Field of Invention

The present invention relates to a stable and pure crystalline form-B of 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol mono hydrochloride and its process for preparation. The present invention also provides highly pure 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol mono hydrochloride represented by structural formula-la by converting it into free base 3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol represented by structural formula-1, followed by converting back to pure hydrochloride salt compound of formula-1a.

3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride (commonly known as Tapentadol hydrochloride) is developed by Grunenthal in conjunction with Johnson & Johnson Pharmaceutical Research and development and is marketed under the trade names Nucynta, Palexia, Zyntap. It is a centrally acting analgesic with dual mode of action as an agonist of μ-opioid receptor and norepinephrine reuptake inhibitor.

Background of the Invention:

3-[(lR,2R)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol hydrochloride and its process for the preparation was first disclosed in US RE39593 and the process involves the demethylation of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine hydrochloroide using hydrobromic acid to provide 3-[(li?,2i?)-3-(dimethylamino)-l-ethyl-2-methylpropyl] phenol as a residue. The obtained residue was dissolved in 2-butanone followed by adding trimethylchloro silane and water provides Tapentadol hydrochloride salt.

The main disadvantage of the above said process is the usage of trimethyl chlorosilane in preparation of hydrochloride salt of Tapentadol, which is hazardous and highly flammable, hence is not advisable to use in the industrial scale.

The crystalline form of Tapentadol hydrochloride obtained by the process disclosed in US RE39593 was later characterized as crystalline form-B in US2009186947.

All the prior art processes for the preparation of Tapentadol hydrochloride involves the usage of ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid in various solvents. All the processes leading to the formation of crystalline form-A, mixture of crystalline form-A and form-B and unstable crystalline form-B of Tapentadol hydrochloride. Hence there is a need in the art to develop a stable crystalline form-B of Tapentadol hydrochloride.

The crystalline modification-B of Tapentadol free base was first disclosed in US8134032. However as on date, there is no alternative processes were reported in the prior art for preparing the said crystalline modification-B of Tapentadol free base. Henceforth, there is a need to develop a novel process for the preparation of said crystalline polymorph.

Summary of the Invention:

The main aspect of the present invention is to provide pure and stable crystalline form-B of Tapentadol hydrochloride compound of formula-la and its process for the preparation.
The first aspect of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la in the presence of lower aliphatic carboxylic acid, comprising the following steps of:

a) Adding a suitable solvent to Tapentadol free base compound of formula-1,
b) cooling the reaction mixture,
c) adding lower aliphatic carboxylic acid to the reaction mixture,
d) adding hydrochloric acid source to the reaction mixture,
e) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-la.

The second aspect of the present invention is to provide another process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la in the presence of alkyl formate, comprising the following steps of:

a) Adding alkyl formate to Tapentadol free base compound of formula-1 in the presence or absence of a suitable solvent,
b) cooling the reaction mixture,
c) adding hydrochloric acid source to the reaction mixture,
d) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-la.

The third aspect of the present invention is to provide a process for the preparation of pure Tapentadol hydrochloride compound of formula-la, comprising the following steps of:

a) Treating the Tapentadol hydrochloride compound of formula-la with a suitable base in a suitable solvent to provide Tapentadol free base compound of formula-1,
b) isolating the compound with a suitable solvent,
c) converting the compound obtained in step-b) into its hydrochloride salt compound of formula-la from the above aspects of the present invention.

The fourth aspect of the present invention is to provide one process for the preparation of pure Tapentadol hydrochloride compound of formula-la, comprising the following steps of:

a) Reacting (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-2 with hydrobromic acid, followed by treating with a suitable base to provide Tapentadol free base compound of formula-1,
b) converting the obtained compound in step-a) into its hydrochloride salt compound of formula-la from the above aspects of the present invention.

The fifth aspect of the present invention is to provide a novel process for the preparation of crystalline modification-B of Tapentadol free base compound of formula-1, comprising the following steps of:

a) Adding cyclohexane to Tapentadol free base compound of formula-1 at 35-40°C,
b) cooling the reaction mixture to 25-30°C and stirring the reaction mixture,
c) cooling the reaction mixture to 10-15°C and stirring the reaction mixture,
d) filtering the solid and then dried to get crystalline modification-B of compound of formula-1.

Advantages of the present invention:

• Provides stable crystalline form-B of Tapentadol hydrochloride compound of formula-la.
• Provides simple process for the preparation of crystalline form-B of Tapentadol hydrochloride compound of formula-la.
• Avoids the usage of trimethylchlorosilane, which is hazardous and highly flammable.
• Provides novel process for the preparation of crystalline modification-B of Tapentadol free base compound of formula-1.

Brief description of the Figures:

Figure-1: Illustrates the powder X-ray diffractogram of Tapentadol hydrochloride compound of formula-la.

Figure-2: Illustrates the powder X-ray diffractogram of Tapentadol free base compound of formula-1.

Detailed description of the Invention:

As used herein the present invention, the term "suitable solvent" wherever necessary, is selected from "ester solvents" like methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, tertiary butyl acetate and the like; "hydrocarbon solvents" like toluene, n-pentane, hexane, heptane, petroleum ether, cyclohexane and the like; "ketone solvents" like acetone, propanone, methyl isobutyl ketone, 2-butanone and the like; "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, tert-butanol diglycol, isobutanol and the like; "chloro solvents" like dichloromethane, chloroform, carbon tetrachloride, dichloroethane and the like; and "polar solvents" like water; and also mixtures thereof.

The term "suitable base" used herein the present invention is selected from inorganic bases like alkali metal, and alkaline earth metal alkoxides, hydroxides, carbonates and bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium tert-

butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; and ammonia.

The term "hydrochloric acid source" used herein the present invention is selected from hydrochloric acid gas, ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid, diisopropyl ether-hydrochloric acid, diethylether-hydrochloric acid.

The "lower aliphatic acid" used herein the present invention is selected from formic acid, acetic acid, propanoic acid and the like.

The "alkyl formate" used herein the present invention is selected from methyl formate, ethyl formate and isopropyl formate.

The present inventors conducted various experiments on recrystallization Tapentadol hydrochloride compound of formula-la from various solvents as mentioned below:

Based on the above table, all the experiments are leading to the formation of crystalline form-A, a mixture crystalline form-A and form-B and in some experiments the product is not isolated.

The present inventors also conducted various experiments on preparation of Tapentadol hydrochloride compound of formula-la from Tapentadol free base compound of formula-1, by salt formation technique using hydrochloric acid source in various solvents as mentioned below:

All the above experiments leading to the formation of crystalline form-A, mixture of crystalline form-A and form-B and unstable crystalline form-B of compound of formula-la (i.e., converting into stable crystalline form-A during storage).

Hence there is a need in the art to develop a stable crystalline form-B of 3-[(li?,2i?)-3-(dimethylamino)-l-ethyl-2-methylpropyl]phenol mono hydrochloride compound of formula-la.
The first aspect of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la in the presence of lower aliphatic carboxylic acid, comprising the following steps of:

a) Adding a suitable solvent to Tapentadol free base compound of formula-1,
b) cooling the reaction mixture,
c) adding lower aliphatic carboxylic acid to the reaction mixture,
d) adding hydrochloric acid source to the reaction mixture,
e) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-la.

Wherein, the lower aliphatic carboxylic acid is selected from formic acid and acetic acid; hydrochloric acid source is selected from hydrochloric acid gas, ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid, diisopropyl ether-hydrochloric acid and diethylether-hydrochloric acid; and the suitable solvent is selected from ester solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and tertiary butyl acetate.

In a preferred embodiment of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la in the presence of formic acid, comprising the following steps of:

a) Adding ethyl acetate to Tapentadol free base compound of formula-1,
b) cooling the reaction mixture,
c) adding formic acid to the reaction mixture,
d) adding ethyl acetate-hydrochloric acid to the reaction mixture,
e) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-la.

In a preferred embodiment of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la in the presence of acetic acid, comprising the following steps of:

a) Adding ethyl acetate to Tapentadol free base compound of formula-1,
b) cooling the reaction mixture,
c) adding acetic acid to the reaction mixture,
d) adding ethyl acetate-hydrochloric acid to the reaction mixture,
e) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-la.

The second aspect of the present invention is to provide another process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la in the presence of alkyl formate, comprising the following steps of:

a) Adding alkyl formate to Tapentadol free base compound of formula-1 in the presence or absence of a suitable solvent,
b) cooling the reaction mixture,
c) adding hydrochloric acid source to the reaction mixture,
d) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-la.

Wherein, the suitable hydrochloric acid source is same as defined above; alkyl formate is selected from methyl formate, ethyl formate and isopropyl formate; and the suitable solvent is selected from ester solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and tertiary butyl acetate.

In a preferred embodiment of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la, comprising the following steps of:

a) Adding ethyl formate to Tapentadol free base compound of formula-1,
b) cooling the reaction mixture,
c) adding ethyl acetate -hydrochloric acid to the reaction mixture,
d) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-la.

In another preferred embodiment of the present invention is to provide a process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la, comprising the following steps of:

a) Adding ethyl formate to Tapentadol free base compound of formula-1 in ethyl acetate,
b) cooling the reaction mixture,
c) adding ethyl acetate -hydrochloric acid to the reaction mixture,
d) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-la.

The third aspect of the present invention is to provide a process for the preparation of pure Tapentadol hydrochloride compound of formula-la, comprising the following steps of:

a) Treating the Tapentadol hydrochloride compound of formula-la with a suitable base in a suitable solvent to provide Tapentadol free base compound of formula-1,
b) isolating the compound with a suitable solvent,
c) converting the compound obtained in step-b) to its hydrochloride salt compound of formula-la from the above aspects of the present invention.

Wherein, the suitable base is selected from inorganic bases like alkali metal, and alkaline earth metal alkoxides, hydroxides, carbonates and bicarbonates; the suitable solvent used in step-a) is selected from ester solvents, polar solvent and mixture thereof; and in step-b) is selected from hydrocarbon solvents.

In a preferred embodiment of the present invention is to provide pure Tapentadol hydrochloride compound of formula-la, comprising the following steps of:

a) Treating the Tapentadol hydrochloride compound of formula-la with sodium carbonate in aqueous ethyl acetate to provide Tapentadol free base compound of formula-1,
b) isolating the compound with cyclohexane,
c) converting the compound obtained in step-b) to its hydrochloride salt compound of formula-la from the above aspects of the present invention.

Tapentadol hydrochloride obtained by the prior art process such as USRE39593 does not able to meet the desired ICH purity. Whereas in the present invention, when converting the Tapentadol hydrochloride into Tapentadol free base and isolating the compound with a suitable solvent like cyclohexane and then converting it into its hydrochloride salt results in the formation of highly pure Tapentadol hydrochloride compound of formula-la.

The fourth aspect of the present invention is to provide one pot process for the preparation of pure Tapentadol hydrochloride compound of formula-la, comprising the following steps of:

a) Reacting (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-2 with hydrobromic acid, followed by treating with a suitable base to provide Tapentadol free base compound of formula-1,
b) converting the obtained compound in step-a) into its hydrochloride salt compound of formula-la from the above aspects of the present invention.

Wherein, in step-a) the suitable base is selected from inorganic bases, in step-b) the suitable solvent is hydrocarbon solvent.

The fifth aspect of the present invention is to provide a novel process for the preparation of crystalline modification B of Tapentadol free base compound of formula-1, comprising the following steps of:

a) Adding cyclohexane to Tapentadol free base compound of formula-1 at 35-40°C,
b) cooling the reaction mixture to 25-30°C and stirring the reaction mixture,
c) cooling the reaction mixture to 10-15 °C and stirring the reaction mixture,
d) filtering the solid and then dried to get crystalline modification-B of compound of formula-1.
(2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-2 of the present invention can be prepared by the known methods.

Stable crystalline form-B of Tapentadol hydrochloride compound of formula-la of the present invention indicates that the crystalline form-B never converts into crystalline form-A as like crystalline form-B obtained as per the prior known methods.

The crystalline form-B of compound of formula-la obtained by the present invention is stable during storage for a longer period of time.

Tapentadol hydrochloride compound of formula-la and Tapentadol Free base compound of formula-1 obtained by the present invention was analyzed by HPLC under the following conditions:

Apparatus: A liquid chromatograph equipped with variable wavelength UV detector; Column: Symmetry C18, 250 x 4.6mm, 5μm or equivalent; Flow rate: 1.0 ml/min; Wavelength: 220 ran;

Column temperature: 45°C; Injection volume: 5 μL; Run time: 55 min; Diluent: acetonitrile:methanol (50:50)v/v; Mobile phase-A: Buffer; Mobile phase-B: Buffer: Acetonitrile:methanol (30:20:50)v/v.

The present invention is schematically represented as follows:

The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of Tapentadol free base (Formula-1) from Tapentadol hydrochloride

A mixture of Tapentadol hydrochloride compound of formula-la (1000 g), ethyl acetate (6000 ml) and water (4000 ml) was cooled to 0-5°C. Basify the reaction mixture with a solution of sodium carbonate (453 g) and water (4500 ml) at 0-5°C. The temperature of the reaction mixture was raised to 20-25°C and then both organic and aqueous layers were separated. The organic layer was dried with sodium sulfate and then distilled off the solvent completely under reduced pressure to obtain a residue. The obtained residue was cooled to 35-40°C and cyclohexane (1000 ml) was added to the residue and stirred for 2 hours at 25-3 0°C. The reaction mixture was cooled to 10-15°C and stirred for 60 minutes. Filtered the solid and then dried to get title compound.
Yield: 802 g; MR: 88-90°C; purity by HPLC: 99.98%. Purity of Input material: 99.78%; impurity at 0.5 RRT: 0.13%

PXRD of the obtained compound was matched with crystalline modification B of Tapentadol free base of US8134032.

Example-2: Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-la) in the presence of ethyl formate

A solution of ethyl acetate - hydrochloric acid was cooled to 0-5°C and drop wise added to a pre-cooled solution of Tapentadol free base compound of formula-1 (100 g), ethyl formate (500 ml) and ethyl acetate (500 ml) at -5 to 0°C under nitrogen atmosphere. Filtered the precipitated product and then dried to get title compound. Yield: 108 g; MR: 156-176°C.
Purity by HPLC: 99.93%, Impurity at 0.19 RRT: 0.06%

Example-3: Process for the preparation of Tapentadol hydrochloride (Formula-la)

Step-A) Preparation of Tapentadol Free base (Formula-1)

A mixture of (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of formula-2 (25 g) and 47 % hydrobromic acid (100 ml) was heated to 115-120°C and stirred for 6 hours. After completion of the reaction, the reaction mixture was cooled to 40-50°C and water was added to it. The reaction mixture was further cooled to 0-5°C and basified the reaction mixture with ammonia solution. The temperature of the reaction mixture was raised to 25-30°C and ethyl acetate was added to the reaction mixture. Both the organic and aqueous layers were separated; the organic layer was dried with sodium sulphate and then distilled off the solvent to get semi solid type of residue of Tapentadol free base compound of formula-1. Purity by HPLC: 99.74%; impurity at 1.77 RRT: 0.12%. Yield: 17.5 g

Step-B) Preparation of Tapentadol Hydrochloride (Formula-la)

To the compound obtained in step-a) ethyl formate (100 ml) and ethyl acetate (100 ml) were added under nitrogen atmosphere and the reaction mixture was cooled to -5 to 0°C. A pre-cooled solution of ethyl acetate-hydrochloric acid (83 ml) was added to the reaction mixture. The precipitated product was isolated and then dried to get Tapentadol hydrochloride compound of formula-la. Purity by HPLC: 99.75%; Impurity at 1.77 RRT: 0.09%

Example-4: Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-la) in the presence of formic acid.

To a clean and dry round bottomed flask Tapentadol free base compound of formula-1 (20 g) was added followed by ethyl acetate (300 ml) and cooled to -5 to 5°C. Formic acid (0.34 ml) was added to the reaction mixture at the same temperature and stirred for 10 minutes. Ethyl acetate-hydrochloric acid (38.1 ml) with assay of 7-8% was added to the reaction mixture for about 2 hours at the same temperature. Filtered the precipitated product and then dried to get title compound. Yield: 21.2 g; MR: 189-194°C; Purity by HPLC: 99.99%; formic acid content: 3.0%; chloride content: 10.9%.

PXRD of the obtained compound was matched with the crystalline form-B of Tapentadol hydrochloride.

Example-5: Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-la) in the presence of acetic acid.

To a clean and dry round bottomed flask Tapentadol free base compound of formula-1 (20 g) was added followed by ethyl acetate (300 ml) and cooled to -5 to 5°C. Acetic acid (0.5 ml) was added to the reaction mixture at the same temperature and stirred for 10 minutes. Ethyl acetate-hydrochloric acid (38.1 ml) with assay of 7-8% was added to the reaction mixture for about 2 hours at the same temperature. Filtered the precipitated product and then dried to get title compound. Yield: 20.0 g; MR: 195.8-201.2°C; Purity by HPLC: 99.97%; chloride content: 12.9%.

PXRD of the obtained compound was matched with the crystalline form-B of Tapentadol hydrochloride.

Example-6: Preparation of stable crystalline form-B of Tapentadol hydrochloride (Formula-la) in the presence of ethyl formate

To a clean and dry round bottomed flask Tapentadol free base compound of formula-1 (350 g) was added followed by ethyl formate (3500 ml) and cooled to -5 to 5°C. Ethyl acetate-hydrochloric acid (38.1 ml) with 13% assay was added to the reaction mixture for about 2 hours at the same temperature. Filtered the precipitated product and then dried to get title compound. Yield: 360 g; MR: 166-179°C; Purity by HPLC: 99.98%.

PXRD of the obtained compound was matched with crystalline form-B of Tapentadol hydrochloride.

We claim:

1. A process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la from Tapentadol free base compound of formula-1 by treating with a suitable hydrochloric acid source in a suitable solvent in the presence of lower aliphatic carboxylic acids.

2. A process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la from Tapentadol free base compound of formula-1 by treating with a suitable hydrochloric acid source in a suitable solvent in the presence of alkyl formate and in presence or absence of a suitable solvent.

3. A process according to claim 1 and claim 2, wherein, a suitable hydrochloric acid source is selected from hydrochloric acid gas, ethyl acetate-hydrochloric acid, isopropanol-hydrochloric acid, diisopropyl ether-hydrochloric acid and diethylether-hydrochloric acid; the suitable solvent is selected from ester solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate and tertiary butyl acetate; the lower aliphatic acid is selected from acetic acid, formic acid and propanoic acid; and alkyl formate is selected from methyl formate and ethyl fomrate.

4. The process according to claim 1 and claim 3, wherein, the process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la in the presence of formic acid, comprising the following steps of:

a) Adding ethyl acetate to Tapentadol free base compound of formula-1,
b) cooling the reaction mixture,
c) adding formic acid to the reaction mixture,
d) adding ethyl acetate-hydrochloric acid to the reaction mixture,
e) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-1a.

5. The process according to claim 1 and claim 3, wherein, the process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la in the presence of acetic acid, comprising the following steps of:

a) Adding ethyl acetate to Tapentadol free base compound of formula-1,
b) cooling the reaction mixture,
c) adding acetic acid to the reaction mixture,
d) adding ethyl acetate-hydrochloric acid to the reaction mixture,
e) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-la.

6. The process according to claim 2 and claim 3, wherein, the process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la in the presence of ethyl formate, comprising the following steps of:

a) Adding ethyl formate to Tapentadol free base compound of formula-1,
b) cooling the reaction mixture,
c) adding ethyl acetate-hydrochloric acid to the reaction mixture,
d) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-1a.

7. The process according to claim 2 and claim 3, wherein, the process for the preparation of stable crystalline form-B of Tapentadol hydrochloride compound of formula-la, comprising the following steps of:

a) Adding ethyl formate to Tapentadol free base compound of formula-1 in ethyl acetate,
b) cooling the reaction mixture,
c) adding ethyl acetate-hydrochloric acid to the reaction mixture,
d) filtering the precipitated product and then dried to get crystalline form-B of compound of formula-la.

8. A process for the preparation of pure Tapentadol hydrochloride compound of formula-la,
comprising the following steps of:

a) Treating the Tapentadol hydrochloride compound of formula-1a with a suitable base
in a suitable solvent to provide Tapentadol free base compound of formula-1,
b) isolating the compound with a suitable solvent,
c) converting the compound obtained in step-b) to its hydrochloride salt compound of formula-la.

9. One pot process for the preparation of pure Tapentadol hydrochloride compound of
formula-la, comprising the following steps of:

a) Reacting (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-l-amine compound of
formula-2

Formula-2 with hydrobromic acid, followed by treating with a suitable base to provide Tapentadol free base compound of formula-1,

b) converting the compound obtained in step-a) into its hydrochloride salt compound of
formula-la.

10. A process for the preparation of crystalline modification-B of Tapentadol free base compound of formula-1, comprising the following steps of:

a) Adding cyclohexane to Tapentadol free base compound of formula-1 at 35-40°C,
b) cooling the reaction mixture to 25-30°C and stirring the reaction mixture,
c) cooling the reaction mixture to 10-15°C and stirring the reaction mixture,
d) filtering the solid and then dried to get crystalline modification-B of compound of formula-1.