CLIAMS:----------- ,TagSPECI:The following specification describes the nature of the invention:

PROCESS FOR PREPARATION OF PREGABALIN

INTRODUCTION
Aspects of the present invention relate to process for preparing pregabalin with low amount of undesired impurity.
BACKGROUND
The drug compound having the adopted name “Pregabalin” has chemical name:
(S)-(+)-3-Aminomethyl-5-methyl hexanoic and is represented by structure of formula I.

I
Pregabalin is a gamma.-amino butyric acid or (S)-3-isobutyl (GABA) analogue.
(S)-Pregabalin 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 brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity. Preparation of (S)-Pregabalin is disclosed in US US5563175, US6197819B1, US 5,616,793, Drugs of Future, 24 (8), 862-870 (1999) and in many other prior references.

SUMMARY

One aspect of the present application provides process for preparation of pregabalin substantially free of undesired 4-ene impurity of formula III

III
which comprises
a) reacting (R)(-)-3-(carbamoylmethyl)-5-methylhexanoic acid (R-CMHA) or a salt of the formula II with hypochlorite in presence of suitable base and solvent;

b) treating the reaction mass with an acid to get pH about 2.0 – 3.0;
c) treating with suitable base to result the pH of the mass about 5.0 – 5.5;
d) isolation of pregabalin;
e) optionally purifying pregabalin in a suitable solvent.
In another embodiment, the present application provides pregabalin substantially free of 4-ene impurity which has RRT 0.51 in HPLC analysis.
Yet another aspect of the present application provides pharmaceutical compositions comprising pregabalin of formula (I) or its pharmaceutically acceptable salts prepared according to process of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.

DETAILED DESCRIPTION

Several patents and published patent applications for example US5,616,793, WO 2006/122258, WO 2006/122255 and WO 2006/121557 disclose a more convenient preparation of pregabalin by means of a Hofmann rearrangement of (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid, a compound of formula II.
US8071808B2 provides a process for preparing pregabalin of formula I substantially free of impurities by reacting (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid of formula II with sodium hypochlorite at a temperature 50-70 degree Celsius.
In the synthesis of pregabalin by carrying out Hoffmann reaction, the formation of ~0.51 RRT impurity was observed and which did not have wash ability in the subsequent conventional purification process. The formation of pregabalin starting from (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid of formula II under Hoffmann reaction conditions is represented as follows:

The pregabalin obtained as per the above reaction conditions by following the process disclosed in prior refernces is having an unknown impurity above the desired levels and was unable to wash the impurity during recrystallization from a solvent. Based on LC-MS analysis this impurity was characterized as 4-ene impurity of pregabalin which is represented by formula III. This impurity has identified at RRT 0.51 in HPLC analysis.

III
Therefore, it is required to control the ~0.51 RRT impurity to a desired level within the process of Hoffmann reaction or during work up process. It has become essential to adjust the pH of the reaction mass at about 2.0 – 3.0 with an acid followed by raising the pH to about 5.0 – 5.5 to control the impurity to a desired level after completion of Hoffmann reaction.
One aspect of the present application provides process for preparation of pregabalin substantially free of undesired 4-ene impurity of formula III,

III
which comprises
a) reacting (R)(-)-3-(carbamoylmethyl)-5-methylhexanoic acid (R-CMHA) or a salt of the formula II with hypochlorite in presence of suitable base and solvent;

b) treating the reaction mass with an acid to get pH about 2.0 – 3.0;
c) treating with suitable base to result the pH of the mass about 5.0 – 5.5;
d) isolation of pregabalin;
e) optionally purifying pregabalin in a suitable solvent.
Step (a) may be carried out in the presence of one or more suitable bases. Suitable bases that may be used in step (a) include, but are not limited to alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline earth metal hydroxides, such as, for example, barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like.
Step (a) may be carried out in one or more suitable solvents. Suitable solvents that may be used in step (a) include, but are not limited to water or mixture of water and suitable organic solvent. Suitable organic solvents that may be used include, but are not limited to alcohol solvents, such as, for example, methanol, ethanol, propanol, 1-propanol, 2-propanol, butanol, pentanol, ethylene glycol, glycerol, or the like; aliphatic or alicyclic hydrocarbon solvents, such as, for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbon solvents, such as, for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; or any mixtures thereof.
Step (a) may be carried out in presence of suitable hypochlorite. Suitable hypochlorite that may be used in step (a) include, but are not limited to sodium hypochlorite, calcium hypochlorite or the like.
(R)(-)-3-(carbamoylmethyl)-5-methylhexanoic acid or a salt of the formula II was prepared according to methods known in prior art. RCMHA may be obtained through chemical synthesis or by enzymatic reaction.
The temperature at which step (a) may be carried out in between about 0 °C and about 100 °C, preferably between about 5°C and about 48°C.
In order to control the ~0.51 RRT (4-ene impurity) the following work up was established. After completion of the reaction in step (a), the reaction mass pH was adjusted to 2-3 by using acid in step (b).
The suitable acids that may be used in step (b) include, but are not limited to mineral acids such as hydrochloric acid, hydrobromic acid, or other acids such as sulfuric acid, nitric acid, phosphoric acid, boric acid or the like; organic acids such as acetic acid, formic acid, methane sulfonic acid, lactic acid, citric acid, oxalic acid, uric acid or the like. The pH adjustment may also done using gaseous acids such as HCl gas.
The temperature at which step (b) may be carried out in between about 0 °C and about 40 °C, preferably between about 5°C and about 35°C.
Further re-adjusting the pH of the reaction mass from 2.0-3.0 to 5.0-5.5 in step (c) was carried out using a base.
The suitable bases that may be used in step (c) include, but are not limited to alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline earth metal hydroxides, such as, for example, barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as, for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like.
The temperature at which step (c) may be carried out in between about 0 °C and about 40 °C, preferably between about 5°C and about 35°C.
Isolation of the pregabalin can be further carried out if desired in step (d), by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, crystallization, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer.
The pregabalin obtained in the step (d) is having the purity in the range of 99% to 99.9% and the content of 4-ene impurity of pregabalin is below 0.15% w/w, preferably less than 0.05% and more preferably in “not detected” level in HPLC analysis.
The pregabalin obtained after step (d) of the present invention may be optionally further purified to get the ICH grade material of API in order to use the same for finished dosage forms in step (e).
Purification in step (e) may be carried out in one or more suitable solvents. Suitable solvents that may be used in step (e) include, but are not limited to water or mixture of water and organic solvent. Suitable organic solvents that may be used include, but are not limited to alcohol solvents, such as, for example, methanol, ethanol, propanol, 1-propanol, 2-propanol, butanol, pentanol, ethylene glycol, glycerol, or the like; aliphatic or alicyclic hydrocarbon solvents, such as, for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbon solvents, such as, for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; or any mixtures thereof.
The temperature at which step (e) may be carried out in between about 0 °C and about 100 °C, preferably between about 5°C and about 75°C.
During the isolation of the crude pregabalin most of the process related impurities were washed out in mother liquor and where as the 4-ene impurity is removed by adjusting the pH acidic.. The following table shows comparison of the content of 4-ene impurity at different pH levels (Table-1).

Table 1: Effect of acidic pH adjustment (pH: 2-3) on content of 4-ene impurity

pH range Content of impurity (%)
13.5-14.0 (as such reaction mass) 0.39
Direct Isolation at pH about 5.0 0.14
Direct Isolation at pH about 6.0 0.16
Adjusting to pH about 2-3 and followed raising to about 5.0-5.5 Not detected

The processes of the present invention may also include isolation of individual intermediate or processed for further steps without isolation of intermediates wherever applicable.
In another embodiment, pregabalin of the present invention is substantially free of 4-ene impurity which has relative retention time of 0.51 in HPLC analysis.
The term Substantially free term means the content of 4-ene impurity in pregabalin is below 0.15% w/w, preferably less than 0.05% and more preferably in “not detected”.
The HPLC conditions described herein is used to ascertain the purity of pregabalin, including analyzing pregabalin produced through present invention for the presence of impurity which has a HPLC relative retention time of ~0.51. A two-component mobile phase (A:B) is prepared by mixing mobile phase A (100% degassed buffer) and mobile phase B (water: acetonitrile, 25:75, v/v).

Typical Chromatographic Conditions:
Column X-Bridge C18 150 x 4.6 mm, 3.5?m?
Flow rate 0.8ml /min
Column oven temperature 25°C
Wave length 210 nm
Injection Volume 15µL
Run time 60 minutes.
Auto sampler temperature 5.0°C + 2°C
Diluent Water:Acetonitrile: Methanol 8:1:1 ratio
Gradient Program Time (min) % Mobile Phase-A % Mobile Phase-B
0.00 97 3
35.0 30 70
45.0 30 70
45.01 97 3
60.0 97 3

The process of the present application is not only environment friendly and also provides better yield with required purity. The process is further suitable to practice at on industrial scale.
Yet another aspect of the present application provides pharmaceutical compositions comprising pregabalin of formula (I) or its pharmaceutically acceptable salts prepared according to process of the present application together with one or more pharmaceutically acceptable excipient, carrier and diluents.
Pharmaceutically acceptable excipients that find use in the present disclosure include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise.
“HPLC or High-performance liquid chromatography” is a chromatographic technique used to separate a mixture of compounds with the purpose of identifying, quantifying or purifying the individual components of the mixture.
“LC-MS or Liquid chromatography–mass spectrometry” is a chemistry technique that combines the physical separation capabilities of liquid chromatography (or HPLC) with the mass analysis capabilities of mass spectrometry.
“Hofmann reaction” is the organic reaction of a primary amide to a primary amine with one fewer carbon atom.
An “alcohol solvent” is an organic solvent containing a carbon bound to a hydroxyl group. “Alcoholic solvents” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, C1-6alcohols, or the like.
A “halogenated hydrocarbon solvent” is an organic solvent containing a carbon bound to a halogen. “Halogenated hydrocarbon solvents” include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.
EXAMPLES
Example 1: Preparation of crude Pregabalin
R-CMHA (20gm, 0.107mol) was added to water (30 ml) and cooled to 5-10°C. To the resulting thick suspension was added 50% w/w aqueous sodium hydroxide solution (20.4gm in 20 ml water, 0.257mol, 2.4 molar eq) dropwise over a period of 25-35 minutes maintaining the temperature at 5-10°C. The reaction mixture stirred for 30minutes. 12% w/w aqueous sodium hypochlorite solution (69.7gm, 0.112 mol, 1.05 molar eq.) was added dropwise to reaction mixture at 5-10°C. The reaction mixture was allowed to warm up slowly and was later heated to a temperature of 45±2°C and stirred for one hour. The completion of the reaction was confirmed by TLC and cooled the mass to RT.
Impurity content (by HPLC) at RRT 0.51: 0.39% w/w.
The above reaction mixture was divided into two parts (Part A and Part B)

Part A: Isolation of crude Pregabalin (with out pH adjustment of 2-3)
The pH of reaction mixture was adjusted to 5.0-5.5 with aqueous sodium hydroxide, cooled to 5-10°C and stirred for one hour. The solid was filtered and washed with 40ml water and dried to give pregabalin.
Impurity content (by HPLC) at RRT 0.51: 0.14% w/w.

Purification of crude Pregabalin obtained from Part A:
The crude pregabalin was added to a mixture of water (47ml) and isopropanol (32ml), heated to 70-75°C till complete dissolution occurred. The resulting solution was filtered to remove insoluble particles at 70-75°C. The filtrate was cooled to 5-10°C and stirred for one hour. The solid was filtered and washed with 15ml of isopropanol and dried at 50°C under vacuum to give pregabalin.
Impurity content (by HPLC) at RRT 0.51: 0.14% w/w

Part B: Isolation of crude Pregabalin (with pH adjustment of 2-3)
To the reaction mixture at 25-35°C was added 35%w/w aqueous hydrochloric acid (34gm) to get the pH of mass to 2-2.5 and stirred for 20-30 minutes. 50% aqueous sodium hydroxide solution (5gm) was added to the reaction mixture to achieve pH 5.0-5.5. A peach colored suspension was obtained which was cooled to 5-10°C and stirred for one hour. The solid was filtered and washed with 40ml water and dried to give pale orange colored crude pregabalin.
Impurity content (by HPLC) at RRT 0.51: Not Detected

Purification of crude Pregabalin obtained from Part B:
The crude pregabalin was added to a mixture of water (47ml) and isopropanol (32ml), heated to 70-75°C till complete dissolution occurred. The resulting solution was filtered to remove insoluble particles at 70-75°C. The solution was cooled to 5-10°C and stirred for one hour. The solid was filtered and washed with 15ml of isopropanol and dried at 50°C under vacuum to give pregabalin.
Impurity content (by HPLC) at RRT 0.51 (by HPLC): Not Detected