WO2017012770A1 - Sels d'addition d'acide de filgotinib - Google Patents

Sels d'addition d'acide de filgotinib Download PDF

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Publication number
WO2017012770A1
WO2017012770A1 PCT/EP2016/063151 EP2016063151W WO2017012770A1 WO 2017012770 A1 WO2017012770 A1 WO 2017012770A1 EP 2016063151 W EP2016063151 W EP 2016063151W WO 2017012770 A1 WO2017012770 A1 WO 2017012770A1
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Prior art keywords
filgotinib
degrees
hydrochloride
sulfate
dichloromethane
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Inventor
Wolfgang Albrecht
Richard Guserle
Annemarie MAIER
Nadine RUH
Roland SELIG
Jens Geier
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Ratiopharm GmbH
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Ratiopharm GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present invention relates to filgotinib acid addition salts, their polymorphs, a method of preparing the same as well as a pharmaceutical composition comprising the same.
  • the IUPAC name of filgotinib is N-[5-[4-[(l,l-dioxo-l,4-thiazinan-4- yl)methyl]phenyl]-[l,2,4]triazolo[l,5-a]pyridin-2-yl]cyclopropanecarboxamide.
  • Filgotinib is represented by the following chemical structure according to Formula (I):
  • Filgotinib also known as GLPG-0634 or N-(5-(4-((l,l- dioxothiomorpholino)methyl) phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl]cyclopro- pane-carboxamide) is an orally available, selective inhibitor of JAKl (Janus kinase 1) being developed by Galapagos for the treatment of rheumatoid arthritis and potentially other inflammatory diseases.
  • JAKl Janus kinase 1
  • JAKs are critical components of signaling mechanisms utilized by a number of cytokines and growth factors, including those that are elevated in rheumatoid arthritis patients.
  • Other non-selective JAK inhibitors have shown long-term efficacy in rheumatoid arthritis trials with an early onset of action. Contrary to baricitinib and ruxolitinib, which are mixed JAKl and JAK2 inhibitors, and tofacitinib, which is a specific JAK3 inhibitor, filgotinib was developed to specifically target JAK1.
  • the active pharmaceutical ingredient filgotinib is known from WO 2010/149769 Al . Similar synthetic routes for obtaining derivatives of filgotinib are also described in WO 2010/010190 Al .
  • Filgotinib in form of the free base is practically insoluble.
  • One option to enhance the solubility is the formation of a filgotinib base or acid addition salt.
  • WO 2010/149769 generally refers to certain filgotinib acid addition salts. However, said document describes neither a method for their preparation nor any properties nor polymorphs thereof. It additionally turned out that some of the described filgotinib acid addition salts do not seem to be enabled. In particular the formation of filgotinib acid addition salt could not be observed in case that the acid was fumaric acid, tartaric acid, maleic acid or oxalic acid.
  • filgotinib acid addition salts should be provided in a form which is easy to prepare.
  • Filgotinib acid addition salt preferably filgotinib hydrochloride and filgotinib sulfate and the corresponding polymorphs thereof, the process of their preparation and pharmaceutical compositions comprising said filgotinib acid addition salts are provided.
  • Filgotinib acid addition salt preferably filgotinib hydrochloride and filgotinib sulfate, might be present in different polymorphic forms or mixtures thereof.
  • the filgotinib acid addition salts of the present invention can be preferably present in crystalline form.
  • a crystal form may be referred to herein as being characterized by data selected from two or more different data groupings, for example by a powder XRD pattern having a group of specific peaks or by a powder XRD pattern as shown in a figure depicting a diffractogram or by "a combination thereof (or “combinations thereof” or “any combination thereof). These expressions, e.g. "any combination thereof, contemplate that the skilled person may characterize a crystal form using any combination of the recited characteristic analytical data.
  • the skilled person may characterize a crystal form using a group of three, four or five characteristic powder XRD peaks and supplement that characterization with one or more additional feature(s) observed in the powder X-ray diffractogram, e.g., an additional peak, a characteristic peak shape, a peak intensity or even the absence of a peak at some position in the powder XRD pattern.
  • the skilled person may in some instances characterize a crystal form using a group of three, four or five characteristic powder XRD peaks and supplement that characterization with one or more additional feature(s) observed using another analytical method, for example using one or more characteristic peaks in a solid state IR spectrum, solid state NMR or characteristics of the DSC thermogram of the crystal form that is being characterized.
  • XRPD peaks are recorded using copper ⁇ / ⁇ 2 radiation with a wavelength 1.5406 A (weighted mean of Cu Kcci and Cu K 2 ). Further, unless indicated otherwise, XRPD peaks are reported as degrees 2 ⁇ values with a standard error of ⁇ 0.2 degrees 2 ⁇ .
  • a crystal form may be referred to herein as being characterized by graphical data "as depicted in" a particular figure.
  • Such data include for example powder X-ray diffractograms.
  • the skilled person will understand that such graphical representations of data may be subject to small variations, e.g. in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data characterize the same crystal form or two different crystal forms.
  • the subject of the present invention is filgotinib hydrochloride having characteristic X-ray powder diffraction peaks at 8.0, 10.5, 20.1, 24.0 and 25.7 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ). That form of filgotinib hydrochloride is hereinafter referred to as polymorphic Form E of filgotinib hydrochloride.
  • the filgotinib hydrochloride Form E can be characterized by one or more further XRPD diffraction peak(s) at 13.9, 18.1, 19.0, 21.1 and/or 23.6 degrees 2 ⁇ (+ 0.2 degrees 2 ⁇ ).
  • filgotinib hydrochloride Form E can be characterized by the XRPD diffraction peak(s) at degrees 2 ⁇ ⁇ 0.2 degrees 2 ⁇ (intensity %): 8.0 (16), 8.6 (2), 9.2 (3), 10.5 (12), 11.1 (8), 12.8 (6), 13.0 (7), 13.9 (38), 14.3 (11), 14.8 (2), 15.7 (26), 16.2 (19), 17.1 (7), 17.5 (8), 18.1 (23), 18.6 (11), 19.0 (27), 20.1 (34), 20.4 (12), 21.1 (70), 21.9 (15), 22.9 (17), 23.6 (62), 24.0 (100), 24.3 (12), 25.3 (35), 25.7 (57), 26.2 (25), 26.6 (17), 27.2 (15), 27.8 (17), 28.9 (11), 29.8 (6), 31.1 (4), 31.8 (45), 32.6 (12), 33.4 (10), 35.9 (6), 36.4 (12), 37.8 (8), 38.7 (5), 39
  • filgotinib hydrochloride Form E can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 3446, 3354, 3097, 2974, 2895, 2798, 2654, 2480, 2374, 1705, 1647, 1591, 1564, 1522, 1504, 1458, 1446, 1425, 1416, 1396, 1348, 1317, 1284, 1254, 1213, 1192, 1153, 1132, 1090, 1066, 1028, 1014, 953, 935, 914, 881, 862, 837, 822, 795, 769, 744, 737, 714, 675, 648, 634, 621.
  • filgotinib hydrochloride in particular Form E of filgotinib hydrochloride, has a residual solvent content within pharmaceutically acceptable limits.
  • residual solvent content within pharmaceutically acceptable limits refers to a concentration limit (in ppm) of the corresponding solvent.
  • Concentration limits for solvents can be found in Guidance for Industry, Q3C- Tables and List, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologies Evaluation and Research (CBER), February 2012, ICH, Revision 2.
  • the solvents are categorized into three classes. Class 1 relates to solvents that should be avoided in pharmaceutical products, such as carbon tetrachloride.
  • Class 2 relates to solvents that should be limited in pharmaceutical products because of their inherent toxicity.
  • Class 2 solvents and their concentration limits Class 3 relates to solvents which should be limited by GMP or other quality-based requirements. These solvents should be present in an amount below 5000 ppm.
  • Table 3 Class 3 solvents having a concentration limit of 5000 ppm.
  • Filgotinib hydrochloride Form E is easily available from the synthesis without the need of a time-consuming and cost-intensive purification step.
  • filgotinib hydrochloride Form E contains an amount of residual organic solvent(s) so small that the compound meets the requirements of the FDA regulations.
  • a further subject of the present invention is a process for preparing filgotinib hydrochloride according to the present invention, in particular filgotinib hydrochloride Form E, characterized by the following steps: a) providing filgotinib
  • step b) suspending filgotinib from step a) in aqueous hydrochloric acid c) isolating filgotinib hydrochloride Form E.
  • filgotinib preferably filgotinib in form of its free base
  • Filgotinib in form of its free base also refers to polymorphs, solvates and hydrates thereof.
  • Filgotinib free base can for example be prepared by reacting cyclopropane carboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5a]pyridine-2yl]- amide with thiomorpholine dioxide until the completion of the reaction and the evaporation of the solvent. Up to this point the reaction steps are carried out as described for example in WO 2010/149769. However, contrary to said prior art, the resulting substance was suspended in an organic solvent or a mixture of organic solvents. After optionally heating and subsequently cooling the mixture, the organic solvent or the mixture of organic solvents is evaporated. Then the resulting substance is suspended in an organic solvent or a mixture of organic solvents once more. Again, after optionally heating and cooling the mixture, the product is filtered off and dried.
  • organic solvents examples include methanol, ethanol, isopropanol, acetone, ethylacetate, dichloromethane, trichloromethane, dioxane, tetrabydrofurane, acetonitrile, diethylether and tert-b tyl methyl ether.
  • the first and second suspending steps of the substance are carried out in a mixture of organic solvents, in particular in a mixture of dichloromethane and methanol, more specifically in a mixture of dichloromethane and methanol with a volume ratio of 1 : 1 to 5: 1.
  • the suspension is subjected to a mechanical movement such as stirring.
  • a mechanical movement such as stirring.
  • the reaction mixture is heated from 23 °C (ambient temperature) to an elevated temperature, preferably to the boiling point of the organic solvent or the mixture of the organic solvents and then cooled down to preferably 23 °C (ambient temperature) again.
  • the conditions of the second optional heating and cooling step preferably correspond to the ones as mentioned above.
  • the step of drying can preferably be carried out at a temperature of 23 °C to 70°C, preferably 30°C to 60°C. Alternatively or additionally the drying can preferably be carried out under reduced pressure of 1 to 500 mbar, in particular 10 to 100 mbar.
  • step b) the filgotinib from step a) is suspended in aqueous hydrochloric acid.
  • the hydrochloric acid is from 8% HCl aq to 32% HCl aq , more preferably from 10% HCl aq to 28% HCl aq , in particular from 12% HCl aq to 24%
  • suspension is subjected to a mechanical movement such as stirring.
  • step b) includes stirring for 1 to 24 hours, preferably 2 to 20 hours, in particular 4 to 16 hours. Further, the stirring can be carried out at temperatures of 10 to 60°C, preferably 15 to 55 °C, in particular 20° to 50°C.
  • Step c) of isolating filgotinib hydrochloride can preferably comprise cooling the suspension of step b), preferably to a temperature of 0°C to 20°C, more preferably 2°C to 15°C, in particular 3°C to 10°C.
  • step c) isolating of filgotinib hydrochloride Form E can preferably be carried out by filtering off the solid. Further, filgotinib hydrochloride Form E can preferably be washed, preferably with half concentrated hydrochloric acid. Subsequently, the filgotinib hydrochloride can preferably be dried. Drying can preferably be carried out at a temperature of 23 °C to 70°C, preferably 30°C to 60°C. Alternatively or additionally the drying can preferably be carried out under reduced pressure of from 1 to 500 mbar, in particular 3 to 45 mbar. As can seen from the above, isolating filgotinib hydrochloride, in particular filgotinib hydrochloride Form E is easily accessible by a process without the use of complex, time and cost intensive process steps.
  • An alternative particularly preferred process for preparing filgotinib hydrochloride according to the present invention is characterized by the following steps: a') dissolving filgotinib in an organic solvent
  • filgotinib preferably filgotinib in form of its free base
  • filgotinib in form of its free base is dissolved, preferably completely dissolved, in an organic solvent or in a mixture of organic solvents.
  • Filgotinib in form of its free base also refers to polymorphs, solvates and hydrates thereof.
  • step a') is carried out under mechanical movement such as stirring.
  • aqueous hydrochloric acid can be preferably added to the solution from step a'). It is preferred that the hydrochloric acid is from 8% HCl aq to 32% HCl aq , more preferably from 10% HCl aq to 28% HCl aq , in particular from 12% HCl aq to It is further preferred that while adding aqueous hydrochloric acid to the solution of step a') the suspension is subjected to a mechanical movement such as stirring.
  • step b') includes further stirring for 1 to 24 hours, preferably 2 to 20 hours, in particular 4 to 16 hours. Further, the stirring can be carried out at temperatures from 10 to 60°C, preferably 15 to 55°C, in particular 20° to 50°C.
  • Step c') of isolating filgotinib hydrochloride Form E can preferably comprise cooling the mixture of step b'), preferably to a temperature of 0°C to 27°C, more preferably 5°C to 25°C, in particular 15°C to 23°C.
  • step c') the isolating of filgotinib hydrochloride Form E can preferably be carried out by filtering off the solid. Further, filgotinib hydrochloride Form E can preferably be washed, preferably with half concentrated aqueous hydrochloric acid. Subsequently, the filgotinib hydrochloride Form E can preferably be dried. Drying can preferably be carried out at a temperature of 23°C to 70°C, preferably 30°C to 60°C. Alternatively or additionally the drying can preferably be carried out under reduced pressure of 1 to 500 mbar, in particular 3 to 45 mbar.
  • isolating filgotinib hydrochloride is easily accessible by a process without the use of complex, time and cost intensive process steps.
  • a further subject of the present invention is filgotinib hydrochloride having characteristic X-ray powder diffraction peaks at 21.4, 21.7, 22.9, 24.3 and/or 25.1 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • This form of filgotinib hydrochloride is hereinafter referred to as polymorphic Form F of filgotinib hydrochloride.
  • the filgotinib hydrochloride Form F can be characterized by one or more further XRPD diffraction peak(s) at 12.2, 13.4, 13.8, 18.7 and/or 20.6 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • filgotinib hydrochloride Form A can be characterized by the XRPD diffraction peak(s) at degrees 2 ⁇ ⁇ 0.2 degrees 2 ⁇ : 6.7, 7.6, 8.5, 9.3, 9.7, 10.6, 11.5, 12.2, 13.1, 13.4, 13.8, 14.0, 15.5, 16.0, 16.6, 17.0, 17.4, 17.8, 18.0, 18.7, 19.3, 19.7, 20.3, 20.6, 21.0, 21.4, 21.7, 21.9, 22.6, 22.9, 24.3, 25.1, 25.7, 25.9, 26.6, 26.9, 27.2, 27.9, 28.2, 29.0, 29.8, 30.3, 30.6, 31.1, 31.6, 32.2, 33.1, 33.8, 34.4
  • Filgotinib hydrochloride Form F can for example be prepared by exposing filgotinib hydrochloride Form E to 40°C in a closed glass vial for four weeks. The product completely transformed in to filgotinib hydrochloride Form F.
  • filgotinib hydrochloride Form F can for example be prepared by exposing filgotinib hydrochloride Form E to 40°C and 75% relative humidity in an open glass vial for weeks. The product completely transformed in to filgotinib hydrochloride Form F.
  • a further subject of the present invention is filgotinib hydrochloride having characteristic X-ray powder diffraction peaks at 14.9, 19.4, 19.9, 24.8 and 28.3 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • This form of filgotinib hydrochloride is hereinafter referred to as polymorphic Form A of filgotinib hydrochloride.
  • the filgotinib hydrochloride Form A can be characterized by one or more further XRPD diffraction peak(s) at 7.1, 9.6, 14.3, 18.6 and/or 26.2 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • filgotinib hydrochloride Form A can be characterized by the XRPD diffraction peak(s) at degrees 2 ⁇ ⁇ 0.2 degrees 2 ⁇ (intensity %): 7.1 (19), 9.6 (100), 13.2 (1 1), 13.9 (8),
  • filgotinib hydrochloride Form A can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 3090, 2987, 2943, 2845, 2777, 2436, 2378, 1693, 1647, 1599, 1572, 1524, 1502, 1470, 1454, 1425, 1396, 1350, 1335, 1298, 1282, 1244, 1213, 1169, 1126, 1120, 1066, 1030, 1012, 980, 951, 935, 916, 895, 870, 841, 816, 783, 754, 735, 719, 704, 681, 671, 654, 644, 633, 623, 604.
  • Filgotinib hydrochloride Form A can for example be prepared by the following steps: a A ) dissolving filgotinib in organic solvent
  • a further subject of the present invention is filgotinib hydrochloride having characteristic X-ray powder diffraction peaks at 13.7, 16.2, 22.3, 23.2 and 25.5 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • This form of filgotinib hydrochloride can be considered as polymorphic Form B of filgotinib hydrochloride.
  • the filgotinib hydrochloride Form B can be characterized by one or more further XRPD diffraction peak(s) at 12.0, 13.2, 15.5, 18.1 and/or 21.1 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • filgotinib hydrochloride Form B can be characterized by the XRPD diffraction peak(s) at degrees 2 ⁇ ⁇ 0.2 degrees 2 ⁇ (intensity ): 9.6 (17), 12.0 (55), 13.2 (51), 13.7 (34), 14.3 (32), 15.5 (45), 16.2 (21), 18.1 (52), 21.1 (59), 22.3 (100), 23.2 (99), 23.7 (64), 24.8 (46), 25.5 (81), 26.6 (74), 27.4 (81), 28.7 (29) and 33.5 (31).
  • filgotinib hydrochloride Form B can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 3084, 2978, 2922, 2482, 1693, 1649, 1633, 1595, 1560, 1522, 1500, 1473, 1448, 1396, 1356, 1311, 1277, 1250, 1184, 1167, 1130, 1063, 1026, 953, 912, 866, 839, 820, 785, 735, 715, 675, 633.
  • Filgotinib hydrochloride Form B can for example be prepared by the following steps: a B ) dissolving filgotinib in a mixture of organic solvents
  • a further subject of the present invention is filgotinib hydrochloride having characteristic X-ray powder diffraction peaks at 8.8, 11.0, 17.7, 21.7 and 22.5 degrees 2 ⁇ (+ 0.2 degrees 2 ⁇ ).
  • This filgotinib hydrochloride can be considered as polymorphic Form C of filgotinib hydrochloride.
  • the filgotinib hydrochloride Form C can be characterized by one or more further XRPD diffraction peak(s) at 7.1, 9.5, 16.3, 21.4 and/or 27.6 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • filgotinib hydrochloride Form C can be characterized by the XRPD diffraction peak(s) at degrees 2 ⁇ + 0.2 degrees 2 ⁇ (intensity ): 7.1 (38), 7.4 (6), 8.8 (7), 9.5 (13), 11.0 (46), 14.2 (7), 15.0 (4), 15.5 (8), 16.3 (13), 17.3 (21), 17.7 (38), 17.8 (31), 18.6 (11), 19.5 (15), 19.8 (19), 21.4 (100), 21.7 (48), 22.5 (22), 23.3 (7), 23.9 (15), 26.0 (31), 27.6 (45), 28.6 (16), 29.9 (25), 30.9 (10), 32.5 (6), 33.4 (5), 35.4 (10), 37.8 (9), 39.8 (8) and 42.1(3).
  • filgotinib hydrochloride Form C can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 3649, 3390, 3091 , 3016, 2980, 2928, 2609, 2519, 2386, 2108, 1691, 1647, 1595, 1566, 1522, 1514, 1502, 1444, 1392, 1342, 1313, 1277, 1250, 1184, 1159, 1132, 1068, 1059, 1026, 953, 912, 877, 866, 841 , 818, 783, 733, 715, 677, 648, 633, 621.
  • Filgotinib hydrochloride Form C can for example be prepared by the following steps: ac) dissolving filgotinib in a mixture of organic solvents
  • a further subject of the present invention is filgotinib hydrochloride having characteristic X-ray powder diffraction peaks at 7.6, 10.4, 10.8, 15.8 and 17.4 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • This form of filgotinib hydrochloride can be considered as polymorphic Form D of filgotinib hydrochloride.
  • the filgotinib hydrochloride Form D can be characterized by one or more further XRPD diffraction peak(s) at 12.0, 18.1, 21.4, 24.2 and/or 27.5 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • filgotinib hydrochloride Form D can be characterized by the XRPD diffraction peak(s) at degrees 2 ⁇ ⁇ 0.2 degrees 2 ⁇ (intensity %): 7.6 (22), 8.5 (1), 10.4 (11), 10.8 (27), 12.0 (25), 12.5 (4), 14.0 (2), 14.4 (6), 15.8 (24), 17.4 (50), 18.1 (22), 19.1 (3), 19.6 (4), 21.4 (100), 22.2 (13), 22.9 (3), 23.7 (16), 24.2 (38), 25.1 (18), 26.3 (7), 26.5 (10), 27.5 (26), 28.4 (17), 29.3 (13), 30.0 (13), 31.0 (11), 31.5 (11), 31.8 (7), 32.9 (6), 33.8 (6), 34.6 (8), 35.9 (8), 36.9 (4), 38.3 (10), 39.0 (17), 42.2 (6), 42.8 (6), 44.3 (4), 45.5 (2), 47.1 (6), 49
  • filgotinib hydrochloride Form D can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 3429, 3093, 2978, 2924, 2891, 2656, 2605, 2499, 2118, 1695, 1647, 1597, 1566, 1522, 1502, 1446, 1394, 1340, 1311, 1275, 1246, 1188, 1167, 1134, 1061 , 1026, 951, 912, 866, 841, 820, 783, 737, 717, 708, 677, 648, 633.
  • Filgotinib hydrochloride Form D can for example be prepared by the following steps: ao) dissolving filgotinib in an organic solvent and heating the solution bo) adding hydrochloric acid in organic solvent
  • a further aspect of the present invention is filgotinib in form of filgotinib sulfuric acid addition salts, in particular specific polymorphs of filgotinib sulfate.
  • a further subject of the present invention is filgotinib sulfate having characteristic X-ray powder diffraction peaks at 11.5, 18.0, 21.3, 22.1 and 23.5 degrees 2 ⁇ (+ 0.2 degrees 2 ⁇ ). This filgotinib sulfate can be considered as polymorphic Form SI of filgotinib sulfate.
  • the filgotinib sulfate Form SI can be characterized by one or more further XRPD diffraction peak(s) at 15.8, 19.0, 19.2, 19.7 and/or 21.8 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • filgotinib sulfate Form S I can be characterized by the XRPD diffraction peak(s) at degrees 2 ⁇ + 0.2 degrees 2 ⁇ (intensity %): 7.9 (3), 8.8 (4), 11.0 (5), 1 1.3 (7), 11.5 (16), 1 1.9 (4), 12.9 (3), 13.1 (3), 14.3 (2), 15.8 (9), 18.0 (27), 19.0 (16), 19.2 (24), 19.7 (37), 20.2 (10), 20.9 (5), 21.3 (21), 21.8 (64), 22.1 (100), 23.5 (30), 23.8 (22), 24.3 (19), 24.7 (10), 25.0 (6), 25.6 (15), 26.5 (13), 27.0 (2), 28.6 (4), 29.1 (8), 29.4 (10), 30.3 (5), 30.7 (6), 31.1 (4), 31.9 (9), 32.2 (3), 33.2 (3), 33.4 (4), 34.5 (3), 35.5 (4), 36.2 (2), 37.1 (2), 38.9 (3),
  • filgotinib sulfate Form S 1 can be characterized by an FT- IR spectrum showing peaks at the following wave numbers: 3103, 2982, 2935, 2735, 2580, 1703, 1647, 1601, 1529, 1510, 1452, 1394, 1315, 1196, 1163, 1132, 1045, 1020, 953, 910, 849, 835, 795, 766, 735, 714, 677, 606. It turned out that filgotinib sulfate, in particular filgotinib sulfate Form S I, shows an improved solubility not only compared to filgotinib free base but also with regard to filgotinib sulfonates.
  • filgotinib sulfate in particular filgotinib sulfate Form S I, shows an advantageous hygroscopicity.
  • Filgotinib sulfate Form SI can for example be prepared by the following steps:
  • filgotinib preferably filgotinib in form of its free base
  • filgotinib in form of its free base is dissolved, preferably completely dissolved, in an organic solvent or in a mixture of organic solvents.
  • Filgotinib in form of its free base also refers to polymorphs, solvates and hydrates thereof.
  • organic solvents examples include methanol, ethanol, isopropanol, acetone, ethylacetate, dichloromethane, trichloromethane, dioxane, tetrahydrofurane, acetonitrile, diethylether and tert-butyl methyl ether.
  • a preferred organic solvent is dichloromethane.
  • Water is preferably not considered as organic solvent. It is further preferred that step 1) is carried out under mechanical movement such as stirring.
  • step m) sulfuric acid can preferably be added to the solution from step 1).
  • step 1) while adding the solution of step 1) the suspension is subjected to a mechanical movement such as stirring.
  • a second organic solvent can be added after the addition of sulfuric acid.
  • the second organic solvent correspond to the organic solvents mentioned above.
  • the second organic solvent is isopropanol.
  • step m) includes further stirring for 1 to 24 hours, preferably 2 to 20 hours, in particular 4 to 16 hours.
  • Step n) of isolating filgotinib sulfate Form S 1 can preferably comprise cooling the mixture of step m), preferably to a temperature of 0°C to 27°C, more preferably 5°C to 25°C, in particular 15 °C to 23°C.
  • step n) isolating filgotinib sulfate Form S I can preferably be carried out by filtering off the solid. Further, filgotinib sulfate Form S I can preferably be washed, preferably with dichloromethane. Subsequently, the filgotinib sulfate Form S I can preferably be dried. Drying can preferably be carried out at a temperature of 23°C to 70°C, preferably of 30°C to 60°C. Alternatively or additionally the drying can preferably be carried out under reduced pressure of 1 to 500 mbar, in particular 3 to 45 mbar.
  • filgotinib sulfate is easily accessible by a process without the use of complex, time and cost intensive process steps.
  • a further subject of the present invention is filgotinib sulfate having characteristic X-ray powder diffraction peaks at 4.5, 6.0, 1 1.4, 16.7 and 22.6 degrees 2 ⁇ (+ 0.2 degrees 2 ⁇ ). This filgotinib sulfate can be considered as polymorphic Form S2 of filgotinib sulfate.
  • the filgotinib sulfate Form S2 can be characterized by one or more further XRPD diffraction peak(s) at 10.5, 15.8, 19.3, 20.9 and/or 25.6 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • filgotinib sulfate Form S2 can be characterized by the XRPD diffraction peak(s) at degrees 2 ⁇ + 0.2 degrees 2 ⁇ (intensity ): 4.5 (10), 6.0 (12), 6.5 (1), 9.0 (2), 9.5 (5), 10.5 (27), 11.4 (20), 12.0 (55), 12.4 (2), 12.8 (5), 13.1 (1), 13.4 (8), 14.0 (9), 14.5 (6),
  • filgotinib sulfate Form S2 can be characterized by an FT- IR spectrum showing peaks at the following wave numbers: 3421, 3205, 3109, 3010, 2985, 2935, 2602, 2118, 1703, 1647, 1597, 1570, 1506, 1460, 1446, 1402, 1392, 1331, 1309, 1230, 1200, 1155, 1132, 1068, 1045, 1018, 953, 912, 866, 847, 796, 785, 731, 710, 683, 633.
  • Filgotinib sulfate Form S2 can for example be prepared by the following steps:
  • a further subject of the present invention is filgotinib sulfate having characteristic X-ray powder diffraction peaks at 8.4, 12.1, 14.9, 16.9 and 20.0 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • This filgotinib sulfate can be considered as polymorphic Form S3 of filgotinib sulfate.
  • the filgotinib sulfate Form S3 can be characterized by one or more further XRPD diffraction peak(s) at 9.9, 10.4, 20.9, 22.3 and/or 26.0 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • filgotinib sulfate Form S3 can be characterized by the XRPD diffraction peak(s) at degrees 2 ⁇ ⁇ 0.2 degrees 2 ⁇ (intensity %): 5.0 (4), 8.4 (71), 9.1 (8), 9.9 (30), 10.4 (36), 12.1 (100), 13.6 (14), 14.9 (14), 15.2 (8), 15.6 (5), 16.9 (30), 18.3 (7), 18.8 (8), 20.0 (37), 20.9 (38), 22.3 (37), 22.7 (18), 24.2 (26), 25.3 (21), 26.0 (45), 26.6 (10), 27.7 (19), 28.2 (22), 29.1 (8), 29.6 (8), 30.1 (2), 30.9 (8), 31.5 (7), 32.3 (10), 34.2 (4), 34.9 (6), 35.2 (7), 37.0 (7), 37.6 (3), 38.6 (2), 40.6 (8), 41.6 (7) and 42.6 (7).
  • filgotinib sulfate Form S3 can be characterized by an FT- IR spectrum showing peaks at the following wave numbers: 2983, 2928, 1695, 1649, 1595, 1576, 1525, 1502, 1452, 1394, 1356, 1302, 1271, 1169, 1122, 1074, 1024, 953, 781 , 733.
  • Filgotinib sulfate Form S3 can be for example be prepared by the following steps: suspending filgotinib in organic solvent
  • Step qs 3 can preferably be carried out in a humidity chamber.
  • step qs 3 ) can preferably be conducted by applying DVS (dynamic vapour sorption) to the raw product of step p S3 , wherein the DVS can preferably be characterized by the differing humidities as follows:
  • a further subject of the present invention is filgotinib sulfate having characteristic X-ray powder diffraction peaks at 5.1, 10.1, 13.0, 15.4 and 17.1 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • This filgotinib sulfate can be considered as polymorphic Form S4 of filgotinib sulfate.
  • the filgotinib sulfate Form S4 can be characterized by one or more further XRPD diffraction peak(s) at 11.0, 18.8, 19.7, 22.3 and/or 25.6 degrees 2 ⁇ ( ⁇ 0.2 degrees 2 ⁇ ).
  • filgotinib sulfate Form S4 can be characterized by the XRPD diffraction peak(s) at degrees 2 ⁇ ⁇ 0.2 degrees 2 ⁇ (intensity %): 5.1 (49), 9.2 (13), 10.1 (45), 10.3 (17), 11.0 (55), 11.4 (2), 12.0 (3), 13.0 (20), 13.7 (9), 15.4 (29), 15.8 (13), 16.0 (8), 17.1 (27), 18.8 (83), 19.1 (26), 19.7 (100), 21.1 (3), 22.3 (53), 22.8 (27), 23.6 (15), 24.8 (24), 25.6 (56), 26.1 (54), 27.5 (24), 27.8 (35), 28.2 (17), 28.9 (13), 29.2 (13), 30.6 (17), 31.2 (14), 31.8 (7), 32.5 (4), 33.5 (17), 35.0 (3), 36.8 (7), 38.2 (3), 38.7 (3), 39.7 (4), 40.4 (4), 41.2 (9),
  • filgotinib sulfate Form S4 can be characterized by an FT- IR spectrum showing peaks at the following wave numbers: 2983, 2929, 1695, 1649, 1595, 1574, 1502, 1454, 1394, 1354, 1304, 1271 , 1165, 1126, 1024, 953, 843, 818, 781, 733, 717, 708, 683.
  • Filgotinib sulfate Form S4 can for example be prepared by the following steps: ls 4 ) suspending filgotinib in organic solvent
  • the present filgotinib sulfate polymorphic forms show a superior solubility, compared with filgotinib and even with the corresponding filgotinib sulfonic acid addition salts.
  • the present filgotinib sulfate shows a low polymorphism, which is advantageous in view of the regulations for pharmaceutical products.
  • the present filgotinib sulfates in particular Form S3 and S4, can be provided essentially free of residual organic solvent. Essentially free of residual organic solvent describes that the corresponding filgotinib sulfate contains an amount of residual organic solvent which is significantly below the concentration limit of an organic solvent as mentioned above with regard to the Guidance for Industry, Q3C-Tables and List.
  • organic solvents being referred to as residual organic solvents as well as organic solvents used in the preparation of the above-mentioned filgotinib sulfate polymorphs
  • organic solvents can be methanol, ethanol, isopropanol, acetone, ethylacetate, dichloro methane, trichloromethane, dioxane, tetrahydrofurane, acetonitrile, diethylether and tert-batyl methyl ether, preferably dichloromethane, methanol and a mixture of dichloromethane and methanol.
  • the present invention furthermore relates to pharmaceutical compositions comprising the compounds of the invention, in particular filgotinib hydrochloride Form E and Form F.
  • the parmaceutical formulation can preferebly be further processed to an oral doasage form, such as a capsule or tablet.
  • the present pharmaceutical composition and/or the oral dosage form of the present invention can be prepared by the methods well known to a person skilled in the art such as dry and wet granulation and direct compresion.
  • the pharmaceutical composition can additionally contain one or more pharmaceutically acceptable excipient(s), such as fillers, binders, glidants, disintegrants, lubricants, flow regulating agents and release agents. Suitable excipients are for example disclosed in "Lexikon der Hilfsscher fiir Pharmazie, Kosmetik und angrenzende füre", published by H.P. Fielder, 4 th Edition and "Handbook of Pharmaceutical Excipients", 3 rd Edition, published by A.H. Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London.
  • filler generally means substances which serve to form the body of the tablet in the case of tablets with small amounts of active agent (e.g. less than 60% by weight). This means that fillers "dilute" the active agent(s) in order to produce an adequate tablet compression mixture. The normal purpose of fillers therefore is to obtain a suitable tablet size.
  • preferred fillers are lactose, lactose derivatives, starch, starch derivatives, treated starch, chitin, cellulose and derivatives thereof, calcium phosphate, calcium hydrogen phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulphate, dextrates, dextrin and/or dextrose, hydrogenated vegetable oil. Fillers can be present in an amount of 0 to 80% by weight, preferably in an amount of 10 to 60% by weight of the total weight of the composition.
  • a binder is generally a substance which is capable of increasing the strength of the resulting dosage form, especially the resulting tablets.
  • Suitable binders are for example polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, sugars, dextran, corn starch. Binders can be present in an amount of 0 to 30% by weight, preferably in an amount of 2 to 15% by weight of the total weight of the composition.
  • Glidants can be used to improve the flowability.
  • Suitable glidants are for example alkaline earth metal salts of fatty acids, like stearic acid.
  • the glidant can be present for example in an amount of 0 to 2% by weight, preferably in an amount of 0.5 to 1.5% by weight of the total weight of the composition.
  • Disintegrants are compounds which enhance the ability of the dosage form, preferably the ability of the tablet, to break into smaller fragments when in contact with a liquid, preferably water.
  • Suitable disintegrants are for example croscarmellose sodium, sodium carboxymefhyl starch, crosslinked polyvinylpyrrolidone (crospovidone), sodium carboxymethylglycolate (such as Explotab) and sodium bicarbonate.
  • the disintegrant can be present in an amount of 0 to 20% by weight, preferably in an amount of 1 to 15% by weight of the total weight of the composition.
  • a suitable flow regulating agent is for example colloidal silica.
  • the flow regulating agent can be present in an amount of 0 to 8% by weight, preferably in an amount of 0.1 to 3% by weight of the total weight of this composition.
  • a suitable release agent is for example talcum.
  • the release agent can be present in an amount of 0 to 5% by weight, preferably in an amount of 0.5 to 3% by weight of the total weight of the composition.
  • the pharmaceutical composition is processed into an oral dosage form.
  • the oral dosage form preferably a tablet or a capsule, more preferably a tablet, can preferably be coated, preferably film coated.
  • film coating without affecting the release of the active ingredient
  • film coatings can be prepared by using film-forming agents such as waxes, cellulose derivatives, poly(meth)acrylate, polyvinylpyrrolidone, polyvinyl acetate phthalate, and/or shellac or natural rubbers such as carrageenan.
  • film-forming agents such as waxes, cellulose derivatives, poly(meth)acrylate, polyvinylpyrrolidone, polyvinyl acetate phthalate, and/or shellac or natural rubbers such as carrageenan.
  • the present tablet is coated with a gastric juice-resistant film coating.
  • a capsule comprising a gastric juice-resistant film coating can be used.
  • the gastric juice-resistant film coating preferably is a film coating being stable in the pH range of about 0.7 to 3.0, which is supposed to be the pH-value of human gastric juice found in the stomach. However, in an environment with a pH value of 5 to 9, which is supposed to be present in the (small) intestine of the human body, the gastric juice-resistant film coating preferably dissolves and the drug can be released.
  • the gastric juice-resistant film coating (often also referred to as enteric coating) can comprise film-forming agents, for example fats, fatty acids, waxes, alginates, shellac, polyvinyl acetate phthalate, cellulose derivatives such as carboxy methyl ethyl cellulose, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate trimellitate, and meth(acrylic)acid copolymers such as methyl acrylate-methacrylic acid copolymers, methyl methacrylate-methacrylic acid copolymers, Eudragits (for example Eudragit ® L30D, Eudragit ® L, Eudragit ® S).
  • film-forming agents for example fats, fatty acids, waxes, alginates, shellac, polyvinyl acetate phthalate, cellulose derivatives such as carb
  • the coating is preferably free of active ingredient. It is further preferred that the thickness of the coating is usually 10 ⁇ to 2 mm, preferably from 50 to 500 ⁇ .
  • the preferred coating may comprise a film-forming agent and one or more of the following: lubricant, surfactant, glidant, pigment and water.
  • the preferred coating according to an embodiment of the present invention can comprise, along with the film-forming agent, e.g. stearic acid as lubricant for plasticizing and dissolving the polymer, sodium lauryl sulfate as a surfactant for wetting and dispersing, talc as glidant, iron oxide yellow and/or titanium oxide as pigment(s) and optionally purified water.
  • the film-forming agent e.g. stearic acid as lubricant for plasticizing and dissolving the polymer
  • sodium lauryl sulfate as a surfactant for wetting and dispersing
  • talc as glidant
  • iron oxide yellow and/or titanium oxide as pigment(s) and optionally purified water.
  • the pharmaceutical composition can be administered one to three times a day, preferably once or twice a day, more preferably once a day.
  • the present invention further relates to the use of the present compound, in particular filgotinib hydrochloride Form E and Form F, for preparing a pharmaceutical preparation for the treatment of patients with rheumatoid arthritis and other inflammatory diseases.
  • Solvent A acetonitrile
  • Method B corresponds to Method A, wherein the injection volume is amended to be 2 ⁇ and the following solvent gradient profile time [min] solvent B [%]
  • Method C corresponds to Method A, wherein the flow is amended to be 1 ml/min and the following solvent gradient profile time [min] solvent B [%]
  • XRPD X-Ray Powder Diffraction
  • FT Fourier Transform
  • IR Infrared
  • Spectroscopy Instrument Thermo Nicolet, Avatar 330 FT-IR. Smart Endurance Diamond-ATR.
  • Software Omnic Vers. 6.1 a. The sample was measured in solid form by pi the sample in the sample holder and directly carrying out the measurement.
  • test substance 75 mg (exactly weighed) test substance was weighed into a glass vial, followed by addition of 3 ml solvent (corresponding buffer system at various pH). A stirring bar was added, the vial was fixed in a block heater at 37°C and the suspension was stirred with approx. 250 rpm. After 15 min and 1 h, samples were withdrawn, filtered through a 0.2 ⁇ disposable filter, 50 ⁇ of the clear filtrate were diluted with 950 ⁇ DMSO and 2 ⁇ thereof were analyzed by HPLC/UV.
  • Carrier gas (flow): He (l.O ml/min)
  • Detection mode Scan (m/z 20 - 300) Identification by EI spectrum and retention time:
  • the obtained filgotinib hydrodrochloride Form E was free of dichloromethane (residual solvent).
  • the following data is identical in Examples 2 and 2'
  • Filgotinib hydrochloride Form E was exposed to 40°C and 75% relative humidity in an open glass vial for 4 weeks. The product completely transformed into Form F. The filgotinib hydrodrochloride Form F was free of dichloromethane (residual solvent).
  • Example 4 Filgotinib hydrochloride Form A
  • the obtained dichloromethane (residual solvent) content of filgotinib hydrochloride Form B was 512 ppm.
  • Example 8 Filgotinib sulfate Form SI 0.5 g (0.12 mmol) filgotinib base were dissolved in 40 ml dichloromethane. At 23 °C sulfuric acid (0.07 ml) was added in one portion into this solution. A syrupy residue was formed. Isopropyl alcohol (2 ml) was added. The reaction mixture was stirred over night at 23°C, forming a white precipiate. The product was filtered off, washed with dichloromethane (10 ml) and dried for 2.5 hours at 50°C / 20 mbar. Name Filgotinib sulfate, Form S 1
  • the obtained filgotinib sulfate Form S3 was free of dichloromethane (residual solvent).
  • a mixture of 4.0 g (9.4 mmol) filgotinib base and 160 ml dichloromethane was heated to reflux and 1 ml methanol was added. While maintaining this temperature, 2.0 ml sulfuric acid (30% aqueous solution) were added dropwise. Precipitation of a solid was observed. Stirring at reflux was continued for 80 minutes. Then, the reaction mixture was slowly cooled down to 23°C and stirred over night. The white product was filtered off, washed with 80 ml dichloromethane and dried at 50°C / 20 mbar for two days. To this product 27 ml water were added and the mixture was stirred for 15 minutes. Thereafter, another 27 ml water were added and stirring was continued for 3 hours, the product was filtered off and dried over night at 50°C.
  • the obtained filgotinib sulfate Form S3 was free of dichloromethane (residual solvent).

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Abstract

La présente invention concerne un sel d'addition d'acide de chlorhydrate de filgotinib, ses polymorphes, un procédé de préparation de celui-ci ainsi qu'une composition pharmaceutique le comprenant.
PCT/EP2016/063151 2015-07-23 2016-06-09 Sels d'addition d'acide de filgotinib Ceased WO2017012770A1 (fr)

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Cited By (9)

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WO2018169875A1 (fr) * 2017-03-14 2018-09-20 Gilead Sciences, Inc. Compositions pharmaceutiques comprenant un inhibiteur de jak
WO2020177705A1 (fr) * 2019-03-05 2020-09-10 苏州科睿思制药有限公司 Forme cristalline csi de maléate de filgotinib, son procédé de préparation et son utilisation
WO2021044327A1 (fr) * 2019-09-03 2021-03-11 Dr. Reddy's Laboratories Limited Formes solides de maléate de filgotinib et procédés associés
US11130796B2 (en) 2017-01-05 2021-09-28 Kahr Medical Ltd. SIRPalpha-41BBL fusion protein and methods of use thereof
US11299530B2 (en) 2017-01-05 2022-04-12 Kahr Medical Ltd. SIRP alpha-CD70 fusion protein and methods of use thereof
US11566060B2 (en) 2017-01-05 2023-01-31 Kahr Medical Ltd. PD1-CD70 fusion protein and methods of use thereof
US11702458B2 (en) 2017-01-05 2023-07-18 Kahr Medical Ltd. PD1-41BBL fusion protein and methods of use thereof
US12134638B2 (en) 2018-07-11 2024-11-05 Kahr Medical Ltd. SIRPalpha-4-1BBL variant fusion protein and methods of use thereof
US12286466B2 (en) 2018-07-11 2025-04-29 Kahr Medical Ltd. PD1-4-1BBL variant fusion protein and methods of use thereof

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WO2010010190A1 (fr) 2008-07-25 2010-01-28 Galapagos Nv Nouveaux composés utiles pour le traitement de maladies dégénératives et inflammatoires
WO2010149769A1 (fr) 2009-06-26 2010-12-29 Galapagos Nv 5-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-carboxamides utilises en tant qu'inhibiteurs de jak

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11702458B2 (en) 2017-01-05 2023-07-18 Kahr Medical Ltd. PD1-41BBL fusion protein and methods of use thereof
US12331098B2 (en) 2017-01-05 2025-06-17 Kahr Medical Ltd. SIRPalpha-41BBL fusion protein and methods of use thereof
US11897937B2 (en) 2017-01-05 2024-02-13 Kahr Medical Ltd. SIRPalpha-41BBL fusion protein and methods of use thereof
US11130796B2 (en) 2017-01-05 2021-09-28 Kahr Medical Ltd. SIRPalpha-41BBL fusion protein and methods of use thereof
US11299530B2 (en) 2017-01-05 2022-04-12 Kahr Medical Ltd. SIRP alpha-CD70 fusion protein and methods of use thereof
US11566060B2 (en) 2017-01-05 2023-01-31 Kahr Medical Ltd. PD1-CD70 fusion protein and methods of use thereof
WO2018169875A1 (fr) * 2017-03-14 2018-09-20 Gilead Sciences, Inc. Compositions pharmaceutiques comprenant un inhibiteur de jak
EP4368173A3 (fr) * 2017-03-14 2024-06-12 Galapagos N.V. Compositions pharmaceutiques comprenant un inhibiteur de jak
EP3595667B1 (fr) 2017-03-14 2023-12-20 Galapagos NV Compositions pharmaceutiques comprenant un inhibiteur de jak
US12502394B2 (en) 2017-03-14 2025-12-23 Alfasigma S.P.A. Pharmaceutical compositions comprising a JAK inhibitor
US12134638B2 (en) 2018-07-11 2024-11-05 Kahr Medical Ltd. SIRPalpha-4-1BBL variant fusion protein and methods of use thereof
US12286466B2 (en) 2018-07-11 2025-04-29 Kahr Medical Ltd. PD1-4-1BBL variant fusion protein and methods of use thereof
WO2020177705A1 (fr) * 2019-03-05 2020-09-10 苏州科睿思制药有限公司 Forme cristalline csi de maléate de filgotinib, son procédé de préparation et son utilisation
WO2021044327A1 (fr) * 2019-09-03 2021-03-11 Dr. Reddy's Laboratories Limited Formes solides de maléate de filgotinib et procédés associés

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