The present invention relates to novel polymorphic form of pregabalin and process for its preparation. The novel polymorphic form of pregabalin has been designated as Form I of pregabalin. The present invention further provides enantiomerically pure pregabalin or salt thereof having less than 0.03% w/w of unwanted (R)-(-)-enantiomer.
y-aminobutyric acid (GABA) is one of the most widely distributed inhibitory neurotransmitter involved in the regulation of brain neuronal activity. The concentration of GABA is regulated by two pyridoxal 5'-phosphate dependent enzymes, L-glutamic acid decarboxylase (GAD), which catalyzes conversion of I-glutamic acid to GABA and GABA aminotransferase, which degrades GABA to succinic semialdehyde. When concentration of GABA diminishes below a threshold level in the brain convulsions result, raising the brain GABA level appears to terminate seizure.
Pregabalin is chemically (S)-(+)-3-aminomethyl-5-methyl-1-hexanoic acid. It is also known as (S)-(+)-3-(2-methylpropyl)-4-aminobutanoic acid or (S)-(+)-3-isobutyl-y-aminobutanoic acid or (S)-(+)-3-isobutyl-GABA having structure of Formula I.
(Formula Removed)
Pregabalin increases the concentration of GABA by activating GAD and is therefore useful therapeutic agent in treatment of pain, convulsions, general anxiety related disorders and epileptic seizures. The (R)-(-)-enantiomer of pregabalin is almost 40 times less active as compared to (S)-(+)-enantiomer.
PCT Patent Applications WO 93/23383; WO 03/093220; WO 01/55090; WO 96/38405 and WO 96/40617 provide several processes for preparation of pregabalin. The melting point of (S)-(+) enantiomer of pregabalin is reported to be 177-179°C with decomposition and that for racemic pregabalin is reported to be 166-167.5°C. A
melting point of 184-186°C for (S)-(+)-enantiomer has also been reported. None of the above-mentioned applications provide any X-Ray Diffraction pattern of pregabalin. The moisture content of the so obtained pregabalin is also not reported. Although the maximum chiral purity of pregabalin is reported to be 100% w/w, the limit for detection of unwanted (R)-(-)-enantiomer by the method applied for determination of chiral purity is reported to be 0.05% w/w.
Present inventors have now surprisingly found that (S)-(+)-pregabalin can be prepared in a novel, hereto unknown, polymorphic form. The novel polymorphic form has been designated as Form I of pregabalin. The new Form I of pregabalin is characteristically different than that known in the art as it has a melting point of about 194-197°C.
The present inventors have now prepared enantiomerically pure pregabalin or salt thereof having less than 0.03% w/w of unwanted (R)-(-)-enantiomer. The limit of detection of unwanted (R)-(-)-enantiomer as per the method used by the present inventors is about 0.01% w/w. Pregabalin or salt thereof having this chiral purity is not known in the art.
A first aspect of the invention provides Form I of pregabalin having X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 1 of the accompanied drawing wherein characteristic 26 values are obtained at 9.5, 16.62, 18.18, 18.32, 19.06, 19.74, 22.14 and 35.62. The XRPD pattern of Form I of pregabalin further comprises of characteristic 29 values obtained at 8.58, 9.5, 10.02, 10.62, 10.96, 11.52, 12.26, 14.44, 16.62, 17.20, 17.74, 18.18, 18.32, 19.06, 19.74, 20.14, 22.14, 22.68, 23.18, 23.46, 23.88, 24.64, 26.16, 26.46, 26.90, 27.60, 27.92, 28.22, 28.58, 28.76, 29.18, 29.86, 30.24, 30.96, 31.38, 31.90, 32.88, 33.14, 33.94, 34.64, 35.62, 36.42, 36.84, 36.94, 37.12, 37.40, 38.48, 38.66 and 39.54. The Fourier Transform Infrared (FTIR) spectrum of Form I of pregabalin in potassium bromide is depicted in Figure 2 of the accompanied drawing. The Form I of pregabalin has characteristic DSC thermogram as depicted in Figure 3 of the accompanied drawing. The DSC thermogram shows a characteristic endothermic peak at 194-205°C.
A second aspect of the present invention provides anhydrous pregabalin having moisture content less than 0.3% w/w when determined by the known techniques. Anhydrous pregabalin of the present invention is non-hygroscopic, colorless and stable during the accelerated stability testing.
A third aspect of the present invention provides (S)-(+)-pregabalin or salt thereof having 0.03% or less of unwanted (R)-(-)-pregabalin or salt thereof when determined by sensitive HPLC method. It is very much necessary to reduce the level of (R)-(-)-enantiomer in pregabalin owing to the fact that it is almost 40 times less active.
A fourth aspect of the present invention provides a process for preparation of Form I of pregabalin wherein the said process comprises of recrystallization of pregabalin from an aqueous alkanol solvent system with a proviso that water content of the reaction mass is above 25% w/w.
Pregabalin is dissolved in an aqueous alkanol solvent system containing more than 25% w/w of water and the resultant mass is heated to reflux and cooled to get the precipitate of Form I of pregabalin which can then be suitably isolated and dried.
A fifth aspect of the present invention provides pharmaceutical composition comprising Form I of pregabalin optionally containing diluent or carrier.
A sixth aspect of the present invention provides pharmaceutical compositions comprising (S)-(+)-pregabalin or salt thereof having 0.03% or less of unwanted (R)-(-)-pregabalin optionally containing diluent or carrier.
A seventh aspect of the present invention provides a method of treating pain, epilepsy, convulsions, attention deficit hypersensitivity disorder (ADHD) and general anxiety related disorders which comprises of administering to a mammal in need thereof a therapeutically effective quantity of Form I of pregabalin.
An eighth aspect of the present invention provides a method of treating pain, epilepsy, convulsions, attention deficit hypersensitivity disorder (ADHD) and general anxiety related disorders which comprises of administering to a mammal in need thereof a
therapeutically effective quantity of (S)-(+)-pregabalin or salt thereof having 0.03% or less of unwanted (R)-(-)-pregabalin.
Powder XRD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A
FT-IR of the samples were determined by using lnstrument:Perkin Elmer,16 PC, SCAN: 16scans, 4.0 cm"1, according to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.
DSC thermograms were recorded using DSC821 e, Mettler Toledo, Sample weight: 3-5 mg, Temperature range: 50-350° C, Heating rate: 20° C/min, Nitrogen 80.0 mL/min, Number of holes in the crucible: 1
Figure I provides XRPD pattern of Form I of pregabalin. Figure II provides FTIR spectrum of Form I of pregabalin. Figure III provides DSC thermogram of Form I of pregabalin.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE-1
3-(AMINOMETHYL)-5-METHYLHEXANOIC ACID (RACEMIC)
A solution of potassium hydroxide (19 g) in methanol (80 ml) was added to a solution of ethyl 2-carboxyethyl-3-cyano-5-methyl hexanoate (90 g) in methanol (31 ml) at 25 to 35°C. The mixture was heated to reflux for 4 to 5 hours, cooled to 25 to 30°C and a solution of potassium hydroxide (37 g) in water (62 ml) was added at 30 to 50°C. The mass was stirred for 15 minutes and concentrated under vacuum to about 180 ml volume. Added water (30 ml) into reaction mixture and further concentrated about to 160 ml. Charged Raney Nickel (15 g wet), water (8.2 ml) and ethyl alcohol (9.2
ml) and stirred the reaction mixture under hydrogen pressure of 3.5 - 4 Kg / cm2 at
35 - 40°C for 24 hours.
After completion of hydrogenation, added ethyl alcohol (18 ml) into reaction mixture.
Filtered the reaction mixture through celite bed and washed the cake with aqueous
ethyl alcohol (110 ml). Charged glacial acetic acid (70 ml) slowly at 40 to 50°C and
heated to 70 to 75°C to dissolve the solids. Reaction mixture was slowly cooled to 0
to 5°C and stirred at 0 to 5°C for 4 hours. The separated product was filtered and
washed with isopropanol (175 ml), then dried under vacuum at 35 to 45°C for 12
hours gives white crystalline powder
Yield: 40 g.
HPLC Purity: 99.6%
1HNMR (D2O, 300 MHz): δ 0.93 - 0.96 (m, 6H), 1.26 - 1.30 (t, 2H, J = 6.9 Hz), 1.7 -
1.74 (m, 1H), 2.2 - 2.4 (m, 3H), 3.0 - 3.07 (m, 2H).
EXAMPLE-2
S (+)-3-(AMINOETHYL)-5-METHYLHEXANOIC ACID (CRUDE)
A mixture of racemic 3-aminoethyl-5-methylhexanoic acid (20 g), S-(+) mandelic acid (26.6 g) and 3% water/isopropanol mixture (340 ml) was heated at 65 - 70°C to get clear solution. The mixture was cooled to 40 to 45°C, seeded with crystals of pregabalin mandelate and then further cooled to 20 to 25°C. Stirred at 20 to 25°C for 4 hours, filtered the solid and washed with 3% water/isopropanol mixture (15 ml). Wet solid was recharged into a mixture of 3% water/isopropanol mixture (70 ml) and S-(+)-mandelic acid (3.9 g). The mixture was heated to 65°C and stirred for 5 minutes at 65 to 70°C. Cooled to 0 to 5°C and stirred at 0 to 5°C for 4 hours. The separated solids were filtered and washed with 3% water/isopropanol mixture (10 ml). Charged the wet material into 5% water/tetrahydrofuran mixture (130 ml) and heated to 50 to 55°C. Cooled to 0 to 5°C and stirred at 0 to 5°C for 4 hours. Product was filtered and washed with tetrahydrofuran (7 ml), followed by isopropanol (2x10 ml). Dried the solid under vacuum at 40 to 45°C for 8 hours gives white solid of the title product Yield: 5 g.
EXAMPLE-3
S(+)-3-(AMINOETHYL)-5-METHYLHEXANOICACID(PREGABALIN)
Crude S-(+)-3-(aminoethyl)-5-methylhexanoic acid (5 g) was charged into 30%
water/isopropanol mixture (80 ml). The mixture was heated to dissolve the product at
75 to 80°C. Filtered the reaction mixture while hot, and cooled to 0 to 5°C. The mass
was further stirred for 4 hours at 0 to 5°C, filtered and the cake was washed with
chilled isopropanol (20 ml). The wet material was dried under vacuum at 35 to 45°C
for 12 hours gives white crystalline solid.
Yield: 4.8 g
HPLC Purity: 99.7% w/w
Chiral Purity: 99.5% (S-isomer), 0.024% (R-isomer)
Water content: 0.03% w/w (Karl Fischer analysis)
1H-NMR (D2O, 300 MHz): δ 0.89 - 0.93 (m, 6H), 1.21 - 1.26 (t, 2H, J = 7.1Hz), 1.65 -
1.7 (m, 1H), 2.15-2.36 (m, 3H), 2.97-3.02 (m, 2H)

WE CLAIM:
1. Form I of pregabalin.
2. Form I of pregabalin having X-Ray Powder Diffraction (XRPD) pattern as depicted in Figure 1 of the accompanied drawing wherein characteristic 20 values are obtained at 9.5, 16.62, 18.18, 18.32, 19.06, 19.74, 22.14 and 35.62.
3. The Form I of pregabalin has characteristic DSC thermogram shows a characteristic endothermic peak at 194-205°C.
4. Anhydrous pregabalin having moisture content less than 0.3% w/w.
5. (S)-(+)-pregabalin or salt thereof having 0.03% or less of unwanted (R)-(-)-pregabalin or salt thereof.
6. A process for preparation of Form I of pregabalin wherein the said process comprises of recrystallization of pregabalin from an aqueous alkanol solvent system with a proviso that water content of the reaction mass is above 25%.
7. A pharmaceutical composition comprising Form I of pregabalin optionally containing diluent or carrier.
8. A pharmaceutical composition comprising (S)-(+)-pregabalin or salt thereof having 0.03% or less of unwanted (R)-(-)-pregabalin optionally containing diluent or carrier.
9. A method of treating pain, epilepsy, convulsions, attention deficit hypersensitivity disorder (ADHD) and general anxiety related disorders which comprises of administering to a mammal in need thereof a therapeutically effective quantity of Form I of pregabalin.
10. A method of treating pain, epilepsy, convulsions, attention deficit hypersensitivity disorder (ADHD) and general anxiety related disorders which comprises of administering to a mammal in need thereof a therapeutically effective quantity of (S)-(+)-pregabalin or salt thereof having 0.03% or less of unwanted (R)-(-)-pregabalin.