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

IMPROVED PROCESS FOR PREPARING
PURE TAPENTADOL HYDROCHLORIDE FORM B

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

The following application describes the nature of this invention
FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for preparing pure tapentadol hydrochloride Form B 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 attractive options for industrial purposes.

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 herein referred as US ‘347 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 preparation 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. The difference in the polymorphic nature of a particular compound may depend on solvent used in synthesis or purification, drying conditions or any other specific reaction condition applied during process. 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. Nevertheless, there is continuing need of new improved process which can provide polymorphic forms consistently to meet challenges in the upcoming pharmaceutical market such as high purity of compound.

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 tapentadol hydrochloride form B.

Another object of the present invention is to provide a process which results in preparation of pure tapentadol hydrochloride form B consistently.

One another object of the present invention is to provide a process for the preparation of pure tapentadol hydrochloride form B, wherein Form B is free from other polymorphs.

Yet another object of the present invention is to provide a process for the preparation of pure tapentadol hydrochloride form B, wherein Form B is free from other polymorphs, result consistently in pure form B and is capable of being implemented on industrial scale.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for preparation of tapentadol hydrochloride Form B comprising the steps of:,
a) dissolving tapentadol base in a suitable solvent,
b) adding a suitable additive to the reaction mass,
c) cooling the resulting mass,
d) optionally seeding the reaction mass with tapentadol hydrochloride Form B,
e) treating the cooled reaction mass with a suitable hydrogen-chloride source,
f) isolating the resulting tapentadol hydrochloride Form B.

In another embodiment, the present invention provides a process for preparation of pure tapentadol hydrochloride Form B comprises of:
a) combining tapentadol hydrochloride, a suitable solvent, an additive 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 tapentadol hydrochloride Form B.

BRIEF DESCRIPTION OF DRAWINGS
Figure-1: Illustrates representative powder X-ray diffractogram of tapentadol hydrochloride Form B.

DETAILED DESCRIPTION OF INVENTION
The present invention provide an improved process for preparation of pure tapentadol hydrochloride Form B. 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 additive and cooling the resulting solution to -10 ºC to 10 ºC; seeding the reaction mixture with Form B of tapentadol hydrochloride before treating with a suitable source of hydrogen chloride.
In the present invention, a suitable additive can be slected from carbonates, bicarbonates and oxalates. The suitable carbonates includes but not limited to alkali or alkaline-earth metal carbonate, ammonium carbonate, dialkyl carbonate and the like. Particularly metal carbonate can be selected from sodium carbonate, potassium carbonate, lithium carbonate, magnesium carbonate, calcium carbonate, barium carbonate and alike. The suitable bicarbonate can be selected from but are not limited to alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and alike; alkaline-earth metal bicarbonate such as magnesium bicarbonate, calcium bicarbonate and the like;. The suitable oxalate includes but are not limited to alkali and alkaline-earth metal oxalate, dialkyl oxalate and the like. Preferably oxalate can be selected from sodium oxalate, calcium oxalate; dimethyl oxalate, diethyl oxalate and the like.
In the present invention, a suitable additive can be added before addition of hydrogen -chloride source and it is not critical whether additive is added before cooling or after cooling. It is preferred to use additives to obtain a specific polymorphic form consistently. An additive inhibit the growth of an unwanted polymorphic form by interfering with the nucleation or growth rates of a unwanted polymorphic form. An additive is chosen by its ability to mimic specific motifs of the molecular assemblies of the desired host polymorph while disrupting the growth of the other unwanted polymorphs. For this technique to be effective, the additive has to inhibit, at least, the fastest growing face of the crystals of the unwanted polymorph without affecting the fastest growing faces of the crystal of the desired polymorphic form.
The suitable solvent which can be used in preparing form B includes but is not limited to halogenated solvents such dichloromethane, dichloroethane, chloroform chlorobenzene; hydrocarbons 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 and/or a mixture of said solvent with a little amount of water.

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 consisting polymorph. It is advantageneous to make a slurry of seeding crystal because not only slurry avoids contamination of the environment due to dusting, but it 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 sequence of addition of the suitable additive or seed crystal and its various permutations and combinations in the reaction conditions can be altered by people skilled in the art to obtain desired result.
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 add source of hydrogen chloride slowly to the reaction mixture and reaction temperature is maintained at -10 to 0 ºC; filtering the solid product and washing the wet product with suitable chilled solvent and then drying the resulting compound to get Form B of tapentadol hydrochloride.
According to another 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 additive and cooling the resulting solution to -10 ºC to 10 ºC; and treating the reaction mass with a suitable source of hydrogen chloride.
In one another aspect, the present invention provides a process for preparation of pure tapentadol hydrochloride Form B by combining tapentadol hydrochloride, a suitable additive, 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.
According to one another aspect, 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 additive 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 optional seed of Form B of tapentadol hydrochloride is added, stirred the reaction mixture for sufficient time to precipitate the desired product. Thereafter, the reaction mixture is filtered and dried to obtain pure Form B of tapentadol hydrochloride.
The resulting pure tapentadol hydrochloride Form B can be characterized by any suitable technique such as XRD, DSC, IR, Raman spectra etc. X-ray powder diffraction analysis of polymorphic form I was measured on a PAN analytical X’pert pro diffractometer with Cu Kα radiation. The X-ray powder diffractometer was equipped with a X’Celerator detector with a 2θ range of 120 ˚C. Real time data were collected using Cu Kα radiation starting at approximately 4 ˚2θ at a resolution of 0-0083556 ˚2θ. 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 2θ 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.
Tapentadol hydrochloride Form B obtained by the present invention is specifically characterized by XRD and melting point. 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 12.4 7.09 5
2 14.6 6.06 100
3 14.9 5.92 11
4 15.4 5.74 21
5 15.7 5.62 38
6 16.0 5.53 11
7 16.7 5.28 24
8 18.0 4.92 88
9 19.5 4.52 49
10 20.1 4.39 38
11 20.9 4.23 27
12 21.4 4.14 28
13 21.9 4.04 96
14 23.6 3.75 7
15 24.7 3.60 73
16 25.0 3.54 30
17 25.7 3.46 73
18 26.3 3.38 16.
19 26.7 3.33 9
20 27.7 3.21 36
21 28.2 3.16 52
22 29.1 3.06 22
23 29.8 2.99 21
24 31.1 2.87 25
25 32.4 2.76 8
26 33.1 2.70 9
27 33.8 2.64 13
28 34.3 2.61 9
29 35.8 2.50 10
30 36.2 2.47 11
31 39.0 2.30 9

The characteristic peaks of Form B of tapentadol hydrochloride at 2θ + 0.1; 12.4, 14.6, 14.9, 15.4, 15.7, 16.0, 16.7, 18.0, 19.5, 20.1, 20.9, 21.4, 21.9, 23.6, 24.7, 25.0, 25.7, 26.3, 26.7, 27.7, 28.2, 29.1, 29.8, 31.1, 32.4, 33.1, 33.8, 34.3, 35.8, 36.2, 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 2θ; 18.9, 22.5, 27.3 are absent, which shows that Form A is absent. Tapentadol hydrochloride form B, prepared is characterized by melting point in the range 180-195 ºC.
Major advantages 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 pure tapentadol hydrochloride Form B
To a solution of tapentadol free base (3.0g) in ethyl acetate (45ml) at 0 to -5 ºC . Sodium carbonate (140mg) was added and the reaction mass was stirred for 10 minutes. Ethylacetate-hydrochloride (3.80ml) was slowly added to the reaction mixture and the reaction mass was further stirred at 0 to -5oC for 1 hour. The resulting solid was filtered, washed with chilled ethyl acetate (10ml) and dried under vacuum at 45 ºC to afford title compound.
Example 2: Preparation of pure tapentadol hydrochloride Form B
Tapentadol free base (4.0g) was dissolved in acetonitrile (80ml) and sodium carbonate (186mg) was added. The reaction mass was cooled to -5 oC and acetonitrile-hydrochloride (5.1ml) was added slowly. The reaction mass was stirred at 0 to -5 oC for 1 hour. The resulting solid was filtered, washed with chilled acetonitrile (15ml) and dried under vacuum at 40-50 ºC to afford title compound.
Having described the invention with reference to certain preferred aspects, other aspects will become apparent to one skilled in the art from consideration of the specification. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
Dated this day 09th of September, 2013

Ind-Swift Laboratories Limited No. of Sheets 1
Application no. Sheet No. 1 of 1

Figure 1