FIELD OF THE INVENTION
The present invention relates to novel polymorph of pregabalin.
BACKGROUND OF THE INVENTION:
(S)-pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the
chemical structure

is also known as γ-amino butyric acid or (S)-3-isobutyl GABA. (S)-pregabalin, marketed
under the name Lyrica®, has been found to activate GAD (L-glutamic acid
decarboxylase). (S)-pregabalin has a dose dependent protective effect on-seizure, and is a
CNS-active compound. (S)-pregabalin is useful in anticonvulsant therapy, due to its
activation of GAD, promoting the production of GABA, one of the brain's major
inhibitory neurotransmitters, which is released at 30 percent of the brain synapses. (S)-
pregabalin has analgesic, anticonvulsant, and anxiolytic activity.
The different physical properties exhibited by polymorphs affect important
pharmaceutical parameters such as storage, stability, compressibility, density and
dissolution rates.
U.S. Patent Application 2006/0270871 Al discloses the polymorphic Form-I of
pregabalin characterized by DSC thermogram showing a characteristic endothermic peak
at 194-205 °C and X-ray powder diffraction (XRPD) pattern comprising characteristics
29 values at 9.5, 16.62, 18.18, 18.32, 19.06, 19.74, 22.14, and 35.62 ° 29± 0.2° 29.

WO2006/121557 A1 discloses the pregabalin substantially free of lactam containing less
than 0.015% area by HPLC of lactam and a process for the preparation thereof. WO '557
Al also provides the HPLC method of analysis for the pregabalin substantially free from
lactam.
WO 2006/108151 A1 discloses the crystalline form of pregabalin. The pregabalin term
disclosed in the specification is about racemic pregabalin. Thus, the invention claims
crystalline pregabalin hemihydrate characterized by X-ray powder diffraction peaks at
about 5.8, 18.4, 19.2, 20.7 and 23.7 ° 29± 0.2° 2θ and by DSC having broad endotherm at
about 60 °C to about 100 °C and another endothermic peak at 181 °C.
IPCOM000073295D of IP prior art database shows the crystal form of the active
ingredient in LYRICA 300 mg hard capsules (3S)-3-(aminomethyl)-5-methylhexanoic
acid was analyzed by XRD. The active ingredient in LYRICA 300 mg hard capsules
pregabalin shows the main XRD peaks of powder diffractogram 20 (± 0.2°) 9.5, 12.3,
16.7, 17.8, 18.3, 19.1, 19.9, 20.3, 22.3, 22.8, 23.3, 23.6, 24.8, 26.2, 26.6, 27.0, 27.7, 28.1,
28.7, 29.3, 30.0, 30.4, 31.0, 31.5, 32.1, 33.0, 33.3, 34.1, 34.8, 35.8, 37.5, 38.8.
WO 2008/ 040935 discloses the Form-I according to the invention is characterized as a
having one or more characteristic XRPD peaks selected from following 20: 11.6, 13.3,
16.5, 20.0, and 23.4± 0.2 ° 20. Form-II according to the present invention is further
characterized as having one or more characteristic XRPD peaks selected from following
20: 5.7, 11.3, 15.5, 17.0, 17.8, 18.6, 22.7 and 24.2 (± 0.2°). Form-Ill characterized as
having one or more characteristic XRPD peaks selected from following 20: 6.3, 12.6,
19.0, 20.8 and 27.0 (± 0.2°). Form-IV characterized as having one or more characteristic
XRPD peaks selected from following 20: 9.5, 12.3, 16.7, 18.3, 18.4, 19.1, 19.8, 20.2,
22.2 and 23.2 (± 0.2°).
OBJECT OF THE INVENTION:
The object of the present invention is to provide a novel polymorph of pregabalin.

SUMMARY OF THE INVENTION:
The present invention relates to novel polymorph of pregabalin characterized by XRPD
having characteristic d spacing values at 9.27, 7.19, 4.66, 4.64, 4.47, 4.00, 3.82 and 3.77
A.
The DSC thermogram shows characteristic peak at 201.28 °C.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to novel polymorph of pregabalin wherein XRPD pattern
was measured using a powder diffractometer equipped with a Cu x-ray tube source.

In accordance with the present invention, there is provided a novel polymorph, which can
be obtained by recrystallization of crude pregabalin. Crude pregabalin was obtained by
treating racemic pregabalin with resolving agent in a polar solvent. Thus racemic
pregabalin in polar solvent was treated with a solution of O, Odibenzoyl-L-tartaric acid
monohydrate (1.0 mol equivalent) in polar solvent. The resultant reaction mixture was
heated to reflux to obtain clear solution and then slowly cooled and stirred for 10-12 h at
ambient temperature to obtain crystals of diastereomeric salt of pregabalin. The salt thus
obtained was taken in tetrahydrofuran -water and was treated with aqueous ammonia and
the pH was adjusted to alkaline. The solid obtained was filtered and dried.

The polar solvent for resolution of the racemic pregabalin can be selected from the group
of acetone, methanol, ethanol, isopropanol, tetrahydrofuran, water and mixture thereof.
The solid thus obtained was recrystallized using a mixture of solvent with water.
The solvent used for recrystallisation can be selected from the group of acetone,
methanol, ethanol, isopropanol and tetrahydrofuran, preferably isopropanol with water.
Thus crude pregabalin was added to a mixture of IPA and water and resultant mixture
was heated to get clear solution. The clear solution was filtered over hyflo bed and slowly
cooled to 0-5 °C and stirred for 30 minutes at the same temperature. The solid thus
obtained was filtered and washed with IPA. The wet solid was dried under vacuum at 50-
55 °C for 10-12 h. The solid thus obtained can be optionally further recrystallized by
using IPA and water. The DSC thermogram shows characteristic peak at 201.28 °C.
EXAMPLE:
A) Preparation of O,O-dibenzoyl tartarate salt
To a mixture of methanol (80 ml) and acetone was added O,Odibenzoyl-L-tartaric acid
(47.5 g) and racemic pregabalin (20 g). This reaction mixture was heated to reflux and
then cooled slowly and stirred for 10-12 h at ambient temperature to obtain crystals of
dibenzoyl tartarate salt of pregabalin. These crystals were filtered and washed with
acetone (40 ml). SOR: -74 ° (c = 0.5, MeOH), Yield: 40%, MP.: 149.7-150.9 °C, IR
(cm-1): 3426.86, 3377.97, 2958.67, 1724.29. 1694.00, 1600.43, 1246.0, 718.40 1HNMR
(MeOD, 400MHz): 5 8.14(d, J = 7.2 Hz, 4H), 7.63(t, J = 7.2 Hz, 2H), 7.50(, 4H), 5.92(s,
2H), 3.65(m, 1H), 2.92(d, J = 6.4 Hz, 1H), 2.37(m, 2H), 2.16(m, 1H), 1.69(m, 1H),
1.25(m, 2H), 0.9(m, 6H). Chiral HPLC: 98.22% S, 1.78% R.

B) Cleavage of O,O-dibenzoyl tartarate salt
A solution was prepared by dissolving O,O-dibenzoyl tartarate salt (5 g) in
tetrahydrofuran- water (65 ml/5 ml) at ambient temperature. To this solution was added
ammonia solution to basic pH. The mixture was stirred for 2 h at ambient temperature.
The solid thus obtained was filtered and washed with tetrahydrofuran-water (10 ml) and
isopropanol (5 ml).
Yield: 40%, M.P.: 180.7-181.5 °C Water (Karl Fischer): 0.5% by weight, HPLC: 99.3
w/w; Chiral HPLC: 99.94% S, 0.06 % R (limit of detection: 0.05%).
C) Recrystallization of pregabalin
To a mixture of IPA (2000 ml) and DM water (600 ml) was added crude pregabalin (100
g) and resultant mixture was heated to get clear solution. The clear solution was filtered
over hyflo bed and slowly cooled to 0-5 °C and stirred for 30 minutes at the same
temperature. The solid thus obtained was filtered and washed with IPA (2 x 100 ml). The
wet solid was dried under vacuum at 50-55 °C for 10-12 h. The solid obtained was further
recrystalized by using IPA and water.

We Claim:
1. Crystalline pregabalin characterized by XRPD characteristic d spacing d spacing
values 9.27, 7.19, 4.66, 4.64, 4.47, 4.00, 3.82 and 3.77.
2. Crystalline pregabalin of claim 1 having the characteristic DSC thermogram
showing a characteristic peak at 201.28 °C.

A crystalline form of pregabalin characterized by XRPD characteristic d spacing values
at 9.27, 7.19, 4.66, 4.64, 4.47, 4.00, 3.82 and 3.77Å. The DSC thermogram shows
characteristic peak at 201.28°C.