WO2017140283A1 - Solvates d'olaparib cristallin avec l'acétone, le 2-propanol et/ou la méthyléthylcétone - Google Patents

Solvates d'olaparib cristallin avec l'acétone, le 2-propanol et/ou la méthyléthylcétone Download PDF

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Publication number
WO2017140283A1
WO2017140283A1 PCT/CZ2017/000006 CZ2017000006W WO2017140283A1 WO 2017140283 A1 WO2017140283 A1 WO 2017140283A1 CZ 2017000006 W CZ2017000006 W CZ 2017000006W WO 2017140283 A1 WO2017140283 A1 WO 2017140283A1
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WO
WIPO (PCT)
Prior art keywords
olaparib
acetone
propanol
ethyl ketone
methyl ethyl
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PCT/CZ2017/000006
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English (en)
Inventor
Ludek Ridvan
Hana TOZICKOVA
Ondrej Dammer
Josef Beranek
Lukas KREJCIK
Jiri MIKSATKO
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Zentiva, K.S.
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Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2017140283A1 publication Critical patent/WO2017140283A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to solvated crystalline forms of olaparib of formula I, with the systematic name 4-[(3-[(4-cyclopropylcarbonyl)piperazin-4-yl]carbonyl)-4-fluorophenyl]methyl(2H)- phtalazin-l-one, a method of their preparation and use for the production of a drug form.
  • Olaparib in the form of the preparation Lynparza®, is used for the treatment of some types of cancer (e.g. ovarian and oviduct cancer). Synthesis of olaparib was first described in the patent application WO2004080976. Polymorphic form A, which is used in the Lynparza preparation, was characterized in the patent application WO2008047082. Then, in the patent application WO2009050469, crystalline form L was disclosed.
  • olaparib is a substance with low solubility and permeability (bioavailability), which means that it belongs to group 4 in the Biopharmaceutical Classification System.
  • Olaparib exhibits polymorphism, i.e. it crystallizes in various modifications that may principally differ with their physicochemical characteristics.
  • the crystalline modification of olaparib used in a drug form may pass into another, less soluble form during the production and storage, which may result in reduced bioavailability of this active substance.
  • the invention provides solvated crystalline forms of olaparib.
  • the solvents used for the preparation of a solvate belong to "Solvents with a low toxic potential" whose safe daily dose may be up to 50 mg or even higher (section 4.3, Tab. 3).
  • the invention provides solvated crystalline forms of olaparib where acetone, 2-propanol, methyl ethyl ketone or a mixture of these solvents is used as the solvate forming solvent.
  • the molar ratio of olaparib:solvent in the crystalline form can vary in the range of 1 :0.05 to 1:2, preferably 1:0.1 to 1 :0.6. If the solvate of olaparib contains two different solvents, the mutual molar ratio of both the solvents, i.e. solvent I : solvent II can be in the range of 4:1 to 1:4.
  • Another object of the invention provides a preparation method of the solvated crystalline forms of olaparib wherein olaparib is dissolved in acetone, 2-propanol, methyl ethyl ketone, or in a mixture of these solvents in a hot state and the resulting solution is then cooled down and/or the solvent is partially evaporated.
  • a saturated solution is prepared at the boiling point of the respective solvent or mixture of solvents, which is then cooled down to a temperature in the range of -20 to 30°C.
  • the preparation of forms by crystallization from a solvent also entails a significant increase of the chemical purity.
  • Another object of the invention provides the use of the solvated crystalline forms of olaparib for the preparation of a pharmaceutical composition.
  • the solvated forms of olaparib in accordance with the present invention are stable at temperatures up to 100°C. At higher temperatures, desolvation occurs, yielding form A. These forms are advantageous especially from the point of view of their relatively high solubility in water.
  • the invention provides solvated crystalline forms of olaparib where acetone, 2-propanol, methyl ethyl ketone or a mixture of these solvents is used as the solvate forming solvent.
  • the molar ratio of olaparib: solvent in the crystalline form can vary in the range of 1 :0.05 to 1 :2, preferably 1:0.1 to 1:0.6.
  • the mutual molar ratio of both the solvents can be in the range of 4:1 to 1:4.
  • the olaparib.acetone solvated crystalline form is characterized by the X-ray powder pattern shown in Figure 1.
  • Tab. 1 X-ray characteristic diffraction peaks corresponding to the olaparib.acetone crystalline form.
  • the olaparib.2-propanol solvated crystalline form is characterized by the X-ray powder pattern shown in Figure 2. Its characteristic diffractions with the use of CuKa radiation are 10.4; 15.4 and 21.4 ⁇ 0.2° 2-theta.
  • the olaparib.2-propanol solvated crystalline form further exhibits the following characteristic reflections: 7.3; 17.4; 19.1 and 27.3 ⁇ 0.2° 2-theta.
  • the diffraction peaks together with their relative intensity are shown in Table 2.
  • the molar ratio of olaparib.2-propanol was determined to be approx. 1 :0.5 with the use of 1H NMR.
  • the stability of the olaparib.2-propanol form was measured with the use of Differential Scanning Calorimetry (DSC). Desolvation occurs at a temperature of over 120°C.
  • DSC Differential Scanning Calorimetry
  • Tab. 2 X-ray characteristic diffraction peaks corresponding to the olaparib.2-propanol crystalline form.
  • the olaparib.methyl ethyl ketone solvated crystalline form is characterized by the X-ray powder pattern shown in Figure 3. Its characteristic diffractions with the use of CuKa radiation are 10.4; 15.5 and 21.3 ⁇ 0.2° 2-theta.
  • the olaparib.methyl ethyl ketone solvated crystalline form further exhibits the following characteristic reflections: 7.3; 12.2; 18.9; 25.1 and 27.2 ⁇ 0.2° 2-theta.
  • the diffraction peaks together with their relative intensity are shown in Table 3.
  • the molar ratio of olaparib.methyl ethyl ketone was determined to be approx. 1:0.5 with the use of 1H NMR.
  • the stability of the olaparib.methyl ethyl ketone form was measured with the use of Differential Scanning Calorimetry (DSC). Desolvation occurs at a temperature of over 120°C.
  • DSC Differential Sca
  • Tab. 3 X-ray characteristic diffraction peaks corresponding to the olaparib.methyl ethyl ketone crystalline form.
  • the olaparib.acetone.methyl ethyl ketone solvated crystalline form is characterized by the X- ray powder pattern shown in Figure 4. Its characteristic diffractions with the use of CuKa radiation are 10.2; 15.3 and 21.1 ⁇ 0.2° 2-theta.
  • the olaparib.acetone.methyl ethyl ketone solvated crystalline form further exhibits the following characteristic reflections: 7.1; 11.9; 18.8; 24.9 and 27.5 ⁇ 0.2° 2-theta.
  • the diffraction peaks together with their relative intensity are shown in Table 4. The molar ratio of olaparib:acetone:methyl ethyl ketone was determined to be approx.
  • Tab. 4 X-ray characteristic diffraction peaks corresponding to the olaparib.acetone.methyl ethyl ketone crystalline form.
  • the olaparib.acetone.2-propanol solvated crystalline form is characterized by the X-ray powder pattern shown in Figure 5. Its characteristic diffractions with the use of CuKa radiation are 10.2; 15.2 and 21.2 ⁇ 0.2° 2-theta.
  • the olaparib.acetone.2-propanol solvated crystalline form further exhibits the following characteristic reflections: 7.1; 11.9; 18.9; 24.9 and 27.0 ⁇ 0.2° 2-theta.
  • the diffraction peaks together with their relative intensity are shown in Table 5.
  • the molar ratio of olaparib:acetone:2-propanol was determined to be approx. 1:0.21:0.24 with the use of 1H NMR.
  • the stability of the olaparib.acetone.2-propanol form was measured with the use of Differential Scanning Calorimetry (DSC). Desolvation occurs at a temperature of over 120°C.
  • DSC Differential Sca
  • the solvated crystalline forms in accordance with the present invention are advantageous from the point of view of their relatively high solubility in water (Fig. 11).
  • the dissolution rate of the new crystalline forms as well as the concentration of olaparib achieved after 10 minutes is several times higher as compared to the non-solvated Form A.
  • the solvated crystalline forms of olaparib in accordance with the present invention can be obtained by crystallization from the respective solvent or mixture of solvents, i.e. by cooling or by concentration (partial evaporation) of the solution.
  • a saturated solution is prepared at the boiling point of the respective solvent or mixture of solvents, which is then cooled down to a temperature in the range of -20 to 30°C.
  • Fig. 2 X-ray pattern of the olaparib.2-propanol solvated crystalline form
  • Fig. 3 X-ray pattern of the olaparib.methyl ethyl ketone solvated crystalline form
  • Fig. 4 X-ray pattern of the olaparib.acetone.methyl ethyl ketone solvated crystalline form
  • Fig. 5 X-ray pattern of the olaparib.acetone.2-propanol solvated crystalline form
  • Fig. 6 DSC record of the olaparib.acetone solvated crystalline form
  • Fig. 7 DSC record of the olaparib.2-propanol solvated crystalline form
  • Fig. 8 DSC record of the olaparib.methyl ethyl ketone solvated crystalline form
  • Fig. 9 DSC record of the olaparib.acetone.methyl ethyl ketone solvated crystalline form
  • Fig. 10 DSC record of the olaparib.acetone.2-propanol solvated crystalline form
  • Fig. 11 Comparison of solubility of the different crystalline forms of olaparib Examples
  • Olaparib form A was prepared according to the procedure disclosed in WO2008047082, Example 1.
  • Example 1 Olaparib form A was prepared according to the procedure disclosed in WO2008047082, Example 1.
  • Olaparib 50 mg was dissolved in acetone (5 ml) under reflux conditions. The solution was slowly evaporated until dry. The evaporation product was dried at a reduced pressure (200 mbar) at the temperature of 40°C for 12 h.
  • Molar ratio of olaparibracetone (determined with the use of 1H NMR): 1 :0.5.
  • XRPD see Fig. 1.
  • Olaparib 50 mg was dissolved in 2-propanol (2 ml) under reflux conditions. The solution was slowly evaporated until dry. The evaporation product was dried at a reduced pressure (200 mbar) at the temperature of 40°C for 12 h. Molar ratio of olaparib:2-propanol (determined with the use of 1H NMR): 1 :0.5. XRPD: see Fig. 2.
  • Olaparib 50 mg was dissolved in methyl ethyl ketone (3 ml) under reflux conditions. The solution was slowly evaporated until dry. The evaporation product was dried at a reduced pressure (200 mbar) at the temperature of 40°C for 12 h. Molar ratio of olaparib.methyl ethyl ketone (determined with the use of 1H NMR): 1 :0.5. XRPD: see Fig. 3.
  • Olaparib (1 g) was refluxed in acetone (50 ml) for 2 h. A part of acetone (approx. 30 ml) was removed by distillation and the solution was slowly cooled down to 25 °C. The mixture was filtered and the product was dried at a reduced pressure (200 mbar) at the temperature of 40°C for 12 h. The amount of 0.78 g of a crystalline substance was obtained. Molar ratio of olaparib:acetone (determined with the use of 1H NMR): 1 :0.45.
  • Olaparib (1 g) was refluxed in 2-propanol (20 ml) for 1 h. After cooling down to 25°C the mixture was filtered and the product was dried at a reduced pressure (200 mbar) at a temperature of 40°C for 12 h. The amount of 0.95 g of a crystalline substance was obtained.
  • Olaparib (1 mg) was refluxed in methyl ethyl ketone (40 ml) under reflux conditions. A part of 2-propanol (approx. 20 ml) was removed by distillation and the solution was slowly cooled down to 25°C. The mixture was filtered and the product was dried at a reduced pressure (200 mbar) at the temperature of 40°C for 12 h. The amount of 0.89 g of a crystalline substance was obtained. Molar ratio of olaparib:methyl ethyl ketone (determined with the use of 1H NMR): 1 :0.47.
  • Olaparib (1 g) was refluxed in an acetone/2-propanol mixture (1 :1, 20 ml) for 1 h. After cooling down to 25 °C, the mixture was filtered and the product was dried at a reduced pressure (200 mbar) at a temperature of 40°C for 12 h. The amount of 0.91 g of a crystalline substance was obtained.
  • Molar ratio of olaparib: acetone:2-propanol (determined with the use of 1H NMR): 1 :0.21:0.24.
  • Olaparib (1 g) was refluxed in an acetone/methyl ethyl ketone mixture (1 :1, 20 ml) for 1 h. After cooling down to 25 °C, the mixture was filtered and the product was dried at a reduced pressure (200 mbar) at a temperature of 40°C for 12 h. The amount of 0.91 g of a crystalline substance was obtained.
  • Molar ratio of olaparib:acetone:methyl ethyl ketone determined with the use of 1H NMR
  • a flat powder sample was used that was placed on a Si plate.
  • 0.02 rad Soller slits and a 1 ⁇ 4° anti-diffusion slit were used.
  • an X'Celerator detector with maximum opening of the detection slot 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.
  • the records of the differential scanning calorimetry (DSC) were measured using a DSC Pyris 1 device made by the company Perkin Elmer.
  • the sample charge in a standard Al pot was between 3-4 mg and the heating rate was 10°C/min.
  • the temperature program that was used consists of 1 min of stabilization at the temperature of 50°C and then of heating up to 250°C at the heating rate of 10°C/min.
  • As the carrier gas 4.0 N 2 was used at the flow of 20 rril/min.

Abstract

L'invention concerne des formes cristallines solvatées d'olaparib de formule I, répondant au nom systématique 4-[(3- [(4-cyclopropylcarbonyl)pipérazin-4-yl]carbonyl)-4-fluorophényl]méthyl(2H)-phtalazin-1-one, un procédé pour les préparer et leur utilisation pour la production d'une forme médicamenteuse. Le solvant utilisé est l'acétone, le 2-propanol ou la méthyléthylcétone ; un mélange de ces solvants peut également être utilisé. Un autre objet de l'invention est un procédé de préparation de solvate d'olaparib.
PCT/CZ2017/000006 2016-02-15 2017-02-07 Solvates d'olaparib cristallin avec l'acétone, le 2-propanol et/ou la méthyléthylcétone WO2017140283A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZPV2016-82 2016-02-15
CZ2016-82A CZ201682A3 (cs) 2016-02-15 2016-02-15 Solvatované krystalické formy olaparibu, jejich příprava a použití

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10662178B2 (en) 2018-01-31 2020-05-26 Apotex Inc. Crystalline form of Olaparib
WO2021220120A1 (fr) 2020-04-28 2021-11-04 Rhizen Pharmaceuticals Ag Nouveaux composés utiles en tant qu'inhibiteurs de la poly(adp-ribose) polymérase (parp)
CN113636979A (zh) * 2021-08-12 2021-11-12 天津理工大学 一种奥拉帕尼与富马酸共晶晶型α及其制备方法与应用
CN114249695A (zh) * 2020-09-21 2022-03-29 齐鲁制药有限公司 一种奥拉帕利的新晶型、制备方法及用途
WO2022090938A1 (fr) 2020-10-31 2022-05-05 Rhizen Pharmaceuticals Ag Dérivés de phtalazinone utiles en tant qu'inhibiteurs de parp
WO2022215034A1 (fr) 2021-04-08 2022-10-13 Rhizen Pharmaceuticals Ag Inhibiteurs de la poly(adp-ribose) polymérase
KR20230030286A (ko) * 2021-08-25 2023-03-06 주식회사 보령 올라파립의 제조방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080976A1 (fr) 2003-03-12 2004-09-23 Kudos Pharmaceuticals Limited Derives de phtalazinone
WO2008047082A2 (fr) 2006-10-17 2008-04-24 Kudos Pharmaceuticals Limited Dérivé de phtalazinone
WO2009050469A1 (fr) 2007-10-17 2009-04-23 Kudos Pharmaceuticals Limited 4-[3-(4-cyclopropanecarbonylpipérazin-1-carbonyl)-4-fluorobenzyl]-2h-phtalazin-1-one

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080976A1 (fr) 2003-03-12 2004-09-23 Kudos Pharmaceuticals Limited Derives de phtalazinone
WO2008047082A2 (fr) 2006-10-17 2008-04-24 Kudos Pharmaceuticals Limited Dérivé de phtalazinone
WO2009050469A1 (fr) 2007-10-17 2009-04-23 Kudos Pharmaceuticals Limited 4-[3-(4-cyclopropanecarbonylpipérazin-1-carbonyl)-4-fluorobenzyl]-2h-phtalazin-1-one

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10662178B2 (en) 2018-01-31 2020-05-26 Apotex Inc. Crystalline form of Olaparib
WO2021220120A1 (fr) 2020-04-28 2021-11-04 Rhizen Pharmaceuticals Ag Nouveaux composés utiles en tant qu'inhibiteurs de la poly(adp-ribose) polymérase (parp)
CN114249695A (zh) * 2020-09-21 2022-03-29 齐鲁制药有限公司 一种奥拉帕利的新晶型、制备方法及用途
WO2022090938A1 (fr) 2020-10-31 2022-05-05 Rhizen Pharmaceuticals Ag Dérivés de phtalazinone utiles en tant qu'inhibiteurs de parp
WO2022215034A1 (fr) 2021-04-08 2022-10-13 Rhizen Pharmaceuticals Ag Inhibiteurs de la poly(adp-ribose) polymérase
CN113636979A (zh) * 2021-08-12 2021-11-12 天津理工大学 一种奥拉帕尼与富马酸共晶晶型α及其制备方法与应用
KR20230030286A (ko) * 2021-08-25 2023-03-06 주식회사 보령 올라파립의 제조방법
KR102645122B1 (ko) 2021-08-25 2024-03-07 주식회사 보령 올라파립의 제조방법

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