WO2017140283A1 - Crystalline olaparib solvates with acetone, 2-propanol and/or methyl ethyl ketone - Google Patents

Crystalline olaparib solvates with acetone, 2-propanol and/or methyl ethyl ketone 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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Prior art keywords
olaparib
acetone
propanol
ethyl ketone
methyl ethyl
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PCT/CZ2017/000006
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French (fr)
Inventor
Ludek Ridvan
Hana TOZICKOVA
Ondrej Dammer
Josef Beranek
Lukas KREJCIK
Jiri MIKSATKO
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Zentiva, K.S.
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Publication of WO2017140283A1 publication Critical patent/WO2017140283A1/en

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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.

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Abstract

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-1-one, a method of their preparation and use for the production of a drug form. The used solvent is acetone, 2-propanol, or methyl ethyl ketone, or a mixture of the said solvents can be used. Another object is a preparation method of olaparib solvate.

Description

CRYSTALLINE OLAPARIB SOLVATES WITH ACETONE, 2-PROPANOL
AND/OR METHYL ETHYL KETONE
Field of the Invention
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.
Figure imgf000002_0001
(I) Background Art
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.
The document of the European Medicines Agency of October 23, 2014 (EMA/CHMP/789139/2014) mentions that 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.
It is therefore obvious that new forms of olaparib with good solubility and bioavailability are required for the development of a stable drug form. Disclosure of the Invention
The invention provides solvated crystalline forms of olaparib. In accordance with recommendations of the European Medicines agency (EMA/CHMP/ICH/82260/2006), 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. Preferably, 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.
Detailed description of the Invention
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. In case that the solvate of olaparib contains two different solvents, 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. Its characteristic diffractions with the use of CuKa radiation are 7.2; 10.2; 15.3 and 21.2 ± 0.2° 2-theta. The olaparib.acetone solvated crystalline form further exhibits the following characteristic reflections: 11.9; 18.9 and 27.1 ± 0.2° 2-theta. The diffraction peaks together with their relative intensity are shown in Table 1. The molar ratio of olaparib.acetone was determined to be approx. 1:0.5 with the use of 1H NMR. The stability of the olaparib.acetone form was measured with the use of Differential Scanning Calonmetry (DSC). Desolvation occurs at a temperature of over approx. 120°C.
Tab. 1: X-ray characteristic diffraction peaks corresponding to the olaparib.acetone crystalline form.
Interplanar spacing [A]
Position [°2Th.] [A]=0.1nm Rel. intensity [%]
7.16 12.337 39.9
10.17 8.687 100.0
11.93 7.412 15.0
12.84 6.892 9.0
13.61 6.501 12.9
14.17 6.243 6.3
14.45 6.123 8.5
14.65 6.041 10.5
15.28 5.794 86.4
16.01 5.530 8.7
17.32 5.115 16.7
18.94 4.682 27.7
19.70 4.502 19.9
20.47 4.336 11.3
21.24 4.180 93.4
21.89 4.057 25.4
23.06 3.854 17.4 Interplanar spacing [A]
Position [°2Th.] [A]=0.1nm Rel. intensity [%]
24.96 3.565 15.6
25.20 3.532 15.5
26.40 3.369 4.4
27.12 3.286 29.4
27.64 3.225 7.6
28.32 3.149 6.9
28.95 3.082 6.4
30.21 2.956 5.6
31.17 2.868 3.4
31.76 2.816 4.6
32.47 2.755 3.6
33.06 2.708 4.8
34.14 2.624 2.6
34.78 2.578 5.6
38.16 2.356 5.0
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.
Tab. 2: X-ray characteristic diffraction peaks corresponding to the olaparib.2-propanol crystalline form.
Interplanar spacing [A]
Position [°2Th.] [A]=0.1nm Rel. intensity [%]
7.30 12.106 23.0
10.37 8.522 82.0
12.05 7.337 15.6 Interplanar spacing [A]
Position [°2Th.] [A]=0.1nm Rel. intensity [%]
13.03 6.789 9.3
13.79 6.415 14.8
14.57 6.076 9.4
15.39 5.754 100.0
16.20 5.466 8.8
17.39 5.096 29.1
19.08 4.647 29.8
19.90 4.458 23.7
20.53 4.324 8.3
20.94 4.239 9.4
21.41 4.146 79.9
21.63 4.104 38.5
22.04 4.030 28.2
23.30 3.815 19.5
25.11 3.544 12.6
25.41 3.502 14.7
26.51 3.359 5.5
27.27 3.268 22.0
27.96 3.189 8.4
28.29 3.153 5.9
29.00 3.077 7.2
30.48 2.930 6.4
31.09 2.875 3.3
31.96 2.798 4.1
33.29 2.690 4.2
34.98 2.563 6.3
38.22 2.353 4.5
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.
Tab. 3: X-ray characteristic diffraction peaks corresponding to the olaparib.methyl ethyl ketone crystalline form.
Interplanar spacing [A]
Position [°2Th.] [A]=0.1nm Rel. intensity [%]
7.31 12.090 16.6
10.42 8.480 85.2
12.11 7.300 12.9
12.91 6.851 7.6
13.80 6.414 9.7
14.78 5.989 7.1
15.46 5.726 89.0
16.12 5.494 9.1
17.44 5.081 19.5
18.93 4.684 27.6
19.82 4.477 19.7
20.77 4.273 15.3
21.28 4.172 100.0
21.74 4.086 13.2
22.07 4.024 33.6
23.10 3.847 15.6
23.35 3.807 12.7
25.09 3.546 27.6
26.58 3.351 9.0
27.23 3.273 36.5
27.64 3.224 7.1 Interplanar spacing [A]
Position [°2Th.] [A]=0.1nm Rel. intensity [%]
28.45 3.135 6.5
29.07 3.069 4.4
30.40 2.938 7.1
32.04 2.791 4.2
32.71 2.735 2.9
33.40 2.680 3.2
34.16 2.623 3.2
35.04 2.559 5.4
38.27 2.350 4.3
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. 1:0.14:0.32 with the use of 1H NMR. The stability of the olaparib.acetone.methyl ethyl ketone form was measured with the use of Differential Scanning Calorimetry (DSC). Desolvation occurs at a temperature of over 120°C.
Tab. 4: X-ray characteristic diffraction peaks corresponding to the olaparib.acetone.methyl ethyl ketone crystalline form.
Position Interplanar spacing [A]
[°2Th.] [A]=0.1nm Rel. intensity [%]
7.10 12.446 25.8
10.18 8.678 100.0
11.92 7.417 14.4
12.76 6.932 6.9
13.60 6.505 10.3
14.58 6.069 5.2
15.26 5.803 64.2 Position Interplanar spacing [A]
[°2Th.] [A]=0.1nm Rel. intensity [%]
15.95 5.552 8.1
17.26 5.133 17.5
18.77 4.724 21.0
19.21 4.617 7.2
19.62 4.522 15.8
20.08 4.419 4.9
20.56 4.317 9.9
21.12 4.203 73.1
21.54 4.122 10.4
21.90 4.056 24.4
22.95 3.873 16.2
24.89 3.574 19.6
26.40 3.373 7.8
27.01 3.299 29.9
27.52 3.238 6.6
28.28 3.154 5.3
28.91 3.086 4.7
30.19 2.958 6.8
31.83 2.810 3.8
33.08 2.706 4.9
34.83 2.574 4.6
38.00 2.364 5.2
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.
Tab. 5: X-ray characteristic diffraction peaks corresponding to the olaparib.acetone.2- propanol crystalline form
Position Interplanar spacing [A]
[°2ThJ [A]=0.1nm Rel. intensity [%]
7.09 12.453 36.7
10.19 8.675 100.0
11.90 7.430 19.6
12.83 6.896 10.1
13.57 6.520 15.0
14.17 6.244 6.0
14.54 6.086 8.0
15.21 5.819 89.8
16.02 5.529 10.6
17.22 5.145 25.8
18.88 4.696 32.9
19.69 4.506 25.8
20.46 4.338 13.1
21.20 4.188 94.3
21.85 4.065 32.7
23.10 3.852 15.2
24.89 3.574 14.5
25.20 3.531 15.4
26.36 3.378 7.1
27.05 3.294 31.1
27.73 3.215 10.3
28.19 3.163 6.2
28.48 3.131 4.9
28.89 3.088 8.3
30.30 2.947 9.3 Position Interplanar spacing [A]
[°2Th.] [A]=0.1nm el. intensity [%]
31.76 2.815 4.7
32.40 2.761 3.6
33.09 2.705 4.7
34.78 2.577 6.1
38.14 2.357 4.2
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. Preferably, 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.
Brief description of the Drawings Fig. 1: X-ray pattern of the olaparib.acetone solvated crystalline form
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.acetone solvate
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.
Example 2
Olaparib.2-propanol solvate
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.
Example 3
Olaparib.methyl ethyl ketone solvate
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.
Example 4
Olaparib.acetone solvate
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. Example 5
Olaparib.2-propanol solvate
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. Molar ratio of olaparib: 2-propanol (determined with the use of 1H NMR): 1 :0.55.
Example 6
Olaparib.methyl ethyl ketone solvate
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.
Example 7
Mixed olaparib.acetone.2-propanol solvate
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. Example 8
Mixed olaparib.acetone.methyl ethyl ketone solvate
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): 1:0.14:0.32. List of analytical methods
X-ray measurement parameters: The diffractograms were measured using an X'PERT PRO MPD PANalytical diffractometer, used radiation CuKa (λ= 1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2-40° 2Θ, increment: 0.02° 2Θ. For the measurement a flat powder sample was used that was placed on a Si plate. For the setting of the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad Soller slits and a ¼° anti-diffusion slit were used. For the setting of the secondary optical equipment 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 N2 was used at the flow of 20 rril/min.
The nuclear magnetic resonance (NMR) records were measured with the use of a Bruker Avance III 500 MHz device with a Prodigy probe. 10 mg of the sample was dissolved in 0.6 ml of deuterated dimethyl sulfoxide (DMSO-d6) and measured at the room temperature with the number of scans NS = 4. The spectra were processed using the Bruker TopSpin 3.2 program. Dissolutions (dissolution rate) were measured using a Sotax AT-7 dissolution device. The dissolution was carried out in 150 ml of a pH 2.0 solution (lOmM HC1) at the constant stirring rate of 125 rpm. Samples were extracted at 5 -minute intervals and the concentration of dissolved olaparib was measured with a Jena Analytik 200 ITVTVis spectrofotometer at the wavelength of 263 nm with the use of 5 mm cuvettes.

Claims

1. Olaparib of formula I in the form of a solvate with acetone, 2-propanol, or methyl ethyl ketone, or a mixed solvate with a variable ratio of said solvents.
Figure imgf000015_0001
(I)
2. Olaparib in the solvate form according to claim 1, wherein the olaparib: solvent molar ratio is in the range of 1:0.05 to 1.2, preferably 1:0.1 to 1:0.6.
3. Olaparib in the solvate form according to claim 1, wherein said mixed solvate contains two different solvents and the molar ratio of solvent I : solvent II is in the range of 4:1 to 1:4.
4. Olaparib in the solvate form according to claims 1 or 2, wherein the solvent is acetone.
5. Olaparib in the solvate form according to claims 1 or 2, wherein the solvent is 2- propanol.
6. Olaparib in the solvate form according to claims 1 or 2, wherein the solvent is methyl ethyl ketone.
7. Olaparib in the solvate form according to claims 1 or 3, wherein the solvents are acetone and methyl ethyl ketone.
8. Olaparib in the solvate form according to claims 1 or 3, wherein the solvents are acetone and 2-propanol.
9. A method for preparing olaparib in the solvate form as defined in any one of claims 1 to 8, characterized in that olaparib is dissolved in acetone, 2-propanol, or methyl ethyl ketone, or in a mixture of solvents that consists of acetone and methyl ethyl ketone or acetone and 2-propanol, at the boiling point of the solvent or the mixture of solvents and the resulting solution is cooled down and/or the solvent is partially evaporated.
10. The method for preparing olaparib solvate according to claim 9, characterized in that the resulting solution is cooled down to a temperature in the range of -20 to 30°C.
11. Use of the olaparib solvate according to any one of claims 1 to 8 for the preparation of a pharmaceutical composition.
PCT/CZ2017/000006 2016-02-15 2017-02-07 Crystalline olaparib solvates with acetone, 2-propanol and/or methyl ethyl ketone WO2017140283A1 (en)

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US10662178B2 (en) 2018-01-31 2020-05-26 Apotex Inc. Crystalline form of Olaparib
WO2021220120A1 (en) 2020-04-28 2021-11-04 Rhizen Pharmaceuticals Ag Novel compounds useful as poly(adp-ribose) polymerase (parp) inhibitors
CN113636979A (en) * 2021-08-12 2021-11-12 天津理工大学 Olaparib and fumaric acid eutectic crystal form alpha, and preparation method and application thereof
CN114249695A (en) * 2020-09-21 2022-03-29 齐鲁制药有限公司 Novel crystal form of olaparide, preparation method and application
WO2022090938A1 (en) 2020-10-31 2022-05-05 Rhizen Pharmaceuticals Ag Phthalazinone derivatives useful as parp inhibitors
WO2022215034A1 (en) 2021-04-08 2022-10-13 Rhizen Pharmaceuticals Ag Inhibitors of poly(adp-ribose) polymerase
KR20230030286A (en) * 2021-08-25 2023-03-06 주식회사 보령 Methods for Preparing Olaparib
JP7492997B2 (en) 2021-08-25 2024-05-30 株式会社保寧 Manufacturing process for olaparib

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Cited By (9)

* 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 (en) 2020-04-28 2021-11-04 Rhizen Pharmaceuticals Ag Novel compounds useful as poly(adp-ribose) polymerase (parp) inhibitors
CN114249695A (en) * 2020-09-21 2022-03-29 齐鲁制药有限公司 Novel crystal form of olaparide, preparation method and application
WO2022090938A1 (en) 2020-10-31 2022-05-05 Rhizen Pharmaceuticals Ag Phthalazinone derivatives useful as parp inhibitors
WO2022215034A1 (en) 2021-04-08 2022-10-13 Rhizen Pharmaceuticals Ag Inhibitors of poly(adp-ribose) polymerase
CN113636979A (en) * 2021-08-12 2021-11-12 天津理工大学 Olaparib and fumaric acid eutectic crystal form alpha, and preparation method and application thereof
KR20230030286A (en) * 2021-08-25 2023-03-06 주식회사 보령 Methods for Preparing Olaparib
KR102645122B1 (en) 2021-08-25 2024-03-07 주식회사 보령 Methods for Preparing Olaparib
JP7492997B2 (en) 2021-08-25 2024-05-30 株式会社保寧 Manufacturing process for olaparib

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