DESC:FORM 2
THE PATENT ACT, 1970
[39 OF 1970]
&
PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

PROCESS FOR THE PREPARATION OF
PURE FORM B OF TAPENTADOL HYDROCHLORIDE

IND-SWIFT LABORATORIES LIMITED
S.C.O. NO. 850, SHIVALIK ENCLAVE,
NAC, MANIMAJRA,
CHANDIGARH-160101

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for the preparation of pure Form B of tapentadol hydrochloride in consistent manner.

BACKGROUND OF THE INVENTION
Tapentadol of formula I, a centrally-acting analgesic compound, is chemically known as 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol and marketed in the form of hydrochloride salt under the trade name Nucynta.

Formula I

Tapentadol and its analogues were first disclosed in US patent 6,248,737 herein referred as US ‘737 (reissue as USRE 39,593). According to the process disclosed in this patent, tapentadol hydrochloride is prepared by demethylation of (2R,3R)-3-(3-methoxyphenyl)-N,N-2-trimethylpentan-1-amine hydrochloride by using hydrobromic acid to give tapentadol free base as a residue. The obtained residue is dissolve in 2-butanone followed by addition of trimethylchlorosilane and water to afford tapentadol hydrochloride.
US patent 7,994,364 herein referred as US ‘364 discloses a more stable crystalline form A of tapentadol hydrochloride and methods of its preparation and designated Form B to the product obtained by the process disclosed in US‘737. Further US ‘364 also discloses processes for the preparation of tapentadol hydrochloride Form B. In one process, tapentadol hydrochloride Form B is prepared by milling of tapentadol hydrochloride Form A for at least 20min followed by drying at 130ºC in oven for 80 minutes.
In another process, tapentadol hydrochloride Form B is prepared by cryogrinding of tapentadol hydrochloride for atleast 15 minutes and then keeping at 125 ºC in a TGA for 30 minutes.
The main drawback of these processes are that, these grindings are not suitable for industrial purpose.
US patent publication US2010/0272815 discloses a process for the preparation of amorphous tapentadol hydrochloride by dissolving tapentadol hydrochloride in a solvent, such as water, organic solvent or mixture thereof and amorphous tapentadol hydrochloride is isolated by removal of solvent by vacuum drying or spray drying.
US patent publication US2013/0096347 discloses a process for the purification of tapentadol hydrochloride comprises of providing a solution of tapentadol hydrochloride in a solvent selected from water, methanol, ethanol, isopropyl alcohol, acetonitrile or a solvent mixture. Optionally, the obtained solution is subjecting to carbon or silica gel treatment and isolating and recovering the highly pure tapentadol hydrochloride after recovering solvents.
PCT publication WO2012/038974 discloses various processes for the preparation of tapentadol hydrochloride wherein tapentadol free base is dissolved in dichloromethane, isopropylether hydrochloride or ethylacetate hydrochloride and the solvent is distilled off and the crude compound thus isolated is purified using suitable solvents. These references have not disclosed any polymorph of tapentadol hydrochloride.
PCT publication WO2013/111161 discloses stable crystalline Form B of tapentadol hydrochloride and processes for its preparation by making use of lower aliphatic carboxylic acids such as formic, acetic and propionic acid during preparation of hydrochloride salt formation from tapentadol base. In an alternative embodiment, stable crystalline Form B of tapentadol hydrochloride is prepared by adding alkyl formate to tapentadol free base in the presence or absence of solvent and followed by cooling the reaction mixture. Finally, a source of hydrochloric acid is added to the resulting mixture and filtering the precipitated product and then dried to get crystalline Form B of tapentadol hydrochloride. It has been observed that by repeating the given example, form B is not always polymorphically pure and is a mixture of other polymorphs including form A.
Indian patent publication 2944/MUM/2011 discloses a process for the preparation of tapentadol hydrochloride wherein tapentadol free base is dissolved in acetone and hydrogen chloride gas is purged into the solution to obtain tapentadol hydrochloride and resulting compound is recrystallized from acetone to afford crystalline tapentadol hydrochloride.
Chinese patent publication CN102924303A discloses a process for the preparation of tapentadol hydrochloride Form C. According to the process disclosed in this Chinese patent publication, tapentadol hydrochloride Form C is prepared by reacting tapentadol free base with hydrochloric acid/ethanol and using acetone as solvent.
In view of the above, most of the prior art processes are either silent about the polymorph of tapentadol hydrochloride or provide process for form B of tapentadol hydrochloride, which are neither suitable for industrial application nor provide pure form B of tapentadol hydrochloride consistently. Processes reported for preparation of Form B lead to the formation of mixture of crystalline Form B with crystalline Form A of tapentadol hydrochloride.
Solid state properties of drugs have received great attention in the pharmaceutical market. The ability of some substances to exist in more than one crystalline form called polymorphism was accredited as one of the most important solid-state property of the drug. While polymorphs have the same chemical composition, they differ in packing and geometrical arrangement and therefore exhibit different physical properties such as melting point, shape, color, X-ray diffraction pattern, infrared absorption, density, hardness, deformability, stability, dissolution, and the like. Depending on their temperature-stability relationship, one crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by techniques such as capillary melting point, thermo-gravimetric analysis (TGA) and differential scanning calorimetry (DSC), which have been used to distinguish polymorphic forms.
It is already known in the prior art that any product can exist in a number of polymorphic forms. The same also applies in case of tapentadol hydrochloride as is evident from the above mentioned references. A single molecule may give rise to a variety of crystalline or a mixture of amorphous and crystalline or amorphous form having distinct crystal structures and physical properties. A large number of factors can influence crystal nucleation and growth during this process, including the composition, the crystallization medium and the processes used to generate super saturation and promote crystallization. The most notable variables of composition and processing are solvent/solvent combinations, degree of super saturation, pH value, heating rate, cooling rate, drying conditions or any other specific reaction condition applied during process.
Nevertheless, there is continuing need of stable and pure polymorphic forms to meet challenges in the upcoming pharmaceutical market such as high purity of compound. Different crystalline forms behave differently in stability or during physical processing like milling and processing. Many process-induced solid-solid transitions of substances are known, that lead to either a crystalline form or an amorphous form of the substance. The solid-state experts are in constants search for new crystalline forms that can remain stable under different condition and withstand physical stress and still retain their original properties.
So, there is an urgent need to develop a process to obtain polymorphically pure tapentadol hydrochloride Form B in a consistent manner which is free from other polymorphs.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved process for the preparation of pure Form B of tapentadol hydrochloride.
Another object of the present invention is to provide a process which results in preparation of pure Form B of tapentadol hydrochloride consistently.
One another object of the present invention is to provide a process for the preparation of pure Form B of tapentadol hydrochloride, wherein Form B is free from other polymorphs.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for preparation of pure Form B of tapentadol hydrochloride of formula Ia,

Formula Ia

comprising the following steps:
a) providing a solution of tapentadol base in a suitable solvent,
b) cooling the resulting solution,
c) adding a suitable carboxylic acid other than lower aliphatic carboxylic acid to the cooled solution,
d) optionally seeding with Form B of tapentadol hydrochloride,
e) treating the reaction mixture with a source of hydrogen chloride, and
f) isolating pure Form B of tapentadol hydrochloride.
In another embodiment, the present invention provides a process for preparation of pure Form B of tapentadol hydrochloride comprises of:
a) combining tapentadol hydrochloride, a suitable solvent, a suitable carboxylic acid other than lower aliphatic carboxylic acid and tapentadol free base to obtain a suspension,
b) cooling the resulting mass,
c) adding a suitable source of hydrogen chloride to the suspension slowly,
d) stirring the reaction mass at a suitable temperature for sufficient time, and
e) isolating the resulting pure Form B of tapentadol hydrochloride.

BRIEF DESCRIPTION OF DRAWINGS
Figure-1: represents powder X-ray diffractogram of Form B of tapentadol hydrochloride.
Figure-2: represents DSC thermogram of tapentadol hydrochloride Form B.

DETAILED DESCRIPTION OF INVENTION
The present invention provide an improved process for preparation of Form B of pure tapentadol hydrochloride. According to one aspect, the present invention provides a process for the preparation of Form B of tapentadol hydrochloride by dissolving tapentadol base in a suitable solvent; adding a suitable carboxylic acid other than lower aliphatic carboxylic acid and cooling the resulting solution to -10ºC to 10ºC; seeding the reaction mixture with Form B of tapentadol hydrochloride before treating with a suitable source of hydrogen chloride.
A suitable carboxylic acid can be a long chain carboxylic acid, an aromatic acid, a di-carboxylic acid and the like. A long chain carboxylic acid includes but not limited to octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid and the like. An aromatic acid includes but not limited to benzoic acid, and substituted benzoic acid like salicylic acid, 3-hydroxy benzoic acid, toluic acid, cinnamic acid, hydroxycinnamic acid and the like. A di-carboxylic acid can be selected from aliphatic or aromatic and having a general formula (R)n-(COOH)2 and wherein R can be selected from -C6H4, –CH2, -CH2CHOH, -CH=CH, -CH=CH-CH2, -(CH2)8-CH=CH, CH=CH-CH=CH ; and n can be selected from 0 to 10. Preferably di-carboxylic acid includes but is not limited to saturated dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid; aromatic dicarboxylic acid such as phthalic acid, isophthalic acid, terephthalic acid; unsaturated dicarboxylic acid such as maleic acid, malic acid, fumaric acid, glutaconic acid, traumatic acid, muconic acid, of which saturated dicarboxylic acid are preferred. A suitable carboxylic acid can be added to reaction mixture before treating with source of hydrogen chloride but it is not critical to add before cooling or after cooling of reaction solution.
The suitable solvent which can be used in preparing Form B of tapentadol hydrochloride includes but is not limited to halogenated solvent such as dichloromethane, dichloroethane, chloroform chlorobenzene; hydrocarbon such as benzene, toluene, xylene; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, isopropyl ether, methyl-tert-butyl ether, diethylether, bis(2-methoxyethyl)ether; nitriles such as acetonitrile, propionitrile, benzonitrile, 2-methoxybenzonitrile; alcohols such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropylacetate, butyl acetate; and mixtures thereof.
Seeding a solution with a crystal of the product is a well-established method to induce crystallization. It has also been used to encourage the formation of particular polymorph consistently. Seeding can also be used to start the crystallization of single enantiomers from racemic mixtures. Seeding is preferably used to obtain crystals of high purity and especially very high perfection and with the desired orientation of consistent polymorph . It is advantageneous to make a slurry of seeding crystal because not only slurry avoids contamination of the environment due to dusting but also activates the surface by dissolution. It is suggested that the seed slurry be added in such a way that it is easily dispersed.
The source of hydrogen-chloride employed for the reaction can be aqueous, concentrated hydrochloric acid, gaseous hydrogen chloride, solvent purged with hydrogen chloride gas or hydrochloric acid in solution with a solvent. Solvent used for the generation of source of hydrochloric acid can be selected from esters, ethers and nitriles such as methyl acetate, ethyl acetate, propyl acetate, isopropylacetate, butyl acetate; isopropyl ether, methyl-tert-butyl ether, diethylether, bis(2-methoxyethyl)ether; acetonitrile, propionitrile, benzonitrile, 2-methoxybenzonitrile etc.
Generally hydrochloride salt formation is carried out at any suitable temperature for sufficient time to obtain desired polymorph. Particularly, the reaction mixture is stirred below 10 ºC, preferably at -10 to 10ºC for 5 minutes to 5 hours. It is advantageous to mix a source of hydrogen chloride slowly to the reaction mixture and reaction temperature is maintained at -10 to 0 ºC. Preferably reaction mixture is stirred for about 0.5-5 hours at temperature below 10°C. The solid compound can then be recovered, such as by filtration. Preferably, filtration is carried out at a temperature of -10 ºC to 20 ºC and more preferably at a temperature of -5ºC to 10ºC. Preferably, the isolated Form B of tapentadol hydrochloride is further died. Preferably, drying is carried out under vacuum at a temperature of about 35 to about 60ºC
The sequence of addition of the di-acid or seed crystal and its various permutations and combinations in the reaction conditions can be altered by people skilled in the art to obtained desired result.
In one another embodiment, the present invention provides a process for preparation of pure Form B of tapentadol hydrochloride by combining tapentadol hydrochloride, a suitable carboxylic acid, as defined above, a suitable solvent and tapentadol free base to obtain a suspension, cooling the reaction mass, and adding a source of hydrochloric acid slowly to the cooled suspension. The resulting suspension is stirred for a sufficient time at a suitable temperature and thereafter the reaction mixture is filtered and dried to obtain pure Form B of tapentadol hydrochloride. Addition of hydrogen chloride source may be carried out at -10 ºC to 10 ºC and tapentadol hydrochloride in an amount of at least 2% weight/weight from the obtained tapentadol hydrochloride and preferably present in an amount up to 20%. The suitable solvents used in the reaction are same as described earlier. After complete precipitation of the product, the resulting material is filtered and washed with a suitable solvent followed by drying to obtain pure Form B of tapentadol hydrochloride.
According to one another embodiment, the present invention provide a process for the preparation of Form B of tapentadol hydrochloride by dissolving tapentadol base in a suitable solvent in which tapentadol hydrochloride is also soluble; adding a suitable carboxylic acid, as defined above and cooling the resulting solution to -10 ºC to 10 ºC; treating the reaction mass with a suitable source of hydrogen chloride, removing the solvent from reaction mixture and adding a suitable anti-solvent to the cooled reaction mass and optionally seed of Form B of tapentadol hydrochloride is added, and stirred the reaction mixture for sufficient time to precipitate the desired product. A suitable solvent used in the reaction can be selected from alcohol such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol and anti solvent can be selected from hydrocarbon such as n-hexane, n-heptane, cyclohexane, toluene,; ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, isopropyl ether, methyl-tert-butyl ether, diethylether, bis(2-methoxyethyl)ether; nitriles such as acetonitrile, propionitrile, benzonitrile, 2-methoxybenzonitrile; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropylacetate, butyl acetate; or mixtures thereof.
Tapentadol base and seed of tapentadol hydrochloride used in any of the above processes can be prepared by using processes disclosed in literature.
The resulting pure Form B of tapentadol hydrochloride can be characterized by any suitable technique such as XRD, DSC, IR, Raman spectra etc. X-ray powder diffraction analysis of polymorphic form B was measured on a PAN analytical X’pert pro diffractometer with Cu Ka radiation. The X-ray powder diffractometer was equipped with a X’Celerator detector with a 2? range of 120 °C. Real time data were collected using Cu Ka radiation starting at approximately 4 °2? at a resolution of 0-0083556 °2?. The tube voltage and amperage were set to 45 kV and 40mA, respectively. The monochromator slit was set at 5 mm by 160 µm. The 2? pattern is displayed from 3-40°. Samples were mounted on sample holder and allowed to spin. Instrument calibration was performed using a silicon reference standard. The samples were analyzed for 10 minutes and expressed in terms of two-theta, d-spacings and relative intensities. One ordinarily skilled in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation or other factors, which can alter the two-theta values, d-spacings and relative intensities slightly. DSC analysis was performed using a TA instruments differential scanning calorimeter Mettler Toledo 823e. The sample was placed in an aluminum DSC pan and recorded the accurate weight. The pan was covered with a lid and then crimped. The sample cell was equilibrated at 50°C and heated under a nitrogen purge at a rate of 10°C/min up to 250°C. Indium metal was used as the calibration standard. The temperature reported was at the transition maxima.
Tapentadol hydrochloride Form B obtained by present invention is specifically characterized by XRD and DSC. Characteristic diffraction angles for Form B of tapentadol hydrochloride are represented below in Table 1:
Table 1

No. Pos.
[º2Th.] d-spacing
[Aº] Rel. Int.
[%]
1 10.0 8.84 2.3
2 12.4 7.09 4.5
3 14.6 6.06 100
4 14.9 5.92 11.6
5 15.4 5.73 21.8
6 15.7 5.61 35.0
7 16.0 5.52 10.2
8 16.7 5.27 22.3
9 17.9 4.92 85.3
10 19.6 4.52 48.7
11 20.2 4.39 36.6
12 21.0 4.22 25.9
13 21.4 4.14 25.5
14 22.0 4.03 91.7
15 23.7 3.75 7.9
16 24.7 3.60 67.9
17 25.1 3.54 27.6
18 25.8 3.44 35.5
19 26.3 3.38 18.5
20 27.7 3.21 33.0
21 28.1 3.16 57.2
22 29.1 3.05 22.6
23 29.9 2.98 21.2
24 31.1 2.86 24.4
25 32.4 2.75 7.9
26 33.1 2.69 9.3
27 33.8 2.64 12.9
28 34.3 2.61 8.9
29 35.8 2.50 10.4
30 36.3 2.47 10.0
31 39.0 2.30 11

The characteristic peaks of Form B of tapentadol hydrochloride at 2? + 0.1; 10.0, 12.4,14.6, 14.9, 15.4, 15.7, 16.0, 16.7, 17.9, 19.6, 20.2, 21.0, 21.4, 22.0, 23.7, 24.7, 25.1, 25.8, 26.3, 27.7, 28.1, 29.1, 29.9, 31.1, 32.4, 33.1, 33.8, 34.3, 35.8, 36.3, 39.0 are present, which clearly reflects that product is pure form B and is not contaminated with other polymorphs. Further, main differentiating characteristic peaks of Form A of tapentadol hydrochloride at 2?; 18.2, 18.9, 22.5, 27.3 are absent, which shows that Form A is absent. Tapentadol hydrochloride form B, thus prepared, is characterized by melting point and DSC. DSC thermogram shows an endothermic peak at 192.23°C.
Major advantage of the present invention is that process is very simple and provides pure Form B of tapentadol hydrochloride consistently and is industrially friendly.
Although, following examples illustrate practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention.

EXEMPLES :
Example 1: Preparation of Form B of tapentadol hydrochloride
To a solution of tapentadol free base (3.0g) in ethylacetate (45ml), oxalic acid dihydrate (170mg) was added and the reaction mass was stirred at 0 to -5 oC for 10 minutes. Ethyl acetate hydrochloride (3.80ml) was slowly added to the reaction mixture and the reaction mass was further stirred at 0 to -5 oC for 2 hours. The solid was filtered, washed with chilled ethyl acetate (15ml) and dried under vacuum at 40-50 ºC to afford pure form B of tapentadol hydrochloride.

Example 2: Preparation of Form B of tapentadol hydrochloride
To a solution of tapentadol free base (3.0g) in methanol (15 ml), oxalic acid dihydrate (170mg) was added and the reaction mass was stirred at 0 to -5oC for 10 minutes. Ethyl acetate hydrochloride (3.8 ml) was slowly added to the reaction mixture and the reaction mass was further stirred at 0 to -5 oC for 1 hour. The solvent was distilled off and to the resulting residue, ethyl acetate (45 ml), seed of tapentadol hydrochloride form B was added and stirred at 0 to -5oC for 2 hour till complete precipitation. The resulting solid was filtered, washed with chilled ethyl acetate (15ml) and dried under vacuum at 40-50 ºC to afford pure form B of tapentadol hydrochloride.

Example 3: Preparation of Form B of tapentadol hydrochloride
To a cooled solution of tapentadol free base (5.0g) in ethyl acetate (75ml), nonanoic acid (0.40 ml) and seed of tapentadol hydrochloride Form B, were added and the reaction mass was stirred at 0 to -5oC for 10 minutes. Ethyl acetate hydrochloride (6.25 ml) was slowly added to the reaction mixture and the reaction mass was further stirred at 0 to -5 oC for 1 hour. The resulting solid was filtered, washed with chilled ethyl acetate (5ml) and dried under vacuum at 40-50 ºC to afford pure form B of tapentadol hydrochloride.

Example 4: Preparation of Form B of tapentadol hydrochloride
To a cooled solution of tapentadol free base (5.0g) in ethyl acetate (75ml), decanoic acid (390mg) was added and the reaction mass was stirred at 0 to -5oC for 10 minutes. Ethyl acetate hydrochloride (6.25 ml) was slowly added to the reaction mixture and the reaction mass was further stirred at 0 to -5 oC for 1 hour. The resulting solid was filtered, washed with chilled ethyl acetate (5ml) and dried under vacuum at 40-50 ºC to afford pure form B of tapentadol hydrochloride. ,

CLAIMS:WE CLAIM:
1. A process for preparation of pure Form B of tapentadol hydrochloride of formula Ia,

Formula Ia

comprising the following steps:
a) providing a solution of tapentadol base in a suitable solvent,
b) cooling the resulting solution,
c) adding a suitable carboxylic acid other than lower aliphatic carboxylic acid to the cooled solution,
d) optionally seeding with Form B of tapentadol hydrochloride,
e) treating the reaction mixture with a source of hydrogen chloride, and
f) isolating pure Form B of tapentadol hydrochloride.
2. The process as claimed in claim 1, wherein in step a) suitable solvent is selected from ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, isopropyl ether, methyl-tert-butyl ether, diethylether, bis(2-methoxyethyl)ether; nitriles such as acetonitrile, propionitrile, benzonitrile, 2-methoxybenzonitrile; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropylacetate, butyl acetate; and mixtures thereof.
3. The process as claimed in claim 1, wherein in step c) a suitable carboxylic acid is selected from long chain carboxylic acid such as octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid; an aromatic acid; benzoic acid; salicylic acid, 3-hydroxy benzoic acid, toluic acid, cinnamic acid, hydroxycinnamic acid; a saturated dicarboxylic acid such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid; aromatic dicarboxylic acid such as phthalic acid, isophthalic acid, terephthalic acid; an unsaturated dicarboxylic acid such as maleic acid, malic acid, fumaric acid, glutaconic acid, traumatic acid and muconic acid.
4. The process as claimed in claim 1, wherein in step e) source of hydrogen-chloride employed for the reaction is aqueous, concentrated hydrochloric acid, gaseous hydrogen chloride, solvent purged with hydrogen chloride gas or hydrochloric acid in solution with a solvent; wherein solvent used for the generation of source of hydrochloric acid is selected from esters, ethers and nitriles such as methyl acetate, ethyl acetate, propyl acetate, isopropylacetate, butyl acetate; isopropyl ether, methyl-tert-butyl ether, diethylether, bis(2-methoxyethyl)ether; acetonitrile, propionitrile, benzonitrile, 2-methoxybenzonitrile.
5. A process for preparation of tapentadol hydrochloride Form B from tapentadol base by treating with a suitable source of hydrogen chloride in a suitable solvent in the presence of a suitable long chain carboxylic acid, an aromatic acid and a di-carboxylic acid.
6. A process for preparation of pure Form B of tapentadol hydrochloride comprises of:
a) combining tapentadol hydrochloride, a suitable solvent, a suitable carboxylic acid other than lower aliphatic carboxylic acid and tapentadol free base to obtain a suspension,
b) cooling the resulting mass,
c) adding a suitable source of hydrogen chloride to the suspension slowly,
d) stirring the reaction mass at a suitable temperature for sufficient time, and
e) isolating the resulting pure Form B of tapentadol hydrochloride.
7. The process as claimed in claim 6, wherein in step a) a suitable solvent is selected from ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, isopropyl ether, methyl-tert-butyl ether, diethylether, bis(2-methoxyethyl)ether; nitriles such as acetonitrile, propionitrile, benzonitrile, 2-methoxybenzonitrile; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropylacetate, butyl acetate; and mixtures thereof.
8. The process as claimed in claim 6, wherein in step a) a suitable carboxylic acid is selected from long chain carboxylic acid an aromatic acid; saturated dicarboxylic acid, aromatic dicarboxylic acid, unsaturated dicarboxylic acid.
9. The process as claimed in claim 6, wherein in step c) source of hydrogen-chloride employed for the reaction is aqueous, concentrated hydrochloric acid, gaseous hydrogen chloride, solvent purged with hydrogen chloride gas or hydrochloric acid in solution with a solvent; wherein solvent used for the generation of source of hydrochloric acid is selected from esters, ethers and nitriles; wherein in step d) the resulting mass is stirred at a temperature of -10 to 10ºC for 5 minutes to 5 hours.
10. A process for preparation of tapentadol hydrochloride Form B by treating tapentadol base with a suitable source of hydrogen chloride in a suitable solvent in the presence a suitable carboxylic acid other than lower aliphatic carboxylic acid, an aromatic acid, a di-carboxylic acid and tapentadol hydrochloride.
Dated this day 10th of September, 2013

(Dr. Asha Aggarwal)
Head-IPM Department
Ind-Swift laboratories Limited