WO2007108009A1

WO2007108009A1 - A process for purification of topiramate

Info

Publication number: WO2007108009A1
Application number: PCT/IN2007/000107
Authority: WO
Inventors: Pandurang Balwant Deshpande; Parven Kumar Luthra; Anand Kumar Pandey; Bhavin Prafulbhai Hamirani
Original assignee: Alembic Limited
Priority date: 2006-03-17
Filing date: 2007-03-15
Publication date: 2007-09-27

Abstract

The present invention provides novel process for the preparation of Topiramate Form I which comprising purifying crude Topiramate base by treating the same with mixture of acetone and water to obtain topiramate of at least 99.5% purity.

Description

A PROCESS FOR PURIFICATION OF TOPIRAMATE FIELD OF INVENTION:

The present invention relates to a process for purification of Topiramate of formula (I).

BACKGROUND OF THE INVENTION:

Topiramate is chemically known as 2, 3:4, 5-Bis-O-(1-methylethylidene)-1-O- sulfamoyl-beta-D-fructopyranose or 2, 3:4, 5-Bis-O-(1-methylethylidene)- beta-D- fructopyranose sulfamate, having molecular formula C1₂H21NO8S and molecular weight 339.36. The current pharmaceutical product containing this drug is being sold by Ortho McNeil using the tradename Topamax^® in the form of tablets.

Topiramate is sulfamate-substituted monosaccharide derivative which are useful in the treatment of epilepsy, obesity, bipolar disorder, neuropathic pain, migraine and smoking cessation. Topiramate acts as a carbonate dehydratase inhibitor, sodium channel blocker, AMPA antagonist, GABA agonist and glutamate antagonist.

Topiramate is first disclosed in US Patent No. 4,513,006 which also discusses its process for preparation. The final product is recrystallized from a mixture of ethyl acetate and hexane. However this process for purification remains silent about purity and yield of Topiramate. US Patent No. 5,387,700 which discloses the recrystallization of Topiramate by using ethanol: water mixture as solvent which requires base treatment. This patent also discloses crystallization by using n-hexane which does not give Topiramate with high purity and yield.

US application No. 2004/0038911 which discloses crystallization of Topiramate by using ethanol: water mixture or ethanol. However these processes also remain silent about purity and yield of Topiramate.

US application No. 2004/0215004 which discloses crystallization of Topiramate in water which requires acid, base treatment before crystallization.

It is observed that all the purification process for Topiramate in prior art are silent with respect to yield and purity and required acid, base treatment.

We have observed that all prior art gives identical form having XRD pattern substantially similar as shown in Fig.1. This form is designated as Form I for the purpose of this specification.

Topiramate Form I obtained by present invention is characterized by its XRD pattern as shown in Fig.1.

The present inventors have observed that this process of purification of Topiramate is operationally simple, easy to handle and easily applicable at an industrial scale.

Surprisingly present inventors have discovered another process for purification of Topiramate which comprises purification of Topiramate by treating Topiramate base with mixture of acetone and water. BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES:

Fig. 1 represnts the powder X-ray diffraction (XRD) pattern of Topiramate Form I.

OBJECTS OF THE INVENTION:

It is therefore an object of the invention to provide a process for the purification of Topiramate to obtain topiramate of at least 99.5% purity (by HPLC).

Another object of the present invention is to provide a process for the purification of Topiramate which is operationally simple, easy to handle and applicable at an industrial scale.

Yet another object of the present invention is to provide process for purification of ^; Topiramate which comprises purification of Topiramate by treating Topiramate base with mixture of acetone and water.

SUMMARY OF THE INVENTION:

According to one aspect of present invention there is provided improved process for preparation of Topiramate Form I comprising steps of:

(i) dissolving crude Topiramate in acetone to form a solution;

(ϋ) addition of water to said solution;

(iii) cooling the suspension and stirring it;

(iv) isolating pure Topiramate Form I of at least 99.5% purity (by HPLC)..

According to another aspect of the present invention there is provided improved process for preparation of Topiramate Form I comprising steps of:

(i) dissolving crude Topiramate in acetone to form a solution

(ii) addition of said solution to chilled water

(iii) stirring the suspension

(iv) isolating pure Topiramate Form I of at least 99.5% purity (by HPLC). DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, present invention relates to a process for the purification of Topiramate comprising a step of treating Topiramate base with a mixture of acetone and water.

The term "crude Topiramate" as used hereinabove is meant to include Topiramate is any form, or hydrate, solvate or their mixtures, or any state of purity. <-

The term "treating" as used hereinabove refers to suspending, dissolving, washing, mixing, crystallizing or recrystallizing Topiramate in any of the solvent described above.

Topiramate Form I as prepared according to aspect of present invention, is characterized by powder X-ray diffraction peaks at about 9.2, 12.1, 13.0, 15.3, 16.1 , 17.2, 19.9, 20.7, 21.1 , 24.5, 25.8, 29.3 and 32.8 ±0.2 degree two-theta.

Crude Topiramate is dissolved in acetone at about 20 ⁰C to 35 ⁰C under stirring to obtain a solution. Water is added to said solution drop wise under stirring. The slurry was cooled to about 0 ⁰C to about 15°C and stirred for about 1 hour to about 4 hours. It is filtered, washed with water and dried to obtain pure crystalline form of Topiramate.

In another embodiment of the present invention, crude Topiramate is dissolved in acetone at about 20 ⁰C to 35 ⁰C under stirring to obtain a solution. The said solution is added to chilled water in one lot. The slurry is stirred for about 1 hour to about 4 hours at about chilled temperature to ambient temperature. It is filtered, washed with water and dried to obtain pure Topiramate Form.

The term "purification" refers to any method known to a person skilled in the art such as purification from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as solvent/antisolvent or precipitation.

Topiramate Form I is isolated from reaction mass by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.

The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.

Crude Topiramate used in the examples is prepared according to methods reported in the literature and prior art.

Example 1 Preparation of pure form of Topiramate

Crude Topiramate (1Og) was dissolved in acetone (20ml) at about 20 ⁰C to 35 ⁰C under stirring to obtain a solution. Water (40 ml) was added to said solution drop wise under stirring. Topiramate crystallized out. The slurry was cooled to 10 ⁰C to 15°C and stirred for 2 hour. It was filtered, washed with water and dried to obtain pure form of Topiramate (8.2 gm), purity of at least 99.5% (HPLC).

Example 2 Preparation of pure form of Topiramate

Crude Topiramate (10g) was dissolved in acetone (20ml) at about 20 ⁰C to 35 ⁰C under stirring to obtain a solution. The said solution was added to chilled water (40 ml) in one lot.Topiramate was started to crystallize out. The slurry was stirred for 2 hour at about chilled temperature to ambient temperature. It was filtered, washed with water and dried to obtain pure form of Topiramate (8.4gm), purity of at least 99.5% (HPLC).

Claims

1. A process for preparation of Topiramate Form I, comprising steps of. i. dissolving crude Topiramate in acetone; ii. addition of water to the solution obtained in step (i); iii. cooling the suspension; iv. isolating Topiramate Form I of at least 99.5% purity.

2. A process for preparation of Topiramate Form I, comprising steps of: i. dissolving crude Topiramate in acetone to form a solution; ii. addition of said solution to chilled water; iii. isolating pure Topiramate Form I of at least 99.5% purity.

3. The process according to any preceding claims, wherein the crude Topiramate used herein is any form, hydrate, clathrate, solvate or their mixtures and in any state of purity.