FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)
A PROCESS FOR THE PREPARATION OF A COMBINATION OF DESLORATADINE POLYMORPHS 1 and 2 IN EQUAL PROPORTIONS BY
CRYSTALISATION
M/S. TONIRA PHARMA LIMITED, 301, Yogi Complex, 44, Sampatrao Colony, Alkapuri, Vadodara - 390 005, an Indian Company incorporated under the Companies Act,
1956.
The following specification particularly describes and ascertains the nature of this invention, and the manner in which it is to be performed.
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This invention relates to "A process for the preparation of a combination of Desloratadine Polymorphs 1 and 2 in equal proportions by crystallization".
The present invention relates to "A process for the preparation of a combination of Desloratadine Polymorphs 1 and 2 in equal proportions by crystallization". Desloratadine Chemical name is 8-Chloro-6,ll-dihydro-ll-(4-piperidylidene)-5H-benzcyclohepta[l,2-b]pyridine.
Desloratadine is the major active metabolite of Loratadine. It is a more potent Hi receptor antagonist than Loratadine itself; however, Desloratadine is also a more potent antimuscarinic agent than Loratadine when tested in concentrations and doses which far exceed those, which exhibit antihistamine activity.
There are two polymorphs of Desloratadine reported as Polymorph "1" and Polymorph "2" and their manufacturing process has been reported by M/s. Schering Corporation U.S. A, in the Patent WO 99/01450 (Jan. 14, 1999), The Desloratadine Polymorph "1" and Desloratadine Polymorph "2" differ in their I.R Spectra, and X-Ray Diffraction Data
The characteristic peaks in the IR Spectra are given in the following table

Polymorph Form 1 Polymorph Form 2
3303 cm"1 3326 cm"1
1290 cm"1 1153 cm"1
803 cm*1 1133 cm1
780 cm*1 795 cm"1
771 cm'1
655 cm"1
Similarly the X-ray powder diffraction pattern distinctive for crystalline polymorph Form 1 and Polymorph Form 2 having characteristic peaks expressed in terms of "d" spacing and relative intensities are given in the following table :

Polymorph Form 1 Polymorph Form 2
9.04 Weak 8.34 Weak
6.42 Weak 6.87 Medium
5.67 Weak 6.20 Medium
5.02 Weak 4.90 Medium
3.58 Weak
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The process for the preparation of the individual Desloratadine Polymorph Form 1 and Polymorph Form 2 , from Loratadine is described in WO 99/01450 (Jan. 14, 1999).This involves the reaction of Loratadine with alcoholic Potassium hydroxide, followed by extraction with Methyl Isobutyl ketone and the organic layer after washing is partially concentrated and crystallized to give crystals , which was dried to give Desloratadine Polymorph 1 Similarly using an ethyl acetate medium and crystallization forms the Desloratadine of Polymorph 2.
Polymorphs of Desloratadine hemifumarate (Polymorph 1 and Polymorph 2) have been described Geneva Pharmaceuticals inc. in WO 2004/012738 (12th February 2004)
Kovacsne et al have filed a U S Patent application US 2004242619 (Dec 2 2004) equivalent to WO2004108700(Dec 16, 2004) for the process for preparation of polymorphic forms of Desloratadine.
Tonira Pharma has filed an Indian Patent Application No 147/MUM/2005 dated 11th February 2005 entitled "A Process for the preparation of combination of Desloratadine Polymorphs 1 and 2 ".
Desloratadine Polymorph 1 and 2 posses antihistaminic properties as demonstrated in standard animal models.
The combination of desloratadine Polymorphs I & II prepared by existing process does not possess desired solubility properties and dissolving is also uncontrollable.
The main object of this invention is to provide "A process for the preparation of a combination of Desloratadine Polymorphs 1 and 2 in equal proportions" where by the dissolving rates can be controlled and the desired solubility properties of the Desloratadine Polymorph 1 and 2 can be achieved.
Accordingly this invention provides
A process for the preparation of a combination of Desloratadine Polymorphs 1 & 2 in Equal Proportion by crystallization comprising the following steps:
a. Dissolving crude Desloratadine in Acetonitrile in the ratio of 1 : 5 to 1 : 15
under reflux conditions.
b. Cooling the solution of step (i) to a temperature of 5 to 0° C at a cooling
rate of 1 to 5° C per minute to achieve a crystalline slurry.
c. Filtering the slurry of step ( ii ) washing & drying the templates between
from 5°to 100°C to obtain a combination of Desloratadine Polymorphs 1 &
2.
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Desloratadine is prepared by reacting Loratadien with Potassium Hydroxide under pressure between 0.5 to 5 Kg / Cm2 temperature between 5°to 100°C.
Isolation of Desloratadine is carried out in the following steps:
a. Dissolving Loratadine in an alcoholic solvent;
b. Replacing the Loratadine solution of step (i) with a solution of Potassium
hydroxide 2.0 to 20.0 moles;
c. Heating the mixture of step (ii) at temperature of 50°to 100°C at a pressure
of 0.5 to 5 Kg / Cm2 carrying out the reaction between 2 to 15 hours.
d. Cooling the reaction mixture of step (iii) and working up by concentration
and extraction with ethyl Acetate to isolate Desloratadine;
The said alchoholic solvent is having C1 to C5 Carbon atoms with straight or branched chains.
The Loratadine is dissolved in Ethanol in a ratio ofl:5tol:15w/v
The Potassium Hydroxide is dissolved in water at the ratio of 1 : 3 to 1 : 5 w/v and added to the solution of Loratadine in ethanol at the temperature between 25 to 30°C.
The residue after solvent is dissolved in Acetonitrile under reflux condition is given carbon treatment and cooled to 5 to 0°C followed by filtering and drying to obtain Crystaline Desloratadine.
A process in which Loratadine is reacted with Methanolic Potassium hydroxide in an autoclave at a temperature of 100° to 120° C for 4 to 8 hrs. The resulting solution is quenched in to water after cooling and extracted with ethyl acetate and after the solvent recovery is crystallized from acetonitrile to give a combination of Desloratadine polymorphs 1 and 2.
(a) Reacting Loratadine (ethyl 4-(8-chloro-5,6-dihydro-l l#-benzo[5,6]cyclohepta [1,2-6]pyridin-l l-ylidene)piperidine-l-carboxylate with ethanolic Potassium hydroxide at 80°C to 85°C for 7-8 hrs under pressure of 2 kg/cm2 in an autoclave.
(b) After the completion of the reaction the pressure is released, the solution filtered and the solvent recovered under vacuum.
(c) The residue is diluted with brine, followed by extraction with Ethyl acetate two to three times to ensure that all the Desloratadine is extracted in to the organic phase.
(d) Concentration of the Ethyl acetate layer under vacuum to give Crude Desloratadine.
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The advantage of this method is in the drastic reduction of time cycle in manufacturing the product compared to the prior art.
The Crude Desloratadine is crystallized to the combination of Polymorphs I and II by the following process.
(a) Crystallisation of Crude Desloratadine by dissolving in Acetonitrile followed by filtration and cooling the filtrate to 0-5°C separates Desloratadine in a crystalline form.
(b) Filtering out the wet crystals of Desloratadine Polymorphs land 2 combination;
(c) Drying the said crystals of Desloratadine Polymorphs 1 and 2 combination in an oven.
(d) In order to confirm the equal content of Desloratadine Polymorph I and Polymorph 2, we prepared the individual Desloratadine polymorphs 1 and 2 by the process described in WO 99/01450 (Jan. 14, 1999). The X Ray diffraction spectra of the Polymorph 1 and Polymorph 2 are given in Fig.l and Fig. 2 respectively.
(e) An equal weight mixture of Desloratadine polymorph 1 and Desloratadine Polymorph 2 was prepared by mixing equally weighed quantity of polymorph 1 and polymorph 2. The X Ray diffraction spectrum of the mixture of polymorphs ingiveninFig.3.
(f) The X Ray diffraction spectrum of the sample prepared by our process of crystallization from Acetonitrile, is given in Fig. 4. The superimposition of this spectrum with that of the X ray diffraction spectrum of the equal weight mixture of Polymorph 1 and Polymorph 2 is given in Fig. 5.
(g) This superimposition clearly indicates that the product prepared by our process of crystallization from Acetonitrile is a combination of Desloratadine polymorphs in equal proportions.
The following examples are illustrations of the process of preparation of Desloratadine polymorph 1, Desloratadine polymorph 2 and a combination of Desloratadine polymorph 1 and 2 (according to this invention).
Preparation of Desloratadine Polymorph 1
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To a solution of 60.0 g Potassium hydroxide flakes in 200 ml of industrial methylated spirit 50.0 g of Loratadine was added. The so formed mixture was heated under reflux for 3 hrs and 150 ml water was added. The so formed mixture was distilled at atmospheric pressure until the temperature of the mixture reached 108° C. The mixture was cooled to 68° C and 150 ml of Methyl Isobutyl ketone (MIBK) were added and the mixture was agitated until all the solids were dissolved. The organic layer was separated and washed with water at 80° C, until the separated aqueous layer had a pH of 9.0. Fifty (50 ml) of MIBK were then removed from the organic layer by distillation at atmospheric pressure and so formed organic layer was cooled to around 0° C for 1 hour. The resulting crystalline product was separated, washed with MIBK (2 X12 ml).The so formed product was dried at 60° C for 6 hrs to give 29.05 g of Polymorph 1 as a white crystalline solid, mp 156.8 to 157.7° C (XRD Spectrum Fig. 1)
Preparation of Desloratadine Polymorph 2
A solution of 36.6 g of descaroethoxyloratadine (prepared as described in Example IV of US Patent 4, 65,716) in 300 ml of ethyl acetate was heated to reflux ; 1.5g of Darco decolorizing charcoal and 2.5 g of supercel filtering aid were added and the so formed mixture was further refluxed for 10 min. The mixture was filtered while hot through a supercel filter mat. The filtrate was concentrated at elevated temperature to 650 ml. The so-formed concentrated filtrate was rapidly cooled to 0° C. The resulting precipitate was filtered, washed with hexane and dried in an air draft oven at 55-60° C to give 33.2 g of polymorphic form 2 descarboethoxyloratadine as a white crystalline solid, having mp 154.0 to 155.5°C. (XRD Spectrum Fig 2)
Example 1
Preparation of combination of Desloratadine polymorphs in equal proportions. (1.1)
In a 5.0 liter autoclave (pressure reactor) Ethanol (780 ml) and Loratadine (100 g) are taken and mixed well by stirring till a clear solution is obtained. A solution of Potassium hydroxide (160 g) in Deionised water (680 ml) and cooled to 20° C. The Potassium hydroxide solution is added to the solution of Loratadine in ethanol at a temperature not exceeding 25-30° C. The autoclave valves are closed and the contents are heated under stirring slowly to 50° C (Pressure : 0.8 kg/cm2 ).The temperature is further raised to 70° C (Pressure : 1.0 kg/cm2) and then to 85° C (Pressure . 2.0 kg/cm2 ). It is maintained at 85° C (Pressure : 2.0 kg/cm2 ) for 7-8 hrs. the completion of the reaction is monitored by TLC for the absence of Loratadine . The autoclave is cooled and the contents are taken out and filtered. The filtered solution is concentrated under vacuum. The residue was diluted with brine solution and extracted with ethyl acetate (3 X 450 ml) at 15°C to 20°C. the organic layer was dried over anhydrous Sodium sulphate. After the solvent recovery, the residue obtained was dissolved in Acetonitrile (800 ml) under reflux conditions. The acetonhrile solution was given a Carbon treatment and cooled to 0°C to 5°C. The crystalline Desloratadine is filtered and dried. (XRD Spectrum Fig. 4)

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We claim:
1. A process for the preparation of a combination of Desloratadine Polymorphs 1 and
2 in Equal Proportion by crystallization comprising the following steps:
i. Dissolving crude Desloratadine in Acetonitrile in the ratio of 1 : 5 to 1 : 15
under reflux conditions; ii. Cooling the solution of step (i) to a temperature of 5 to 0° C at a cooling
rate of 1 to 5° C per minute to achieve a crystalline slurry; iii. Filtering the slurry of step (ii) washing and drying the templates between
from 5°to 100°C to obtain a combination of Desloratadine Polymorphs 1 and
2.
2. The process as claimed in claim 1 wherein Desloratadine is prepared by reacting Loratadien with Potassium Hydroxide under pressure between 0.5 to 5 Kg / Cm temperature between 50 to 100°C.
3. The process as claimed in claim 1 or 2 wherein isolation of Desloratadine is carried out in the following steps :
i. Dissolving Loratadine in an alcoholic solvent;
ii. Reacting the Loratadine solution of step (i) with aqueous solution of
Potassium hydroxide 2.0 to 20.0 moles; iii. Heating the mixture of step (ii) at temperature of 50°to 100°C at a pressure
of 0.5 to 5 Kg / Cm2 and carrying out the reaction between 2 to 15 hours; iv. Cooling the reaction mixture of step (Hi) and working up by concentration
and extraction with ethyl Acetate to isolate Desloratadine.
4. The process as claimed in claim 3 wherein the said alcoholic solvent is having C1 to C5 Carbon atoms with straight or branched chains.
5. The process claimed in claim 3 wherein the Loratadine is dissolved in Ethanol in a ratio of 1 : 5 to 1 : 15 w / v.
6. The process as claimed in claim 3 wherein the Potassium Hydroxide is dissolved in deionised water in the ratio of 1 : 3 to 1 : 5 w/v and added to the solution of Loratadine in ethanol at the temperature between 25 to 30°C.
7. The process as claimed in claim 3 wherein the residue after solvent recovery is dissolved in Acetonitrile under reflux condition is given carbon treatment and cooled to 5 to 0°C followed by filtering and drying to obtain Crystalline Desloratadine.

8. A process for the preparation of a combination of Desloratadine Polymorphs 1 and 2 in equal proportions by crystallization substantially as herein described and illustrated in the figures 1 to 5 of the drawing accompanying the specification.
9. Desloratadine Polymorphs I & II combination in equal proportion obtained by the process as claimed in claim 1 to 8
Dated this 13th day of April 2006
V RAMU
Agent for the Applicant

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ABSTRACT
A process for the preparation of a combination of Desloratadine Polymorphs 1 & 2 in Equal Proportion by crystallization comprising the following steps:
i. Dissolving crude Desloratadine in Acetonitrile in the ratio of 1 : 5 to 1 : 15 under reflux conditions.
ii. Cooling the solution of step (i) to a temperature of 5 to 0° C at a cooling rate of I to 5° C per minute to achieve a crystalline slurry.
iii. Filtering the slurry of step (ii) washing & drying the templates between from 5°to 100°C to obtain a combination of Desloratadine Polymorphs I & 2.

Dated this 13m day of April 2006

VRAMU
Agent for the Applicant

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