IL119890A - Gabapentin form iii and preparation of gabapentin form ii - Google Patents

Gabapentin form iii and preparation of gabapentin form ii

Info

Publication number
IL119890A
IL119890A IL11989096A IL11989096A IL119890A IL 119890 A IL119890 A IL 119890A IL 11989096 A IL11989096 A IL 11989096A IL 11989096 A IL11989096 A IL 11989096A IL 119890 A IL119890 A IL 119890A
Authority
IL
Israel
Prior art keywords
gabapentin
solvent
methanol
inorganic salts
butanol
Prior art date
Application number
IL11989096A
Other versions
IL119890A0 (en
Original Assignee
Teva Pharma
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 Teva Pharma filed Critical Teva Pharma
Priority to IL11989096A priority Critical patent/IL119890A/en
Publication of IL119890A0 publication Critical patent/IL119890A0/en
Priority to DE0000950044T priority patent/DE97954134T1/en
Priority to PCT/US1997/023164 priority patent/WO1998028255A1/en
Priority to US09/331,555 priority patent/US6255526B1/en
Priority to AU57990/98A priority patent/AU5799098A/en
Priority to ES97954134T priority patent/ES2204362T1/en
Priority to CA002275912A priority patent/CA2275912A1/en
Priority to EP97954134A priority patent/EP0950044A4/en
Publication of IL119890A publication Critical patent/IL119890A/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A method of converting gabapentin hydrochloride substantially free of inorganic salts to gabapentin form II comprising: (i) mixing a solution of gabapentin hydrochloride substantially free of inorganic salts with an amine in a first solvent to obtain gabapentin form III; and (ii) contacting the gabapentin form III with methanol, to produce gabapentin form II. 379 כ" ו באדר התשס" ב - March 10, 2002

Description

1 19890/2 II aiiD^ia V>U3QKIK¾ room HI DTtK tm O3DK:IN¾ NOVEL GABAPENTIN FORM III AND PREPARATION OF GABAPENTIN FORM II TEVA PHARMACEUTICAL INDUSTRIES LTD.
C. 104869 104869 .D FIELD OF THE INVENTION This invention relates to a new process for converting gabapentin hydrochloride salt to gabapentin via a novel polymorphic form of gabapentin.
BACKGROUND OF THE INVENTION Gabapentin is the compound l-(aminomethyl)cyclohexane acetic acid, used in the treatment of epilepsy. The literature describes many ways of preparing gabapentin from a variety of starting materials. US Patent 4,025, 174 describes at least three methods of preparing gabapentin from cylcohexyl-l , l-diacetic acid. All these methods result in the formation of gabapentin hydrochloride salt.
US Patent 4,894,476 specifically discloses an improved method for converting the hydrochloride salt into the free amino acid. This involves pouring a deionized water solution of the salt over an ion exchange column, eluting with deionized water, producing a slurry from the eluate, adding an alcohol to the slurry, centrifuging and drying the slurry to obtain the free amino acid.
Alternative methods for preparing gabapentin to the exclusion of hydrochloride additives, involve methods of preparation that do not proceed via the hydrochloride or any other mineral acid salt.
Such methods, include those described in US Patents 5,132,451, 5,095,148, 5,068,413. Each of these methods involve a cyanic intermediate which is hydrogenated under severe conditions to produce the free amino acid.
These methods are industrially impractical. The use of ion exchange columns involves use of larger amounts of ion exchanger for lengthy periods in order to lower the level of chloride ions to the desired level. The alternative methods involve further more demanding steps.
Investigation of commercially available gabapentin has revealed that the gabapentin exists in a specific polymorphic form having an X-ray diffraction pattern with peaks of values of 2 theta at 7.8, 13.3, 15.0, 17.0, 20.4, 21.3, 23.1, 23.6, 25.7, 27.0 and 28.2 degrees. Hereinafter the commercially available polymorphic form of gabapentin will be referred to as polymorph form "Π".
SUMMARY OF THE INVENTION The present invention relates to an improved method of converting gabapentin hydrochloride salt to gabapentin Form II. The present inventionn avoids the disadvantages associated with prior art methods, by adding an alternative steps and proceeding via a novel polymorphic form of gabapentin.
Accordingly, the present invention relates to a method of converting gabapentin hydrochloride substantially free of inorganic salts to gabapentin form II, comprising: i) mixing a solution of gabapentin hydrocloride substantially free of inorganic salts with an amine in a first solvent; ii) reslurring the gabapentin form III in methanol, to produce gabapentin Form II.
The novel polymorphic form of gabapentin herein disclosed for the first time has been designated as form ΙΠ. The polymorph may be identified by the possession of unique peaks as observed by X-ray diffraction.
A further aspect of the present invention relates to the novel polymorphic form of gabapentin that is of use as an intermediate in the preparation of polymorphic form Π.
DESCRIPTION OF THE PREFERRED EMBODIMENTS Accordingly the method of the present invention comprises; (i) mixing gabapentin hydrochloride substantially free of inorganic salts with an amine in a first solvent to obtain gabapentin form ΓΠ, (ii) reslurrying the gabapentin form ΙΠ in methanol, to produce gabapentin form Π.
Thus, gabapentin hydrochloride is suspended in a first solvent to which an amine is added. The first solvent is one wherein gabapentin form ΓΠ is insoluble but the amine hydrochloride is soluble. Such solvents are preferably selected from the group consisting of ethyl acetate, dimethylcarbonate, ethanol, butanol, t-butanol, n-butanol, methanol, acetonitrile, toluene, isopropylacetate, isopropanol, methylethylketone, acetone, ethyleneglycolmonomethylether, methylene chloride, chloroform, benzylalcohol or dimethylacetamide. The precipitated gabapentin is a novel polymorphic form of gabapentin, possessing a crystalline structure characteristic to polymorph ΓΠ.
Polymorph ΙΠ is then suspended in methanol, to induce the transformation into the gabapentin form Π which is the commercially available polymorphic form of gabapentin. Gabapentin form Π may then be filtered off and washed.
The polymorphic form ΙΠ is characterized by peaks in the powder X ray diff action pattern at values of 2 theta at 6.1, 12.2, 17.0, 17.7, 18.3, 20.0, 20.8, 24.6 and 25.5 degrees.
Suitable amines for use in the present invention include triethylamine, rributylamine, tripropylamine, trihexylarnine, diethylamine, ethanolamine and benzylamine. Preferably the amine is rributylamine.
Preferably the gabapentin hydrochloride used as a starting material in the process of the present invention is substantially free of other inorganic salts such as sodium chloride and sodium bromide that is, such impurities are only present in trace amounts. Alternatively gabapentin hydrochloride containing inorganic salts may be used subject to the addition of a further step prior to the mixing of gabapentin hydrochloride with the amine.
Thus, the gabapentin hydrochloride containing inorganic salts may optionally be mixed in a second solvent prior to the addition of the amine in the first solvent. The second solvent is preferably one wherein gabapentin hydrochloride is soluble but the inorganic salts are not. Such solvents include those selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, t-butanol, n-butanol, ethyleneglycolmonomethylether, benzylalcohol or dimethylacetamide. The filtrate contains gabapentin hydrochloride substantially free of inorganic salts and is then evaporated to dryness to yield solid gabapentin hydrochloride substantially free of inorganic salts.
In a prefered embodiment the second solvent is identical to the first solvent.
The gabapentin obtained by the methods of the present invention may be crystallized using processes known in the art.
EXAMPLES Example 1 Preparation of gabapentin Removal of Inorganic Salts Gabapentin hydrochloride containing inorganic salts (NaCl, NaBr) was dissolved in 150ml isopropanol and mixed at 25°C. Active carbon (0.9g) was added and the suspension mixed for a further 2 hours. The inorganic salts were removed by filtering. The filter cake was washed twice with 15ml isopropanol and the washings were added to the gabapentin hydrochloride solution.
Gabapentin Base The gabapentin hydrochloride solution was concentrated to dryness in vacuum ensuring that the temperature of the heating bath did not exceed 35°C. 210ml ethylacetate and 16.5ml tributylamine were added and the solution then mixed for a further 2 hours at 25°C. Gabapentin was then separated by filtration, the filter cake being washed with 20ml ethylacetate and then 20ml methanol. The filter cake contains gabapentin form ΓΠ which when drid dispalys a characteristic X-ray diffraction pattern at values of 2 theta at 6.1, 12.2, 17.0, 17.7, 18.3, 20.0, 20.8, 24.6 and 25.5 degrees.
The still humid filter cake was suspended in 52.5ml methanol and for about 14 hours at 25°C. Solid gabapentin was separated from the suspension by filtration. The filter cake was washed with 20ml methanol and then dried under vacuum at 35°C. 10.8g crystalline gabapentin (yield 72%) was obtained.
Examples 2-20 The method of Example I was followed using the amines and solvents shown in Table I below. The percent yields marked with an asterik were measured at the stage prior to the reslurrying in methanol.
Table I IPA iso-propanol Et Ac ethyl acetate IPA Ac iso-propylacetate ACN acetonitrile DMA dimethylacetamide DMC dimethylcarbonate BzOH benzyl alcohol MEK methyl ethyl ketone (t)-BuOH (tert)-butanol MeOH methanol EGMME ethylglycol monomethylether CH2C12 methylene chloride TBA tnbutylamine TEA triethylamine THA trihexylamine BzA benzylamine DEA diethylamine TPA tripropylamine 119890/2 -7-

Claims (16)

1. ) A method of converting gabapentin hydrochloride substantially free of inorganic salts to gabapentin form II comprising: (i) mixing a solution of gabapentin hydrochloride substantially free of inorganic salts with an amine in a first solvent to achieve gabapentin form III; and (ii) contacting the gabapentin form III with methanol, to produce gabapentin form II.
2. ) The method of claim 1 wherein the methanol is contacted by suspension.
3. ) The method of claim 1 wherein the methanol is contacted by reslurrying.
4. ) The method of claim 1 wherein the gabapentin form Π is recrystallized from methanol.
5. ) The method of claim 2 wherein the temperature is maintained at about 25 degrees centigrade for about 14 hours.
6. ) The method of claim 3 wherein the temperature is maintained at about 25 degrees centigrade for about 14 hours.
7. ) The method of claim 4 wherein the temperature at which the methanol is contacted is above about 30°C.
8. ) A method according to claim 1 wherein the amine is selected from the group consisting of triethylmine, tributylamine, tripropylamine, trihexylamine, diethylamine, ethanolamine and benzylamine.
9. ) A method according to claim 8 wherein the amine is tributylamine.
10. ) A method according to any preceding claim, wherein the first solvent is one wherein gabapentin is insoluble and the amine hydrochloride is soluble. 1 19890 /2
11. 1 1) A method according to claim 10, wherein the first solvent is selected from the group consisting of ethyl acetate, dimethylcarbonate, ethanol, butanol, t-butanol, n-butanol, methanol, acetonitrile, toluene, isopropylacetate, isopropanol,methylethylketone, acetone, ethyleneglycolmonomethylether, methylene chloride,chloroform, benzylalcohol or dimethylacetamide.
12. ) A method according to claim 1 wherein the gabapentin hydrochloride substantially free of inorganic salts is prepared by mixing a solution of gabapentin hydrochloride containing inorganic salts with a second solvent and filtering the resulting mixture to remove said inorganic salts.
13. ) A method according to claim 12, wherein the second solvent is one wherein gabapentin hydrochloride is soluble and the inorganic salts are insoluble.
14. ) A method according to claim 13, wherein the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, butanol, t-butanol, n-butanol, ethyleneglycolmonomethylether, ben2ylalcohol and dimethylacetamide .
15. ) A method according to any of claims 6-8, wherein the second solvent is identical to the first solvent
16. ) Gabapentin form III characterized by peaks in the powder X-ray diffraction pattern at values of 2 theta of 6.1, 12.2, 17.0, 17.7, 18.3, 20.0, 20.8, 24.6 and 25.5 degrees.
IL11989096A 1996-12-24 1996-12-24 Gabapentin form iii and preparation of gabapentin form ii IL119890A (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
IL11989096A IL119890A (en) 1996-12-24 1996-12-24 Gabapentin form iii and preparation of gabapentin form ii
DE0000950044T DE97954134T1 (en) 1996-12-24 1997-12-24 PRODUCTION OF GABAPENTIN
PCT/US1997/023164 WO1998028255A1 (en) 1996-12-24 1997-12-24 Preparation of gabapentin
US09/331,555 US6255526B1 (en) 1996-12-24 1997-12-24 Preparation of gabapentin
AU57990/98A AU5799098A (en) 1996-12-24 1997-12-24 Preparation of gabapentin
ES97954134T ES2204362T1 (en) 1996-12-24 1997-12-24 PREPARATION OF GABAPENTINA.
CA002275912A CA2275912A1 (en) 1996-12-24 1997-12-24 Preparation of gabapentin
EP97954134A EP0950044A4 (en) 1996-12-24 1997-12-24 Preparation of gabapentin

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
IL11989096A IL119890A (en) 1996-12-24 1996-12-24 Gabapentin form iii and preparation of gabapentin form ii

Publications (2)

Publication Number Publication Date
IL119890A0 IL119890A0 (en) 1997-03-18
IL119890A true IL119890A (en) 2002-03-10

Family

ID=11069615

Family Applications (1)

Application Number Title Priority Date Filing Date
IL11989096A IL119890A (en) 1996-12-24 1996-12-24 Gabapentin form iii and preparation of gabapentin form ii

Country Status (7)

Country Link
EP (1) EP0950044A4 (en)
AU (1) AU5799098A (en)
CA (1) CA2275912A1 (en)
DE (1) DE97954134T1 (en)
ES (1) ES2204362T1 (en)
IL (1) IL119890A (en)
WO (1) WO1998028255A1 (en)

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ES2137137B1 (en) * 1998-05-25 2000-08-16 Medichem Sa NEW POLYMORPH OF UNHYDRATED GABAPENTINE, ITS PROCEDURE FOR OBTAINING AND ITS USE FOR THE OBTAINING OF PHARMACEUTICAL QUALITY GABAPENTINE.
IT1311984B1 (en) * 1999-03-26 2002-03-22 Bioindustria Lab Italiano Medi PROCEDURE FOR THE PREPARATION OF GABAPENTIN.
ATE303162T1 (en) 1999-04-09 2005-09-15 Euro Celtique Sa SODIUM CHANNEL BLOCKING COMPOSITIONS AND USE THEREOF
ES2164527B1 (en) * 1999-04-26 2003-04-01 Medichen S A PROCEDURE FOR OBTAINING GABAPENTINA OF PHARMACEUTICAL QUALITY.
US6294198B1 (en) 1999-08-24 2001-09-25 Purepac Pharmaceutical Co. Pharmaceutical tablet formulation containing gabapentin with improved physical and chemical characteristics and method of making the same
TR200302296T4 (en) * 2000-06-16 2004-02-23 Teva Pharmaceutical Industries Ltd. Stable gabapentin containing more than 20 ppm chlorine ion
EP1430893A1 (en) * 2000-06-16 2004-06-23 Teva Pharmaceutical Industries Ltd. Stable gabapentin containing more than 20 ppm of chloride ion
EP1384473A1 (en) * 2000-06-16 2004-01-28 Teva Pharmaceutical Industries Ltd. Stable gabapentin containing more than 20 ppm of chlorine ion
AU2001266992B8 (en) * 2000-06-16 2005-12-01 Teva Pharmaceutical Industries Ltd. Stable gabapentin having pH within a controlled range
US7056951B2 (en) 2000-09-26 2006-06-06 Mutual Pharmaceutical Co., Inc. Stable solid dosage forms of amino acids and processes for producing same
IT1319674B1 (en) * 2000-12-01 2003-10-23 Erregierre Spa PROCESS FOR THE PREPARATION OF CYCLOHEXANACETIC ACID1- (AMINOMETHYL).
SI1423168T1 (en) 2001-09-03 2006-06-30 Newron Pharm Spa Pharmaceutical composition comprising gabapentin or an analogue thereof and an alpha-aminoamide and its analgesic use
US6800782B2 (en) 2001-10-09 2004-10-05 Warner-Lambert Co. Anhydrous crystalline forms of gabapentin
US20030158254A1 (en) * 2002-01-24 2003-08-21 Xenoport, Inc. Engineering absorption of therapeutic compounds via colonic transporters
DE60230552D1 (en) 2002-11-18 2009-02-05 Nicholas Piramal India Ltd IMPROVED PROCESS FOR THE PREPARATION OF GABAPENTIN
CA2506563C (en) * 2002-11-20 2011-10-18 Hikal Ltd. An improved process for the preparation of amino methyl cyclo alkane acetic acids
WO2004093780A2 (en) * 2003-04-21 2004-11-04 Matrix Laboratories Ltd Process for the preparation of gabapentin form-ii
WO2004093779A2 (en) * 2003-04-21 2004-11-04 Matrix Laboratories Ltd Process for the preparation of gabapentin form-ii
WO2004106281A1 (en) * 2003-05-30 2004-12-09 Ranbaxy Laboratories Limited Crystalline gabapentin
WO2004110981A1 (en) * 2003-06-12 2004-12-23 Matrix Laboratories Ltd A process for the preparation of gabapentin form-ii
WO2004110342A2 (en) * 2003-06-12 2004-12-23 Matrix Laboratories Ltd Novel polymorph of gabapentin and its conversion to gabapentin form-ii
US7169812B2 (en) 2003-07-01 2007-01-30 Medtronic, Inc. Process for producing injectable gabapentin compositions
ITMI20040579A1 (en) 2004-03-25 2004-06-25 Zambon Spa GABAPENTINA PREPARATION PROCESS
GB0415076D0 (en) * 2004-07-05 2004-08-04 Sandoz Ind Products S A Process for the preparation of gabapentin
GB0416228D0 (en) 2004-07-20 2004-08-25 Sandoz Ind Products S A Process for the preparation of gabapentin
EP2007710A1 (en) * 2007-02-28 2008-12-31 Teva Pharmaceutical Industries Ltd. Preparation of gabapentin by liquid-liquid extraction
EP2183211A1 (en) 2007-07-27 2010-05-12 Medichem, S.A. Method for preparing polymorph form ii of gabapentin
CN102363598B (en) * 2011-11-25 2014-02-12 浙江精进药业有限公司 Method for preparing high-purity gabapentin
ITMI20131757A1 (en) 2013-10-22 2015-04-23 Zach System Spa GABAPENTINE PREPARATION PROCESS

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DE2460891C2 (en) * 1974-12-21 1982-09-23 Gödecke AG, 1000 Berlin 1-aminomethyl-1-cycloalkaneacetic acids and their esters, processes for their preparation and medicaments containing these compounds
US4960931A (en) * 1988-05-02 1990-10-02 Warner-Lambert Company Gabapentin mohohydrate and a process for producing the same
DE3928184A1 (en) * 1989-08-25 1991-02-28 Goedecke Ag METHOD FOR PRODUCING CYCLIC AMINO ACID DERIVATIVES AND INTERMEDIATE PRODUCTS

Also Published As

Publication number Publication date
CA2275912A1 (en) 1998-07-02
IL119890A0 (en) 1997-03-18
WO1998028255A1 (en) 1998-07-02
ES2204362T1 (en) 2004-05-01
DE97954134T1 (en) 2004-04-15
AU5799098A (en) 1998-07-17
EP0950044A1 (en) 1999-10-20
EP0950044A4 (en) 2003-03-26

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