DESC:FORM 2
THE PATENT ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)

“PROCESS FOR THE PREPARATION OF BUPROPION HYDROBROMIDE FORM-II”

HIKAL LIMITED,
AN INDIAN COMPANY OF 3A & 3B, INTERNATIONAL BIOTECH PARK, HINJEWADI,
PUNE – 411057, MAHARASHTRA, INDIA

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 the preparation of bupropion hydrobromide form -II by treating bupropion hydrobromide in an aqueous alcoholic solvent.

BACKGROUND OF THE INVENTION
Bupropion is chemically known as (±)-2-(tert-butylamino)-3'-chloropropiophenone and structurally represented as below:

Bupropion is an antidepressant, which is approved as hydrochloride salt and hydrobromide salt, and marketed under the brand name Wellbutrin® and Aplenzin® respectively.

The US Patent 3,819,706 A disclosed bupropion or its acid addition salts, and process for preparation thereof.
The US patent 7,553,992 B2 disclosed crystalline polymorphic forms I, II, and III of bupropion hydrobromide and process for its preparation.
US patent 8,349,900 B2 disclosed polymorphic forms IV, V, VI, VII, and amorphous form of bupropion hydrobromide and process for its preparation. The patent also disclosed the preparation of bupropion hydrobromide form - II using form-I in an excess volume of solvent under stirring at room temperature to 50°C for 7 days in a slurry technique. The patent further disclosed that the bupropion hydrobromide form - I is metastable form and form - II is the thermodynamically stable form.

It is well known that different crystalline forms of active pharmaceutical ingredient can display different characteristics of solubility and hence bioavailability, and thus permit more appropriate use of the same according to whether one requires slow release (in that case using a less-soluble polymorphic form) or quicker availability (using a more-soluble polymorphic form). Accordingly, it is useful to have different polymorphic forms, with different chemical and physical properties, at one's disposal.

The prior art(s) disclosed the preparation of form-II of bupropion hydrobromide which involves the recrystallization of form-I using various solvents selected from acetone-water, methanol, dichloromethane, toluene-methanol, and dimethyl carbonate-methanol.

Although, several processes have been reported for the preparation of bupropion hydrobromide form - II they suffer from one or more drawbacks such as i) use of multiple solvents; ii) use of high volume of solvent; & iii) longer cycle time; thus, the process does not render economical.

To overcome the limitation of prior art processes, the inventors of the present invention have developed a recrystallisation technique with an aqueous alcoholic solvent having moisture content 2% to 5%. The inventors developed a unique volume ratio 1:6 to 1:7 of bupropion hydrobromide and aqueous alcoholic solvent for the preparation of crystalline bupropion hydrobromide form-II.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of bupropion hydrobromide form - II comprising the steps of:
a) adding bupropion hydrobromide to aqueous alcoholic solvent, having moisture content 2% to 5%,
b) heating to obtain clear solution,
c) cooling,
d) adding seed crystals of bupropion hydrobromide form - II,
e) isolating bupropion hydrobromide form - II.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an X-ray powder diffractogram of the bupropion hydrobromide form - II prepared as per Example 1.
FIG. 2 shows an X-ray powder diffractogram of the bupropion hydrobromide form - I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described in more detail hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a,” “an,” “the,” include plural referents unless the context clearly indicates otherwise.

The term solvent used herein refers to the single solvent or mixture of solvents.

The bupropion hydrobromide used for the preparation of form - II is either form - I, mixture of form - I and form - II or any other form or mixtures thereof.

In an embodiment, the present invention relates to a process for the preparation of bupropion hydrobromide form - II comprising the steps of:
a) adding bupropion hydrobromide to aqueous alcoholic solvent, wherein moisture content of solvent is 2% to 5%,
b) heating to obtain clear solution,
c) cooling,
d) adding seed crystals of bupropion hydrobromide form - II,
e) isolating bupropion hydrobromide form - II.
In an embodiment of the present invention, aqueous alcoholic solvent is prepared by adding water to alcoholic solvent, wherein moisture content of solvent is 2% to 5%.

In another embodiment of the present invention, alcoholic solvent is selected from methanol, ethanol, isopropanol, isobutanol, n-butanol and the like, more preferably isopropanol.

In another embodiment of the present invention, wherein water used in process is industrial water, distilled water, or demineralized water (DM water).

In another embodiment of present invention, wherein volume ratio of bupropion hydrobromide to aqueous alcoholic solvent is 1:6 to 1:7.

In another embodiment of the present invention, addition of bupropion hydrobromide is performed at room temperature and heating is performed 80°C to 90°C to obtain clear solution.

In another embodiment of the present invention, wherein the clear solution of step (b) is cooled at 60°C to 70°C.

In another embodiment of the present invention, wherein seeding is performed using seed crystals of bupropion hydrobromide form - II at 60° to 70°C.

In another embodiment of the present invention, wherein the isolation is performed by sequential steps which involve cooling at 25°C to 35°C, maintaining at same temperature for 20 to 22 hours, further cooling at 0°C to 5°C for 1 to 2 hours and then filtering to obtain bupropion hydrobromide form - II.

In an embodiment, the bupropion hydrobromide form - II obtained by the process of the present invention has X-ray powder diffractogram as depicted in FIG. 1.

In another embodiment of the present invention, the bupropion hydrobromide form - II obtained by the process of the present invention is characterized by powder X-ray diffraction pattern and recorded on Bruker D8 advance diffractometer using Cu-Ka X-radiation (? = 1.5406 Å) at 40 kV and 40 mA powers. X-ray diffraction patterns were collected over the 2? range 2° to 40° with time per step 0.5(s).

In another embodiment of the present invention, the bupropion hydrobromide form- II has an X-ray diffraction pattern that comprises characteristic peaks at 6.4, 12.8, 15.7, 16.4, 17.9, 21.8, 23.0, 25.7, 26.7, and 29.9 ± 0.2 degrees 2?. The X-ray diffraction pattern is shown in FIG. 1.

The bupropion hydrobromide form - II obtained by the process of the present invention has purity greater than 99%, as measured by HPLC.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL
Example 1: Preparation of bupropion hydrobromide form - II.
To a solution of isopropyl alcohol (6.2 to 6.6 V) and water (0.12 to 0.33 V), bupropion hydrobromide (1.0 eq) was added at 20°C to 35°C and stirred for 10 minutes. The slurry was heated at 75°C to 90°C to obtain clear solution. The above solution was treated with activated charcoal, filtered through hyflo-bed, and washed with hot isopropyl alcohol (0.5 to 1.0 V) at 60°C to 70°C. To the clear filtrate seed crystal of bupropion hydrobromide form-II was added at 60°C to 70°C. The solvent was removed by distillation under vacuum till the reaction concentrate remains up to 1.5 to 2.5 Vol. The reaction concentrate was then cooled 25°C to 30°C, stirred for 20-24 hours and further cool to 0°C to 5°C, stirred for 1-2 hours, the precipitated compound was filtered, washed with pre-cooled isopropyl alcohol (0.5 to 1.0 V), and dried under vacuum to obtain bupropion hydrobromide form - II characterized by X-ray powder diffractogram as shown in FIG. 1.
(Yield: 88%, HPLC purity: 99.8%).

Example 2: Preparation of bupropion hydrobromide form - II from form - I
To a solution of isopropyl alcohol (6.2 to 6.6 V) and water (0.12 to 0.33 V), bupropion hydrobromide form-I (1.0 eq., characterized by X-ray powder diffractogram as shown in FIG. 2) was added at 20°C to 35°C and stirred for 10 minutes. The slurry was heated at 75°C to 90°C to obtain clear solution. The above solution was treated with activated charcoal, filtered through hyflo-bed, and washed with hot isopropyl alcohol (0.5 to 1.0 V) at 60°C to 70°C. To the clear filtrate seed crystal of bupropion hydrobromide form-II was added at 60°C to 70°C. The solvent was removed by distillation under vacuum till the reaction concentrate remains up to 1.5 to 2.5 Vol. The reaction concentrate was then cooled 25°C to 30°C, stirred for 20-24 hours and further cool to 0°C to 5°C, stirred for 1-2 hours, the precipitated compound was filtered, washed with pre-cooled isopropyl alcohol (0.5 to 1.0 V), and dried under vacuum to obtain bupropion hydrobromide form - II characterized by X-ray powder diffractogram as shown in FIG. 1.
(Yield: 88%, HPLC purity: 99.8%).

,CLAIMS:We claim:

1) A process for the preparation of bupropion hydrobromide form - II comprising the steps of:
a) adding bupropion hydrobromide to aqueous alcoholic solvent, having moisture content 2% to 5%,
b) heating to obtain clear solution,
c) cooling,
d) adding seed crystals of bupropion hydrobromide form - II,
e) isolating bupropion hydrobromide form - II.

2) The process as claimed in claim 1, wherein bupropion hydrobromide is selected from bupropion hydrobromide form - I, mixture of form - I and form – II, and any other form or mixtures.

3) The process as claimed in claim 1, wherein alcoholic solvent is selected from methanol, ethanol, isopropanol, isobutanol, and n-butanol.

4) The process as claimed in claim 1, wherein volume ratio of bupropion hydrobromide to aqueous alcoholic solvent is 1:6 to 1:7.

5) The process as claimed in claim 1, wherein aqueous alcoholic solvent having moisture content 2% to 5% is prepared by adding water in an alcoholic solvent.

6) The process as claimed in claim 5, wherein water is selected from an industrial water, distilled water, and demineralized water.