WO2005003104A2

WO2005003104A2 - Crystalline forms of lamotrigine monohydrate and anhydrous lamotrigine and a process for their preparation

Info

Publication number: WO2005003104A2
Application number: PCT/IN2004/000186
Authority: WO
Inventors: Charugundla Kishore; Bokka Ravisankar; Sulur G. Manjunatha; Ashok Krishna Kulkarni
Original assignee: Jubilant Organosys Limited
Priority date: 2003-07-03
Filing date: 2004-06-28
Publication date: 2005-01-13
Also published as: GB0315608D0; GB2395483A; WO2005003104A3

Abstract

The invention relates to lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) monohydrate (Ia) and anhydrous lamotrigine, and a process for preparing the same. An improved process is provided for manufacturing the lamotrigine (I). The process comprises of reacting 2,3-dichlorobenzoyl cyanide (II) with aminoguanidine bicarbonate in aqueous mineral acid, optionally together with a water miscible organic solvent, at 30 - 80 °C to produce the 2-(2,3-dichlorophenyl)-2-(guanidinylamino)acetonitrile (Schiff base). The Schiff base is further cyclised in aqueous alcohol to produce pure lamotrigine of a pharmaceutically acceptable quality which on further drying at 45 - 50 °C under vacuum yields lamotrigine monohydrate, and/or on further drying at 100 - 110 °C yields anhydrous lamotrigine. The lamotrigine monohydrate or anhydrous lamotrigine thereby produced may then be brought into association with a pharmaceutically acceptable carrier for administration to a patient in need thereof.

Description

LAMOTRIGINE MONOHYDRATE

Background of the Invention

Field of the Invention: 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.

(I) (la)

Description of the Prior Art 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. In these procedures, 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. 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. Further cychsation of the Schiff base (III) in either aqueous potassium hydroxide or alcoholic potassium hydroxide at 75 to 90°C gives crude lamotrigine, which may be further purified by recrystallisation to provide lamotrigine of a pharmaceutically acceptable quality. Scheme 1 :

2,3-dichlorobenzoylcyanide (II) Schiff base (III) lamotrigine (I) Major drawbacks of these processes are that (a) a large excess of aqueous mineral acid and water-miscible organic solvent is used for the reaction, which not only increases the process cost but also results in large quantities of highly acidic effluent, (b) the condensation reaction of 2,3-dichlorobenzoylcyanide with aminoguanidine in a mixture of an aqueous mineral acid, such as nitric acid or sulfuric acid, and an organic solvent, such as DMSO or acetonitrile, is very slow and usually takes 60 to 168 hours (7 days) to complete at room temperature, resulting in a long reaction cycle time, and (c) under these reaction conditions decomposition of 2,3-dichlorobenzoylcyanide (II) is observed, resulting in a poor yield of the Schiff base. Therefore, these processes are not feasible for industrial scale production. Another process for the preparation of the Schiff base has been described in EP-A- 1127873. The process disclosed here includes the condensation of 2,3-dichlorobenzoylcyanide with aminoguanidine bicarbonate in acetonitrile in the presence of polyphosphoric acid, and in the absence of water, at 50°C for 22 hrs. The process provides an improved yield of the Schiff base. However, as well as using large quantities of polyphosphoric acid and acetonitrile, which add to the cost of the product, the process produces a large quantity of acidic effluent. These drawbacks make the process commercially unattractive. Details of these prior art processes for producing the Schiff base are summarized in Table 1 below: Table 1

Recently, 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%. 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. As 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):

(la) characterized by exhibiting X-ray diffraction pattern 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, 36J, 39.7 and 48.9 +0.2 degrees two-theta. 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):

(I) characterized by exhibiting X-ray diffraction pattern peaks at about 3.8, 4J, 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 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. According to the present invention, there is also provided 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. Accordingly, 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

(I) which comprises: a) reacting an aminoguanidine salt with 2,3-dichlorobenzoylcyanide of formula (II)

(II) in aqueous mineral acid, optionally in mixture with a water-miscible organic solvent, to produce the Schiff base of formula (III)

(III) b) reacting the Schiff base of formula (III) in a mixture of water and a water- miscible or water-soluble organic solvent to produce lamotrigine; and c) crystallizing and drying the lamotrigine to provide pure lamotrigine monohydrate or anhydrous lamotrigine. According to a first aspect of the process of the present invention, the condensation reaction step (a) is carried out in aqueous mineral acid in the absence of any water-miscible organic solvent. According to a second aspect, the condensation reaction step (a) is carried out at a temperature in the range from 40 to 90 °C. Brief Description of the Drawings 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. Detailed Description of the Invention According to the process of the present invention, in 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. For example, 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. According to the second aspect of the process of the present invention, however, 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. During the present investigations, it was observed that at higher temperatures the rate of the condensation reaction appeared to be faster than the rate of decomposition of the ketonitrile compound (II). Therefore, it is found that at temperatures of 40 to 90 °C, according to the second aspect of the invention, the reaction can be completed in much shorter period, e.g. within 3 to 12 hours, resulting in an increased yield of the Schiff base (e.g. 78%). This finding is in total contrast to those prior art processes in which the reaction was carried out at 25 to 30 °C over a period of about 60 to 168 hours, whereby the Schiff base was isolated in only about 58.5% yield. According to a preferred embodiment of the first and second aspects, 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. According to the present invention, in step (b) 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. Preferably, 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

°C, and most preferably 80 to 85 °C. The reaction may be conducted over a period from preferably 3 to 10 hours, more preferably 4 to 6 hours. The reaction mixture is preferably stirred throughout. At the end of the reaction, a clear solution is obtained. For step (c), according to a preferred embodiment, activated carbon is then added to the clear solution, the solution is stirred, e.g. for an additional 30 minutes, and the hot solution is filtered. The filtrate is further cooled, e.g. to 5 to 15 °C, to provide crystalline lamotrigine. The crystallization in 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. 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. According to a preferred embodiment, 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. As mentioned previously, 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. By contrast, 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, from the TGA studies, 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. As mentioned previously, 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. Thus, 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 characteristic IR absorption peaks represented by wave numbers (cm^"1) are 3451, 3317, 3212 and a sharp peak at 792. The overall yield of lamotrigine from 2,3-dichlorobenzoylcyanide by the above described embodiment of the process is 62% and is much higher when compared to the yield of about 35% from prior art processes. Referring to Scheme 2 below, illustrating an embodiment in accordance with the first aspect of the invention, the process of preparing the Schiff base (III) involves the condensation of 2,3-dichlorobenzoylcyanide (II) with aminoguanidine bicarbonate in aqueous mineral acid or in a mixture of aqueous mineral acid and a water-miscible organic solvent. Scheme 2:

2,3-DlchIorobenzolc acid 2,3-dichlorobenzoyl 2,3-dichlorobenzoyl cyanlde(ll) chloπde(IV) Aminoguanidine . Bicarbonate A . H2SO4

Lamotrigine(l) ^Schiff base(lll) 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. EXAMPLES The invention will be further illustrated by the following non-limiting exalmples: 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.

Yield = 210g

Purity = 98% (when analyzed by gas chromatography). (ii) Preparation of 2,3-dichlorobenzoyl cyanide (II): Dried copper cyanide (120g) is added to a suitably sized round bottom flask containing 2,3-dichlorobenzoyl chloride (200g). The reaction mixture is heated to 160-165°C under nitrogen blanket and the temperature is maintained at 160-165°C for 6 hours. The reaction mixture is then cooled to 80°C, diluted with 600mL toluene and filtered to remove inorganic salts. The solution is concentrated to dryness under vacuum at 60-70°C and the residual oil is crystallized from hexane to obtain pure 2,3-dichlorobenzoyl cyanide (II) as a yellow solid.

Yield = 140g

Purity = 97% (when analyzed by gas chromatography). (iii) Preparation of 2-(2,3-dichlorophenyl)-2-(guanidinylamino)-acetonitriIe (Schiff base) (HI): Aminoguanidine bicarbonate (200g) is added to an aqueous sulfuric acid (50% v/v)

1200ml, then solid 2,3-dichloroben_zoyl cyanide (200g) is added and the suspension is stirred at 55-60°C for 6 hours. The reaction is monitored by TLC for the completion of the reaction. The sohd Schiff base salt is collected by filtration to give the wet sulphate salt of the Schiff base. The wet Schiff base sulphate salt is suspended in water at room temperature and the pH is adjusted to 9 to 10 by using aqueous sodium hydroxide solution. The mixture is further stirred for 30 minutes at pH 9 to 10. The product Schiff base is filtered, washed thoroughly with water and dried at 80-100°C to provide Schiff base (III) as a yellow solid.

Yield = 200g (78%)

Purity = 98.8% (by HPLC)

EXAMPLE 2 Following the general procedure of Example 1 with different acids, solvents and temperatures, the Schiff base was obtained in the yields and purities given in Table 2: Table 2

EXAMPLE 3

Preparation of lamotrigine monohydrate (la): 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 Hyflo™ 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). Yield: 160 Purity: 99.9% (when analyzed by HPLC) Single impurities : <0J%. EXAMPLE 4 Preparation of lamotrigine (anhydrous): A mixture of Schiff base (200g), isopropyl alcohol (2.2L) and water (0.6 L) 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 30min. The mixture is filtered through Hyflo™ bed, and the filtrate is cooled to 10°C. The white crystals of lamotrigine are collected by filtration, washed with IPA and dried at 100°C to provide high purity lamotrigine (anhydrous). Yield: 160g

Purity: 99.9% (when analyzed by HPLC). Single impurities : <0J%. Purification of lamotrigine: A mixture of lamotrigine (100g), isopropyl alcohol (1JL) and water (0.3 L) is stirred at 80-85°C for 4-6h to obtain a clear homogeneous solution. Activated carbon (10g) is added and stirred at the same temperature for an additional 30 minutes. The mixture is filtered through Hyflo bed, and the filtrate is cooled to 10°C. The white crystals of lamotrigine are collected by filtration, and washed with IPA. Lamotrigine thus made and when dried at 50°C gives lamotrigine monohydrate, and when dried at 100°C gives lamotrigine. Yield: 80g

Purity: 99.9% (when analyzed by HPLC). Single impurities: <0J%.

Claims

CLAIMS:

1. Crystalline lamotrigine monohydrate of formula (la) :

(la) characterized by exhibiting X-ray diffraction pattern peaks at about 11.4, 13.2, 14.8, 16.3, 18.9, 22.2, 22.9, 23.2, 24.8, 25.1, 26.7, 27.6, 28.4, 29.1, 29.7, 30.2, 31.2, 33.1, 34.3, 35.5, 36.1, 39.7 and 48.9 ±0.2 degrees two-theta.

2. Crystalline lamotrigine monohydrate according to claim 1, characterized by the X-ray diffraction pattern substantially as shown in Figure 1.

3. Crystalline lamotrigine monohydrate of formula (la) :

(la) characterized by having characteristic infrared absorption peaks at 3497, 3345, 3218, 3172 and a broad peak at 686.

4. Crystalline lamotrigine monohydrate according to claim 3, characterized by the infrared (IR) absorption spectrum substantially as shown in Figure 2.

5. Crystalline lamotrigine monohydrate of formula (la):

(la) characterized by the C, H, N, elemental analysis:

6. Crystalline anhydrous lamotrigine of formula (I):

(I) characterized by exhibiting X-ray diffraction pattern peaks at about 3.8, 4.5, 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, 28.9,29.5, 31.0, 31.7, 33.4, 35.3, 38J, 39J, 41.3, 43.2, 47J, 47.6 and 48.9 ±0.2 degrees two-theta.

7. Crystalline anhydrous lamotrigine according to claim 6, characterized by the X-ray diffraction pattern substantially as shown in Figure 3.

8. Crystalline anhydrous lamotrigine of formula (I):

(I) characterized by having characteristic infrared absorption peaks at 3451, 3317, 3212 and a ' sharp peak at 792.

9. Crystalline anhydrous lamotrigine according to claim 8, characterized by the infrared (IR) absorption spectrum substantially as shown in Figure 4.

10. A process for preparing lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-l,2,4- triazine) of formula (I) in monohydrate or anhydrous form

(I) which comprises: a) reacting an aminoguanidine salt with 2,3-dichlorobenzoylcyanide of formula

(II)

(II) in aqueous mineral acid, optionally in mixture with a water-miscible organic solvent, to produce the Schiff base [2-(2,3-dichlorophenyl)-2-(guanidinylamino)acetonitrile] of formula (III)

(III) b) reacting the Schiff base of formula (III) in a mixture of water and a water- miscible or water-soluble organic solvent to produce lamotrigine; and c) crystallizing and drying the lamotrigine to provide pure lamotrigine monohydrate or anhydrous lamotrigine.

11. A process according to claim 10, wherein said aminoguanidine salt is selected from bicarbonate, nitrate, sulfate and hydrochloride salts of aminoguanidine, and mixtures thereof.

12. A process according to claim 11, wherein said aminoguanidine salt is aminoguanidine bicarbonate.

13. A process according to claim 10, wherein said aqueous mineral acid is selected from nitric acid, sulfuric acid, hydrobromic acid, hydrochloric acid, phosphoric acid, and mixtures thereof.

14. A process according to claim 13, wherein said aqueous mineral acid is sulfuric acid.

15. A process according to claim 10, wherein said aqueous mineral acid strength is in the range from 35% to 70% (v/v).

16. A process according to claim 15, wherein said aqueous mineral acid strength is about 50% (v/v).

17. A process according to claim 10, wherein said water-miscible organic solvent in step (a) is selected from acetonitrile, dimethylsulfoxide (DMSO), dimethylformamide and 1,4- dioxane.

18. A process according to claim 10, wherein water-miscible organic solvent is absent in step (a).

19. A process according to claim 10, wherein said reaction in step (a) is carried out at a temperature in the range from 40 to 75°C.

20. A process according to claim 19, wherein said reaction in step (a) is carried out at a temperature in the range from 55 to 60°C.

21. A process according to claim 10, wherein said organic solvent in step (b) is selected from methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, ter-butanol, diethylene glycol, and acetonitrile.

22. A process according to claim 21, wherein said organic solvent in step (b) is isopropyl alcohol.

23. A process according to claim 10, wherein said crystallization in step (c) is carried out in a mixture of water and a water-miscible solvent selected from methanol, ethanol, isopropyl alcohol, and mixtures thereof.

24. A process according to claim 23, wherein said crystallization in step (c) is carried out in a mixture of water and isopropyl alcohol.

25. A process according to claim 10, wherein said drying in step (c) is carried out at a temperature in the range from 45 to 50 °C to produce crystalline lamotrigine monohydrate.

26. A process according to claim 10, wherein said drying in step (c) is carried out at a temperature in the range from 100 to 110°C to produce crystalline anhydrous lamotrigine.

27. A process according to claim 25, further comprising (d) drying the lamotrigine monohydrate at a temperature in the range from 100 to 110°C to produce crystalline anhydrous lamotrigine.

28. A process for the preparation of a pharmaceutical formulation comprising lamotrigine monohydrate or anhydrous lamotrigine, which process comprises: a) preparing lamotrigine monohydrate or anhydrous lamotrigine by a process according to any preceding claim; and b) bringing the lamotrigine monohydrate or anhydrous lamotrigine into association with a pharmaceutically acceptable carrier therefor.