WO2005054211A1 - A method of purification of lorazepam - Google Patents
A method of purification of lorazepam Download PDFInfo
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- WO2005054211A1 WO2005054211A1 PCT/SK2004/000015 SK2004000015W WO2005054211A1 WO 2005054211 A1 WO2005054211 A1 WO 2005054211A1 SK 2004000015 W SK2004000015 W SK 2004000015W WO 2005054211 A1 WO2005054211 A1 WO 2005054211A1
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- lorazepam
- carried out
- crystallization
- desolvation
- tetrahydrofuran
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
Definitions
- the present invention relates to a method of purification of Lorazepam, which is used in the pharmaceutical industry to manufacture pharmaceuticals designed to treat psychic diseases.
- Lorazepam 7-chloro-5-(2-chlorophenyl)-l ,3-dihydro-3-hydroxy-2H-l ,4-benzodiaze- pin-2-one, is a substance that belongs to the above-mentioned group of pharmaceutical substances. Lorazepam can be prepared by several methods disclosed for example in DE 2043614, CH 538490, CH590852 or ES 386 050.
- 3-acetoxy-7-chloro-5-(2-chlorophenyl)-l ,3-dihydrobenzo[e] [1 ,4]-dia- zepin-2-one (2) is prepared from 7-chloro-5-(2-chlorophenyl)-4-oxo-l,3-dihydrobenzo- [e][l,4]-diazepin-2-one (1, Scheme 1) and subsequent hydrolysis in an alkaline environment yields Lorazepam (3).
- Lorazepam prepared via the mentioned method, or other methods contains, beside impurities from the synthesis and/or products of decomposition, especially N-oxide 1. It also contains a solvent bound in the crystal lattice, for example water, acetone, alcohols (Rimbaud J. et al. II Farmaco 44, 519 (1989); acetonitrile, tetrachloromethane (Chauvet A. et al. J. Thermal Anal. 38, 1593 (1992), and the like.
- a solvent bound in the crystal lattice for example water, acetone, alcohols (Rimbaud J. et al. II Farmaco 44, 519 (1989); acetonitrile, tetrachloromethane (Chauvet A. et al. J. Thermal Anal. 38, 1593 (1992), and the like.
- US 3,296,249 describes a method of preparation of Lorazepam during which the acetyl group is removed from 7-chloro-5-(2-chlorophenyl)-l,3-dihydro-3-acetoxy-2H-l,4- benzodiazepin-2-one (2) by hydrolysis with an ethanolic solution of sodium hydroxide; after hydrolysis is completed, the obtained precipitate is filtered off, washed with water and crystallized from ethanol.
- the obtained Lorazepam is, however, an ethanol solvate of Lorazepam (II Farmaco, 44, 512-529; 1989).
- Lorazepam is a thermolabile substance and it rearranges at increased temperature to 6-chloro-4-(2-chlorophenyl)quinazoline-2-carbaldehyde (Chauvet, Ann.pharm.fr. 53, 256 (1995), it is impossible to remove bound solvents by increasing temperature.
- Non-solvated Lorazepam has been prepared for example by treating the respective solvate with benzene (J. Therm. Anal. 38, 1593 (1992)).
- Disadvantages of this method include the fact that it does not remove polar substances carried over into the process or those formed in the process, or during storing and manipulation, especially 7-chloro-5-(2-chlorophenyl)-4-oxo- 1 ,3-dihydrobenzo[e] [1 ,4]-dia- zepin-2-one, and that it uses environmentally problematic solvents to remove the solvents bound in the crystal lattice, especially dicl loromethane.
- the present invention provides a method of purification of Lorazepam from accompanying substances, formed during its synthesis, or from its decomposition products, especially 7-chloro-5-(2-chlorophenyl)-4-oxo-l,3-dihydrobenzo[e][l,4]diazepin-2-one, and from solvents forming solvates with Lorazepam, by crystallization or stirring in an organic solvent from the group consisting of ethers, esters and ketones.
- the method of purification of Lorazepam according to this invention is advantageous compared to the known methods in that it removes the impurities formed by the reaction or decomposition as well as the solvents that form solvates with Lorazepam, especially the hydrate and alcoholates, and that it provides Lorazepam of required physical properties in high yields.
- Lorazepam prepared via this method can be used for the preparation of pharmaceutical dosage forms.
- the method of purification of Lorazepam from the products of synthesis, decomposition products, water or other solvents that form solvates with Lorazepam, for example the hydrate or alcoholates, according to the present invention comprises crystallizing the Lorazepam solvate in solvents of the ether or ketone type, separating the crystals, and desolvating the same by stirring in solvents of the ether, ester or ketone type at increased temperatures, followed by isolating the product after cooling down.
- Suitable organic solvents for crystallization of Lorazepam include, in particular, cyclic ethers, especially tetrahydrofuran or the ketones methyl isobutyl ketone and methyl ethyl ketone.
- Crystallization from tetrahydrofuran removes selectively for example 7-chloro-5-(2- chlorophenyl)-4-oxo- 1 ,3-dihydrobenzo[e][l ,4]diazepin-2-one or 3-acetoxy-7-chloro-5-(2- chlorophenyI)-l,3-dihydrobenzo[e][l,4]-diazepin-2-one.
- tetrahydrofuran forms a solvate with Lorazepam, which is decomposed by desolvation via stirring in organic solvents of the ether type, such as aliphatic ethers with 6 to 8 carbons, of the type of acetic acid esters with alcohols having 1 to 4, especially 1, 3 or 4 carbons, of the type of aromatic carbohydrates, especially toluene, or of the ketone type, especially methyl isobutyl ketone.
- the ether type such as aliphatic ethers with 6 to 8 carbons, of the type of acetic acid esters with alcohols having 1 to 4, especially 1, 3 or 4 carbons, of the type of aromatic carbohydrates, especially toluene, or of the ketone type, especially methyl isobutyl ketone.
- the Lorazepam solvate is stirred with the organic solvent, or with a mixture of organic solvents, in the ratio 1 : 0.5 to 20 w/v, preferably 1 : 3 to 9 w/v, at temperatures in the range from 30 °C up to the boiling point of the solvent employed, preferably at 35 to 70 °C, for 0.1 to 48 hours. Subsequently, the solution, or suspension, is cooled down to below 25 °C, preferably 10 to 15 °C. Lorazepam is then separated by filtration, decantation or centrifuging, washed with the pure solvent used for purification and dried at temperatures 20 to 100 °C, preferably 40 to 60 °C.
- the following examples describe the method of purification according to the present invention in more detail but they do not limit its extent in any respect.
- Lorazepam methanolate (5 g) is dissolved in tetrahydrofuran (25 ml), the suspension is stirred at 65 °C for 1 hour, cooled down to 15 °C, the crystals of Lorazepam are filtered off, washed with tetrahydrofuran, and dried at 30 °C under reduced pressure for 2 hours. This procedure yielded 4.37 g of Lorazepam (HPLC purity 99.9 %), content of tetrahydrofuran more than 3000 ppm.
- the solvate (4.5 g) is stirred in diisopropyl ether (t-Pr) 2 O (40 ml) at temperature of 65 °C for 60 min, the suspension is cooled down to 15 °C, the crystals are filtered off, washed with diisopropyl ether, dried at 35 °C for 2 hours under reduced pressure. This procedure yielded 4.4 g of pure Lorazepam (purity 99.9 %); residual solvents: 650 ppm of diisopropyl ether.
- Lorazepam methanolate (5 g) is dissolved in methyl isobutyl ketone (40 ml), the solution is stirred at 50 °C for 30 min, then it is cooled down to 15 °C, the crystals of pure Lorazepam are filtered off, washed with methyl isobutyl ketone and dried at 20 °C first under atmospheric pressure and then in vacuo (26 mm Hg) for 1 hour. This procedure yielded the product (purity 99.7 %) in the amount 3.82 g; residual solvents: 420 ppm, methyl isobutyl ketone.
- Lorazepam ethanolate (5 g) is dissolved in methyl ethyl ketone (30 ml), the solution is stirred at 50 °C for 30 min, then it is cooled down to 15 °C, the crystals of pure Lorazepam are filtered off, washed with methyl ethyl ketone and dried at 50 °C under atmospheric pressure for 3 hours. This procedure yielded the product (purity 99.7 %) in the amount 3.94 g; residual solvents: 350 ppm, methyl ethyl ketone.
- Lorazepam ethanolate (5 g) is stirred in diisopropyl ether (z ' -Pr) 2 O (40 ml) at the temperature of 60 °C for 80 min, the suspension is cooled down to 15 °C, the crystals are filtered off, washed with diisopropyl ether, dried at 35 °C for 2 hours under reduced pressure. 4.21 g of pure Lorazepam were obtained (purity 99.6 %); residual solvents: 700 ppm, diisopropyl ether.
- Lorazepam methanolate (5 g) is stirred in n-dibutyl ether (35 ml). The suspension is heated for 1 hour at 80 °C, then it is cooled down to 12 °C. The crystals of pure Lorazepam are sucked off, washed with dibutyl ether and dried at 80 °C under reduced pressure for 3 hours. 4.41 g of pure Lorazepam were obtained (purity 99.6 %); residual solvents: 500 ppm, n-dibutyl ether.
- Lorazepam acetone solvate (5 g) is stirred in 35 ml of the mixture tetrahydrofuran - diisopropyl ether 1:1 (v/v). The suspension is heated at 65 °C for 1 hour, then it is cooled down to 15 °C. The crystals of Lorazepam are sucked off, washed with diisopropyl ether and dried at 40 °C under reduced pressure. Pure Lorazepam (purity 99.8 %) in the amount 4.40 g was obtained.
- Lorazepam hydrate (5 g) is stirred in 40 ml of the mixture of tetrahydrofuran - diisopropyl ether 1:1 (v/v) at 65 °C for 1 hour, the next procedure being as described in Example 6. Pure Lorazepam (purity 99.7 %) in the amount 4.49 g was obtained.
- Lorazepam etanolate (5 g) is dissolved in tetrahydrofuran (25 ml), the suspension is stirred at 65 °C for 1 hour, cooled down to 12 °C, the crystals of Lorazepam are filtered off, washed with tetrahydrofuran, and dried at 45 °C under reduced pressure for 2 hours. This procedure yielded 4.60 g of Lorazepam (HPLC purity 99.9 %); content of tetrahydrofuran: more than 3000 ppm.
- This solvate (4.5 g) is stirred in toluene (35 ml) at 75 °C for 60 min, the suspension is cooled down to 15 °C, the crystals are filtered off, washed with toluene, and dried at 45 °C for 2 hrs under reduced pressure. This procedure yielded 4.4 g of pure Lorazepam (purity 99.9 %); residual solvents: 400 ppm, toluene.
- Lorazepam prepared via this method can be utilized in the pharmaceutical industry for the manufacture of pharmaceuticals.
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Abstract
A new method of purification of Lorazepam is disclosed that consists in removing products of synthesis, decomposition products, water or other solvent that forms a solvate with Lorazepam, by crystallization or stirring in an organic solvent of the ether, ester or ketone type. Lorazepam prepared via this method can be utilized in the pharmaceutical industry for the manufacture of pharmaceuticals.
Description
A method of purification of Lorazepam
Technical Field
The present invention relates to a method of purification of Lorazepam, which is used in the pharmaceutical industry to manufacture pharmaceuticals designed to treat psychic diseases.
Background Art
The first benzodiazepine drug was introduced in the 50s. Since then, a large number of benzodiazepine derivatives has been discovered, which have sedative, relaxing and muscle- relaxing properties. These substances are used to treat for example depression, phobias, insomnia, myospasms. Lorazepam, 7-chloro-5-(2-chlorophenyl)-l ,3-dihydro-3-hydroxy-2H-l ,4-benzodiaze- pin-2-one, is a substance that belongs to the above-mentioned group of pharmaceutical substances. Lorazepam can be prepared by several methods disclosed for example in DE 2043614, CH 538490, CH590852 or ES 386 050. The last mentioned document is based on Polonovsky reaction of 7-chloro-5-phenyl-4-oxo-l,3-dihydrobenzo[e][l,4]diazepin-2-one and acetic anhydride in the presence of acetic acid (the procedure described in detail for preparation of 2- dechlorolorazepam (Oxazepam) in Spanish patent document ES 386 050 (1970)). Using an analogical procedure, 3-acetoxy-7-chloro-5-(2-chlorophenyl)-l ,3-dihydrobenzo[e] [1 ,4]-dia- zepin-2-one (2) is prepared from 7-chloro-5-(2-chlorophenyl)-4-oxo-l,3-dihydrobenzo- [e][l,4]-diazepin-2-one (1, Scheme 1) and subsequent hydrolysis in an alkaline environment yields Lorazepam (3).
Scheme 1. Method of preparation of Lorazepam
Lorazepam prepared via the mentioned method, or other methods, contains, beside impurities from the synthesis and/or products of decomposition, especially N-oxide 1. It also contains a solvent bound in the crystal lattice, for example water, acetone, alcohols (Rimbaud J. et al. II Farmaco 44, 519 (1989); acetonitrile, tetrachloromethane (Chauvet A. et al. J. Thermal Anal. 38, 1593 (1992), and the like. US 3,296,249 describes a method of preparation of Lorazepam during which the acetyl group is removed from 7-chloro-5-(2-chlorophenyl)-l,3-dihydro-3-acetoxy-2H-l,4- benzodiazepin-2-one (2) by hydrolysis with an ethanolic solution of sodium hydroxide; after hydrolysis is completed, the obtained precipitate is filtered off, washed with water and crystallized from ethanol. The obtained Lorazepam is, however, an ethanol solvate of Lorazepam (II Farmaco, 44, 512-529; 1989). Considering that Lorazepam is a thermolabile substance and it rearranges at increased temperature to 6-chloro-4-(2-chlorophenyl)quinazoline-2-carbaldehyde (Chauvet, Ann.pharm.fr. 53, 256 (1995), it is impossible to remove bound solvents by increasing temperature. Non-solvated Lorazepam has been prepared for example by treating the respective solvate with benzene (J. Therm. Anal. 38, 1593 (1992)). Preparation of Lorazepam free of solvents is the subject of US 6,350,870, according to which desolvation is achieved via heating (42 — 80 °C) the Lorazepam solvate (hydrate, alcoholate) in a strictly defined organic solvent: ethyl acetate, cyclohexane, dichloromethane, toluene and their mixtures; cooling the suspension down to 10 - 15 °C, washing the crystals with an organic solvent and drying. Disadvantages of this method include the fact that it does not remove polar substances carried over into the process or those formed in the process, or during storing and manipulation, especially 7-chloro-5-(2-chlorophenyl)-4-oxo- 1 ,3-dihydrobenzo[e] [1 ,4]-dia-
zepin-2-one, and that it uses environmentally problematic solvents to remove the solvents bound in the crystal lattice, especially dicl loromethane.
Disclosure of Invention
The present invention provides a method of purification of Lorazepam from accompanying substances, formed during its synthesis, or from its decomposition products, especially 7-chloro-5-(2-chlorophenyl)-4-oxo-l,3-dihydrobenzo[e][l,4]diazepin-2-one, and from solvents forming solvates with Lorazepam, by crystallization or stirring in an organic solvent from the group consisting of ethers, esters and ketones. The method of purification of Lorazepam according to this invention is advantageous compared to the known methods in that it removes the impurities formed by the reaction or decomposition as well as the solvents that form solvates with Lorazepam, especially the hydrate and alcoholates, and that it provides Lorazepam of required physical properties in high yields. Lorazepam prepared via this method can be used for the preparation of pharmaceutical dosage forms. The method of purification of Lorazepam from the products of synthesis, decomposition products, water or other solvents that form solvates with Lorazepam, for example the hydrate or alcoholates, according to the present invention, comprises crystallizing the Lorazepam solvate in solvents of the ether or ketone type, separating the crystals, and desolvating the same by stirring in solvents of the ether, ester or ketone type at increased temperatures, followed by isolating the product after cooling down. Suitable organic solvents for crystallization of Lorazepam include, in particular, cyclic ethers, especially tetrahydrofuran or the ketones methyl isobutyl ketone and methyl ethyl ketone. Crystallization from tetrahydrofuran removes selectively for example 7-chloro-5-(2- chlorophenyl)-4-oxo- 1 ,3-dihydrobenzo[e][l ,4]diazepin-2-one or 3-acetoxy-7-chloro-5-(2- chlorophenyI)-l,3-dihydrobenzo[e][l,4]-diazepin-2-one. However, tetrahydrofuran forms a solvate with Lorazepam, which is decomposed by desolvation via stirring in organic solvents of the ether type, such as aliphatic ethers with 6 to 8 carbons, of the type of acetic acid esters with alcohols having 1 to 4, especially 1, 3 or 4 carbons, of the type of aromatic carbohydrates, especially toluene, or of the ketone type, especially methyl isobutyl ketone. The Lorazepam solvate is stirred with the organic solvent, or with a mixture of organic solvents, in the ratio 1 : 0.5 to 20 w/v, preferably 1 : 3 to 9 w/v, at temperatures in the range
from 30 °C up to the boiling point of the solvent employed, preferably at 35 to 70 °C, for 0.1 to 48 hours. Subsequently, the solution, or suspension, is cooled down to below 25 °C, preferably 10 to 15 °C. Lorazepam is then separated by filtration, decantation or centrifuging, washed with the pure solvent used for purification and dried at temperatures 20 to 100 °C, preferably 40 to 60 °C. The following examples describe the method of purification according to the present invention in more detail but they do not limit its extent in any respect.
Examples
Example 1
Lorazepam methanolate (5 g) is dissolved in tetrahydrofuran (25 ml), the suspension is stirred at 65 °C for 1 hour, cooled down to 15 °C, the crystals of Lorazepam are filtered off, washed with tetrahydrofuran, and dried at 30 °C under reduced pressure for 2 hours. This procedure yielded 4.37 g of Lorazepam (HPLC purity 99.9 %), content of tetrahydrofuran more than 3000 ppm. The solvate (4.5 g) is stirred in diisopropyl ether (t-Pr)2O (40 ml) at temperature of 65 °C for 60 min, the suspension is cooled down to 15 °C, the crystals are filtered off, washed with diisopropyl ether, dried at 35 °C for 2 hours under reduced pressure. This procedure yielded 4.4 g of pure Lorazepam (purity 99.9 %); residual solvents: 650 ppm of diisopropyl ether.
Example 2
Lorazepam methanolate (5 g) is dissolved in methyl isobutyl ketone (40 ml), the solution is stirred at 50 °C for 30 min, then it is cooled down to 15 °C, the crystals of pure Lorazepam are filtered off, washed with methyl isobutyl ketone and dried at 20 °C first under atmospheric pressure and then in vacuo (26 mm Hg) for 1 hour. This procedure yielded the product (purity 99.7 %) in the amount 3.82 g; residual solvents: 420 ppm, methyl isobutyl ketone.
Example 3
Lorazepam ethanolate (5 g) is dissolved in methyl ethyl ketone (30 ml), the solution is stirred at 50 °C for 30 min, then it is cooled down to 15 °C, the crystals of pure Lorazepam are filtered off, washed with methyl ethyl ketone and dried at 50 °C under atmospheric pressure
for 3 hours. This procedure yielded the product (purity 99.7 %) in the amount 3.94 g; residual solvents: 350 ppm, methyl ethyl ketone.
Example 4
Lorazepam ethanolate (5 g) is stirred in diisopropyl ether (z'-Pr)2O (40 ml) at the temperature of 60 °C for 80 min, the suspension is cooled down to 15 °C, the crystals are filtered off, washed with diisopropyl ether, dried at 35 °C for 2 hours under reduced pressure. 4.21 g of pure Lorazepam were obtained (purity 99.6 %); residual solvents: 700 ppm, diisopropyl ether.
Example 5
Lorazepam methanolate (5 g) is stirred in n-dibutyl ether (35 ml). The suspension is heated for 1 hour at 80 °C, then it is cooled down to 12 °C. The crystals of pure Lorazepam are sucked off, washed with dibutyl ether and dried at 80 °C under reduced pressure for 3 hours. 4.41 g of pure Lorazepam were obtained (purity 99.6 %); residual solvents: 500 ppm, n-dibutyl ether.
Example 6
Lorazepam ethanolate (5 g) is stirred in 30 ml of butyl acetate. The next procedure is as described in Example 4. Pure Lorazepam in the amount 4.02 g was obtained (purity 99.8 %); residual solvents: 600 ppm, butyl acetate.
Example 7
Lorazepam acetone solvate (5 g) is stirred in 35 ml of the mixture tetrahydrofuran - diisopropyl ether 1:1 (v/v). The suspension is heated at 65 °C for 1 hour, then it is cooled down to 15 °C. The crystals of Lorazepam are sucked off, washed with diisopropyl ether and dried at 40 °C under reduced pressure. Pure Lorazepam (purity 99.8 %) in the amount 4.40 g was obtained.
Example 8
Lorazepam tetrahydrofuran solvate (5 g) is stirred in 45 ml of the mixture diisopropyl ether - dibutyl ether 1:1 (v/v) for 1 hour. The next procedure is as described in Example 4. Pure Lorazepam (purity 99.9 %) in the amount 4.47 g was obtained.
Example 9
Lorazepam hydrate (5 g) is stirred in 45 ml of diethyl ether at 35 °C for 1 hour, the next procedure being as described in Example 1. Pure Lorazepam (purity 99.6 %) in the amount 4.51 g was obtained.
Example 10
Lorazepam hydrate (5 g) is stirred in 40 ml of the mixture of tetrahydrofuran - diisopropyl ether 1:1 (v/v) at 65 °C for 1 hour, the next procedure being as described in Example 6. Pure Lorazepam (purity 99.7 %) in the amount 4.49 g was obtained.
Example 11
Lorazepam etanolate (5 g) is dissolved in tetrahydrofuran (25 ml), the suspension is stirred at 65 °C for 1 hour, cooled down to 12 °C, the crystals of Lorazepam are filtered off, washed with tetrahydrofuran, and dried at 45 °C under reduced pressure for 2 hours. This procedure yielded 4.60 g of Lorazepam (HPLC purity 99.9 %); content of tetrahydrofuran: more than 3000 ppm. This solvate (4.5 g) is stirred in toluene (35 ml) at 75 °C for 60 min, the suspension is cooled down to 15 °C, the crystals are filtered off, washed with toluene, and dried at 45 °C for 2 hrs under reduced pressure. This procedure yielded 4.4 g of pure Lorazepam (purity 99.9 %); residual solvents: 400 ppm, toluene.
Industrial applicability
The method of purification of Lorazepam according to this invention offers a significant advantage with respect to the technical demand factor, yield and environmental burden compared to the known methods. Lorazepam prepared via this method can be utilized in the pharmaceutical industry for the manufacture of pharmaceuticals.
Claims
1. A method of purification of Lorazepam from products of synthesis, decomposition products, water or other solvents that form solvates with Lorazepam characterized in that crude Lorazepam solvate is crystallized in a solvent selected from ethers and ketones, the resulting Lorazepam crystal is separated and optionally desolvated by stirring in a solvent selected from ethers, esters, aromatic hydrocarbons and ketones, individually or in mixtures, at increased temperatures, and, after cooling down, the product is isolated.
2. The method according to claim 1 characterized in that said crystallization is carried out in a cyclic ether.
3. The method according to claim 1 characterized in that said crystallization is carried out in tetrahydrofuran.
4. The method according to claim 1 characterized in that said crystallization is carried out in methyl isobutyl ketone.
5. The method according to claim 1 characterized in that said crystallization is carried out in methyl ethyl ketone.
6. The method according to claim 1 characterized in that said desolvation is carried out in aliphatic ethers having 6 to 8 carbons.
7. The method according to claim 1 characterized in that said desolvation is carried out in esters of acetic acid with aliphatic alcohols having 1 to 4 carbon atoms.
8. The method according to claim 1 characterized in that said desolvation is carried out in toluene.
9. The method according to claim 1 characterized in that said desolvation is carried out in ethyl acetate.
10. The method according to claim 1 characterized in that said crystallization is carried out in tetrahydrofuran and said desolvation is carried out in one or a mixture of more aliphatic ethers having 6 to 8 carbons.
11. The method according to claim 1 characterized in that said crystallization is carried out in tetrahydrofuran and said desolvation is carried out in toluene.
12. The method according to claim 1 characterized in that the ratio of the used organic solvent, or their mixture, and the solvate is 0.5 to 20: 1 (v/w).
13. The method according to claim 1 characterized in that the system is stirred at temperature from 30 °C up to the boiling point of the solvent.
14. The method according to claim 1 characterized in that the system is stirred for 0.1 to 48 hours.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SK1483-2003A SK286118B6 (en) | 2003-12-03 | 2003-12-03 | Method of purifying lorazepam |
| SKPP1483-2003 | 2003-12-03 |
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| WO2005054211A1 true WO2005054211A1 (en) | 2005-06-16 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110683994A (en) * | 2019-11-19 | 2020-01-14 | 湖南洞庭药业股份有限公司 | Novel crystal form of lorazepam, preparation method and pharmaceutical application thereof |
| CN110776473A (en) * | 2019-11-19 | 2020-02-11 | 湖南洞庭药业股份有限公司 | Process for the preparation of lorazepam |
| CN110804023A (en) * | 2019-12-09 | 2020-02-18 | 华中药业股份有限公司 | Lorazepam purification method |
| CN110840898A (en) * | 2019-11-19 | 2020-02-28 | 湖南洞庭药业股份有限公司 | Light-stabilized pharmaceutical composition, preparation method and pharmaceutical application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001066062A2 (en) * | 2000-03-06 | 2001-09-13 | Teva Pharmaqceutical Industries Ltd. | Process for preparing pure crystalline lorazepam |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001066062A2 (en) * | 2000-03-06 | 2001-09-13 | Teva Pharmaqceutical Industries Ltd. | Process for preparing pure crystalline lorazepam |
Non-Patent Citations (4)
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| CN110776473A (en) * | 2019-11-19 | 2020-02-11 | 湖南洞庭药业股份有限公司 | Process for the preparation of lorazepam |
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| CN110683994B (en) * | 2019-11-19 | 2022-10-11 | 湖南洞庭药业股份有限公司 | Novel crystal form of lorazepam, preparation method and pharmaceutical application thereof |
| CN110776473B (en) * | 2019-11-19 | 2023-09-15 | 湖南洞庭药业股份有限公司 | Process for preparing lorazepam |
| CN110804023A (en) * | 2019-12-09 | 2020-02-18 | 华中药业股份有限公司 | Lorazepam purification method |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005054211A8 (en) | 2005-10-13 |
| SK14832003A3 (en) | 2005-07-01 |
| SK286118B6 (en) | 2008-04-07 |
| CZ298518B6 (en) | 2007-10-24 |
| CZ20041138A3 (en) | 2006-12-13 |
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