US20010039340A1 - Process for preparing pure crystalline lorazepam - Google Patents

Process for preparing pure crystalline lorazepam Download PDF

Info

Publication number
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
Authority
US
United States
Prior art keywords
lorazepam
solvate
suspension
ethyl acetate
dichloromethane
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
US09/799,318
Other versions
US6350870B2 (en
Inventor
Igor Lifshitz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceuticals USA Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to US09/799,318 priority Critical patent/US6350870B2/en
Assigned to TEVA PHARMACEUTICAL INDUSTRIES, LTD. reassignment TEVA PHARMACEUTICAL INDUSTRIES, LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LIFSHITZ, IGOR
Publication of US20010039340A1 publication Critical patent/US20010039340A1/en
Assigned to TEVA PHARMACEUTICALS USA, INC. reassignment TEVA PHARMACEUTICALS USA, INC. ASSIGNMENT OF RIGHTS IN BARBADOS Assignors: TEVA PHARMACEUTICALS INDUSTRIES LTD.
Application granted granted Critical
Publication of US6350870B2 publication Critical patent/US6350870B2/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D243/00Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10Heterocyclic 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
    • C07D243/141,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/161,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/181,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24Oxygen 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%).

Landscapes

  • 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

The present invention provides a process for preparing crystalline lorazepam substantially free of bound solvent from a lorazepam alcohol solvate or hydrate by suspending the lorazepam solvate in an organic medium selected from ethyl acetate, cyclohexane, dichloromethane, toluene and mixtures thereof. This process is useful in producing the anti-anxiety and sedative agent lorazepam in increased yields. A process for converting lorazepam lower alcohol solvates to lorazepam hydrate is also disclosed.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims the benefit of provisional application Serial No. 60/187,990, filed Mar. 6, 2001, which is incorporated herein by reference.[0001]
  • FIELD OF THE INVENTION
  • The present invention relates to desolvation processes and, in particular, to a process for desolvating lorazepam lower alcohol solvates and lorazepam hydrate. [0002]
  • BACKGROUND OF THE INVENTION
  • The first benzodiazepine sedative, chlordiazepoxide, was introduced as a treatment for anxiety in humans after the discovery of its “taming” effect on animals in the [0003] 1950'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. [0004]
  • 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. [0005]
  • 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. [0006]
  • SUMMARY OF THE INVENTION
  • 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. [0007]
  • 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. [0008]
  • 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. [0009]
  • 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. [0010]
  • DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • 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. [0011]
  • 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. [0012]
  • 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. [0013]
  • 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. [0014]
  • 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. [0015]
  • 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. [0016]
  • 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. [0017]
  • 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. [0018]
  • Lorazepam obtained from these suspensions contains less than 0.5% of the lower alcohol or water of solvation present in the starting material. [0019]
  • 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. [0020]
  • 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.[0021]
  • EXAMPLES Example 1
  • 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%). [0022]
  • Example 2
  • 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%). [0023]
  • Example 3
  • 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. [0024]
  • Example 4
  • 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%). [0025]
  • Example 5
  • 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%) [0026]
  • Example 6
  • 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%). [0027]
  • Example 7
  • 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%). [0028]
  • Example 8
  • 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%). [0029]

Claims (49)

What is claimed is:
1. A process for preparing crystalline lorazepam substantially free of bound solvent from a lorazepam solvate with water or a lower alcohol comprising the steps of suspending the lorazepam solvate in a liquid organic medium selected from the group consisting of ethyl acetate, cyclohexane, toluene, dichloromethane and mixtures thereof under conditions effective to desolvate the lorazepam and isolating crystalline lorazepam substantially free of bound solvent from the suspension.
2. The process of
claim 1
wherein the bound solvent is water.
3. The process of
claim 1
wherein the bound solvent is methanol, ethanol or isopropanol.
4. The process of
claim 3
wherein the bound solvent is ethanol.
5. The process of
claim 1
wherein the liquid organic medium is ethyl acetate.
6. The process of
claim 5
wherein the ethyl acetate is used in an amount of from about 2 to about 10 milliliters per gram of lorazepam solvate.
7. The process of
claim 6
wherein the ethyl acetate is used in an amount of from about 3 to about 5 milliliters per gram of lorazepam solvate.
8. The process of
claim 7
wherein the ethyl acetate is used in an amount of about 5 milliliters per gram of lorazepam solvate.
9. The process of
claim 1
wherein the liquid organic medium is a mixture of ethyl acetate and cyclohexane.
10. The process of
claim 9
wherein the liquid organic medium is a mixture of cyclohexane and ethyl acetate in a volume ratio of from about 1 volume of cyclohexane to 2 volumes of ethyl acetate to about 2 volumes of cyclohexane to 1 volume of ethyl acetate.
11. The process of
claim 10
wherein the volume ratio of ethyl acetate to cyclohexane is about 1:1.
12. The process of
claim 9
wherein the liquid organic medium is used in an amount of from about 3 to about 20 milliliters per gram of lorazepam solvate.
13. The process of
claim 12
wherein the liquid organic medium is used in an amount of from about 4 to about 8 milliliters per gram of lorazepam solvate.
14. The process of
claim 1
wherein the liquid organic medium is dichloromethane.
15. The process of
claim 14
wherein the dichloromethane is used in an amount of from about 2 to about 100 milliliters per gram of lorazepam solvate.
16. The process of
claim 15
wherein the dichloromethane is used in an amount of from about 4 to about 8 milliliters per gram of lorazepam solvate.
17. The process of
claim 1
wherein the liquid organic medium is a mixture of dichloromethane and toluene.
18. The process of
claim 17
wherein the liquid organic medium is a mixture of dichloromethane and toluene in a volume ratio of from about 1 volume of dichloromethane to 1000 volumes of toluene to about 1000 volumes of dichloromethane to 1 volume of toluene.
19. The process of
claim 18
wherein the volume ratio of dichloromethane and toluene is about 1 to 1.
20. The process of
claim 17
wherein the liquid organic medium is used in an amount of from about 2 to about 100 milliliters per gram of lorazepam solvate.
21. The process of
claim 1
wherein the conditions effective for desolvating the lorazepam include heating the suspension to an elevated temperature.
22. The process of
claim 21
wherein the elevated temperature is in the range of from about 40° C. to about 80° C.
23. The process of
claim 22
wherein the liquid organic medium is ethyl acetate and the elevated temperature is in the range of from about 55° C. to about 65° C.
24. The process of
claim 22
wherein the liquid organic medium is a mixture of ethyl acetate and cyclohexane and the elevated temperature is in a range of from about 50° C. to about 70° C.
25. The process of
claim 21
wherein the liquid organic medium is dichloromethane and the elevated temperature is about 42° C. or a lower temperature.
26. The process of
claim 21
wherein the liquid organic medium is a mixture of dichloromethane and toluene and the elevated temperature is about 80° C. or lower temperature.
27. The process of
claim 26
wherein the elevated temperature is about 60° C.
28. The process of
claim 21
further comprising the step of cooling the suspension from elevated temperature before isolating the crystalline lorazepam substantially free of bound alcohol from the suspension.
29. The process of
claim 28
wherein the suspension is cooled to a temperature in the range of from about 0° C. to about 50° C. before isolating the crystalline lorazepam substantially free of bound alcohol from the suspension.
30. The process of
claim 29
wherein the cooling temperature is in the range of from about 15° C. to about 20° C.
31. The process of
claim 1
wherein the crystalline lorazepam substantially free of bound alcohol is isolated by filtering the suspension and recovering lorazepam crystals on the filter and wherein the process further includes washing the lorazepam crystals and drying them.
32. The process of
claim 31
wherein the wash solvent is selected from the group consisting of dichloromethane, cyclohexane, toluene, xylene, chloroform, pentane dichloroethane, hexane, heptane and ethyl acetate.
33. The process of
claim 31
wherein the lorazepam crystals are dried at a temperature in the range of from about 20° C. to about 80° C.
34. The process of
claim 33
wherein the lorazepam crystals are dried at a temperature in the range of from about 40° C. to about 60° C.
35. The process of
claim 31
wherein the lorazepam crystals are dried under vacuum.
36. A process for desolvating a lorazepam solvate with water or a lower alcohol comprising the steps of suspending the lorazepam solvate in ethyl acetate in an amount of from about 2 to about 10 milliliters of ethyl acetate per gram of lorazepam solvate, heating the suspension to a temperature of from about 55° C. to about 65° C. for a time sufficient to desolvate the lorazepam, cooling the suspension to a temperature in the range of about 15° C. to about 20° C., and separating the ethyl acetate either by filtration or decantation, and then drying the lorazepam to obtain crystalline lorazepam free of bound solvent.
37. A process for desolvating a lorazepam solvate with water or a lower alcohol comprising the steps of suspending the lorazepam solvate in a liquid organic medium comprising ethyl acetate and cyclohexane in an amount of from about 3 to about 20 milliliters of the liquid organic medium per gram of lorazepam solvate, heating the suspension to a temperature of from about 50° C. to about 70° C. for a time sufficient to desolvate the lorazepam, cooling the suspension to a temperature in the range of about 15° C. to about 20 C., and separating the liquid organic medium from the lorazepam either by filtration or decantation, and then drying the lorazepam to obtain crystalline lorazepam free of bound solvent.
38. A process for desolvating a lorazepam solvate with water or a lower alcohol comprising the steps of suspending the lorazepam solvate in dichloromethane in an amount of from about 2 to about 100 milliliters of dichloromethane per gram of lorazepam solvate for a time sufficient to desolvate the lorazepam, with optional heating of the suspension to a temperature in the range of from about 25° C. to about 42° C. and optionally cooling the suspension to a temperature in the range of about 15° C. to about 20° C., and separating the dichloromethane either by filtration or decantation, and then drying the lorazepam to obtain crystalline lorazepam free of bound solvent.
39. A process for desolvating a lorazepam solvate with water or a lower alcohol comprising the steps of suspending the lorazepam solvate in a liquid organic medium comprising dichloromethane and toluene in an amount of from about 2 to about 100 milliliters of liquid organic medium per gram of lorazepam solvate, heating the suspension to a temperature of from about 25° C. to about 60° C. for a time sufficient to desolvate the lorazepam, cooling the suspension to a temperature in the range of about 15° C. to about 20° C., and separating the liquid organic medium either by filtration or decantation, and then drying the lorazepam to obtain crystalline lorazepam free of bound solvent.
40. A process for preparing lorazepam hydrate from a lorazepam lower alcohol solvate comprising the steps of suspending the lorazepam lower alcohol solvate in water under conditions effective to substantially convert the suspended lorazepam lower alcohol solvate to lorazepam hydrate and then isolating lorazepam hydrate from the aqueous suspension.
41. The process of
claim 40
wherein the water is used in an amount of from about 2 milliliters to about 1000 milliliters per gram of lorazepam lower alcohol solvate.
42. The process of
claim 41
wherein the water is used in an amount of from about 3 milliliters to about 10 milliliters per gram of lorazepam lower alcohol solvate.
43. The process of
claim 42
wherein the water is used in an amount of about 5 milliliters per gram of lorazepam lower alcohol solvate.
44. The process of
claim 40
wherein the conditions effective for converting the suspended lorazepam lower alcohol solvate to lorazepam hydrate include adjusting the temperature of the suspension to from about 10° C. to about 80° C.
45. The process of
claim 44
wherein the suspension is heated to an elevated temperature of from about 30° C. to about 80° C.
46. The process of
claim 45
further comprising the step of cooling the aqueous suspension from the elevated temperature before isolating the lorazepam hydrate from the aqueous suspension.
47. The process of
claim 46
wherein the lorazepam hydrate is isolated from the aqueous suspension by filtering the aqueous suspension and recovering the lorazepam hydrate on the filter and wherein the process further comprises the steps of washing and drying the lorazepam hydrate.
48. The process of
claim 49
wherein the lorazepam hydrate is dried at a temperature in the range of from about 40° C. to about 80° C.
49. The process of
claim 48
wherein the lorazepam hydrate is dried under vacuum.
US09/799,318 2000-03-06 2001-03-05 Process for preparing pure crystalline lorazepam Expired - Fee Related US6350870B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US09/799,318 US6350870B2 (en) 2000-03-06 2001-03-05 Process for preparing pure crystalline lorazepam

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US18799000P 2000-03-06 2000-03-06
US09/799,318 US6350870B2 (en) 2000-03-06 2001-03-05 Process for preparing pure crystalline lorazepam

Publications (2)

Publication Number Publication Date
US20010039340A1 true US20010039340A1 (en) 2001-11-08
US6350870B2 US6350870B2 (en) 2002-02-26

Family

ID=22691327

Family Applications (1)

Application Number Title Priority Date Filing Date
US09/799,318 Expired - Fee Related US6350870B2 (en) 2000-03-06 2001-03-05 Process for preparing pure crystalline lorazepam

Country Status (6)

Country Link
US (1) US6350870B2 (en)
EP (1) EP1265875A4 (en)
AU (1) AU2001245429A1 (en)
CA (1) CA2401928A1 (en)
IL (1) IL151632A0 (en)
WO (1) WO2001066062A2 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SK286118B6 (en) * 2003-12-03 2008-04-07 Zentiva, A. S. Method of purifying lorazepam
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
CN110840898B (en) * 2019-11-19 2022-05-13 湖南洞庭药业股份有限公司 Light-stabilized pharmaceutical composition, 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

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE621819A (en) * 1961-08-29
NL298071A (en) 1963-06-04
US3873604A (en) * 1972-10-03 1975-03-25 American Home Prod Synthesis of 1,4-benzodiazepin-2-ones

Also Published As

Publication number Publication date
CA2401928A1 (en) 2001-09-13
EP1265875A2 (en) 2002-12-18
WO2001066062A3 (en) 2002-04-18
AU2001245429A1 (en) 2001-09-17
IL151632A0 (en) 2003-04-10
WO2001066062A2 (en) 2001-09-13
US6350870B2 (en) 2002-02-26
EP1265875A4 (en) 2003-07-09

Similar Documents

Publication Publication Date Title
DE2845417C2 (en)
US6350870B2 (en) Process for preparing pure crystalline lorazepam
HU229102B1 (en) 1,4-diazabicyclo[3.2.2]nonabenzoxazole, -benzothiazole and benzimidazole derivatives, preparation and therapeutic use thereof
CN109641905B (en) Process for purifying methotrexate or salt thereof
JPH08134055A (en) Production of 3-o-substituted-ascorbic acid
CN1315953A (en) Process for preparation of imidazodiazepine intermediates
US7829700B2 (en) Process for preparation of a pharmaceutically pure polymorphic form I of Olanzapine
JP2007031434A (en) Streptogramin derivative
KR20070053697A (en) Improved process for the manufacture of mirtazapine
JP4789383B2 (en) Method for the formation of epinastine hydrochloride with high-temperature melting crystal transformation
WO2005054211A1 (en) A method of purification of lorazepam
JP2002538948A (en) Emulsion crystallization with recirculation
US3520878A (en) Preparation of diazepam
SU1080744A3 (en) Process for preparing derivatives of benzodiazepine
EP1730153B1 (en) Isopropanol water solvate of olanzapine
CN113121466B (en) Recrystallizing solvent of acotiamide hydrochloride and refining method thereof
JP2002544265A (en) Diazepine manufacturing method
WO2008007390A2 (en) An improved process for purification of zolmitriptan
US7714129B2 (en) Methods of preparing anhydrous aripiprazole form II
CN113045574A (en) Process for preparing diazepine derivative and intermediates thereof
JP2003530404A (en) Method for producing 3-amino-1,5-benzodiazepine derivative
HU214583B (en) Process for purifying 5h-dibenz[b,f]azepine
DK160307B (en) ANALOGY PROCEDURE FOR PREPARING 1,7-DIHYDROPYRROLOOE3,4-EAAOE1,4AADIAZEPIN-2 (1H) -ON DERIVATIVES
JPH051053A (en) New process for producing 6-(3-dimethylamino-propionyl) forskolin
US3875213A (en) Intermediates for the synthesis of 1,4-benzodiazepin-2-ones

Legal Events

Date Code Title Description
AS Assignment

Owner name: TEVA PHARMACEUTICAL INDUSTRIES, LTD., ISRAEL

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:LIFSHITZ, IGOR;REEL/FRAME:011966/0618

Effective date: 20010516

AS Assignment

Owner name: TEVA PHARMACEUTICALS USA, INC., PENNSYLVANIA

Free format text: ASSIGNMENT OF RIGHTS IN BARBADOS;ASSIGNOR:TEVA PHARMACEUTICALS INDUSTRIES LTD.;REEL/FRAME:012541/0862

Effective date: 20010522

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20060226