EP1636163A1 - Procede de preparation de gabapentine - Google Patents

Procede de preparation de gabapentine

Info

Publication number
EP1636163A1
EP1636163A1 EP03816962A EP03816962A EP1636163A1 EP 1636163 A1 EP1636163 A1 EP 1636163A1 EP 03816962 A EP03816962 A EP 03816962A EP 03816962 A EP03816962 A EP 03816962A EP 1636163 A1 EP1636163 A1 EP 1636163A1
Authority
EP
European Patent Office
Prior art keywords
gabapentin
acid addition
addition salt
alcohol
amine
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.)
Withdrawn
Application number
EP03816962A
Other languages
German (de)
English (en)
Other versions
EP1636163A4 (fr
Inventor
Thakashina Moorty Chandiran
Jothi Shobana
Kumar Minor Senthil
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.)
Shasun Chemicals and Drugs Ltd
Original Assignee
Shasun Chemicals and Drugs Ltd
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 Shasun Chemicals and Drugs Ltd filed Critical Shasun Chemicals and Drugs Ltd
Publication of EP1636163A1 publication Critical patent/EP1636163A1/fr
Publication of EP1636163A4 publication Critical patent/EP1636163A4/fr
Withdrawn legal-status Critical Current

Links

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
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups

Definitions

  • the present invention relates to the process for the preparation of anhydrous Gabapentin of pharmaceutical grade from the Gabapentin acid addition salts. More particularly, the present invention relates to a process for the preparation of anhydrous gabapentin form II from Gabapentin hydrochloride or Gabapentin hydrobromide salt. BACKGROUND OF THE INVENTION
  • Gabapentin is l-(aminomethyl)cyclohexaneacetic acid having the chemical structure of formula (I).
  • the U.S. Pat. No. 4,894,476 described a method to prepare essentially the same anhydrous Gabapentin described in the U.S. Pat. No. 4,024,175 through pure Gabapentin monohydrate of defined physical characteristics.
  • the process described in this patent comprises of: a) pouring a solution of an acid salt of l-(aminomethyl)cyclohexaneacetic acid in deionised water onto an ion exchange column in the basic form and eluting the column with deionized water; b) concentrating the elute producing a slurry; c) cooling and adding alcohol to the slurry from step (b); d) cooling and centrifuging the slurry from step (c); e) drying the precipitate to obtain Gabapentin monohydrate, f) The Gabapentin monohydrate was then dissolved in methanol and diluted with isopropyl alcohol to produce a slurry. The slurry was then centrifuged and the precipitate
  • the PCT international publication WO 00/01660 described a method to prepare the anhydrous Gabapentin from Gabapentin hydrochloride.
  • the method described in this publication consists of, treating the hydrochloride salt with ion exchange resin, and the aqueous solution thus obtained was concentrated to certain level and the left over water was removed by azeotropic distillation. Further the mass was diluted with isopropyl alcohol and cooled to get anhydrous Gabapentin crystallized from the mass.
  • Another PCT international publication WO 00/58268 described a method to prepare the anhydrous Gabapentin from Gabapentin hydrochloride.
  • the method described in this publication consisted of, treating the hydrochloride salt aqueous solution with a base to Gabapentin isoelectric point and then diafiltering the solution through highly selective membrane to separate chloride ion and Gabapentin substantially free from chloride ions.
  • the PCT international publication WO 02/34709 described a process for the purification of Gabapentin hydrochloride from the inorganic salts and its conversion into Gabapentin by treatment of an aqueous Gabapentin hydrochloride solution with a cation exchange resin.
  • the object of the present invention was therefore to develop a simple and viable alternate method to produce anhydrous Gabapentin form II, starting from Gabapentin acid addition salts.
  • the present invention provides a novel method to prepare anhydrous Gabapentin form II from Gabapentin acid addition salts such as Gabapentin hydrochloride and Gabapentin hydrobromide.
  • the process consists of neutralizing the said acid addition salts with an organic base in water to get an aqueous solution comprising of Gabapentin and amine acid addition salt dissolved in water.
  • the process further comprises of a method to separate the Gabapentin and the amine acid addition salt from such an aqueous solution and to recover Gabapentin as an anhydrous Gabapentin form II.
  • the preferred embodiment of the present invention provides a method for preparing anhydrous gabapentin form II comprising: (a) dissolution of Gabapentin acid addition salt in water, (b) neutralization of the acid addition salt with a base to get a aqueous solution comprising of Gabapentin and amine acid addition salt dissolved in water, (c) distillation of water from the solution obtained in step (b) under reduced pressure, (d) seeding the concentrate with Gabapentin form II at an appropriate instance during said distillation to initiate the crystallization of Gabapentin form II while the solution is being concentrated, (e) addition of alcohol or mixture of alcohols in to the concentrate to enable the amine acid addition salt dissolved in it, (f) recovery of the crystallized Gabapentin form II from the mixture by filtration and (g) purification of the product by recrystallization from a solvent.
  • the Gabapentin acid addition salt in step (a) is inorganic acid addition salt such as hydrochloride or hydrobromide salts of gabapentin and like.
  • the said acid addition salt is dissolved in water to get an aqueous solution.
  • the dissolution is preferably carried out with 2 to 5 times the weight of water in proportion to the Gabapentin acid addition salt.
  • the dissolution is carried out at a temperature between 20 to 50°C and preferably at 25 to 30°C.
  • the neutralization step (b) is carried out with base, preferably with organic bases, such as amines.
  • the preferred amines are primary, secondary and tertiary alkyl amines. The most preferred amines are triethylamine, tripropyl amine and tributylamine.
  • 0.9 to 1.2 mole equivalence of amines is used, preferably 0.95 to 1.05 mole equivalence of amine is used for the neutralization.
  • the pH of the solution is 6.5 to 7.5 after the neutralization and the preferred pH of neutralization is 6.8 to 7.2.
  • the neutralization step is earned out at a temperature ranging between 10- 50 ° C, preferably at a temperature ranging between 20-30 ° C to get an aqueous solution comprising of Gabapentin and amine acid addition salt dissolved in water.
  • step-c water is removed from the aqueous solution by distillation under reduced pressure. Water is distilled at 30 to 70°C under reduced pressure, preferably at 45 to 55°C.
  • step (d) Gabapentin from II seeds are added after distilling out 20 to 50% of water quantity used for the dissolution of the Gabapentin acid addition salt. How ever the appropriate seeding instance could vary with the temperature of the distillation and quantity of the water used in the process. The addition of Gabapentin form II seeds at this instance initiates the crystallization of Gabapentin form II during the water distillation.
  • the Gabapentin form II seeds added are about 1 to 5 g for every 100 g of Gabapentin acid addition salt and preferably 2 g seeds for every 100 g of Gabapentin acid addition salt used in the process. Water distillation is continued till 80 to 95% quantity of water used for the dissolution of the Gabapentin acid addition salt is distilled out. A small sample is removed from the concentrate at this point and filtered, washed with chilled water and dried under vacuum. Examined the product obtained by IR (KBr) and X-ray diffraction, and it is identified to match with those recorded from Gabapentin form II.
  • the concentrate is then diluted with alcohol or with mixture of alcohols in step (e) and then cooled to 0 to 20°C.
  • the dilution with alcoholic solvent facilitates the dissolution of the amine acid addition salts in the solvent and removal from the concentrate so as to enable the separation of Gabapentin form the amine acid addition salts.
  • the preferred alcohols are methyl alcohol, ethyl alcohol, isopropyl alcohol and butyl alcohol or their mixture of one in another.
  • the preferred alcohol mixture ia a mixture of methyl alcohol and isopropyl alcohol.
  • the slurry obtained from step (e) is then filter and washed with the solvent to get the product Gabapentin form II.
  • a sample from the product is again re-examined by IR (KBr) and X-ray diffraction and it is identified to match with those recorded from Gabapentin form II.
  • the product is then recrystallized from methyl alcohol or ethyl alcohol to obtain a pure product with anion content less than 100 ppm by silver nitrate solution titration or by ion chromatography and lactam impurity of formula (II) content less than 0.1% wt/wt by HPLC analysis.
  • Gabapentin hydrobromide is dissolved in twice the weight of water at 25 to 30°C to get an aqueous solution.
  • the aqueous solution is then neutralized with tributylamine at 25 to 30°C over a period of 30 min.
  • the solution is then stirred at 25 to 30°C over a period of 30 min.
  • the aqueous solution is then heated to 45 to 50°C and distilled out 35% of water under reduced pressure.
  • Added Gabapentin form II seed crystals to the solution and continued the water distillation to the extent of around 90% of the total water used for the dissolution of the gabapentin salt in the process.
  • the concentrate is then diluted with a mixture of methyl alcohol and isopropyl alcohol.
  • the slurry so obtained is then cooled to 0 to 5°C and filtered.
  • the product is then recrystallized from methyl alcohol.
  • Gabapentin hydrobromide 200 g, 0.793 mole was dissolved in water (400 ml) at 30° C. Into this solution was added tributylamine (154 g, 0.83 mole) at 25-30° C. The ⁇ H of the solution was 6.9 at the end of tributylamine addition. The solution was then warmed to 50°C and distilled out water at 45 to 50°C at 35 to 40 mm Hg. Added in to the content, Gabapentin form II seeds (4 g) when water (160 ml) was distilled out from the solution. Continued the distillation at 45 to 50°C at 35 to 34 mm Hg till water (360 ml) was collected.
  • Gabapentin hydrobromide 200 g, 0.793 mole was dissolved in water (400 ml) at 30° C. Into this solution was added tributylamine (154 g, 0.83 mole) at 25-30° C. The p H of the solution was 6.9 at the end of tributylamine addition. The solution was then warmed to 50°C and distilled out water at 45 to 50°C at 35 to 40 mm Hg. Added in to the content Gabapentin form II seeds (4 g) when water (140 ml) was distilled out. Continued the distillation at 45 to 50°C at 35 to 34 mm Hg till water (360 ml) was collected.
  • Gabapentin hydrobromide 50 g, 0.198 mole was dissolved in water (100 ml) at 30° C. Into this solution was added tributylamine (38.5 g, 0.207 mole) at 25-30° C. The ⁇ H of the solution was 6.8 at the end of tributylamine addition. The solution was then warmed to 50°C and distilled out water at 45 to 50°C at 35 to 40 mm Hg. Added in to the content Gabapentin form II seeds (1 g) when water (35 ml) was distilled out. The distillation was continued till water (85 ml) was collected.
  • Gabapentin hydrobromide (100 g, 0.396 mole ) was dissolved in water (200 ml) at 30° C. Into this solution was added tributylamine (77 g, 0.415 mole) at 25-30° C. The p H of the solution was 7.13 at the end of tributylamine addition. The solution was then warmed to 50°C and distilled out water at 45 to 50°C at 35 to 40 mm Hg. Added in to the content Gabapentin form II seeds (2 g) when water (100 ml) was distilled out. Continued the distillation at 45 to 50°C at 35 to 34 mm Hg till water (180 ml) was collected.

Landscapes

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

Abstract

La présente invention concerne le processus de préparation de Gabapentine anhydre de qualité pharmaceutique à partir de sels d'addition d'acides de Gabapentine. Le processus consiste à neutraliser lesdits sels d'addition d'acides avec une base organique dans l'eau pour obtenir une solution aqueuse contenant de la Gabapentine et un sel d'addition d'acide aminé dissous dans l'eau. Le procédé comprend aussi un procédé pour séparer la Gabapentine et le sel d'addition d'acide aminé à partir de cette solution aqueuse et pour récupérer la Gabapentine sous forme de Gabapentine anhydre forme II.
EP03816962A 2003-05-19 2003-07-21 Procede de preparation de gabapentine Withdrawn EP1636163A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN416CH2003 2003-05-19
PCT/IN2003/000246 WO2004101489A1 (fr) 2003-05-19 2003-07-21 Procede de preparation de gabapentine

Publications (2)

Publication Number Publication Date
EP1636163A1 true EP1636163A1 (fr) 2006-03-22
EP1636163A4 EP1636163A4 (fr) 2006-08-09

Family

ID=33446372

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03816962A Withdrawn EP1636163A4 (fr) 2003-05-19 2003-07-21 Procede de preparation de gabapentine

Country Status (3)

Country Link
EP (1) EP1636163A4 (fr)
AU (1) AU2003259544A1 (fr)
WO (1) WO2004101489A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0415076D0 (en) * 2004-07-05 2004-08-04 Sandoz Ind Products S A Process for the preparation of gabapentin
WO2009015685A1 (fr) 2007-07-27 2009-02-05 Medichem, S.A. Procédé de préparation de la forme polymorphe ii de la gabapentine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044123A1 (fr) * 2000-12-01 2002-06-06 Erregierre S.P.A. Procede de preparation d'acide cyclohexaneacetique 1-(aminomethyl)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6255526B1 (en) * 1996-12-24 2001-07-03 Teva Pharmaceutical Industries Ltd. Preparation of gabapentin
ITMI20012750A1 (it) * 2001-12-21 2003-06-21 Procos Spa Processo per la produzione dell'acido 1-(amminometil)-cicloesil-acetico in forma pura

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002044123A1 (fr) * 2000-12-01 2002-06-06 Erregierre S.P.A. Procede de preparation d'acide cyclohexaneacetique 1-(aminomethyl)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO2004101489A1 *

Also Published As

Publication number Publication date
AU2003259544A1 (en) 2004-12-03
WO2004101489A1 (fr) 2004-11-25
EP1636163A4 (fr) 2006-08-09

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