMR data obtained were the same as those of Example 1. Purity (HPLC): 99% |
| 74% |
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5 Preparation of 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one Hydrochloride Dihydrate
The crude product was suspended in 30 ml of acetonitrile and 2.54 ml of 6N HCl was slowly added thereto at 10° C. or below, stirred at the same temperature for 3 hrs, and filtered, to obtain 4.07 g of the title compound (yield: 74%). The melting point and 1H-NMR data obtained were the same as those of Example 1. Purity (HPLC): 99%. |
| 74% |
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5 Example 5
The crude product was suspended in 30 ml of acetonitrile and 2.54 ml of 6N HCl was slowly added thereto at 10°C or below, stirred at the same temperature for 3 hrs, and filtered, to obtain 4.07 g of the title compound (yield: 74%). The melting point and 1H-NMR data obtained were the same as those of Example 1. Purity (HPLC): 99% |
| 73% |
|
3 Preparation of 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one Hydrochloride Dihydrate
50 ml of acetone was added to the crude product and 2.2 ml of 6N HCl was slowly added thereto at 10° C. or below, stirred at the same temperature for 3 hrs, and filtered to obtain 4.02 g of the title compound (yield: 73%). The melting point and 1H-NMR data obtained were the same as those of Example 1. Purity (HPLC): 99%. |
| 73% |
|
3 Example 3
50 ml of acetone was added to the crude product and 2.2 ml of 6N HCl was slowly added thereto at 10°C or below, stirred at the sametemperature for 3 hrs, and filtered to obtain 4.02 g of the title compound (yield: 73%). The melting point and 1H-NMR data obtained were the same as those of Example 1. Purity (HPLC): 99% |
| 70% |
|
4 Example 4
The crude product was suspended in 40 ml of acetone and 2.4 ml of 6N HCl was slowly added thereto at 5°C or below, stirred at the same temperature for 3 hrs, and filtered, to obtain 3.85 g of the title compound (yield: 70%). The melting point and 1H-NMR data obtained were the same as those of Example 1. Purity (HPLC): 99% |
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1; 2; 3; 4; 5; 6; 7
Particles Crude ondansetron hydrochloride dihydrate (5.5 kg, 15.1 mol) and water (10 L) were added to a first vessel containing isopropanol (10 L). The mixture was heated to 60°C-70°C until the ondansetron hydrochloride dihydrate was completely dissolved. Isopropanol (47 L) was added to a second vessel, and the temperature was maintained at not more than 20°C (i. e., about 15°C). The hot solution of ondansetron hydrochloride dihydrate was transferred slowly into the second vessel over the course of about 5-10 minutes, while maintaining the temperature of the resulting mixture at not more than 35°C (i. e., about 25°C). After the addition, the mixture was cooled to about 20°C and stirred for about one hour. The resulting precipitate was filtered, washed with isopropanol (10 L), and dried under a nitrogen atmosphere (N2 flow about 20 L/min, N2 pressure about 1 bar) at 35°C- 40°C for about 6 hours to provide ondansetron hydrochloride dihydrate particles (5.43 kg; 99% yield). The particle size of the obtained ondansetron hydrochloride dihydrate particles was determined as set forth above (See Methodology and Protocols). The mean particle size and particle size distribution of the particles (fraction of particles by volume smaller than specified diameter) are presented in the following table. Mean < 60 µm < 150 µm < 250 µm 96 µm 19% 90% 100% Example 2 Commercial Scale Preparation of Ondansetron Hydrochloride Dihydrate Particles A commercial scale batch of ondansetron hydrochloride dihydrate particles was prepared using a procedure analogous to the procedure set forth in Example 1. In particular, crude ondansetron hydrochloride dihydrate (5.9 kg, 16.2 mol) and water (8.3 L) were added to a first vessel containing isopropanol (8.3 L). The mixture was heated to 65°C-75°C until the ondansetron hydrochloride dihydrate was completely dissolved. Isopropanol (42 L) was added to a second vessel, and the temperature was maintained at not more than 20°C. The hot solution of ondansetron hydrochloride dihydrate was transferred slowly into the second vessel over the course of about 20 minutes, while maintaining the temperature of the resulting mixture at not more than 35°C. After the addition, the mixture was cooled to about 20°C and stirred for about one hour. The resulting precipitate was filtered, washed with isopropanol, and dried in a rotary evaporator at 35°C and 60 mbar. The yield of ondansetron hydrochloride dihydrate particles was 91%. The particle size was measured as in Example 1. The results are presented in the following table. Mean < 63 µm < 150 µm < 250 m 81 µm 31% 90% 100% Example 3 Commercial Scale Preparation of Ondansetron Hydrochloride Dihydrate Particles A commercial scale batch of ondansetron hydrochloride dihydrate particles was prepared using a procedure analogous to the procedure set forth in Example 1. In particular, ondansetron hydrochloride dihydrate prepared in Example 2 (4.9 kg, 13.4 mol) and water (8.3 L) were added to a first vessel containing isopropanol (8.3 L). The mixture was heated to 65°C-75°C until the ondansetron hydrochloride dihydrate was completely dissolved. Isopropanol (42 L) was added to a second vessel, and the temperature was maintained at not more than 20°C. The hot solution of ondansetron hydrochloride dihydrate was transferred slowly into the second vessel over the course of about 20 minutes, while maintaining the temperature of the resulting mixture at not more than 35°C. After the addition, the mixture was cooled to about 20°C and stirred for about one hour. The resulting precipitate was filtered, washed with isopropanol, and dried at not more than 40°C. The yield of ondansetron hydrochloride dihydrate particles was 89%. The particle size was measured as in Example 1. The results are presented in the following table. Mean- < 63 µm < 150 µm < 250 m 81 µm 34% 85% 100% Example 4 Commercial Scale Preparation of Ondansetron Hydrochloride Dihydrate Particles A commercial scale batch of ondansetron hydrochloride dihydrate particles was prepared using a procedure analogous to the procedure set forth in Example 1. In particular, ondansetron hydrochloride dihydrate (3.98 kg, 10.88 mol) and water (7.0 L) were added to a first vessel containing isopropanol (7.0 L). The mixture was heated to 65°C-75°C until the ondansetron hydrochloride dihydrate was completely dissolved. Isopropanol (34 L) was added to a second vessel, and the temperature was maintained at not more than 20°C. The hot solution of ondansetron hydrochloride dihydrate was transferred slowly into the second vessel over the course of about 20 minutes, while maintaining the temperature of the resulting mixture at not more than 35°C. After the addition, the mixture was cooled to about 20°C and stirred for about one hour. The resulting precipitate was filtered, washed with isopropanol, and dried at not more than 40°C. The yield of ondansetron hydrochloride dihydrate particles was 89%. The particle size was measured as in Example 1. The results are presented in the following table. Mean < 63 µm < 150 µm < 250 µm 81 µm 12% 85% 100% Example 5 Preparation of Ondansetron Hydrochloride Dihydrate Particles Ondansetron hydrochloride dihydrate particles were prepared using a procedure analogous to the procedure set forth in Example 1. In particular, ondansetron hydrochloride dihydrate (20 grams, 5.5 mmol) and water (20 mL) were added to a first vessel containing isopropanol (20 mL). The mixture was heated to 65°C-75°C until the ondansetron hydrochloride dihydrate was completely dissolved. Isopropanol (100 mL) was added to a second vessel, and the temperature was maintained at not more than 20°C. The hot solution of ondansetron hydrochloride dihydrate was transferred slowly into the second vessel over the course of about five (5) minutes, while maintaining the temperature of the resulting mixture at not more than 35°C. After the addition, the mixture was cooled to about 20°C and stirred for about one hour. The resulting precipitate was filtered, washed with isopropanol, and dried at not more than 40°C. The yield of ondansetron hydrochloride dihydrate particles was 90%. The particle size was measured as in Example 1. The results are presented in the following table. Mean < 63 µm < 150 µm < 250 pm 89 µm 26% 85% 100% Example 6 Preparation of Ondansetron Hydrochloride Dihydrate Particles Using Solution That Does Not Contain Isopropanol Ondansetron hydrochloride dihydrate (100 g, 274 mmol) was dissolved in water (140 mL) in a first vessel. The mixture was heated to 65°C-70°C until the ondansetron hydrochloride dihydrate was completely dissolved. Isopropanol (700 mL) was added to a second vessel at a temperature of 20°C. The hot solution of ondansetron hydrochloride dihydrate was transferred slowly into the second vessel over the course of about 10-15 minutes, while maintaining the temperature of the resulting mixture at not more than 30°C. After the addition, the mixture was cooled to 16°C and stirred for about one hour. The resulting precipitate was filtered and washed with isopropanol. The particle size of the obtained wet ondansetron hydrochloride dihydrate particles was measured without drying (i. e., immediately after filtration). In addition, the particle size of four samples of the wet ondansetron hydrochloride dihydrate particles was measured after drying under varying conditions: (a) six (6) hours drying under ambient conditions, (b) two (2) hours drying at 40°C, (c) four (4) hours drying at 40°C, and (d) eight (8) hours drying at 40°C, followed by two (2) days at 25°C. The particle size was determined as in Example 1. The results are presented in the following table. Drying Conditions < 60 µm < 280 µm < 290 µm < 350 µm None (i. e., wet particles after filtration) 31% 100% Ambient conditions, six (6) hours 28% 100% 40°C, two (2) hours 35% 100% 40°C, four (4) hours 28% 100% 40°C, eight (8) hours; 25°C, two (2) days 15% 100% This Example demonstrates that the particle size of the ondansetron hydrochloride dihydrate particles of the present invention remains substantially unchanged before and after drying. Thus, it is not necessary to perform an additional particle size reduction step (e. g., grinding, sieving, prolonged drying under vigorous conditions, etc. ) before formulating the particles into ondansetron hydrochloride dihydrate tablets. Example 7 Purity Determination The purity of the ondansetron hydrochloride dihydrate particles prepared in Examples 1 and 4 was determined using HPLC as set forth above (See Methodology and Protocols). The quantities of known and unknown impurities are presented in the following table: Compound Example 1 Example 4 1,2,3,9-tetrahydro-9-methyl-3- 0.03% < 0.01% methylene-4H-carbazol-4-one 3- [(dimethylamino)methyl]- < 0.02% 0.03% 1,2,3,9-tetrahydro-9-methyl-4H- carbazol-4-one Methyl imidazole < 0.02% < 0.02% 1,2,3,9-tetrahydro-9-methyl-4H- < 0.02% < 0.01% carbazol-4-one Individual unknown (RRT 0.51) 0.04% < 0.01 % Individual unknown (RRT 0.54) < 0.03% < 0.01% Individual unknown (RRT 0.78) < 0.03% < 0.01% Individual unknown (RRT 0.89) 0.05% < 0.03% Total 0.1% 0.03% The purity of the ondansetron hydrochloride particles prepared in Example 1 was 99.9%. The purity of the ondansetron hydrochloride particles prepared in Example 4 was >99.9%. Thus, it is not necessary to perform an additional purification step before formulating the particles into ondansetron hydrochloride dihydrate tablets. |
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EXAMPLES
Ondansetron base (400 mg, 1.36*10-3 mole) was suspended in 16 ml of a 1:1 mixture of ethanol and isopropanol at room temperature. The suspension was heated to reflux to dissolve the ondansetron. After 20 min. of stirring at reflux, an ethanolic solution containing 1.1 equivalents of HCl was added. The reaction mixture was stirred at this temperature for an additional 10 min. Evaporation of the solvent gave ondansetron hydrochloride dihydrate Form A. |
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3 Preparation of Pure Ondansetron Hydrochloride Dihydrate
Example 3 Preparation of Pure Ondansetron Hydrochloride Dihydrate Into 100 ml of water 20 gram ondansetron-base were introduced. To the stirred suspension 7.5 ml (1.1 equivalents) of about 32% hydrochloric acid (HCl) was added. A slightly exothermic reaction occurred, the suspension turned almost clear and a precipitate began to form. The reaction was cooled down and kept at about 3-5° C. for an additional 1 hour filtered, washed, with about 10 ml cold isopropanol and dried at about 50° C. under vacuum. |
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1 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate wherein the crystals are less than 250 μm
EXAMPLE 1 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate wherein the crystals are less than 250 μm A solution of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidezol-1-yl)methyl]-4H-carbazol-4-one (147 g) in a mixture of isopropanol (670 mι), water (250 mι) and glacial acetic acid (76 mι) at ca. 60° was clarified by filtration and diluted with more water (61 mι) and isopropanol (650 mι). The solution was treated at 70° with 36%w/w hydrochloric acid (46 mι) and cooled to ca. 5°. The resulting suspension was filtered and the filtered solid was washed by displacement with isopropanol (600 mι) to give a solvent wet solid (269 g). A portion of this solid (91 g) was dried at ca. 50° and 200 torr for ca. 16h to give a solid (55 g). A portion of the dried solid (26 g) was placed in a current of humidified air at ambient temperature until there was no further gain in weight and the title compound (29 g) was obtained. |
| 2.40 g (65.6%) |
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11 Preparation of 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one hydrochloride dihydrate
EXAMPLE 11 Preparation of 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one hydrochloride dihydrate The process described in Example 8 is followed, except that after cooling down the reaction mixture to room temperature after boiling, 20 ml of 37% aqueous hydrochloric acid are added thereto. Then, the precipitate is filtered off, washed with isopropanol and dried to obtain 2.40 g (65.6%) of the title salt, m.p.: 178°-180° C. The active agent content of the product was found to be 100.3% based on potentiometric titration with sodium hydroxide solution. The theoretical water content is 9.85% (calculated for C18 H19 N3 O.HCl.2H2 O). The water content measured is 10.03%. |
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2 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate
EXAMPLE 2 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (18.3 g) in a hot mixture of isopropanol (90 ml) and water (18.3 ml) was treated with concentrated hydrochloric acid (6.25 ml). The hot mixture was filtered and the filtrate diluted with isopropanol (90 ml) and stirred at room temperature for 17 h, cooled to 2° and the solid filtered off (21.6 g). A sample (6 g) was recrystallized from a mixture of water (6 ml) and isopropanol (10 ml) to give the title compound as a white crystalline solid (6 g) m.p. 178.5°-179.5°. Analysis Found: C,59.45;H,6.45;N,11.5. C18 H19 N3 O.HCl.2H2 O requires C,59.1;H,6.6;N,11.5%. |
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3 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate
EXAMPLE 3 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4Hcarbazol-4-one (18.3 g) in a hot mixture of isopropanol (90 ml) and water (18.3 ml) was treated with concentrated hydrochloric acid (6.25 ml). The hot mixture was filtered and the filtrate diluted with isopropanol (90 ml) and stirred at room temperature for 17 h, cooled to 2° and the solid filtered off (21.6 g). A sample (6 g) was recrystallized from a mixture of water (6 ml) and isopropanol (10 ml) to give the title compound as a white crystalline solid (6 g) m.p. 178.5°-179.5°. Analysis Found: C, 59.45; H, 6.45; N, 11.5. C18 H19 N3 O.HCl.2H2 O requires C, 59.1; H, 6.6; N, 11.5%. |
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2 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate
EXAMPLE 2 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (18.3 g) in a hot mixture of isopropanol (90 ml) and water (18.3 ml) was treated with concentrated hydrochloric acid (6.25 ml). The hot mixture was filtered and the filtrate diluted with isopropanol (90 ml) and stirred at room temperature for 17 h, cooled to 2° and the solid filtered off (21.6 g). A sample (6 g) was recrystallized from a mixture of water (6 ml) and isopropanol (10 ml) to give the title compound as a white crystalline solid (6 g) m.p. 178.5°-179.5°. Analysis Found: C, 59.45; H, 6.45; N, 11.5. C18 H19 N3 O.HCl.2H2 O requires C, 59.1; H, 6.6; N, 11.5%. |
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2 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate
EXAMPLE 2 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate 1,2,3,9,-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (18.3g) in a hot mixture of isopropanol (90ml) and water (18.3ml) was treated with concentrated hydrochloric acid (6.25ml). The hot mixture was filtered and the filtrate diluted with isopropanol (90ml) and stirred at room temperature for 17h, cooled to 2° and the solid filtered off (21.6g). A sample (6g) was recrystallized from a mixture of water (6ml) and isopropanol (10ml) to give the title compound as a white crystalline solid (6g) m.p. 178.5°-179.5°. Analysis Found: C,59.45;H,6.45;N,11.5. C18 H19 N3 0.HCl.2H2 O requires C,59.1;H,6.6;N,11.5%. |
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3 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate
EXAMPLE 3 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (18.3 g) in a hot mixture of isopropanol (90 ml) and water (18.3 ml) was treated with concentrated hydrochloric acid (6.25 ml). The hot mixture was filtered and the filtrate diluted with isopropanol (90 ml) and stirred at room temperature for 17 h, cooled to 2° and the solid filtered off (21.6 g). A sample (6 g) was recrystallized from a mixture of water (6 ml) and isopropanol (10 ml) to give the title compound as a white crystalline solid (6 g) m.p. 178.5°-179.5°. Analysis Found: C,59.45;H,6.45;N,11.5. C18 H19 N3 O.HCl.2H2 O requires C,59.1;H,6.6;N,11.5%. |
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2 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate
Example 2 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (18.3g) in a hot mixture of isopropanol (90ml) and water (18.3ml) was treated with concentrated hydrochloric acid (6.25ml). The hot mixture was filtered and the filtrate diluted with isopropanol (90ml) and stirred at room temperature for 17h, cooled to 2° and the solid filtered off (21.6g). A sample (6g) was recrystallized from a mixture of water (6ml) and isopropanol (10ml) to give the title compound as a white crystalline solid (6g) m.p. 178.5-179.5°. The following examples illustrate pharmaceutical formulations for use according to the invention, containing ondansetron hydrochloride dihydrate as the active ingredient (1.25g of the hydrochloride dihydrate contains 1.00g of the free base). |
| 2.40 g (65.6%) |
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11 Preparation of 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one hydrochloride dihydrate
Example 11 Preparation of 9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one hydrochloride dihydrate The process described in Example 8 is followed, except that after cooling down the reaction mixture to room temperature after boiling, 20 ml of 37% aqueous hydrochloric acid are added thereto. Then, the precipitate is filtered off, washed with isopropanol and dried to obtain 2.40 g (65.6%) of the title salt, m.p.: 178-180°C. The active agent content of the product was found to be 100.3% based on potentiometric titration with sodium hydroxide solution. The theoretical water content is 9.85% (calculated for C18H19N30·HCl·2H20). The water content measured is 10.03%. |
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