FIELD OF THE INVENTION
The present invention relates to a novel process of preparation of highly pure anhydrous Fexofenadine hydrochloride.
BACKGROUND OF THE INVENTION
Fexofenadine hydrochloride, namely 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl] l-hydroxybutyl]-α, α-dimethylbenzene acetic acid hydrochloride of formula-1 is an HI receptor antagonist and a useful antihistamine drug.

(Figure Removed)
It is a terfenadine carboxylic acid metabolite and lacks the cardiac toxicity associated with terfenadine and may also have greater therapeutic efficacy than the parent drug.
Fexofenadine and pharmaceutically acceptable salts were first disclosed in US Patent 4,254, 129. According to the 129 patent, fexofenadine can be prepared starting from ethyl α,α dimethylphenyl acetate and 4-chlorobutyroyl chloride, which are reacted under Freidel-Crafts conditions. Chloride is displaced from the Freidel-Crafts product with a,a-diphenyl-4-piperidinemethanol to give 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]-α,α-dimethylbenzene acetate, which is isolated as its hydrochloride salt. The ketone is then reduced with PtO/H2 and the ester group is hydrolyzed to yield fexofenadine base.

Other methods of preparing fexofenadine are discussed in US Patents such as 5, 578, 610,5, 589, 487, 5, 581, 011,5, 663,412, 5,750, 703,5, 994,549, 5,618, 940,5, 631375, 5,644, 061,5, 650,516, 5,652, 370,5, 654,433, 5,663, 353,5, 675,009, 5,375, 693 and 6,147,216.
Active pharmaceutical ingredients and their salts are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process. A large number of factors can influence crystal nucleation and growth during this process, including the composition, the crystallization medium and the processes used to generate super saturation and promote crystallization. The most notable variables of composition and processing are solvent/solvent combinations, degree of super saturation, pH value, heating rate, cooling rate, etc. Various polymorphs of Fexofenadine hydrochloride have been disclosed in different patents that are referred herein.
PCT Publication WO 93/021156 Al relates to the fexofenadine hydrochloride and describes dissolving fexofenadine base in methylene chloride and acidifying with hydogen chloride gas to pH 3. The reaction mass is then concentrated to residue and ether is added and stirred to obtain solid, which is filtered to give fexofenadine hydrochloride. The process leads to the formation of amorphous fexofenadine hydrochloride which has the tendency to pick up moisture and forms lumps on storage, and as such difficult to handle during formulation of tablets and capsules. Further the use of ether is not advisable on commercial scale; hence process is unsuitable for industrial application.
PCT Publication WO 95/031437 Al discloses four crystal forms of Fexofenadine hydrochloride which have been designated Forms I-IV. Forms II and IV are hydrates and Forms I and III are anhydrous. Each form was characterized by its melting point, onset of endotherm in the DSC profile, and PXRD.

It further discusses methods of interconverting Forms I-IV. Aqueous recrystallization of Form I can be used to produce Form II. Water-minimizing recrystallization or azeotropic distillation of either Form II or Form IV can yield Form I. Crystal digestion of Form III can be used to obtain Form I.
PCT Publication WO 00/71124 Al discloses amorphous fexofenadine hydrochloride, which can be prepared by lyophilizing or spray drying a solution of fexofenadine hydrochloride.
US patent 6,613,906 describes Form A, hydrous form of Fexofenadine hydrochloride having characteristic melting point in the range of 138-148°C.
US patent application no. 2004/004038A1 describes a process for preparing crystalline Fexofenadine hydrochloride Form XVI comprising combining fexofenadine base with a solution of hydrochloric acid and methanol and isopropyl alcohol, followed by evaporation and addition of methanol-heptane to the residue to precipitate Fexofinadine hydrochloride having DSC profile with an endothermic peak at 125°C and an additional peak at 135°C.
US patent application no. 2004/0077683A1 discloses a process for the preparation of anhydrous fexofenadine hydrochloride by suspending fexofenadine base in non polar organic solvent and treating with a solvent containing hydrogen chloride.
US patent application no. 2005/0165056A1 discloses a process for the preparation of non-hydrated fexofenadine hydrochloride by suspending fexofenadine base in acetonitrile and treating with a solution of hydrogen chloride.
There is need to provide an industrially viable process for the preparation of anhydrous Fexofenadine hydrochloride. The present invention provides an industrially advantageous process for the preparation of highly pure anhydrous

Fexofenadine hydrochloride, which uses conditions which are convenient to operate on commercial scale and operationally safe.
SUMMARY OF THE INVENTION
The present invention provides a novel process for preparing anhydrous Fexofenadine hydrochloride from Fexofenadine base of formula-II,
(Figure Removed)
which comprises the steps of:
(a) suspending fexofenadine base in an organic solvent,
(b) adjusting the pH of reaction mixture to 1.0-4.0 with an alcoholic solvent
containing hydrogen chloride,
(c) optionally distilling solvent under vacuum below 40°C,
(d) adding another organic solvent and anti-solvent at 35-55°C,
(e) heating the reaction mixture at 40-70°C till complete crystallization,
(f) cooling the reaction mixture to ambient temperature and
(g) isolating the anhydrous Fexofenadine hydrochloride.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a PXRD pattern for anhydrous Fexofenadine hydrochloride. Fig. 2 is a DSC thermogram of anhydrous Fexofenadine hydrochloride. DETAILED DESCRIPTION OF THE INVENTION
The instant invention relates to an improved, simple, efficient and industrially advantageous process for the preparation of highly pure anhydrous Fexofenadine hydrochloride.
Specifically, the present invention relates to a process for the preparation of highly pure crystalline anhydrous fexofenadine hydrochloride from fexofenadine base without isolating any hydrous form of fexofenadine hydrochloride.
Fexofenadine base used as a starting material in the present invention can be prepared by any of the methods disclosed in prior art such as US patent 4,254,129, WO 1995/00480 or by the process disclosed in Ind Swift's co-pending application no 28867 DEL/2005 in India.
The present invention provides a process for preparing anhydrous fexofenadine hydrochloride by suspending fexofenadine base in an organic solvent followed by acidification using a solution of hydrogen chloride in alcoholic solvents.
In a preferred embodiment, the suitable solvent is selected from alcohols, ketones and the like or mixtures thereof. The alcohols can be selected from C1-C3 alcohols and ketones can be selected from C1-C3 ketones.
Generally, fexofenadine base is suspended in suitable solvent at ambient temperature and hydrochloride salt preparation is conducted by adjusting the pH of the reaction mixture to 1-4 by addition of alcoholic hydrogen chloride solution. The alcoholic hydrogen chloride solution can be selected from any C1-C3 alcohols and preferably
isopropanol-hydrogen chloride solution is used. Typically, alcohol-hydrogen chloride solution is prepared by purging dry hydrogen chloride in alcohol by following the methods reported in the prior art. The percentage of hydrogen chloride in alcohol is preferably selected between 20-25%. The reaction mixture becomes a clear solution when hydrochloride salt formation is complete. Thereafter the clear solution is optionally treated with carbon or filtered to remove any foreign particle. The solvent is distilled off under vacuum. The residue obtained, is dissolved in an organic solvent at a temperature of 35-55°C. Organic solvent is selected from alcohols such as methanol, ethanol, isopropanol or the like and mixture thereof. The reaction mixture is heated at 40-70°C and to this an anti-solvent is added. The anti-solvent is selected from an ester
formed from C1-C2 alcohol and C1-C2 acid and preferably ethyl acetate is used. Thereafter reaction mass is heated at 40-70°C till complete crystallization. Usually it takes about 2-4 hours for complete crystallization.
It is followed by cooling of the reaction mixture to ambient temperature and stirring at this temperature for further 0-2 hours. The precipitate thus forms, can be separated by techniques well known in art such as filtration. The resulting wet precipitate is dried under vacuum at a temperature of about 40-60°C to yield the anhydrous Fexofenadine hydrochloride having purity greater than 99.7%. The following examples will illustrate the invention without in any way limiting its scope.
EXAMPLES
Examplc-1
Preparation of anhydrous Fexofenadine hydrochloride
Isopropyl alcohol (150ml) was added to fexofenadine base (50g) at ambient temperature. The reaction mass was stirred for 15 minutes and pH was adjusted to 2.9-3.0 with isopropyl alcohol-hydrogen chloride (15ml). The reaction mixture was
further stirred for 15 minutes and was filtered to remove any foreign particle. The
filtrate was distilled off under vacuum at 35-40°C. To the residue, isopropyl alcohol
(25ml) was added followed by addition of ethyl acetate (250ml) at 50°C. The reaction
mixture was heated at 45-50°C for 3 hours (till complete crystallization). The
resulting mixture was cooled to 30-35°C and stirred for 30 minutes. The reaction
mixture was filtered, washed with ethyl acetate (50ml) and dried at 40-50°C to yield
47.3g of the title compound having purity 99.88% by high performance liquid
chromatography.
Example-2
Preparation of anhydrous Fexofenadine hydrochloride
Isopropyl alcohol (150ml) was added to Fexofenadine base (50g) at ambient
temperature. The reaction mass was stirred for 15 minutes and pH was adjusted to
2.7-2.8 with isopropyl alcohol-hydrogen chloride (15ml). The reaction mixture was
further stirred for 15 minutes and was treated with carbon at 25-35°C.The filtrate was
distilled off under vacuum at 35-40°C. To the residue, isopropyl alcohol (25ml) was
added followed by addition of ethyl acetate (250ml) at 50°C. The reaction mixture
was heated at 45-50°C for 3 hours (till complete crystallization). The resulting
mixture was cooled to 30-35°C and stirred for 30 minutes. The reaction mixture was
filtered, washed with ethyl acetate (50ml) and dried at 40-50°C to yield 47.5g of the
title compound having purity 99.82% by high performance liquid chromatography.
Example-3
Preparation of anhydrous Fexofenadine hydrochloride
Methanol (150ml) was added to Fexofenadine base (50g) at ambient temperature. The
reaction mass was stirred for 15 minutes and pH was adjusted to 2.7-2.8 with
isopropyl alcohol-hydrogen chloride (15ml). The reaction mixture was further stirred
for 15 minutes and was filtered to remove any foreign particle. The filtrate was
distilled off under vacuum at 35-40°C. To the residue, methanol (25ml) was added
followed by addition of ethyl acetate (250ml) at 50°C. The reaction mixture was
heated at 45-50°C for 3 hours (till complete crystallization). The resulting mixture
was cooled to 30-35°C and stirred for 30 minutes. The reaction mixture was filtered,
washed with ethyl acetate (50ml) and dried at 40-50°C to yield 44g of the title
compound.
Example-4
Preparation of anhydrous Fexofenadine hydrochloride
Ethanol (150ml) was added to Fexofenadine base (50g) at ambient temperature. The
reaction mass was stirred for 15 minutes and pH was adjusted to 2.8-2.9 with
isopropyl alcohol-hydrogen chloride (15ml). The reaction mixture was further stirred
for 15 minutes and was filtered to remove any foreign particle. The filtrate was
distilled off under vacuum at 35-40°C. To the residue, ethanol (25ml) was added
followed by addition of ethyl acetate (250ml) at 50°C. The reaction mixture was
heated at 25-50°C for 3 hours (till complete crystallization). The resulting mixture
was cooled to 30-35°C and stirred for 30 minutes. The reaction mixture was filtered,
washed with ethyl acetate (50ml) and dried at 40-50°C to yield 46g of the title
compound.
Example-5
Preparation of anhydrous Fexofenadine hydrochloridc
Acetone (150ml) was added to Fexofenadine base (50g) at ambient temperature .
The reaction mass was stirred for 15 minutes and pH was adjusted to 1.6-1.7 with
isopropyl alcohol-hydrochloric acid. Reaction mixture was further stirred for 15
minutes and was filtered to remove any foreign particle followed by washing with
minimum amount of acetone. The filtrate was stirred for 1 hour at ambient
temperature. Ethyl acetate
(300ml) was added to it and the reaction mixture was stirred at 25-35°C for 3 hours
(till complete crystallization). The resulting mixture was cooled to 0-5 °C and was
stirred for 1.5 hours. The reaction mixture was filtered and washed with ethyl
acetate (15ml) and dried at 50-60°C to yield 47.5g of the title compound having
purity 99.89% by high performance liquid chromatography.

Example-6
Preparation of anhydrous Fexofenadine hydrochloride
Acetone (129ml) was added to Fexofenadine base (43g) at ambient temperature. The reaction mass was stirred for 15 minutes and pH was adjusted to 1.1-1.2 with isopropyl alcohol-hydrochloric acid. Reaction mixture was further stirred for 30 minutes, filtered to remove any foreign particle followed by washing with minimum amount of acetone. The filtrate was stirred for 1 hour at ambient temperature. It was followed by addition of Ethyl acetate (258ml) and stirring at 25-35°C for 3hours (till complete crystallization). The resulting mixture was cooled to 0-5 °C for about 1.5 hours. The reaction mixture was filtered and washed with ethyl acetate (13ml) and dried at 50-60°C to yield 41.3g of the title compound having purity 99.78% by high performance liquid chromatography. ExampIe-7
Preparation of anhydrous Fexofenadine hydrochloride
Isopropyl alcohol (3.0L) was added to Fexofenadine base (1kg) at ambient temperature. The reaction mass was stirred and pH was adjusted to 2.5-2.6 with isopropyl alcohol-hydrochloric acid (0.40L) at 25-30°C. After checking the clarity of the solution, it was filtered through sparkler and washed with isopropyl alcohol (l.OL) which was distilled off completely under vacuum at 35-40°C. To the residue, isopropyl alcohol (0.5L) was added followed by addition of ethyl acetate (5.0L) at 35-45°C. The reaction mixture was stirred and heated at 45-50°C for about Ihour (till complete crystallization).The resulting mixture was cooled to 25-30°C and stirred and centrifuged . The reaction mixture was filtered, washed with ethyl acetate (l.OL) and dried at 40-50°C to yield 0.94kg of the title compound having purity 99.76% by high performance liquid chromatography.

WE CLAIM
1. A process for preparing highly pure anhydrous Fexofenadine hydrochloride which comprising the steps of:
a. suspending fexofenadine base in an organic solvent,
b. adjusting the pH of reaction mixture to 1.0-4.0 with an alcoholic solvent
containing hydrogen hydrochloride at ambient temperature,
c. distilling the organic solvent under vacuum below 40°C,
d. adding another organic solvent and anti-solvent at 35-55°C,
e. heating the reaction mixture at 40-70°C till complete crystallization,
f. cooling the reaction mixture to ambient temperature and
g. isolating the anhydrous Fexofenadine hydrochloride.
2. The process according to claim 1, wherein the organic solvent in step a, is
selected from C1-C3 alcohols, acetone and the like or mixture thereof.
3. The process according to claim 1, wherein the alcoholic solvent in step b, is
selected from Ci-Cs alcohols.
4. The process according to claim 1, wherein the organic solvent in step d, is
selected from an alcohol and acetone.
5. The process according to claim 1, wherein the anti solvent in step d, is selected
from an ester formed from C1-C2 alcohol and C1-C2 acid.
6. A process for preparing highly pure anhydrous Fexofenadine hydrochloride
which comprising the steps of:
a. suspending fexofenadine base in an organic solvent,

b. adjusting the pH of reaction mixture to 1.0-4.0 with an alcoholic solvent
containing hydrogen hydrochloride at ambient temperature,
c. adding another organic solvent at 35-55°C,
d. heating the reaction mixture at 40-70°C till complete crystallization,
e. cooling the reaction mixture to ambient temperature and
f. isolating the anhydrous Fexofenadine hydrochloride.
7. The process according to claim 6, wherein the organic solvent in step a, is
selected from C1-C3 alcohol, acetone and the like or mixture thereof.
8. The process according to claim 7, wherein C1-C3 alcohol is selected from
methanol, ethanol, and isopropanol.
9. The process according to claim 6, wherein the alcoholic solvent in step b, is
selected from C1-C3 alcohol.
10. The process according to claim 6, wherein the organic solvent in step c, is selected from an ester formed from C1-C2 alcohol and C1-C2 acid.