PROCESS FOR THE PREPARATION OF AMORPHOUS CABERGOLINE

Field of the Invention

The present invention relates to processes for the preparation of amorphous cabergoline by agitated thin film drying or spray drying.

Background of the Invention

1 - [( 6-allyler golin- 8β-yl)-c arbonyl] - 1 - [3 -(dimethylamino)propyl] -3 - ethyl urea, commonly known as cabergoline is a dopamine receptor antagonist.

FORMULA I

Cabergoline is indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas.

GB 2,074,566 B provides a process for preparing cabergoline, wherein the final product is isolated as a diphosphate salt. WO 03/078433 provides a process for preparing a mixture of amorphous cabergoline and Form I, by drying the toluene solvate Form V. WO 04/094368 provides processes for preparing amorphous cabergoline from tert-butyl methyl ether solvate Form A by vacuum drying or lyophilization. WO 05/085243 provides a process for preparing amorphous cabergoline, wherein the process involves dissolving

chromatographically purified oily cabergoline in acetone and partially removing the solvent several times in vacuum. The prior art processes for preparing amorphous cabergoline require the preparation of solvated forms of cabergoline and subsequent desolvation, which also lead to crystalline contamination. Further the prior art processes, which involve conversion of oily cabergoline into amorphous form, require repeated crystallization. J. Org. Chem. 2002, 67, 7147-7150 reports isolation of crude amorphous cabergoline from the reaction mixture after a deprotection step. However, further chromatographic purification of the amorphous solid is needed to get cabergoline of acceptable purity. Thus, there is a need for a process to prepare amorphous cabergoline that does not involve the use of solvates as intermediates or use expensive and tedious chromatographic processes.

Summary of the Invention

The present inventors have developed novel processes for preparing amorphous cabergoline. The present processes do not require lyophilization or repeated crystallizations. The present process is simple and provides amorphous cabergoline in a single step by agitated thin film drying or spray drying. The present processes also provide amorphous cabergoline substantially free from crystalline contamination.

The term "collecting" according to the present inventions includes unloading, amassing, gathering, scaling and/or piling.

Detailed Description of the Invention In one aspect of the present invention is provided a process for the preparation of amorphous cabergoline, wherein the process comprises, a) dissolving cabergoline in an organic solvent, b) removing the solvent from the solution obtained in step a) by agitated thin film drying, and c) collecting amorphous cabergoline from the agitated thin film dryer.

Cabergoline present in any solid or solvated form known to the person skilled in the art can be used as a starting material. Cabergoline present in oily form can also be used as a starting material. The starting material of cabergoline can be prepared according to the

methods provided in the prior art references, for example, WO 03/078433. The cabergoline is dissolved in an organic solvent. The organic solvent is selected from a group consisting of acetone, diethyl ether, cyclohexane and isopropanol. The organic solvent is preferably acetone. The solution so obtained is filtered and fed to an agitated thin film dryer. The solvent is subsequently removed from the solution by agitated thin film drying. The drying process is accompanied by heating at a temperature of about 35 ⁰ C or above. The feeding rate of the solution is controlled in such a way to facilitate the thin film formation and the evaporation rate. The rotor and vapor duct can have a sealing system so that the drying can preferably be carried under vacuum. Vacuum operation also facilitates amorphous cabergoline to be obtained without degradation. The amorphous cabergoline is collected from the agitated thin film dryer. The amorphous cabergoline can optionally be further dried under vacuum to obtain amorphous cabergoline with desired residual solvent content. The amorphous cabergoline so obtained has substantially the same XRPD pattern as depicted in Figure 1.

In another aspect of the present invention is provided a process for the preparation of amorphous cabergoline, wherein the process comprises, a) dissolving cabergoline in an organic solvent, b) removing the solvent from the solution obtained in step a) by spray drying, and c) collecting amorphous cabergoline from the spray dryer.

Cabergoline for use as the starting material in the processes described herein can be prepared according to the methods provided in the prior art references, for example, WO

03/078433. It can be used as a solid or an oil.. Cabergoline is dissolved in an organic solvent. Alternatively, cabergoline in the from a solution in organic solvent from a previous step can also be used. The organic solvent is selected from a group consisting of acetone, diethyl ether, cyclohexane and isopropanol. The organic solvent is preferably acetone. The solution is filtered and fed to a spray dryer. The inlet and outlet temperatures, feed rate, and atomizer type can be adjusted to optimize output and particle size. The air inlet temperature is preferably controlled from about 5O ⁰ C to about 80 ⁰ C. The outlet temperature is preferably controlled from about 35 ⁰ C to about 45 ⁰ C. An inert gas, for example, nitrogen gas can be used as a carrier gas. After the drying process, the cabergoline is collected from the spray dryer and

optionally further dried under vacuum to obtain amorphous cabergoline with desired residual solvent content. The amorphous cabergoline so obtained has substantially the same XRPD pattern as depicted in Figure 2.

Figure 1 depicts XRPD of amorphous cabergoHne obtained by agitated thin film drying.

Figure 2 depicts XRPD of amorphous cabergoline obtained by spray drying.

Powder XRD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLE 1 PREPARATION OF AMORPHOUS CABERGOLINE BY AGITATED THIN FILM DRYING:

Cabergoline (5 g) was added into acetone (50 ml) in a round bottom flask. The mixture was stirred to dissolve cabergoline. The solution was filtered and fed to a Buchi Rotavapor ^® (Model No. R-205; 500 mL) in small lots so as to form a thin film. The solvent was evaporated at 40°-45°C under vacuum (30-40 mm Hg, abs). The solid residue was further stirred for 30 minutes at 40° to 45 ⁰ C under vacuum. The solid so obtained was collected from the Buchi Rotavapor ^® and dried at 40° to 45 ⁰ C under vacuum for 8 to 1O h to obtain the title compound having an XRPD pattern as depicted in Figure 1.

Yield: 2.7 g Purity (HPLC): 99.02%

EXAMPLE 2 PREPARATION OF AMORPHOUS CABERGOLINE BY SPRAY DRYING:

Cabergoline (5 g) was added into acetone (50 ml) in a round bottom flask. The mixture was stirred to dissolve cabergoline. The solution was filtered and fed to a spray dryer (Lab plant SD-5) at feed pump RPM of 6 to 7. The following parameters were controlled in the spray drying process:

Nozzle Diameter: 0.5 mm Carrier gas: Nitrogen at 2 to 2.2 kg/cm ² Air inlet temperature: 50°-52°C Outlet temperature: 45°C

Type of atomizer: Two fluids nozzle

The solvent was evaporated at about 40° to about 45 ⁰ C by spray drying. The solid so obtained was collected from the spray dryer and dried at 40°-45°C under vacuum for 8 to 1O h to obtain the title compound having an XRPD pattern as depicted in Figure 2. Yield: 2.9 g

Purity (by HPLC): 99,02%