Title of Invention	A PROCESS FOR THE PREPARATION OF AMORPHOUS FORM OF 2-[4-[(4-CHLOROPHENYL)-PHENYLMETHYL]-1-PIPERAZINYL]ETHOXY]ACETIC ACID (CETIRIZINE)
Abstract	The present invention relates to the novel amorphous form of Cetirizine and the process for their preparation there of. The process for the preparation of amorphous form of Cetirizine comprises reacting [2-[4-[(4-chlorophenyl)-phenylmethyl]-l-piperizinyl]ethoxy]acetamide with an alkaline base in water at reflux, adjusting the pH of the reaction mas to 9.5-9.8 with hydrochloric acid followed by washing the aqueous part with solvent and further acidified the aqueous part by adjusting the pH to 5-5.5 with hydrochloric acid further extracting the aqueous solution with an organic solvent. Upon distillation of the solvent and getting the amorphous Cetirizine . Cetirizine can be depicted by the Formula (I)

Title of Invention

A PROCESS FOR THE PREPARATION OF AMORPHOUS FORM OF 2-[4-[(4-CHLOROPHENYL)-PHENYLMETHYL]-1-PIPERAZINYL]ETHOXY]ACETIC ACID (CETIRIZINE)

Abstract

The present invention relates to the novel amorphous form of Cetirizine and the process for their preparation there of. The process for the preparation of amorphous form of Cetirizine comprises reacting [2-[4-[(4-chlorophenyl)-phenylmethyl]-l-piperizinyl]ethoxy]acetamide with an alkaline base in water at reflux, adjusting the pH of the reaction mas to 9.5-9.8 with hydrochloric acid followed by washing the aqueous part with solvent and further acidified the aqueous part by adjusting the pH to 5-5.5 with hydrochloric acid further extracting the aqueous solution with an organic solvent. Upon distillation of the solvent and getting the amorphous Cetirizine . Cetirizine can be depicted by the Formula (I)

Full Text	FIELD OF THE INVENTION The present invention relates to novel amorphous form of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid. It is generically known as cetirizine and its dihydrochloride salt is marketed under brand name "Zyrtec" in Europe market. The present invention also relates to the process for the preparation of novel amorphous form of Cetirizine, which can be depicted as Formula (1). BACKGROUND OF THE INVENTION Cetirizine is used for the treatment of allergic syndromes such as chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria etc. The product was proved to be remarkably free from side effects on the central nervous system. US 4,525,358 discloses the pure crystalline Cetirizine having the melting point of 110-115°C and its pharmaceutical salts and the process for the preparation of Cetirizine. Many of the related patents were disclosed the process for the preparation of Cetirizine and its salts including dihydrochloride in various methods, but none of these patents were described the existence of an amorphous form of Cetirizine or its dihydrochloride. During our laboratory experimentation as a part of process development, novel amorphous form of Cetirizine was resulted while isolating the Cetirizine. Hence, the main aspect of the present invention is to provide novel amorphous form of Cetirizine. The aspect of the present invention is to provide the novel amorphous form of Cetirizine and process for the preparation thereof The novel amorphous form of Cetirizine was characterized by X-ray powder diffractogram. The processes of the present invention are simple, eco-friendly and easily scalable. SUMMARY OF INVENTION The present invention relates to the novel amorphous form of Cetirizine and the process for their preparation there of The process for the preparation of amorphous form of Cetirizine comprises reacting [2-[4-[(4-chlorophenyl)-phenylmethyl]-l-piperizinyl]ethoxy]acetamide with an alkaline base in water at reflux, adjusting the pH of the reaction mas to 9.5-9.8 with hydrochloric acid followed by washing the aqueous part with solvent and further acidified the aqueous part by adjusting the pH to 5-5.5 with hydrochloric acid further extracting the aqueous solution with an organic solvent. Upon distillation of the solvent and getting the amorphous Cetirizine by scraching the residue. BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS Fig-1 is a diagram showing the X-ray powder diffraction of amorphous form of Cetirizine. Fig.2 is a characteristic infrared pattem of novel amorphous form of Cetirizine. Fig.3 is a characteristic defferentional Scanning Calorimetry of novel amorphous form of Cetirizine. DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel amorphous form of Cetirizine. The present invention also provides a process for preparing novel amorphous form of Cetirizine. The present invention of amorphous form of Cetirizine was characterized by melting point between 45 - 55°C, endotherm peak around 46°C by differential scanning calorimetry and by X-ray powder diffractogram. The X-ray powder diffraction pattem of amorphous form of Cetirizine was measured on a Bruker Axs, D8 Advance Powder X-ray Diffractometer with Cu K alpha-1 Radiation source. The differential scanning calorimetry was measured on a perkin elmer. The present invention is to prepare novel amorphous form of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-1- piperazinyl] ethoxy] acetic acid (Cetirizine), which comprises; a. reacting the [2-[4-[(4-Chlorophenyl)-phenyl methyl]-1- piperazinyl] ethoxy] acetamide with an alkaline base in water at reflux temparature and adjusting the pH to 9-10 preferably to 9.5-9.8 with a suitable protic acids like hydrochloric acid, acetic acid or sulfuric acid preferably hydrochloric acid followed by washing the aqueous part with polar organic solvents preferably ethyl acetate; b. adjusting the pH of the aqueous solution to 5 - 6 preferably to 5 -5.5 with suitable protic acids such as hydrochloric acid, acetic acid or sulphuric acid preferably hydrochloric acid; c. extracting the compound into a suitable halogenated hydrocarbon solvents such as dichloromethane, chloroform, and dichloroethane or acetate sovents such as ethylacetate and methyl acetate preferably dichloromethane; d. washing the organicsolvent with water followed by sodium chloride solution (10%) and water; e. addition of charcoal to the organic solution and heating to reflux for 15-45 minutes preferably 30 minutes and filtering the reaction solution thriugh hyflow bed followed by washing the bed with halogenated hydrocarbon solvents such as dichloromethane, chloroform, and dichloroethane preferably dichloromethane; f drying the organic solvent with sodium or magnesium sulphates preferably sodium sulphate; g. distilling off the solvent under reduced pressure to afford the desired amorphous form of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid (Cetirizine) of the formula-1. The novel amorphous form of the present invention is characterized by X-ray powder diffractogram. The amorphous form of Cetirizine of the present invention is having the X-ray powder diffractogram pattern substantially as depicted in Figure (1). The process for the preparation of amorphous form of Cetirizine is simple and eco- friendly. The present invention is illustrated by the following examples, which are not intended to limit the effective scope of the claims. Example-1: Preparation of novel amorphous form of Cetirizine: 2-[4-[(4-Chlorophenyl)-phenyl methyl]-l- piperazinyl] ethoxy] acetamide (50 grams) was charged into a solution of sodium hydroxide (12.9 grams) and water (200ml). Heated the reaction mass to reflux and mainted at reflux for 12 hours. Cooled the reaction mass to 50-60°C and water (300ml) added further cooled the reaction solution to 20-25'C followed by pH adjusted to 9.5 to 9.8 with hydrochloric acid. Washed the aqueous solution with ethyl acetate (200ml) and pH of the aqueous solution further adjusted to 7.0-7.5 with hydrochloric acid. Distilled off water (100 ml) from the aqueous solution under reduced pressure at 60-80°C and fresh water (100ml) charged and again distilled off (50ml) of water under reduced pressure at 60-80°C. Fresh water (50 ml) was added to the reaction solution and pH adjusted to 5-5.5 with hydrochloric acid at 25-35°C. Extractions were given to the aqueous solution with dichloromethane (2x150 ml) followed by washing the combined organic solution with water (2x150ml) and 10% sodium chloride solution. Separated the organic layer and treated with charcoal at reflux temparature for 15-20 minutes. Filtered the reaction mass through hyflow bed and washed the bed with dichloromethane (50 ml). Dried the organic solution under sodium sulphate and distilled off the organic solvent under reduced pressure to get the amorphous form of Cetirizine base. (Weight: 32.1 grams) Melting point 45 - 48°C. £xample-2: 2-[4-[(4-chlorophenyl) phenyl methyl]-l-piperizinyl]ethanol (50.0gram) was charged into a mixture of dimethyl formamide (150.0ml), potassium hydroxide (25.4 gram) sodium monochloroacetate (26.4 gram) and maintained at 25-35° for 10-12 hours. And water (500ml) was added to the reaction mass follwed by washing the aqueous layer with toluene (4x100ml). Then aqueous layer pH adjusted to 5-5.5 with hydrochloric acid at 25-35°C. Extractions were given to the aqueous solution with dichloromethane (2x150 ml) followed by washing the combined organic solution with water (2x150ml) and 10% sodium chloride solution. Separated the organic layer and treated with charcoal at reflux temparature for 15-20 minutes. Filtered the reaction mass through hyflow bed and washed the bed with dichloromethane (50 ml). Dried the organic solution under sodium sulphate and distilled off the organic solvent under reduced pressure to get the amorphous form of Cetirizine base. (Weight: 31.1 grams) Melting point 45 ~48°C. DETAILED DESCRIPTION OF THE ACCOMPANYING DRAWING Fig.l is a characteristic X-ray powder diffraction pattern of novel amorphous form of Cetirizine. Fig.2 is a characteristic infrared pattern of novel amorphous form of Cetirizine. Fig.3 is a characteristic defferentional Scanning Calorimetry of novel amorphous form of Cetirizine. We claims: 1. Novel amorphous form of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid (Cetirizine) and process for the preparation of thereof, which comprises, a. reacting the[2-[4-[(4-Chlorophenyl)-phenylmethyl]-1 -piperazinyl] ethoxy] acetamide with an alkaline base in water at reflux temparature and adjusting the pH to 9-10 preferably to 9.5-9.8 with a suitable protic acids like hydrochloric acid, acetic acid or sulfuric acid preferably hydrochloric acid followed by washing the aqueous part with polar organic solvents preferably ethyl acetate; b. adjusting the pH of aqueous soltion of step a, to 7-7.5 distilling off water(some portion of water) at reduced presssure and adding fresh water to the reaction solution. c. adjusting the pH of the aqueous solution of step b, to 5 - 6 preferably to 5 -5.5 with suitable protic acids such as hydrochloric acid, acetic acid or sulphuric acid preferably hydrochloric acid; d. extracting the compound into a suitable halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane or acetate solvents such as ethylacetate and methyl acetate preferably dichloromethane; e. washing the organicsolvent with water followed by sodium chloride solution (10%) and water; f. addition of charcoal to the organic solution and heating to reflux for 15-45 minutes preferably 30 minutes and fiUering the reaction solution thriugh hyflow bed followed by washing the bed with halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane preferably dichloromethane; g. drying the organic solvent with sodium or magnesium sulphates preferably sodium sulphate; h. distilling off the solvent under reduced pressure to afford the desired amorphous form of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid (Cetirizine) of the formula-1. 2. The process according to claim 1 step a), where the alkaline base is sodium hydroxide. 3. The process according to claim 1 step a), where the protic acid is hydrochloric acid. 4. The process according to claim 1 step b), where the protic acid is hydrochloric acid. 5. The process according to claim 1 step c), where the organic solvent is dichloro methane. 6. The amorphous form of Cetirizine as dipcted in X-ray powder diffraction pattern. The amorphous form of Cetirizine having the melting point 45-48°C. 8. The process for the preparation novel amorphous form of Cetirizine is substantially as herein described and exemplified.

Full Text

FIELD OF THE INVENTION
The present invention relates to novel amorphous form of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid. It is generically known as cetirizine and its dihydrochloride salt is marketed under brand name "Zyrtec" in Europe market. The present invention also relates to the process for the preparation of novel amorphous form of Cetirizine, which can be depicted as Formula (1).

BACKGROUND OF THE INVENTION
Cetirizine is used for the treatment of allergic syndromes such as chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria etc. The product was proved to be remarkably free from side effects on the central nervous system. US 4,525,358 discloses the pure crystalline Cetirizine having the melting point of 110-115°C and its pharmaceutical salts and the process for the preparation of Cetirizine. Many of the related patents were disclosed the process for the preparation of Cetirizine and its salts including dihydrochloride in various methods, but none of these patents were described the existence of an amorphous form of Cetirizine or its dihydrochloride. During our laboratory experimentation as a part of process development, novel amorphous form of Cetirizine was resulted while isolating the Cetirizine.

Hence, the main aspect of the present invention is to provide novel amorphous form of
Cetirizine.
The aspect of the present invention is to provide the novel amorphous form of Cetirizine
and process for the preparation thereof
The novel amorphous form of Cetirizine was characterized by X-ray powder
diffractogram.
The processes of the present invention are simple, eco-friendly and easily scalable.
SUMMARY OF INVENTION
The present invention relates to the novel amorphous form of Cetirizine and the process for their preparation there of
The process for the preparation of amorphous form of Cetirizine comprises reacting [2-[4-[(4-chlorophenyl)-phenylmethyl]-l-piperizinyl]ethoxy]acetamide with an alkaline base in water at reflux, adjusting the pH of the reaction mas to 9.5-9.8 with hydrochloric acid followed by washing the aqueous part with solvent and further acidified the aqueous part by adjusting the pH to 5-5.5 with hydrochloric acid further extracting the aqueous solution with an organic solvent. Upon distillation of the solvent and getting the amorphous Cetirizine by scraching the residue.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Fig-1 is a diagram showing the X-ray powder diffraction of amorphous form of
Cetirizine.
Fig.2 is a characteristic infrared pattem of novel amorphous form of Cetirizine.
Fig.3 is a characteristic defferentional Scanning Calorimetry of novel amorphous form
of Cetirizine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel amorphous form of Cetirizine. The present invention also provides a process for preparing novel amorphous form of Cetirizine. The present invention of amorphous form of Cetirizine was characterized by melting point between 45 - 55°C, endotherm peak around 46°C by differential scanning calorimetry and by X-ray powder diffractogram. The X-ray powder diffraction pattem of amorphous form of Cetirizine was measured on a Bruker Axs, D8 Advance Powder X-ray Diffractometer with Cu K alpha-1 Radiation source. The differential scanning calorimetry was measured on a perkin elmer.
The present invention is to prepare novel amorphous form of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-1- piperazinyl] ethoxy] acetic acid (Cetirizine), which comprises;
a. reacting the [2-[4-[(4-Chlorophenyl)-phenyl methyl]-1- piperazinyl] ethoxy]
acetamide with an alkaline base in water at reflux temparature and adjusting the pH to 9-10 preferably to 9.5-9.8 with a suitable protic acids like hydrochloric acid, acetic acid or sulfuric acid preferably hydrochloric acid

followed by washing the aqueous part with polar organic solvents preferably ethyl acetate;
b. adjusting the pH of the aqueous solution to 5 - 6 preferably to 5 -5.5 with
suitable protic acids such as hydrochloric acid, acetic acid or sulphuric acid
preferably hydrochloric acid;
c. extracting the compound into a suitable halogenated hydrocarbon solvents
such as dichloromethane, chloroform, and dichloroethane or acetate sovents
such as ethylacetate and methyl acetate preferably dichloromethane;
d. washing the organicsolvent with water followed by sodium chloride solution
(10%) and water;
e. addition of charcoal to the organic solution and heating to reflux for 15-45
minutes preferably 30 minutes and filtering the reaction solution thriugh
hyflow bed followed by washing the bed with halogenated hydrocarbon
solvents such as dichloromethane, chloroform, and dichloroethane preferably
dichloromethane;
f drying the organic solvent with sodium or magnesium sulphates preferably
sodium sulphate;
g. distilling off the solvent under reduced pressure to afford the desired
amorphous form of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid (Cetirizine) of the formula-1. The novel amorphous form of the present invention is characterized by X-ray powder diffractogram.

The amorphous form of Cetirizine of the present invention is having the X-ray powder
diffractogram pattern substantially as depicted in Figure (1).
The process for the preparation of amorphous form of Cetirizine is simple and eco-
friendly.
The present invention is illustrated by the following examples, which are not intended to
limit the effective scope of the claims.
Example-1:
Preparation of novel amorphous form of Cetirizine:
2-[4-[(4-Chlorophenyl)-phenyl methyl]-l- piperazinyl] ethoxy] acetamide (50 grams) was charged into a solution of sodium hydroxide (12.9 grams) and water (200ml). Heated the reaction mass to reflux and mainted at reflux for 12 hours. Cooled the reaction mass to 50-60°C and water (300ml) added further cooled the reaction solution to 20-25'C followed by pH adjusted to 9.5 to 9.8 with hydrochloric acid. Washed the aqueous solution with ethyl acetate (200ml) and pH of the aqueous solution further adjusted to 7.0-7.5 with hydrochloric acid. Distilled off water (100 ml) from the aqueous solution under reduced pressure at 60-80°C and fresh water (100ml) charged and again distilled off (50ml) of water under reduced pressure at 60-80°C. Fresh water (50 ml) was added to the reaction solution and pH adjusted to 5-5.5 with hydrochloric acid at 25-35°C. Extractions were given to the aqueous solution with dichloromethane (2x150 ml)

followed by washing the combined organic solution with water (2x150ml) and 10% sodium chloride solution. Separated the organic layer and treated with charcoal at reflux temparature for 15-20 minutes. Filtered the reaction mass through hyflow bed and washed the bed with dichloromethane (50 ml). Dried the organic solution under sodium sulphate and distilled off the organic solvent under reduced pressure to get the amorphous form of Cetirizine base.
(Weight: 32.1 grams) Melting point 45 - 48°C. £xample-2:
2-[4-[(4-chlorophenyl) phenyl methyl]-l-piperizinyl]ethanol (50.0gram) was charged into a mixture of dimethyl formamide (150.0ml), potassium hydroxide (25.4 gram) sodium monochloroacetate (26.4 gram) and maintained at 25-35° for 10-12 hours. And water (500ml) was added to the reaction mass follwed by washing the aqueous layer with toluene (4x100ml). Then aqueous layer pH adjusted to 5-5.5 with hydrochloric acid at 25-35°C. Extractions were given to the aqueous solution with dichloromethane (2x150 ml) followed by washing the combined organic solution with water (2x150ml) and 10% sodium chloride solution. Separated the organic layer and treated with charcoal at reflux temparature for 15-20 minutes. Filtered the reaction mass through hyflow bed and washed the bed with dichloromethane (50 ml). Dried the organic solution under sodium sulphate and distilled off the organic solvent under reduced pressure to get the amorphous form of Cetirizine base.
(Weight: 31.1 grams) Melting point 45 ~48°C.

DETAILED DESCRIPTION OF THE ACCOMPANYING DRAWING
Fig.l is a characteristic X-ray powder diffraction pattern of novel amorphous form of
Cetirizine.
Fig.2 is a characteristic infrared pattern of novel amorphous form of Cetirizine.
Fig.3 is a characteristic defferentional Scanning Calorimetry of novel amorphous form
of Cetirizine.

We claims:
1. Novel amorphous form of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid (Cetirizine) and process for the preparation of thereof, which comprises,
a. reacting the[2-[4-[(4-Chlorophenyl)-phenylmethyl]-1 -piperazinyl] ethoxy]
acetamide with an alkaline base in water at reflux temparature and adjusting the
pH to 9-10 preferably to 9.5-9.8 with a suitable protic acids like hydrochloric
acid, acetic acid or sulfuric acid preferably hydrochloric acid followed by
washing the aqueous part with polar organic solvents preferably ethyl acetate;
b. adjusting the pH of aqueous soltion of step a, to 7-7.5 distilling off water(some
portion of water) at reduced presssure and adding fresh water to the reaction
solution.
c. adjusting the pH of the aqueous solution of step b, to 5 - 6 preferably to 5 -5.5
with suitable protic acids such as hydrochloric acid, acetic acid or sulphuric acid
preferably hydrochloric acid;

d. extracting the compound into a suitable halogenated hydrocarbon solvents such
as dichloromethane, chloroform and dichloroethane or acetate solvents such as
ethylacetate and methyl acetate preferably dichloromethane;
e. washing the organicsolvent with water followed by sodium chloride solution
(10%) and water;
f. addition of charcoal to the organic solution and heating to reflux for 15-45
minutes preferably 30 minutes and fiUering the reaction solution thriugh hyflow
bed followed by washing the bed with halogenated hydrocarbon solvents such as
dichloromethane, chloroform and dichloroethane preferably dichloromethane;
g. drying the organic solvent with sodium or magnesium sulphates preferably
sodium sulphate;
h. distilling off the solvent under reduced pressure to afford the desired amorphous form of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid (Cetirizine) of the formula-1.
2. The process according to claim 1 step a), where the alkaline base is sodium hydroxide.
3. The process according to claim 1 step a), where the protic acid is hydrochloric acid.
4. The process according to claim 1 step b), where the protic acid is hydrochloric acid.
5. The process according to claim 1 step c), where the organic solvent is dichloro methane.
6. The amorphous form of Cetirizine as dipcted in X-ray powder diffraction pattern. The amorphous form of Cetirizine having the melting point 45-48°C.

8. The process for the preparation novel amorphous form of Cetirizine is substantially as herein described and exemplified.

Documents:

253-CHE-2003 AMANDED PAGE OF SPECIFICATION 10-11-2009.pdf

253-che-2003 claims granted.pdf

253-CHE-2003 DESCRIPTION (COMPLETE) 20-07-2009.pdf

253-CHE-2003 EXAMINATION REPORT REPLY RECEIVED 20-07-2009.pdf

253-CHE-2003 EXAMINATION REPORT REPLY RECIEVED 10-11-2009.pdf

253-CHE-2003 FORM-3 10-11-2009.pdf

253-CHE-2003 FORM-3 20-07-2009.pdf

253-CHE-2003 OTHER DOCUMENT 20-07-2009.pdf

253-che-2003-abstract.pdf

253-che-2003-claims.pdf

253-che-2003-correspondnece-others.pdf

253-che-2003-description(complete).pdf

253-che-2003-drawings.pdf

253-che-2003-form 1.pdf

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Patent Number

241292

Indian Patent Application Number

253/CHE/2003

PG Journal Number

27/2010

Publication Date

02-Jul-2010

Grant Date

28-Jun-2010

Date of Filing

25-Mar-2003

Name of Patentee

DR. REDDY'S LABORATORIES LIMITED

Applicant Address

7-1-27, AMEERPET HYDERABAD-500 016.

Inventors:

#	Inventor's Name	Inventor's Address
1	MANNE SATYANARAYANA REDDY	7-1-27, AMEERPET HYDERABAD-500 016.
2	SRINIVASAN THIRUMALAI RAJAN	7-1-27, AMEERPET HYDERABAD-500 016.
3	UPPALA VENKATA BHASKARA RAO	7-1-27, AMEERPET HYDERABAD-500 016.
4	KONDA SRINIVASA REDDY	7-1-27, AMEERPET HYDERABAD-500 016.

PCT International Classification Number

A61K9/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA