EP1507777A4 - Procede de preparation d'une forme i cristalline de cabergoline - Google Patents

Procede de preparation d'une forme i cristalline de cabergoline

Info

Publication number
EP1507777A4
EP1507777A4 EP03721346A EP03721346A EP1507777A4 EP 1507777 A4 EP1507777 A4 EP 1507777A4 EP 03721346 A EP03721346 A EP 03721346A EP 03721346 A EP03721346 A EP 03721346A EP 1507777 A4 EP1507777 A4 EP 1507777A4
Authority
EP
European Patent Office
Prior art keywords
cabergoline
toluene
process according
solvate form
solvate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03721346A
Other languages
German (de)
English (en)
Other versions
EP1507777A2 (fr
Inventor
Ahmad Y Sheikh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia LLC
Original Assignee
Pharmacia LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharmacia LLC filed Critical Pharmacia LLC
Publication of EP1507777A2 publication Critical patent/EP1507777A2/fr
Publication of EP1507777A4 publication Critical patent/EP1507777A4/fr
Withdrawn legal-status Critical Current

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%.

Abstract

L'invention concerne un procédé d'obtention d'une forme I cristalline de cabergoline, comprenant la cristallisation de la forme souhaitée à partir d'un toluène/heptane ou d'un mélange de toluène/hexane à partir d'une cabergoline brute, suivie de la récupération et de l'élimination du solvant de la forme X du solvate de toluène obtenu. La nouvelle forme X de solvate de cabergoline, servant d'intermédiaire, et sa préparation font également l'objet de cette invention.
EP03721346A 2002-03-15 2003-03-10 Procede de preparation d'une forme i cristalline de cabergoline Withdrawn EP1507777A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US36456702P 2002-03-15 2002-03-15
US364567P 2002-03-15
US41025302P 2002-09-12 2002-09-12
US410253P 2002-09-12
PCT/US2003/007138 WO2003078392A2 (fr) 2002-03-15 2003-03-10 Procede de preparation d'une forme i cristalline de cabergoline

Publications (2)

Publication Number Publication Date
EP1507777A2 EP1507777A2 (fr) 2005-02-23
EP1507777A4 true EP1507777A4 (fr) 2007-03-07

Family

ID=28045415

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03721346A Withdrawn EP1507777A4 (fr) 2002-03-15 2003-03-10 Procede de preparation d'une forme i cristalline de cabergoline

Country Status (14)

Country Link
EP (1) EP1507777A4 (fr)
JP (1) JP2005520831A (fr)
KR (1) KR100605794B1 (fr)
CN (1) CN1642953A (fr)
AU (1) AU2003224665A1 (fr)
BR (1) BR0308472A (fr)
CA (1) CA2478149A1 (fr)
IL (1) IL163779A0 (fr)
MX (1) MXPA04008935A (fr)
PL (1) PL372371A1 (fr)
RS (1) RS77704A (fr)
RU (1) RU2277536C2 (fr)
TW (1) TW200306312A (fr)
WO (1) WO2003078392A2 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL155545A (en) 2003-04-21 2009-12-24 Finetech Pharmaceutical Ltd Solvate form of cabergoline
CA2525104A1 (fr) 2003-05-08 2004-11-25 Ivax Pharmaceuticals S.R.O. Polymorphes de la cabergoline
GB0409785D0 (en) 2004-04-30 2004-06-09 Resolution Chemicals Ltd Preparation of cabergoline
GB0505965D0 (en) 2005-03-23 2005-04-27 Resolution Chemicals Ltd Preparation of cabergoline
GB0515430D0 (en) * 2005-07-27 2005-08-31 Resolution Chemicals Ltd Preparation of cabergoline
US7339060B2 (en) 2005-03-23 2008-03-04 Resolution Chemicals, Ltd. Preparation of cabergoline
EP1953157A1 (fr) * 2007-01-31 2008-08-06 LEK Pharmaceuticals D.D. Nouvelle forme cristalline de cabergoline

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003078433A1 (fr) * 2002-03-15 2003-09-25 Pharmacia Corporation Procede de preparation de la forme cristalline i de la cabergoline

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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
GB0007308D0 (en) * 2000-03-24 2000-05-17 Pharmacia & Upjohn Spa Process for preparing crystalline form | of cabergoline

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003078433A1 (fr) * 2002-03-15 2003-09-25 Pharmacia Corporation Procede de preparation de la forme cristalline i de la cabergoline

Also Published As

Publication number Publication date
RU2004127582A (ru) 2006-01-27
RS77704A (en) 2006-10-27
TW200306312A (en) 2003-11-16
BR0308472A (pt) 2005-01-11
MXPA04008935A (es) 2004-11-26
KR20050002858A (ko) 2005-01-10
AU2003224665A1 (en) 2003-09-29
EP1507777A2 (fr) 2005-02-23
CA2478149A1 (fr) 2003-09-25
KR100605794B1 (ko) 2006-08-01
PL372371A1 (en) 2005-07-25
JP2005520831A (ja) 2005-07-14
CN1642953A (zh) 2005-07-20
WO2003078392A3 (fr) 2003-12-11
RU2277536C2 (ru) 2006-06-10
WO2003078392A2 (fr) 2003-09-25
IL163779A0 (en) 2005-12-18

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