This application claims priority to Indian patent application No. 689/CHE/2009 filed on March 24, 2009, the contents of which are incorporated by reference in their entirety

FIELD OF THE INVENTION

The present invention relates to novel processes for the preparation of amorphous Fexofenadine hydrochloride. The invention further relates to a novel process for the preparation of amorphous Fexofenadine hydrochloride from Fexofenadine DMF solvate.

BACKGROUND OF THE INVENTION

Fexofenadine hydrochloride having structural formula-I, is an Hi receptor antagonist and a useful antihistamine drug and is chemically known as 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-hydroxybutyl]-a,a-dimethylbenzene acetic acid hydrochloride.

Fexofenadine and pharmaceutically acceptable salts were first disclosed in US patent no. 4,254,129. US patents 5,738,872, 5,932,247 and 5,855,912, describe four crystal forms of Fexofenadine hydrochloride which are designated as Forms I-IV. According to the aforesaid patents. Forms 11 and IV are hydrates and Forms I and III are anhydrates.

WO 2000/71124 Al publication, describes a process for the preparation of amorphous Fexofenadine hydrochloride by lyophilizing or spray drying a solution of Fexofenadine hydrochloride.

US Patent Application 2003/0021849 describes a process for preparing amorphous Fexofenadine hydrochloride by preparing a solution of Fexofenadine hydrochloride in tetrahydrofuran (THF); removing a portion of THF from the solution; adding a C5 to C12 saturated hydrocarbon to THF to form layers; separating and drying the lower layer to obtain amorphous Fexofenadine hydrochloride.

US Patent Application 2005/0256163 describes a process for preparing amorphous Fexofenadine hydrochloride by heating crystalline Fexofenadine hydrochloride form XVI at 80-100 °C.

All the prior art processes are required to remove the solvent from the reaction mass by using the different techniques such as distillation, spray drying and freeze drying. These solvent removing techniques are time consuming and not suitable in commercial scale.

Thus, there is a need to develop a highly advantageous process for the preparation of stable amorphous form of Fexofenadine hydrochloride in a simple manner, without the employing tedious operations such as distillation, spray drying or freeze drying.

The present invention provides a process for the preparation of amorphous Fexofenadine hydrochloride, whereas Fexofenadine hydrochloride is dissolved in water miscible organic solvent and adding anti-solvent to precipitate the solid, followed by drying to get pure amorphous Fexofenadine hydrochloride.

OBJECT OF THE INVENTION

The main object of the present invention is to provide a novel process for the preparation of amorphous Fexofenadine hydrochloride.

Another object of the present invention is to provide a process for the preparation of amorphous Fexofenadine hydrochloride from DMF solvate of Fexofenadine free base.

Yet another object of the present invention is to provide a stable amorphous Fexofenadine hydrochloride.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide a process for the preparation of amorphous Fexofenadine hydrochloride, which comprising the steps of: a) dissolving Fexofenadine hydrochloride in water miscible organic solvent b) adding anti-solvent to precipitate the solid, filtering and d) drying the solid to give amorphous Fexofenadine hydrochloride.

Another aspect of the present invention is to provide a process for the preparation of amorphous Fexofenadine hydrochloride from DMF solvate of Fexofenadine free base which comprising the steps of; a) treating Fexofenadine DMF solvate with hydrochloric acid in water miscible organic solvent b) adding anti-solvent to precipitate the solid, filtering and c) drying the solid to give amorphous Fexofenadine hydrochloride.

Another aspect of the present invention is to provide a process for the preparation of amorphous Fexofenadine hydrochloride, which comprising the steps of: a) dissolving Fexofenadine hydrochloride in water miscible organic solvent b) adding the solution to an anti-solvent to precipitate the solid, filtering and d) drying the solid to give amorphous Fexofenadine hydrochloride.

Yet another aspect of the present invention is to provide stable amorphous Fexofenadine hydrochloride in different conditions.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: Powdered X-ray diffraction pattern of amorphous Fexofenadine hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to process for the preparation of amorphous Fexofenadine hydrochloride, wherein Fexofenadine hydrochloride salt is dissolved in water miscible organic solvent, anti-solvent is added to the above solution to precipitate the solid, filtered and subjected to drying to get the amorphous Fexofenadine hydrochloride.

According to one aspect, the present invention provides process for the preparation of amorphous Fexofenadine hydrochloride which comprising the steps of: a) dissolving Fexofenadine hydrochloride in water miscible organic solvent b) adding anti-solvent to precipitate the solid, filtering and c) drying the solid to give amorphous Fexofenadine hydrochloride.

According to one more embodiment, the water miscible organic solvent is selected from the group consisting of acetone, acetic acid, n-propanol, methanol and pyridine or mixtures thereof

According to one more embodiment, the anti-solvent is selected from the group consisting of water, isopropyl ether and ethyl acetate.

According to the present invention, Fexofenadine hydrochloride is dissolved in water miscible organic solvent, selected from the group comprising of acetone, acetic acid, n-propanol, methanol and pyridine or mixtures thereof at a temperature between 50-80°C to get the clear solution. Anti-solvent is added to the resulting solution at 20-40°C to precipitate the solid. The precipitated solid is cooled to 0-10°C, filtered and further subjected to drying at about 80-100°C to give amorphous Fexofenadine hydrochloride. Drying is carried out under reduced pressure.

According to another aspect, the present invention provides process for the preparation of amorphous Fexofenadine hydrochloride which comprising the steps of: a) treating Fexofenadine DMF solvate with hydrochloric acid in water miscible organic solvent b) adding anti-solvent to precipitate the solid, filtering and c) drying the solid to give amorphous Fexofenadine hydrochloride.

According to one more embodiment, the water miscible organic solvent is selected from the group consisting of acetone, acetic acid, n-propanol, methanol and pyridine or mixtures thereof.

According to one more embodiment, the anti-solvent is selected from the group consisting of water, isopropyl ether and ethyl acetate.

According to the present invention, DMF solvate of Fexofenadine free base is suspended in water miscible organic solvent, selected from the group comprising of acetone, acetic acid, n-propanol, methanol and pyridine or mixtures thereof at a temperature between 10-30°C. The resulting suspention is treated with hydrochloric acid source at 0-5°C to get clear solution. Anti-solvent is added to the above reaction mixture to precipitate the solid. The precipitated solid is filtered and further subjected to drying at about 60-100°C to give amorphous Fexofenadine hydrochloride. Drying is carried out under reduced pressure.

According to one more aspect, the present invention provides process for the preparation of amorphous Fexofenadine hydrochloride which comprising the steps of: a) dissolving Fexofenadine hydrochloride in water miscible organic solvent b) adding the above solution to anti-solvent to precipitate the solid, filtering and c) drying the solid to give amorphous Fexofenadine hydrochloride.

According to one more embodiment, the water miscible organic solvent is selected from the group consisting of acetone, acetic acid, n-propanol, methanol and pyridine or mixtures thereof.

According to one more embodiment, the anti-solvent is selected from the group consisting of water, isopropyl ether and ethyl acetate.

According to the present invention. Fexofenadine hydrochloride is dissolved in water miscible organic solvent, selected from the group comprising of acetone, acetic acid, n-propanol, methanol and pyridine or mixtures thereof This solution is added to anti-solvent at 0°C to precipitate the solid, filtered and further subjected to drying at about 40-60°C under reduced pressure to give amorphous Fexofenadine hydrochloride.

According to one more aspect, the present invention provides a pharmaceutical composition that includes a therapeutically effective amount of amorphous Fexofenadine hydrochloride prepared according to the processes of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.

Accordingly, the pharmaceutical composition comprising amorphous Fexofenadine hydrochloride along with one or more pharmaceutically acceptable carriers of this invention may further be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions, and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. The compositions may be prepared by direct blending, dry granulation, or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Instrumentation:

Powder X-rav Diffraction (PXRD)

The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 6/B configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 29 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.

Preparation of Amorphous Fexofenadine hydrochloride Example 1:

10g of Fexofenadine hydrochloride was dissolved in n-Propanol (50 ml) at about 60-65°C and stirred for 30 minutes. The resulting solution was cooled to 25-30°C and then further to 5-10°C. To this solution slowly added water (250 ml) at 5-10°C and stirred for 30 min. The resulting solid was filtered and dried under vacuum at 70-80°C for 3-6 hrs. The solid obtained was identified as amorphous Fexofenadine hydrochloride.

Example 2:

10g of Fexofenadine hydrochloride was dissolved in acetone (100 ml) at about 50-60°C and stirred for 30 minutes. The resulting solution was cooled to 25-30°C and then further to 5-10°C. To this solution slowly added water (500 ml) at 5-10°C and stirred for 30 min. The resuhing solid was fdtered and dried under vacuum at 70-80°C for 3-6 hrs. The solid obtained was identified as amorphous Fexofenadine hydrochloride.

Example 3:

10g of Fexofenadine hydrochloride was dissolved in methanol (50 ml) at about 60-70°C and stirred for 30 minutes. The resulting solution was cooled to 25-30°C and then further to 5-10°C. To this solution slowly added water (250 ml) at 5-10°C and stirred for 30 min. The resulting solid was filtered and dried under vacuum at 70-80°C for 3-6 hrs. The solid obtained was identified as amorphous Fexofenadine hydrochloride.

Example 4:

100g of DMF solvate Fexofenadine free base was suspended in methanol (300 ml) at about 25-30°C and stirred for 30 minutes. The resulting solution was cooled to 0-5°C, hydrochloric acid (23 gm) was added at 5-10°C to get the clear solution. To this solution slowly added water (700 ml) at 5-10°C and stirred for 30 min. The resulting solid was filtered and dried under vacuum at 70-80°C for 3-6 hrs. The solid obtained was identified as amorphous Fexofenadine hydrochloride.

Example 5:

5g of Fexofenadine hydrochloride was dissolved in acetic acid (10ml) at 25-30°C. The clear solution was then slowly added to pre-cooled isopropyl ether (75ml) at 0°C and stirred at 0°C for 10 min. The resulting solid was filtered and dried under vacuum at 40°C for 1h. The solid obtained was identified as amorphous Fexofenadine Hydrochloride.

Example 6:

5g of Fexofenadine hydrochloride was dissolved in pyridine (10ml) at 25-30°C. To the clear solufion, ethyl acetate (150ml) was added slowly and stirred for 2h at 25-30°C. The resulting solid was filtered and dried under vacuum at 40°C for 1h. The solid obtained was identified as amorphous Fexofenadine Hydrochloride.

We claim:

1. A process for the preparation of amorphous Fexofenadine hydrochloride comprising the steps of:

a) dissolving Fexofenadine hydrochloride in water miscible organic solvent;

b) adding an anti-solvent to precipitate the solid, filtering; and

c) isolating amorphous Fexofenadine hydrochloride.

2. The process according to claim 1, wherein the water miscible organic solvent is selected from acetone, acetic acid, n-propanol, methanol, pyridine or mixtures thereof

3. The process according to claim 1, wherein the anti-solvent is selected from water, isopropyl ether, ethyl acetate or mixtures thereof

4. A process for the preparation of amorphous Fexofenadine hydrochloride comprising the steps of:

a) treating Fexofenadine DMF solvate with hydrochloric acid in water miscible organic solvent;

b) adding anti-solvent to precipitate the solid, filtering; and

c) isolating amorphous Fexofenadine hydrochloride

5. The process according to claim 4, wherein the water miscible organic solvent is selected from acetone, acetic acid, n-propanol, methanol, pyridine or mixtures thereof

6. The process according to claim 4, wherein the anti-solvent is selected from water, isopropyl ether, ethyl acetate or mixtures thereof.

7. A process for the preparation of amorphous Fexofenadine hydrochloride comprising the steps of:

a) dissolving Fexofenadine hydrochloride in water miscible organic solvent;

b) adding the solution to an anti-solvent to precipitate the solid, filtering; and

c) isolating amorphous Fexofenadine hydrochloride.

8. The process according to claim 7, wherein the water miscible organic solvent is selected from acetone, acetic acid, n-propanol, methanol, pyridine or mixtures thereof

9. The process according to claim 7, wherein the anti-solvent is selected from water, isopropyl ether, ethyl acetate or mixtures thereof.

10. A pharmaceutical composition comprising the amorphous Fexofenadine hydrochloride obtained by any of the claims 1-9.