WO2019008126A1 - New crystalline form of a bcl-2 inhibitor, a process for its preparation and pharmaceutical compositions containing it - Google Patents
New crystalline form of a bcl-2 inhibitor, a process for its preparation and pharmaceutical compositions containing it Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the invention relates to crystalline form II of N-(4-hydroxyphenyl)-3 - ⁇ 6- [((3 S)-3 -(4- mo holinylmethyl)-3,4-dihydro-2(lH)-isc ⁇ uinolinyl)carbonyl]-l ,3-benzodio ol-5-yl ⁇ -N- phenyl-5,6,7,8-tetrahydro-l-indolizine carboxamide hydrochloride, referred to herein as 'Compound A.HCF, and pharmaceutical compositions for oral administration comprising said crystalline form II.
- the invention also relates to the use of such compositions for the treatment of cancer, diseases of the immune system and auto-immune diseases.
- the present invention also describes a process for obtaining Compound A.HC1 in a well-defined, perfectly reproducible crystalline form having very good stability that is compatible with the industrial constraints of preparation, especially filtration, and storage of pharmaceutical compositions.
- Figure 1 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form II.
- Figure 2 shows the solid-state 13 C NMR spectrum of Compound A. HC1 crystalline form
- Figure 3 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form I.
- Figure 4 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form IV.
- Figure 5 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form V.
- composition for oral administration means for example a tablet, a dragee, a granule, a sublingual tablet, a capsule or a lozenge, in particular a tablet. Such tablet may optionally be film-coated.
- 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 50 mg to 1500 mg of Compound A.HC1 per day expressed in terms of the free base. 'Compound A.
- HO' or 'Compound A.HC1 salt' means the hydrochloride salt of N-(4- hydroxyphenyl)-3- ⁇ 6-[((35)-3-(4-morpholinylmethyl)-3,4-dihydro-2(lH)- isoquinolinyl)carbonyl]-l,3-benzodioxol-5-yl ⁇ -N-phenyl-5,6,7,8-tetrahydro-l-indolizine carboxamide.
- the term 'comprising' means 'including', and is not intended to exclude the presence of any additional component, unless the context suggests otherwise, for example when the components together sum to 100%.
- alcohols means Ci-C 6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol, 2-pentanol, 3-pentanol, isopentanol, hexanol.
- ketones means a C 3 -C 6 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 C 3 -Cg ester such as ethyl formate, isopropyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ferf-butyl acetate, pentyl acetate, isopentyl acetate, hexyl acetate.
- 'Cancer' means a class of disease in which a group of cells display uncontrolled growth. Cancer types include haematological cancer (lymphoma and leukemia) and solid tumors including carcinoma, sarcoma, or blastoma. 'Cancer' includes cancer of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.
- 'free molecule' and 'free base' are used interchangeably herein and refer to Compound A when not in salt form.
- HCl characterised in that it has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14 or all of the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ⁇ 0.2°): 4.09; 8.19; 9.15; 10.82; 12.83; 15.23; 15.47; 16.40; 19.17; 19.87; 20.39; 20.88; 21.76; 23.19; 24.06.
- HCl according to E2, characterised 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°): 4.09; 9.15; 10.82; 12.83; 15.47.
- E6 Crystalline form II of Compound A. HC1 according to any of El to E5, characterised in that it has a solid-state l3 C CP/MAS NMR spectrum having the following peaks (expressed in ppm ⁇ 0.2 ppm): 170.6 ppm, 140.9 ppm, 1 13.0 ppm, 107.2 ppm, 104.5 ppm, 62.0 ppm, 60.4 ppm, 32.1 ppm, 25.0 ppm, 22.5 ppm, 18.7 ppm.
- E7 Crystalline form II of Compound A. HC1 according to any of El to E6 which is a monohydrate.
- composition comprising as active ingredient crystalline form II of Compound A. HC1 according to any one of El to E7 in association with one or more pharmaceutically acceptable excipients.
- composition according to E9 wherein the cancer is selected from the bladder, brain, breast and uterus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small- cell lung cancer, prostate cancer and small-cell lung cancer.
- E16 Process for the preparation of crystalline form II of Compound A. HC1 according to El 5, wherein the polar medium is a binary mixture selected from: isopropanol/water, n- propanol/water, n-butanol/water, DMSO/water and acetone/water.
- E17 Process for the preparation of crystalline form II of Compound A. HC1 according to El 6, wherein the percent of water in the binary mixture is comprised between 10 to 50 % in weight.
- crystalline form II of Compound A.HC1 has the advantage of making it possible to prepare pharmaceutical formulations having a consistent and reproducible composition and having good characteristics of stability. More specifically, crystalline form II of Compound A.HC1 obtained through a crystallisation step at a temperature of 60°C is especially valuable in an industrial context in view of its filtration property. Furthermore, the crystalline form II of Compound A. HC1 thereby obtained is sufficiently stable to allow its storage for an extended period without particular conditions for temperature, light, humidity or oxygen levels. In particular, the crystalline form II of Compound A. HC1 has been found to be very stable over periods of up to 18 months under at 25 °C with a humidity level of 60% in an airtight glass bottle.
- Example 1 Process for obtaining crystalline form II of Compound A. HC1
- Example 2 Process for obtaining crystalline form II of Compound A.
- HC1 seeding 1 kg of Compound A (free base) was placed in 4.711 kg of isopropanol at ambient temperature. The mixture was then heated at 60°C. A hydrochloric solution (0.197 kg of HC1 10N + 1.4 kg of water) was then added. The mixture was stirred for 30 minutes, before being seeded with crystalline form II of Compound A. HC1 (1% to 2% in weight of starting material). The mixture was further stirred for 60 minutes and was cooled to 10°C. When the crystallisation was complete, the suspension was filtered, washed with water and dried at 50°C. After drying, crystalline form II of Compound A. HC1 was obtained in a yield of about 80% and with a purity greater than 97%. The solid was characterised by the X-ray powder as set out in Example 4.
- the seeding step with crystalline form II of Compound A. HC1 was performed before the addition of the hydrochloric solution.
- Example 4 Crystalline form II of Compound A. HCl (X-ray powder diffraction diagram)
- Measurement mode continuous from 3° to 55° (Bragg's angle 2 theta) in increments of 0.017°, Measurement time per step: 34.9250 s.
- Example 5 Tablet comprising Compound A.HC1 (standard formulation)
- Example 1 The product obtained in Example 1 or 2 is then micronised before being blended with excipients as follows:
- the micronised product is mixed with sodium lauryl sulfate. Then, the premix is added to microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and hydroxypopylcellulose. The mixing is granulated using wet granulation (conventional manufacturing process) in a planetary granulator. After being dried in the planetary granulator or in an oven system, the granulate is sifted. Magnesium stearate (lubricant) and silica (glidant) are then added for the external phase: the lubricated granulate is sifted and compressed to obtain the tablets. Finally, tablets are film-coated with a white premix (Sepifilm No. 37781 RBC).
- composition per tablet with film coating (% weight per weight of tablet):
- the hygroscopicity of crystalline form II of Compound A. HCl was assessed using the dynamic vapour sorption (DVS) technique. 5 to 10 mg of the micronised drug substance test sample were accurately weighed into a DVS sample pan working at 25°C under controlled humidity. The mass of the sample was recorded at 50 per cent RH (relative humidity) until reaching a stable value. Thereafter the mass variation was recorded between 50 per cent RH and 90 per cent RH at a rate of 10 per cent per hour. Mass variations were also recorded between 90 per cent RH and 0 per cent RH and from 0 per cent RH back to 50 per cent RH. 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.
- DVS dynamic vapour sorption
- a decrease in sample mass was of approximately 1.0 per cent was recorded between 90% to 0% RH, whilst an increase in sample mass of approximately 0.5 per cent was recorded between 0% to 50% RH.
- the DVS profile shows that water sorption and desorption are perfectly reversible.
- HC1 can be considered as being slightly hygroscopic according to the European Pharmacopoeia (Ph. Eur.).
- the water content of micronised crystalline form II of Compound A. HC1 was determined by coulometric titration using a Metrohm Coulometer composed of a 774 oven sample processor, a 774 SC controller, 831 KF coulometer and a 846 Dosing interface with Tiamo 1.2 software. About 10 mg of accurately weighed micronised drug substance were introduced in vials heated for 10 min at 140 °C.
- the water content in the test samples amounted to 2.5% in weight, corresponding to a monohydrate.
- Crystalline form II of Compound A HCl remains stable towards temperature and humidity after an 18 -month storage period at 25°C with a humidity level of 60% in airtight glass bottles and after a 6-month storage period in open glass bottles in various conditions.
- a 24-month storage period in airtight glass bottles at 25 °C/60 % RH a 12-month storage period in airtight glass bottles at 30°C/65 % RH
- a 6-month storage period in open glass bottles at 25°C/90 % RH and 40°C/75 % RH and after a 6-week storage period in airtight and open glass bottles at 70°C the physical parameters tested such as identification by IR and water content did not show significant signs of modifications in relation to the initial control.
- the chemical parameters no significant increase of the related substances nor the isomer content was observed.
- the drug substance content (determined using LC) remained constant over storage in airtight or
- Compound A HCl crystalline form II can be defined by the presence of the following peaks in the NMR spectrum (expressed in ppm ⁇ 0.2 ppm):
- Example 10 Process for obtaining crystalline form I of Compound A. HCl and X-ray powder diffraction diagram of the same
- the solid was isolated by filtration and dried during 15 hours at 50°C.
- the solid was characterised by the X-ray powder as described below.
- Example 11 Process for obtaining crystalline form IV of Compound A. HCl and X- ray powder diffraction diagram of the same
- Measurement mode continuous from 3° to 55° (Bragg's angle 2 theta) in increments of 0.017°
- Example 12 Process for obtaining crystalline form V of Compound A. HC1 and X- ray powder diffraction diagram of the same
- HC1 amorphous or crystalline
- ethanol/water 50/50 10 mL
- This suspension was heated to reflux during 15 minutes.
- This solution was cooled to 30°C and 5 mL of ethanol/water 50/50 was added.
- the suspension was cooled to 5°C.
- the solid was isolated by filtration and dried during 15 hours at 40°C.
- the solid was characterised by the X-ray powder as described below.
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Abstract
L'invention concerne la forme cristalline II du composé A.HCl : (formule) caractérisée par son diagramme de diffraction de rayons X sur poudres et le spectre RMN 13C à l'état solide, et des compositions pharmaceutiques la contenant.The invention relates to the crystalline form II of the compound A.HCl: (formula) characterized by its X-ray powder diffraction pattern and the 13C NMR spectrum in the solid state, and pharmaceutical compositions containing it.
Description
NEW CRYSTALLINE FORM OF A BCL-2 INHIBITOR,
A PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT
BACKGROUND OF THE INVENTION
The invention relates to crystalline form II of N-(4-hydroxyphenyl)-3 - { 6- [((3 S)-3 -(4- mo holinylmethyl)-3,4-dihydro-2(lH)-isc }uinolinyl)carbonyl]-l ,3-benzodio ol-5-yl}-N- phenyl-5,6,7,8-tetrahydro-l-indolizine carboxamide hydrochloride, referred to herein as 'Compound A.HCF, and pharmaceutical compositions for oral administration comprising said crystalline form II. The invention also relates to the use of such compositions for the treatment of cancer, diseases of the immune system and auto-immune diseases.
The chemical structure of Compound A is:
Its preparation, its use as a Bcl-2 inhibitor for the treatment of cancer and pharmaceutical formulations thereof are described in WO 2013/1 10890 (Example 1), the content of which is incorporated by reference. The preparation of Compound A in the form of a hydrochloride salt ('Compound A.HCF) is specifically disclosed in this document. It is obtained as a lyophilisate.
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.
The present invention also describes a process for obtaining Compound A.HC1 in a well-defined, perfectly reproducible crystalline form having very good stability that is compatible with the industrial constraints of preparation, especially filtration, and storage of pharmaceutical compositions.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form II.
Figure 2 shows the solid-state 13C NMR spectrum of Compound A. HC1 crystalline form
II.
Figure 3 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form I.
Figure 4 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form IV.
Figure 5 shows the X-ray powder diffraction pattern (XPRD) of Compound A. HC1 crystalline form V.
DETAILED DESCRIPTION OF THE INVENTION
The term 'pharmaceutical composition for oral administration' means for example a tablet, a dragee, a granule, a sublingual tablet, a capsule or a lozenge, in particular a tablet. Such tablet may optionally be film-coated. 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 50 mg to 1500 mg of Compound A.HC1 per day expressed in terms of the free base. 'Compound A. HO' or 'Compound A.HC1 salt' means the hydrochloride salt of N-(4- hydroxyphenyl)-3-{6-[((35)-3-(4-morpholinylmethyl)-3,4-dihydro-2(lH)-
isoquinolinyl)carbonyl]-l,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-l-indolizine carboxamide.
As used herein, the term 'comprising' means 'including', and is not intended to exclude the presence of any additional component, unless the context suggests otherwise, for example when the components together sum to 100%.
The term "alcohols" means Ci-C6 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol, 2-pentanol, 3-pentanol, isopentanol, hexanol.
The term "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.
The term "esters" means C3-Cg ester such as ethyl formate, isopropyl formate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ferf-butyl acetate, pentyl acetate, isopentyl acetate, hexyl acetate.
'Cancer' means a class of disease in which a group of cells display uncontrolled growth. Cancer types include haematological cancer (lymphoma and leukemia) and solid tumors including carcinoma, sarcoma, or blastoma. 'Cancer' includes cancer of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer.
'free molecule' and 'free base' are used interchangeably herein and refer to Compound A when not in salt form.
Embodiments of the invention
Described below are a number of embodiments of the invention. EL Crystalline form II of N-(4-hydroxyphenyl)-3-{6-[((35)-3-(4-morpholinylmethyl)- 3 ,4-dihydro-2( lH)-isoquinolinyl)carbonyl] - 1 ,3 -benzodioxol-5-yl } -N-phenyl-5,6,7,8- tetrahydro- 1 -indolizine carboxamide hydrochloride (Compound A. HCl) showing at least
the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 15.23 and 15.47.
E2. Crystalline form II of N-(4-hydroxyphenyl)-3-{6-[((3S)-3-{4-morpholinylmethyl)- 3,4-dihydro-2(lH)-isoquinolinyl)carbonyl]-l,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8- tetrahydro- 1 -indolizine carboxamide hydrochloride (Compound A. HCl), characterised in that it has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14 or all of the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 4.09; 8.19; 9.15; 10.82; 12.83; 15.23; 15.47; 16.40; 19.17; 19.87; 20.39; 20.88; 21.76; 23.19; 24.06. E3. Crystalline form II of Compound A. HCl according to E2, characterised 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°): 4.09; 9.15; 10.82; 12.83; 15.47.
E4. Crystalline form II of Compound A. HCl according to E2, characterised 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°): 4.09; 8.19; 9.15; 10.82; 12.83; 15.23; 15.47; 16.40; 19.17; 19.87; 20.39; 20.88; 21.76; 23.19; 24.06.
E5. Crystalline form II of Compound A. HCl according to E4, characterised in that it has the following X-ray powder diffraction diagram, 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 A):
Angle 2-theta Interplanar
Line no.
(degrees) distance (A)
1 4.09 21.61
2 8.19 10.80
3 9.15 9.67
4 10.82 8.18
5 12.83 6.90
6 15.23 5.82
7 15.47 5.73
8 16.40 5.40
9 19.17 4.63
10 19.87 4.47
11 20.39 4.35
12 20.88 4.25
13 21.76 4.08
14 23.19 3.84
15 24.06 3.70
E6. Crystalline form II of Compound A. HC1 according to any of El to E5, characterised in that it has a solid-state l3C CP/MAS NMR spectrum having the following peaks (expressed in ppm ± 0.2 ppm): 170.6 ppm, 140.9 ppm, 1 13.0 ppm, 107.2 ppm, 104.5 ppm, 62.0 ppm, 60.4 ppm, 32.1 ppm, 25.0 ppm, 22.5 ppm, 18.7 ppm. E7. Crystalline form II of Compound A. HC1 according to any of El to E6 which is a monohydrate.
E8. Pharmaceutical composition comprising as active ingredient crystalline form II of Compound A. HC1 according to any one of El to E7 in association with one or more pharmaceutically acceptable excipients. E9. Pharmaceutical composition according to E8 for use in the treatment of cancers, auto-immune diseases and diseases of the immune system.
E1Q. Pharmaceutical composition according to E9, wherein the cancer is selected from the bladder, brain, breast and uterus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small- cell lung cancer, prostate cancer and small-cell lung cancer.
Ell. Process for the preparation of crystalline form II of Compound A. HC1 according to any one of E l to E7, wherein Compound A. HC1 is crystallised in a polar medium.
E12. Process for the preparation of crystalline form II of Compound A. HC1 according to El 1, wherein the polar medium is composed of one or more solvents selected from water, DMSO, nitrobenzene, alcohols, ketones and esters.
E13. Process for the preparation of crystalline form II of Compound A. HC1 according to El 2, wherein the ketone is acetone.
E14. Process for the preparation of crystalline form II of Compound A. HQ according to El 2, wherein the alcohol is selected from methanol, isopropanol, n-propanol and n- butanol.
E15. Process for the preparation of crystalline form II of Compound A. HC1 according to El 2, wherein the polar medium is a binary mixture, one of the constituents of which is water.
E16. Process for the preparation of crystalline form II of Compound A. HC1 according to El 5, wherein the polar medium is a binary mixture selected from: isopropanol/water, n- propanol/water, n-butanol/water, DMSO/water and acetone/water. E17. Process for the preparation of crystalline form II of Compound A. HC1 according to El 6, wherein the percent of water in the binary mixture is comprised between 10 to 50 % in weight.
E18. Process for the preparation of crystalline form II of Compound A. HC1 according to any one of El 1 to El 7, in which process the crystallisation is seeded using a very small amount of crystalline form II of Compound A. HC1.
E19. Process for the preparation of crystalline form II of Compound A. HC1 according to El 8, wherein the crystallisation is seeded at a temperature comprised between 20°C and
E20. Process for the preparation of crystalline form II of Compound A. HC1 according to El 9, wherein the crystallisation is seeded at 60°C.
Obtaining crystalline form II of Compound A.HC1 has the advantage of making it possible to prepare pharmaceutical formulations having a consistent and reproducible composition and having good characteristics of stability. More specifically, crystalline form II of Compound A.HC1 obtained through a crystallisation step at a temperature of 60°C is especially valuable in an industrial context in view of its filtration property. Furthermore, the crystalline form II of Compound A. HC1 thereby obtained is sufficiently stable to allow its storage for an extended period without particular conditions for temperature, light, humidity or oxygen levels. In particular, the crystalline form II of Compound A. HC1 has been found to be very stable over periods of up to 18 months under at 25 °C with a humidity level of 60% in an airtight glass bottle.
The Examples hereinbelow illustrate the invention but do not limit it in any way.
Example 1: Process for obtaining crystalline form II of Compound A. HC1
1 kg of Compound A (free base) was placed in 4.711 kg of isopropanol at ambient temperature. The mixture was then heated at 60°C. A hydrochloric solution (0.197 kg of HC1 10N + 1.4 kg of water) was then added. The mixture was stirred for 90 minutes before being cooled to 10°C. When the crystallisation was complete, the suspension was filtered, washed with water and dried at 50°C. After drying, crystalline form II of Compound A. HC1 was obtained in a yield of about 85% and with a purity greater than 97%. The solid was characterised by the X-ray powder as set out in Example 4.
In the crystallisation process according to the invention, Compound A (free base) obtained by any process may be used.
Example 2; Process for obtaining crystalline form II of Compound A. HC1 (seeding) 1 kg of Compound A (free base) was placed in 4.711 kg of isopropanol at ambient temperature. The mixture was then heated at 60°C. A hydrochloric solution (0.197 kg of HC1 10N + 1.4 kg of water) was then added. The mixture was stirred for 30 minutes,
before being seeded with crystalline form II of Compound A. HC1 (1% to 2% in weight of starting material). The mixture was further stirred for 60 minutes and was cooled to 10°C. When the crystallisation was complete, the suspension was filtered, washed with water and dried at 50°C. After drying, crystalline form II of Compound A. HC1 was obtained in a yield of about 80% and with a purity greater than 97%. The solid was characterised by the X-ray powder as set out in Example 4.
In this second crystallisation process according to the invention, Compound A (free base) obtained by any process may also be used.
In an alternative process, the seeding step with crystalline form II of Compound A. HC1 was performed before the addition of the hydrochloric solution.
Example 3: Alternative process for obtaining crystalline form II of Compound A. HC1
60 mg of amorphous Compound A. HC1 was dissolved in 1 mL of nitrobenzene. The resulting mixture was then heated at 60°C with magnetic stirring (700rpm) and held at this temperature for lh. The resulting suspension was cooled to 10°C at a rate of 0.1°C/min. When the crystallisation was complete, the suspension was filtered and dried under vacuum (10 mbar) over 2 hours at 25°C. The solid was characterised by the X-ray powder as set out in Example 4.
Example 4: Crystalline form II of Compound A. HCl (X-ray powder diffraction diagram)
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 A,
- K alpha-2 wavelength: 1.54443 A,
- 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: 34.9250 s.
The X-ray powder diffraction diagram of form II of Compound A. HC1 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 A) and relative intensity (expressed as a percentage relative to the most intense line) (Figure 1). The significant lines have been collated in the following table:
Example 5: Tablet comprising Compound A.HC1 (standard formulation)
The product obtained in Example 1 or 2 is then micronised before being blended with excipients as follows:
The micronised product is mixed with sodium lauryl sulfate. Then, the premix is added to microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and hydroxypopylcellulose. The mixing is granulated using wet granulation (conventional manufacturing process) in a planetary granulator. After being dried in the planetary granulator or in an oven system, the granulate is sifted. Magnesium stearate (lubricant) and silica (glidant) are then added for the external phase: the lubricated granulate is sifted and
compressed to obtain the tablets. Finally, tablets are film-coated with a white premix (Sepifilm No. 37781 RBC).
Composition per tablet with film coating (% weight per weight of tablet):
Compound A.HC1 15.17% Cellulose microcrystalline 22.72%
Croscarmellose sodium 2.90%
Hydroxypropylcellulose 6.77%
Lactose monohydrate 45.04%
Sodium laurylsulfate 2.90% Magnesium stearate 0.97%
Silica, colloidal anhydrous 0.19%
Film coating
Glycerol 0.15%
Hypromellose 2.43% Macrogol 6000 0.16%
Magnesium stearate 0.15%
Titanium dioxide 0.47%
Example 6; Hygroscopicity
The hygroscopicity of crystalline form II of Compound A. HCl was assessed using the dynamic vapour sorption (DVS) technique. 5 to 10 mg of the micronised drug substance test sample were accurately weighed into a DVS sample pan working at 25°C under controlled humidity. The mass of the sample was recorded at 50 per cent RH (relative
humidity) until reaching a stable value. Thereafter the mass variation was recorded between 50 per cent RH and 90 per cent RH at a rate of 10 per cent per hour. Mass variations were also recorded between 90 per cent RH and 0 per cent RH and from 0 per cent RH back to 50 per cent RH. 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 sample mass of approximately 0.5 per cent was recorded by DVS analysis when a sample was exposed to relative humidities from 50% to 90% at 25°C.
A decrease in sample mass was of approximately 1.0 per cent was recorded between 90% to 0% RH, whilst an increase in sample mass of approximately 0.5 per cent was recorded between 0% to 50% RH.
The DVS profile shows that water sorption and desorption are perfectly reversible.
Crystalline form II of Compound A. HC1 can be considered as being slightly hygroscopic according to the European Pharmacopoeia (Ph. Eur.).
By contrast, an increase in sample mass of approximately 4.2 per cent was recorded by DVS analysis when a sample of the amorphous form of Compound A. HC1 was exposed to relative humidities from 50% to 90% at 25°C.
Example 7; Coulometric titration
The water content of micronised crystalline form II of Compound A. HC1 was determined by coulometric titration using a Metrohm Coulometer composed of a 774 oven sample processor, a 774 SC controller, 831 KF coulometer and a 846 Dosing interface with Tiamo 1.2 software. About 10 mg of accurately weighed micronised drug substance were introduced in vials heated for 10 min at 140 °C.
The water content in the test samples amounted to 2.5% in weight, corresponding to a monohydrate.
Example 8; Stability Studies
For all storage conditions and storage periods, 20 mg of micronised crystalline form II of Compound A. HC1 were introduced in a 30-mL vial for post-storage HPLC analysis.
Packaging : Open Glass Bottle
drug substance content determined by LC (% m/m)
N.D: Not Determined
Packaging : Airtight Glass Bottle
drug substance content determined by LC (% m/m)
N.D: Not Determined
Crystalline form II of Compound A. HCl remains stable towards temperature and humidity after an 18 -month storage period at 25°C with a humidity level of 60% in airtight glass bottles and after a 6-month storage period in open glass bottles in various conditions.
After a 24-month storage period in airtight glass bottles at 25 °C/60 % RH, a 12-month storage period in airtight glass bottles at 30°C/65 % RH, a 6-month storage period in airtight glass bottles at 40°C/75 % RH and 50°C, a 6-month storage period in open glass bottles at 25°C/90 % RH and 40°C/75 % RH and after a 6-week storage period in airtight and open glass bottles at 70°C, the physical parameters tested such as identification by IR and water content did not show significant signs of modifications in relation to the initial control. Regarding the chemical parameters, no significant increase of the related substances nor the isomer content was observed. The drug substance content (determined using LC) remained constant over storage in airtight or open bottles at all conditions.
Example 9: Crystalline form II of Compound A. HCl (solid NMR Spectrum)
Form II of Compound A. HCl was also characterised by solid-state Nuclear Magnetic Resonance spectroscopy (Figure 2). The solid-state l3C NMR spectrum of Compound A. HCl crystalline form II was recorded at ambient temperature using a Bruker SB Avance III 500 spectrometer with a 4-mm CP/MAS SB VTN type probe under the following conditions:
Frequency: 125.7 MHz
Spectral width: 37.5 kHz
Magic angle spinning rate: 13 kHz
Pulse program: Cross Polarization with SPINAL64 decoupling
Recycle delay: 10 s
Acquisition time: 46 ms
Contact time: 4 ms
Number of scans: 4096
The spectrum thereby obtained was referenced relative to a sample of adamantane (the high frequency peak of adamantane is set to 38.48 ppm).
Compound A HCl crystalline form II can be defined by the presence of the following peaks in the NMR spectrum (expressed in ppm ± 0.2 ppm):
Example 10: Process for obtaining crystalline form I of Compound A. HCl and X-ray powder diffraction diagram of the same
lg of Compound A. HCl (amorphous or crystalline) was suspended in water (10 mL) at room temperature. This suspension was heated to reflux during 1 hour. Then, this suspension was cooled to 25°C with a cooling rate of 0.5°C/min.
At 25°C, the solid was isolated by filtration and dried during 15 hours at 50°C. The solid was characterised by the X-ray powder as described below.
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 A,
- K alpha-2 wavelength: 1.54443 A,
- K alpha-2/K alpha- 1 ratio : 0.5,
- Measurement mode: continuous from 3° to 55° (Bragg's angle 2 theta) in increments of0.017°,
- Measurement time per step: 34.9250 s.
The X-ray powder diffraction diagram of form I of Compound A. HC1 is expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ±0.2°), interplanar distance (expressed in A) and relative intensity (expressed as a percentage relative to the most intense line) (Figure 3). The significant lines have been collated in the following table:
Example 11: Process for obtaining crystalline form IV of Compound A. HCl and X- ray powder diffraction diagram of the same
lg of Compound A. HCl (amorphous or crystalline) was suspended in ethanol (11 mL) at room temperature. This suspension was heated to reflux and 0,7 mL of methanol was added in order to obtain a solution. After 40 minutes, this solution was distilled out completely under vacuum at 40°C. The solid obtained was washed by 4 mL of cold
ethanol. The product was dried during 15 hours at 40°C. The solid was characterised by the X-ray powder as described below.
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 A,
- K alpha-2 wavelength: 1.54443 A,
- 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: 34.9250 s.
The X-ray powder diffraction diagram of form IV of Compound A. HCl is expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ±0.2°), interplanar distance (expressed in A) and relative intensity (expressed as a percentage relative to the most intense line) (Figure 4). The significant lines have been collated in the following table:
Angle 2-theta Interplanar
Line no.
(degrees) distance (A)
1 5.43 16.27
2 7.01 12.61
3 8.45 10.47
4 10.89 8.13
5 12.93 6.85
6 13.12 6.75
7 14.96 5.92
8 15.08 5.87
9 16.32 5.43
10 17.42 5.09
11 19.83 4.48
12 20.20 4.40
13 20.42 4.35
14 20.79 4.27
15 22.20 4.00
Example 12: Process for obtaining crystalline form V of Compound A. HC1 and X- ray powder diffraction diagram of the same
lg of Compound A. HC1 (amorphous or crystalline) was suspended in ethanol/water 50/50 (10 mL) at room temperature. This suspension was heated to reflux during 15 minutes. This solution was cooled to 30°C and 5 mL of ethanol/water 50/50 was added. The suspension was cooled to 5°C. After 15 minutes, the solid was isolated by filtration and dried during 15 hours at 40°C. The solid was characterised by the X-ray powder as described below.
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 A,
- K alpha-2 wavelength: 1.54443 A,
- 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: 34.9250 s.
The X-ray powder diffraction diagram of form V of Compound A. HCl is expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ±0.2°), interplanar distance (expressed in A) and relative intensity (expressed as a percentage relative to the most intense line) (Figure 5). The significant lines have been collated in the following table:
Angle 2-ttaeta Interplanar
Line no.
(degrees) distance (A)
1 3.97 22.27
2 7.96 1 1.1 1
3 8.76 10.10
4 9.67 9.15
5 10.77 8.21
6 1 1.1 1 7.97
7 13.69 6.47
8 14.83 5.97
9 16.09 5.51
10 16.65 5.32
11 17.83 4.97
12 21.65 4.11
13 21.93 4.05
14 23.26 3.82
15 28.13 3.17
Claims
1. Crystalline form II of N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)- 3,4-dihydro-2(lH)-isoquinolinyl)carbonyl]-l ,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8- tetrahydro- 1 -indolizine carboxamide hydrochloride (Compound A. HCl) showing at least the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 15.23 and 15.47.
2. Crystalline form II of N-(4-hydroxyphenyl)-3-{6-[((35)-3-(4-morpholinylmethyl)- 3,4-dihydro-2(lH)-isoquinolinyl)carbonyl]-l ,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8- tetrahydro-1 -indolizine carboxamide hydrochloride (Compound A. HCl) characterised in that it has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or all of the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 4.09; 8.19; 9.15; 10.82; 12.83; 15.23; 15.47; 16.40; 19.17; 19.87; 20.39; 20.88; 21.76; 23.19; 24.06.
3. Crystalline form II of Compound A. HCl according to claim 2, characterised 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°): 4.09; 9.15; 10.82; 12.83; 15.47.
4. Crystalline form II of Compound A. HCl according to claim 2, characterised 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°): 4.09; 8.19; 9.15; 10.82; 12.83; 15.23; 15.47; 16.40; 19.17; 19.87; 20.39; 20.88; 21.76; 23.19; 24.06.
5. Crystalline form II of Compound A. HCl according to claim 4, characterised in that it has the following X-ray powder diffraction diagram, 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 A):
Ang!e 2-theta Interplanar
Line no.
(degrees) distance (A)
1 4.09 21.61
2 8.19 10.80
3 9.15 9.67
4 10.82 8.18
5 12.83 6.90
6 15.23 5.82
7 15.47 5.73
8 16.40 5.40
9 19.17 4.63
10 19.87 4.47
11 20.39 4.35
12 20.88 4.25
13 21.76 4.08
14 23.19 3.84
15 24.06 3.70
6. Crystalline form II of Compound A. HCl according to any one of claims 1 to 5, characterised in that it has a solid-state 13C CP/MAS NMR spectrum having the following peaks (expressed in ppm ± 0.2 ppm): 170.6 ppm, 140.9 ppm, 113.0 ppm, 107.2 ppm, 104.5 ppm, 62.0 ppm, 60.4 ppm, 32.1 ppm, 25.0 ppm, 22.5 ppm, 18.7 ppm.
7. Crystalline form II of Compound A. HCl according to any of claims 1 to 6 which is a monohydrate.
8. Pharmaceutical composition comprising as active ingredient crystalline form II of Compound A. HCl according to one of claims 1 to 7 in association with one or more pharmaceutically acceptable excipients.
9. Pharmaceutical composition according to claim 8 for use in the treatment of cancers, auto-immune diseases and diseases of the immune system.
10. Pharmaceutical composition according to claim 9, wherein the cancer is selected from the bladder, brain, breast and uterus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the oesophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small- cell lung cancer, prostate cancer and small-cell lung cancer.
11. Process for the preparation of crystalline form II of Compound A. HCl according to one of claims 1 to 7, wherein Compound A. HCl is crystallised in nitrobenzene or in a binary mixture selected from: isopropanol/water, n-propanol/water, n-butanol/water, DMSO/water and acetone/water.
12. Process for the preparation of crystalline form II of Compound A. HCl according to claim 11, wherein the percent of water in the binary mixture is comprised between 10 to 50 % in weight.
13. Process for the preparation of crystalline form II of Compound A. HCl according to claim 11 or 12, in which process the crystallisation is seeded using a very small amount of crystalline form II of Compound A. HCl.
14. Process for the preparation of crystalline form II of Compound A. HCl according to claim 13, wherein the crystallisation is seeded at a temperature comprised between 20°C and 70°C.
15. Process for the preparation of crystalline form II of Compound A. HCl according to claim 14, wherein the crystallisation is seeded at 60°C.
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| WO2019134970A1 (en) * | 2018-01-05 | 2019-07-11 | Les Laboratoires Servier | Novel salts of a bcl-2 inhibitor,related crystalline forms,method for preparing the same and pharmaceutical compositions containing the same |
| US11311347B2 (en) | 2016-11-11 | 2022-04-26 | Intuitive Surgical Operations, Inc. | Teleoperated surgical system with surgical instrument wear tracking |
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Non-Patent Citations (2)
| Title |
|---|
| CAIRA ED - MONTCHAMP JEAN-LUC: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY; [TOPICS IN CURRENT CHEMISTRY], SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP008166276, ISSN: 0340-1022 * |
| JOHN F BAUER: "Pharmaceutical Solids- The Amorphous Phase", JOURNAL OF VALIDATION TECHNOLOGY, vol. 15, no. 3, 1 January 2009 (2009-01-01), Netherlands, pages 63 - 68, XP055280414 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11311347B2 (en) | 2016-11-11 | 2022-04-26 | Intuitive Surgical Operations, Inc. | Teleoperated surgical system with surgical instrument wear tracking |
| WO2019134970A1 (en) * | 2018-01-05 | 2019-07-11 | Les Laboratoires Servier | Novel salts of a bcl-2 inhibitor,related crystalline forms,method for preparing the same and pharmaceutical compositions containing the same |
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