EP1883648A1 - Process for the preparation of pure crystalline tibolone - Google Patents

Process for the preparation of pure crystalline tibolone

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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
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EP
European Patent Office
Prior art keywords
tibolone
process according
water
crystals
solution
Prior art date
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EP05745217A
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German (de)
French (fr)
Inventor
Giuseppe Caricato
Elisa Boseggia
Monica Coletti
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Newchem SpA
Original Assignee
Newchem SpA
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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:

Abstract

There is disclosed a process for the preparation of Tibolone crystalline forms I and II characterized by high purity and low particle size.

Description

PROCESS FOR THE PREPARATION OF PURE CRYSTALLINE TIBOLONE
The present invention provides a process for the preparation of Tibolone crystalline forms I and II characterised by high purity and low particle size.
, The compound (7α,17α)-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%. In addition, according to EP389035 the crystallisation of Tibolone using mixtures of methanol and water yields only mixtures of the two crystalline forms.
Contrary to the teaching of EP389035, it has surprisingly been found that methanol and water mixtures, under specific conditions, can be used to prepare pure crystalline forms of Tibolone. Additionally, experimental evidence has been produced that the crystalline purity of the products obtained is not affected by the presence of crystal seed mixtures enriched in one of the crystalline forms. Furthermore it has been discovered that the process of crystallization could be properly oriented applying controlled variations in temperature, concentration, stirring and rate of crystallization to afford product crystals characterized not only by extremely high purity but also by a well defined distribution of particle size. Processes yielding very low particle size, are particularly suitable for the preparation of solid pharmaceutical compositions. Accordingly, the invention provides a process for preparing pure crystalline forms of the compound (7α,17α)-17-hydroxy-7-methyl-19-nor-17-pregn- 5(10)-en-20-yn-3-one (Tibolone), which essentially comprises the steps of:
(a) dissolving polymorphous Tibolone in methanol in the presence of an organic base;
(b) pouring the solution obtained from (a) on a water solution containing an organic base, whereby Tibolone crystals are formed;
(c) filtering the crystals and, optionally;
(d) washing the crystals with water. Either the dry polymorphous compound or the wet compound obtained from deprotection of the dimethoxy ketal precursor 3,3-Dimethoxy-17α- ethynyl-17β-hydroxy-7α-methyl-5(10)-estrene, can be used as the starting material. 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. Preferably, 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. Surprisingly, it was found that 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). In particular, it was found that by maintaining the water solution of step (b) at temperatures ranging from 40 to 5O0C 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). At the end of the process, 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 μm, the obtained Tibolone could be considered particularly suitable for direct use in the preparation of solid pharmaceutical compositions, without prior micronization.
The invention will be further illustrated by the following examples and figures.
EXAMPLES
1)
Ref. Code: EB2/TBL 0286;
Starting Material: Dry Polymorphous Tibolone; Crystal Seeds: None;
Atmosphere Nitrogen.
All the operations described in the present example are carried out in Nitrogen atmosphere. Two solutions are preliminarily prepared mixing respectively Methanol (900.0 ml) with Pyridine (1.5 ml) and Water (900 ml) with Pyridine (1.5 ml). Nitrogen is bubbled in the two solutions for at least three hours at 200C.
Polymorphic Tibolone (60.00 g) is suspended in 720 ml of CH3OH/Py solution and stirred at 27°C for 10'. The slurry is heated at 400C and stirred until dissolution occurs. Tibolone solution is filtered and washed with 180 ml of CH3OH/Py and thermostated at 400C.
The H2O/Py mixture is filtered and thermostated at 45°C.
The methanolic solution containing Tibolone is added over a period of 42' over the H2O/Py solution constantly kept under nitrogen atmosphere. During the addition the temperature of H2O/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:
HPLC purity > 99.0%
Particle Size 100% < 40 μm d50: 9.4 μm
SSNMR polymorphic composition F1 100% Fn n.d.
In figure n°l is reported the solid state NMR spectrum in the region 210÷220 ppm of EB2/TBL 0286.
2)
Ref. Code: EB2/TBL 0297;
Starting Material: Wet polymorphous Tibolone; Crystal Seeds: Mixture F1ZFn 90: 10; Atmosphere: Conventional.
All the operations described in the present example are carried out in conventional atmosphere.
24.0 g of 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 CH3OH/Py (230.4 ml) at 400C, the solution is filtered, washed with CH3OH/Py (57.6 ml) and constantly kept at a temperature of 400C. The methanolic solution is then gradually transferred on a H2O/Py (288 ml) solution over a period of 30' containing seed-crystals of Tibolone mixture F/Fn 90:10. The crystallized
Tibolone is allowed to stir for 5' before filtration. Crystals are washed with
H2O, dried for 16 hours at a temperature of 35°C, thus yielding 18.40 g of dry Tibolone of the following quality:
HPLC purity > 99.0%
Particle Size 100% < 40 μm d50: 10.4 μm
SSNMR polymorphic composition Fi 100% Fπ n.d.
In figure n°2 is reported the solid state NMR spectrum in the region 210÷220 ppm of EB2/TBL 0297.
3)
Ref. Code: EB2/TBL 0298;
Starting Material: Wet polymorphous Tibolone;
Crystal Seeds: Mixture F1ZFn 85:15; Atmosphere: Conventional.
All the operations described in the present example are carried out in conventional atmosphere.
24.0 g of 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 CH3OHZPy (230.4 ml) at 400C, the solution is filtered, washed with CH3OH/Py (57.6 ml) and constantly kept at a temperature of 400C. The methanolic solution is then gradually transferred on a H2O/Py (288 ml) solution over a period of 30' containing seed-crystals of Tibolone mixture Fi/Fπ 85: 15. The crystallized Tibolone is allowed to stir for 5' before filtration. Crystals are washed with H2O, dried for 16 hours at a temperature of 35°C, thus yielding 18.44 g of dry Tibolone of the following quality:
HPLC purity > 99.0%
Particle Size 100% < 40 μm d50: 8.7 μm
SSNMR polymorphic composition Fi 100% Fn n.d.
In figure n°3 is reported the solid state NMR spectrum in the region 210÷220 ppm of EB2/TBL 0298.
4)
Ref. Code: EB2/TBL 0299;
Starting Material: Wet polymorphous Tibolone;
Crystal Seeds: Mixture F1ZFn 80:20; Atmosphere: Conventional.
All the operations described in the present example are carried out in conventional atmosphere.
24.0 g of 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 CH3OH/Py (230.4 ml) at 400C, the solution is filtered, washed with CH3OH/Py (57.6 ml) and constantly kept at a temperature of 4O0C. The methanolic solution is then gradually transferred on a H2O/Py (288 ml) solution over a period of 30' containing seed-crystals of Tibolone mixture Fi/Fπ 80:20. The crystallized Tibolone is allowed to stir for 5' before filtration. Crystals are washed with H2O, 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%
Particle Size 100% < 40 μm d50: 11.5 μm
SSNMR polymorphic composition Fi 100% Fn n.d.
In figure n°4 is reported the solid state NMR spectrum in the region 210÷220 ppm of EB2/TBL 0299.
5)
Ref. Code: EB2/TBL 0304;
Starting Material: Wet polymorphous Tibolone;
Crystal Seeds: none; Atmosphere: Conventional.
All the operations described in the present example are carried out in conventional atmosphere.
79.1 g of 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 CH3OH/Py (806.3 ml) at 400C, the solution is filtered, washed with CH3OH/Py (201.6 ml) and constantly kept at a temperature of 400C. The methanolic solution is then gradually transferred, over a period of 30', on a H2O/Py (1000.0 ml) solution under slow stirring. The crystallized Tibolone is allowed to stir for 5' before filtration. Crystals are washed with H2O5 dried for 16 hours at a temperature of 35°C, thus yielding 63.8 g of dry Tibolone of the following quality:
HPLC purity > 99,0%
Particle Size 100% < 80 μ d50: 35.1 μm SSNMR polymorphic composition F1 98.7% F11 1.3%
In figure n°5 is reported the solid state NMR spectrum in the region
210÷220 ppm of EB2/TBL 0304. 6)
Ref. Code: EBl /TBL 0203;
Starting Material: Dry Polymorphous Tibolone; Crystal Seeds: None; Atmosphere: Conventional.
All the operations described in the present example are carried out in conventional atmosphere.
Dry polymorphous Tibolone (52.0 g) is added to a CH3OH/Py solution (520.0 ml). The slurry is heated at 4O0C until a clear solution is obtained. The solution is then filtered, washed with CH3OH/Py (70.0 ml) and kept at a temperature of 4O0C. The solution is quickly added over a previously filtered and cooled mixture (-5/O0C) of H2O/Py (1011.0 ml).The mixture is allowed to stir at 0/20C 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 51.0 of dry Tibolone of the following quality: HPLC purity > 99,0%
Particle Size 100% < 30 μ d50: 7.9 μm
SSNMR polymorphic composition Fi n.d.% Fn 100%
In figure n°6 is reported the solid state NMR spectrum in the region 210÷220 ppm of EBl/TBL 203.
7)
Ref. Code: EB2/TBL 0381 ;
Starting Material: Wet polymorphous Tibolone; Crystal Seeds: None; Atmosphere: Conventional.
All the operations described in the present example are carried out in conventional atmosphere.
16.0 g of 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 23.0 g of wet Tibolone.
The humid polymorphous product is dissolved in CH3OH/Py (118.0 ml) at 400C, the solution is filtered, washed with CH3OH/Py (16.0 ml) and constantly kept at a temperature of 400C. The methanolic solution is then gradually transferred in a period of 15 minutes on a filtered and cooled mixture (-5/00C) of H2O/Py (229.0 ml). The mixture is allowed to stir at 0/20C 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:
HPLC purity > 99,0%
Particle Size 100% < 100 μ d50: 45.9 μm
SSNMR polymorphic composition Fi n.d. Fn 100%.
In figure n°7 is reported the solid state NMR spectrum in the region 210÷220 ppm of EB2/TBL 0381.

Claims

1. A process for preparing pure crystalline forms of the compound (7α,17α)- 17-hydroxy-7-methyl- 19-nor- 17-pregn-5( 10)-en-20-yn-3 -one (Tibolone), which essentially comprises the steps of:
(a) dissolving polymorphous Tibolone in methanol in the presence of an organic base;
(b) pouring the solution obtained from (a) on a water solution containing an organic base, whereby Tibolone crystals are formed; (c) filtering the crystals and, optionally;
(d) washing the crystals with water.
2. A process according to claim 1, wherein the organic bases used in steps (a) and (b) are independently aliphatic or aromatic amines.
3. A process according to claim 2, wherein said organic bases are selected from triethylamine and pyridine.
4. A process according to claim 1, wherein the ratio between the amine and the methanol or water respectively used in steps (a) and (b), vary from 1 :600 to 1 :50.
5. The process of claim 4, wherein said ratio is 1 : 1.
6. A process according to claim 1, wherein the ratio between the amounts of methanol and water ranges from 2: 1 to 1 :2.
7. A process according to claim 1, wherein the dissolution of step (a) is carried out at a temperature ranging from 35 to 45°C.
8. A process according to claim 1, for the preparation of pure crystalline form I, wherein the water solution of step (b) is maintained at a temperature ranging from 40 to 500C.
9. A process according to claim 1, for the preparation of pure crystalline form II, wherein the water solution of step (b) is maintained at a temperature ranging from -10 to 50C.
10. A process according to claim I5 further comprising the addition of crystal-seed mixtures enriched in one of the crystalline forms I or II, to the water solution of step (b).
11. A process according to claim I5 further comprising drying the crystalline product.
EP05745217A 2005-05-23 2005-05-23 Process for the preparation of pure crystalline tibolone Withdrawn EP1883648A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2005/005560 WO2006125453A1 (en) 2005-05-23 2005-05-23 Process for the preparation of pure crystalline tibolone

Publications (1)

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

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ITMI20130120A1 (en) * 2013-01-25 2014-07-26 Ind Chimica Srl PROCESS FOR PREPARATION IN THE CRYSTAL FORM OF TIBOLONE, (7ALFA, 17ALFA) -17-HYDROSSI-7-METHYL-19-NORPREGN-5 (10) -EN-20-IN-3-ONE
CN114409717B (en) * 2021-12-17 2023-03-17 湖南科益新生物医药有限公司 Tibolone intermediate etherate and preparation method of tibolone

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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
ES2197677T3 (en) * 1998-10-16 2004-01-01 Akzo Nobel N.V. HIGH PURITY COMPOSITIONS THAT INCLUDE (7ALFA-17ALFA) -17-HIDROXI-7-METIL-19-NOR-17-PREGN-5 (10) -EN-20-IN-3-ONA.

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Title
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