OA20227A - Novel salt of A BCL-2 inhibitor, related crystalline form, method for preparing the same and pharmaceutical compositions containing the same. - Google Patents
Novel salt of A BCL-2 inhibitor, related crystalline form, method for preparing the same and pharmaceutical compositions containing the same. Download PDFInfo
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- OA20227A OA20227A OA1202100188 OA20227A OA 20227 A OA20227 A OA 20227A OA 1202100188 OA1202100188 OA 1202100188 OA 20227 A OA20227 A OA 20227A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 150000003839 salts Chemical class 0.000 title abstract description 4
- 239000011780 sodium chloride Substances 0.000 title abstract description 4
- 102100013894 BCL2 Human genes 0.000 title description 3
- 108060000885 BCL2 Proteins 0.000 title description 3
- 239000003112 inhibitor Substances 0.000 title description 3
- 230000002401 inhibitory effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 94
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical class OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims abstract description 67
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 21
- 238000010586 diagram Methods 0.000 claims abstract description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 29
- 235000011149 sulphuric acid Nutrition 0.000 claims description 29
- 201000011510 cancer Diseases 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 10
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000005712 crystallization Effects 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 8
- 206010003816 Autoimmune disease Diseases 0.000 claims description 7
- 206010024324 Leukaemias Diseases 0.000 claims description 7
- 206010025323 Lymphomas Diseases 0.000 claims description 7
- 210000000987 Immune System Anatomy 0.000 claims description 6
- 208000003950 B-Cell Lymphoma Diseases 0.000 claims description 5
- 210000004556 Brain Anatomy 0.000 claims description 5
- 210000000481 Breast Anatomy 0.000 claims description 5
- 206010008958 Chronic lymphocytic leukaemia Diseases 0.000 claims description 5
- 210000004185 Liver Anatomy 0.000 claims description 5
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 claims description 5
- 108009000071 Non-small cell lung cancer Proteins 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 208000008443 Pancreatic Carcinoma Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 claims description 5
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 5
- 108009000491 Small cell lung cancer Proteins 0.000 claims description 5
- 210000003932 Urinary Bladder Anatomy 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 201000011231 colorectal cancer Diseases 0.000 claims description 5
- 230000003211 malignant Effects 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 201000009251 multiple myeloma Diseases 0.000 claims description 5
- 201000003793 myelodysplastic syndrome Diseases 0.000 claims description 5
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 206010000880 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 206010012818 Diffuse large B-cell lymphoma Diseases 0.000 claims description 4
- 206010020243 Hodgkin's disease Diseases 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 239000000546 pharmaceutic aid Substances 0.000 claims description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000001875 carbon-13 cross-polarisation magic angle spinning nuclear magnetic resonance spectrum Methods 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 238000003860 storage Methods 0.000 description 11
- 239000012458 free base Substances 0.000 description 10
- 239000000523 sample Substances 0.000 description 9
- 238000000113 differential scanning calorimetry Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 238000001757 thermogravimetry curve Methods 0.000 description 5
- 239000004411 aluminium Substances 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000001117 sulphuric acid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- -1 éthanol Chemical compound 0.000 description 4
- 239000004698 Polyethylene (PE) Substances 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drugs Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010899 nucleation Methods 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- JYVLIDXNZAXMDK-UHFFFAOYSA-N 2-Pentanol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N Isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 206010025310 Other lymphomas Diseases 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N 1-Hexanol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 1
- AQIXEPGDORPWBJ-UHFFFAOYSA-N 3-Pentanol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 206010021425 Immune system disease Diseases 0.000 description 1
- PHTQWCKDNZKARW-UHFFFAOYSA-N Isoamyl alcohol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 1
- 238000005004 MAS NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 201000000053 blastoma Diseases 0.000 description 1
- 201000009030 carcinoma Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cells Anatomy 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 238000005388 cross polarization Methods 0.000 description 1
- 238000005384 cross polarization magic-angle spinning Methods 0.000 description 1
- 230000004059 degradation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 201000008184 embryoma Diseases 0.000 description 1
- 230000002489 hematologic Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N n-pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920003223 poly(pyromellitimide-1,4-diphenyl ether) Polymers 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000003595 spectral Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
Abstract
Novel salt and related crystalline forms of Compound A:
Description
NOVEL SALT OF A BCL-2 INHIBITOR, RELATED CRYSTALLINE FORM, METHOD FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
FIELD OFTHE INVENTION
The invention relates to a novel sait of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(lH)-yl]carbonyl} phenyl)-A/-(5-cyano-l,2-dimethyl-l/7-pyrrol-3-yl)-/V(4-hydroxyphenyl)-l,2-dimethyl-l/7-pyrrole-3-carboxamide, referred to herein as 'Compound A', or polymorphs or solvatés thereof, methods for preparing the same as well as pharmaceutical compositions thereof. In particular, the invention relates to the hydrogen sulfate sait of Compound A, referred to herein as 'Compound A, H2SO4', and the crystalline form I thereof. The présent invention further discloses a process for preparing said crystalline form and pharmaceutical compositions comprising said crystalline form. The invention also relates to the use of such compositions for the treatment of cancer, diseases ofthe immune System and auto-immune diseases. Last, an anhydrous crystalline form of Compound A, H2SO4 is disclosed.
BACKGROUND OF THE INVENTION
The Chemical structure of Compound A is:
Its préparation, its use as a Bcl-2 inhibitor for the treatment of cancer and pharmaceutical formulations thereof are described in WO 2015/011400 (Example 386), the content of which is incorporated by reference. The préparation of Compound A in the form of a hydrochloride sait ('Compound A.HCI') is specifically disclosed in this document. It is obtained as a lyophilisate.
Although Compound A is a very promising drug, it is a difficult compound to formulate. In particular, it is slightly soluble in water (< 0.01 mg/mL for the free base). As a Chemical substance can exhibit different physical properties being in one or another sait form or crystalline form thereof, this polymorphism of the drug molécule can affect the shelf life, solubility, formulation properties, processing properties, and the action of a drug. In addition, different polymorphs can hâve different rates of uptake in the body, leading to lower or higher biological activity than desired. In extreme cases, an undesired polymorph can even show toxicity. Understanding and controlling polymorphism, then, gives a decided advantage in bringing new drugs to the marketplace, which may be more active, more stable, or more cheaply manufactured. However, even though polymorphism has been a subject for intensive investigations, understanding and controlling this phenomenon represents a substantial scientific challenge. It is hard to predict whether a given molécule will crystallize in one or several crystal forms, and to find conditions leading to such crystallization.
From the industrial point of view, it is impérative to be able to synthesise the compound with excellent purity, and in particular in a highly reproducible form, having valuable characteristics of dissolution, filtration, drying, ease of formulation and stability enabling 20 the prolonged storage thereof without particular requirements for température, light, humidity or oxygen levels.
The présent invention also describes a process for obtaining Compound A, H2SO4 in a well-defined, perfectly reproducible crystalline form (Form I) having very good stability that is compatible with the industrial constraints of préparation, especially filtration, and 25 storage of pharmaceutical compositions.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the X-ray powder diffraction pattern (XPRD) of the crystalline form I of Compound A, H2SO4.
Figure 2 shows the X-ray powder diffraction pattern (XPRD) of the anhydrous crystalline form of Compound A, hydrogen sulfate sait.
Figure 3 shows the X-ray powder diffraction pattern (XPRD) of the crystalline form I of Compound A, hydrochloride sait
Figure 4 shows the DSC and TGA profiles of the crystalline form I of Compound A, hydrogen sulfate sait
Figure 5 shows the DSC and TGA profiles of the crystalline form I of Compound A, 10 hydrochloride sait
Figure 6 shows the solid-state 13C NMR spectrum of the crystalline form I of Compound A, H2SO4.
DETAILED DESCRIPTION OFTHE INVENTION
As used herein, the term 'comprising' means 'including', and is not intended to exclude 15 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-Ce alcohols such as methanol, éthanol, n-propanol, isopropanol, n-butanol, isobutanol, pentanol, 2-pentanol, 3-pentanol, isopentanol, hexanol.
'Cancer' means a class of disease in which a group of cells display uncontrolled growth. Cancer types include haematological cancers (lymphoma and leukemia) and solid tumors including carcinoma, sarcoma, or blastoma. 'Cancer' includes cancer of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas,
I for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
'free molécule' and 'free base' are used interchangeably herein and refer to Compound A when not in sait form.
Embodiments of the invention
Described below are a number of embodiments of the invention.
El. The hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(lH)-yl]carbonyl} phenyl)-/V-(5-cyano-l,2-dimethyl-l/-/-pyrrol-3-yl)-/V(4-hydroxyphenyl)-l,2-dimethyl-lH-pyrrole-3-carboxamide (Compound A, H2SO4).
E2. A crystalline form I of the hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/7)-yl]carbonyl} phenyl)-A/-(5-cyano-l,2dimethyl-lH-pyrrol-3-yl)-/\/-(4-hydroxyphenyl)-l,2-dimethyl-l/7-pyrrole-3-carboxamide (Compound A, H2SO4) according to El, wherein the crystalline form has an X-ray powder diffraction diagram showing the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55 ; 6.62 and 7.39.
E3. A crystalline form I of the hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl} phenyl)-/V-(5-cyano-l,2dimethyl-l/-/-pyrrol-3-yl)-A/-(4-hydroxyphenyl)-l,2-dimethyl-lH-pyrrole-3-carboxamide (Compound A, H2SO4) according to El, wherein the crystalline form has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or ail of the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55; 5.62; 6.62; 7.39; 10.17; 11.49; 11.83; 16.01; 16.54; 17.04; 18.98; 19.18; 21.90; 22.28; 24.89.
E4. The crystalline form I of the hydrogen sulfate sait of Compound A according to E3, characterized in that it has an X-ray powder diffraction diagram having the following !
diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55; 5.62; 6.62; 7.39; 10.17; 11.49; 11.83; 16.01; 16.54; 17.04; 18.98; 19.18; 21.90; 22.28; 24.89.
E5. The crystalline form I of the hydrogen sulfate sait of Compound A according to E4, characterized in that it has the following X-ray powder diffraction diagram, measured 5 using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector and expressed in terms of line position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and interplanar distances d (expressed in Â):
Line no. | Angle 2-theta (degrees) | Interplanar distance (Â) |
1 | 5.55 | 15.93 |
2 | 5.62 | 15.73 |
3 | 6.62 | 13.36 |
4 | 7.39 | 11.95 |
5 | 10.17 | 8.70 |
6 | 11.49 | 7.70 |
7 | 11.83 | 7.48 |
8 | 16.01 | 5.53 |
9 | 16.54 | 5.36 |
10 | 17.04 | 5.20 |
11 | 18.98 | 4.67 |
12 | 19.18 | 4.63 |
13 | 21.90 | 4.06 |
14 | 22.28 | 3.99 |
15 | 24.89 | 3.58 |
E6. The crystalline form I of the hydrogen sulfate sait of Compound A according to any one of El to E5, characterised in that it has a solid-state 13C CP/MAS NMR spectrum having the following peaks (expressed in ppm ± 0.2 ppm): 173.31 ppm, 155.32 ppm, 140.46 ppm, 139.19 ppm, 137.42 ppm, 134.68 ppm, 131.65 ppm, 131.14 ppm, 129.37 ppm, 126.32 ppm, 118.77 ppm, 117.36 ppm, 116.54 ppm, 113.61 ppm, 112.69 ppm,
110.74 ppm, 102.33 ppm, 101.45 ppm, 63.06 ppm, 57.19 ppm, 54.87 ppm, 52.06 ppm, 44.71 ppm, 43.94 ppm, 34.42 ppm, 32.89 ppm, 31.28 ppm, 30.66 ppm, 14.40 ppm, 13.34 ppm, 12.49 ppm and 10.50 ppm.
E7. Pharmaceutical composition comprising as active ingrédient the hydrogen sulfate 5 sait of Compound A according to El in association with one or more pharmaceutically acceptable excipients.
E8. Pharmaceutical composition comprising as active ingrédient the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of E2 to E6 in association with one or more pharmaceutically acceptable excipients.
E9. Pharmaceutical composition according to E7 or E8 for use in the treatment of cancers, auto-immune diseases and diseases of the immune system.
E10. Pharmaceutical composition according to E9, wherein the cancer is selected from the bladder, brain, breast and utérus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid 15 leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large Bcell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas, for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
Eli. The hydrogen sulfate sait of Compound A according to El for use as a 20 médicament.
E12. The hydrogen sulfate sait of Compound A according to El for use in the treatment of cancers, auto-immune diseases and diseases of the immune system.
E13. The hydrogen sulfate sait of Compound A according to E12 wherein the cancer is selected from the bladder, brain, breast and utérus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas, for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
E14. The crystalline form I of the hydrogen sulfate sait of Compound A according to any one of E2 to E6 for use as a médicament.
E15. The crystalline form I of the hydrogen sulfate sait of Compound A according to any one of E2 to E6 for use in the treatment of cancers, auto-immune diseases and diseases of the immune System.
E16. The crystalline form 1 of the hydrogen sulfate sait of Compound A according to E15 wherein the cancer is selected from the bladder, brain, breast and utérus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example nonHodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, for example myelodysplastic syndrome, myelomas, for example multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
E17. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of E2 to E6, wherein the hydrogen sulfate sait of Compound A is crystallised in a polar medium.
E18. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to E17, wherein the polar medium is composed of one or more solvents selected from water and alcohols.
E19. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of 5 Compound A according to E18, wherein the alcohol is éthanol.
E20. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to E18, wherein the polar medium is an ethanol/water mixture.
E21. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of E17 to E20, in which process the crystallisation is 10 seeded using a very small amount of the crystalline form I of the hydrogen sulfate sait of
Compound A.
E22. Anhydrous crystalline form of the hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl} phenyl)-A/-(5-cyano-l,2dimethyl-lE/-pyrrol-3-yl)-A/-(4-hydroxyphenyl)-l,2-dimethyl-lH-pyrrole-3-carboxamide 15 (Compound A, H2SO4) according to El, wherein the crystalline form has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or ail of the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.19; 5.64; 6.74; 7.14; 8.04; 8.33; 9.17; 9.40; 10.68; 11.03; 11.35; 12.18; 12.59; 13.64; 14.78; 15.09.
E23. The anhydrous crystalline form according to E22, characterized in that it has the 20 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 thêta, expressed in degrees ±0.2°) and interplanar distances d (expressed in Â):
Line no. | Angle 2-theta (degrees) | Interplanar distance (Â) |
1 | 5.19 | 17.03 |
2 | 5.64 | 15.66 |
3 | 6.74 | 13.12 |
4 | 7.14 | 12.39 |
5 | 8.04 | 10.99 |
6 | 8.33 | 10.61 |
7 | 9.17 | 9.64 |
8 | 9.40 | 9.41 |
9 | 10.68 | 8.29 |
10 | 11.03 | 8.02 |
11 | 11.35 | 7.79 |
12 | 12.18 | 7.26 |
13 | 12.59 | 7.03 |
14 | 13.64 | 6.49 |
15 | 14.78 | 5.99 |
16 | 15.09 | 5.87 |
Obtaining the crystalline form I of the hydrogen sulfate sait of Compound A has the advantage of having good characteristics of stability. More especially, only one crystalline form was observed in the range of solvents and températures used for the screening, showing a limited polymorphism of the hydrogen sulfate sait in the tested conditions.
Furthermore, the crystalline form I of the hydrogen sulfate sait of Compound A thereby obtained is sufficiently stable to allow its storage for an extended period without particular conditions for température, light, humidity or oxygen levels.
The Examples herein below illustrate the invention but do not limit it in any way.
Example 1: Process for obtaining crystalline form I of the hydrogen sulfate sait of
Compound A g of Compound A (free base) was placed in 239.5 g of éthanol at ambient température.
The mixture was then heated at 65°C. A solution of sulphuric acid in water (4.27 g of H2SO4 + 59.87 g of water) was then added gradually. The mixture was stirred for 1 h
-10before being cooled to 10°C. When the crystallisation was complété, the suspension was filtered, washed with an ethanol/water mixture à 10°C, filtered and dried under reduced pressure. After drying, crystalline form I of the hydrogen sulfate sait of Compound A was obtained in a yield of about 70% and with a purity greater than 99.8%. The solid was 5 characterised by the X-ray powder as set out in Example 3.
In the crystallisation process according to the invention, Compound A (free base) is obtained by any process which may be used.
Example 2: Process for obtaining crystalline form I of the hydrogen sulfate sait of Compound A (seeding)
25 g of Compound A (free base) was placed in 239.5 g of éthanol at ambient température.
The mixture was then heated at 65°C. A solution of sulphuric acid in water (4.27 g of H2SO4 + 59.87 g of water) was then added gradually. The mixture was stirred for 30 minutes. The mixture was then cooled slightly before being seeded with the crystalline form I of the hydrogen sulfate sait of Compound A (2% by weight of starting material).
The mixture was stirred for 30 minutes before being cooled to 10°C. When the crystallisation was complété, the suspension was filtered, washed with an ethanol/water mixture à 10°C, filtered and dried under reduced pressure. After drying, crystalline form I of the hydrogen sulfate sait of Compound A was obtained in a yield of about 70% and with a purity greater than 99.8%. The solid was characterised by the X-ray powder as set out in Example 3.
In the crystallisation process according to the invention, Compound A (free base) is obtained by any process which may be used.
Example 3: Crystalline form I of the hydrogen sulfate sait of Compound A (X-ray powder diffraction diagram)
Recording of the data was carried out in the transmission mode 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,
-11Anode: copper,
K alpha-1 wavelength: 1.54060 Â,
K alpha-2 wavelength: 1.54443 Â,
K alpha-2/K alpha-1 ratio: 0.5,
- Measurement mode: continuous from 3° to 55° (Bragg's angle 2 thêta) in incréments of 0.017°,
Measurement time per step: 35.5301 s.
The X-ray powder diffraction diagram of the form I of the hydrogen sulfate sait of Compound A obtained according to the process of Example 1 or 2 is expressed in terms of line position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and interplanar distances (expressed in Â) (Figure 1). The significant lines hâve been collated in the following table:
Line no. | Angle 2-theta (degrees) | Interplanar distance (Â) |
1 | 5.55 | 15.93 |
2 | 5.62 | 15.73 |
3 | 6.62 | 13.36 |
4 | 7.39 | 11.95 |
5 | 10.17 | 8.70 |
6 | 11.49 | 7.70 |
7 | 11.83 | 7.48 |
8 | 16.01 | 5.53 |
9 | 16.54 | 5.36 |
10 | 17.04 | 5.20 |
11 | 18.98 | 4.67 |
12 | 19.18 | 4.63 |
13 | 21.90 | 4.06 |
14 | 22.28 | 3.99 |
15 | 24.89 | 3.58 |
Example 4: Stability Studies
For ail storage conditions and storage periods, 20 mg of crystalline form of the sait of
Compound A were introduced in a 30-mL vial for post-storage HPLC analysis.
-12The drug substance content was determined by LC (% m/m).
Température | Packaging | Hydrogen sulfate sait, crystalline form 1 |
To | >99.9 | |
25°C/60%RH | Double polyethylene bag placed in a plastic drum | 100.7 after 3 months of storage |
30°C/65%RH | Double polyethylene bag placed in a plastic drum | 100.6 after 3 months of storage |
40°C/75%RH | Double polyethylene bag placed in a plastic drum | 100.0 after 3 months of storage |
50°C/75%RH | Open glass bottle | 101.0 after 6 weeks of storage |
The appearance of the powder (white) and Chemical stability remains unchanged under ail conditions tested: over 3 months at 25°C/60%RH, 30°C/65%RH, 4O°C/75°/oRH, and for 6 weeks at 50°C/75%RH.
Furthermore, the X-ray diffraction results show that the form does not change after analysis at To and after 6 weeks storage in open glass bottles at 25°C/90%RH.
In conclusion, the drug substance can be considered physically and chemically stable over the periods tested.
Example 5: Process for obtaining the anhydrous crystalline form of the hydrogen sulfate sait of Compound A (seeding)
5.83 kg of Compound A (free base) was placed in 55.85 kg of éthanol at ambient température. The mixture was then heated at 65°C. A solution of sulphuric acid in water (1 kg of H2SO4 + 13,96 kg of water) was then added gradually. The mixture was stirred for 30 minutes. The mixture was then cooled slightly before being seeded with the crystalline form I of the hydrogen sulfate sait of Compound A (2% by weight of starting material). The mixture was stirred for 30 minutes before being cooled to 10°C. When the
-13crystallisation was complété, the suspension was filtered, washed with an ethanol/water mixture à 10°C, filtered and dried under reduced pressure. Then, the dried product is stored under an inert atmosphère (nitrogen). The anhydrous crystalline form of the hydrogen sulfate sait of Compound A was obtained in a yield of about 78 ± 5% and with a purity greater than 99.9% and a water content of about 0.43%. The solid was characterised by the X-ray powder as set out in Example 6.
In the crystallisation process according to the invention, Compound A (free base) is obtained by any process which may be used.
Example 6: Anhydrous crystalline form of the hydrogen sulfate sait of Compound A (Xray powder diffraction diagram)
Recording of the data was carried out in the following conditions:
Approximately 30-50 mg of the sample to be analysed is placed between two polymeric films (Kapton®) fixed in a sample holder dise. The X-ray diffraction pattern of the test sample is recorded from 3° 2theta to at least 40° 2-theta in 15 min using an X-ray diffractometer operating in the transmission mode with CuKa radiation (λ = 1.5418 Â) at 40kV and 30mA and with a step size ranging from 0.01 to 0.02° 2-theta. These settings may vary according to the diffractometer used.
The X-ray powder diffraction diagram of the anhydrous form of the hydrogen sulfate sait 20 of Compound A obtained according to the process of Example 5 is expressed in terms of line position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and interplanar distances (expressed in Â) (Figure 2). The significant lines hâve been collated in the following table:
Line no. | Angle 2-theta (degrees) | Interplanar distance (Â) |
1 | 5.19 | 17.03 |
2 | 5.64 | 15.66 |
3 | 6.74 | 13.12 |
4 | 7.14 | 12.39 |
5 | 8.04 | 10.99 |
6 | 8.33 | 10.61 |
• | -14- | ||
7 | 9.17 | 9.64 | |
8 | 9.40 | 9.41 | |
9 | 10.68 | 8.29 | |
10 | 11.03 | 8.02 | |
11 | 11.35 | 7.79 | |
12 | 12.18 | 7.26 | |
13 | 12.59 | 7.03 | |
14 | 13.64 | 6.49 | |
15 | 14.78 | 5.99 | |
16 | 15.09 | 5.87 |
Example 7: Process for obtaining crystalline form I of the hydrogen sulfate sait of Compound A (seeding, batch size of the order of the kilogram)
5.83 kg of Compound A (free base) was placed in 55.85 kg of éthanol at ambient température. The mixture was then heated at 65°C. A solution of sulphuric acid in water (1 kg of H2SO4 + 13.96 kg of water) was then added gradually. The mixture was stirred for 30 minutes. The mixture was then cooled slightly before being seeded with the crystalline form I of the hydrogen sulfate sait of Compound A (2% by weight of starting material). The mixture was stirred for 30 minutes before being cooled to 10°C. When the crystallisation was complété, the suspension was filtered, washed with an ethanol/water mixture at 10°C, filtered and dried under reduced pressure. The product was rehydrated thereafter at 40°C under an atmosphère with 50% of relative humidity (RH). The resulting product was stored under an inert atmosphère (nitrogen). The crystalline form I of the hydrogen sulfate sait of Compound A was obtained in a yield of about 78 ± 5% and with a purity greater than 99.9% and a water content of about 6.5 ± 1%. The solid was characterised by the X-ray powder as set out in Example 3.
In the crystallisation process according to the invention, Compound A (free base) is obtained by any process which may be used.
Example 8: Process for obtaining the crystalline form I of the hydrochloride sait of Compound A and the X-ray powder diffraction diagram characterising it
1510 mg of the amorphous hydrochloride sait of Compound A (Example 386 of WO 2015/011400) was converted into its crystalline éthanol solvaté by slurrying in 15 mL of 5 éthanol for 48h hours. The residual solid was filtered, washed twice with 1 mL of éthanol and then suspended in 10 mL of water for 5 min. After a difficult filtration, the residual solid was dried overnight at 30°C/10 mbar and analysed by X-ray diffraction (3-30° 2 theta/10 min).
The mode of préparation for the HCl sait is complicated by the fact that it initiaHy results 10 in an éthanol solvaté which is replaced by H2O after resuspension in water to give the hydrated form. The resulting hydrated HCl sait formed fine needles which were quite difficult to filter.
The X-ray powder diffraction diagram of the form I of the hydrochloride sait of Compound A obtained according to the process described previously is expressed in terms of line 15 position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and relative intensity (expressed in %) (Figure 3). The significant lines hâve been collated in the following table:
Line no. | Angle 2-theta (degrees) | Relative lntensity(%) |
1 | 5.53 | 100.00 |
2 | 7.37 | 65.92 |
3 | 9.96 | 92.98 |
4 | 11.26 | 31.90 |
5 | 11.62 | 30.11 |
6 | 12.29 | 67.53 |
7 | 12.76 | 25.47 |
8 | 15.34 | 29.27 |
9 | 17.04 | 32.91 |
10 | 18.82 | 25.98 |
11 | 19.07 | 27.10 |
12 | 19.48 | 27.89 |
13 | 20.41 | 25.05 |
• | -16- | ||
14 | 21.99 | 28.88 | |
15 | 23.14 | 29.52 | |
16 | 24.69 | 23.99 | |
17 | 25.66 | 29.09 | |
18 | 27.28 | 25.49 |
Example 9: DSC and TGA profiles of the crystalline forms I of the hydrochloride and hydrogen sulfate salts of Compound A
H2SO4 sait
The Differential Scanning Calorimetry (DSC) profile of a sample of the hydrogensulfate 5 sait, form I weighing approximately 4 mg was recorded between 0°C and 250°C at 10°C/min in pin-hole pierced aluminium pans under a positive flow of nitrogen on a TA Instruments Q1000 (or Q2000) Differential Scanning Calorimeter (Figure 4).
The Thermal Gravimétrie Analysis (TGA) profile of a sample of the hydrogensulfate sait, form I weighing approximately 10 mg was recorded between 25°C and 250°C at 10°C/min 10 in an open aluminium pan under a positive flow of nitrogen on a TA Instruments Q5000
Thermogravimetric Analyser (Figure 4).
HCI sait
The DSC profile of a sample of the hydrochloride sait, form I weighing approximately 4 mg 15 was recorded between 0°C and 250°C at 10°C/min in pin-hole pierced aluminium pans under a positive flow of nitrogen on a TA Instruments Q1000 (or Q2000) Differential Scanning Calorimeter (Figure 5).
The TGA profile of a sample of the hydrochloride sait, form I weighing approximately 6 mg was recorded between 25°C and 250°C at 10°C/min in an open aluminium pan under a 20 positive flow of nitrogen on a TA Instruments Q5000 Thermogravimetric Analyser (Figure 5).
The DSC profile of the H2SO4 sait is less complicated compared to that of the HCl sait.
Water loss is visible in the TGA profile of the H2SO4 sait between 25 and 100°C. A 25 melting/degradation endotherm is visible in the DSC profile towards 224°C. The melting temperature and enthalpy of the HCl sait is lower than that of the H2SO4 sait. This may suggest that the HCl has a lower degree of crystallinity following déhydration compared to the H2SO4 sait.
Example 10: Crystalline form I of Compound A, H2SO4(solid NMR Spectrum)
Crystalline form I of Compound A, H2SO4 was also characterized by solid-state Nuclear Magnetic Résonance spectroscopy (Figure 6). Solid-state 13C NMR spectra of Compound A, H2SO4 were recorded at ambient température using a Bruker SB Avance III HD 500 spectrometer with a 4 mm CP/MAS SB VTN type probe under the following conditions:
- Frequency: 125.76 MHz,
Spectral width: 37 kHz,
Magic angle spinning rate: 10 kHz,
Puise program: Cross Polarization with SPINAL64 decoupling
Recycle delay: 10 s,
- Acquisition time: 46 ms,
Contact time: 4 ms, Number of scans: 4096.
A 5 Hz line-broadening was applied prior to Fourier Transformation.
The spectrum thereby obtained was referenced relative to a sample of adamantane (the high frequency peak of adamantane was set to 38.5 ppm).
Crystalline form I of Compound A, H2SO4 can be defined by the presence of a set of peaks whose Chemical shifts are given in the table below (expressed in ppm ± 0.2 ppm):
No. | (PPm) |
1 | 173.31 |
2 | 155.32 |
3 | 140.46 |
4 | 139.19 |
5 | 137.42 |
6 | 134.68 |
7 | 131.65 |
8 | 131.14 |
9 | 129.37 |
10 | 126.32 |
11 | 118.77 |
12 | 117.36 |
13 | 116.54 |
14 | 113.61 |
15 | 112.69 |
16 | 110.74 |
17 | 102.33 |
18 | 101.45 |
19 | 63.06 |
20 | 57.19 |
21 | 54.87 |
22 | 52.06 |
23 | 44.71 |
24 | 43.94 |
25 | 34.42 |
26 | 32.89 |
27 | 31.28 |
28 | 30.66 |
29 | 14.40 |
30 | 13.34 |
31 | 12.49 |
32 | 10.50 |
Claims (19)
1. The hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4dihydroisoquinolin-2(l/7)-yl]carbonyl] phenyl)-/V-(5-cyano-l,2-dimethyl-l/-/-pyrrol-3-yl)-/\/(4-hydroxyphenyl)-l,2-dimethyl-lA/-pyrrole-3-carboxamide (Compound A, H2SO4).
2. A crystalline form I of the hydrogen sulfate sait of 5-(5-chloro-2-{[(35)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/-/)-yl]carbonyl}phenyl)-A/-(5-cyano-l,2dimethyl-l/-/-pyrrol-3-yl)-/V-(4-hydroxyphenyl)-l,2-dimethyl-l/-/-pyrrole-3-carboxamide (Compound A, H2SO4) according to claim 1, wherein the crystalline form has an X-ray powder diffraction diagram showing the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55 ; 6.62 and 7.39.
3. A crystalline form I of the hydrogen sulfate sait of 5-(5-chloro-2-{[(35)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/7)-yl]carbonyl) phenyl)-/V-(5-cyano-l,2dimethyl-l/-/-pyrrol-3-yl)-/V-(4-hydroxyphenyl)-l,2-dimethyl-lH-pyrrole-3-carboxamide (Compound A, H2SO4) according to claim 1, wherein the crystalline form has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or ail of the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55; 5.62; 6.62; 7.39; 10.17; 11.49; 11.83; 16.01; 16.54; 17.04; 18.98; 19.18; 21.90; 22.28; 24.89.
4. The crystalline form I of the hydrogen sulfate sait of Compound A according to claim 3, characterized in that it has an X-ray powder diffraction diagram having the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.55; 5.62; 6.62; 7.39; 10.17; 11.49; 11.83; 16.01; 16.54; 17.04; 18.98; 19.18; 21.90; 22.28; 24.89.
5. The crystalline form I of the hydrogen sulfate sait of Compound A according to claim 4, characterized 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
-20and expressed in terms of line position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and interplanar distances d (expressed in Â):
Line no.
Angle 2-theta (degrees)
Interplanar distance (Â)
1
5.55
15.93
2
5.62
15.73
3
6.62
13.36
4
7.39
11.95
5
10.17
8.70
6
11.49
7.70
7
11.83
7.48
8
16.01
5.53
9
16.54
5.36
10
17.04
5.20
11
18.98
4.67
12
19.18
4.63
13
21.90
4.06
14
22.28
3.99
15
24.89
3.58
6. The crystalline form I ofthe hydrogen sulfate sait of Compound A according to any one of claims 2 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): 173.31 ppm, 155.32 ppm, 140.46 ppm, 139.19 ppm, 137.42 ppm, 134.68 ppm, 131.65 ppm, 131.14 ppm, 129.37 ppm, 126.32 ppm, 118.77 ppm, 117.36 ppm, 116.54 ppm, 113.61 ppm, 112.69 ppm, 110.74 ppm, 102.33 ppm, 101.45 ppm, 63.06 ppm, 57.19 ppm, 54.87 ppm, 52.06 ppm, 44.71 ppm, 43.94 ppm, 34.42 ppm, 32.89 ppm, 31.28 ppm, 30.66 ppm, 14.40 ppm, 13.34 ppm, 12.49 ppm and 10.50 ppm.
7. Pharmaceutical composition comprising as active ingrédient the hydrogen sulfate sait of Compound A according to claim 1 in association with one or more pharmaceutically acceptable excipients.
8. Pharmaceutical composition comprising as active ingrédient the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of daims 2 to 6 in association with one or more pharmaceutically acceptable excipients.
9. Pharmaceutical composition according to claim 7 or 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 utérus cancers, chronic lymphoid leukaemias, colorectal cancer, cancers of the œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, including non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, including myelodysplastic syndrome, myelomas, including multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
11. The hydrogen sulfate sait of Compound A according to claim 1 for use as a médicament for treating cancers, auto-immune diseases and diseases of the immune System.
12. The crystalline form I of the hydrogen sulfate sait of Compound A according to any one of daims 2 to 6 for use as a médicament for treating cancers, auto-immune diseases and diseases of the immune System.
13. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of daims 2 to 6, wherein the hydrogen sulfate sait of Compound A is crystallised in a polar medium.
14. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to claim 13, wherein the polar medium is composed of one or more solvents selected from water and alcohols.
15. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to claim 14, wherein the alcohol is éthanol.
16. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to claim 14, wherein the polar medium is an ethanol/water mixture.
17. Process for the préparation of the crystalline form I of the hydrogen sulfate sait of Compound A according to any one of claim 13 to 16, in which process the crystallisation is seeded using a very small amount of the crystalline form I of the hydrogen sulfate sait of Compound A.
18. Anhydrous crystalline form of the hydrogen sulfate sait of 5-(5-chloro-2-{[(3S)-3(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(l/7)-yl]carbonyl) phenyl)-/V-(5-cyano-l,2dimethyl-l/-/-pyrrol-3-yl)-/V-(4-hydroxyphenyl)-l,2-dimethyl-l/-/-pyrrole-3-carboxamide (Compound A, H2SO4) according to claim 1, wherein the crystalline form has an X-ray powder diffraction diagram showing at least 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or ail of the following diffraction lines (Bragg's angle 2 thêta, expressed in degrees ±0.2°): 5.19; 5.64; 6.74; 7.14; 8.04; 8.33; 9.17; 9.40; 10.68; 11.03; 11.35; 12.18; 12.59; 13.64; 14.78; 15.09.
19. The anhydrous crystalline form of the hydrogen sulfate sait of Compound A according to claim 18, characterized in that it has the following X-ray powder diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator
-23detector and expressed in terms of line position (Bragg's angle 2 thêta, expressed in degrees ±0.2°) and interplanar distances d (expressed in Â):
Line no.
Angle 2-theta (degrees)
Interplanar distance (Â)
1
5.19
17.03
2
5.64
15.66
3
6.74
13.12
4
7.14
12.39
5
8.04
10.99
6
8.33
10.61
7
9.17
9.64
8
9.40
9.41
9
10.68
8.29
10
11.03
8.02
11
11.35
7.79
12
12.18
7.26
13
12.59
7.03
14
13.64
6.49
15
14.78
5.99
16
15.09
5.87
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP18306430.2 | 2018-10-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
OA20227A true OA20227A (en) | 2022-03-18 |
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