WO2003078392A2 - Process for preparing crystalline form i of cabergoline - Google Patents
Process for preparing crystalline form i of cabergoline Download PDFInfo
- Publication number
- WO2003078392A2 WO2003078392A2 PCT/US2003/007138 US0307138W WO03078392A2 WO 2003078392 A2 WO2003078392 A2 WO 2003078392A2 US 0307138 W US0307138 W US 0307138W WO 03078392 A2 WO03078392 A2 WO 03078392A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cabergoline
- toluene
- process according
- solvate form
- solvate
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
- C07D457/06—Lysergic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
Definitions
- 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 l((6-allylergolin-8 ⁇ -yl)-carbonyl)-l-(3- dimethylaminopropyl)-3-ethylurea, described and claimed in US 4,526,892. The synthesis of cabergoline molecule is reported also in Eur. J. Med. Chem., 24,421,(1989) and in GB-
- Cabergoline Form I like cabergoline, displays a significant inhibitory effect with regard prolactine and has therapeutic properties that make it possible to treat patients who have pathological conditions associated with an abnormal prolactine level, thus is useful in human and/or veterinary medicine.
- Cabergoline is also active, alone or in combination, in the treatment of reversible obstructive airways diseases, for controlling intra-ocular pressure and for the treatment of glaucoma. It is also employed in the veterinary field, as antiprolactin agent and in cutting down drastically the proliferation of vertebrate animals.
- cabergoline The several uses of cabergoline are for example described in WO99/48484, WO99/36095, US5705510, WO95/05176, EP040,325.
- Cabergoline Form I is particularly useful in the treatment of Parkinson's disease (PD), Restless Legs Syndrome (RLS), treatment of diseases like Progressive Supranuclear Palsy (PSP) and Multysystemic atrophy (MSA).
- PD Parkinson's disease
- RLS Restless Legs Syndrome
- PSP Progressive Supranuclear Palsy
- MSA Multysystemic atrophy
- Crystalline cabergoline Form I an anhydrous not solvated form of cabergoline, was firstly prepared by crystallization from diethyl ether, as described in H Farmaco, 50 (3), 175-178
- the present invention concerns a new process for preparing crystalline Form I of cabergoline.
- the method of the present invention comprises the preparation of a new toluene solvate of cabergoline and its exclusive conversion into crystalline Form I of cabergoline.
- the new toluene solvate of cabergoline is a crystalline form fully characterized herein below, but it is referred to for convenience as "Form X".
- the invention provides solvated crystalline Form X of cabergoline that, when de-solvated, can quickly and exclusively yield crystalline Form I of cabergoline.
- the invention provides processes for preparing solvated crystalline
- FIG. 1 is an x-ray powder diffraction (XRD) pattern showing peaks characteristic of crystalline cabergoline solvate Form X, made in accordance with Example 1.
- FIG. 2 is an x-ray powder diffraction (XRD) pattern showing peaks characteristic of crystalline cabergoline Form I, according to Example 2.
- FIG. 3 is an x-ray powder diffraction (XRD) pattern showing peak characteristic of the original toluene solvate, referred to as Form N made in accordance with procedure outlined in OOl/70740.
- XRD x-ray powder diffraction
- FIG. 4 is a differential scanning calorimeter (DSC) profile of Form X, showing thermal event associated with eutectic melting of cabergoline with toluene.
- FIG. 5 is a differential scanning calorimeter (DSC) profile of Form N, showing thermal event associated with eutectic melting of cabergoline with toluene
- FIG. 6 is the time resolved powder x-ray data of the de-solvation phase transformation of
- Form I can be readily prepared starting from crude material by crystallization from a toluene/heptane or toluene/hexane mixture, through a new solvate Form X of cabergoline.
- the present process for preparing Form I shows advantages with respect to the old ones because of the rapid and exclusive conversion of solvate Form X of cabergoline into Form I.
- the new solvate Form X of cabergoline, a novel gel-mediated process for its preparation and a process for its conversion into crystalline cabergoline Form I are also provided. Characterisation
- X-ray powder diffraction was used to characterise the new solvate Form X of cabergoline and compare it to Forms I and N.
- the de-solvation and phase conversion of form X to form I was studied by studying the solvate in a special cell on the X-ray diffractometer at elevated temperatures under high vacuum over a period of time.
- Differential scanning calorimeter (DSC) profiles were also obtained for Forms N and X to show the distinct nature of these solvates.
- DSC Differential scanning calorimeter
- Powder X-ray diffraction was performed using either a Siemens D5000 powder diffractometer or an Inel multipurpose diffractometer.
- Siemens D5000 powder diffractometer the raw data were measured for 2 ⁇ (two theta) values from 2 to 50, with steps of 0.020 and step periods of two seconds.
- Inel multi-purpose diffractometer samples were placed in an aluminium sample holder and raw data were collected for one thousand seconds at all 2 ⁇ values simultaneously. The data so obtained are shown in the tables I to IH herein below.
- the Inel multi-purpose diffractometer was programmed to collect X-ray diffraction data for ten minutes every half an hour for a total experimentation time of two hours and forty minutes (including data collection).
- DSC Differential Scanning Calorimeter analysis
- Differential scanning calorimeter profiles were obtained from a Mettler-Toledo 822 e differential scanning calorimeter. The data was collected between 25 and 150° C at a heating ramp of 10° C/min. Forty micro-liter hermetically sealed aluminium pans with a pinpricked hole in the lid were used.
- Differential scanning calorimeter profile for Form X ( Figure 4, shows a major endothermic thermal event centred around 53 C, followed by a minor and broad endothermic thermal event centred around 74° C.
- the former corresponds to eutectic melting of Form X with toluene, while the latter could be associated with the gradual loss of toluene through vaporization.
- eutectic melting is defined as the transformation of solvent containing solids into a homogeneous liquid solution without any significant loss of solvent associated with the solids.
- Differential scanning calorimeter profile for Form N ( Figure 5) shows a single endothermic thermal event centred around 66° C. This thermal event corresponds to the eutectic melting of Form N in toluene.
- Comparison of Figures 4 and 5 also shows the distinct nature of Forms X and N.
- the process of the present invention for producing crystalline cabergoline Form I is characterized by crystallization from toluene/heptane. Hexane can also be used instead of heptane. Heptane is however, preferred for its toxicological properties, which are better suited for pharmaceutical application.
- the process comprises dissolving cabergoline in a suitable amount of toluene, preferably in an amount of from 2.5 to 4.0 g of toluene per gram of cabergoline, more preferably about 3.5 g of toluene per gram of cabergoline, at room temperature.
- the cabergoline used as starting material can an oil obtained through the synthesis described in Eur. J. Med. Chem.,24, 421,(1989), or can be any crystalline form of cabergoline or mixture thereof, including Form I crystals, obtained from the procedures described in the aforementioned references.
- the resulting solution is cooled to temperatures below -10 °C and stirred overnight, preferably for a minimum of 18 hours.
- the solution of cabergoline in toluene turns into a gel, which for the purposes of this invention is defined as a thick non-Newtonian suspension of bi-refringent solids in equilibrium with a saturated solution within the suspension.
- Cold heptane or hexane preferably around 10 to 20 g per gram of cabergoline in the gel phase, is then added to the gel.
- This addition of cold heptane or hexane is termed as the "quenching" of the gel phase. It refers to very strong anti-solvent properties of heptane or hexane for cabergoline toluene solutions. These properties essentially help freeze a solid suspension like the aforementioned gel, in a given solid state by eliminating the driving force for subsequent solid phase conversions to crystalline forms that may be more stable than Form X.
- Form X Upon the addition of heptane or hexane the gel turns into easily suspendable slurry, which is stirred at sub-ambient temperatures. Under these conditions, the toluene solvate Form X is obtained, that may be recovered by common procedures, for example by filtration under reduced pressure or by centrifugal filtration, followed by washing of the solids with pure heptane or hexane to remove residual mother Hquor and free toluene. The resulting crystals of Form X are very unstable when removed from their mother liquor and essentially convert to Form I without applying any heat under ambient storage within twenty four hours.
- Form I crystals obtained in this particular manner may contain residual toluene at levels unacceptable for pharmaceutical use and therefore preferably the solids are heated in a vacuum oven for lowering toluene content to within the acceptable range.
- This drying process can be accomplished by any suitable means such as, but not limited to, heating the solids, reducing the ambient pressure surrounding the solids, or combinations thereof.
- the drying pressure and time of drying are not narrowly critical.
- the drying pressure preferably is about 101 kPa or less.
- the temperature at which the drying can be carried out and/or the time of drying likewise is reduced. Particularly for solids wet with high boiling solvents like toluene, drying under vacuum will permit the use of lower drying temperatures.
- the optimum combination of pressure and temperature is usually determined from the vapour pressure versus temperature diagram for toluene and operational factors related to the design of the dryer.
- the time of drying need only be sufficient to allow for the reduction in the level of toluene to a pharmaceutically acceptable level.
- a temperature that preferably does not exceed about 150°C is selected.
- Form I cabergoline can be prepared directly from the solvated crystalline Form X obtained immediately after filtration through a combined de-solvation and drying step. Given the exceedingly fast kinetics of de-solvation and phase conversion of Form X to Form I, this combined operation can be conducted without requiring any modifications to the schematics of the drying process described in the preceding paragraph.
- the crystals of Form I of cabergoline prepared according to the process of the present invention have preferably a polymorph purity > 95%, more preferably >98% at yields in excess of 90% w/w, compared to about 60% for the route described in WOOl/70740.
- Toluene solvate Form X is also object of the present invention.
- the x-ray powder diffraction pattern for Form X ( Figure 1) shows a crystalline structure. These data indicate that cabergoline solvate Form X is easily distinguishable by XRD and DSC.
- the solvate X of this invention is a true solvate having a fixed composition of about 0.5 toluene moles per mole of cabergoline. The significant differences with the known hemi solvate form described in WOOl/70740 can be readily appreciated looking at the respective XRD and DSC spectra.
- Example 1 Preparation of solvated crystalline Form X of cabergoline.
- the crystal solvate Form X obtained in example 1 was placed in vacuum oven under 94.8 kPa of vacuum at ambient temperature for two hours. The temperature was then increased to 43 °C and the solids were further dried for 24 hours. Another 24 hours of drying was afforded at 60 °C.
- XRD and solvent content analysis on the solid samples pulled after each phase of the drying indicated that solids had converted to Form I after first phase of drying (at ambient temperature and high vacuum), however the toluene content was not within the specifications on the product. The solids met all the product specifications after the second phase of drying (24 hours at 43 °C under high vacuum). After drying, the resultant crystal Form I was identified by XRD data shown in Figure 2. The overall yield was about 93% on the basis of pure cabergoline initial content. The assayed polymorph purity was >98%.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003576398A JP2005520831A (en) | 2002-03-15 | 2003-03-10 | Method for producing crystalline form I of cabergoline |
YU77704A RS77704A (en) | 2002-03-15 | 2003-03-10 | Process for preparing crystalline form 1 of cabergoline |
CA002478149A CA2478149A1 (en) | 2002-03-15 | 2003-03-10 | Process for preparing crystalline form i of cabergoline |
AU2003224665A AU2003224665A1 (en) | 2002-03-15 | 2003-03-10 | Process for preparing crystalline form i of cabergoline |
MXPA04008935A MXPA04008935A (en) | 2002-03-15 | 2003-03-10 | Process for preparing crystalline form i of cabergoline. |
BR0308472-8A BR0308472A (en) | 2002-03-15 | 2003-03-10 | Process for preparing crystalline cabergoline form i |
KR1020047014429A KR100605794B1 (en) | 2002-03-15 | 2003-03-10 | Process for preparing crystalline form i of cabergoline |
EP03721346A EP1507777A4 (en) | 2002-03-15 | 2003-03-10 | Process for preparing crystalline form i of cabergoline |
IL16377903A IL163779A0 (en) | 2002-03-15 | 2003-03-10 | Process for preparing crystalline form i of cabergoline |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US36456702P | 2002-03-15 | 2002-03-15 | |
US60/364,567 | 2002-03-15 | ||
US41025302P | 2002-09-12 | 2002-09-12 | |
US60/410,253 | 2002-09-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2003078392A2 true WO2003078392A2 (en) | 2003-09-25 |
WO2003078392A3 WO2003078392A3 (en) | 2003-12-11 |
Family
ID=28045415
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2003/007138 WO2003078392A2 (en) | 2002-03-15 | 2003-03-10 | Process for preparing crystalline form i of cabergoline |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP1507777A4 (en) |
JP (1) | JP2005520831A (en) |
KR (1) | KR100605794B1 (en) |
CN (1) | CN1642953A (en) |
AU (1) | AU2003224665A1 (en) |
BR (1) | BR0308472A (en) |
CA (1) | CA2478149A1 (en) |
IL (1) | IL163779A0 (en) |
MX (1) | MXPA04008935A (en) |
PL (1) | PL372371A1 (en) |
RS (1) | RS77704A (en) |
RU (1) | RU2277536C2 (en) |
TW (1) | TW200306312A (en) |
WO (1) | WO2003078392A2 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1591445A1 (en) * | 2004-04-30 | 2005-11-02 | Resolution Chemicals Limited | Preparation of cabergoline form I und solvate therof |
EP1620101A2 (en) * | 2003-05-08 | 2006-02-01 | IVAX Pharmaceuticals s.r.o. | Polymorphs of cabergoline |
US7026483B2 (en) | 2003-04-21 | 2006-04-11 | Finetech Laboratories, Ltd. | Forms of cabergoline |
WO2006100492A2 (en) * | 2005-03-23 | 2006-09-28 | Resolution Chemicals Limited | Preparation of cabergoline |
WO2007012846A1 (en) * | 2005-07-27 | 2007-02-01 | Resolution Chemicals Limited | Solvate of cabergoline and preparations of cabergoline form i |
US7238810B2 (en) | 2005-03-23 | 2007-07-03 | Parveen Bhatarah | Preparation of cabergoline |
EP1953157A1 (en) * | 2007-01-31 | 2008-08-06 | LEK Pharmaceuticals D.D. | New crystal form of cabergoline |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4526892A (en) * | 1981-03-03 | 1985-07-02 | Farmitalia Carlo Erba, S.P.A. | Dimethylaminoalkyl-3-(ergoline-8'βcarbonyl)-ureas |
WO2001070740A1 (en) * | 2000-03-24 | 2001-09-27 | Pharmacia Italia Spa | Process for preparing crystalline form i of cabergoline |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003078433A1 (en) * | 2002-03-15 | 2003-09-25 | Pharmacia Corporation | Process for preparing crystalline form i of cabergoline |
-
2003
- 2003-03-10 JP JP2003576398A patent/JP2005520831A/en active Pending
- 2003-03-10 MX MXPA04008935A patent/MXPA04008935A/en not_active Application Discontinuation
- 2003-03-10 WO PCT/US2003/007138 patent/WO2003078392A2/en not_active Application Discontinuation
- 2003-03-10 PL PL03372371A patent/PL372371A1/en not_active Application Discontinuation
- 2003-03-10 RU RU2004127582/04A patent/RU2277536C2/en not_active IP Right Cessation
- 2003-03-10 KR KR1020047014429A patent/KR100605794B1/en not_active IP Right Cessation
- 2003-03-10 CN CNA038061309A patent/CN1642953A/en active Pending
- 2003-03-10 AU AU2003224665A patent/AU2003224665A1/en not_active Abandoned
- 2003-03-10 IL IL16377903A patent/IL163779A0/en unknown
- 2003-03-10 EP EP03721346A patent/EP1507777A4/en not_active Withdrawn
- 2003-03-10 CA CA002478149A patent/CA2478149A1/en not_active Abandoned
- 2003-03-10 BR BR0308472-8A patent/BR0308472A/en not_active IP Right Cessation
- 2003-03-10 RS YU77704A patent/RS77704A/en unknown
- 2003-03-13 TW TW092105467A patent/TW200306312A/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4526892A (en) * | 1981-03-03 | 1985-07-02 | Farmitalia Carlo Erba, S.P.A. | Dimethylaminoalkyl-3-(ergoline-8'βcarbonyl)-ureas |
WO2001070740A1 (en) * | 2000-03-24 | 2001-09-27 | Pharmacia Italia Spa | Process for preparing crystalline form i of cabergoline |
Non-Patent Citations (1)
Title |
---|
See also references of EP1507777A2 * |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7026483B2 (en) | 2003-04-21 | 2006-04-11 | Finetech Laboratories, Ltd. | Forms of cabergoline |
EP1620101A2 (en) * | 2003-05-08 | 2006-02-01 | IVAX Pharmaceuticals s.r.o. | Polymorphs of cabergoline |
US7531551B2 (en) | 2003-05-08 | 2009-05-12 | Ivax Pharmaceuticals S.R.O. | Polymorphs of cabergoline |
EP1620101A4 (en) * | 2003-05-08 | 2008-07-09 | Ivax Pharmaceuticals Sro | Polymorphs of cabergoline |
JP2007535526A (en) * | 2004-04-30 | 2007-12-06 | レゾリューション ケミカルズ リミテッド | Preparation of cabergoline |
WO2005105796A1 (en) * | 2004-04-30 | 2005-11-10 | Resolution Chemicals Limited | Preparation of cabergoline |
AU2005238276B2 (en) * | 2004-04-30 | 2011-08-18 | Resolution Chemicals Limited | Preparation of cabergoline |
US7186837B2 (en) | 2004-04-30 | 2007-03-06 | Resolution Chemicals | Preparation of cabergoline |
EP1591445A1 (en) * | 2004-04-30 | 2005-11-02 | Resolution Chemicals Limited | Preparation of cabergoline form I und solvate therof |
US7238810B2 (en) | 2005-03-23 | 2007-07-03 | Parveen Bhatarah | Preparation of cabergoline |
US7339060B2 (en) | 2005-03-23 | 2008-03-04 | Resolution Chemicals, Ltd. | Preparation of cabergoline |
WO2006100492A3 (en) * | 2005-03-23 | 2007-01-04 | Resolution Chemicals Ltd | Preparation of cabergoline |
EP2135869A1 (en) | 2005-03-23 | 2009-12-23 | Resolution Chemicals Limited | Preparation of a crystalline form of cabergoline |
WO2006100492A2 (en) * | 2005-03-23 | 2006-09-28 | Resolution Chemicals Limited | Preparation of cabergoline |
WO2007012846A1 (en) * | 2005-07-27 | 2007-02-01 | Resolution Chemicals Limited | Solvate of cabergoline and preparations of cabergoline form i |
EP1953157A1 (en) * | 2007-01-31 | 2008-08-06 | LEK Pharmaceuticals D.D. | New crystal form of cabergoline |
WO2008092881A1 (en) | 2007-01-31 | 2008-08-07 | Lek Pharmaceuticals D.D. | New crystal form of cabergoline |
US8338445B2 (en) | 2007-01-31 | 2012-12-25 | Lek Pharmaceuticals D.D. | Crystal form of cabergoline |
Also Published As
Publication number | Publication date |
---|---|
KR100605794B1 (en) | 2006-08-01 |
BR0308472A (en) | 2005-01-11 |
RU2004127582A (en) | 2006-01-27 |
JP2005520831A (en) | 2005-07-14 |
RU2277536C2 (en) | 2006-06-10 |
CN1642953A (en) | 2005-07-20 |
IL163779A0 (en) | 2005-12-18 |
KR20050002858A (en) | 2005-01-10 |
WO2003078392A3 (en) | 2003-12-11 |
EP1507777A2 (en) | 2005-02-23 |
MXPA04008935A (en) | 2004-11-26 |
PL372371A1 (en) | 2005-07-25 |
TW200306312A (en) | 2003-11-16 |
RS77704A (en) | 2006-10-27 |
AU2003224665A1 (en) | 2003-09-29 |
CA2478149A1 (en) | 2003-09-25 |
EP1507777A4 (en) | 2007-03-07 |
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