HK1075047A - Process for preparing crystalline form i of cabergoline - Google Patents

Description

Process for preparing crystalline form I of cabergoline

This application claims priority from U.S. application No.60/364,567 filed on 3/15/2002 and U.S. application No.60/410,253 filed on 12/9/2002, each of which is incorporated herein by reference in its entirety.

Cabergoline is an ergoline derivative acting on the D2 dopamine receptor, endowed with different useful pharmaceutical activities, useful for the treatment of hyperprolactinemia, central nervous system disorders (CNS) and other related diseases. Cabergoline, commonly known by the name 1- ((6-allylergoline-8 β -yl) carbonyl) -1- (3-dimethylaminopropyl) -3-ethylurea, is described and claimed in US 4,526,892. The synthesis of cabergoline molecules has also been reported in eur.j.med.chem., 24, 421(1989) and GB-2,103,603-B.

Cabergoline form I, like cabergoline, shows a significant inhibitory effect on prolactin, and has therapeutic properties making it possible to treat patients with pathological conditions associated with abnormal prolactin levels, and thus can be used in humans and/or veterinary medicine. Cabergoline is also active, alone or in combination, for the treatment of reversible obstructive airways diseases, the control of intraocular pressure, the treatment of glaucoma. It is also used in the veterinary field as an anti-prolactin agent for the sterilisation of vertebrates. Several applications of cabergoline are described, for example, in WO 99/48484, WO 99/36095, US 5,705,510, WO 95/05176, EP 040,325.

Cabergoline type I is particularly useful in the treatment of Parkinson's Disease (PD), Restless Legs Syndrome (RLS), in the treatment of diseases like Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA).

Crystalline cabergoline form I is an anhydrous unsolvated form of cabergoline and was originally prepared by crystallization from diethyl ether as described in J Farmaco, 50(3), 175-.

WO 01/70740 describes another process for the preparation of crystalline form I of cabergoline by toluene solvate form V.

In order to reduce the batch cost, it is urgently required to improve the industrial production yield of crystalline form I of cabergoline, avoiding the lengthy process. It is therefore an object of the present invention to provide highly pure cabergoline form I using an organic solvent system which has never been used to date. Efficient preparation of highly pure crystalline form I of cabergoline may provide benefits in terms of industrial cost and environmental considerations.

The present invention relates to a novel process for the preparation of crystalline form I of cabergoline.

The process of the present invention comprises the preparation of a novel toluene solvate of cabergoline and its exclusive conversion to crystalline form I of cabergoline. The novel toluene solvate of cabergoline is a crystalline form fully identified hereinafter but referred to as "form X" for convenience.

In another aspect, the present invention provides solvated crystalline form X of cabergoline which, when desolvated, is capable of rapidly and exclusively providing crystalline form I of cabergoline.

In a fourth aspect, the present invention provides methods of preparing solvated crystalline form X of cabergoline and methods of preparing crystalline form I of cabergoline from solvated crystalline form X of cabergoline.

FIG. 1 is an X-ray powder diffraction (XRD) pattern showing the peak characteristics of crystalline cabergoline solvate form X, prepared as in example 1.

FIG. 2 is an X-ray powder diffraction (XRD) pattern showing the peak characteristics of crystalline cabergoline form I according to example 2.

FIG. 3 is an X-ray powder diffraction (XRD) pattern showing the peak characteristics of the original toluene solvate, designated form V, prepared according to the process described in WO 01/70740.

FIG. 4 is a Differential Scanning Calorimetry (DSC) plot of form X showing thermal events associated with the co-melting of cabergoline with toluene.

Figure 5 is a Differential Scanning Calorimetry (DSC) plot of form V showing thermal events associated with the co-melting of cabergoline with toluene.

FIG. 6 is time resolved powder X-ray data for the solvation phase change of form X under high vacuum (94.8kPa) at 43 ℃.

According to the present invention, form I can be easily prepared by: starting from the crude material, crystallization from toluene/heptane or toluene/hexane mixtures is carried out by the novel cabergoline solvate form X. This process for preparing form I is advantageous over the old processes because the cabergoline solvate form X is rapidly and exclusively converted to form I. Also provided are novel solvate form X of cabergoline, novel gel-mediated processes for its preparation and its conversion to crystalline cabergoline form I.

Feature identification

The new solvate form X of cabergoline was identified by X-ray powder diffraction (XRD) and compared to forms I and V. The desolvation and phase transition of form X to form I was studied by studying solvates in a dedicated unit on an X-ray diffractometer over a period of time at high temperature under high vacuum. Differential Scanning Calorimetry (DSC) profiles for form V and form X were also obtained to show the characteristics of these solvates.

X-ray diffraction analysis

Powder X-ray diffraction was performed using a Siemens D5000 powder diffractometer or an Inel multipurpose diffractometer. For the Siemens D5000 powder diffractometer, raw data of 2 θ were measured from 2 to 50, step size 0.020, step size 2 seconds. For the Inel multi-purpose diffractometer, the samples were placed in an aluminum sample container while raw data for all 20 values were collected for one thousand seconds. The data obtained are shown in tables I to III below.

The desolvation and phase change behavior from X to I was studied on an Inel multipurpose diffractometer using a dedicated unit that could be heated and evacuated by a vacuum pump. The desolvation and phase transition behavior of form X to form I was studied at 43 ℃ and 94.8kPa vacuum. The high vapor pressure of toluene necessitates a high vacuum for effective solvent removal. For X-form to I desolvation and phase transition, the Inel multi-purpose diffractometer was arranged to collect ten minutes of X-ray diffraction data every half hour for a total experimental time of two hours and forty minutes (including data collection).

The X-ray powder diffraction pattern of solvate form X (fig. 1) shows a crystalline structure with useful characteristic peaks, as described in table I below.

Table I: x-ray diffraction data of X-type

Angle 2 theta	Intensity Cps X1000	Strength%
			7.988	6899	100.00
10.937	837	11.97
			12.067	477	6.82
14.927	2213	31.66
			17.162	2603	37.25
17.320	3163	45.26
			19.938	855	12.22
21.075	2720	38.92
			23.892	1371	19.61
26.779	1086	15.54

The X-ray powder diffraction pattern of cabergoline form I (fig. 2) shows a crystalline structure with characteristic peaks, as described in table II below.

Table II: x-ray diffraction data of type I

Angle 2 theta	Intensity Cps X1000	Strength%
			9.870	4458	99.86
10.497	1498	33.55
			12.193	1244	27.86
14.707	1556	34.86
			16.658	1743	39.94
16.721	1644	36.83
			18.707	4464	100.00
20.822	2330	52.19
			22.688	1172	26.25
24.652	2341	52.44

The X-ray powder diffraction pattern of cabergoline toluene solvate form V (fig. 3) known as described in WO 01/70740 has a characteristic peak crystal structure as described in table III below.

Table III: x-ray diffraction data of V-shape

Angle 2 theta	Intensity Cps X1000	Strength%
			8.866	5930	100.00
12.287	705	11.88
			16.375	1440	24.28
18.171	1169	19.71
			18.991	1167	19.67
21.043	1214	20.47
			24.938	751	12.66

These data clearly show that cabergoline form X is a novel crystalline polymorphic solvate, XRD is readily distinguishable from solvate V, which is known as described in the prior art. The desolvation and phase transition behavior of form X to form I under the above conditions (fig. 6) shows that most of form X (the main peak at 2 theta of 7.988 degrees) has been converted to form I (the main peak at 2 theta of 9.870 and 18.707 degrees) within thirty minutes. The conversion was complete within one hour, as indicated by the complete disappearance of the 7.988 degree 2 θ peak.

Figure 6 clearly shows the good kinetics of desolvation and phase transition from form X to form I. The data also demonstrate that the short time to prepare form I via form X is very significant.

Differential scanning calorimetry analysis (DSC)

Differential scanning calorimetry traces were obtained from a Mettler-Toledo 822e differential scanning calorimeter. Data were collected at a 10 ℃/min heating gradient between 25 and 150 ℃. A40 μ L sealed aluminum pan was used with a pinhole in the lid.

The differential scanning calorimetry graph of type X (figure 4) shows that the main endothermic events are concentrated around 53 ℃, followed by a minor and extensive endothermic event, concentrated around 74 ℃. The former corresponds to the eutectic of form X with toluene, while the latter may be associated with the gradual loss of toluene by vaporization. For the purposes of the present invention, eutectic is defined as the conversion of a solid containing a solvent into a homogeneous liquid solution without any significant loss of solvent associated with the solid.

The differential scanning calorimetry trace of form V (fig. 5) shows that a single endothermic event is concentrated around 66 ℃. This thermal event corresponded to the co-melting of form V in toluene.

Comparison of fig. 4 and 5 also shows the X-and V-shaped characteristics.

The process of the present invention for the production of crystalline cabergoline form I is characterized by crystallization from toluene/heptane. Hexane may also be used instead of heptane. However, due to its toxicological properties, heptane is preferred, more suitable for pharmaceutical applications.

The process comprises dissolving cabergoline in an amount of toluene, preferably from 2.5 to 4.0g of toluene per gram of cabergoline, more preferably about 3.5g of toluene per gram of cabergoline, at room temperature.

Cabergoline used as a starting material may be an oil obtained by the synthesis described in eur.j.med.chem., 24, 421, (1989), or may be any crystalline form of cabergoline or mixtures thereof, including form I crystals, obtained by the processes described in the above references.

The resulting solution is cooled to below-10 ℃ and stirred overnight, preferably for a minimum of 18 hours.

During the overnight period, the solution of cabergoline in toluene became a gel, which for the purposes of the present invention was defined as a non-newtonian suspension of a thick birefringent solid, in equilibrium with a saturated solution in this suspension. Cold heptane or hexane, preferably around 10 to 20g per gram of cabergoline in the gel phase, is then added to the gel. The addition of cold heptane or hexane is referred to as "quenching" of the gel phase. It means that heptane or hexane has very strong anti-solvent properties against toluene solutions of cabergoline. These properties inherently aid in freezing solid suspensions, like the gels described above, into a defined solid state by eliminating the driving force for subsequent solid phase transformation into a crystalline form that may be more stable than form X.

Upon addition of heptane or hexane, the gel became a suspendable slurry, which was stirred at sub-ambient temperature. Under these conditions, form X is obtained as a toluene solvate which can be recovered by means of conventional processes, such as filtration under reduced pressure or centrifugation, followed by washing the solid with pure heptane or hexane to remove residual mother liquor and free toluene. The resulting form X crystals are very unstable after removal from their mother liquor and are substantially converted to form I within 24 hours of storage at ambient conditions without heating.

However, the form I crystals obtained in this particular manner may contain residual toluene at levels unacceptable for pharmaceutical use, and therefore it is preferred to heat the solids in a vacuum oven to reduce the toluene content to an acceptable range. Such drying may be accomplished by any suitable means, such as, but not limited to, heating the solids, reducing the ambient pressure around the solids, or a combination thereof. The drying pressure and the time of drying are not critical. The drying pressure is preferably about 101kPa or less. However, as the drying pressure decreases, the temperature at which drying can be performed and/or the time for drying also decreases.

Drying under vacuum will allow the use of lower drying temperatures, particularly for solids wetted with high melting solvents like toluene. The optimum combination of pressure and temperature is generally determined from the vapor pressure-temperature profile of toluene and operating factors related to the dryer design. The time for drying need only be sufficient to allow the toluene level to be reduced to a pharmaceutically acceptable level. When heating the solid to remove the solvent, for example in an oven, a temperature is selected that preferably does not exceed about 150 ℃.

Alternatively, cabergoline form I may be prepared by a combined desolvation and drying step directly from solvated crystalline form X obtained immediately after filtration. This combination of procedures can be performed without any modification to the drying process flow described in the previous paragraph, since the kinetics of desolvation and phase transition from form X to form I are very fast.

The crystalline form I cabergoline prepared according to the process of the present invention preferably has a polymorphic purity of > 95%, more preferably > 98%, and a yield of more than 90% w/w, compared to about 60% by the route described in WO 01/70740. Toluene solvate form X is also a guest of the present invention. The X-ray powder diffraction pattern of the X-form (fig. 1) shows the crystalline structure. These data indicate that cabergoline solvate form X is readily distinguishable by XRD and DSC. Solvate X of the present invention is a true solvate with a fixed composition of about 0.5 moles of toluene per mole of cabergoline. The significant difference from the known hemisolvate forms described in WO 01/70740 can be readily appreciated by reference to the respective XRD and DSC spectra.

The following examples contain detailed descriptions of the methods for preparing the solid state forms of cabergoline described herein. These detailed descriptions fall within the scope of the invention, which is set forth without limiting the scope in any way. All percentages are by weight unless otherwise indicated.

Example 1: preparation of cabergoline solvated crystalline form X

In a 125mL jacketed reactor equipped with an overhead stirring system, 3g of cabergoline was dissolved in 10.5g of toluene. Once a clear solution was formed, the reactor was cooled to a setpoint of-18 ℃ with stirring at 142 revolutions per minute in order to bring the temperature in the reactor to-15 ℃. The solution was stirred overnight (minimum 18 hours). During which time it became a thick gel. In another reactor, 45g of heptane was cooled to-15 ℃ and then transferred over 15 minutes to the gel containing reactor. The resulting slurry was stirred at-15 ℃ for three and a half hours and then discharged to a filter flask operating under reduced pressure. The filter cake was washed with 6mL heptane to remove mother liquor and wash excess toluene from the solid. These solids were left in the filter for 30 minutes.

They were identified by XRD as form X and the data are shown in figure 1 and table I. The yield was about 102% (w/w) based on the initial pure "toluene-free" cabergoline content.

Example 2: preparation of crystalline form I of cabergoline

The crystalline solvate form X obtained in example 1 was placed in a vacuum oven at ambient temperature under a vacuum of 94.8kPa for 2 hours. The temperature was then increased to 43 ℃ and the solid was further dried for 24 hours. Drying was carried out at 60 ℃ for a further 24 hours. Samples of the solids were taken after each drying stage and XRD and solvent content analysis showed that the solids had been converted to form I after the first drying stage (ambient temperature, high vacuum) but the toluene content was not within product specifications. The solids meet all product specifications after the second drying stage (24 hours at 43 ℃ under high vacuum). After drying, form I was identified by XRD and the data is shown in figure 2. The overall yield was about 93% based on the initial content of pure cabergoline. The polymorphic purity was determined to be > 98%.

Claims (15)

1. A process for producing crystalline form I of cabergoline, which process comprises the preparation of toluene solvate form X of cabergoline and its conversion to crystalline form I of cabergoline.

2. A process according to claim 1, wherein the preparation of toluene solvate form X comprises dissolving cabergoline in an appropriate amount of toluene, cooling and stirring the resulting solution, quenching the resulting gel with cold heptane or hexane, collecting the resulting cabergoline solvate form X having the XRD powder pattern of figure 1, and converting solvate form X into cabergoline form I by storage at room temperature and/or drying.

3. A process according to claim 2, wherein the suitable amount of toluene is from 2.5 to 4.0g of toluene per gram of cabergoline.

4. The process according to claim 2, wherein the suitable amount of toluene is about 3.5g of toluene per gram of cabergoline.

5. A process according to claim 2, wherein the cabergoline used as starting material is an oil, a crystalline form or a mixture thereof.

6. A process according to claim 2, wherein the solution of cabergoline in toluene is cooled to a temperature below-10 ℃ and stirred overnight.

7. A process according to claims 2 to 6, wherein the resulting gel is quenched with cold heptane.

8. A process according to claim 7 wherein cold heptane is added to the gel in an amount of from 10 to 20g heptane per gram cabergoline.

9. The process according to claim 2, wherein the final drying is carried out by heating the solid of solvate form X, reducing the ambient pressure around the solid, or a combination thereof.

10. A process according to claim 2, characterized in that the desolvation and drying steps are combined.

11. Solvate form X of cabergoline having the XRD powder pattern of figure 1.

12. Solvate form X of cabergoline having the characteristic peaks in powder X-ray diffraction as shown in table I below:

angle 2 theta Intensity Cps X1000 Strength% 7.988 6899 100.00 10.937 837 11.97 12.067 477 6.82 14.927 2213 31.66 17.162 2603 37.25 17.320 3163 45.26 19.938 855 12.22 21.075 2720 38.92 23.892 1371 19.61 26.779 1086 15.54

13. A process for the production of cabergoline solvate form X as defined in claim 11 or 12, which process comprises dissolving cabergoline in an amount of toluene, cooling the resulting solution, stirring it, quenching the resulting gel with cold heptane or hexane and collecting the resulting cabergoline solvate form X.

14. A process according to claim 13 wherein the resulting gel is quenched with cold heptane.

15. A process according to claim 14, wherein the amount of cold heptane added to quench the gel is from 10 to 20g per gram of cabergoline.