The present invention relates to novel processes for the preparation of Form 2 of desloratadine.
Background Of The Invention
Desloratadine, which is chemically 8-Chloro-6, 11-dihydro-11- (4-piperidinylidene)-5H-benzo[5,6] cyclohepta [1,2-b] pyridine, is represented by Formula I
(Formula Removed)
Formula I
It is a metabolite of loratadine, having non-sedative antihistaminic activity and is known from US 4659716. Several methods for the preparation of desloratadine are known in the literature such as those described in US 5151423, US 4873335, US 5595997, US 2004242619, US 20050131046, WO 03/ 086275, WO 04/ 029039, WO 04/ 029039, which are herein incorporated by reference only.
Three different polymorphs of desloratadine, viz. Form 1, Form 2 and amorphous form, are known in the literature.
WO 05/ 084674 describes amorphous form of desloratadine and process for its preparation.
US 6506767 describe crystalline polymorph Form 1 of desloratadine essentially free of polymorph Form 2 and polymorph Form 2 of desloratadine substantially free of polymorph Form 1.
It describes specific solvents such as alcohols, chlorinated hydrocarbons, ethers and ketones to produce 100% pure crystalline Form 1 of desloratadine, Form 1 substantially free of Form 2 and Form 1 having significant amount of Form 2.
It also describes the preparation of crystalline Form 2 substantially free of Form 1 of desloratadine, by precipitation from a reaction mixture containing a solution of desloratadine in di-n-butyl ether, and of pure Form 2 by refluxing desloratadine in ethyl acetate followed by hot filtration and rapid cooling of the reaction mixture.
WO 04/ 080461 describes the preparation of mixtures of Form 1 and Form 2 of desloratadine. It describes that Form 2 having substantial amount of Form 1 may be obtained by addition of small amount
of 2-propanol to a solution of desloratadine in toluene whereas substantially Form 2 is obtained when only toluene is used without adding 2-propanol.
US 2004242619 describes processes for the preparation of crystalline Form 2 of desloratadine comprising the steps of melting desloratadine, cooling the molten desloratadine to obtain a solid and grinding the solid. It also describes the preparation of Form 2 of desloratadine by precipitation from a solution in dimethylcarbonate or by crystallization from toluene.
The present invention provides novel processes for the preparation of Form 2 of desloratadine by spray drying or agitated thin film drying.
Summary of The Invention
A first aspect of the invention provides a process for the preparation of Form 2 of desloratadine comprising:
a) providing a solution of desloratadine in a suitable solvent, and
b) recovering Form 2 of desloratadine by spray drying.
A second aspect of the invention provides a process for the preparation of Form 2 of desloratadine comprising:
a) providing a solution of desloratadine in a suitable solvent, and
b) recovering Form 2 of desloratadine by agitated thin film drying technique.
A third aspect of the invention provides Form 2 of desloratadine prepared by the process described in the first aspect of the invention, having an X-ray diffraction pattern as depicted in Figure I.
A fourth aspect of the invention provides Form 2 of desloratadine prepared by the process described in the first aspect of the invention, having an IR spectrum as depicted in Figure II.
A fifth aspect of the invention provides Form 2 of desloratadine prepared by the process described in the second aspect of the invention, having an X-ray diffraction pattern as depicted in Figure III.
A sixth aspect of the invention provides Form 2 of desloratadine prepared by the process described in the second aspect of the invention, having an IR spectrum as depicted in Figure IV.
Brief Description of the Figures
Figure I depicts the X-ray diffraction pattern of Form 2 of desloratadine obtained by spray drying.
Figure II depicts the IR spectrum of Form 2 of desloratadine obtained by spray drying.
Figure III depicts the X-ray diffraction pattern of Form 2 of desloratadine obtained by agitated thin film
drying.
Figure IV depicts the IR spectrum of Form 2 of desloratadine obtained by agitated thin film drying.
Detailed Description Of The Invention
Desloratadine used for the preparation of Form 2 of desloratadine can be obtained by any of the methods known in the art including those described in US 5151423, US 4873335, US 5595997, US 2004242619, US 20050131046, WO 037 086275, WO 04/ 029039, WO 04/ 029039, which are herein incorporated by reference only. The starting desloratadine may be obtained as a solution directly from a reaction mixture in which desloratadine is formed and used as such without isolation.
The suitable solvent used to prepare the solution of desloratadine may be an organic solvent or its mixture with water.
The organic solvent(s) may be selected from the group comprising of alkyl acetates, dipolar aprotic solvents and/ or mixtures thereof. Examples of alkyl acetate may include ethyl acetate, n-propyl acetate, n-butyl acetate, iso-propyl acetate, iso-butyl acetate and the like. Examples of dipolar aprotic solvents may include acetonitrile, dimethylformamide, dimethylsulphoxide and the like. Preferably, mixture of ethyl acetate and water is used.
The mixture of desloratadine in organic solvent and water may be filtered to remove any un-dissolved foreign particulate matter.
Desloratadine may be added to a mixture of organic solvent and water at a temperature of about 15-50°C. Preferably, it may be added at a temperature of about 30-35°C.
Water may be separated from the above mixture by azeotropic distillation or by layer separation to obtain a solution of desloratadine in organic solvent.
A spray dryer may be used for spray drying. The spray dryer operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction. The drying gas can be air or inert gas such as nitrogen, argon or carbon dioxide. Preferably the drying gas is nitrogen.
The flow rate may range from 750-900 mL/ hour. Preferably, the flow rate is 825 mL/ hour. The spray drying may be carried out at an inlet temperature of about 120-160°C and at an outlet temperature of 90-120°C. Preferably, the inlet temperature is 130°C and the outlet temperature is 100°C.
Agitated thin film drying involves separating the volatile component using indirect heat transfer coupled with mechanical agitation of the flowing film under controlled condition. Preferably, a vertical agitated thin film dryer is used.
In vertical agitated thin-film drying, the starting material is fed from the top into a cylindrical space between a centered rotary agitator and an outside heating jacket. The rotor agitates the downside flowing solution while the heating jacket heats it.
The heating jacket may be maintained at a temperature of about 75-110°C. Preferably, the heating jacket is maintained at a temperature of about 90-92°C.
In the foregoing section embodiments are described by way of examples to illustrate the process of invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art.
Methods
Powder XRD
X-Ray Difractometer, Rigaku Coorperation, RU-H3R
Goniometer CN2155A3
X-Ray tube with Cu target anode
Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1 0
Power: 40 KV, 100mA
Scanning speed: 2 deg/min step: 0.02 deg
Wavelength: 1.5406 A
Spray Dryer: PST 01
Example 1- Preparation of Form 2 of Desloratadine by Spray drying
Desloratadine (100 g) was dissolved in a mixture of ethyl acetate (1000 ml) and de-ioniozed water (100 ml) at a temperature of 30-35°C. The solution was filtered through a hyflobed. The organic layer was separated and fed into a spray dryer in an atmosphere of nitrogen. The inlet temperature was kept at 130°C and the outlet temperature was kept at 100°C for 1 hour 20 minutes. Flow Rate: 825 mL/hour Yield: 0.5 w/w HPLC purity: 99.53%
Example 2- Preparation of Form 2 of Desloratadine by Agitated Thin Film Drying
Desloratadine (10 g) was dissolved in a mixture of ethyl acetate (50 ml) and de-ioniozed water (10 ml)
at a temperature of 30-35°C. The organic layer was separated and fed into an agitated thin film dryer at a
temperature of 90-92°C for 5-6 hours under reduced pressure.
Yield: 7.6 g
HPLC purity: 99.71%

WE CLAIM:
1. A process for the preparation of Form 2 of desloratadine comprising:
a) providing a solution of desloratadine in a suitable solvent, and
b) recovering Form 2 of desloratadine by spray drying.
A process for the preparation of Form 2 of desloratadine comprising:
a) providing a solution of desloratadine in a suitable solvent, and
b) recovering Form 2 of desloratadine by agitated thin film drying.
3. Form 2 of desloratadine, obtained by the process of claim 1, characterized by at least one of the following characteristic:
a) X-ray powder diffraction pattern as depicted in Figure I;
b) Infra-red spectrum as depicted in Figure II.
4. Form 2 of desloratadine, obtained by the process of claim 2, characterized by at least one of the following characteristic:
a) X-ray powder diffraction pattern as depicted in Figure III;
b) Infra-red spectrum as depicted in Figure IV.
5. The process according to claims 1 or 2, wherein suitable solvent is selected from the group comprising of an organic solvent selected from alkyl acetates and dipolar aprotic solvents and/ or mixtures thereof, or their mixture with water.
6. The process according to claims 6, wherein the alkyl acetate is selected from the group comprising of ethyl acetate, n-propyl acetate, n-butyl acetate, iso-propyl acetate, iso-butyl acetate.
7. The process according to claim 5, wherein a mixture of ethyl acetate and water is used.
8. The process according to claim 1, wherein the spray drying is carried out at an inlet temperature about 120-160°C and an outlet temperature of about 90-120°C.

9. The process according to claim 2, wherein the heating jacket of the agitated thin film dryer is maintained at a temperature of about 75-100°C.
10. A process for the preparation of Form 2 of desloratadine as described and illustrated by the examples herein.