[go: up one dir, main page]

EP2183211A1 - Procédé de préparation de la forme polymorphe ii de la gabapentine - Google Patents

Procédé de préparation de la forme polymorphe ii de la gabapentine

Info

Publication number
EP2183211A1
EP2183211A1 EP07787983A EP07787983A EP2183211A1 EP 2183211 A1 EP2183211 A1 EP 2183211A1 EP 07787983 A EP07787983 A EP 07787983A EP 07787983 A EP07787983 A EP 07787983A EP 2183211 A1 EP2183211 A1 EP 2183211A1
Authority
EP
European Patent Office
Prior art keywords
gabapentin
suspension
gabapentin form
producing
water
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Withdrawn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
EP07787983A
Other languages
German (de)
English (en)
Inventor
Maria Carmen Burgarolas Montero
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.)
Medichem SA
Original Assignee
Medichem SA
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 Medichem SA filed Critical Medichem SA
Publication of EP2183211A1 publication Critical patent/EP2183211A1/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Withdrawn legal-status Critical Current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
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification
    • C07C227/42—Crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • 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

Definitions

  • the present invention may be included in the pharmaceutical field. Specifically, this invention refers to an improved method for preparing polymorph Form II of gabapentin.
  • Gabapentin, [l-(aminomethyl)cyclohexyl] acetic acid is an anticonvulsant having the chemical structure:
  • Anticonvulsants are used to control seizure disorders.
  • gabapentin has been successfully used to treat and/or control seizures associated with cerebral diseases including, for example, epilepsy.
  • Gabapentin has also been used to manage postherpetic neuralgia (i.e., the pain after "shingles") and it may also be useful for mood stabilization and treating anxiety.
  • gabapentin is related to the brain chemical gamma amino butyric acid (GABA), its exact mechanism of action remains unknown.
  • Gabapentin is known to exist in at least three polymorphic forms that differ from each other based primarily on their crystal structure and associated water content:
  • Form I is the monohydrate (gabapentin hydrate).
  • Form II is anhydrous gabapentin, and is the form present in the marketed pharmaceutical speciality.
  • Form III is another form of anhydrous gabapentin.
  • the different forms of gabapentin can be readily distinguished based upon their IR spectra and x-ray diffraction patterns as discussed in U.S. Patent No. 6,255,526 and PCT Application No. PCT/YS97/23164 (Publication No. WO 98/28255).
  • gabapentin A number of conventional methods are known for preparing gabapentin. Some of these methodologies are summarized in WO 2004/101489. Such methods include, for example, preparing gabapentin from cyclohexyl-l,l-diacetic acid via formation of the gabapentin hydrochloride ("gabapentin HCl") salt. Gabapentin HCl is then converted to gabapentin.
  • gabapentin HCl gabapentin hydrochloride
  • U.S. Patent No. 6,054,482 discloses that in order to ensure the storage stability not only of the gabapentin active material but also of the corresponding pharmaceutical forms of preparation, the active gabapentin should be produced containing less than 20 ppm of an anion of a mineral acid, e.g. chloride ion.
  • Patent application WO 98/28255 discloses a method of converting gabapentin hydrochloride to gabapentin form II.
  • the method comprises neutralizing gabapentin hydrochloride with an amine in different solvents so as to obtain a precipitate, which is gabapentin form III.
  • it is necessary to reprocess said gabapentin form III by slurrying or crystallizing it in methanol, to be able to prepare the marketed gabapentin form II.
  • WO2004/093779 reports the preparation of gabapentin form II by neutralizing a gabapentin hydrochloride solution in a short chain alcohol, preferably ethanol, with a base, preferably triethylamine or diisopropylethylamine, at temperatures of about 70 0 C, followed by slow cooling, to isolate gabapentin Form II. Said gabapentin Form II is further purified. However, the gabapentin form II finally obtained contains an amount of chloride ions in the range of about 20-100 ppm, an amount which can not ensure the stability of the product.
  • US 7151193 Bl also discloses a method for obtaining gabapentin form II directly from gabapentin hydrochloride by dissolving gabapentin hydrochloride in dry ethanol, filtering off the insoluble inorganic salts, then adding the filtered solution with tertiary amines, preferably the so-called "H ⁇ nig base" (N-ethyl-diisopropylamine), and a small amount of water.
  • tertiary amines preferably the so-called “H ⁇ nig base” (N-ethyl-diisopropylamine)
  • the desired polymorph precipitates with content in chloride ions not higher than 200- 250 ppm.
  • the chlorine ions content may be reduced below 100 ppm by treatment with a mixture of ethanol and water.
  • WO2004/101489 and EP1347951B1 describe the direct formation of gabapentin form II from gabapentin hydrochloride via neutralizing the gabapentin hydrochloride with an amine in water.
  • the water must be distilled off under reduced pressure, which may represent an important drawback when scaling-up the reaction.
  • These applications are silent about the chloride content of the obtained gabapentin, which may be an important feature to ensure the stability of the product.
  • This invention refers to an improved method, method of the invention, for preparing polymorph Form II of gabapentin, and to the utility thereof as a starting product for the preparation of the marketed pharmaceutical speciality.
  • the method of the invention comprises obtaining gabapentin Form II directly from gabapentin hydrochloride by using an amine base, which is suitable for industrial implementation, which affords gabapentin Form II containing chloride amounts lower than 20 ppm.
  • the objective technical problem solved by the present invention refers to a simple, effective and economic method for obtaining gabapentin form II:
  • the present invention provides a simple, effective and economic method for obtaining gabapentin form II directly from gabapentin hydrochloride using an amine base, which may be suitable for industrial implementation, which affords gabapentin Form II containing chloride amounts not greater than 20 ppm, and which hence can be used directly as a starting product for the preparation of marketed pharmaceutical speciality.
  • the method of the invention exposes that by (I) neutralizing gabapentin hydrochloride in a mixture of an organic solvent and water wherein the % content of water is between 5 and 30% with an amine, and (II) crystallizing the obtained product, gabapentin Form II containing chloride amounts not greater than 20 ppm is obtained.
  • the first embodiment of the present invention refers to a method for producing gabapentin Form II containing chloride amounts not greater than 20 ppm, said method comprising: (I) combining gabapentin hydrochloride and a mixture of an organic solvent and water wherein the percentage content of water is between 5 and 30%, to form a suspension, (II) adjusting the pH of the suspension to 4.0-5.0 with an amine, to obtain a solution, (III) seeding the solution with gabapentin Form II, (IV) adjusting the pH of the suspension to 7.4-8.0 with an amine, to obtain a suspension, (V) isolating crude gabapentin Form II from the suspension, optionally (VI) suspending the crude gabapentin Form II in a mixture of an organic solvent and water wherein the % content of water is between 5 and 30% and isolating crude gabapentin Form II from the suspension, (VII) crystallizing crude gabapentin Form II, and (VIII) isolating gaba
  • the method of the invention is characterized in that the percentage content of water in step (I) is preferably between 15 and 20%, and more preferably about 15%.
  • the method of the invention is characterized in that the organic solvent of step (I) is selected from the group comprised by: ethanol, isopropanol or acetone, more preferably acetone.
  • the method of the invention is characterized in that the volume of the mixture of an organic solvent and water of step (I) per Kg of gabapentin hydrochloride is about 3 L to about 8 L per Kg of gabapentin hydrochloride, preferably about 4.5 L to about 6 L per Kg of gabapentin hydrochloride.
  • the method of the invention is characterized in that the pH of the suspension of step (II) is adjusted to about 4.5-5.0, more preferably to about 4.8.
  • the method of the invention is characterized in that the amine of step (II) is a secondary or tertiary alkyl amine, preferably a secondary amine, more preferably diethylamine.
  • the method of the invention is characterized in that the seeding with gabapentin form II of step (III) is performed with an amount of 0.22% of gabapentin form II with respect to the initial amount of gabapentin hydrochloride, preferably an amount of about 0.14% of gabapentin form II with respect to the initial amount of gabapentin hydrochloride.
  • the method of the invention is characterized in that the pH of the suspension of step (IV) is adjusted to 7.2-8.4, preferably to 7.4-8.0 and more preferably to about 7.8.
  • the method of the invention is characterized in that the amine of step (IV) is a secondary or tertiary alkyl amine, preferably a secondary amine, more preferably diethylamine.
  • the amine of step (IV) may be the same amine as step (II).
  • the suspension obtained in step (IV) is stirred at 20-25 0 C for between 1-16 hours, preferably 2 hours.
  • the resulting suspension is further cooled to 0- 5 0 C and stirred at this temperature for between 1-16 hours, preferably 2 hours.
  • the method of the invention is characterized in that the isolation of the crude gabapentin Form II from the suspension of step (V) comprises filtering the suspension and washing the obtained solid at least twice with an organic solvent, preferably acetone.
  • the method of the invention is characterized in that the percentage content of water in step (VI) is preferably between 15 and 20%, more preferably about 15%.
  • the method of the invention is characterized in that the organic solvent of step (VI) is acetone.
  • step (VI) The suspension obtained in step (VI) is heated at 30-40 0 C and stirred at this temperature for between 1-3 hours, preferably 1 hour. Afterwards, the resulting suspension is cooled to 20-25 0 C and stirred at this temperature for between 1-16 hours, preferably 2 hours. The resulting suspension is further cooled to 0-5 0 C and stirred at this temperature for between 1-16 hours, preferably 2 hours.
  • the method of the invention is characterized in that the isolation of the crude gabapentin Form II from the suspension of step (VI) comprises filtering the suspension and washing the obtained solid at least twice with an organic solvent, preferably acetone.
  • step (VII) comprises dissolving wet gabapentin in a mixture of methanol and water, and precipitating gabapentin with isopropanol.
  • the invention further includes a method for preparing gabapentin Form II of high purity, wherein the gabapentin Form II is more than approximately 98.8% pure when analyzed by high performance chromatography (HPLC), and more preferably wherein the gabapentin Form II is more than approximately 99.7% pure when analyzed by HPLC.
  • HPLC high performance chromatography
  • Another aspect of the invention includes gabapentin Form II having less than approximately 20 ppm of residual chloride ions, as measured by ionic chromatography.
  • Another aspect of the invention includes gabapentin Form II which can be used directly as a starting product for the preparation of marketed pharmaceutical specialty of gabapentin.
  • the chromatographic separation was carried out in a ⁇ Bondapack C 18, 10 ⁇ m, 30O x 3.9 mm LD column; at room temperature (20-25 0 C).
  • the chromatograph was equipped with a 210 nm detector and the flow rate was 1.0 ml per minute. 50 ⁇ l of the test samples, prepared dissolving the appropriate amount of sample to obtain 6.25 mg per ml of mobile phase, were injected.
  • the chromatographic separation was carried out in a Waters IC-Pak Anion HC, 10 ⁇ m, 150 x 4.6 mm LD column; at 35 0 C for detector temperature and 3O 0 C for column temperature.
  • the mobile phase was prepared by mixing 20 ml of 1.3 mM borate- gluconate solution with 500 ml of HPLC grade water and 120 ml of acetonitrile, and diluting this mixture to a 1000 ml with HPLC grade water. This mobile phase was mixed and filtered through 0.45 ⁇ m aqueous/organic membrane under vacuum and stored in a plastic container. The approximate conductivity of the mobile phase is about 280 ⁇ S cm "1 .
  • Borate-gluconate solution was prepared from 8 g of sodium gluconate, 9 g of boric acid, 12.5 g sodium tetraborate decahydrate and 125 ml of glycerine in 500 ml of HPLC grade water. This solution was stored in a plastic container at 4 0 C and warm to ambient temperature before use.
  • the chromatograph was equipped with a conductivity detector (base range 500 ⁇ S, sensitivity 0.01 and polarity positive) and the flow rate was 1.5 ml per minute. 100 ⁇ l of the test samples, prepared dissolving the appropriate amount of dry sample to obtain 100 mg per ml of mobile phase, were injected.
  • the pH of the resulting suspension was adjusted to 7.4-8.0 with Diethylamine at 20- 3O 0 C (15 ml, 10.61 g, 1.004 molar equivalents of amine were needed). Between pH 4.28-4.90 a clear or almost clear solution was obtained. At pH 4.90 it was seeded with the desired polymorphic form of gabapentin Form II. Reaction mixture was stirred for 15 minutes (initial pH actual value 7.68, final pH actual value 7.89 after stirring).
  • IR The IR spectrum was substantially identical to the IR shown in Fig. 1.
  • IR The IR spectrum was substantially identical to the IR shown in Fig. 1.
  • IR The IR spectrum was substantially identical to the IR shown in Fig. 1.
  • the suspension was heated to reflux temperature (66 0 C). At this point deionised water was added until a complete or nearly complete dissolution was observed (there were needed 1.550 Kg of water).
  • Reaction mixture was cooled to 25- 3O 0 C, 4.21 Kg (5.36 L) of isopropanol were added in about 1.5-2 hours, cooled to 0-5 0 C in about 2 hours, stirred during about 5 hours at this temperature and filtered, washing the solid twice with 0.6 Kg (0.76 L) of isopropanol. After drying it at 4O 0 C under vacuum till constant weight, there were obtained 1.70 kg of dry product. Yield: 80.00% (global yield from Gabapentin Hydrochloride: 69.58%).
  • the pH of the resulting suspension was adjusted to 7.4-8.0 with Diethylamine at 15- 25 0 C (31.2 ml, 22.06 g, 1.044 molar equivalents of amine were needed). Between pH 4.20-4.90 a clear or almost clear solution was obtained. At pH 4.8 ⁇ 0.1 it was seeded with the desired polymorphic form of gabapentin Form II. Reaction mixture was stirred for 15 minutes (initial pH actual value 7.90, final pH actual value 7.96 after stirring).
  • IR The IR spectrum was substantially identical to the IR shown in Fig. 1.

Landscapes

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

Abstract

L'invention concerne un procédé de préparation de la forme polymorphe II de la gabapentine. Cette invention porte sur un procédé perfectionné pour préparer la Forme polymorphe II de la gabapentine, et sur l'utilité de celle-ci comme produit de départ pour la préparation de la spécialité pharmaceutique commercialisée.
EP07787983A 2007-07-27 2007-07-27 Procédé de préparation de la forme polymorphe ii de la gabapentine Withdrawn EP2183211A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2007/057768 WO2009015685A1 (fr) 2007-07-27 2007-07-27 Procédé de préparation de la forme polymorphe ii de la gabapentine

Publications (1)

Publication Number Publication Date
EP2183211A1 true EP2183211A1 (fr) 2010-05-12

Family

ID=39273339

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07787983A Withdrawn EP2183211A1 (fr) 2007-07-27 2007-07-27 Procédé de préparation de la forme polymorphe ii de la gabapentine

Country Status (2)

Country Link
EP (1) EP2183211A1 (fr)
WO (1) WO2009015685A1 (fr)

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3928183A1 (de) 1989-08-25 1991-02-28 Goedecke Ag Lactamfreie cyclische aminosaeuren
US6255526B1 (en) 1996-12-24 2001-07-03 Teva Pharmaceutical Industries Ltd. Preparation of gabapentin
IL119890A (en) 1996-12-24 2002-03-10 Teva Pharma Gabapentin form iii and preparation of gabapentin form ii
IT1319674B1 (it) 2000-12-01 2003-10-23 Erregierre Spa Processo per la preparazione dell'acido1-(aminometil)cicloesanacetico.
AU2003262383A1 (en) * 2002-04-16 2003-11-03 Taro Pharmaceutical Industries Ltd. Process for preparing gabapentin
ITMI20030176A1 (it) 2003-02-04 2004-08-05 Farchemia Srl Procedimento per la preparazione di gabapentina "forma ii" pura
WO2004093779A2 (fr) 2003-04-21 2004-11-04 Matrix Laboratories Ltd Procede relatif a l'elaboration de gabapentine de forme-ii
WO2004101489A1 (fr) 2003-05-19 2004-11-25 Shasun Chemicals And Drugs Limited Procede de preparation de gabapentine
US20050187295A1 (en) * 2004-02-19 2005-08-25 Surendra Kalyan Processes for the preparation of gabapentin
WO2005117526A2 (fr) * 2004-06-03 2005-12-15 Matrix Laboratories Ltd Procede ameliore pour la purification de la gabapentine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2009015685A1 *

Also Published As

Publication number Publication date
WO2009015685A1 (fr) 2009-02-05

Similar Documents

Publication Publication Date Title
TWI546311B (zh) 固殺草ｐ游離酸之製造方法
EP2951158B1 (fr) Procédé de préparation d'ivacaftor et de solvates de celui-ci
US9233963B2 (en) Method for preparing meropenem using zinc powder
EP2225198B1 (fr) Procédés de préparation d'un acide aminé à substitution gamma
US20080103334A1 (en) Process For Synthesis Of Gabapentin
CN101730690A (zh) 磺酰胺化合物及其结晶
NZ577293A (en) A new method for preparing 4,4'-(1-methyl-1,2-ethandiyl)-bis-(2,6-piperazinedione)
EP2139902A1 (fr) Procédé de préparation de la forme 1 polymorphe pure d'hydrogénosulfate de clopidogrel
WO2009046581A1 (fr) Procédé de résolution d'acide (6r,s)-5-formyltetrahydrofolique et sa salification
EP1896455A2 (fr) Procede de preparation de composes tetrazolyle
US20130225832A1 (en) Process for the resolution of medetomidine and recovery of the unwanted enantiomer
WO2009015685A1 (fr) Procédé de préparation de la forme polymorphe ii de la gabapentine
CN112979552B (zh) 一种高纯度盐酸右美托咪定的制备方法
JP4942511B2 (ja) ２，２’−ビス（トリフルオロメチル）−４，４’−ジアミノビフェニルの製造方法
US8362269B2 (en) Preparation of 1,7′-dimethyl-2′-propyl-2,5′-bi-1H-benzimidazole
WO2009039241A2 (fr) Procédé perfectionné permettant de préparer du chlorhydrate de cinacalcet
EP1619181B1 (fr) Procédé de préparation de gabapentine
ES2386079T3 (es) Procedimiento para la preparación de tricianometanuros de metal alcalino o alcalintérreo
AU2016236659A1 (en) AHU377 crystal form, preparation method and use thereof
CA3132628A1 (fr) Inhibition de la proteine de liaison a un element sensible a l'amp cyclique (creb)
JP2011195500A (ja) （ｓ）−４−［４−［（４−クロロフェニル）（２−ピリジル）メトキシ］ピペリジノ］ブタン酸一ベンゼンスルホン酸塩の製造方法
US11505549B2 (en) Process for preparation of Deutetrabenazine
WO2005117526A2 (fr) Procede ameliore pour la purification de la gabapentine
WO2015092502A1 (fr) Procédé de préparation de levomilnacipran
WO2006002972A1 (fr) Methode servant a preparer gabapentine

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20100223

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Effective date: 20110331