FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)

A PROCESS FOR THE PREPARATION OF A COMBINATION OF POLYMORPHS 1
and 2 OF DESLORATADINE AND DESLORATADINE POLYMORPHS 1 and 2
COMBINATION PREPARED BY THE SAME.

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.


The present invention relates to A process for the preparation of a combination of Polymorphs 1 and 2 of Desloratadine and Desloratadine Polymorphs 1 and 2 combination prepared by the same. (8-Chloro-6, ll-dihydro-ll-(4-piperidylidene)-5H-benzcycloheptaf 1,2-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 USA, 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 cm"1
780 cm"' 795 cm"1
771 cm"1
655 cm"
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

The process for the preparation of the individual Desloratadine Polymorph Form 1 and Desloratadine 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 Form 1. Similarly using an ethyl acetate medium and crystallization forms the Desloratadine of Polymorph Form 2.
Polymorphs of Desloratadine hemifumarate (Polymorph Form 1 and Polymorph Form 2) have been described in Geneva Pharmaceuticals Inc. in WO 2004/012738 (12th February 2004).
Recently Kovacsne et al have filed a US Patent application US 2004242619 (Dec 2 2004) equivalent to WO2004108700 (Dec. 16, 2004) for the process for preparation of polymorphic forms of Desloratadine.
Desloratadine Polymorph Form 1 and Form 2 posses antihistaminic properties as demonstrated in standard animal models.
We have developed a process for the manufacture of a combination of Desloratadine Polymorphs 1 and 2 preferably in the ratio of 1.1.
The main object of this invention is to provide "A process for the preparation of a combination of Polymorphs 1 and 2 of Desloratadine and Desloratadine Polymorphs 1 and 2 combination prepared by the same" where by the dissolving rates can be controlled and the desired solubility properties of the Desloratadine Polymorphs 1 and 2 can be achieved.
Accordingly this invention provides a process in which Loratadine is reacted with Potassium hydroxide in an autoclave at a temperature of 50° to 150° C under pressure between 0.5 kg/cm2 to 5 kg/cm2 for 2 to 15 hours , the resulting solution is quenched in to water after cooling and extracted with ethyl acetate forming crude Desloratadine which after the solvent recovery is crystallized from acetonitrile to give a combination of Desloratadine polymorphs 1 and 2.
(a) dissolving Loratadine (ethyl 4-(8-chloro-5, 6-dihydro-l \H-benzo[5,6] cyclohepta [1,2-6]pyridin-l l-ylidene)piperidine-l-carboxylate in an alcoholic solvent having Q to C5 carbon atoms (straight or branched chains) 10%w/v to 30%w/v solution preferably around 20%w/v solution;
(b) reacting Loratadine solution with aqueous solution of Potassium hydroxide or Sodium hydroxide at 50°C to 150°C preferably 80°C to 85°C for 2 to 15 hours preferably for 7 to 8 hours under pressure of 0.5kg/cm2 to 5 kg/cm2 preferably 2kg/cm2 in an autoclave (20 moles to 200 moles);
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(c) after the completion of the reaction the pressure is released, the solution filtered and the solvent recovered under vacuum;
(d) the residue is diluted with brine, followed by extraction with Ethyl acetate two to three times to ensure that all the Desloratadine and Loratadine is extracted in to the organic phase;
(e) concentration of the Ethyl acetate layer under vacuum to give Crude Desloratadine. 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 preparation of the above step (e) is crystallized to prepare the combination of Polymorphs I and II by the following process steps
(f) crystallisation of Crude Desloratadine by dissolving in Acetonitrile followed by,
filtration and cooling the filtrate to 0 to 5°C for separating Desloratadine in a
crystalline form;
(g) filtering out the wet crystals of Desloratadine Polymorphs land 2 combination;
(h) drying the said crystals of Desloratadine Polymorphs 1 and 2 combination in an
oven at 50 to 100°C preferably 70°C for 4 to 8 hours preferably 6 hours;
The High Resolution Infra Red Spectrum of the product shows specific absorption at 3324.49 cm"1 and 3302.42 cm"1. Incidentally the absorption at 3301.90 cm"1 is characteristic of Polymorph 1 and 3324.49 cm"1 is characteristic of Polymorph 2.
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.
Example 1
Preparation of Desloratadine Polymorph 1
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 XI2 ml).The so formed product was dried at 60° C for 6 hours to give 29.05 g of Polymorph 1 as a white crystalline solid, mp 156.8 to 157.7° C
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Example 2
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 and containing 100% form 2 by FTIR spectrophotometry.
Example 3
Preparation of Combination of Desloratadine polymorphs 1 and 2.
In a 5.0 litre 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) is preferred and cooled to 20°C. The Potassium hydroxide solution is added to the solution of Loratadine in ethanol at a temperature not exceeding 25 to 30°C. The autoclave valves are closed and the contents are heated under stirring slowly to 50°C (Pressure: 0.8kg/cm2). The temperature is further raised to 70°C (Pressure: 1.0kg/cm2) and then to 85°C (Pressure: 2.0kg/cm2). It is maintained at 85°C (Pressure: 2.0kg/cm2) for 7 to 8 hours, 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 acetonitrile solution was given a Carbon treatment and cooled to 0°C to 5°C. The crystalline Desloratadine is filtered and dried in an oven at 70°C for 6 hours.
Example 4
Preparation of Combination of Desloratadine polymorphs 1 and 2.
In a 5.0 litre autoclave (pressure reactor) Methanol (400 ml) and Loratadine
(100 g) are taken and mixed well by stirring till a clear solution is obtained. A solution of
Sodium hydroxide (55 g) is added at onceand the exotherm takes place . The autoclave
valves are closed and the contents are heated under stirring slowly to 50°C (Pressure:
0.8kg/cm2). The temperature is further raised to 70°C (Pressure: 1.0kg/cm2) and then to
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85°C (Pressure: 2.0kg/cm2). It is maintained at 85°C (Pressure: 2.0kg/cm2) for 4.0 hours, 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 solution is cooled to 20°C and D M Water 250 ml is added. The mixing is effected for 1.0 hrs at 20°C and the resulting slurry is centrifuged, washed with D M Water till free from alkali and dried in an oven at 50°C. The product is dissolved in Acetonitrile (400 ml) and the solution is given a Carbon treatment and cooled to 0°C to 5°C. The crystalline Desloratadine is filtered and dried in an oven at 70°C for 6 hours. The product obtained is an equal mixture of Desloratadine Polymorph 1 and 2.
Figures 1 to 4 of the drawing accompanying the specification shows the relevant graphs.
Figure 1 of the accompanying drawing shows the relevant graphs confirmed by checking the IR spectrum of the individual Polymorphs and the combination of the Polymorphs 1 and 2 exhibiting the characteristic bands.
Figure 2 of the accompanying drawing shows the relevant XRDs of Polymorph 1.
Figure 3 of the accompanying drawing shows the XRD of Polymorph mixture 1 and 2 and
Figure 4 of the accompanying drawing shows the XRDs of the combination of Polymorphs2.
The combination of polymorphs is confirmed by checking the IR spectrum of the Individual polymorphs and the combination which exhibits characteristic bands at 3302 cm"1 (Polymorphic form 1) and 3324.29cm-1 (Polymorphic form 2). The relevant graphs are enclosed in Figure 1.
The XRD pattern of the combination of polymorphs, when compared with the XRD of the individual polymorphs clearly indicates the characteristic peaks of 1 and 2. The relevant XRDs of Polymorph 1 (Figure 2), XRD of Polymorph 2 (Figure 4) and the combination of polymorphs (Figure 3) are enclosed.
The above description with reference to examples and figures has been given just to understand the invention rather than to limit its scope.
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We claim:
(1) The process for the preparation of a combination of Polymorphs 1 and 2
Desloratadine (8-chloro-11 -piperidin-4-ylidene-6,11 -dihydro-5//-
benzo[5,6]cyclohepta[l,2-6]pyridine):
(a) dissolving Loratadine (ethyl 4-(8-chloro-5, 6-dihydro-ll//-benzo|5,6] cyclohepta [l,2-6]pyridin-ll-ylidene)piperidine-l-carboxylate in an alcoholic solvent having Ci to C5 carbon atoms (straight or branched chains) 10%w/v to 30%w/v solution preferably around 20%w/v solution;
(b) reacting Loratadine solution with aqueous solution of Potassium hydroxide at 50°C to 150°C preferably 80°C to 85°C for 2 to 15 hours preferably for 7 to 8 hours under pressure of 0.5kg/cm2 to 5 kg/cm2 preferably 2kg/cm2 in an autoclave (20 moles to 200 moles);
(c) releasing the pressure of the above reaction of step (b) and filtering the solution with solvent recovery under vacuum;
(d) diluting the residue of step ( c) with brine followed by concentration and extracting ethyl acetate to isolate crude Desloratadine;
(e) Crystallization of crude Desloratadine of step (d) by dissolving in acetonitrite followed by filtration and cooling the filtrate at 0 to 5°C for separating out Desloratadine in crystalline form;
(f) Filtering out the wet crystals of Desloratadine polymorphs 1 and 2 combination and drying the said crystals in an oven at 50 to 100°C preferably at 70°C for 4 to 8 hours preferably at 6 hours.

(2) The process for the preparation of a combination of Polymorphs 1 and 2 Desloratadine as claimed in claim 1 wherein alcoholic solvent used in step 1 of claim 1 is ethanol.
(3) The process for the preparation of a combination of Polymorphs 1 and 2 Desloratadine as claimed in claim 1 wherein the Potassium hydroxide used in the reaction is methanolic Potassium hydroxide.
(4) The process for the preparation of a combination of Polymorphs 1 and 2 Desloratadine as claimed in claim 1 wherein hydroxide is ethanolic.
(5) The process for the preparation of a combination of Polymorphs 1 and 2 Desloratadine as claimed in claim 1 wherein the crude Desloratadine of step (d) is dissolved in 5 to 15 times preferably 8 to 9 times in volumes of Acetonitrite under reflux conditions.
(6) The process for the preparation of a combination of Polymorphs 1 and 2 Desloratadine as claimed in claim 5 wherein the solution obtained is cooled to 0 to 5°C at a cooling rate of 1°C to 5°C preferably 2°C per minute to get a crystalline slurry.
(7) The process for the preparation of a combination of Polymorphs 1 and 2 Desloratadine substantially as herein described and illustrated in the example 3 and figures 1 to 4.
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(8) The combination of polymorph 1 and 2 of Desloratadine as prepared by the process as claimed in claim 1 to 7 preferably having polymorph 1 and 2in the ratio of 1:1 and having characteristic confirmed by IR spectrum shown in Figure 1 and characteristic XRD shown in figure 3.
(9) The combination of polymorph 1 and 2 of Desloratadine substantially as herein described and illustrated in the examples and figures 1 to 4.
Dated this 8th day of February, 2005
(Anuradha Ramu) Agent for the Applicant.
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