FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. -A process for purification of Topiramate
2. Applicant(s)
(a) NAME . ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Field of Invention:
The present invention relates to an improved process for purification of Topiramate of formula (I).


H,C

Background of the invention:
Topiramate is chemically known as 2, 3:4, 5-Bis-0-(l-methylethylidene)-l-0-sulfamoyl-beta-D-fructopyranose or 2, 3:4, 5-Bis-0-(l-methylethylidene)- beta-D-fructopyranose sulfamate, having molecular formula CnHbiNOgS 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.
It is well known that a compound of formula (II) is used as starting material for the preparation of topiramate of formula (I) as disclosed in US 4513006. However, it has
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been observed by the present inventor that by preparing Topiramate as disclosed in US4513006, the resulting product always contain impurity of staring compound of formula (II) which is affecting the purity of final product.
-OH

There is several other purification process reported for Topiramate, for example WO2004/108732 which discloses a process of purification of Topiramate. However, even after purification the content of impurity of formula (II) still remains more than 0.1 % in final product.
US 2004/0038911 disclose processes for preparation of Topiramate. However, this application remains silent about impurity of formula II in final product.
US 2004/0158081 disclose continuous processes for preparation of Topiramate. However, this application discloses that impurity of formula (II) increases after ammonolysis of compound of formula (III).
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,0

o
Ii
O—S-CI
/ n
V/CH3

H,C
0 CH3

III

Schematic representation for formation of impurity of formula (II) during ammonolysis of compound of formula (III) as disclosed in US 5387700,


H,C
O—S-CI
/ o
CH,
X
CH3

0—S-NH2

H3C
O
II
V*
^CH3+CTNH2
H,C
CHo

III

CH3


The process for preparation of Topiramate by utilizing a compound of formula (II) as starting material disclosed in US 5387700 which remain silent about reduction of content of impurity of formula (II) in final product.
US 2004/0215004 disclose process for preparation of Topiramate by treating sulfamide with compound of formula (II) in presence of pyridine and O-xylene. However, the major disadvantage of this process is utilization of O-xylene as this solvent is expensive and not applicable for industrial scale. Moreover, this application remains silent about impurity of formula (II) in final product.
US 2005/0203287 disclose a process for preparation of Topiramate by utilizing a compound of formula (II) as starting material. However, this application remains silent about impurity of formula (II) in final product.
In summary, the removal of content of impurity i.e. starting material of formula (II) and preparing Topiramate with purity 99% has been an unsolved problem by the prior art.
Therefore, it is necessary to develop a process for purification of Topiramate which removes the starting material impurity of formula (II) as well as applicable for industrial scale.
Unexpectedly, present inventors found that it is indeed possible to remove the
impurity of starting material i.e. formula (II) by employing a process for purification
of Topiramate comprising steps of:
i) treating Topiramate with aqueous alkali solution;
ii) washing aqueous alkali solution of Topiramate obtain in step (i) with water
immiscible solvent; and
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iii) neutralizing the solution obtain in step (ii) to obtain Topiramate having purity more than 99%.
Surprisingly, the present inventors have found that this process of purification removes the starting material impurity of formula (II) up to less than 0.1 % which gives Topiramate having purity more than 99%.
Summary of the invention:
It is therefore an object of the present invention is to provide improved process for the purification of Topiramate.
Another object of the present invention is to provide the 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 an improved process for
purification of Topiramate comprising steps of:
i) treating Topiramate with aqueous alkali solution;
ii) washing aqueous alkali solution of Topiramate obtain in step (i) with water
immiscible solvent; and
iii) neutralizing the solution obtain in step (ii) to obtain Topiramate having purity
more than 99%.
A further object of the present invention is to provide an improved process for
purification of Topiramate comprising steps of:
i) treating Topiramate with aqueous alkali solution;
ii) washing aqueous alkali solution of Topiramate obtain in step (i) with water
immiscible solvent; and
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iii) neutralizing the solution obtain in step (ii) to obtain Topiramate having purity more than 99% and impurity of formula (II) less than 0.1 %.
Detailed description of the invention:
According to one aspect, present invention provides an improved process for the purification of Topiramate.
According to another aspect, present invention provides an improved process for the purification of Topiramate which is operationally simple, easy to handle and applicable at an industrial scale.
According to yet another aspect, present invention provides an improved process for
purification of Topiramate comprising steps of:
i) treating Topiramate with aqueous alkali solution;
ii) washing aqueous alkali solution of Topiramate obtain in step (i) with water
immiscible solvent; and
iii) neutralizing the solution obtain in step (ii) to obtain Topiramate having purity
more than 99%.
According to further aspect present invention provides an improved process for
purification of Topiramate comprising steps of:
i) treating Topiramate with aqueous alkali solution;
ii) washing aqueous alkali solution of Topiramate obtain in step (i) with water
immiscible solvent; and
iii) neutralizing the solution obtain in step (ii) to obtain Topiramate having purity
more than 99% and impurity of formula (II) less than 0.1 %.
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In embodiment, present invention provides the process for purification of Topiramate
which comprises steps of:
i) ammonolysis of compound of formula (III) in presence of base and suitable solvent
to obtain Topiramate
ii) treating Topiramate obtain in step (i) with aqueous alkali solution;
iii) washing aqueous alkali solution of Topiramate obtain in step (ii) with water
immiscible solvent; and
iv) neutralizing the solution obtain in (iii) to obtain Topiramate having purity more
than 99%.
For the purpose of this specification, the meaning of the term "Topiramate" used as starting material hereinabove that include topiramate is any form, or hydrate, solvate or their mixtures, or any state of purity.
For the purpose of this specification, the meaning of the term "treating" as used hereinabove that includes suspending, dissolving, washing, mixing, crystallizing or recrystallizing Topiramate in any of the solvent described above.
For the purpose of this specification, the meaning of the term "base" as used herein above includes organic bases such as substituted or unsubstituted aliphatic amines, aromatic amines or mixture thereof.
For the purpose of this specification, the meaning of the term "suitable solvent" as used hereinabove includes substituted or unsubstituted alcoholic solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ester solvent, ether solvent, cyclic ether solvent, nitrile solvent and aqueous solvent or mixture thereof. It also includes polar or nonpolar protic solvent, polar or nonpolar aprotic solvent or mixture thereof.
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For the purpose of this specification, the meaning of the term "water immiscible solvent" as used hereinabove that includes dichlorometane, ethyl acetate, toluene, dimethyl formamide, hexane, dimethyl acetamide and dimethyl sulfoxide etc.
For the purpose of this specification, the meaning of the term the term "alkali" as used hereinabove that includes an alkoxide, an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali or alkaline earth metal carbonate or hydrogencarbonate salt.
Topiramate is isolated from reaction mass by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.
Topiramate used as starting material in the examples is prepared according to methods reported in the literature and prior art.
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.
Example 1
2,3:4,5-bis-0-(l- methylethylidiene) - P- D- fructopyranose sulfonyl chloride (formula III) (65gm) and tetrahydrofuran (480ml) was taken in a autoclave & stirred under ammonia gas up to 1-2 kg pressure for 2-3 hr. After completion of reaction, the reaction mixture was filtered. The filterate was distilled off to get wet residue of Topiramate. 5 % sodium hydroxide solution (200 ml) was added to wet residue of Topiramate to give alkali solution of Topiramate which was washed with dichloromethane. The aqueous layer was neutralized with dilute acetic acid to
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crystallize pure Topiramate which was filtered, washed with water to get pure
Topiramate (51 gm).
Purity ~ 99.85 % (by HPLC)
Content of impurity of formula II ~ 0.06 % (by HPLC)
Example 2
Topiramate (5gm) was dissolved in 3.5% sodium hydroxide solution (20 ml) and
toluene (40ml). The layers were separated. The aqueous layer was washed with
toluene (20ml). The aqueous layer was neutralized with dilute acetic acid to
crystallize Topiramate which was filtered and washed with water to get pure
Topiramate (3.8 gm).
Purity ~ 99.61 % (by HPLC)
Content of impurity of formula II ~ 0.06 % (by HPLC)
Dated this 25th day of May 2006.
Sonali Bhokarikar ofS.MAJUMDAR&CO. Applicants' Agent
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