FIELD OF THE INVENTION
The present invention relates to the process for the preparation of mixture of crystalline Form I and Form II of 8-chloro-6,ll-dihydro-ll"(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[l,2-b]pyridine of Formula (I) in the ratio between 85:15 and 98:2.

BACKGROUND OF THE INVENTION
8-Chloro-6,ll-dihydro-ll-(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[l,2-
bjpyridine is generically known as Desloratadine. Desloratadine is an active
metabolite of Loratadine, which is orally active' long-acting histamine H1 receptor
antagonist. It belongs to a second generation of h1 histamine receptor antagonists
that has advantages over the first generation compounds. Desloratadine is currently
marketed under the trade name Clarinex® in the United States. Clarinex is indicated
for the relief of the nasal and non-nasal symptoms of seasonal allergic rhinitis, nasal
and non-nasal symptoms of perennial allergic rhinitis and symptomatic relief of
pruritus, reduction in the number and size of hives in patients with chronic
idiopathic urticaria. [Ref: Physician's Desk Reference, "Clarinex," 60th Edition, pp.
3009-12 (2005)].
US 4,659,716 ("the 716 patent") assigned to Schering Corporation, discloses Desloratadine. The 716 patent further discloses methods for preparing and administering Desloratadine and its pharmaceutically acceptable salts. The 716 discloses that Desloratadine is crystallized from a large volume of hexane (Examples V and VI).

US 6,506,767 ("the '767 patent") disclose crystalline polymorph Forms I and II of Desloratadine and their use in pharmaceutical compositions. The '767 patent further discloses that polymorph Form I can be essentially free of polymorph Form II and is defined as containing less than about 1% of Form II as measured by infrared spectral analysis on a FTIR spectrometer and that polymorph Form II can be substantially free of polymorph Form I and is defined as containing less than about 15% of Form L The '767 patent further reveals that Desloratadine as obtained in examples V and VI of US patent No. 4,659,716 is a mixture of polymorphic forms.
The US '767 patent discloses a process for the preparation of Form I of Desloratadine using the solvents selected from hexanol, methanol, 3-methyl-l-butanol, cyclohexanol, dichloromethane, dioxane, di-isopropyl ether and methyl isobutyl ketone. Form II of Desloratadine is prepared using solvents such as ethyl acetate, di-n-butyl ether.
US 2004/0229896 Al, discloses a pharmaceutical composition of Desloratadine comprising of a mixture of crystalline form Desloratadine I and II in a weight to weight ratio of about 25% to about 75% of either form to the other and a pharmaceutically acceptable excipient. US '896 also discloses a stable mixture of crystalline form Desloratadine in a weight-to-weight ratio of about 20-40% Form II to about 60-80% Form I.
WO 2005/084674 Al, discloses an amorphous form of Desloratadine and also discloses a composition that includes Desloratadine in a solid form, wherein at least 80 % by weight of the solid Desloratadine is an amorphous form of Desloratadine. This patent also discloses a process for preparation of the amorphous form of Desloratadine by providing a solution of Desloratadine in an organic solvent selected from alcoholic solvents having C1-5 carbon atoms and aromatic or non-aromatic carbocyles and removing the solvent by spray drying or agitated thin film drying to obtain a solid residue which is the amorphous form of Desloratadine.

Us 2007/00135472 Al, discloses crystalline polymorph Forms III and V of Desloratadine and their use in pharmaceutical compositions. Further this patent discloses the preparation of Form III and V using the solvents selected from straight or branched chain aliphatic hydrocarbons, chlorinated solvents, cyclic solvents having 6 to 15 carbon atoms and the like and mixtures thereof
US 2006/00135547 Al, discloses a process for preparing a mixture of crystalline Form I and Form II of Desloratadine which comprises combining a solution of Desloratadine in an organic solvent selected from the group consisting of C2 to C5 alkyl acetate, butanol, isobutanol, toluene and chloroform with C5 to C12 hydrocarbon to precipitate the mixture, recovering the mixture, wherein before combining, the solution has a temperature that is at least about 40°C higher than the hydrocarbon. Further it is disclosed that the mixture comprises of about 35-82% Desloratadine Form I and about 18-65% Desloratadine Form II.
To prepare pharmaceutical compositions containing Desloratadine for administration to mammals in accordance with exact health registration requirements of the U.S. and international health registration authorities, e.g. the FDA's Good Manufacturing Practices ("GMP") requirements, there is a need to produce Desloratadine in as pure form as possible, especially a form having constant physical properties.
The present invention relates to the solid-state physical properties of Desloratadine. These properties can be influenced by controlling the conditions under which Desloratadine is obtained in solid form. Solid-state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product.
Another important solid-state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper

limit on the rate at which an orally administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid-state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid-state 13C NMR spectrometry and infrared spectrometry.
In view of the above, the instant invention describes a process for the crystallisation of Desloratadine as a mixture of polymorphs in such a way that the ratio between the polymorphs is consistent. As used here in consistent ratio refers to a ratio of Form I compared to Form II (wt/wt) that is between a range of about 85-98%.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple and effective process for the preparation of mixture of crystalline Desloratadine Form I and Form II in the ratio between 85:15 to 98:2 with high purity and good yields on a commercial scale.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of mixture of crystalline Desloratadine Form I and Form II in the ratio between 85:15 and 98:2 comprises;

(i) preparing a solution of Desloratadine in a ketonic solvent;
(ii) optionally, treating the resulting solution with carbon,
(iii) adding anti solvent,
(iv) isolating mixture of crystalline Desloratadine Form I and Form II.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of mixture of crystalline Form I and Form II of 8-chloro-6,ll-dihydro-ll-(4-piperdinylidene)-5H-benzo[5,6]cyclohepta [l,2-b]pyridine of Formula (I).
The process comprises dissolving Desloratadine in a solvent selected from ketone such as acetone, methyl isobutyl ketone, methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or mixtures thereof. Dissolution may be carried out by adding Desloratadine to the ketone solvent to obtain a clear solution. The resulting clear solution is optionally treated with carbon, followed by filtration to remove insoluble material. A suitable anti-solvent selected from C5-C12 hydrocarbons such as hexanes, heptane, cylohexane, ethers such as diethyl ether, di-isopropyl ether, preferably cyclohexane or diisopropyl ether to precipitate mixtxore of crystalline Desloratadine Form I and Form II. The ratio of the solvent and anti-solvent may vary depending on the solvent/anti-solvent used, crystallization temperature and the temperature of the solution. When the anti-solvent is added to a solution of Desloratadine having a temperature of about 80-85°C, followed by crystallization at a temperature of from about 20 to about 30°C. The resulting Desloratadine Form I contains from about 2 to 10% Form II, in comparison to Form 1. The isolation of mixture of crystalline Desloratadine Form I and Form II obtained by the present invention may then be recovered by techniques well known in the art, such as filtration, and optionally dried. The ratio of Desloratadine Form I to Form II is analyzed by X-ray powder diffraction technique.

The Desloratadine used in the present invention may be prepared from Loratadine, by the procedure disclosed in US 4,659,716 and US 4,282,233. The process disclosed in US '716 involves hydrolysis followed by decarboxylation of 8-chloro-6,11 -dihydro-11 -(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[ 1,2-bjpyridinecarboxylic acid ethyl ester (Loratadine) using ethanolic solution of KOH to produce Desloratadine. The Desloratadine, used in the present invention may or may not be the isolated as a solid.
Pharmaceutical formulations of the present invention contain Desloratadine Form I prepared by the processes of the present invention are ideal for pharmaceutical composition. In addition to the active ingredient(s), the pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for a variety of purposes.
The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
EXAMPLES: EXAMPLE 1
Preparation of Desloratadine Form I containing upto 10% of Form II:
Desloratadine (3 g) was dissolved in methyl isobutyl ketone (10.5 ml) at 95-100*^0. The resulting solution was treated with carbon (0.15 g) at SO-SS^'C for 20 minutes. Carbon was removed by filtration and the residue was washed with preheated methyl isobutyl ketone (3 ml, 80-85^C). Cyclohexane (13.5 ml) was added to the above filtrate at 80-85°C. The reaction mass was slowly cooled to 20-25°C during which product starts crystallizing out and stirred at 20-25°C for another 2 hrs and thereafter, the slurry was cooled to 2°C nd continued stirring at 2-5°C for 2 hrs. The product was filtered, washed with precooled cylcohexane (2x3 ml, 2-5°C ) and dried at 45-50°C under reduced pressure to obtain 1.75 g of Desloratadine. The X-ray

powder diffraction showed that product is a mixture of Desloratadine Form I containing Form II.
EXAMPLE 2:
Preparation of Desloratadine Form I containing upto 10% of Form II:
Loratadine (130 g) was added to the solution of sodium hydroxide (136 g) in ethanol (780 ml) and DM water (195 ml), at 70°C . The reaction mass was stirred at 80±2°C for 9 hrs to complete the carbamate hydrolysis. The reaction mass was cooled to 45°C and concentrated at 45-50°C under reduced pressure to remove ethanol. DM water (1300 ml) was added to the residue at 25°C and pH was adjusted to 9.5 using concentrated hydrochloric acid (310 ml) at 2-30°C. The reaction mass was extracted with methylene chloride (650 ml). Water (650 ml) was added to methylene chloride extract and pH was adjusted to 2.0 using concentrated hydrochloric acid (50 ml). The aqueous layer-containing product was treated with carbon (6.5 g) for 20 min and carbon was removed by filtration through hyflo and the residue was washed with DM water (130 ml, 25°C ). The pH of the filtrate was adjusted to 8.0 using 10% w/v aqueous sodium carbonate solution (420 ml) and methylene chloride (650 ml) was added. Further pH was adjusted to 9.6 using 10% w/v aqueous sodium carbonate solution (250 ml). The methylene chloride layer was separated and concentrated under reduced pressure to dryness. Methyl isobutyl ketone (100 ml) was added to the residue obtained, and continued distillation at 50-60°C under reduced pressure and collected 50 ml of distillate, to remove traces of methylene chloride. The residue thus obtained was dissolved in methyl isobutyl ketone (405 ml) at 85-90°C , filtered and washed with preheated methyl isobutyl ketone (65 ml, 80°C). Cyclohexane (520 ml) was added to the filtrate at 80-85°C , slowly cooled to ITC and stirred at 25-27°C for 2 hrs. The slurry thus obtained, was cooled to 5°C and stirred at 2-5°C for 4 hrs. The product was filtered, washed with precooled cyclohexane (2x130 ml, 2-5°C) and dried at 45-50°C imder reduced pressure to obtain 67 g of Desloratadine. The X-ray powder diffiraction showed that product is mixture of Desloratadine Form I containing Form 11.

EXAMPLE 3
Preparation of Desloratadine Form I containing upto 10% of Form II:
Desloratadine (3 g) was dissolved in methyl isobutyl ketone (13.5 ml) at 95-100°C. The resulting solution was cooled to 80°C and hexanes (13.5 ml) added at 78-80°C. The reaction mass was slowly cooled to 20°C and stirred at 20-25°C for 12 hrs. Further the slurry obtained was cooled to 2°Cand stirred at 2-5°C for Ihr. The product was filtered, washed with precooled hexanes (3 ml, 2-5°C) and dried at 45-50°C under reduced pressure to obtain 2.60 g of Desloratadine. The X-ray powder diffraction showed that product is mixture of Desloratadine Form I containing Form II.
EXAMPLE 4
Preparation of Desloratadine Form I containing upto 10% of Form II:
Desloratadine (3 g) was dissolved in methyl isobutyl ketone (13.5 ml) at 95-100°C. The resulting solution was cooled to 80°C and added di-isopropyl ether (13.5 ml) at 80 ± 2°C. The reaction mass was slowly cooled to 20°Cand stirred at 20-25°C for 12 hrs. Further the slurry obtained was cooled to 2°C and stirred at 2-5°C for 1 hr. The product was filtered, washed with precooled di-isopropyl ether (3 ml, 2-5°C) and dried at 45-50°C under reduced pressure to obtain 2.53 g of Desloratadine. The X-ray powder diffraction showed that product is mixture of Desloratadine Form I containing Form II.

We claim:
1. A process for the preparation of mixture of crystalline Desloratadine Form I
and Form II in the ratio between 85:15 and 98:2 comprises:
i) preparing a solution of Desloratadine in a ketonic solvent;
ii) optionally, treating the resulting solution with carbon,
iii) adding anti solvent,
iv) isolating mixture of crystalline Desloratadine Form I and Form II.
2. The process according to claim 1, wherein the ketone is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl propyl ketone, methyl isopropyl ketone, diethyl ketone or mixtures thereof.
3. The process according to claim 1, wherein the anti solvent is selected from C5-C12 hydrocarbon or ether.
4. The process according to claim 3, wherein the C5-C12 hydrocarbons is selected from hexanes, heptane, cyclohexane, preferably cyclohexane.
5. The process according to claim 3, wherein the ether is selected from diethyl ether, di-isopropyl ether, preferably diisopropyl ether.
6. A pharmaceutical composition comprising a mixture of crystalline Desloratadine Form I and Form II in the ratio between 85:15 and 98:2.
7. A pharmaceutical composition according to claim 6, comprising a mixture of crystalline Desloratadine Form I and Form II in the ratio between 85:15.
8. A pharmaceutical composition according to claim 6, comprising a mixture of crystalline Desloratadine Form I and Form II in the ratio between 90:10.
9. A pharmaceutical composition according to claim 6, comprising a mixture of crystalline Desloratadine Form I and Form II in the ratio between 95:5.

10. A pharmaceutical composition according to claim 6, comprising a mixture of crystalline Desloratadine Form I and Form II in the ratio between 98:2.