CA2616738A1 - Solvate of cabergoline and preparations of cabergoline form i - Google Patents

Abstract

A method of preparing cabergoline Form I, comprising forming a solvate including cabergoline and a p-disubstituted benzene of formula (A) and obtaining cabergoline Form I from the solvate. Another aspect of the present invention provides a method for preparing cabergoline Form I comprising dissolving cabergoline in p-disubstituted benzene and recovering the cabergoline Form I polymorph, suitably by direct crystallization of Form I or by recovery of a solvate which can be converted to Form I.

Description

SOLVATE OF CABERGOLINE AND PREPARATIONS OF CABERGOLINE FORM I
FIELD OF THE INVENTION

[0001] The present application relates to the preparation of cabergoline, in particular to a new process for preparing cabergoline Form I.
BACKGROUND OF THE INVENTION

[0002] Cabergoline is an ergoline derivative with formula 1-((6-allylergolin-8j3-yI)-carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea. It is known for treatment of a number of diseases, including CNS disorders, reversible obstructive airways disease, prolactin inhibition, for controlling intra-ocular pressure and for treating glaucoma.

[0003] A number of different forms of cabergoline are known and, by way of example, PCT patent publication no. WO 01/72747 describes cabergoline Form II and PCT patent publication no. WO 01/72746 describes cabergoline Form VII.

[0004] Preparation of cabergoline Form I is described in PCT patent publication nos. WO 01/70740, WO 03/078392 and WO 03/078433. For example, PCT patent publication no. WO 01/70740 teaches the preparation of crystalline cabergoline Form I from a solvent comprising a toluene/diethylether mixture whereas PCT patent publication nos. WO 03/078392 and WO 03/078433 teach crystalline cabergoline Form I that is obtained by drying a solvate of cabergoline and toluene.

[0005] Pending U.K. patent application no. GB 0409785.3 teaches a process for preparing cabergoline Form I of high yield and purity and with desirable particle size distribution using ethylbenzene optionally in conjunction with an anti-solvent such as n-heptane. GB 0409785.3 further describes a cabergoline ethylbenzene solvate.

6 PCT/GB2006/002784 [0006] A series of cabergoline polymorphs are also described in PCT patent publication no. WO 2004/101510.

[0007] It is desired in the present invention to prepare crystalline cabergoline Form I having high purity. It is also desired to prepare cabergoline having a particle size (following crystallization) which is relatively small and which requires no or relatively little milling to obtain the particle size desired in the eventual pharmaceutical product. Milling and other such processing is undesirable as it tends to lead to conversion of pure polymorphic forms of cabergoline into polymorphic mixtures. One problem with the methods described in PCT patent publication no. WO 03/078433, for example, is that crystals of cabergoline Form I obtained have a relatively large particle size.

[0008] It is also desired to provide a process for preparation of cabergoline in which conversion of an intermediate solvate to the final cabergoline Form I product is quick and efficient. A difficulty with known processes for this conversion is that protracted drying periods are required to remove the solvent from the solvate - in excess of 48 hours - for the methods set forth in PCT patent publication no. WO 03/078433.

SUMMARY OF THE INVENTION

[0009] One aspect of the present invention provides a method for preparing cabergoline Form I comprising dissolving cabergoline in a p-disubstituted benzene of formula (A) x (A) ~

where X is a halogen, and Y is selected from the group consisting of a halogen or a C2 to C5 linear alkyl, and recovering the cabergoline Form I
polymorph from the solution in the p-disubstituted benzene, suitably by direct crystallization or recovery of a solvate which can be converted into cabergoline Form I.

BRIEF DESCRIPTION OF THE DRAWINGS

[00010] Figure 1 is an X-ray powder diffraction pattern for the cabergoline Form I obtained using 4-fluorotoluene as solvent (Example 1);

[00011] Figure 2 is a 13C CPMAS spectrum of cabergoline Form I

obtained using 4-fluorotoluene as solvent (Example 1);

[00012] Figure 3 is an X-ray powder diffraction pattern of cabergoline Form I obtained using 1-chloro-4-fluorotoluene as solvent (Example 4);

[00013] Figure 4 is a differential scanning calorimetry (DSC) trace of damp cabergoline Form I obtained using 1-chloro-4-fluorobenzene as solvent (Example 4);

[00014] Figure 5 is a differential scanning calorimetry (DSC) trace of dry cabergoline Form I obtained using 1-chloro-4-fluorobenzene as solvent (Example 4);

[00015] Figure 6 is an FTIR scan of cabergoline Form I obtained using 1-chloro-4-fluorobenzene as solvent (Example 4);

[00016] Figure 7 is a 13C CPMAS spectrum of cabergoline Form I
obtained using 1-chloro-4-fluorobenzene as solvent (Example 4);

[00017] Figure 8 is an X-ray powder diffraction pattern of cabergoline Form I obtained using 1,4-difluorobenzene as solvent (Example 6); and

[00018] Figure 9 is a!3C CPMAS spectrum of cabergoline Form I
obtained using 1,4-difluorobenzene as solvent (Example 6).

DETAILED DESCRIPTION OF THE INVENTION

[00019] The present invention involves preparing cabergoline Form I
by dissolving cabergoline in a p-disubstituted benzene of formula (A), x (A) Y

where X is a halogen, and Y is selected from the group consisting of halogens preferably bromine or iodine, more preferably bromine, or C2 to C5 alkyl, preferably C2 to C4 alkyl and still more preferably C2 or C3 alkyl, to form a solution, and then recovering the cabergoline Form I polymorph. Cabergoline Form I can be recovered from the solution, suitably by direct crystallization to obtain cabergoline Form I or by recovery of a solvate which can be converted into cabergoline Form I.

[00020] Preferably, the p-disubstituted benzene of formula (A) is substituted with fluorine at the X position. More preferably, the p-disubstituted benzene of formula (A) is substituted with fluorine at the X
position and where Y is selected from the group consisting of C2 to C5 linear alkyl, preferably C2 to C4 alkyl and still more preferably C2 or C3 alkyl, or halo, preferably bromine.

[00021] In one preferred embodiment of the invention, cabergoline Form I may be obtained by forming a solvate of cabergoline and a p-disubstituted benzene of formula (A), optionally further comprising an anti-solvent (for example heptane), and obtaining cabergoline Form I from this solvate. Cabergoline Form I may be obtained from the solvate by either direct crystallization of Form I, or recovery of a solvate which can be converted to Form

[00022] In another embodiment of the present invention, cabergoline Form I is prepared by dissolving cabergoline in a solvent comprising a p-disubstituted benzene of formula (A), optionally adding an anti-solvent (for example heptane) to form a solvate, and the solvate is dried to obtain cabergoline Form I.

[00023] In another embodiment of the present invention, cabergoline is dissolved in a solvent which comprises a p-disubstituted benzene of formula (A) (and optionally 1,3,5-trimethylbenzene) and the solution is cooled to a temperature of -5 C or below. The solvent preferably comprises at least 75%
by volume of a p-disubstituted benzene of formula (A). It is contemplated in accordance with the present invention that the solvent may consist solely of a p-disubstituted benzene of formula (A).

[00024] In a further embodiment of the present invention, cabergoline is dissolved in a solvent selected from a p-disubstituted benzene of formula (A) (and optionally 1,3,5-trimethylbenzene). The dissolving process is optionally performed at room temperature, typically about 25-30 C and the resulting solution is preferably filtered to remove particulate material. The temperature of the solution is then lowered to about -17 C or below, preferably -23 C or below, thereby forming a precipitate of cabergoline. Formation of the cabergoline precipitate can optionally be encouraged by stirring or seeding using crystalline cabergoline Form I.

[00025] To the cabergoline precipitate an anti-solvent is added. As used herein, an anti-solvent is generally a liquid in which cabergoline, and/or cabergoline/p-disubstituted benzene of formula (A) solvate is highly insoluble.
The anti-solvent preferably comprises hexane, heptane, diethylether, diisopropylether, tertiarybutylmethyl ether or mixtures of these solvents. The anti-solvent more preferably comprises heptane, and most preferably comprises n-heptane.

[00026] The addition of the anti-solvent results in formation and precipitation of cabergoline, or a cabergoline/p-disubstituted benzene of formula (A) solvate, forming a slurry that can be filtered to recover a solid, which is optionally washed, for example with further anti-solvent, and then dried to yield cabergoline Form I having high purity.

[00027] The ratio of the first solvent, i.e., the solvent comprising a p-disubstituted benzene of formula (A) to the second solvent, i.e., the anti-solvent, is generally in the range of 4-10:5-20 volumes, preferably in the range of 5-7:8-volumes and more preferably in the range of 5-7:10-12 volumes. It is most preferable that the ratio of the first solvent to the second solvent is approximately 5-6:11.

[00028] Advantageously, wet solvate of the present invention that can be recovered by filtration can be rapidly dried to form crystals of cabergoline Form I.

[00029] Drying of the wet solvate can be achieved in a number of different ways. For example, drying has been carried out under reduced pressure, at pressures of 900 mbar or less, 800 mbar or less and 700 mbar or less. In each of these examples, a dried, pure cabergoline Form I was obtained within 30 hours. Drying can also be carried out at elevated temperatures. It is contemplated in accordance with the present invention that the wet solvate can be rapidly dried at 40 C to 60 C.

[00030] Yet another option is to dry the wet solvate in an inert gas atmosphere. The inert gas atmosphere comprises nitrogen, argon and/or other inert gases at a concentration of 80% or higher by volume. Preferably the inert gas atmosphere comprises 5% or less oxygen. In addition, a nitrogen or other inert gas blanket can be used to dry the wet solvate or drying can be carried out in a stream of an inert gas. It has been found that drying using an inert gas can be completed in less than approximately 20 hours. This is especially an advantage when preparing cabergoline Form I at large scale.

[00031] The above methods have been found, advantageously, to yield cabergoline Form I having a relatively small particle size, typically with a volume median diameter (VMD) of less than 90 microns. [Example 8 below illustrates the particle size advantages associated with cabergoline Form I
prepared using solvents of the type presently claimed, for example, 4-fluorotoluene, 1-chloro-4-fluorobenzene, and 1,4-difluorobenzene respectively.] Any milling of the product after crystallization tends to result in loss of polymorph purity, and therefore this relatively small particle size is a significant advantage in preparation of a pharmaceutical product having cabergoline Form I of high purity.

[00032] Also provided by the present invention is cabergoline Form 1, obtained by the methods of the invention, and a solvate of cabergoline comprising cabergoline and a p-disubstituted benzene of formula (A).

[00033] The following examples illustrate the invention without intending to limit the scope of the invention.

EXAMPLES
Example I

Preparation of Cabergoline Form I using 4-fluorotoluene

[00034] 5.0 grams of cabergoline (purity 99.9% by HPLC percentage peak area) was dissolved in 15 mL of a solvent (4-fluorotoluene) to form a solution. The solution was cooled to -20 C to give a gel. After 7 hours, 110 mL of a pre-filtered solution of an anti-solvent (n-heptane), also at -20 C, was added dropwise over a 20-minute period.

[00035] Once the addition was complete, the slurry was stirred at -20 to -15 C for 3.5 hours. The product was then collected by filtration under a blanket of nitrogen and the filter cake washed with cold (-20 to -15 C) n-heptane. The filter cake was then dried under a blanket of nitrogen for 30 minutes.

[00036] The resulting solid was then placed in a vacuum oven with a nitrogen purge at 45-50 C. Full vacuum was then appiied to the solid in the vacuum oven at 40 to 50 C until the sample was at constant weight.

[00037] Samples of the product were subjected to chromatographic tests such as FTIR, DSC and X-ray crystallographic analysis (as set forth in Figure 1) and determined to be pure cabergoline Form I. The yield was 96.7%.
Example 2 Preparation of Cabergoline Form I using 4-fluorotoluene

[00038] The procedure of Example 1 was repeated; except that 2.0 grams of cabergoline were dissolved in 10 mL of 4-fluorotoluene and 22 mL of n-heptane were added in the subsequent stage.

[00039] Samples of the product were subjected to FTIR and determined to be pure cabergoline Form I. DSC analysis of damp material showed a peak at 52.5 C and DSC analysis of dry material showed a peak at 104.20 C. The yield was 77.8%.

Example 3 Preparation of Cabergoline Form I using 4-fluorotoluene

[00040] The procedure of Example 1 was repeated; except that 2.0 grams of cabergoline were dissolved in 6 mL of 4-fluorotoluene and 44 mL of n-heptane were added in the subsequent stage.

[00041] Samples of the product were subjected to FTIR, DSC

and X-ray crystallographic analysis and determined to be pure cabergoline Form 1. DSC analysis of damp material showed a peak at 52.5 C and DSC analysis of dry material showed a peak at 104.16 C. The yield was 82%.

Example 4 Preparation of Cabergoline Form I using 1-chloro-4-fluorobenzene

[00042] 2.0 grams of cabergoline was dissolved in 8 mL of solvent (1-chloro-4-fluorobenzene) by warming to form a solution. The solution was then filtered through a 0.45p filter which was then washed with 2 mL of 1-chloro-4-fluorobenzene. The solution was then stirred in a freezer at -15 to -20 C for hours. 44 mL of cold n-heptane was added in over 20 minutes.

[00043] Once the addition was complete, the suspension was stirred at -15 to -20 C for 3.5 hours. The product was then collected by filtration and the filtrate was washed with cold heptane. The filtrate was then dried under a blanket of nitrogen for 30 minutes, yielding 2.3 g (damp weight) of product (DSC = 67 C).

[00044] The resulting solid was then subjected to a nitrogen flow at 40 C followed by drying in vacuo at 40 C for 24 hours (DSC = 67 C) and then drying the dried solid in vacuo at 50 C for an additional 96 hours (DSC = 103.1 C).

[00045] Samples of the product at both drying stages were subjected to chromatographic tests such as FTIR, DSC and '3C CPMAS
analysis (as set forth in Figures 3-7) and determined to be pure cabergoline Form I.

46 PCT/GB2006/002784 Example 5 Preparation of Cabergoline Form I using I-chloro-4-fluorobenzene [00046] 2.25 grams of cabergoline was dissolved in 6.75 mL of solvent (1-chloro-4-fluorobenzene) at 19.5 C to form yellow homogenous solution. The solution was then polish filtered and the filter was washed with 2.25 mL of 1-chloro-4-fluorobenzene. The solution was then stirred in a freezer at -15 to -17 C until a white solid precipitated without seeding. 49.5 mL
of cold n-heptane was added (at -20 to -25 C) under a blanket of nitrogen over a period of 15 minutes. The flask containing the mixture was returned to the freezer and stirred overnight.

[00047] The solid was then filtered off the next day and washed with cold filtrate (mother liquor) to help transfer the solid. The filtered solid was then kept under suction and a positive stream of nitrogen for 20 minutes and then transferred to a hot (40 C) oven with nitrogen for 3 hours. The damp weight was 2.69g.

[00048] The solid was then dried in an oven in vacuo at 45 C
overnight to yield 2.113g of dry solid.

[00049] Samples of the product were subjected to DSC analysis resulting in the following results and confirming that the product formed was pure cabergoline Form I.

Very Small Peak Main Peak Integral -3.23 mJ -126.69 mJ
Onset 62.62 C 95.45 C
Peak 65.50 C 102.20 C
Endset 68.17 C 104.84 C

Example 6 Preparation of Cabergoline Form I using 1,4-difluorobenzene

[00050] 2.0 grams of cabergoline was dissolved in 6 mL of solvent (1,4-difluorobenzene) at 18 C. The solution was then polish filtered and the filter was washed with I mL of 1,4-difiuorobenzene. The solution was then kept in a freezer at -17 C with no stirring. No precipitate formed and the solution was seeded with cabergoline Form I and left overnight at -17 C in a freezer with no stirring. 44 mL of cold n-heptane was added in over a period of 15 minutes.
The flask containing the mixture was returned to the freezer to stand overnight -17 C with no stirring.

[00051] The next day the solid was filtered and washed with cold filtrate (mother liquor) to help transfer the solid. The filtered solid was then kept under suction and a positive stream of nitrogen for 20 minutes and then transferred to a hot (40 C) oven with nitrogen for 3 hours. The damp weight was 2.203g. The solid was then dried in an oven in vacuo at 45 C for 24 hours to yield 1.82g of dry solid.

[00052] Samples of the product were subjected to FTIR analysis resulting in a determination that the product formed was pure cabergoline Form I.
Example 7 Preparation of Cabergoline Form I using 1,3,5-trimethylbenzene

[00053] The procedure of Example 1 was repeated using 1,3,5-trimethylbenzene (mesitylene) as the solvent. Specifically, 2.0 grams of cabergoline was dissolved in 50 mL of 1,3,5-trimethylebenzene and the resulting solution, was processed as described in Example 1.

[00054] Analysis of the resulting product showed that it consisted predominantly of cabergoline Form I, together with a minor amount (3.8%) of the Form II.

Example 8 Comparison of Polymorphs Obtained from Different Solvents.

[00055] The procedure of Example 4 was repeated using the solvents indicated in the following table. The polymorphic form obtained is indicated in the right hand column.

Solvent Polymorphic form 1 -chloro-4-fluorobenzene/heptane Form I
4-methylanisole Form II
chlorobenzene/heptane A mixture of polymorphic forms.
Fluorobenzene/heptane A new polymorphic form according to DSC, X-ray and SS13C analysis (designated Form FB) Comparison of Particle Size of Cabergoline Polymorphs Obtained from Different Solvents.

[00056] The procedure of Example I was repeated using 4-fluorotoluene/heptane, 1,3,5-trimethylbenzene, 1-chloro-4-fluorobenzene/heptane, and 1,4-difluorobenzene respectively. The particle size of the cabergoline Form I polymorph obtained in each instance was measured and compared to the particle size of cabergoline Form I obtained according to WO 03/078433, disclosing the preparation from toluene/heptane and to the particle size of cabergoline Form II. The results are shown in the Table below.

Polymorph; Solvent Xio X50 X90 VMD
iam pm pm pm Form I 1.76 106.21 158.01 84.95 4-fluorotoluene/heptane Form I 2,96 45.01 141.84 61.80 1,3,5-trimethylbenzene Form I 9.17 28.42 69.74 34.02 1,chloro-4-fluorobenzene Form 1 24.35 42.83 77.64 47.54 1 ,4-difluorobenzene Form I 36.67 100.05 149.69 96.01 Toluene / heptane Form li 46.68 117.56 159.36 111.26

[00057] Accordingly, the present invention provides methods for obtaining crystalline cabergoline Form I with high purity, which is easy to dry from the intermediate solvate and which has a particle size that facilitates preparation of a pharmaceutical product with reduced post-crystallization processing.

[00058] The use of the terms "a" and "an" and "the" and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[00059] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description.
The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims (66)

1. A method of preparing cabergoline Form I, comprising: forming a solvate of cabergoline and a p-disubstituted benzene of formula (A) wherein X is a halogen, and Y is selected from the group consisting of halogens or C2 to C5 linear alkyl; and, obtaining cabergoline Form I from that solvate.

2. The method of claim 1, comprising forming a solvate of cabergoline and a p-disubstituted benzene of formula (A) wherein X is fluorine.

3. The method of claim 1 or claim 2, comprising forming a solvate of cabergoline and a p-disubstituted benzene of formula (A) wherein Y is selected from the group consisting of C2 to C4 alkyl or bromine.

4. The method of claim 3, comprising forming a solvate of cabergoline and a p-disubstituted benzene of formula (A) wherein X is fluorine and Y is C2 to C3 alkyl.

5. The method of claim 3, comprising forming a solvate of cabergoline and a p-disubstituted benzene of formula (A) wherein X is fluorine and Y is ethyl.

6. The method of claim 3, comprising forming a solvate of cabergoline and a p-disubstituted benzene of formula (A) wherein X is fluorine and Y is propyl.

7. The method of claim 1, where the solvate is formed by dissolving cabergoline in a solvent comprising a p-disubstituted benzene of formula (A).

8. The method of claim 7, wherein the solvent comprises at least 75%
by volume of a p-disubstituted benzene of formula (A).

9. The method of claim 8, wherein the solvent comprises a p-disubstituted benzene of formula (A) alone.

10. The method of claim 7, further comprising the step of cooling the solution formed by dissolving cabergoline in a p-disubstituted benzene of formula (A) to a temperature of at most -5°C.

11. The method of claim 7, further comprising the step of filtering the solution formed by dissolving cabergoline in a p-disubstituted benzene of formula (A).

12. The method of claim 7, further comprising the step of adding an anti-solvent to form the solvate.

13. The method of claim 12, wherein the anti-solvent is selected from the group consisting of hexane, heptane, diethylether, diisopropylether, tertiarybutylmethyl ether, and mixtures thereof.

14. The method of claim 13, wherein the anti-solvent is heptane.

15. The method of claim 14, wherein the anti-solvent is n-heptane.

16. The method of claim 1, wherein cabergoline Form I is obtained from the solvate by drying.

17. The method of claim 16, wherein the drying is performed at a pressure of 900 mbar or less.

18. The method of claim 16, wherein the drying occurs at a temperature of at least 40°C.

19. The method of claim 16, wherein the drying occurs in an inert gas atmosphere.

29. The method of claim 19, wherein the inert gas atmosphere comprises less than 5% of oxygen.

21. The method of claim 19, wherein the inert gas atmosphere comprises an inert gas selected from the group consisting of nitrogen gas and argon gas.

22. The method of claim 19, wherein the inert gas atmosphere comprises a gas mixture including at least 80% inert gas.

23. The method of claim 22, wherein the gas mixture comprises nitrogen gas.

24. The method of claim 22, wherein the gas mixture comprises argon gas.

25. Cabergoline Form I, obtained by the method according to any one of the preceding claims.

26. A solvate of cabergoline comprising cabergoline and a p-disubstituted benzene of formula (A) wherein X is a halogen, and Y is selected from the group consisting of halogens or C2 to C5 linear alkyls.

27. The solvate of claim 26, comprising cabergoline and a p-disubstituted benzene of formula (A) wherein X is fluorine.

28. The solvate of claim 26 or claim 27, comprising cabergoline and a p-disubstituted benzene of formula (A) wherein Y is selected from the group consisting of C2 to C4 alkyl or bromine.

29. The solvate of claim 28, comprising cabergoline and a p-disubstituted benzene of formula (A) wherein X is fluorine and Y is C2 to C3 alkyl.

30. The solvate of claim 28, comprising cabergoline and a p-disubstituted benzene of formula (A) wherein X is fluorine and Y is ethyl.

31. The solvate of claim 28, comprising cabergoline and a p-disubstituted benzene of formula (A) wherein X is fluorine and Y is propyl.

32. The solvate of claim 29, further comprising an anti-solvent.

33. The solvate of claim 32, wherein the anti-solvent is selected from the group consisting of hexane, heptane, diethylether, diisopropylether, tertiarybutylmethyl ether, and mixtures thereof.

34. The solvate of claim 33, wherein the anti-solvent is heptane.

35. The solvate of claim 34, wherein the anti-solvent is n-heptane.

36. A method of preparing cabergoline Form I comprising dissolving cabergoline in a solvent comprising a p-disubstituted benzene of formula (A) wherein X is a halogen, and Y is selected from the group consisting of a halogen or a linear C2 to C5 alkyl to form a solution and obtaining cabergoline Form I from the solution.

37. The method of claim 36, wherein the solvent comprises a p-disubstituted benzene of formula (A) wherein X is fluorine.

38. The method of claim 36 or claim 37, wherein the solvent comprises a p-disubstituted benzene of formula (A) wherein Y is selected from the group consisting of C2 to C4 alkyl or bromine.

39. The method of claim 38, wherein the solvent comprises a p-disubstituted benzene of formula (A) wherein X is fluorine and Y is C2 to C3 alkyl.

40. The method of claim 38, wherein the solvent comprises a p-disubstituted benzene of formula (A) wherein X is fluorine and Y is ethyl.

41. The method of claim 38, wherein the solvent comprises a p-disubstituted benzene of formula (A) wherein X is fluorine and Y is propyl.

42. The method of claim 36, wherein the solvent comprises at least 75% by volume of said p-disubstituted benzene of formula (A).

43. The method of claim 42, wherein the solvent comprises a p-disubstituted benzene of formula (A) alone.

44. The method of claim 36, further comprising the step of cooling the solution to a temperature of at most -5°C.

45. The method of claim 36, wherein the dissolving takes place at room temperature.

46. The method of claim 45, wherein the dissolving takes place between 25-30°C.

47. The method of claim 36, further comprising the step of filtering the solution to remove particulate material.

48. The method of claim 36, further comprising the step of cooling the solution to a temperature of at most -17°C to form a precipitate.

49. The method of claim 48, wherein the solution is cooled to a temperature of at most -23°C to form a precipitate.

50. The method of claim 36, further comprising the step of adding a second solvent to the solution.

51. The method of claim 50, wherein the second solvent is selected from the group consisting of hexane, heptane, diethylether, diisopropylether, tertiarybutylmethyl ether, and mixtures thereof.

52. The method of claim 51: wherein the anti-solvent is heptane.

53. The method of claim 52, wherein the anti-solvent is n-heptane.

54. The method of claim 50, where the ratio of the p-substituted benzene of formula (A) to the second solvent is 4-10:5-20 volumes.

55. The method of claim 54, where the ratio of the p-substituted benzene of formula (A) to the second solvent is 5-7:10-1 2 volumes.

56. The method of claim 55, where the ratio of the p-substituted benzene of formula (A) to the second solvent is 5-6:11 volumes.

57. The method of claim 36, further comprising the step of drying the solution to obtain cabergoline Form I.

58. The method of claim 57, wherein the drying is performed at a pressure of 900 mbar or less.

59. The method of claim 57, wherein the drying occurs at a temperature of at least 40°C.

60. The method of claim 57, wherein the drying occurs in an inert gas atmosphere.

61. The method of claim 60, wherein the inert gas atmosphere contains less than 5% oxygen.

62. The method of claim 60, wherein the inert gas atmosphere comprises an inert gas selected from the group consisting of nitrogen gas and argon gas.

63. The method of claim 60, wherein the inert gas atmosphere comprises a gas mixture including at least 80% inert gas.

64. The method of claim 63, wherein the gas mixture comprises nitrogen gas.

65. The method of claim 63, wherein the gas mixture comprises argon gas.

66. Cabergoline Form I, obtained by the method of any one of Claims 36 to 65.