US20010039340A1 - Process for preparing pure crystalline lorazepam - Google Patents
Process for preparing pure crystalline lorazepam Download PDFInfo
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- US20010039340A1 US20010039340A1 US09/799,318 US79931801A US2001039340A1 US 20010039340 A1 US20010039340 A1 US 20010039340A1 US 79931801 A US79931801 A US 79931801A US 2001039340 A1 US2001039340 A1 US 2001039340A1
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- lorazepam
- solvate
- suspension
- ethyl acetate
- dichloromethane
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- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 title claims abstract description 150
- 229960004391 lorazepam Drugs 0.000 title claims abstract description 150
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 144
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 111
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 84
- 239000012453 solvate Substances 0.000 claims abstract description 68
- 238000000034 method Methods 0.000 claims abstract description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000000203 mixture Substances 0.000 claims abstract description 29
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 239000000725 suspension Substances 0.000 claims description 47
- 239000007788 liquid Substances 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000013078 crystal Substances 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000010908 decantation Methods 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims 7
- 238000001035 drying Methods 0.000 claims 6
- 239000007900 aqueous suspension Substances 0.000 claims 5
- 238000005406 washing Methods 0.000 claims 2
- OVHACJWPFMTJJG-UHFFFAOYSA-N 1,1-dichloroethane;pentane Chemical compound CC(Cl)Cl.CCCCC OVHACJWPFMTJJG-UHFFFAOYSA-N 0.000 claims 1
- 239000000932 sedative agent Substances 0.000 abstract description 3
- 230000000049 anti-anxiety effect Effects 0.000 abstract description 2
- 239000002249 anxiolytic agent Substances 0.000 abstract description 2
- 229940125723 sedative agent Drugs 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 8
- KYYSGHAGRQPUSK-UHFFFAOYSA-N 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one;ethanol Chemical compound CCO.C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1Cl KYYSGHAGRQPUSK-UHFFFAOYSA-N 0.000 description 7
- 238000004807 desolvation Methods 0.000 description 7
- 229940049706 benzodiazepine Drugs 0.000 description 4
- 208000019901 Anxiety disease Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000001624 sedative effect Effects 0.000 description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000007614 solvation Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- DIWRORZWFLOCLC-UHFFFAOYSA-N Lorazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-UHFFFAOYSA-N 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- CYDZMDOLVUBPNL-UHFFFAOYSA-N [7-chloro-5-(2-chlorophenyl)-2-oxo-1,3-dihydro-1,4-benzodiazepin-3-yl] acetate Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(OC(=O)C)N=C1C1=CC=CC=C1Cl CYDZMDOLVUBPNL-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 description 1
- 229960004782 chlordiazepoxide Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000000816 effect on animals Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007669 thermal treatment Methods 0.000 description 1
Classifications
-
- 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 desolvation processes and, in particular, to a process for desolvating lorazepam lower alcohol solvates and lorazepam hydrate.
- Lorazepam is a benzodiazepine with anti-anxiety and sedative effects that is widely used for treating human anxiety disorders and for pre-operative sedation.
- Lorazepam is the generic name of the compound 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one.
- the precipitated product of the last step of the process is a one-to-one ethanol solvate of lorazepam which must be desolvated before it can be incorporated into a pharmaceutical for administration to humans.
- Substitution of solvents that do not form solvates with lorazepam in the last step of the '249 patent is not practical due to solubility problems.
- Ethanol, methanol or water bound to lorazepam can be removed by contacting the lorazepam solvate with ethyl acetate or a mixture of ethyl acetate/cyclohexane or dichloromethane or toluene or a mixture of ethyl acetate and toluene, or a mixture of dichloromethane and toluene.
- lorazepam lower alcohol solvates can be converted to lorazepam hydrate by suspending the solvate in water under conditions that convert it to lorazepam hydrate.
- the two processes can be combined to convert lower alcohol solvates of lorazepam into crystalline lorazepam substantially free of bound solvent by first converting the lower alcohol solvate into lorazepam hydrate and then converting lorazepam hydrate into crystalline anhydrous lorazepam.
- the present invention provides a new process for preparing pure crystalline lorazepam from a lower alcohol solvate of lorazepam or lorazepam hydrate (collectively “lorazepam solvates”).
- “Lower alcohol” means an alcohol having from 1 to 4 carbon atoms and therefore includes methanol, ethanol and isopropanol.
- Suspending the lorazepam solvate in certain liquid organic media can be used to desolvate the lorazepam and enables isolation of lorazepam in a crystalline state that is substantially free of bound solvent.
- the desolvation may be accelerated by heating the suspension to an elevated temperature.
- the lorazepam may then be washed and dried by conventional means.
- a suitable liquid organic medium is an organic compound that is liquid at room temperature and, in particular, is ethyl acetate, cyclohexane, dichloromethane, toluene and mixtures thereof.
- Preferred liquid organic media are ethyl acetate, mixtures of ethyl acetate and cyclohexane, dichloromethane, toluene, mixtures of ethyl acetate and toluene, and mixtures of dichloromethane and toluene.
- the invention is further illustrated with ethyl acetate, dichloromethane, mixtures of ethyl acetate with cyclohexane and mixtures of dichloromethane with toluene.
- the lorazepam solvate is suspended in ethyl acetate in an amount of about 3 to about 5 milliliters of ethyl acetate per gram of lorazepam, most preferably about 4 ml/g.
- the desolvation may be conducted at any temperature between about 20° C. and 80° C.
- the suspension is heated to an elevated temperature of from about 55° C. to about 65° C. with mechanical agitation, e.g. stirring.
- desolvation can take from 5 minutes to about 24 h.
- the lorazepam desolvates in about an hour.
- the suspension is then cooled most preferably to a temperature in the range of from about 15° C. to about 20° C.
- the desolvated lorazepam crystals may be separated from the liquid organic medium by filtration or decantation.
- the desolvated lorazepam is then washed with a solvent; dichloromethane, cyclohexane, toluene, xylene, chloroform, pentane, dichloroethane, hexane, heptane, and ethyl acetate being preferred, with ethyl acetate being most preferred.
- the washed desolvated lorazepam can be dried at a temperature in the range of from about 20° C. to about 90° C., more preferably in the range of from about 40° C. to about 60° C., and most preferably at a temperature of about 50° C., either at ambient pressure or under vacuum.
- the lorazepam solvate is suspended in a mixture of ethyl acetate and cyclohexane. Addition of an equal amount of cyclohexane to a suspension of the lorazepam solvate in ethyl acetate eases stirring and improves recovery of desolvated lorazepam (compare Examples 1 and 2).
- the ratio of ethyl acetate to cyclohexane is from about 1000:1 to about 1:3, more preferably from about 1:2 to about 2:1 and most preferably about 1:1; and the ratio of lorazepam solvate to the mixture of ethyl acetate and cyclohexane is from about 1:3 (g:ml) to about 1:20 (g:ml), and most preferably from about 1:4 to about 1:8.
- the suspension is preferably heated to about 40° C. to about 80° C., more preferably about 50° C. to about 70° C. Desolvation occurs in about an hour when the suspension is heated to 50-70° C.
- the lorazepam solvate is suspended in dichloromethane.
- the ratio of lorazepam solvate to dichloromethane is preferably from about 1:2 (g:ml) to about 1:100 (g:ml), and most preferably from about 1:4 to about 1:8.
- the suspension is stirred for several hours. If the suspension is heated to a temperature of about 40° C. the desolvation is substantially complete in about an hour.
- the lorazepam solvate is suspended in a mixture of dichloromethane and toluene.
- Preferred dichloromethane and toluene mixtures contain dichloromethane and toluene in a ratio of from about 1:1000 to about 1000:1 (v:v), i.e. about any ratio is well suited, with a preferred mixture having about a 1:1 ratio of dichloromethane to toluene.
- the ratio of lorazepam solvate to the dichloromethane/toluene mixture is preferably from about 2 to about 100 milliliters of the mixture per gram of lorazepam solvate.
- Heated suspensions should be cooled as described with reference to the ethyl acetate suspension before isolating the lorazepam.
- Lorazepam substantially free of bound solvent may be isolated from suspension in ethyl acetate/cyclohexane mixtures, dichloromethane, dichloromethane/toluene mixtures and other suitable liquid organic media, washed and dried by the techniques described with reference to desolvation by suspension in ethyl acetate.
- Lorazepam obtained from these suspensions contains less than 0.5% of the lower alcohol or water of solvation present in the starting material.
- the invention also provides a new process for preparing lorazepam hydrate from lorazepam lower alcohol solvates by suspending the lower alcohol solvate in water.
- the ratio of lorazepam lower alcohol solvate to water is from about 1:2 to 1:1000, and most preferably from about 1:3 to 1:10.
- the lower alcohol solvate is added to water in an amount of about 0.2 grams per milliliter and is stirred for about 0.2 to about 1 hour at 10° C. to 80° C.
- the suspension is then cooled preferably to a temperature in the range of from about 0° C. to about 25° C., and the lorazepam hydrate is washed with water.
- the washed lorazepam hydrate is dried for about 1 hour to about 20 hours at a temperature in the range of from about 20° C. to about 90° C., more preferably in the range of from 40° C. to 60° C. and most preferably at 50° C., either at ambient pressure or under vacuum.
- Lorazepam ethanol solvate 100 g was suspended in a 1:1 mixture of ethyl acetate and cyclohexane (800 ml). The suspension was heated to 60° C. for 1 hour with rapid stirring and then cooled to 15° C. The cooled suspension was filtered to recover the lorazepam crystals and the crystals were then washed with ethyl acetate (20 ml). The crystals were dried at 50° C. under 65 mm Hg vacuum for two hours to give crystalline lorazepam (85 g, 90%).
- Lorazepam ethanol solvate 100 g was suspended in a 1:1 mixture of ethyl acetate and toluene (400 ml). The suspension was heated to 60° C. for 1 hour with rapid stirring and then cooled to 15° C. The suspension was filtered to recover the lorazepam. The lorazepam crystals were then washed with ethyl acetate (20 ml) and dried under 65 mm Hg vacuum at about 50° C. for about two hours to give crystalline lorazepam (83 g) in 88% yield.
- Lorazepam ethanol solvate 100 g was suspended in dichloromethane (600 ml). The suspension was heated to about 40° C. for 1 hour with rapid stirring and then cooled to 10° C. The suspension was filtered to recover the lorazepam crystals. The crystals were washed with dichloromethane (20 ml) and dried at 50° C. under 65 mm Hg vacuum for two hours to give crystalline lorazepam (85.5 g, 90%).
- Lorazepam ethanol solvate 100 g was suspended in a 1:1 mixture of dichloromethane and toluene (600 ml). The suspension was then heated to 25° C. for one hour and then cooled to 15° C. The suspension was filtered to recover the lorazepam crystals. The crystals were washed with toluene (20 ml) and dried at 50° C. under 65 mm Hg vacuum for two hours to give crystalline lorazepam (85 g, 90%)
- Lorazepam methanol solvate 100 g was suspended in ethyl acetate (400 ml). The suspension was heated to 60° C. for one hour with rapid stirring and then cooled to 15° C. The suspension was filtered to recover the lorazepam crystals. The crystals were washed with ethyl acetate (50 ml) and dried at 50° C. under 65 mm Hg vacuum for two hours to give crystalline lorazepam (85 g, 80%).
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
- This application claims the benefit of provisional application Serial No. 60/187,990, filed Mar. 6, 2001, which is incorporated herein by reference.
- The present invention relates to desolvation processes and, in particular, to a process for desolvating lorazepam lower alcohol solvates and lorazepam hydrate.
- The first benzodiazepine sedative, chlordiazepoxide, was introduced as a treatment for anxiety in humans after the discovery of its “taming” effect on animals in the1950's. Since that time, a large number of benzodiazepines have been found to possess sedative, anti-convulsant, and muscle-relaxant properties. Benzodiazepines are used clinically to treat a variety of ailments, including depression, anxiety, insomnia and muscle spasms.
- Lorazepam is a benzodiazepine with anti-anxiety and sedative effects that is widely used for treating human anxiety disorders and for pre-operative sedation. Lorazepam is the generic name of the compound 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one.
- U.S. Pat. No. 3,296,249, which is incorporated herein by reference, describes a process for preparing lorazepam. In the last step of that process, the acetyl group is removed from 3-acetoxy-7-chloro-5-(o-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one by treatment with sodium hydroxide in ethanol. The resulting lorazepam solution is allowed to stand until a precipitate is formed. The precipitate is then filtered, washed with water, and recrystallized from ethanol. Although the process for making lorazepam disclosed in the '249 patent is efficient, the precipitated product of the last step of the process is a one-to-one ethanol solvate of lorazepam which must be desolvated before it can be incorporated into a pharmaceutical for administration to humans. Substitution of solvents that do not form solvates with lorazepam in the last step of the '249 patent is not practical due to solubility problems.
- Lorazepam's poorly solubility in solvents commonly used by the pharmaceutical industry makes subsequent processing to desolvate the lorazepam problematic. Heating of lorazepam ethanol solvate to drive off the ethanol is not effective, demands prolonged thermal treatment and may cause partial chemical decomposition. There is a need for a process that removes the alcohol from a lorazepam alcohol solvate and yields lorazepam in a crystalline state.
- It has been found that water and lower alcohol molecules of solvation can be removed from lorazepam solvates by suspending the solvate in certain organic solvents and organic solvent mixtures. An advantage of the most preferred embodiments of the invention is that they use a minimum of solvent, which is advantageous because it keeps the cost of the process down and maximizes the recovery of desolvated crystalline lorazepam.
- Ethanol, methanol or water bound to lorazepam can be removed by contacting the lorazepam solvate with ethyl acetate or a mixture of ethyl acetate/cyclohexane or dichloromethane or toluene or a mixture of ethyl acetate and toluene, or a mixture of dichloromethane and toluene.
- It also has been found that lorazepam lower alcohol solvates can be converted to lorazepam hydrate by suspending the solvate in water under conditions that convert it to lorazepam hydrate.
- If desired, the two processes can be combined to convert lower alcohol solvates of lorazepam into crystalline lorazepam substantially free of bound solvent by first converting the lower alcohol solvate into lorazepam hydrate and then converting lorazepam hydrate into crystalline anhydrous lorazepam.
- The present invention provides a new process for preparing pure crystalline lorazepam from a lower alcohol solvate of lorazepam or lorazepam hydrate (collectively “lorazepam solvates”). “Lower alcohol” means an alcohol having from 1 to 4 carbon atoms and therefore includes methanol, ethanol and isopropanol.
- Suspending the lorazepam solvate in certain liquid organic media can be used to desolvate the lorazepam and enables isolation of lorazepam in a crystalline state that is substantially free of bound solvent. The desolvation may be accelerated by heating the suspension to an elevated temperature. After the lorazepam is desolvated of alcohol or water, it is separated from the liquid organic medium by, for example, filtration or decantation. The lorazepam may then be washed and dried by conventional means.
- A suitable liquid organic medium is an organic compound that is liquid at room temperature and, in particular, is ethyl acetate, cyclohexane, dichloromethane, toluene and mixtures thereof. Preferred liquid organic media are ethyl acetate, mixtures of ethyl acetate and cyclohexane, dichloromethane, toluene, mixtures of ethyl acetate and toluene, and mixtures of dichloromethane and toluene. The invention is further illustrated with ethyl acetate, dichloromethane, mixtures of ethyl acetate with cyclohexane and mixtures of dichloromethane with toluene.
- In one embodiment, the lorazepam solvate is suspended in ethyl acetate in an amount of about 3 to about 5 milliliters of ethyl acetate per gram of lorazepam, most preferably about 4 ml/g. The desolvation may be conducted at any temperature between about 20° C. and 80° C. Preferably, the suspension is heated to an elevated temperature of from about 55° C. to about 65° C. with mechanical agitation, e.g. stirring. Depending upon the temperature, desolvation can take from 5 minutes to about 24 h. When the suspension is stirred at 60° C. the lorazepam desolvates in about an hour. The suspension is then cooled most preferably to a temperature in the range of from about 15° C. to about 20° C. After the suspension is cooled, the desolvated lorazepam crystals may be separated from the liquid organic medium by filtration or decantation. The desolvated lorazepam is then washed with a solvent; dichloromethane, cyclohexane, toluene, xylene, chloroform, pentane, dichloroethane, hexane, heptane, and ethyl acetate being preferred, with ethyl acetate being most preferred. The washed desolvated lorazepam can be dried at a temperature in the range of from about 20° C. to about 90° C., more preferably in the range of from about 40° C. to about 60° C., and most preferably at a temperature of about 50° C., either at ambient pressure or under vacuum.
- According to another embodiment, the lorazepam solvate is suspended in a mixture of ethyl acetate and cyclohexane. Addition of an equal amount of cyclohexane to a suspension of the lorazepam solvate in ethyl acetate eases stirring and improves recovery of desolvated lorazepam (compare Examples 1 and 2). Preferably, the ratio of ethyl acetate to cyclohexane is from about 1000:1 to about 1:3, more preferably from about 1:2 to about 2:1 and most preferably about 1:1; and the ratio of lorazepam solvate to the mixture of ethyl acetate and cyclohexane is from about 1:3 (g:ml) to about 1:20 (g:ml), and most preferably from about 1:4 to about 1:8. The suspension is preferably heated to about 40° C. to about 80° C., more preferably about 50° C. to about 70° C. Desolvation occurs in about an hour when the suspension is heated to 50-70° C.
- According to another illustrative embodiment, the lorazepam solvate is suspended in dichloromethane. The ratio of lorazepam solvate to dichloromethane is preferably from about 1:2 (g:ml) to about 1:100 (g:ml), and most preferably from about 1:4 to about 1:8. The suspension is stirred for several hours. If the suspension is heated to a temperature of about 40° C. the desolvation is substantially complete in about an hour.
- In yet another embodiment, the lorazepam solvate is suspended in a mixture of dichloromethane and toluene. Preferred dichloromethane and toluene mixtures contain dichloromethane and toluene in a ratio of from about 1:1000 to about 1000:1 (v:v), i.e. about any ratio is well suited, with a preferred mixture having about a 1:1 ratio of dichloromethane to toluene. The ratio of lorazepam solvate to the dichloromethane/toluene mixture is preferably from about 2 to about 100 milliliters of the mixture per gram of lorazepam solvate.
- Heated suspensions should be cooled as described with reference to the ethyl acetate suspension before isolating the lorazepam. Lorazepam substantially free of bound solvent may be isolated from suspension in ethyl acetate/cyclohexane mixtures, dichloromethane, dichloromethane/toluene mixtures and other suitable liquid organic media, washed and dried by the techniques described with reference to desolvation by suspension in ethyl acetate.
- Lorazepam obtained from these suspensions contains less than 0.5% of the lower alcohol or water of solvation present in the starting material.
- The invention also provides a new process for preparing lorazepam hydrate from lorazepam lower alcohol solvates by suspending the lower alcohol solvate in water. Preferably, the ratio of lorazepam lower alcohol solvate to water is from about 1:2 to 1:1000, and most preferably from about 1:3 to 1:10. According to a particularly preferred set of conditions for converting a lower alcohol solvate of lorazepam to the lorazepam hydrate, the lower alcohol solvate is added to water in an amount of about 0.2 grams per milliliter and is stirred for about 0.2 to about 1 hour at 10° C. to 80° C. If heated, the suspension is then cooled preferably to a temperature in the range of from about 0° C. to about 25° C., and the lorazepam hydrate is washed with water. The washed lorazepam hydrate is dried for about 1 hour to about 20 hours at a temperature in the range of from about 20° C. to about 90° C., more preferably in the range of from 40° C. to 60° C. and most preferably at 50° C., either at ambient pressure or under vacuum.
- Having thus described the present invention with reference to certain preferred embodiments, the following examples are provided to further illustrate the processes by which crystalline lorazepam substantially free of bound solvent may be obtained. One skilled in the art will recognize variations and substitutions in the processes as described and exemplified which do not depart from the spirit and scope of the invention as defined by the claims.
- Lorazepam ethanol solvate (5 kg) was suspended in ethyl acetate (20 L). The suspension was heated to 60° C. for one hour with rapid stirring and then cooled to 15° C. The suspension was filtered to recover the lorazepam crystals. The crystals were then washed with ethyl acetate (2L) and dried at 50° C. under 65 mm Hg vacuum for two hours to give crystalline lorazepam (3.8 kg, 80%).
- Lorazepam ethanol solvate (100 g) was suspended in a 1:1 mixture of ethyl acetate and cyclohexane (800 ml). The suspension was heated to 60° C. for 1 hour with rapid stirring and then cooled to 15° C. The cooled suspension was filtered to recover the lorazepam crystals and the crystals were then washed with ethyl acetate (20 ml). The crystals were dried at 50° C. under 65 mm Hg vacuum for two hours to give crystalline lorazepam (85 g, 90%).
- Lorazepam ethanol solvate (100 g) was suspended in a 1:1 mixture of ethyl acetate and toluene (400 ml). The suspension was heated to 60° C. for 1 hour with rapid stirring and then cooled to 15° C. The suspension was filtered to recover the lorazepam. The lorazepam crystals were then washed with ethyl acetate (20 ml) and dried under 65 mm Hg vacuum at about 50° C. for about two hours to give crystalline lorazepam (83 g) in 88% yield.
- Lorazepam ethanol solvate (100 g) was suspended in dichloromethane (600 ml). The suspension was heated to about 40° C. for 1 hour with rapid stirring and then cooled to 10° C. The suspension was filtered to recover the lorazepam crystals. The crystals were washed with dichloromethane (20 ml) and dried at 50° C. under 65 mm Hg vacuum for two hours to give crystalline lorazepam (85.5 g, 90%).
- Lorazepam ethanol solvate (100 g) was suspended in a 1:1 mixture of dichloromethane and toluene (600 ml). The suspension was then heated to 25° C. for one hour and then cooled to 15° C. The suspension was filtered to recover the lorazepam crystals. The crystals were washed with toluene (20 ml) and dried at 50° C. under 65 mm Hg vacuum for two hours to give crystalline lorazepam (85 g, 90%)
- Lorazepam methanol solvate (100 g) was suspended in ethyl acetate (400 ml). The suspension was heated to 60° C. for one hour with rapid stirring and then cooled to 15° C. The suspension was filtered to recover the lorazepam crystals. The crystals were washed with ethyl acetate (50 ml) and dried at 50° C. under 65 mm Hg vacuum for two hours to give crystalline lorazepam (85 g, 80%).
- Lorazepam ethanol solvate (100 g) was suspended in water (500 ml). The suspension was rapidly stirred at room temperature for 1 hour and then filtered to recover lorazepam hydrate. The hydrate crystals were washed with water (100 ml) and dried at 50° C. under 65 mm Hg vacuum for 5 h to give lorazepam hydrate (90%).
- Lorazepam hydrate (100 g) was suspended in ethyl acetate (400 ml). The slurry was heated to 60° C. for 1 hour with rapid stirring and then cooled to 15° C. The suspension was filtered to recover the lorazepam crystals. The crystals were then washed with ethyl acetate (50 ml) and dried at 50° C. under 65 mm Hg vacuum for four hours to give crystalline lorazepam (80 g, 85%).
Claims (49)
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US09/799,318 US6350870B2 (en) | 2000-03-06 | 2001-03-05 | Process for preparing pure crystalline lorazepam |
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US09/799,318 US6350870B2 (en) | 2000-03-06 | 2001-03-05 | Process for preparing pure crystalline lorazepam |
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EP (1) | EP1265875A4 (en) |
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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 |
CN110804023A (en) * | 2019-12-09 | 2020-02-18 | 华中药业股份有限公司 | Lorazepam purification method |
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