WO2005003104A2 - Monohydrate de lamotrigine - Google Patents

Monohydrate de lamotrigine Download PDF

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Publication number
WO2005003104A2
WO2005003104A2 PCT/IN2004/000186 IN2004000186W WO2005003104A2 WO 2005003104 A2 WO2005003104 A2 WO 2005003104A2 IN 2004000186 W IN2004000186 W IN 2004000186W WO 2005003104 A2 WO2005003104 A2 WO 2005003104A2
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WO
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Prior art keywords
lamotrigine
process according
monohydrate
anhydrous
crystalline
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PCT/IN2004/000186
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English (en)
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WO2005003104A3 (fr
Inventor
Charugundla Kishore
Bokka Ravisankar
Sulur G. Manjunatha
Ashok Krishna Kulkarni
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Jubilant Organosys Limited
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Publication of WO2005003104A2 publication Critical patent/WO2005003104A2/fr
Publication of WO2005003104A3 publication Critical patent/WO2005003104A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D253/075—Two hetero atoms, in positions 3 and 5
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • This invention relates generally to the preparation of lamotrigine, i.e. 3,5-diamino-6- (2,3-dichlorophenyl)-l,2,4-triazine of formula (I), and, more particularly, to its hydrate form lamotrigine monohydrate of formula (la) and its anhydrous form.
  • the invention provides novel forms of lamotrigine monohydrate and anhydrous lamotrigine, processes for preparing the same, and an improved, economical and eco-friendly manufacturing process for producing lamotrigine.
  • Lamotrigine is the known triazine compound 3,5-diamino-6-(2,3-dichlorophenyl)- 1,2,4-triazine. It is useful in the treatment of disorders of the central nervous system (CNS), in particular epilepsy, as described, for example, in EP-A-0021121. Furthermore, triazines of this type are believed to be non-depressant at hkely therapeutic dose levels and therefore are advantageous as compared with depressant anti-epileptic compounds such as phenobarbitone.
  • Lamotrigine (compound I) can be prepared according to Scheme 1 by the procedures described in, for example, EP-A-0021121, US-A-4602017 and US-A-6111101.
  • a condensation reaction of 2,3-dichlorobenzoylcyanide (ketonitrile compound II) with aminoguanidine is carried out in a mixture of a large excess of an aqueous mineral acid such as nitric acid or sulfuric acid and a water-miscible organic solvent such as dimethylsulfoxide (DMSO) or acetonitrile.
  • DMSO dimethylsulfoxide
  • the condensation reaction is generally completed over a period of 60 to 168 hours to produce 2-(2,3-dichlorophenyl)-2- (guanidinylamino)acetonitrile (compound III), also known as dichlorobenzoyl cyanide amidinohydrozone, herein referred to as the Schiff base.
  • solvated and hydrated crystal forms of lamotrigine have been disclosed in WO-A-02/068398, wherein a process for preparing a hydrated form of lamotrigine from an anhydrous lamotrigine form is described.
  • the anhydrous lamotrigine is suspended in water medium and stirred for 24 hours, then filtered, followed by drying, to obtain the hydrated crystalline lamotrigine form.
  • This hydrated crystalline form of lamotrigine, denominated form N is disclosed as exhibiting strong X-ray powder diffraction peaks at about 11.6, 13.4, 15.0, 26.9, 27.7 ⁇ 0.2 degrees two-theta, and other typical peaks at about 15.9, 16.5, 19J, 22,2, 22.4, 23.2, 23.5, 26.7, 28.6, 29.9, 30.1, 30.4, 30.7, 31.4, 31.9, 32.9, 33.3, 34.4, 35.0, 36.2 degrees two-theta, and as showing a weight loss by thermogravimetric analysis (TGA) of about 6.6%.
  • TGA thermogravimetric analysis
  • WO-A-02/068398 also discloses crystalline forms of anhydrous lamotrigine, designated forms A and S.
  • Form S is stated to be characterized by an X-ray powder diffraction pattern having strong peaks at about 13.4, and 18. 7+0. 2 degrees two-theta and other typical peaks at about 22.4,26.0,27.6, and 31.3 +0.2 degrees two-theta.
  • lamotrigine has emerged to be one of the more promising anti-epileptic and anti- convulsant agents for treating CNS disorders, its commercial production has assumed greater significance. Whilst various routes are known for synthesizing lamotrigine, there remains a need for a route which is safe, convenient, efficient, economical and less time consuming. Therefore, an objective of the present invention is to develop an efficient process for the preparation of the Schiff base and thus increase the overall efficiency of processes for producing lamotrigine.
  • Another objective is to develop an eco-friendly process for producing lamotrigine, which process would have minimal environmental impact. Yet another objective is to provide a process for producing lamotrigine in a minimum reaction cycle time. Yet another objective is to provide a novel monohydrate form of lamotrigine. Yet another objective is to provide a novel anhydrous form of lamotrigine. Summary of the Invention Accordingly, the present invention provides crystalline lamotrigine monohydrate of formula (la):
  • the invention further provides crystalline lamotrigine monohydrate of formula (la) characterized by having characteristic infrared absorption peaks at 3497, 3345, 3218, 3172 and a broad peak at 686 cm "1 .
  • the invention further provides crystalline lamotrigine monohydrate of formula (la) characterized by the C, H, N, elemental analysis:
  • the invention further provides crystalline anhydrous lamotrigine of formula (I):
  • the invention further provides crystalline anhydrous lamotrigine of formula (I) characterized by having characteristic infrared absorption peaks at 3451, 3317, 3212 and a sharp peak at 792 cm "1 .
  • a simple, economical and eco-friendly process for producing lamotrigine and its monohydrate form or anhydrous form by condensing an aminoguanidine salt with 2,3-dichlorobenzoylcyanide to obtain the Schiff base, and cyclising the Schiff base in aqueous organic solvent to provide lamotrigine of a pharmaceutically acceptable quality.
  • the lamotrigine thus obtained when dried, for example at 45 to 50°C, gives lamotrigine monohydrate or, when dried at 100 °C gives anhydrous lamotrigine.
  • the present invention further provides a process for preparing lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine) of formula (I) in monohydrate or anhydrous form
  • the condensation reaction step (a) is carried out in aqueous mineral acid in the absence of any water-miscible organic solvent.
  • the condensation reaction step (a) is carried out at a temperature in the range from 40 to 90 °C.
  • Figure 1 shows the X-ray diffraction pattern of a crystalline lamotrigine monohydrate obtained in accordance with an embodiment of the invention
  • Figure 2 shows the infrared (IR) absorption spectrum of the crystalline lamotrigine monohydrate of Figure 1
  • Figure 3 shows the X-ray diffraction pattern of a crystalline anhydrous lamotrigine obtained in accordance with another embodiment of the invention
  • Figure 4 shows the infrared (IR) absorption spectrum of the crystalline anhydrous lamotrigine of Figure 3.
  • Figure 5 shows the termogravimetric analysis (TGA) curve of the crystalline anhydrous lamotrigine of Figure 1.
  • TGA termogravimetric analysis
  • step (a) for the condensation reaction of the aminoguanidine salt with 2,3-dichlorobenzoylcyanide to produce the Schiff base the reaction is carried out in an aqueous mineral acid or in a mixture of aqueous mineral acid and water-miscible organic solvent.
  • the aminoguanidine salt is suitably one or more selected from bicarbonate, nitrate, sulfate and hydrochloride salts of aminoguanidine, and most preferably is aminoguanidine bicarbonate.
  • the aqueous mineral acid is suitably one or more selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
  • the concentration of the acid is preferably in the range from 35% v/v to 75% v/v, more preferably in the range from 40% v/v to 65% v/v, still more preferably in the range from 45% v/v to 55% v/v, and most preferably about 50% v/v.
  • the most preferred acid is sulfuric acid.
  • the water-miscible organic solvent if used, is suitably one or more selected from acetonitrile, dimethylsulfoxide (DMSO), dimethylformamide and 1,4-dioxane. According to the first aspect of the present invention, however, the condensation reaction is carried out in aqueous mineral acid in the absence of any water-miscible organic solvent.
  • the condensation reaction when carried out in only aqueous mineral acid according to the first aspect of the present invention, gives a higher yield of Schiff base than when a water-miscible organic solvent is additionally present.
  • the 2,3-dichlorobenzoylcyanide is preferably added to a solution of aminoguanidine bicarbonate, in aqueous mineral acid or in a mixture of aqueous mineral acid and water- miscible organic solvent, at 20 to 30 °C.
  • the condensation reaction may be carried out at a temperature in the range from 25 to 90 °C, preferably in the range from 40 to 75 °C, more preferably in the range from 50 to 65 °C, and most preferably in the range from 55 to 60 °C.
  • the reaction may be carried out for 2 to 75 hours, preferably for 3 to 72 hours, and more preferably for 3 to 12 hours.
  • the reaction may be carried out for 4 to 20 hours, preferably 6 to 12 hours, at temperature in the range from 55 to 60 °C or for 2 to 4 hours, preferably 2.5 to 3.5 hours, at temperature in the range from 80 to 85 °C.
  • the reaction mixture is preferably stirred throughout.
  • the condensation reaction is carried out at a temperature in the range from 40 to 90 °C, preferably in the range from 40 to 75 °C, more preferably in the range from 50 to 65 °C, and most preferably in the range from 55 to 60 °C.
  • the condensation reaction is most preferably carried out in aqueous mineral acid in the absence of any water-miscible organic solvent, at 55 to 60 °C.
  • the condensation reaction precipitates Schiff base salt, and the precipitated Schiff base salt preferably is then filtered.
  • the filtrate can be re-used for the condensation reaction by adjusting the strength of the acid back to the desired concentration, e.g. 50%. In this manner, the filtrate can be recycled for at least two times without affecting the quality and yield of the Schiff base. It will be appreciated that the main objective of recycling the aqueous acidic filtrate is to minimize the environmental impact of the process.
  • the residue, comprising Schiff base salt is preferably washed, preferably with water, and then resuspended, preferably in water.
  • the pH is adjusted to basic, preferably to a pH of about 9-10, for example with aqueous solution of carbonate, bicarbonate or hydroxide of an alkali metal such as sodium or potassium.
  • the liberated base may be filtered and dried, for example at 80 to 100 °C, to obtain the dried free Schiff base.
  • the Schiff base is cyclised in aqueous organic solvent to provide lamotrigine of a pharmaceutically acceptable quality in a single step.
  • the organic solvent used for the cychsation step according to the present invention is a water-miscible solvent, suitably an alcohol such as one or more selected from methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, tert-butanol and diethylene glycol, or a water-soluble solvent such as acetonitrile.
  • the organic solvent is an alcohol, most preferably isopropyl alcohol.
  • the reaction in step (b) according to the present invention is suitably carried out at a temperature in the range from 60 to 100 °C, preferably 70 to 95 °C, more preferably 75 to 90
  • step (c) may be carried out in a mixture of water and a water- miscible solvent.
  • the water-miscible solvent preferably is selected from methanol, ethanol, isopropyl alcohol, and mixtures thereof, and more preferably is isopropyl alcohol.
  • the crystalline solid is separated by filtration to obtain lamotrigine of pharmaceutically acceptable quality (purity > 99.5%), wherein each of the impurities, as analyzed by HPLC, is below 0.1%.
  • the lamotrigine may be repurified, if necessary, using aqueous organic solvent as previously described.
  • Lamotrigine prepared by the above process may be dried to produce lamotrigine monohydrate or anhydrous lamotrigine.
  • lamotrigine monohydrate When lamotrigine prepared by the above process is dried at a temperature below 60°C, preferably at 45-55°C, and preferably under vacuum, lamotrigine monohydrate is obtained.
  • the lamotrigine monohydrate thus obtained is characterized by the powder X-ray diffraction pattern as depicted in Figure 1 having peaks at about 11.4, 13.2, 14.8, 16.3, 18.9, 22.2, 22.9, 23.2, 24.8, 25.1, 26.2, 27.6, 28.4, 29.1, 29.7, 30.2, 31.2, 33.1, 34.3, 35.5, 36.1, 39.7 ⁇ 0.2 degrees two- theta.
  • the crystalline lamotrigine form N disclosed in WO-A-02/068398 stated to be a monohydrate form of lamotrigine, exhibits X-ray diffraction peaks at about 11.6, 13.4, 15.0, 26.9, 27.7 ⁇ 0.2 degrees two-theta, and other typical peaks at about 15.9, 16.5, 19.1, 22.2, 22.4, 23.2, 23.5, 26.7, 28.6, 29.9, 30.1, 30.4, 30.7, 31.4, 31.9, 32.9, 33.3, 34.4, 35.0, 36.2 degrees two-theta.
  • the crystalline lamotrigine monohydrate prepared according to the process of the present invention exhibits a typical X-ray diffraction pattern showing fewer X-ray diffraction peaks.
  • the thermogravimetric analysis (TGA) of Lamotrigine monohydrate prepared according to the present investigation is showing a weight loss of 6.11% at 227°C which is just above the melting point of lamotrigine ( Figure - 5). This is in contrast to the hydrated form N disclosed in WO - A-02/068398 wherein the weight loss by thermogravimetric analysis (TGA) is about 6.6% at 128°C.
  • the x-ray diffraction and TGA data on Lamotrigine monohydrate prepared according to the present investigation therefore indicates that the water molecule is strongly bonded with the lamotrigine molecule compared with the N-form disclosed in WO-A-02/068398.
  • the water molecule in the crystalline lamotrigine form - N appears to be weekly bonded on the surface of the crystal.
  • the lamotrigine monohydrate prepared by the above process in accordance with the present invention is also characterized by infrared (IR) absorption spectroscopy as depicted in Figure 2 having characteristic absorption peaks represented by wave numbers (cm "1 ) at 3497, 3345, 3218, 3172 and a broad peak at 686.
  • the lamotrigine monohydrate is also characterized by C,H,N elemental analysis as having C: 39.4%, H: 3.28%, N: 25.54%.
  • Lamotrigine or lamotrigine monohydrate produced by the above process when dried above 60°C, preferably at 100 to 110°C, yields lamotrigine anhydrous form.
  • This lamotrigine anhydrous form is characterized by X-ray powder diffraction as depicted in Figure 3 having peaks at about 3.8, 4.1, 9.8, 11.4, 12.5, 13.9, 16.7, 17.4, 18.0, 19.5, 20.6, 22.3, 22.9, 23.7, 25.5, 26.3, 26.7, 27.9, 28.4, 28.9, 31.0, 31.7, 33.4, 35.3, 38.1, 39.1, 41.3, 43.2, 47.1, 47.6 and 48.9 ⁇ 0.2 degrees two-theta.
  • the crystalline anhydrous lamotrigine form S disclosed in WO-A-02/068398 exhibits X-ray diffraction peaks at about 13.4, and 18.7+0.2 degrees two- theta and other typical peaks at about 22.4,26.0,27.6, and 31.3+0.2 degrees two-theta.
  • the crystalline anhydrous lamotrigine prepared according to the process of the present invention exhibits a different X-ray diffraction pattern from that exhibited by form S disclosed in WO-A-02/068398.
  • the anhydrous lamotrigine prepared by the above process in accordance with the present invention is also characterized by infrared (IR) absorption spectroscopy as depicted in Figure 4.
  • the 2,3-dichlorobenzoylcyanide (ketonitrile compound (II)) used in the present invention is preferably prepared, as illustrated in Scheme-2, by the reaction of 2,3-dichlorobenzoyl chloride (IV) with cuprous cyanide in the absence of any solvent medium, preferably at 160 to 165 °C.
  • the 2,3-dichlorobenzoyl chloride is preferably prepared by reacting of 2,3-dichlorobenzoic acid with thionyl chloride.
  • the crude isolated ketonitrile is preferably further purified by crystallization from hexane fractions.
  • EXAMPLE 1 Preparation of Schiff base: (i) Preparation of 2,3-dichlorobenzoyl chloride (TV): 2,3-Dichlorobenzoic acid (200g) is charged into a suitably sized round bottom flask containing thionyl chloride (917g) and heated at 80°C for 2hrs. Excess thionyl chloride is removed by distillation under vacuum to obtain 2,3-dichlorobenzoyl chloride (IN) as a viscous liquid.
  • TV 2,3-dichlorobenzoyl chloride
  • thionyl chloride 917g
  • Excess thionyl chloride is removed by distillation under vacuum to obtain 2,3-dichlorobenzoyl chloride (IN) as a viscous liquid.
  • la lamotrigine monohydrate
  • a mixture of Schiff base (200g), isopropyl alcohol (2.2L) and water (0.6L) is stirred at 80-85°C for 4-6h to obtain a clear homogeneous solution.
  • Activated carbon (lOg) is added and stirred at the same temperature for an additional 30minutes.
  • the mixture is filtered through a HyfloTM bed, and the filtrate is cooled to 10°C.
  • the white crystals of lamotrigine obtained are collected by filtration, washed with isopropyl alcohol (IP A) and dried at 50°C to provide high purity lamotrigine monohydrate (I).

Abstract

L'invention concerne du monohydrate de (3,5-diamino-6-(2,3-dichlorophényl)-1,2,4-triazine) lamotrigine (Ia) et de la lamotrigine anhydre, ainsi qu'un procédé de préparation associé. L'invention concerne également un procédé amélioré de production de lamotrigine (I). Ce procédé consiste à mettre en réaction du 2,3-dichlorobenzoyl cyanure (II) et du bicarbonate d'aminoguanidine dans un acide minéral aqueux, facultativement avec un solvant organique miscible dans l'eau, à une température comprise entre 30 et 80 °C, de sorte à produire du 2-(2,3-dichlorophényl)-2-(guanidinylamino)acétonitrile (base de Schiff). La base de Schiff est ensuite cyclisée dans un alcool aqueux, de sorte à produire de la lamotrigine pure de qualité pharmaceutiquement acceptable qui, pendant un séchage à vide à une température comprise entre 45 et 50 °C, produit du monohydrate de lamotrigine et/ou, pendant un autre séchage à une température comprise entre 100 et 110 °C, produit de la lamotrigine anhydre. Le monohydrate de lamotrigine ou la lamotrigine anhydre ainsi produit(e) peut ensuite être associé(e) à un excipient pharmaceutiquement acceptable pour être administré(e) à un patient.
PCT/IN2004/000186 2003-07-03 2004-06-28 Monohydrate de lamotrigine WO2005003104A2 (fr)

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Application Number Priority Date Filing Date Title
GB0315608.0 2003-07-03
GB0315608A GB2395483A (en) 2003-07-03 2003-07-03 Crystalline lamotrigine and its monohydrate

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WO2005003104A2 true WO2005003104A2 (fr) 2005-01-13
WO2005003104A3 WO2005003104A3 (fr) 2005-09-22

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008068619A2 (fr) * 2006-08-02 2008-06-12 Medichem, S.A. Procédé perfectionné pour synthétiser la lamotrigine
CN103570637A (zh) * 2013-09-13 2014-02-12 盐城凯利药业有限公司 一种拉莫三嗪的制备方法
CN106083753A (zh) * 2016-06-07 2016-11-09 浙江奇彩环境科技股份有限公司 一种改进的拉莫三嗪合成工艺
CN113214177A (zh) * 2021-04-16 2021-08-06 上海奥科达生物医药科技有限公司 一种拉莫三嗪水合物的晶体形式、其制备方法及包含其的组合物
CN115068422A (zh) * 2022-08-19 2022-09-20 上海奥科达生物医药科技有限公司 一种拉莫三嗪湿混悬剂及其制备方法和应用

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DE102005027149A1 (de) * 2005-06-11 2006-12-14 Lanxess Deutschland Gmbh Verfahren zur Herstellung von substituierten Benzoylcyaniden

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008068619A2 (fr) * 2006-08-02 2008-06-12 Medichem, S.A. Procédé perfectionné pour synthétiser la lamotrigine
WO2008068619A3 (fr) * 2006-08-02 2008-11-27 Medichem Sa Procédé perfectionné pour synthétiser la lamotrigine
EP2128145A3 (fr) * 2006-08-02 2010-03-31 Medichem, S.A. Procédé amélioré pour synthétiser la lamotrigine
CN103570637A (zh) * 2013-09-13 2014-02-12 盐城凯利药业有限公司 一种拉莫三嗪的制备方法
CN106083753A (zh) * 2016-06-07 2016-11-09 浙江奇彩环境科技股份有限公司 一种改进的拉莫三嗪合成工艺
CN113214177A (zh) * 2021-04-16 2021-08-06 上海奥科达生物医药科技有限公司 一种拉莫三嗪水合物的晶体形式、其制备方法及包含其的组合物
CN114948868A (zh) * 2021-04-16 2022-08-30 上海奥科达生物医药科技有限公司 一种拉莫三嗪水合物的晶体形式、其制备方法及包含其的组合物
US11447456B1 (en) 2021-04-16 2022-09-20 Shanghai Aucta Pharmaceuticals Co., Ltd. Crystalline form of lamotrigine hydrate, method for preparing the same and composition comprising the same
WO2022218437A1 (fr) * 2021-04-16 2022-10-20 上海奥科达生物医药科技有限公司 Forme cristalline d'hydrate de lamotrigine, son procédé de préparation et composition la contenant
CN115068422A (zh) * 2022-08-19 2022-09-20 上海奥科达生物医药科技有限公司 一种拉莫三嗪湿混悬剂及其制备方法和应用
CN115068422B (zh) * 2022-08-19 2022-11-29 上海奥科达生物医药科技有限公司 一种拉莫三嗪湿混悬剂及其制备方法和应用

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