CRYSTALLINE FORM VII OF CABERGOLINE

Abstract: Crystalline form VII of cabergoline, a pharmaceutical composition containing it and a process for its preparation are disclosed. The process may comprise a slurry procedure using form I or mixture of forms I and VII of cabergoline in a solvent at a temperature above 30 DEG C.

Description: Crystalline form VII of cabergoline The present invention concerns a new crystalline form of cabergoline, a pharmaceutical composition thereof and its use as therapeutically active agent, alone or in combination. Another aspect of the present invention relates to the preparation of this crystalline form. Cabergoline is an ergoline derivative interacting with D2 dopamine receptors and is endowed with different useful pharmaceutical activities and it is used in the treatment of hyperprolactinemia, central nervous system disorders (CNS) and other related diseases. Cabergoline is the generic name of 1 ( (6-allylergolin-8beta- yl) -carbonyl) -1- (3 -dimethylaminopropyl) -3-ethylurea, described and claimed in US 4,526,892. The synthesis of Cabergoline molecule is reported also in European. J. Med. Chem., 24,421,(1989) and in GB-2 , 103 , 603 -B . During our work we discovered that cabergoline can exist in at least two crystalline forms under ambient conditions . One form (coded Form I) is an anhydrous not solvated form and, to our knowledge, it is the only form reported in the literature to date. Form VII is an anhydrous not solvated form too. Thus, the present invention concerns a new polymorph (Form VII) of cabergoline and the preparation thereof. Another aspect relates to samples of cabergoline Form VII having a % polymorphic purity >90%, preferably >99% . The invention further provides a pharmaceutical composition of cabergoline Form VII and its use as therapeutic agent. Description of figures Figure 1 XRD powder pattern of cabergoline Form VII. Figure 2 DSC curve of cabergoline Form VII. Figure 3 IR spectrum of cabergoline Form VII (sample prepared by KBr powder technique) . Figure 4. Solid state "C-NMR spectrum of cabergoline form VII. Form VII is the thermodynamically most stable polymorph in a range of temperature between +30° and +80 °C. It can be readily prepared by slurry of form I or mixture of form I and VII in a solvent at a temperature over 30°C. The importance of cabergoline form VII rests primarily (but not exclusively) in thermodynamic stability. Form VII shows advantages with respect to form I because of its greater stability. Characterisation X-ray powder diffraction (XRD) , differential scanning calorimetry (DSC) , infrared (IR) spectroscopy and solid state "C-NMR were used to characterise the new form. X-Ray Powder Diffraction Powder X-ray diffraction was performed using either a Scintag XI or X2 Advanced Diffraction System operating under Scintag DMS/NT ® Ver 1.30a and 1.36b respectively, and Microsoft Windows NT 4.0™ software. The system used a copper X-ray source maintained at 45 kV and 40 mA to provide CuKα x emission of 1.5406 angstroms and a solid state peltier cooled detector. Beam aperture was controlled using tube divergence and anti-scatter slits of 2 and 4 mm and detector anti-scatter and receiving slits of 0.5 and 0.3 mm width. Data were collected from 2 to 40° two-theta using a step scan of 0.03°/point with a one second/point counting time. The samples were hand ground using a pestle and mortar and packed into an aluminum sample tray with a 12 mm (diam.) x 0.5 mm cavity. DSC Measurements of differential scanning calorimetry were obtained on a Mettler TA 4000 thermal analysis system. Approximately 8.5 mg samples were accurately weighed into a DSC Pan. The pans were hermetically sealed and a pinhole was punched into the Pan lid. The use of the pinhole allows for pressure release, but still assures that the thermal reactions proceed under controlled conditions. The samples were introduced into the DSC oven and then heated at a rate of 5°C/min, up to a final temperature of 135°C. 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After 24 hours the obtained solid was filtered on sintered-glass G4 filter and then dried at from 30 °C to 65 °C under N 2 and vacuum. The resultant crystals form VII were identified by DSC and IR. Yield was 45.2%.

Claims: CT.A TMS 1. Crystalline form VII of cabergoline. 2. Crystalline form VII of cabergoline according to claim 1 which is anhydrous, non- solvated and has a percentage purity greater than 92%. 3. Crystalline form VII of cabergoline according to claim 1 which is anhydrous, non-solvated and has a percentage purity greater than 99%. 4. Crystalline form VII of cabergoline having the XRD powder pattern of Figure 1. 5. A pharmaceutical composition which comprises an effective amount of crystalline Form VII, as defined in any one of claims 1 to 4 in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants. 6. A process for producing cabergoline Form VII as defined in any one of claims 1 to 4, which process comprises subjecting crystals of form I, or' a mixture of forms I and VII, of cabergoline to a slurry procedure at a temperature above 30°C, followed by recovery and drying of the resulting crystals. 7. A process according to claim 6 in which the slurry procedure comprises suspending crystals of form I or a mixture of forms I and VII of cabergoline in an organic solvent, at a temperature of from +30°to +80°C, and stirring the resultant suspension for from 24 to 120 hours. 8. A process according to claim 7 in which the solvent is diethyl ether, n-heptane or n-hexane.

Inventors: BUDELLI RAFFAELLA, CANDIANI ILARIA, PANDOLFI MARCO, UNGARI MARIO, BUDELLI, RAFFAELLA, CANDIANI, ILARIA, PANDOLFI, MARCO, UNGARI, MARIO
Applicants: BUDELLI RAFFAELLA, CANDIANI ILARIA, PANDOLFI MARCO, PHARMACIA & UPJOHN SPA, UNGARI MARIO, BUDELLI, RAFFAELLA, CANDIANI, ILARIA, PANDOLFI, MARCO, UNGARI, MARIO
Application year: 2001
Main classification: C07D457
IPC codes: A61K31, A61P5, A61P25, C07D457