TECHNICAL FIELD OF THE INVENTION:
The present invention relates to the chemical arts and is specifically directed towards the
polymorph of a pharmaceutically active compound - Levetiracetam.
BACKGROUND OF THE INVENTION:
Levetiracetam, CAS number [102767-28-2], is the S-enantiomer of Etiracetam. Etiracetam,
chemically known as 2-(2-oxopyrrolidin-l-yl)butanamide, is a racemic compound and was
intended to be used therapeutically for the treatment of motion-sickness, hyperkinesia,
hypertonia and epilepsy. The compound Etiracetam was disclosed in the patent GB1309692.
Upon the discovery that the S-enantiomer possessed a higher biological activity as compared
to the racemate, the optically pure Levetiracetam of Formula I was formulated to be used as an
anti-convulsive agent for the treatment of partial onset of seizures and epilepsy.

FORMULA I
Further studies have also been conducted for the use of Levetiracetam in the treatment of
cognition disorders, anxiety disorders, and in patients at risk for deep venous thrombosis.
Levetiracetam is claimed in the patent EP0162036.
The crystal structure of Levetiracetam was reported by Song et al. in 2003 (Acta Cryst. 2003,
E59, 1772). Levetiracetam, like any chemical compound, can exist in various polymorphic
forms. Three crystalline forms of Levetiracetam are disclosed in the PCT application
published as WO2004/083180 (Applicant: Hetero Drugs), namely, crystalline forms I, II and
III.
SUMMARY OF THE INVENTION:
According to one aspect of the present invention there is provided a novel crystalline Form IV
of Levetiracetam.
According to another aspect of the invention, there is provided a method for the preparation of
the polymorph by crystallization.
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DESCRIPTION OF THE INVENTION:
The present inventors have now found a novel form of Levetiracetam that is not only stable
but can also be prepared on an industrial scale.
According to one aspect of this invention, there is provided a novel crystalline form regarded
herein as form IV of Levetiracetam that has been characterized using powder X-ray
Diffraction techniques. Form IV has the X-ray diffraction pattern as depicted in Figure 1. (The
diffractogram was generated under the following conditions: Cu - Kα1 = 1.54060A, Kα2 =
1.54443Å Kβ= 1.39225Å, 40mA, 45kV). Form IV of Levetiracetam may be further
characterized as having peaks at 10.14, 14.87, 15.01, 15.12, 18.55, 20.53, 20.59, 22.18, 23.36,
23.86, 26.82, 26.96, 28.92, 29.98, 30.06, 30.29, 30.38, 30.57, 30.75, 32.04 degrees 2 Theta.
In another aspect of the invention is provided a process for the preparation of the crystalline
form IV. This crystalline Form IV can be prepared by crystallizing crude Levetiracetam from
a suitable organic solvent such as organic esters. The most preferred solvent is ethyl acetate.
The crude Levetiracetam is dissolved in the organic solvent at an elevated temperature and the
solution is allowed to cool naturally for crystallization to occur. Slow cooling allows for the
formation of better crystals. The crude Levetiracetam can be obtained by any process as
described in the prior art, for example the process as given in the patent EP0162036.
The following example illustrates the practice of the invention without being limiting in any
way.
Example:
100g of Levetiracetam was added to 2.2L of ethyl acetate at ambient temperature. The
mixture was heated to about 75 °C, stirred and cooled gradually over a period of 3 - 4 hours.
Levetiracetam was allowed to crystallize and the crystals were filtered and washed with
chilled (0 - 5°C) ethyl acetate. The crystals were dried under vacuum at 40 - 50°C. (Yield =
85.5%)
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WE CLAIM:
1. A crystalline form of Levetiracetam characterized by an XRD pattern as depicted in
Figure 1.
2. A crystalline form of Levetiracetam having the following values of 20: 10.14, 14.87,
15.01, 15.12, 18.55, 20.53, 20.59, 22.18, 23.36, 23.86, 26.82, 26.96, 28.92, 29.98,
30.06, 30.29, 30.38, 30.57.
3. A process for the preparation of Levetiracetam of claim 1, wherein Levetiracetam is
added to an organic solvent, dissolved at a temperature of about 75°C, cooled
gradually until crystals have formed and finally isolating the crystals by filtration.
4. A process for preparing crystalline Levetiracetam of claim 1, wherein the organic
solvent is an organic ester.
5. A process according to claim 4, wherein the organic solvent is ethyl acetate.
Dated this 15th day of October 2007
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The invention relates to Form IV of Levetiracetam characterized by an XRD pattern as
depicted in Figure 1 and a process for its preparation.