The present invention relates to processes for the preparation of amorphous cabergoline by agitated thin film drying or spray drying.
1-[(6-allylergolin-8U-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea, commonly known as cabergoline is a dopamine receptor antagonist.
(Figure Removed)
Cabergoline is indicated for the treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas.
GB Patent No 2,074,566 B provides a process for preparing cabergoline, wherein the final product is isolated as a diphosphate salt. J. Org. Chem. 2002, 67, 7147-7150 provides a process for preparing cabergoline as an amorphous solid by concentrating a solution of cabergoline in ethyl acetate. PCT Publication No WO 03/078433 provides a process for preparing a mixture of amorphous cabergoline and Form I, by drying the toluene solvate Form V. PCT Publication No WO 04/094368 provides processes for preparing amorphous cabergoline from tert-butyl methyl ether solvate Form A by vacuum drying or lyophilization. PCT Publication No 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 involve the use of solvated forms or oily form of cabergoline as a starting material.
The present inventors have developed a novel process for preparing amorphous cabergoline, by agitated thin film drying or spray drying. The present process does not require the preparation of any solvated cabergoline as a starting substrate. The present process is simple and provides amorphous cabergoline in a single step.
The term "collecting" of the present invention includes unloading, amassing, gathering, scaling or piling.
A first aspect of the present invention provides a process for the preparation of amorphous cabergoline, wherein the said 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 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°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.
A second aspect of the present invention provides a process for the preparation of amorphous cabergoline, wherein the said 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 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 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 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 50°C to about 80°C. The outlet temperature is preferably controlled from about 35°C to about 45°C. An inert gas such as nitrogen 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.
Figure 1 depicts XRPD of amorphous cabergoline obtained by agitated thin film drying. Figure 1 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°C under vacuum. The solid so obtained was collected from the Buchi Rotavapor® and dried at 40° to 45°C under vacuum for 8 to 10 h to obtain the title compound.
Yield: 2.7 g
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/cm2
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°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 10 h to obtain the title compound.
Yield: 2.9 g

WE CLAIM:
1. A process for the preparation of amorphous cabergoline, wherein the said 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.

2. A process as claimed in claim 1, wherein the organic solvent is selected from a group
consisting of acetone, diethyl ether, cyclohexane and isopropanol.
3. A process as claimed in claim 2, wherein the organic solvent is acetone.
4. A process as claimed in claim 1, wherein the agitated thin film drying is carried out under
vacuum.
5. A process for the preparation of amorphous cabergoline, wherein the said 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.

6. A process as claimed in claim 5, wherein the organic solvent is selected from a group
comprising of acetone, diethyl ether, cyclohexane and isopropanol.
7. A process as claimed in claim 6, wherein the organic solvent is acetone.
8. A process as claimed in claim 5, wherein the spray drying is carried out by controlling the
inlet temperature from about 50°C to about 80°C.

9. A process as claimed in claim 5, wherein the spray drying is carried out by using nitrogen as
a carrier gas.
10. A process as claimed in claim 5, wherein the amorphous cabergoline has an XRD pattern
as depicted in Figure 2.