NEW SALT OF ABEXINOSTAT, ASSOCIATED CRYSTALLINE FORM, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract

Abexinostat tosylate of formula (II):

##STR00001##

and its crystalline form I characterised by its X-ray powder diffraction diagram, its Raman spectrum and its solid-state .sup.13C CP/MAS NMR spectrum.

Medicinal products containing the same which are useful in the treatment of cancer.

Claims

1-6. (canceled)

7. A process for preparing crystalline form I of abexinostat tosylate, comprising crystallizing abexinostat in the presence of para-toluenesulfonic acid in a polar medium, wherein the polar medium is a binary mixture of isopropanol and water.

8. The process of claim 7, wherein the polar medium is a 50/50 weight/weight mixture of isopropanol and water.

9. The process of claim 7, wherein the polar medium is a 45/54 weight/weight mixture of isopropanol and water.

10. The process of claim 7, further comprising seeding the crystallization with crystalline form I of abexinostat tosylate.

11. The process of claim 7, wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 6.50, 9.94, 11.35, 14.08, 18.95, 21.08, and 27.05.

12. The process of claim 11, wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 6.50, 9.94, 11.35, 12.33, 14.08, 18.95, 19.96,21.08, 22.82, 23.61, and 27.05.

13. The process of claim 7, wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has the following X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2, expressed in degrees ±0.2°) and interreticular distance d (expressed in Å): TABLE-US-00006 Line Angle 2 theta Interreticular Distance No. (degrees) (Å) 1 6.50 13.581 2 9.94 8.894 3 11.35 7.789 4 12.33 7.173 5 14.08 6.285 6 18.95 4.683 7 19.61 4.526 8 19.96 4.449 9 21.08 4.215 10 22.82 3.897 11 23.61 3.768 12 27.05 3.296

14. The process of claim 7, wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has a Raman spectrum having a peak at position 1608 cm.sup.−1.

15. The process of claim 14, wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has a Raman spectrum having peaks at positions 940 cm.sup.−, 1088 cm.sup.−, 1132 cm.sup.−, 1242 cm.sup.−, 1360 cm.sup.−1, and 1608 cm.sup.−1.

16. The process of claim 7, wherein the crystallizing step results in forming crystalline form I of abexinostat tosylate, characterized in that it has a solid-state .sup.13C CP/MAS NMR spectrum having the following peaks (expressed in ppm ±0.2 ppm): 121.2 ppm, 122.1 ppm, 123.5 ppm 126.0ppm, 126.8 ppm, 128.2 ppm, 128.9 ppm, 143.4 ppm, 144.6 ppm, 153.8 ppm, 159 ppm, 161.2 ppm and 162.1 ppm.

17. The process of claim 16, wherein the crystallizing step results in forming Crystalline form I of abexinostat tosylate, characterized in that it has a solid-state .sup.13C CP/MAS NMR spectrum having the following peaks (expressed in ppm ±0.2 ppm): TABLE-US-00007 Peak Chemical Shift No. (ppm) 1 162.1 2 161.2 3 159.0 4 153.8 5 144.6 6 143.4 7 128.9 8 128.2 9 126.8 10 126.0 11 123.5 12 122.1 13 121.3 14 65.9 15 50.6 16 46.9 17 45.0 18 21.9

18. A pharmaceutical composition comprising crystalline form I of abexinostat tosylate, lactose monohydrate, and maize starch.

Description

[0030] The Examples hereinbelow illustrate the invention but do not limit it in any way.

Example 1: Process for Obtaining Crystalline Form I of Abexinostat Tosylate

[0031] 1.66 kg of abexinostat (free base) are placed in 9.48 kg of a mixture of isopropanol/water (50/50 weight/weight) at ambient temperature. para-Toluenesulphonic acid monohydrate (0.83 kg) in 2.36 kg of water is added at ambient temperature. The mixture is then heated at 75° C. for 30 minutes before being cooled to 0° C. When crystallisation is complete, the suspension is filtered at 20° C. After drying, crystalline form 1 of abexinostat tosylate is obtained in a yield of about 85% and with a purity greater than 99%. The solid was characterised by the X-ray powder diffraction diagram, Raman spectrum and NMR spectrum as set out in Examples 3-5 and 6 hereinbelow.

Example 2: Process for Obtaining Crystalline Form I of Abexinostat Tosylate (Seeding)

[0032] 33.9 kg of abexinostat (free base) are placed in 170 kg of a mixture of isopropanol/water (45.6/54.4 weight/weight) at ambient temperature. A solution composed of para-toluenesulphonic acid monohydrate (17.06 kg) in water (24.1 kg) is added. The mixture is then heated at 70-75° C., cooled and seeded with 1.935 kg of crystalline form I of abexinostat tosylate. The suspension is then filtered at 20° C. After drying, crystalline form I of abexinostat tosylate is obtained in a yield of about 86% and with a purity greater than 99%. The solid was characterised by the X-ray powder diffraction diagram, Raman spectrum and NMR spectrum as set out in Examples 3-5 and 6 hereinbelow.

Example 3: Crystalline Form I of Abexinostat Tosylate (X-Ray Powder Diffraction Diagram)

[0033] Recording of the data was carried out using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector under the following conditions: [0034] Voltage 45 kV, current 40 mA, [0035] Mounting: theta/theta, [0036] Anode: copper, [0037] K alpha-1 wavelength: 1.54060 Å, [0038] K alpha-2 wavelength: 1.54443 Å, [0039] K alpha-2/K alpha-1 ratio: 0.5, [0040] Measurement mode: continuous from 3° to 55° (Bragg's angle 2 theta) in increments of 0.017°, [0041] Measurement time per step: 35.53 s.

[0042] The X-ray powder diffraction diagram of form I of abexinostat tosylate obtained according to the process of Example 1 or 2 is expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ±0.2°), interplanar distance (expressed in Å) and relative intensity (expressed as a percentage relative to the most intense fine). The significant lines have been collated in the following table:

TABLE-US-00003 Line Angle 2-theta Interplanar distance Relative intensity no. (degrees) (Å) (%) 1 6.50 13.581 75.6 2 9.94 8.894 58.4 3 11.35 7.789 19.1 4 12.33 7.173 23.7 5 14.08 6.285 33.1 6 18.95 4.683 100 7 19.61 4.526 53.9 8 19.96 4.449 50.9 9 21.08 4.215 93.5 10 22.82 3.897 28.5 11 23.61 3.768 32.6 12 27.05 3.296 16.0

Example 4: Crystalline Form I of Abexinostat Tosylate (Crystal Unit Cell)

[0043] A saturated solution of abexinostat tosylate in 2,2,2-trifluoroethanol is prepared by stirring a suspension for 24 hours at ambient temperature, followed by filtration. 1 mL of the resulting solution is then poured into a 1.8-mL HPLC vial, to which 0.25 mL of water is added. The solution is maintained at ambient temperature for 75 minutes. After centrifuging and then drying, the solid is isolated for analysis. From among the crystals obtained a crystal of sufficient quality is taken for single-crystal X-ray diffraction analysis. The crystalline structure of the above single crystal was determined using a Bruker Kappa CCD diffractometer equipped with an FR590 generator having a molybdenum anticathode (λMoKα1=0.7093 Å) with an angular range from 2° to 27.5° in terms of θ. The following parameters were established: [0044] crystal unit cell: triclinic [0045] unit cell parameters: a=10.467 Å, b=14.631 Å, c=20.159 Å, α=73.971°, β=79.040°, γ=72.683° [0046] space group: P−1 [0047] number of molecules in the unit cell: 4 [0048] volume of the unit cell: V.sub.unit cell=2813.0 Å.sup.3 [0049] density: d=1.345 g/cm.sup.3.

Example 5: Crystalline Form I of Abexinostat Tosylate (Raman Spectrum)

[0050] Form 1 of abexinostat tosylate was characterised by Raman spectroscopy. The spectra were recorded in diffuse reflectance mode (Raman Station 400, PerkinElmer) using a 785 nm laser. The signal was recorded by a CCD detector. The wavelength shift depends on the material and is characteristic of that material, which allows analysis of the chemical composition and of the molecular arrangement of the sample studied. The spectra were acquired with maximum power (100% laser capacity), a spot size of 100 μm, twenty exposures of 2 seconds and a spectral resolution of 2 cm.sup.−1. The spectral range explored ranges from 0 to 3278 cm.sup.−1.

[0051] Significant peaks were observed at the following positions: 940 cm.sup.−, 1088 cm.sup.−1, 1132 cm.sup.−, 1242 cm.sup.−1, 1360 cm.sup.−1, 1608 cm.sup.−1.

Example 6: Crystalline Form I of Abexinostat Tosylate (Solid NMR Spectrum)

[0052] Form I of abexinostat tosylate was also characterised by solid-state NMR spectroscopy. The .sup.13C NMR spectra were recorded at ambient temperature using a Bruker SB Avance spectrometer with a 4-mm CP/MAS SB VTN type probe under the following conditions: [0053] Frequency: 125.76 MHz, [0054] Spectral width: 40 kHz, [0055] Magic angle spinning rate of sample: 10 kHz, [0056] Pulse sequence: CP (Cross Polarization) with SPINAL64 decoupling (decoupling power: 80 kHz), [0057] Repetition delay: 10 s, [0058] Acquisition time: 35 ms, [0059] Contact time: 4 ms, [0060] Number of scans: 4096.

[0061] An apodisation function (“5 Hz line broadening”) is applied to the collected signal before the Fourier transform. The spectra thereby obtained were referenced relative to a sample of adamantane (the highest-frequency peak of adamantane has a chemical shift of 38.48 ppm).

[0062] The peaks observed have been collated in the following table (expressed in ppm ±0.2 ppm):

TABLE-US-00004 Peak Chemical shift no. (ppm) 1 162.1 2 161.2 3 159.0 4 153.8 5 144.6 6 143.4 7 128.9 8 128.2 9 126.8 10 126.0 11 123.5 12 122.1 13 121.3 14 65.9 15 50.6 16 46.9 17 45.0 18 21.9

Example 7: Pharmaceutical Composition

[0063] Formula for the preparation of 1000 tablets each containing 100 mg of abexinostat (expressed in terms of the base equivalent):

TABLE-US-00005 Abexinostat tosylate 143.4 g   Lactose monohydrate 213.1 g   Magnesium stearate 2.5 g  Maize starch 75 g Maltodextrin 50 g Anhydrous colloidal silica  1 g Sodium carboxymethylcellulose 15 g

Example 8: Hygroscopicity

[0064] Hygroscopicity of form I of abexinostat tosylate was assessed using dynamic vapor sorption (DVS) technique. 5 to 10 mg of the drug substance test sample were accurately weighed into a DVS sample pan working at 25° C. under controlled humidity. The mass variation was recorded whilst drying under 0 percent RH (relative humidity) and during two subsequent cycles of increasing and decreasing linear variations of relative humidity in the range 0-90 percent RH at a rate of 10 percent per hour. The relative humidity was maintained constant when it reached either 0 or 90 percent RH until the mass variation was less than 0.002 percent, per minute within a limit of time of 15 h.

[0065] An increase in weight lower than 0.5% was detected by DVS analysis when a sample was exposed to relative humidities from 0% to 90% at 25° C.