FORM 2

THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION (See section 10 and rule 13)

1. TITLE OF THE INVENTION
Process for the preparation of Desloratadine polymorphic mixtures
2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LIMITED
(b) NATIONALITY: An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad
-382210, Gujarat, India
3. PREAMBLE TO THE DESCRITION
PROVISIONAL SPECIFICATION
The following specification describes the invention.
COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner which it is to be performed
4. DESCRIPTION
(Description starts from next page)


Field of the Invention
The present invention relates to a process for the preparation of desired ratio of
polymorphic form-l and form-ll of desloratadine.
Background of the Invention
Desloratadine is chemically known as 8-chloro-6,1l-dihydro-11-(4-piperidinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and is represented by the structural formula 1.

Desloratadine is a metabolic derivative of loratadine. Desloratadine is prescribed as an antihistamine for prevention or treatment of allergenic reactions, which may result in symptoms such as sneezing, itchy eyes and hives.
U.S. patent no. 4,659,716 discloses descarbonylethoxyloratadine (also known as Desloratadine), which possesses antihistaminic properties with substantially no sedative properties. The 716 patent describes a process for the preparation of Desloratadine by dissolving loratadine in water and basifying with dilute solution of potassium carbonate to obtain a pink colored oil. The organic material is extracted with chloroform, washed with water and triturated with hexane. Desloratadine is obtained by recrystallisation of the extracted organic material with large volume of hexane after charcolisation.
U.S. patent no. 6,506,767 (US 767 patent) discloses two polymorphic forms of desloratadine, labeled Form I and II. US 767 patent discloses XRPD peaks and FTIR spectrum for the given forms I and II. According to 767 patent, certain alcoholic solvents, e.g., hexanol and methanol produce 100% polymorph form 1, but others, e. g., 3-methyi-1-butanOl and cyclohexanol produce significant amounts of form 2. Chlorinated solvents, e. g., dichloromethane produce form 1 substantially free of form 2. Ether solvents such as dioxane produce form 1 substantially free of form 2 but other alkane ethers, e.g., di-isopropyl ether produce form 1 with significant amounts of form 2 and di-n-butyl ether favors formation of form 2. Ketones such as methyl isobutyi ketone produced crystalline
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polymorph form 1 essentially free of form 2 but methyl butyl ketone produce 8:1 ratio of form 1 to form 2. Use of methyl isobutyl ketone is preferred to produce crystalline polymorph form 1 essentially free of form 2. Only ethyl acetate and di-n-butyl ether were found to produce crystalline polymorph form 2 substantially free of form 1. Use of di-n-butyl ether is preferred for producing crystalline fonm 2 substantially free of form 1. According to this patent (767), the polymorph form obtained from U.S. Pat. No. 4,659,716 is a mixture of form I and form II.
It is advantageous to have a single process which can give any desired ratio of the two polymorphic forms I & II by varying the process parameters.
SUMMARY OF THE INVENTION
The object of present invention is to provide a process which gives a desired ratio of the mixture of polymorphic form I and form II of desloratadine by controlling the process parameters.
Yet another object of the present invention is to provide a process for getting the mixture of desloratadine polymorphs from I and from II, in a desired ratio, comprises:
a) providing a solution of desloratadine in a hydrocarbon solvent,
b) maintaining the water content of the solution obtained in step a) to a specific moisture level,
c) Isolating the desired mixtures of forms.
Yet another object of the present invention is to provide a process for getting the mixture of desloratadine polymorphs from I and from IE which is industrially scalable and economic.
DETAILED DESCRIPTION OF THE INVENTION
In the preferred embodiment of the present invention which relates to a process for the preparation of a desired ratio of desloratadine polymorphs form I and form II.
Yet another embodiment of the present invention relates to a process for the preparation of a desired ratio of desloratadine polymorphs form I and form II, characterized by the Infrared spectral analysis on a FTIR spectrometer.
The term 'desired ratio' as used herein, includes variable ratios of form I to form II. In an embodiment of the present invention the ratio of from I and form II is between about 86-96:14-4 by weight. In an embodiment of the present ratio of from I and form II is between about 91-97:9-3 by weight.
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In another embodiment the present ratio of from I and form II is between about 81-91:19-9 by weight. The above mentioned mixtures of crystalline forms of desloratadine are characterized by their Infrared spectral patterns. All IR information herein was generated on a Shimadzu FTIR -8400 with DRS system.
The IR patterns of the mixtures of forms have characteristic peaks of both crystalline form I and form II of desloratadine. Depending on the weight ratios of the forms, the intensities of characteristic peaks will vary.
In embodiment of the present invention, the process for the preparation of a desired ratio of desloratadine polymorphic form I and form II comprises:
a) providing a solution of desloratadine in a hydrocarbon solvent,
b) Maintaining the water content of the solution obtained in step a) to a specific moisture level,
c) Isolating the desired mixtures of forms.
Step a) providing a solution of Desloratadine:
The solution of desloratadine may be obtained by dissolving desloratadine in a suitable solvent, or such a solution may be obtained directly from the reaction in which desloratadine is formed. Desloratadine may be prepared by any of the methods described in U.S. patent numbers 4,659,716; 4, 826, 853 and 5, 925, 648 which describe desloratadine or its pharmaceutical^ acceptable salts and its pharmaceutical composition. U.S. patent number 6,506,767 discloses substantially pure crystalline forms of desloratadine designated as form I and form M, and processes for their preparation.
In an embodiment of the present invention, the solution of desloratadine is obtained directly from the reaction, in which loratadine is dissolved in SDS and hydrolyzed with potassium hydroxide in SDS to get solid residue. The organic material is extracted with toluene, washed with water and treated with activated carbon and filtered by using hyflo and dried over anhydrous sodium sulfate.
The term SDS as used herein, means Denatured ethanol or denatured spirit having up to 8% water and 1% acetone.
When the solution is prepared by dissolving desloratadine in hydrocarbon solvent, any form of desloratadine such as a crystalline or amorphous form, including any salts, solvates and hydrates may be utilized for preparing the solution.
Suitable hydrocarbon solvents that can be used for the dissolution of desloratadine include C5 to C12 aliphatic or alicyclic hydrocarbons such as pentane, isopentane, hexane, heptane, cyclohexane; aromatic hydrocarbons such as toluene,
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xylene, or mixtures thereof. In an embodiment of the present invention, the solvent is toluene.
The moisture content of the desloratadine solution may generally range from about 1 to 4% w/w. optionally; the solution obtained above can be filtered to remove the undissolved particles before proceeding for further processing.
b) maintaining the water content of the solution obtained in step a):
The water content of the solution may be measured suitably using Karl-Fischer. The moisture content of desloratadine solution determines the percentages of the polymorphic forms I and II in the final product.
When the moisture content of desloratadine solution drops from about 2 wt/wt to about 1 wt/wt or below , the percentage of form II in the product increases, and when the moisture content of desloratadine solution is increased from about 2 wt/wt to about 4 wt/wt, the percentage of form I in the product gradually increases.
In an embodiment of the present invention, when the moisture content of the solution is about 1.0% to about 1.4%wt / wt, the ratio of form I to form II obtained in the product is about 71-81:29-19. In another embodiment of the present invention, when the moisture content of the solution is about 1.4% wt/wt to about 2.5%wt/wt the ratio of form I to form II obtained in the product is about 81-91:19-9. In yet another embodiment of the present invention, when the moisture content of the solution is about 2.5% to about 4%, the ratio of form I to form II obtained in the product is about 91-97:9-3.
By suitably adjusting the moisture content, the desired ratio of form I and form II can be obtained in the mixture.
c) isolating the desired mixtures of forms :
The solution obtained in step b) may be further maintained at temperatures below 20°C. for a period of time as required for isolation of the product. Preferably the temperature is brought down at about 0-5°C. The exact cooling temperature and time required for complete isolation can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
The mixture of forms obtained from step c) can be collected from the equipment using techniques such as filtration or by suction, centrifugation, and the like.
The wet cake may be further dried. Drying can be carried out under vacuum at temperatures such as 50-75°C and drying can be carried out for any desired time period
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that achieves the desired product purity. The dried product can optionally be milled to get the low amount of residual organic solvents. Milling can be done suitably by using conventional milling equipment.
The present invention provides a process suitable for use on an industrial scale for preparation of desloratadine. Desloratadine may be crystallized as a desired ratio of polymorphs in such a way that the ratio between the polymorphs is consistent. As used herein, a 'consistent ratio' refers to a ratio of form I and form II (wt/wt) that varies within a range of less than about ±5% between lots, as measured by IR.
The details of analytical method ascertaining desloratadine form ratio as as mentioned below.
Instrument used: - Shimadzu FTIR -8400 with DRS system
Procedure:
Infra red spectrum of Desloratadine (crystalline mixture of Form-I and Form-ll) is obtained using KBr powder which is previously dried at 105°C for 3 hours. Grind previously dried KBr powder in mortal pestle to a fine powder. Add 25 mg test sample without grinding and mix it thoroughly. Fill the sample in DRS sample holder and carry out IR spectrum. Using multipoint baseline correction system corrects the baseline of spectrum. Correct the baseline by integrating two characteristic peaks of Form-I at 3303±1 cm-1 and Form-ll at 3326±1 cm-1.
Calculate absorbance at wave number of Form-I and Form-ll. Calculate % of
each form using formula:
Absorbance of Form-I
%Form-l =
Total absorbance of Focm-l and Form-ll
Absorbance of Form-ll
%Form-ll =
Total absorbance of Form-I and Form-ll
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.
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Example 1 Preparation of 89:11 ratio of combination of Desloratadine polymorphic forms I & II
A mixture of SDS (250ml) and potassium hydroxide (128.2gm) was stirred at 40°C to get clear solution. Loratadine (100gm) and SDS (250 ml) were added at 40-45°C and the temperature of the reaction mass was raised to 78-83°C. The reaction mass was stirred at 78-83°C for 4-5 hrs. The solvent was distilled out completely under vacuum up to 55-60°C. Water (100ml) and Toluene (100ml) were added and stirred for 15 minutes. The layers were separated. Toluene (100ml) was added to aqueous layer and stirred for 15 minutes. The layers were separated. The combined toluene layer was washed with water. Activated charcoal (5.0gm) was added to toluene layer and stirred for 30 minutes at 25-35°C. The reaction mass was filtered through hyflo bed and washed with toluene (25ml). The organic layer was dried over sodium sulphate and the moisture was maintained to - 2.44% wt/wt. The reaction mass was cooled to about 0-5°C. The reaction mass was maintained for 2 hours at 0-5°C. The material.was filtered at 0-5°C and washed with toluene. The material was dried under vacuum at 55-65°C for 6 hrs. The solid was dried for 18 hrs under vacuum at 55-65°C. Dry weight = 57 gm % of form I by IR: 89.0% wt/wt, the balanced quantity being form-ll
Example 2 Preparation of 81:19 ratio of combination of Desloratadine polymorphic forms I & II
A mixture of SDS (125ml) and potassium hydroxide (64.1gm) was stirred at 40°C to get clear solution. Loratadine (50gm) and SDS (125 ml) were added at 40-45°C and the temperature of the reaction mass was raised to 78-83°C. The reaction mass was stirred at 78-83°C for 4-5 hrs. The solvent was distilled out under vacuum up to 55-60°C. Water (50ml) and Toluene (50ml) were added and stirred for 15 minutes. The layers were separated. Toluene (50ml) was added to aqueous layer and stirred for 15 minutes. The layers were separated. The combined toluene layer was washed with water. Activated charcoal (2.5gm) was added to toluene layer and stirred for 30 minutes at 25-35°C. The reaction mass was filtered through hyflo bed and washed with Toluene (12.5ml). The toluene layer was dried the layer over anhydrous sodium sulphate and the moisture was maintained to about 1.88% wt/wt. The reaction mass was cooled to 0-5°C. and maintained for 2 hr at 0-5°C. The material was filtered at 0-5°C and washed with toluene. The material was dried under vacuum at 55-65°C for 6 hrs. The solid was dried for 18 hrs under vacuum at 55-65°C.
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Dry weight: - 23.4 gm % of form I by IR: 81.8% wt/wt., the balanced quantity being form-
II
Example 3 Preparation of 92:8 ratio of combination of Desioratadine polymorphic forms
l&ll
A mixture of SDS (250ml) and potassium hydroxide (128.2gm) was stirred at 40°C to get clear solution. Loratadine (100gm) and SDS (250 ml) were added at 40-45°C and the temperature of the reaction mass was raised to about 78-83°C. The reaction mass was stirred at 78-83°C for 4-5 hrs. The solvent was distilled under vacuum up to 55-60°C. Water (100ml) and Toluene (100ml) were added and stirred for 15 minutes. The layers were separated. Toluene (100ml) was added to aqueous layer and stirred for 15 minutes. The layers were separated. The combined toluene layer was washed with water. Activated charcoal (5.0gm) was added to toluene layer and stirred for 30 minutes at 25-35°C. The reaction mass was through hyflo bed and washed with toluene (25ml). The tofuene fayer was dried over anhydrous sodium sufphate and the moisture content was maintained at about 2.6% wt/wt The reaction mass was cooled to 0-5°C. The reaction mass was maintained for 2 hr at 0-5°C. The material was filtered at 0-5°C and washed with toluene. The material was dried under vacuum at 55-65°C for 6 hrs. The solid was dried for 18 hrs under vacuum at 55-65°C. Dry weight =53 gm % of form I by IR: 92.0% wt/wt., the balanced quantity being form-ll
Date: 3 July 2009
ForCadila Pharmaceuticals Ltd,,
Dr. Bakulesh M. Khamar Executive Director - Research
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