US20150315167A1 - New salt of abexinostat, associated crystalline form, a process for their preparation and pharmaceutical compositions containing them - Google Patents
New salt of abexinostat, associated crystalline form, a process for their preparation and pharmaceutical compositions containing them Download PDFInfo
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- US20150315167A1 US20150315167A1 US14/798,412 US201514798412A US2015315167A1 US 20150315167 A1 US20150315167 A1 US 20150315167A1 US 201514798412 A US201514798412 A US 201514798412A US 2015315167 A1 US2015315167 A1 US 2015315167A1
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- abexinostat
- tosylate
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- MAUCONCHVWBMHK-UHFFFAOYSA-N CC1=CC=C(S(=O)(=O)O)C=C1.CN(C)CC1=C(C(=O)NCCOC2=CC=C(C(=O)NO)C=C2)OC2=CC=CC=C21 Chemical compound CC1=CC=C(S(=O)(=O)O)C=C1.CN(C)CC1=C(C(=O)NCCOC2=CC=C(C(=O)NO)C=C2)OC2=CC=CC=C21 MAUCONCHVWBMHK-UHFFFAOYSA-N 0.000 description 3
- OVOOMFKAZTZDOS-UHFFFAOYSA-N C=C(NO)C1=CC=C(OCCNC(=O)C2=C(CN(C)C)C3=CC=CC=C3O2)C=C1 Chemical compound C=C(NO)C1=CC=C(OCCNC(=O)C2=C(CN(C)C)C3=CC=CC=C3O2)C=C1 OVOOMFKAZTZDOS-UHFFFAOYSA-N 0.000 description 1
- NBCZKVVPOWCAEX-UHFFFAOYSA-N CC1=CC=C(C)C=C1.CN(C)CC1=C(C(=O)NCCOC2=CC=C(C(=O)NO)C=C2)OC2=CC=CC=C21 Chemical compound CC1=CC=C(C)C=C1.CN(C)CC1=C(C(=O)NCCOC2=CC=C(C(=O)NO)C=C2)OC2=CC=CC=C21 NBCZKVVPOWCAEX-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
- C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
Definitions
- the present invention relates to N-hydroxy-4- ⁇ 2-[3-(N,N-dimethylaminomethyl)-benzofuran-2-ylcarbonylamino]ethoxy ⁇ benzamide tosylate, or a solvate thereof.
- the subject-matter of the invention relates to a tosylate salt of abexinostat of formula (I):
- the present invention relates also to crystalline form I of N-hydroxy-4- ⁇ 2-[3-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy ⁇ benzamide tosylate, to a process for its preparation and also to pharmaceutical compositions comprising it.
- N-hydroxy-4- ⁇ 2-[3-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy ⁇ -benzamide also known as abexinostat
- abexinostat is a historic deacetylase (HDAC) inhibitor described in patent application WO2004/092115. It allows inhibition of cell growth and induces apoptosis in cultured tumour cells in vitro, and it inhibits tumour growth in vivo in xenograft models (Buggy et al., Mol. Cancer Ther 2006 5(5) 1309). In view of its pharmacological profile, abexinostat is intended for use in the treatment of cancer.
- HDAC histone deacetylase
- Patent application WO2004/092115 describes two different routes for obtaining abexinostat.
- 3-methyl-benzofuran-2-carboxylic acid is used as starting material, but functionalisation of this central nucleus by the dimethylaminomethyl group in the 3-position is carried out at different stages in the synthesis process, namely before or after coupling of the benzofuran-2-carboxylic acid compound with methyl 4-(2aminoethoxy)benzoate.
- Obtaining abexinostat hydrochloride is specifically described in the WO2004/092115 application.
- using this salt on an industrial scale is problematic because of its hygroscopic properties.
- the present invention describes a process for obtaining abexinostat tosylate (abexinostat 4-methylbenzenesulfonate) in a well-defined, perfectly reproducible crystalline form having very good stability that is compatible with the industrial constraints of preparation (especially drying) and storage of pharmaceutical compositions.
- Crystalline form I of abexinostat tosylate is characterised by 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; 21.08; 27.05. Even more especially, crystalline form I of abexinostat tosylate is characterised by the following diffraction lines: 6.50; 9.94; 11.35; 12.33; 14.08; 18.95; 19.61; 19.96; 21.08; 22.82; 23.61; 27.05.
- crystalline form I of abexinostat tosylate is characterised by the X-ray powder diffraction diagram hereinbelow, measured using a PANalytical X′Pert Pro MPD diffractometer with an X′Celerator detector and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°) and interplanar distance d (expressed in ⁇ ):
- crystalline form I of abexinostat tosylate has been characterised by Raman spectroscopy. Significant peaks were observed at the following positions: 940 cm ⁇ 1 , 1088 cm ⁇ 1 , 1132 cm ⁇ 1 , 1242 cm ⁇ 1 , 1360 cm ⁇ 1 , 1608 cm ⁇ 1 .
- crystalline form 1 of abexinostat tosylate may be characterised by the X-ray powder diffraction diagram which includes the 12 significant lines given hereinabove and also by a Raman spectrum having a significant peak at the position 1608 cm ⁇ 1 .
- crystalline form I of abexinostat tosylate has also been characterised by solid-state NMR spectroscopy, Significant peaks were observed at 121.2 ppm, 122.1 ppm, 123.5 ppm, 126.0 ppm, 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.
- the 13 C CP/MAS (Cross Polarization Magic Angle Spinning) spectra have the following peaks (expressed in ppm ⁇ 0.2 ppm):
- the invention relates also to a process for the preparation of crystalline form I of abexinostat tosylate, which process is characterised in that abexinostat is crystallised from a polar medium in the presence of paro-toluenesulphonic acid.
- the polar medium is composed of one or more solvents selected from water, alcohols ketones and esters, it being understood that:
- Preferred alcohols are ethanol and isopropanol.
- preference will also be given to acetone and methyl ethyl ketone among the ketones and to ethyl acetate among the esters.
- the polar medium is a binary mixture, one of the constituents of which is water. Even more preferably, the polar medium is a binary mixture selected from: acetone/water, ethanol/water, isopropanol/water and methyl ethyl ketone/water.
- abexinostat free base obtained by any process may be used.
- the invention relates also to another process for the preparation of crystalline form I of abexinostat tosylate, in which process the crystallisation is seeded using a very small amount of crystalline form I of abexinostat tosylate.
- abexinostat free base obtained by any process may also be used.
- crystalline form I of abexinostat tosylate has the advantage of making it possible to prepare pharmaceutical formulations having a consistent and reproducible composition and having good characteristics of dissolution and stability, which is especially advantageous when the formulations are intended for oral administration. More specifically, use of crystalline form I of abexinostat tosylate is especially valuable in an industrial context in view of its low hygroscopicity.
- Crystalline form I of abexinostat tosylate is intended for the treatment of cancer, more especially the treatment of a carcinoma, a tumour, a neoplasm, a lymphoma, a melanoma, a glioma, a sarcoma or a blastoma.
- the invention relates also to pharmaceutical compositions comprising, as active ingredient, tosylate salt of abexinostat, even more especially crystalline form I of abexinostat tosylate, together with one or more appropriate, non-toxic, inert excipients.
- tosylate salt of abexinostat even more especially crystalline form I of abexinostat tosylate
- pharmaceutical compositions according to the invention there may be more especially mentioned those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragées, granules, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions and chewing gums.
- the useful dosage varies according to the sex, age and weight of the patient, the administration route, the nature of the cancer and any associated treatments; the useful dosage ranges from 20 mg to 480 mg of N-hydroxy-4- ⁇ 2-[3-(N,N-dimethylaminomethyl)-benzofuran-2-ylcarbonylamino]ethoxy ⁇ benzamide per day expressed in terms of the free base.
- Crystalline form I of aboxinostat tosylate (X-ray powder diffraction diagram)
- 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 ⁇ ) and relative intensity (expressed as a percentage relative to the most intense line).
- line position Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°
- interplanar distance expressed in degrees ⁇ 0.2°
- relative intensity expressed as a percentage relative to the most intense line.
- Crystalline form I of abexinostat tosylate (crystal unit cell)
- 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.
- Form I 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 ⁇ m, twenty exposures of 2 seconds and a spectral resolution of 2 cm ⁇ 1 .
- the spectral range explored ranges from 0 to 3278 cm ⁇ 1 .
- Form I of abexinostat tosylate was also characterised by solid-state NMR spectroscopy.
- the 13 C 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:
- 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
- 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 per cent RH (relative humidity) and during two subsequent cycles of increasing and decreasing linear variations of relative humidity in the range 0-90 per cent RH at a rate of 10 per cent per hour. The relative humidity was maintained constant when it reached either 0 or 90 per cent RH until the mass variation was less than 0.002 per cent per minute within a limit of time of 15 h.
- RH relative humidity
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Abstract
Description
- The present invention relates to N-hydroxy-4-{2-[3-(N,N-dimethylaminomethyl)-benzofuran-2-ylcarbonylamino]ethoxy}benzamide tosylate, or a solvate thereof.
- Alternatively, the subject-matter of the invention relates to a tosylate salt of abexinostat of formula (I):
- More especially, the invention is directed to the salt of formula (II):
- The present invention relates also to crystalline form I of N-hydroxy-4-{2-[3-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}benzamide tosylate, to a process for its preparation and also to pharmaceutical compositions comprising it.
- N-hydroxy-4-{2-[3-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}-benzamide, also known as abexinostat, is a historic deacetylase (HDAC) inhibitor described in patent application WO2004/092115. it allows inhibition of cell growth and induces apoptosis in cultured tumour cells in vitro, and it inhibits tumour growth in vivo in xenograft models (Buggy et al., Mol. Cancer Ther 2006 5(5) 1309). In view of its pharmacological profile, abexinostat is intended for use in the treatment of cancer.
- From the industrial point of view it is imperative to be able to synthesise the compound with excellent purity, especially in a perfectly reproducible form, having valuable characteristics of dissolution, filtration, drying, ease of formulation and stability allowing its prolonged storage without particular requirements for temperature, light, humidity or oxygen levels.
- Patent application WO2004/092115 describes two different routes for obtaining abexinostat. In both cases, 3-methyl-benzofuran-2-carboxylic acid is used as starting material, but functionalisation of this central nucleus by the dimethylaminomethyl group in the 3-position is carried out at different stages in the synthesis process, namely before or after coupling of the benzofuran-2-carboxylic acid compound with methyl 4-(2aminoethoxy)benzoate. Obtaining abexinostat hydrochloride is specifically described in the WO2004/092115 application. However, using this salt on an industrial scale is problematic because of its hygroscopic properties.
- The present invention describes a process for obtaining abexinostat tosylate (abexinostat 4-methylbenzenesulfonate) in a well-defined, perfectly reproducible crystalline form having very good stability that is compatible with the industrial constraints of preparation (especially drying) and storage of pharmaceutical compositions.
- Crystalline form I of abexinostat tosylate is characterised by 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; 21.08; 27.05. Even more especially, crystalline form I of abexinostat tosylate is characterised by the following diffraction lines: 6.50; 9.94; 11.35; 12.33; 14.08; 18.95; 19.61; 19.96; 21.08; 22.82; 23.61; 27.05.
- More specifically, crystalline form I of abexinostat tosylate is characterised by the X-ray powder diffraction diagram hereinbelow, measured using a PANalytical X′Pert Pro MPD diffractometer with an X′Celerator detector and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ±0.2°) and interplanar distance d (expressed in Å):
-
Angle 2-theta Interplanar Line no. (degrees) distance (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 - Besides that, crystalline form I of abexinostat tosylate has been characterised by Raman spectroscopy. Significant peaks were observed at the following positions: 940 cm−1, 1088 cm−1, 1132 cm−1, 1242 cm−1, 1360 cm−1, 1608 cm−1.
- Alternatively, crystalline form 1 of abexinostat tosylate may be characterised by the X-ray powder diffraction diagram which includes the 12 significant lines given hereinabove and also by a Raman spectrum having a significant peak at the position 1608 cm−1.
- Finally, crystalline form I of abexinostat tosylate has also been characterised by solid-state NMR spectroscopy, Significant peaks were observed at 121.2 ppm, 122.1 ppm, 123.5 ppm, 126.0 ppm, 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.
- More specifically, the 13C CP/MAS (Cross Polarization Magic Angle Spinning) spectra have the following peaks (expressed in ppm±0.2 ppm):
-
Chemical shift Peak 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 - The invention relates also to a process for the preparation of crystalline form I of abexinostat tosylate, which process is characterised in that abexinostat is crystallised from a polar medium in the presence of paro-toluenesulphonic acid. Preferably, the polar medium is composed of one or more solvents selected from water, alcohols ketones and esters, it being understood that:
-
- “alcohols” means C1-C6 alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, 2-pentanol, 3-pentanol, isopentanol, hexanol,
- “ketones” means a C3-C6 ketone such as acetone, methyl ethyl ketone, 2-pentanone, 3-pentanone, 3-methyl-2-butanone, 2-hexanone, 3-hexanone, ethyl isopropyl ketone, methyl isopropyl ketone, 2,2-dimethyl-3-butanone,
- “esters” means C3-C8 ester such as ethyl formate, isopropyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tert-butyl acetate, pentyl acetate, isopentyl acetate, hexyl acetate.
- Preferred alcohols are ethanol and isopropanol. Among the preferred solvents preference will also be given to acetone and methyl ethyl ketone among the ketones and to ethyl acetate among the esters.
- Alternatively, the polar medium is a binary mixture, one of the constituents of which is water. Even more preferably, the polar medium is a binary mixture selected from: acetone/water, ethanol/water, isopropanol/water and methyl ethyl ketone/water.
- In the crystallisation process according to the invention, abexinostat (free base) obtained by any process may be used.
- The invention relates also to another process for the preparation of crystalline form I of abexinostat tosylate, in which process the crystallisation is seeded using a very small amount of crystalline form I of abexinostat tosylate.
- In this second crystallisation process according to the invention, abexinostat (free base) obtained by any process may also be used.
- Obtaining crystalline form I of abexinostat tosylate has the advantage of making it possible to prepare pharmaceutical formulations having a consistent and reproducible composition and having good characteristics of dissolution and stability, which is especially advantageous when the formulations are intended for oral administration. More specifically, use of crystalline form I of abexinostat tosylate is especially valuable in an industrial context in view of its low hygroscopicity.
- Crystalline form I of abexinostat tosylate is intended for the treatment of cancer, more especially the treatment of a carcinoma, a tumour, a neoplasm, a lymphoma, a melanoma, a glioma, a sarcoma or a blastoma.
- The invention relates also to pharmaceutical compositions comprising, as active ingredient, tosylate salt of abexinostat, even more especially crystalline form I of abexinostat tosylate, together with one or more appropriate, non-toxic, inert excipients. Among the pharmaceutical compositions according to the invention there may be more especially mentioned those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragées, granules, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions and chewing gums.
- Preference is given to pharmaceutical compositions administered via the oral route.
- The useful dosage varies according to the sex, age and weight of the patient, the administration route, the nature of the cancer and any associated treatments; the useful dosage ranges from 20 mg to 480 mg of N-hydroxy-4-{2-[3-(N,N-dimethylaminomethyl)-benzofuran-2-ylcarbonylamino]ethoxy}benzamide per day expressed in terms of the free base.
- The Examples hereinbelow illustrate the invention but do not limit it in any way.
- 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 I 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.
- 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.
- Recording of the data was carried out using a PANalytical X′Pert Pro MPD diffractometer with an X′Celerator detector under the following conditions:
-
- Voltage 45 kV, current 40 mA,
- Mounting: theta/theta,
- Anode: copper,
- K alpha-1 wavelength: 1.54060 Å,
- K alpha-2 wavelength: 1.54443 Å,
- K alpha-2/K alpha-1 ratio: 0.5,
- Measurement mode: continuous from 3° to 55° (Bragg's angle 2 theta) in increments of 0.017°,
- Measurement time per step: 35.53 s.
- 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 line). The significant lines have been collated in the following table:
-
Angle 2-theta Interplanar Relative Line no. (degrees) distance (Å) intensity (%) 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 - 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:
-
- crystal unit cell: triclinic
- unit cell parameters: a=10.467 Å, b=14.631 Å, c=20.159 Å, α=73.971°, β=79.040°, γ=72.683°
- space group: P-1
- number of molecules in the unit cell: 4
- volume of the unit cell: Vunit cell=2813.0 Å3
- density: d=1.345 g/cm3.
- Form I 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−1. The spectral range explored ranges from 0 to 3278 cm−1.
- Significant peaks were observed at the following positions: 940 cm−1, 1088 cm−1, 1132 cm−1, 1242 cm−1, 1360 cm−1, 1608 cm−1,
- Form I of abexinostat tosylate was also characterised by solid-state NMR spectroscopy. The 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:
-
- Frequency: 125.76 MHz,
- Spectral width: 40 kHz,
- Magic angle spinning rate of sample: 10 kHz,
- Pulse sequence: CP (Cross Polarization) with SPINAL64 decoupling (decoupling power: 80 kHz),
- Repetition delay: 10 s.
- Acquisition time: 35 ms,
- Contact time: 4 ms,
- Number of scans: 4096.
- 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).
- The peaks observed have been collated in the following table (expressed in ppm±0.2 ppm):
-
Chemical shift Peak 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 - Formula for the preparation of 1000 tablets each containing 100 mg of abexinostat (expressed in terms of the base equivalent):
-
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 - 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 per cent RH (relative humidity) and during two subsequent cycles of increasing and decreasing linear variations of relative humidity in the range 0-90 per cent RH at a rate of 10 per cent per hour. The relative humidity was maintained constant when it reached either 0 or 90 per cent RH until the mass variation was less than 0.002 per cent per minute within a limit of time of 15 h.
- 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.
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US15/405,021 US10150748B2 (en) | 2013-03-04 | 2017-01-12 | Salt or abexinostat, associated crystalline form, a process for their preparation and pharmaceutical compositions containing them |
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US14/195,186 US9115108B2 (en) | 2013-03-04 | 2014-03-03 | Salt of abexinostat, associated crystalline form, a process for their preparation and pharmaceutical compositions containing them |
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AU2011261185A1 (en) | 2010-06-03 | 2013-01-10 | Pharmacyclics, Inc. | The use of inhibitors of Bruton's tyrosine kinase (Btk) |
KR20150032340A (en) | 2012-07-24 | 2015-03-25 | 파마시클릭스, 인코포레이티드 | Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (btk) |
CA2888960C (en) | 2012-11-02 | 2017-08-15 | Pfizer Inc. | Bruton's tyrosine kinase inhibitors |
FR3002733B1 (en) | 2013-03-04 | 2015-08-14 | Servier Lab | NOVEL SALT OF THE ABEXINOSTAT, THE CRYSTALLINE FORM ASSOCIATED WITH THEM, THE PROCESS FOR PREPARING THEM AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
CA2942528A1 (en) | 2014-03-20 | 2015-09-24 | Pharmacyclics Inc. | Phospholipase c gamma 2 and resistance associated mutations |
FR3025196B1 (en) * | 2014-09-03 | 2019-09-06 | Pharmacyclics, Inc. | NOVEL 3 - [(DIMETHYLAMINO) METHYL] -N- {2- [4- (HYDROXYCARBAMOYL) PHENOXY] ETHYL} -1-BENZOFURAN-2-CARBOXAMIDE SALTS, ASSOCIATED CRYSTALLINE FORMS, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS THEREOF CONTAIN |
KR20170043648A (en) * | 2014-09-03 | 2017-04-21 | 파마싸이클릭스 엘엘씨 | 3-[]-n-2-[4-]-1--2- novel salts of 3-dimethylaminomethyl-n-2-[4-hydroxycarbamoylphenoxy]ethyl-1-benzofuran-2-carboxamide related crystalline forms method for preparing the same and pharmaceutical compositions containing the same |
FR3025197B1 (en) * | 2014-09-03 | 2019-09-06 | Pharmacyclics, Inc. | NOVEL SALT OF 3 - [(DIMETHYLAMINO) METHYL] -N- {2- [4- (HYDROXYCARBAMOYL) PHENOXY] ETHYL} -1-BENZOFURAN-2-CARBOXAMIDE, ASSOCIATED CRYSTALLINE FORMS, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS THEREOF CONTAIN |
WO2017011314A1 (en) * | 2015-07-10 | 2017-01-19 | Paharmacyclics Llc | Btk and hdac combinations |
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