EP1883648A1 - Procede de preparation de tibolone cristalline pure - Google Patents

Procede de preparation de tibolone cristalline pure

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Publication number
EP1883648A1
EP1883648A1 EP05745217A EP05745217A EP1883648A1 EP 1883648 A1 EP1883648 A1 EP 1883648A1 EP 05745217 A EP05745217 A EP 05745217A EP 05745217 A EP05745217 A EP 05745217A EP 1883648 A1 EP1883648 A1 EP 1883648A1
Authority
EP
European Patent Office
Prior art keywords
tibolone
process according
water
crystals
solution
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Withdrawn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
EP05745217A
Other languages
German (de)
English (en)
Inventor
Giuseppe Caricato
Elisa Boseggia
Monica Coletti
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.)
Newchem SpA
Original Assignee
Newchem SpA
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 Newchem SpA filed Critical Newchem SpA
Publication of EP1883648A1 publication Critical patent/EP1883648A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0081—Substituted in position 17 alfa and 17 beta
    • C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
    • C07J1/0096—Alkynyl derivatives

Definitions

  • the present invention provides a process for the preparation of Tibolone crystalline forms I and II characterised by high purity and low particle size.
  • Tibolone The compound (7 ⁇ ,17 ⁇ )-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)- en-20-yn-3-one, known as Tibolone, is a steroid drug having combined estrogenic, progestagenic and androgenic characteristics, and is described in US patents Nos. 3340279 and 4701450. Tibolone is known to crystallize in two different polymorphic forms conventionally known as form I and form II. Form I, which proved more stable in pharmaceutical compositions, is preferably used in the production of tablets.
  • EP389035 discloses a method of preparing crystalline pure Tibolone for use in a pharmaceutical composition, characterized in that the polymorphous compound is crystallized from mixtures of water and acetone or ethanol, or from ethyl acetate, acetonitrile, or acetone-hexane mixtures, or from an apolar solvent.
  • the process disclosed in EP389035 allows the production of Form I with crystalline purity higher than 95%.
  • the crystallisation of Tibolone using mixtures of methanol and water yields only mixtures of the two crystalline forms.
  • the invention provides a process for preparing pure crystalline forms of the compound (7 ⁇ ,17 ⁇ )-17-hydroxy-7-methyl-19-nor-17-pregn- 5(10)-en-20-yn-3-one (Tibolone), which essentially comprises the steps of:
  • step (d) washing the crystals with water.
  • the organic bases used in steps (a) and (b), which can be the same or different, are preferably selected from aliphatic or aromatic (tertiary) amines, such as triethylamine and pyridine.
  • the ratio between the amine and methanol or water, according to steps (a) and (b), respectively, can vary from 1 :600 to 1 :50 by volume.
  • methanol and water are used in respective amounts ranging from 2: 1 to 1 :2 by volume, more preferably 1 : 1.
  • the dissolution of Tibolone in methanol, according to step (a), is generally carried out by heating a suspension of the compound to a temperature of 35 ⁇ 45°C, preferably 38 ⁇ 42°C, under constant stirring.
  • Pouring of the methanol solution into water according to step (b) is carried out in a time sufficient for the crystals to form, depending on the solution volumes and the equipment/apparatus utilized, generally variable between 30 and 60 min, preferably between 40 and 50 min.
  • the crystallization process can be selectively oriented to the production of pure crystalline forms I or II by simply varying the temperature of the water solution used in step (b).
  • the water solution of step (b) at temperatures ranging from 40 to 5O 0 C and from -5 to +5°C, highly pure crystalline forms I and II can be obtained, respectively.
  • Preferred temperatures ranges are 43 ⁇ 47°C and -5 ⁇ 0°C, for crystalline forms I and II, respectively.
  • the filtration and the washing steps (c) and (d) are preferably perfomed at the same temperature used in the crystallization step (b).
  • wet crystalline Tibolone is dried, preferably at temperatures of 20 ⁇ 50°C for a time that can vary from few hours to some days.
  • the product thus obtained is characterised by a high crystalline purity. Moreover when the 100% of the resulting particle size distribution is below 40 ⁇ m, the obtained Tibolone could be considered particularly suitable for direct use in the preparation of solid pharmaceutical compositions, without prior micronization.
  • Polymorphic Tibolone (60.00 g) is suspended in 720 ml of CH 3 OH/Py solution and stirred at 27°C for 10'. The slurry is heated at 40 0 C and stirred until dissolution occurs. Tibolone solution is filtered and washed with 180 ml of CH 3 OH/Py and thermostated at 40 0 C.
  • the H 2 O/Py mixture is filtered and thermostated at 45°C.
  • the methanolic solution containing Tibolone is added over a period of 42' over the H 2 O/Py solution constantly kept under nitrogen atmosphere. During the addition the temperature of H 2 O/Py is 45°C. At the end of the addition the crystallized Tibolone is allowed to stir for 5', then filtered when the temperature is 42°C. The cake is washed with water and the product dried in a static dryer for 60 hours at 35°C. 57.0 g of Tibolone are obtained with the following characteristics:
  • Tibolone Dimethoxy Ketal are hydrolyzed in mild acidic conditions, following one of the suitable procedures well known to the person skilled in the art, thus obtaining 36.0 g of wet Tibolone.
  • the humid polymorphous product is dissolved in CH 3 OH/Py (230.4 ml) at 40 0 C, the solution is filtered, washed with CH 3 OH/Py (57.6 ml) and constantly kept at a temperature of 40 0 C.
  • the methanolic solution is then gradually transferred on a H 2 O/Py (288 ml) solution over a period of 30' containing seed-crystals of Tibolone mixture F/Fn 90:10.
  • n°2 is reported the solid state NMR spectrum in the region 210 ⁇ 220 ppm of EB2/TBL 0297.
  • Crystal Seeds Mixture F 1 ZF n 85:15; Atmosphere: Conventional.
  • Tibolone Dimethoxy Ketal are hydrolyzed in mild acidic conditions, following one of the suitable procedures well known to the person skilled in the art, thus obtaining 36.0 g of wet Tibolone.
  • the humid polymorphous product is dissolved in CH 3 OHZPy (230.4 ml) at 40 0 C, the solution is filtered, washed with CH 3 OH/Py (57.6 ml) and constantly kept at a temperature of 40 0 C.
  • the methanolic solution is then gradually transferred on a H 2 O/Py (288 ml) solution over a period of 30' containing seed-crystals of Tibolone mixture Fi/F ⁇ 85: 15.
  • the crystallized Tibolone is allowed to stir for 5' before filtration. Crystals are washed with H 2 O, dried for 16 hours at a temperature of 35°C, thus yielding 18.44 g of dry Tibolone of the following quality:
  • n°3 is reported the solid state NMR spectrum in the region 210 ⁇ 220 ppm of EB2/TBL 0298.
  • Crystal Seeds Mixture F 1 ZF n 80:20; Atmosphere: Conventional.
  • Tibolone Dimethoxy Ketal are hydrolyzed in mild acidic conditions, following one of the suitable procedures well known to the person skilled in the art, thus obtaining 36.0 g of wet Tibolone.
  • the humid polymorphous product is dissolved in CH 3 OH/Py (230.4 ml) at 40 0 C, the solution is filtered, washed with CH 3 OH/Py (57.6 ml) and constantly kept at a temperature of 4O 0 C.
  • the methanolic solution is then gradually transferred on a H 2 O/Py (288 ml) solution over a period of 30' containing seed-crystals of Tibolone mixture Fi/F ⁇ 80:20.
  • the crystallized Tibolone is allowed to stir for 5' before filtration. Crystals are washed with H 2 O, dried for 16 hours at a temperature of 35°C, thus yielding 17.38 g of dry Tibolone of the following quality: HPLC purity > 99,0%
  • n°4 is reported the solid state NMR spectrum in the region 210 ⁇ 220 ppm of EB2/TBL 0299.
  • Tibolone Dimethoxy Ketal are hydrolyzed in mild acidic conditions, following one of the suitable procedures well known to the person skilled in the art, thus obtaining 131.0 g of wet Tibolone.
  • the humid polymorphous product is dissolved in CH 3 OH/Py (806.3 ml) at 40 0 C, the solution is filtered, washed with CH 3 OH/Py (201.6 ml) and constantly kept at a temperature of 40 0 C. The methanolic solution is then gradually transferred, over a period of 30', on a H 2 O/Py (1000.0 ml) solution under slow stirring. The crystallized Tibolone is allowed to stir for 5' before filtration. Crystals are washed with H 2 O 5 dried for 16 hours at a temperature of 35°C, thus yielding 63.8 g of dry Tibolone of the following quality:
  • n°6 is reported the solid state NMR spectrum in the region 210 ⁇ 220 ppm of EBl/TBL 203.
  • Tibolone Dimethoxy Ketal 16.0 g are hydrolyzed in mild acidic conditions, following one of the suitable procedures well known to the person skilled in the art, thus obtaining 23.0 g of wet Tibolone.
  • the humid polymorphous product is dissolved in CH 3 OH/Py (118.0 ml) at 40 0 C, the solution is filtered, washed with CH 3 OH/Py (16.0 ml) and constantly kept at a temperature of 40 0 C.
  • the methanolic solution is then gradually transferred in a period of 15 minutes on a filtered and cooled mixture (-5/0 0 C) of H 2 O/Py (229.0 ml).
  • the mixture is allowed to stir at 0/2 0 C for 10', before proceeding to crystals filtration and washing with water.
  • the obtained product is dried for 12 hours at a temperature of 35°C, thus yielding 8.5 g of dry Tibolone of the following quality:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne un procédé destiné à la préparation de formes cristallines I et II de la tibolone, se caractérisant par un niveau de pureté élevé et une faible granulométrie.
EP05745217A 2005-05-23 2005-05-23 Procede de preparation de tibolone cristalline pure Withdrawn EP1883648A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2005/005560 WO2006125453A1 (fr) 2005-05-23 2005-05-23 Procede de preparation de tibolone cristalline pure

Publications (1)

Publication Number Publication Date
EP1883648A1 true EP1883648A1 (fr) 2008-02-06

Family

ID=35811772

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05745217A Withdrawn EP1883648A1 (fr) 2005-05-23 2005-05-23 Procede de preparation de tibolone cristalline pure

Country Status (2)

Country Link
EP (1) EP1883648A1 (fr)
WO (1) WO2006125453A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20130120A1 (it) * 2013-01-25 2014-07-26 Ind Chimica Srl Processo per la preparazione in forma cristallina di tibolone, (7alfa,17alfa)-17-idrossi-7-metil-19-norpregn-5(10)-en-20-in-3-one
CN114409717B (zh) * 2021-12-17 2023-03-17 湖南科益新生物医药有限公司 替勃龙中间体醚化物和替勃龙的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE63051B1 (en) * 1989-03-18 1995-03-22 Akzo Nv Pharmaceutical composition which contains a pharmaceutically suitable carrier and the compound having the structure (7alpha, 17alpha)-17-Hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn- 3-one
CZ298703B6 (cs) * 1998-10-16 2007-12-27 N.V. Organon Vysoce cistý (7alfa, 17alfa)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-on se zvýšenou stabilitou

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006125453A1 *

Also Published As

Publication number Publication date
WO2006125453A1 (fr) 2006-11-30

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