FORM2THE PATENTS ACT, 1970(39 of 1970)&The Patents Rules, 2006COMPLETE SPECIFICATION(See section 10; rule 13)
1. Title of the invention. - A NEW POLYMORPHIC FORM
OF LAMOTRIGINE
2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic 003, Gujarat, India. Road, Vadodara-390
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION

The present invention relates to a new polymorph of Lamotrigine and a process for preparation thereof.
The structural formula of Lamotrigine is represented by formula (I)

ci
A
M2IN hT ^NH2
(I)
BACKGROUND OF THE INVENTION
The chemical name of Lamotrigine is 6-(2,3-Dichlorophenyl)-l,2,4-triazine-3,5-diamine, molecular formula is C9H7C12N5 and molecular weight is 256.09. The current pharmaceutical product containing this drug is being sold by Glaxo Wellcome using tradename Lamictal, in the form of tablets.
Lamotrigine of formula (I) is from the phenyltriazine class and useful as anticonvulsant. The precise mechanism by which Lamotrigine exerts its anticonvulsant action are unknown but In Vitro pharmacological studies suggest that Lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids such as glutamate and aspartate.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Lamotrigine, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum, melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC"), which have been used to distinguish polymorphic forms.
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The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
A process for preparing Lamotrigine is set forth in U.S. Pat. No.4,602,017. The crystallographic structure of Lamotrigine methanolate is shown in Acta Cryst., 1989, C45, 129-132.
US6,586,593 disclose Lamotrigine monohydrate and anhydrous forms with XRD figures.
US20050119265 disclose Form I, II and III of Lamotrigine. The process for preparation comprises crystallization from ester solvent, dioxane and mixture of isopropylacetate, chloroform and DMF for respective forms.
US6,861,426 and its family patent application US20050171107 disclose various solvated forms and hydrate forms of Lamotrigine. It discloses Form B, C, D, El, F, H, J, K, L, M, N, P, Q, R, S, U, E and O. The process for preparation involves crystallization from various solvents as well as solvent/antisolvent methods. However solvated forms of drug is not desirable for human intake due to hazard and toxicity point of view.
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Therefore, there is a need to develop a new polymorph of Lamotrigine which have improved properties over the prior art forms.
Surprisingly, the present inventors have observed that when the drying of form II obtained by following the process of example 2 mentioned in US20050119265 is carried out at 100-105°C, new polymorphic form is obtained which have an improved property over the prior art forms such as flowability, solubility and improved bulk density. Moreover this form is much more stable than the form II of US20050119265. Stability is very important factor considered when designing new formulation. This new polymorph of Lamotrigine is designated as Form IV.
OBJECT OF THE INVENTION
Therefore, it is an object of the present invention to provide a new polymorph, Form IV of Lamotrigine.
Another object of the present invention is to provide a new polymorph, Form IV of Lamotrigine with improved stability.
Another object of the present invention is to provide a process for preparation of polymorph, Form IV.
SUMMARY OF THE INVENTION
According to one aspect of the present invention, there is provided a new polymorph Form IV of Lamotrigine characterized by an X-ray powder diffraction pattern having peaks expressed at 29 at about 11.4, 12.5, 13.9, 14.2, 16.7, 17.4, 18.0,20.6,23.0,23.6, 26.8 28.4, 28.9, 29.5, 31.0, 32.3+0.2 degrees 29.
According to another aspect of the' present invention, there is provided a process for
preparation of a new polymorph Form IV of Lamotrigine comprising the steps of:
(i) Providing a solution of Lamotrigine by dissolving Lamotrigine in 1,4 dioxan;
(ii) crystallizing the product from the said solution;
(iii) isolating the solid and drying at 75-150°C to give new polymorph of Lamotrigine.
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BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS
FIG. 1 shows the X-ray powder diffraction pattern of new polymorph Form IV of Lamotrigine of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided a new polymorph of Lamotrigine characterized by an X-ray powder diffraction pattern having peaks expressed at 29 at about 11.4, 12.5, 13.9, 14.2, 16.7, 17.4, 18.0, 20.6, 23.0, 23.6, 26.8 28.4, 28.9, 29.5, 31.0, 32.3+0.2 degrees 29. The x-ray powder diffraction pattern of this form is essentially as depicted in FIG. 1. X-ray powder diffraction spectrum was measured on a Philips X'Pert PRO PANalytical X-ray powder diffractometer having a copper-Ka radiation.
According to another aspect of the present invention, there is provided a process for
preparation of a new polymorph of Lamotrigine comprising the steps of:
(i) Providing a solution of Lamotrigine by dissolving Lamotrigine in 1,4 dioxan;
(ii) crystallizing the product from the said solution;
(iii) isolating the solid and drying at 75-150°C to give new polymorph of Lamotrigine.
Thus, a solution of Lamotrigine is prepared by dissolving Lamotrigine in 1,4 dioxan optionally at elevated temperature. The elevated temperature is in the range from about 60°C to about 65°C. The solution is cooled at 20-25°C or room temperature to form crystals. It may optionally cool further to get maximal yield. The crystals are isolated by methods known in the art such as filtration, decantation or centrifugation. The solid is suck dried and then dried in oven optionally under vacuum at 75-150°C, and preferably 100-105°C to give the new polymorph of Lamotrigine.
Crystallization can be achieved by the methods known in the art such as reducing the volume of the solution or cooling the solution or both.
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The following example illustrates the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.
Example-1
Preparation of new polymorphic form IV of Lamotrigine
Lamotrigine (10.0 g) was added to 1, 4-Dioxane (150 ml) and heated to 60-65°C for 30 minutes and then cooled to 20-25°C and stirred further for 120 minutes. The solid material was filtered and suck dried for 15 minutes. The material was under vacuum at 100-105°C to yield 8.0 g new polymorph Form IV of Lamotrigine.
The X-ray powder diffraction pattern of this compound is as shown in FIG. 1.
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We Claim
1. A polymorphic form of Lamotrigine characterized by an X-ray powder diffraction pattern having peaks expressed as 20 at about 11.4, 12.5, 13.9, 14.2, 16.7, 17.4, 18.0, 20.6, 23.0, 23.6, 26.8 28.4,28.9, 29.5, 31.0, 32.3±0.2 degrees 20.
2. A polymorphic form of Lamotrigine of claim 1, further characterized by an X-ray powder diffraction pattern as in FIG. 1.
3. A process of preparation of a novel polymorphic form comprising the steps of:
(i) Providing a solution of Lamotrigine by dissolving Lamotrigine in 1,4 dioxan; (ii) crystallizing the product from the said solution;
(iii) isolating the solid and drying at 75-150°C to give new polymorph of Lamotrigine.
4. The process as claimed in claim 3, wherein a solution of Lamotrigine is prepared by
dissolving Lamotrigine in 1,4 dioxan is optionally carried out at elevated
temperature.
Dated this 16th Day of October, 2006.
Sonali Bhokarikar
Of S. Majumdar&Co.
Applicant's Agent
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ABSTRACT
TITLE: A NEW POLYMORPHIC FORM OF LAMOTRIGINE
The present invention provides a new polymorph Form IV of Lamotrigine and a process for preparation thereof.