Title of Invention

NOVEL POLYMORPHIC FORMS OF DEXTRO AND LEVO ROTATORY DIHYDROCHLORIDE SALTS OF 2-[4-[(4-CHLOROPHENYL)- PHENYL METHYL]-1-PIPERAZINYL] ETHOXY] ACETIC ACID (DEXTRO AND LEVO ROTATORY DIHYDROCHLORIDE SALTS OF CETIRIZINE)

Abstract Title of the Invention: "Novel Polymorphic fonns of Dextro and Levo rotatory dihydrochloride salts of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-1 - piperazinyl] ethoxy] acetic acid (Dextro and Levo rotatory dihydrochloride salts of Cetirizine)" The present invention relates to novel Polymorphic forms of Dextro and Levorotatory dihydrochloride salts of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-1- piperazinyl] ethoxy] acetic acid (Dextro and Levo rotatory dihydrochloride salts of Cetirizine), which can be depicted as following Formula (I). The first aspect of the present invention relates to the novel crystalline Form-I of Dextro and Levo rotatory dihydrochloride salts of Cetirizine and process for preparation there of. The process for the preparation of crystalline Form-I of Dextro and Levo rotatory dihydrochloride salts of Cetirizine comprises the purification of crude dihydrochloride salt of Dextro or Levo rotatory Cetirizine in aqueous keto solvents such as aqueous acetone to afford the novel crystalline Form-I of Dextro or Levo rotatoiy dihydrochloride salt of Cetirizine. The second aspect of the present invention relates to the novel amorphous form of Dextro and Levo rotatory dihydrochloride salts of Cetirizine and the process for the preparation there of. The process for the preparation of novel amorphous form of Dextro and Levo rotatory dihydrochloride salts of Cetirizine comprises the dissolution of crude dihydrochloride salt of Dextro or Levo rotatory Cetirizine in aqueous keto solvents such as aqueous acetone and subjecting the resultant solution to flash distillation under reduced pressure to afford the novel amorphous form of Dextro or Levo rotatory dihydrochloride salts of Cetirizine. The processes of the present invention are simple, eco-friendly and commercially viable.
Full Text

FIELD OF THE INVENTION
The present invention relates to novel Polymorphic forms of Dextro and Levorotatory dihydrochloride salts of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid (Dextro and I-evo rotatory dihydrochloride salts of Cetirizine). Herein after Levorotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!-piperazinyl] ethoxy] acetic acid is referred as Levorotatory dihydrochloride salt of Cetirizine and Dextrorotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid is referred as Dextrorotatory dihydrochloride salt of Cetirizine for convenience. More specifically, the present invention relates to novel crystalline and novel amorphous forms of Dextro and Levorotatory dihydrochloride salts of Cetirizine. The present invention also relates to process for the preparation of these novel Polymorphic forms of Dextro and I^vo rotatory dihydrochloride salts of [2-[4-[(4-Ch]oropheny])-pheny] methylj-l - piperazinyl] ethoxy] acetic acid (Dextro and Levo rotatory dihydrochloride salts of Cetirizme), which can be depicted as following Formula (I)-

Dextrorotatory dihydrochloride salt of 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 &om side effects on the central nervous system.

BACKGROUND OF THE INVENTION
GB 2 225 321 A disclosed the process for the preparation of Dextro and Levo rotatory
dihydrochloride salts of Cetirizine, which comprises treating the Levo or Dextro rotatory
Cetirizine with hydrochloric acid in acetone.
The journal of Tetrahedron Lett 37(28), 4837-4840 1996 disclosed the enantio
selective synthesis of Dextro and Levo rotatory dihydrochloride salts of Cetirizine and
purification via ion exchange chromatography.
Many of the related patents were disclosed the process for the preparation of enantiomers
Cetirizine and its salts including dihydrochloride in various methods, but none of these
patents were described the existence of crystalline or amorphous forms of dextro or
levorotatory dihydrochloride salts of Cetirizine.
During our laboratory experimentation as a part of process development, novel crystalline
and amorphous forms of Dextro and Levorotatory dihydrochloride salts of Cetirizine
were resulted while crystallizing the pharmaceuticalJy acceptable salts of Cetirizine in
different solvents.
Hence, the main aspect of the present invention is to provide novel crystalline and
amorphous forms of Dextro and Levorotatory dihydrochloride salts of Cetirizine.
The present invention of novel crystallme fonn of Dextro and Levo rotatoiy
dihydrochloride salts of Cetkizine is collectively designated as crystalline Form-I for
convenience and herein after it is referred as novel crystalline Form-I of Dextro and Levo
rotatory dihydrochloride salts of Cetirizine.
The second aspect of the present invention is to provide the process for the preparation of
novel crystalline form of Dextro and Levorotatory dihydrochloride salts of Cetirizine.

Another aspect of the present invention is to provide the process for the preparation of
novel amorphous form of Dextro and Levorotatory dihydrochlonde salts of Cetirizine.
The novel crystalline Form-I of Dextro and Levo rotatory dihydrochlonde salts of
Cetirizine is characterized by X-ray powder diffractogram, which has the well-resolved
peaks. The pattern of X-ray diffractogram for both dextro and levorotatory
dihydrochlonde salts of Cetirizine is similar.
The novel amorphous form of Dextro and Levorotatory dihydrochlonde salts of
Cetirizine is characterized by X-ray powder diffractogram, which has no well-resolved
peaks.
Both novel crystalline and amorphous forms of Dextro and Levorotatory dihydrochlonde
salts of Cetirizine are free flowing and non-solvated solids. These solids are well suitable
for pharmaceutical applications.
The processes of the present invention are simple, eco-fiiendly and easily scalable.
SUMIWARY OF INVENTION
The first aspect of the present invention relates to the novel crj^talline Form-I of Dextro
and Levo rotatory dihydrochloride salts of Cetirizine and the process for the preparation
there of.
The process for the preparation of crystalline Form-I of Dextro and Levo rotatory
dihydrochloride salts of Cetirizine comprises the purification of crude dihydrochloride
saU of Dextro or Levo rotatory Cetirizine in aqueous keto solvents such as aqueous
acetone to afford die novel cr^talline Form-I of Dextro or Levo rotatory dihydrochloride
salt of Cetirizine.

The second aspect of the present invention relates to the novel amorphous form of Dextro
and Levo rotatory dihydrochloride saUs of Cetirizine and the process for the preparation
there of
The process for the preparation of novel amorphous form of Dextro and Levo rotatory
dihydrochloride salts of Cetirizine comprises the dissolution of crude dihydrochloride salt
of Dextro or Levo rotatory Cetirizine in aqueous keto solvents such as aqueous acetone
and subjecting the resultant solution to flash distillation under reduced pressure to afford
the novel amorphous form of Dextro or Levo rotatory dihydrochloride salts of Cetirizine.
The crystalline or amorphous nature of present invention is characterized by X-ray
diffractogram, Differential Scanning Calorimetry thermogram and Infra red spectrum.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Fig-1 is a diagram showing the X-ray powder diffraction of crystalUne Form-I of Dextto
rotatory dihydrochloride salt of Cetirizine.
Fig-2 is a diagram showing the X-ray powder diffraction of crystalline Fonn-I of Levo
rotatory dihydrochloride salt of Cetirizine.
Fig-3 is a diagram showing the X-ray powder diffraction of amorphous form of
Dextrorotatory dihydrochloride salt of Cetirizine.
Fig-4 is a diagram showing the X-ray powder diffraction of amorphous form of
Levorotatory dihydrochloride salt of Cetirizine.
DETAILED DESCRIPTION OF THE INVENTION
The first aspect of the present mvention relates to the novel crystalline Form-I of Dextro
and Levo rotatory dihydrochloride salts of Cetirizine and the process for the preparation
there of

The present invention of novel crystalline Form-I of Dextro and Levo rotatory dihydrochloride salts of Cetirizine is characterized by X-ray powder diffractogram. The X-ray powder diffraction pattern of novel crystalline Form-I of Dextro and Levo rotatory dihydrochloride salts of Cetirizine of the present invention is measured on a Bruker Axs, D8 Advance Powder X-ray Diffractometer with Cu K alpha-1 Radiation source. The novel crystalline Form-I of dihydrochloride salts of Dextro and Levo rotatory Cetirizine of the present invention is having the similar X-ray powder diffractogram pattern there by for our convenience, it is being represented as crystalline Form-I of dihydrochloride salt of Cetirizine.
The novel crystalline Form-I of Dextro and Levo rotatory dihydrochloride salts of Cetirizine of the present invention is having significant peaks in X-ray powder diffractogram, which are having the intensity percentages more than 15 are shown in the Table-1. The X-ray powder diffraction pattem is expressed in terms of the 2 theta (degrees), and percentage of intensity (in %).



The novel crystalline Form-I of Dextro rotatory and levorotatory dihydrochloride salt of Cetirizine of the present invention is having the X-ray powder dif&actogram pattern substantially as depicted in Figure (1) and (2) respectively.
The present invention also provides the Differential Scanning Calorimetry thermogram of novel crystalline Form-I of Dextro and levorotatory dihydrochloride salt of Cetirizine. The Differential Scanning Calorimetry thermogram exhibits a similar significant endotherm peaks in between 195 and 215'C.
The present invention finther provides the Infrared spectral data for novel crystalline Form-I of dextro and levorotatory dihydrochloride salts of Cetirizine, which were measured by KBr-transmission method with significant peaks at about 3430.22, 2949.03, 2375.88,1745.88.1496.74,1496.74,1320.06,1136.79,919.85, 758.53, 719.86, 700.45 and 534.10 cm-'.
Another embodiment of the present invention is to provide the process for the preparation of novel crystalline Form-I of Dextro and Levorotatory dihydrochloride salts of [2-[4-[(4-Chloraphenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid (Dextro and Levo rotatory dihydrochloride salt of Cetirizine), which comprises;
a, heating the reaction mixture of Levo or Dextro rotatory Cetirizine in ketone solvents comprising of acetone, methyl ethyl ketone, dimethyl

ketone, 2-pentanone or mixture there of, preferably aqueous acetone at a temperature of 40-50°C;
b. optionally subjecting the reaction mixture to carbon treatment;
c. adding aqueous hydrochloric acid or spurging hydrochloric acid gas to
the filtrate obtained in step (b) at a temperature of 40-50'^C and further
stirring for 1-2 hours;
d. coolmg the reaction mass obtained in step (c) to an ambient
temperature and stirring the mass till the solid separates;
e. filtering the solid obtained in step (d) by conventional methods;
f optionally subjecting the compound obtained in step (e) for
purification in aqueous ketone solvents as described in step (a), preferably aqueous acetone; g. drying the compound obtained in step (e) or (f) at a temperature of 40-lOO^C, preferably SS-es'^C to afford the desired novel crystalline Form-I of Dextro or Levo rotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid. The crystalline Form-I of Dextro and Levo rotatory dihydrochloride salts of cetirizine obtained in the above process are having >99.5% enantiomeric excess purity. The Optical rotation for these crystalline forms have studied in 1% aqueous solution at 365 nm wavelength and found that +12.4" and -12.5° for Dextro and Levorotatory dihydrochloride salts respectively.
The second aspect of the present invention relates to novel amorphous form of Dextro and Levorotatory dihydrochloride salts of Cetirizine and process for preparation thereof

The novel amorphous form of dihydrochloride salts of Dextro and Levorotatory
Cetirizine of the present invention is characterized by X-ray powder diffractogram and
both are showing no well-resolved peaks.
The novel amorphous fomi of Dextro and levorotatory dihydrochloride salts of Cetirizine
of the present invention is having the X-ray powder diffractogram pattem substantially as
depicted in Figure (3) and (4) respectively.
Yet another embodiment of the present invention is to provide the process for the
preparation of novel amoiphous form of Dextro and Levorotatory dihydrochloride salts
of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!-piperazinyl] ethoxy] acetic acid (Dextro
and Levo rotatory dihydrochloride salt of Cetirizine), which comprises;
a. dissolving the Levo or Dextro rotatory dihydrochloride salt of Cetirizine in
aqueous ketone solvents comprising of acetone, methyl ethyl ketone,
dimethyl ketone, 2-pentanone or mixture there of, preferably aqueous
acetone at a temperature of 25-40'C;
b. filtering the reaction solution of step (a) to make the particle free solution;
c. distilling off the solvent from the reaction solution of step (b) under
reduced pressure at a temperature of below 80°C till the solid substantially
separates;
d. drying the solid obtained in step (c) at a temperature of 40-100°C,
preferably 80-90*^C to afford the desired novel amorphous form of Dextro
or Levo rotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl
methyl]-!- piperazinyl] ethoxy] acetic acid.

The amorphous form of dextro and levo rotatory dihydrochloride salts of Cetirizine
obtained in the above process is having moisture content varying from 0.3 to 12.0% by
KF method usually the moisture content of these compounds are having around
1.5 to 7.5% by KF method.
The moisture content of present inventive compounds are measured on Mettler DL-35
instrument using Karl-Fischer reagent.
The present inventive substances are &ee flowing, non-solvated and thermally stable;
hence these may be well suited for pharmaceutical formulations.
The processes of the present invention are simple, eco-fiiendly and commercially viable.
The present invention is illustrated by the following examples, which are not intended to
limit the effective scope of the claims.
PreparativeExample-1: Preparation of crude Levo rotatory [2-[4-[(4-Chlorophenyl)-
pbenyl methyl]-!- piperazjnyl] ethoxy] acetic acid (Levo rotatory cetirizine):
Dissolved the Levo rotatory 2-[4-[(4-Ch]orophenyl)-phenyl methyl}-! - piperazinyl]
ethanol (55 grams) in dimethyl formamide (165 ml) and cooled the reaction mixture to a
temperature of O-S^'C. Potassium hydroxide (28.0 grams) and sodium mono chloro
acetate (29.0 grams) were added to the cooled reaction solution, slowly raised the
temperature to room temperature and maintained at the same temperature till the reaction
substantially completes. Then the resulting reaction mass was diluted with water (605
ml) and heated to a temperature of 40-50°C, accompanied by washing the reaction mass
with toluene (4x110 ml). Then adjusted the P" of the aqueous layer to 4.0-4,5 with
concentrated hydrochloric acid, accompanied by extracting the reaction mass with
dichloromethane (2x165 ml). Washed the resulting organic layer with 10% sodium

chloride solution (2x165 ml) followed by water (2x165 ml). Carbon (2.7 grams) was added to the washed organic layer and heated to reflux temperature. Then the reaction mass was filtered and washed with dichJoromethane (55 mi) followed by evaporating solvent under vacuum to yield the crude Levo rotatory [2-[4-[(4-Chlorophenyl)-phenyl methy]]-] - piperazinyl] ethoxy] acetic acid in residual mass (60.6 grams). PreparativeEzamp!e-2: Preparation of crude Dextro rotatory [2-[4-[(4-Cbioropbmyiy-pbenyl metfaylj-l- piperazinyl] etboxy] acetic acid (Dextro rotatory cetirizine):
Dextro rotatory 2-[4-[(4-Chlorophenyl)-phenyl methyl]-l- piperazinyl] ethanol (105 grams) was added to the stirred reaction mixture of dimethyl foimamide (357 ml) and Potassium hydroxide (53.3 grams) accompanied by cooling the reaction mixture to a temperature of 0-5°C. Sodium mono chloro acetate (55.5 grams) was added to the cooled reaction solution, slowly raised the temperature to room temperature and maintained at the same temperature till the reaction substantially completes. Then the resulting reaction mass was diluted with water (1155 ml) and separated the bi-layer mixture accompanied by adjusting the P" of resulting aqueous layer to 9.5 with hydrochloric acid. Then fiirther separated the aqueous layer and washed with ethyl acetate (280x1+245x2 ml) accompanied by separation of aqueous layer form organic layer. Then adjusted the P of the aqueous layer to 4.0-4.5 with concentrated hydrochloric acid, accompanied by extractmg the reaction mass with dichloromethane (385x1+2x245 ml). Washed the resulting total organic layer with 10% sodium chloride solution (1x200 ml) followed by water (200 ml). The solvent from the resulting organic layer was evoporated under

vacuum to yield the crude Dextro rotatory [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!-
piperazinyl] ethoxy] acetic acid.
(Weight: 123.0 grams).
Example-l:
Preparation of novel crystalline Form-I of Dextro rotatory dihydrochloride salt of
Cetirizine:
The crude Levo rotatory [2-[4-[(4-Chlorophenyl)-phenyl methyl]-l- piperazinyl] ethoxy]
acetic acid (56.6 grams, prepared as per the Preparative Example-l) was dissolved in
acetone (825 ml) and heated to a temperature of 40-45'^C. Hydrochloric acid (32.0 ml)
was added and stirred the mass till the solid separates. Then separated solid was filtered,
washed with acetone (55 ml) and dried at a temperature of 55-60°C to get the required
crude product of Dextro rotatory dihydrochloride salt of 2-[2-[4-[(4-Chlorophenyl)-
phenyl methyl]-!- piperazinyl] ethoxy] acetic acid (Dextro rotatory dihydrochloride salt
of Cetirizine) (42.0 grams). Thus resulted crude product (40.0 grams) was further purified
in aqueous acetone to yield the required novel crystalline Form-I of Dextro rotatory
dihydrochloride salt of [2-[4-[(4-Ch]oTophaiy!)-phenyl methylj-l- pipCTazinyl] ethoxy]
acetic acid.
(Weight: 33.9 grams. Optical Rotation = (+) 12.5°, C=l% in water at 365 nm).
Ezample-Z:
Preparation of novel crystalline Form-I of Levo rotatory dihydrochloride salt of
Cetirizine:
Heated the reaction mixture of Dextro rotatory [2-[4-[(4-Chlorophenyl)-phenyl metiiyl]-
1- piperazinyl] ethoxy] acetic acid ([110 grams] prepared as per the Preparative

Example-2) and acetone (1100 ml) at a temperature of 40-50^C. Carbon (5.5 grams) was added to the resulting hot reaction mixture and stirred at the same temperature for 15-30 minutes accompanied by filtering and washing with acetone (550 ml). Then hydrochloric acid (64 ml) was added to the resulting filtrate at a temperature of 40-50°C and continued stirring for 1-2 hours. Then cooled the reaction mass to room temperature and stirred for 1-2 hours to separate the solid. The separated solid was filtered, washed with acetone (550 ml) and dried at a temperature of SS-es'^C to yield the required novel crystalline Form-I of Levo rotatory dihydrochloride salt of piu^ [2-[4-[(4-Chlorophenyl)-phenyl methylj-l- piperazinyl] ethoxy] acetic acid (71.4 grams). Thus resulted crude product (70.0 grams) was further purified in aqueous acetone to yield the required novel crystalline Form-I of Dextro rotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid.
(Weight; 58.5 grams. Optical Rotation = (-) 12.2°, C=l% in water at 365 nm). Example-3:
Preparatioii of novel amorphous form of Dextro rotatory dihydrochloride salt of Cetirizine:
Crystalline dextrorotatory dihydrochloride salt of [2-i;4-[(4-Chlorophenyl)-phenyl methylJ-l- piperazinyl] ethoxy] acetic acid (10 grams) was dissolved in mixture of acetone (40 ml) and water (100 ml) at 25-40°C. Filtered off the clear solution to eliminate the particles. The solvent was distilled off fi-om the filtered clear solution at below 80°C under vacuum till the solid separates. The separated solid was taken out and further dried at a temperature of 80-90°C to a constant weight to afford the novel amorphous form of title compound.

(Weight: 9.5 grams, M.C. by KF: 1.5%, Optical Rotation = {+) 12.1*^, C=l in water at
365 nm).
Example-4:
Levorotatory Cetirizine (10 grams) was dissolved in a mixtiu*e of water (40 ml) and
acetone (100 ml) at the room temperature. Hydrochloric acid (10 ml) was added to
reaction mixture and stirred for 10 to 30 min at a temperature of 30 to 35 " C. Then, the
reaction solution was filtered and distilled off the solvent completely to dryness at a
temperature of below 80 " C. Cyclohexane (100 ml) was added to the residual mass and
stirred for 30-^0 minutes at a temperature of 30-35°C. TTie obtained product was filtered
and washed with cyclohexane (50 ml) and on subsequent drying at a temperature of
80-85 ° C to a constant weight resulted the novel amorphous form of dextrorotatory
dihydrochloride salt of Cetirizine.
(Weight: 9.9 grams)
Example-5:
Preparation of novel amorphous form of Levo rotatory dihydrochloride salt of
Cetirizine:
Crystalline Levorotatory dihydrochloride salt of Cetirizine (5.0 grams) was dissolved in a
mixture of acetone (20 ml) and water (50 ml) further the reaction mixture was stirred at a
temperature of 25-35*^0 to get a clear solution. The reaction solution was filtered and
solvent was distilled off from the reaction solution completely to dryness at a temperature
of 50-75°C under reduced pressure to result the amorphous form of Levo Cetirizine
dihydrochloride. The amorphous form of Levo Cetirizine dihydnachloride was further

dried at a temperature of 65-70 "C to a constant weight to afford the novel amoiphous
form of Levo Cetirizine dihydrochloride.
{Weight: 4.2 grams; M.C. by KF: 5.8%, Optical Rotation = (-) 11.7°, C=l in water at 365
nm).
£xsiiip)e-6:
Dextro Cetirizine (5 grams) was dissolved in a mixture of water (20 ml) and acetone (50
ml) at the room temperature. Hydrochloric acid (5 ml) was added to reaction mixture and
stirred for 10 to 30 min at a temperature of 30 to 35 ° C. Then, the reaction solution was
filtered and distilled offtfie solvent completely to dryness at a temperature of below 80 °
C. Cyclohexane (50 ml) was added to the residual mass and stirred for 30 minutes at a
temperature of 30-35°C. The obtained product was filtered and washed with cyclohexane
(25 ml) and on subsequent drying at a temperature of 60-110° C to a constant weigjit
resulted the novel amorphous form of Levo rotatory dihydrochloride salt of cetirizine
(Weight: 4.7 grams, M.C by KF: 1.7%)
DETAILED DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Fig.l is a characteristic X-ray powder diffraction pattern of novel crystalline Form-I of
Dextro rotatory dihydrochloride salt of Cetirizine.
Vertical axis: Intensity (CPS); Horizontal axis; Two Tbeta (degrees).
The significant 2-theta values are 7.053, 7.955, 14.347, 14.805, 17.394, 18.170, 18.591,
18.815, 20.327, 22.330, 23.354, 24.158, 24.325, 24.727, 25.247, 26.514, 26.799, 27.347
and 30.571two-theta degrees.
Iilg.2 is a characteristic X-ray powder diffraction pattern of novel crystalline Form-I of
Levo rotatory dihydrochloride salt of Cetirizine.

Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees).
The significant 2-theta values are 7.096. 8.018, 14.408, 14.87, 17.475, 18.244, 18.648,
18.855, 22.388, 23.415, 24.211, 24.361, 24.812. 25.311, 26.602 and 29.282 two-theta
degrees.
Fig: 3 is characteristic X-ray powder diffraction pattern of novel amorphous form of
Dextro rotatory dihydrochloride salt of Cetirizine.
Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees).
It shows a plain halo with no peaks, which is characteristic of the amorphous nature of
product.
Fig: 4 is characteristic X-ray powder diffraction pattern of novel amorphous form of
Levo rotatory dihydrochloride salt of Cetirizine.
Vertical axis: Intensity (CPS); Horizontal axis: Two Theta (degrees).
It shows a plain halo with no peaks, which is characteristic of the amorphous nature of
product.



We claim:
A novel crystalline Form-I of Dextro and Levo rotatory dihydrochloride salts of [2-[4-t(4-Chlorophenyl)-phenyl methyl]-!- piperazlnyl] ethoxy] acetic acid (Dextro and Levq 'rotatory dihydrochloride salts of Cetirizine).
The novel crystalline Form-I of dihydrochloride salts of Cetirizine as claimed in claim 1
is Dextro rotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-1-
' piperazinyl] ethoxy] acetic acid (Dextro rotatory dihydrochloride salt of Cetirizine).
3. The novel crystalline Fonn-I of dihydrochloride salts of Cetirizine as claimed in claim 1 is Levo rotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenylmethyl]-l-piperazinyl] ethoxy] acetic acid (Levo rotatory dihydrochloride salt of Cetirizine). The novel crvstalline Form-I of Dextro rotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid of claim 2 has X-ray Powder diffraction pattern with significant 2-theta values are 7.053, 7.955,14.347, 14.805. 17.394,18.170, 18.591, 18.815,20.327,22.330,23.354,24.158,24.325, 24.727,25.247,26.514,26.799,27.347 and 3D.571two-theta degrees. The noy« crystalline Form-I of Dextro rotatory dihydrochloride salt of [2-i;4-[(4-

Chlorophenyl)-phenyl methyl]-l- piperazinyl] ethoxy] acetic acid of claims 2 and 4, \ which provides X-ray powder diffraction pattern substantially in accordance
6. The novel crystalline Form-I of Levo rotatory dihydrochloride salt of [2-[4-[(4-
Chlorophenyl)-phenyl methyl]-l- piperazinyl] ethoxy] acetic acid of claim 3 has X-ray Powder diffraction pattern with significant 2-theta values 7.096, 8.018,14.408,14.87,

17.475, 18.244,18.648, 18.855, 22.388, 23.415,24.211, 24.361, 24.812;;25.311,26.602 and 29.282 two-theta degrees.
7. The novel crystalline Form-I of Levo rotatory dihydrochloride salt of [2-|4-[(4-Chlor6phenyl)-phenyl methy]-l- piperazinyl] ethoxy] acetic acid of claim 3 and 6' which provides X-ray powder diffraction pattern substantially in accordance ivith Figure (2).
8. A process for the preparation of novel crystalline Forni-I of Dextro and Levo rotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-1 - piperaiinyl] ethoxy] acetic acid, which comprises;
a. heating the reaction mixture of Levo or Dextro rotatory Cetirizine in
ketone solvents comprising of acetone, methyl ethyl ketone, dimethyl
ketone, 2-pentanone or mixture there of, preferably acetone at a
temperature 40-50°C;
b. optionally subjecting the reaction mixture to carbon treatment
c. adding aqueous hydrochloric acid or spurgjng hydrochloric acid gas to the
filtrate obtained in step (b) at a temperature of 40-50°C and further sturing
for 1-2 hours;
d. cooling the reaction mass obtained in step (c) to an ambient temperature
and stirring the mass till the soUd separates;
e. filtering the solid obtained in step (d) by conventional methods;
f optionally subjecting me compoimd obtained in step (e) for purification in aqueous ketone solvents as described in step (a), preferably aqueous acetone;

g. drying the compound obtained in step (e) or (f) at a temperature of 40-100C, preferably 55-65°C to afford the desired novel crystalline Form-I of Dextro or Levo rotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid. 9. The process according to steps (a) and (f) of claim 8, where in the said ketone solvent is acetone.
A novel amorphous form of Dextro and Levorotatoiy dihydrochloride salts of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid (Dextro and Levo rotatory dihydrochloride salts of Cetirizine).
The novel amorphous form of dihydrochloride salts of Cetirizine as claimed in claim 10 is Dextro rotatory (^hydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!-piperazinylj'ethoxy] acetic acid (Dextro rotatory dihydrochloride salt of Cetirizine). The novel amorphous form ofdihydrochloride salts of Cetirizine as claimed in claim 10 ' is Levo rotatory dihydrochloride salt of [2-[4-[(4-ChlorophenyI)-phenyl methyl]-!-piperazinyl] ethoxy] acetic acid (Levo rotatory dihydrocliloride salt of Cetirizine). The amorphous form of dextrorotatory dihydrochloride salt of Cetirizine according to claim 1!, which provides X-ray powder diffraction pattern substantially in accordance with Figure (3).
The amorphous form of levorotatoiy dihydrochloride salt of Cetirizine according to claim 12, which provides X-ray powder diffraction pattern substantially in accord^ce with Figure (4).

15. The amorphous form of dextro and levo rotatory dihydiopchloride salt of Cetirizine of
claims 11 and 12, which is having moisture content varying from0.3 to 12.0% by KF method.
16. The amorphous form of dextro and levo rotatory dihydrochloride saR of Cetirizine of claim 15, which is having moisture content from 1.5 to 7.5 % hy KF method.
17. A process for the preparation of novel amorphous form of l^extro and X^vorotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl methyl]-!- piperazinyl] ethoxy] acetic acid, which comprises;

a) dissolving the Levo or Dextro rotatory dihydrochloride salt of Cetirizine in aqueous ketone solvents comprising of acetone, methyl ethyl ketone, dimethyl ketone, 2-pentanone or mixture there of, preferably aqueous acetone at a temperature of 25-40'^C;
b) filtering the reaction solution of step (a) to make the particle free solution;
c) distilling off the solvent from the reaction solution of step (b) iftider ■ -reduced pressure at a temperature of below 80°C till the solid
I
substantially separates; ^
d) drying the solid obtained in step (c) at a temperature of 40-100°C,
preferably 80-90*^C to afford the desired novel amorphous^form of
Dextro or Levo rotatory dihydrochloride salt of [2-[4-[(4-
Chloropheny])-phenyl methyl];:;! - pip^i-azinyl] ethoxy] acetic acilJ.
18. The process according to sten fa! of claim 17.Where in fee siid ketone solvent is
acetone.

19. The processes for the preparation of novel crystalline Form-I and amorphous forms of
I ■■;
Dextro and Levo rotatory dihydrochloride salt of [2-[4-[(4-Chlorophenyl)-phenyl ■'
methy-1- piperazinyl] ethoxy] acetic acid are substantially as here in described and
exemplified.


Documents:

0908-mas-2002 abstract.pdf

0908-mas-2002 claims.pdf

0908-mas-2002 correspondence-others.pdf

0908-mas-2002 correspondence-po.pdf

0908-mas-2002 description (complete).pdf

0908-mas-2002 drawings.pdf

0908-mas-2002 form-1.pdf

0908-mas-2002 form-18.pdf

0908-mas-2002 form-3.pdf

908-mas-2002 claims 04-02-2011.pdf

908-mas-2002 claims 11-09-2009.pdf

908-mas-2002 correspondence others 04-02-2011.pdf

908-MAS-2002 CORRESPONDENCE-OTHERS 07-12-2009.pdf

908-MAS-2002 CORRESPONDENCE-OTHERS 11-09-2009.pdf

abs-908-mas-2002.jpg


Patent Number 246854
Indian Patent Application Number 908/MAS/2002
PG Journal Number 12/2011
Publication Date 25-Mar-2011
Grant Date 17-Mar-2011
Date of Filing 04-Dec-2002
Name of Patentee DR. REDDY'S LABORATORIES LIMITED
Applicant Address INDIAN COMPANY HAVING ITS REGISTERED OFFICE AT 7-1-27, AMEERPET, HYDERABAD, ANDHRA PRADESH, INDIA, 500 016.
Inventors:
# Inventor's Name Inventor's Address
1 SATYANARAYANA REDDY MANNE, INDIAN COMPANY HAVING ITS REGISTERED OFFICE AT 7-1-27, AMEERPET, HYDERABAD, ANDHRA PRADESH, INDIA, 500 016.
2 THIRUMALAI RAJAN SRINIVASAN, INDIAN COMPANY HAVING ITS REGISTERED OFFICE AT 7-1-27, AMEERPET, HYDERABAD, ANDHRA PRADESH, INDIA, 500 016.
3 VENKATA BHASKARA RAO UPPALA INDIAN COMPANY HAVING ITS REGISTERED OFFICE AT 7-1-27, AMEERPET, HYDERABAD, ANDHRA PRADESH, INDIA, 500 016.
4 PATTABHI RAMAYYA VADDADI INDIAN COMPANY HAVING ITS REGISTERED OFFICE AT 7-1-27, AMEERPET, HYDERABAD, ANDHRA PRADESH, INDIA, 500 016.
5 RAJENDER JOGA INDIAN COMPANY HAVING ITS REGISTERED OFFICE AT 7-1-27, AMEERPET, HYDERABAD, ANDHRA PRADESH, INDIA, 500 016.
PCT International Classification Number A61K31/13
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA