DESC:
FORM 2

THE PATENTS ACTS, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See Section 10; rule 13)

“A PROCESS FOR THE PREPARATION OF VENLAFAXINE HYDROCHLORIDE HAVING COARSER PARTICLE SIZE”

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 INVENTION:

The present invention relates to a process for the preparation of venlafaxine hydrochloride having coarser particle sized90not less than 300 microns, d50not less than 50 microns, and d10not less than 20 microns.
BACKGROUND OF THE INVENTION:
Venlafaxine hydrochloride is chemically known as (±)-1-[2-(Dimethylamino)-1-(4-ethyoxyphenyl) ethyl] cyclohexanol hydrochloride, having molecular formula C17H27NO2.HCl, molecular weight 313.86, and structurally represented as:

Venlafaxine hydrochloride is a serotonin noradrenalin reuptake inhibitor (with a brand name Effexor®) is indicated for the treatment of moderate to severe major depressive disorder including depression accompanied by anxiety.

The U.S. Patent No. 4,535,186 specifically discloses venlafaxine hydrochloride, process for its preparation, and its use in the treatment of depression.

The PCT publications WO 2003/080560 A2, WO 2007/049302 A2, WO 2007/069277 A2, WO 2007/094008 A2, WO 2008/059525 A2 and WO 2010/046808 A2 discloses process for the preparation of venlafaxine hydrochloride.

The PCT publication WO 2007/138301 A2 discloses pharmaceutical formulation of venlafaxine hydrochloride anhydrate Form I particles, wherein d90 is not more than around 450 microns and d10 is not more than around 20 microns. However, it does not disclose the process for preparing and controlling the particle size of venlafaxine hydrochloride.

A particle size of drug substance is a crucial parameter in the pharmaceutical industry, and it is a demand from formulators for uneven particle size of drug substance. The supply and maintenance of inventory of various particle size as per demand of formulators is practically difficult. Hence, it is still an unmet need for other particle size(s) and process to produce the same, especially for coarser particle which is a reserve source to obtain small particle size. Coarser particle size of drug substance provides flexibility to formulators to study formulation aspects.

The inventors have developed a process to produce venlafaxine hydrochloride having coarser particle size by extensively studying and synchronising all process parameters such as solvents, quantities, temperature and time for heating, cooling, crystallization, and stirring. The process developed is robust, reproducible, consistent, cost-effective, and suitable for industrial implementation, without involving any tedious mechanical operations such as jet milling, hammer milling, compression milling, tumble milling, and the like.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide a process for the preparation of venlafaxine hydrochloride having coarser particle size d90 not less than 300 microns, d50 not less than 50 microns, and d10 not less than 20 microns comprising the steps of:
(i) Preparing a solution of venlafaxine free base in a suitable solvent;
(ii) treating with suitable alcoholic hydrochloride to obtain venlafaxine hydrochloride;
(iii) preparing a solution of venlafaxine hydrochloride in a suitable solvent;
(iv) heating the solution;
(v) adding seed crystals of venlafaxine hydrochloride;
(vi) isolating venlafaxine hydrochloride having coarser particle size.

Another aspect of the present invention is to provide a process for the preparation of venlafaxine hydrochloride having coarser particle size d90 not less than 300 microns, d50 not less than 50 microns, and d10 not less than 20 microns comprising the steps of:
(i) preparing a solution of venlafaxine hydrochloride in a suitable solvent;
(ii) heating the solution;
(iii) adding seed crystals of venlafaxine hydrochloride;
(iv) isolating venlafaxine hydrochloride having coarser particle size.
BRIEF DESCRIPTION OF THE FIGURES

The Figure 1 - shows the specimen of particle size distribution data of venlafaxine hydrochloride having coarser particle size, prepared as per example 2.

The Figure 2 - shows the specimen of particle size distribution data of venlafaxine hydrochloride having coarser particle size, prepared as per example 3.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention relates to a process for the preparation of venlafaxine hydrochloride having coarser particle sized90 not less than 300 microns, d50 not less than 50 microns, and d10 not less than 20 microns.

In another embodiment, the present invention relates to a process for the preparation of venlafaxine hydrochloride having coarser particle size d90 not less than 300 microns, d50 not less than 50 microns, and d10 not less than 20 microns comprising the steps of:
(i) preparing a solution of venlafaxine free base in a suitable solvent;
(ii) treating with suitable alcoholic hydrochloride to obtain venlafaxine hydrochloride;
(iii) preparing a solution of venlafaxine hydrochloride in a suitable solvent;
(iv) heating the solution;
(v) adding seed crystals of venlafaxine hydrochloride;
(vi) isolating venlafaxine hydrochloride having coarser particle size.

In another embodiment, the present invention relates to a process for the preparation of venlafaxine hydrochloride having coarser particle size d90 not less than 300 microns, d50 not less than 50 microns, and d10 not less than 20 microns comprising the steps of:
(i) preparing a solution of venlafaxine hydrochloride in a suitable solvent;
(ii) heating the solution;
(iii) adding seed crystals of venlafaxine hydrochloride;
(iv) isolating venlafaxine hydrochloride having coarser particle size.

The term d90not less than 300 microns as used herein, refers to 90% of the volume of particles of venlafaxine hydrochloride have a diameter not less than 300 microns. Preferably d90 is not more than 1000 microns.

The term d50not less than 50microns as used herein, refers to 50% of the volume of particles of venlafaxine hydrochloride have a diameter not less than 50 microns.

The term d10not less than 20microns as used herein, refers to 10% of the volume of particles of venlafaxine hydrochloride have a diameter not less than 20 microns.

The term ‘preparing a solution’ as used hereinabove refers to dissolving venlafaxine free base or venlafaxine hydrochloride in a suitable solvent, if required by heating.

It is advantageous to treat the above obtained solution of venlafaxine free base or venlafaxine hydrochloride in a suitable solvent with activated carbon before the crystallization process.

Examples of suitable alcoholic hydrochlorides include, but are not limited to, methanolic hydrochloride, ethanolic hydrochloride, isopropanol hydrochloride, and mixtures thereof.

The term “suitable solvent” as used hereinabove refers to the single solvent or mixture of solvents. The suitable solvent used in process of the present invention is selected from but not limited to alcohol, ketone, ester, ether, polar aprotic, water or mixtures thereof; preferably alcoholic solvent.

The suitable alcoholic solvent is selected from, but not limited to, Cl to C4 straight or branched chain alcohol solvents or mixtures thereof, and in particular methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, or mixtures thereof; preferable alcoholic solvent is isopropyl alcohol.

The suitable ketonic solvent is selected from, but not limited to, acetone, methyl ethyl ketone, methyl isopropyl ketone, or mixtures thereof, and in particular acetone, methyl ethyl ketone, or mixtures thereof.

The suitable ester solvent is selected from, but not limited to, ethyl acetate, propyl acetate, isobutyl acetate, isopropyl acetate, or mixtures thereof, and more particularly isobutyl acetate. Suitable ether solvent is selected from, but are not limited to, diethylether, methyl tert- butyl ether, cyclic ethers, or mixtures thereof, and in particular tetrahydrofuran, 1,4- dioxane, 2-methyltetrahydrofuran, 1,3-dioxolane, or mixtures thereof.

The suitable polar aprotic solvent is selected from, but not limited to, dimethylformamide, dimethylsulfoxide, dimethylacetamide, acetonitrile, or mixtures thereof.

In another embodiment of the present invention, process involves heating at a suitable temperature, wherein suitable temperature is 75± 5°C or till the mixture becomes clearwith stirring for 0.5-1 hour.

In another embodiment of the present invention, process involves cooling the above mixture to 65 ± 5°C, adding seed crystals of venlafaxine hydrochloride at 65 ± 5°C and maintaining the mixture for 1-2 hours.

In another embodiment of the present invention, process involves cooling the above mixture to 60 ± 5°C and maintaining the mixture for 1-2 hours.

In another embodiment of the present invention, process involves further cooling the above mixture to 0-5°Cand maintaining the mixture for 3-4 hours.

In another embodiment of the present invention, process involves isolating venlafaxine hydrochloride having coarser particle size d90 not less than 300 microns, d50 not less than 50 microns, and d10 not less than 20 microns by conventional isolation procedure such as filtration, centrifugation, washing the wet cake and drying or by evaporation of solvent.

The venlafaxine free base or venlafaxine hydrochloride used herein can be obtained by a known method, for example as disclosed in WO 2003/080560 A2, WO 2007/049302 A2, WO 2007/069277 A2, WO 2007/094008 A2, WO 2008/059525 A2 and WO 2010/046808 A2which are incorporated as a reference.

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES
General Experimental Conditions: The particle size of venlafaxine hydrochloride was measured using a laser diffraction technique (Malvern Mastersizer).

Example 1: A process for the preparation of venlafaxine hydrochloride from venlafaxine free base
Venlafaxine free base (100 gm) and isopropyl alcohol (300 ml) was charged in reaction vessel. The reaction mixture was heated to 55°C till solution becomes clear. Activated charcoal(1g) was added to the reaction mixture at 55°C and maintained for 1-2 hours. The hot reaction mixture was filtered through hyflobed and washed with hot isopropyl alcohol (40 ml). The hot reaction mixture was transferred into reaction vessel and cooled to 35°C. Isopropanol hydrochloride was charged to the above reaction mixture, and the reaction mixture was then cooled to 0 -5°C, stirred for 1-2 hours, filtered to isolate the wet solid.
Yield: 123 gm

Example 2: A process for the preparation of venlafaxine hydrochloride having coarser particle size
Venlafaxine hydrochloride (100 gm, w.r.t venlafaxine base) and isopropyl alcohol (500 ml) was charged in reaction vessel. The reaction mixture was heated up to 75°C and maintained till the solution becomes clear. Hot reaction mixture was filtered throughhy flobed, washed with hot isopropyl alcohol (20 ml).The reaction mixture was transferred in a clean reaction vessel and heated to 75°C till the solution becomes clear. The reaction mixture was cooled to 70°C, seeded with venlafaxine hydrochloride and maintained at same temperature for 1-2 hours. The reaction mixture was cooled to 65°C in1-2 hours, maintained for 1-2 hours. The reaction mixture was then cooled to 0 -5°C in 3-4 hours, maintained for1-2 hours. The solid obtained was filtered, washed with chilled isopropyl alcohol, and dried under vacuum to give venlafaxine hydrochloride having coarser particle size.
PSD results: d90: 592 microns, d50:212 microns, d10:46.1 microns
Yield: 89.97 gm (79.62 %)
HPLC Purity: 99.98%

Example 3: A process for the preparation of venlafaxine hydrochloride havingcoarser particle size
Venlafaxine hydrochloride (1750 gm, w.r.t Venlafaxine base) and isopropyl alcohol (8750 ml) was charged in reaction vessel. The reaction mixture was heated up to 75°C and maintained till the solution becomes clear. Hot reaction mixture was filtered through hyflobed, washed with hot isopropyl alcohol (350 ml).The reaction mixture was transferred in a clean reaction vessel and heated to 75°C till the solution becomes clear. The reaction mixture was cooled to 70°C, seeded with venlafaxine hydrochloride and maintained at same temperature for 1-2 hours. The reaction mixture was cooled to 65°C in 1-2 hours, maintained for 1-2 hours. The reaction mixture was then cooled to 0 -5°C in 3-4 hours, maintained for 1-2 hours. The solid obtained was filtered, washed with chilled isopropyl alcohol, and dried under vacuum to give venlafaxine hydrochloride having coarser particle size.
PSD results: d90: 674 microns, d50: 270 microns, d10: 79.4 microns
Yield: 1658 gm (83.84 %)
HPLC Purity: 99.98 % Bulk Density: 0.402 g/ml Tap Density: 0.474 g/ml
,CLAIMS:We claim:

1) A process preparation of venlafaxine hydrochloride having coarser particle size d90 not less than 300 microns, d50 not less than 50 microns, and d10 not less than 20 microns comprising the steps of:
a. preparing a solution of venlafaxine free base in solvent;
b. treating with alcoholic hydrochloride to obtain venlafaxine hydrochloride;
c. preparing a solution of venlafaxine hydrochloride in solvent;
d. heating the solution;
e. adding seed crystals of venlafaxine hydrochloride;
f. isolating venlafaxine hydrochloride having coarser particle size.

2) A process preparation of venlafaxine hydrochloride having coarser particle size d90 not less than 300 microns, d50 not less than 50 microns, and d10 not less than 20 microns comprising the steps of:
a. preparing a solution of venlafaxine hydrochloride in solvent;
b. heating the solution;
c. adding seed crystals of venlafaxine hydrochloride;
d. isolating venlafaxine hydrochloride having coarser particle size.

3) The process according to claim 1 and 2, wherein the solvent is selected from water, alcohol, ketone, ester, ether, polar aprotic or mixtures thereof.

4) The process according to claim 3, wherein the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol; ketonic solvent is selected from acetone, methyl ethyl ketone, methyl isopropyl ketone; ester solvent include ethyl acetate, propyl acetate, isobutyl acetate, isopropyl acetate; ether solvent is selected from diethylether, methyl tert- butyl ether, tetrahydrofuran, 1,4- dioxane, 2-methyltetrahydrofuran, 1,3-dioxolane; polar aprotic solvent is selected from dimethylformamide, dimethylsulfoxide, dimethylacetamide, acetonitrile; or mixtures thereof.

5) The process according to claim 1, wherein alcoholic hydrochloride is selected from methanolic hydrochloride, ethanolic hydrochloride, isopropanol hydrochloride, and mixtures thereof.

6) The process according to claim 1 and 2, wherein the solution is heated to temperature 75 ± 5°C.

7) Venlafaxine hydrochloride having coarser particle size d90 not less than 300 microns, d50 not less than 50 microns, and d10 not less than 20 microns obtained by the process according to claim 1 and 2.