DESCRIPTION
The present invention relates to process of preparation of preparation of polymorph-I and amorphous fexofenadine hydrochloride. The process involves the removal of moisture from the solution or suspension of fexofenadine base or hydrochloride in suitable solvent to yield polymorph I and or amorphous fexofenadine hydrochloride.

Fexofenadine hydrochloride of Formula I, marketed under the name Allegra. for the relief of symptoms associated with seasonal allergic rhinitis in adults and children 2 years of age and older. It is chemically, known as (±)-4-[1 -hydroxydiphenylmethyl)-1-piperidinyl]-butyl]- a, a-dimethylhydroxy-4-benzeneacetic acid hydrochloride.

Formula I

Fexofenadine and its intermediate reported in US patent numbers US 4,254,129 US 5,578,610, US 5,925,761, US 6,974,872, US 6,448,406 US 6,815,549 US 6903232 US 6,613,906 and US patent number US 7,135,571, US 7,138,524, and application number US 20040058955, US 20050165056, US2004077683A1, US2002177608A1 US2004167168, US2005256163A, US2006025444A are related to different polymorph of fexofenadine hydrochloride.

The US patent 7,135,571 and US 7,138,524 on Form-I and Form-II on fexofenadine hydrochloride are incorporated herein for reference.

The present inventors while working on the process of making fexofenadine hydrochloride have developed a process of making Form-I and amorphous fexofenadine hydrochloride. The inventors also developed the method to convert any polymorph known to skilled art artisan into Form-I of fexofenadine hydrochloride.

In one of the aspect of the process for the preparation of fexofedadine hydrochloride Form-I, includes the step of:
a) admixing fexofenadine in suitable solvent, contacting said mixture with hydrochloric acid solution,
b) removal of solvent from reaction mixture and adding acetone,
c) isolating fexofenadine hydrochloride polymorph-I from the reaction mixture thereof.

In another aspect of the invention wherein process involves the refluxing of fexofenadine hydrochloride with acetone and form-I of the fexofenadine is isolated from reaction mixture thereof.

Yet in another aspect of the invention a process for preparing amorphous fexofenadine hydrochloride includes step of;
a) removing the moisture from fexofenadine base in suitable solvent,
b) contacting with anhydrous hydrochloric acid,
c) isolating amorphous fexofenadine hydrochloride from reaction mixture.

The preparation of fexofenadine and fexofenadine hydrochloride polymorphs is known through the US patent nos. 4,254,129, 5,578,610, 7,135,571 and 7,138,524 to skilled artisan.

The process involves the admixing of fexofenadine base in suitable solvent and converting it to its hydrochloride salt by addition of hydrochloric acid solution to get clear solution. The solution obtained is concentrated under reduced pressure and then acetone is added in to the concentrated mass and it is also distilled out. The process of adding acetone and its removal continue till the completely moisture is removed from the reaction mixture. Finally reaction mass is refluxed with acetone and precipitated product is filtered and dried to get Form-I of fexofenadine hydrochloride.

In another embodiment where any polymorph known to the skilled artisan is refluxed with acetone for 2-6 hours to get the Form-I of fexofenadine hydrochloride it is filtered and dried.

The polymorph Form-I is confirmed with the XRPD d space value and melting point provided in US 7,138,524.

Yet in another embodiment where moisture of fexofenadine base is removed from its suspension in suitable solvent qualified to make azeotropic distillation water or by drying the suspension over molecular sieve. The fexofenadine base prepared via process known to skilled artisan retains 4-7% moisture content. After complete removal of the moisture the dry hydrochloric acid gas or its solution in ethyl acetate, methanol, and isopropanol is added to convert it in to hydrochloride salt. The amorphous material is isolated by removal of solvent or adding anti solvent in the reaction mass. The precipitated material filtered, dried and confers as amorphous by XRPD.

In general, the moisture can be removed by drying under vacuum, suspending fexofenadine base in a solvent capable of removing moisture by azeotropic distillation or by passing the solution of fexofenadine base through a bed of activated molecular sieves or variant thereof wherein the activated bed removes moisture. For removing moisture by azeotropic distillation, methylene chloride, toluene, methanol can be employed.

The term suitable solvent may include one or more ethyl acetate, methanol, acetonitrile, dichloromethane, chloroform, toluene and acetone.

The term hydrochloric acid solution used herein includes its commercial available solution, its solution in ethyl acetate, methanol, ethanol, isopropanol and in toluene.

The term “isolating” used herein is referred to, but not limited to, removal of solvent, addition of anti solvent, cooling of reaction mixture to suitable temperature and drying.

The term anti solvent refer here in the solvent which is not capable to dissolve practically fexofenadine hydrochloride includes of hexane, methyl ethyl ketone, diethyl ether, pentane and isopropyl ether.

Removal of the solvents may include, for example, one or more of filtration, filtration under vacuum, distillation, distillation under vacuum, evaporation, decantation and centrifugation. The process may include further forming of the product so obtained into a finished dosage form.

The process may include further drying of the product obtained. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Dryer.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example-1: Preparation of Fexofenadine hydrochloride Form-I from Fexofenadine Base
In methanol (25 ml) and chloroform (25 ml) charged fexofenadine base (10 gm, moisture 6.70%), stirred the mass for 30 minutes and then cooled 0-5°C. To the suspension aqueous hydrochloric acid was added to obtain clear solution. After 1 hour stirring solvent from reaction mixture was removed under vacuum. To the solid mass acetone (25 ml) was added and distilled out to ensure that there was no moisture and solvent left in reaction mass. Finally in mass acetone (70 ml) was added and refluxed for 6-10 hour. The reaction mass is cooled 0-5°C and stirred for one hour filtered and dried.
Yield: 8.0gm
Moisture: 0.20 %
XRD: Confers with Form-I

Example-2 Preparation of Fexofenadine hydrochloride Form-I from Fexofenadine hydrochloride amorphous

Amorphous fexofenadine hydrochloride (5 gm) was suspended in acetone (50 ml) and reflux for 10 hours. Cool the mass to 0-5°C and stirred for one hour. Filtered and dried the product to get Form-I of fexofenadine hydrochloride.
Yield: 4.2 gm
moisture: 0.4%
XRD: Confers with Form-I

Example-3 Preparation of amorphous Fexofenadine hydrochloride from Fexofenadine base

In Toluene (50 ml) charged fexofenadine base (15 gm, moisture 6.70%) removed toluene from the reaction mass and in syrupy mass fresh toluene (25 ml) was added and stirred the mass for 30 minutes and then cooled 0-5°C. To the reaction mixture alcoholic hydrochloric acid solution was added (1.8 ml, 20%HCl w/v in isopropanol). Stirred the reaction mixture for 10 hours filtered and dried to obtain amorphous product.
Yield: 14.4 gm
Moisture: 0.35%
XRD: Amorphous

We Claim:
1. A process of preparation of a fexofenadine hydrochloride polymorph-I comprising;
a)admixing fexofenadine in suitable solvent, contacting said mixture with hydrochloric acid
solution,
b)removal of solvent from reaction mixture and adding acetone,
c)isolating fexofenadine hydrochloride polymorph-I from the reaction mixture thereof.
2.The process of claim 1, wherein suitable solvent comprises one or more of ethyl acetate,
methanol, acetonitrile, dichloromethane, chloroform, toluene and acetone.
3.The process of claim 1, wherein hydrochloric acid solution comprises its solution in water or in
methanol, ethyl acetate, isopropanol or in toluene.
4.A process for preparing fexofenadine hydrochloride polymorph-I comprising refluxing
fexofenadine hydrochloride in acetone and isolating form-I from reaction mixture.
5.The process of claim 4, wherein fexofenadine hydrochloride comprises any polymorph of
fexofenadine hydrochloride.
6.A process for preparing amorphous fexofenadine hydrochloride comprising;
a)removing the moisture from fexofenadine base in suitable solvent,
b)contacting with anhydrous hydrochloric acid,
c)isolating amorphous fexofenadine hydrochloride from reaction mixture.
7.The process of claim 6, wherein moisture from the fexofenadine base suspension is removed by
one or more of azeotropic distillation and passing through a bed of activated molecular sieves.
8.The process of claim 6, wherein suitable solvent comprises of dichloromethane, chloroform,
toluene, methanol, isopropanol and ethyl acetate.
9.The process of claim 6,wherein anhydrous hydrochloric acid comprises gas or it solution in
methanol, ethyl acetate, isopropanol and in toluene.
10.The process of claim1, 4 and 6 , wherein isolation comprises of cooling of reaction mass, removal of solvent or addition of anti-solvent capable to precipitate the product.

Dated: 03rd Feb 2010 For Wockhardt Limited

(Mandar Kodgule)
Authorized Signatory