WO2017012771A1 - Crystalline filgotinib sulfonic acid addition salts - Google Patents

Abstract

The present invention relates to filgotinib sulfonic acid addition salts, their polymorphs, a method of preparing the same as well as a pharmaceutical composition comprising the same.

Description

CRYSTALLINE FILGOTINIB SULFONIC ACID ADDITION SALTS

The present invention relates to filgotinib sulfonic 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

Formula (I)

Filgotinib (also known as GLPG-0634 or N-(5-(4-((l , l -dioxothio- morpholino)methyl)phenyl)-[l,2,4]triazolo[l ,5-a]pyridin-2-yl]cyclopropane- carboxamide) is an orally available, selective inhibitor of JAK1 (Janus kinase 1) being developed by Galapagos for the treatment of rheumatoid arthritis and potentially other inflammatory diseases.

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 JAK1 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 in water. One option to enhance the solubility is the formation of a filgotinib basic 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.

Additionally, due to necessary preparation methods several filgotinib acid addition salts contain an unacceptably high residual content. However, according to FDA regulations any solvent is only acceptable to a certain concentration. These concentrations depend on the solvent and can be low or very low. For example, according to FDA regulations, dichloromethane, dioxane and ethanol are only allowable in amounts of 600 ppm, 380 ppm and 5000 ppm respectively. These values are difficult to achieve since employing conventional drying methods like drying at elevated temperatures with and without vacuum did not lead to pharmaceutically acceptable solvent levels and/or drug purity levels.

Consequently, there is still a need for filgotinib acid addition salts which are present in a pure and/or stable form.

Hence, it was an object of the present invention to overcome the drawbacks of the above-mentioned prior art. Additionally filgotinib acid addition salts should be provided in a form which is easy to prepare.

Further, a form of filgotimb addition salt having a residual solvent content within pharmaceutically acceptable limits should be provided.

Summary of the invention

According to the present invention, the above objectives are unexpectedly achieved by providing Filgotinib sulfonic acid addition salts having a residual solvent content within pharmaceutically acceptable limits, the process of their preparation and pharmaceutical compositions comprising said filgotinib sulfonic acid addition salts are provided. Filgotinib sulfonic acid addition salts might be present in different polymorphic forms or mixtures thereof.

Filgotinib sulfonic acid addition salt 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. For example, 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 features 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. Alternatively, 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 peak(s) in a solid state IR spectrum, solid state NMR or characteristics of the DSC thermogram of the crystal form that is being characterized.

Unless indicated otherwise, XRPD peaks are recorded using copper Και/ Ka₂ radiation with a wavelength 1.5406A (weighted mean of Cu Κα,ι and Cu Ka₂). Further, unless indicated otherwise, XRPD peaks are reported as degrees 2 theta values with a standard error of + 0.2 degrees 2 theta.

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 sulfonic acid addition salt having a residual solvent content within pharmaceutically acceptable limits.

In the present application residual solvent content within pharmaceutically acceptable limits refers to a concentration limit (in ppm) of the corresponding solvent. Further, water is not considered to be a 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, whose concentration limit is 2 ppm.

centration Limit

Solvent Concern

(ppm)

Benzene 2 Carcinogen

Carbon tetrachloride 4 Toxic and environmental hazard

1 ,2-Dichloroethane 5 Toxic

1 , 1 -Dichloroethene 8 Toxic

1 ,1, 1 -Trichloroethane 1 ,500 Environmental hazard

Table 1: Class 1 solvents and their concentration limits

Class 2 relates to solvents that should be limited in pharmaceutical products because of their inherent toxicity.

Solvent PDE (mg/day) Concentration Limit (ppm)

Acetonitrile 4.1 410

Chlorobenzene 3.6 360

Chloroform 0.6 60

Cyclohexane 38.8 3,880

Cumene 0.7 70

1 ,2-Dichloroethene 18.7 1 ,870

Dichloromethane 6.0 600

1 ,2-Dimethoxyethane 1.0 100

N,N-Dimethylacetamide 10.9 1 ,090

N,N-Dimethylformamide 8.8 880

1 ,4-Dioxane 3.8 380

2-Ethoxyethanol 1 .6 160

Ethyleneglycol 6.2 620

Form amide 2.2 220

Hexane 2.9 290

Methanol 30.0 3,000

2-Methoxyethanol 0.5 50

Methylbutyl ketone 0.5 50

Methyl cyclohexane 1 1.8 1 ,180

N-Methylpyrrolidone 5.3 530

Nitromethane 0.5 50

Pyridine 2.0 200

Sulfolane 1.6 160

Tetrahydro furan 7.2 720

Tetralin 1.0 100

Toluene 8.9 890

1 , 1 ,2-Trichloroethene 0.8 80

Xylene¹ 21.7 2,170

Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.

Table 2: 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.

The acids which are used to prepare filgotinib sulfonic acid addition salt are sulfonic acids. Sulfonic acids are acids with the general formula RS(0)₂OH, wherein R is an alkyl or aryl group. Salts of sulfonic acids can be referred to as sulfonates.

Examples of sulfonic acid are methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid and ethanedisulfonic acid. The salts of the corresponding acids are referred to as methanesulfonate or mesylate, ethanesulfonate or esylate, toluenesulfonate or tosylate, benzenesulfonate or besylate, and ethanedisulfonate or edisylate, respectively. EP2016/063157

Consequently a filgotinib sulfonic addition salt containing filgotinib and two identical sulfonic acids can be referred to as filgotinib disulfonate.

A possible embodiment of the present invention is filgotinib dimesylate having characteristic X-ray powder diffraction peaks at 8.6, 16.6, 17.2, 20.1 and 22.8 degrees 2Θ (+ 0.2 degrees 2Θ). This filgotinib dimesylate can be considered as polymorphic Form DM1 of filgotinib dimesylate.

In a preferred embodiment the filgotinib dimesylate Form DM1 can be characterized by one or more further XRPD diffraction peak(s) at 10.2, 10.5, 18.6, 20.7 and/or 21.1 degrees 2Θ (± 0.2 degrees 2Θ).

In an alternatively further preferred embodiment of the present invention filgotinib dimesylate Form DM1 can be characterized by the XRPD diffraction peak(s) at degrees 2Θ ± 0.2 degrees 2Θ (intensity %): 8.6 (57), 10.2 (8), 10.5 (6), 11.5 (5), 13.4 (3), 16.6 (21), 17.2 (65), 18.1 (7), 18.6 (18), 19.3 (6), 20.1 (59), 20.7 (35),

21.1 (100), 21.4 (9), 22.2 (12), 22.8 (40), 23.1 (15), 24.1 (15), 24.9 (26), 25.8 (5),

26.2 (8), 26.7 (6), 28.0 (9), 29.5 (6), 30.0 (9), 30.8 (6), 31.8 (9), 32.7 ( 10), 34.2 (12), 37.9 (9), 38.5 (5), 39.5 (5), 40.9 (3), 43.3 (3), 44.0 (4) and 44.8 (2).

Alternatively preferred, filgotinib dimesylate Form DM1 can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 3007, 2931, 1711, 1647, 1595, 1568, 1504, 1471, 1458, 1421, 1400, 1344, 1313, 1277, 1228, 1219, 1194, 1169, 1126, 1072, 1036, 953, 912, 866, 841, 822, 785, 771, 731, 715, 675, 650, 634, 625, 607.

Filgotinib dimesylate Form DM1 can for example be prepared by the following steps: aDMi) suspending/dissolving filgotinib in an organic solvent or a mixture of organic solvents

boM i) heating the mixture to reflux to form a solution CDMI) adding methanesulfonic acid in organic solvent

dDMi ) isolating filgotinib dimesylate Form DM1

In an alternatively preferred embodiment filgotinib dimesylate Form DM1 can be prepared by the following steps:

¾>M I') suspending/dissolving filgotinib in an organic solvent or a mixture of organic solvents

bDMi heating the mixture to reflux to form a solution

CDM I adding methanesulfonic acid in organic solvent

DMi cooling to room temperature

e_DMi isolating filgotinib dimesylate Form DM1

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)- [ 1 ,2,4 ]triazolo[ 1 ,5 a]pyridine-2yl]- amide with thiomorpholine dioxide until the completion of the reaction and the evaporation of the solvent. Up to this point the reactions steps were 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 solvent. Subsequently, the product was filtered off and dried. Examples of organic solvents are methanol, ethanol, isopropanol, acetone, ethylacetate, dichloromethane, trichloromethane, dioxane, tetrahydrofurane, acetonitrile, diethylether and tert-Butylmethylether.

Another possible embodiment of the present invention is filgotinib diesylate having characteristic X-ray powder diffraction peaks at 8.1 , 10.3, 16.2, 19.9 and 21.1 degrees 2Θ (± 0.2 degrees 2Θ). This filgotinib diesylate can be considered as polymorphic Form DEI of filgotinib diesylate. In a preferred embodiment the filgotinib diesylate Form DEI can be characterized by one or more further XRPD diffraction peak(s) at 11.2, 18.2, 18.9, 23.4 and/or 23.7 degrees 2Θ (± 0.2 degrees 2Θ). In an alternatively further preferred embodiment of the present invention filgotinib diesylate Form DEI can be characterized by the XRPD diffraction peak(s) at degrees 2Θ ± 0.2 degrees 2Θ (intensity %) : 8.1 (49), 8.4 (1), 10.3 (9), 11.2 (9), 12.0 (3), 13.4 (1), 15.3 (2), 15.9 (3), 16.2 (38), 16.5 (5), 16.8 (3), 17.7 (2), 17.9 (5), 18.2 (30), 18.3 (13), 18.7 (3), 18.9 (28), 19.9 (13), 21.1 (100), 22.1 (3), 22.4 (3), 22.9 (10), 23.4 (15), 23.7 (18), 24.3 (6), 24.5 (5), 24.8 (2), 25.1 (4), 25.7 (7), 26.6 (6), 26.9 (9), 27.3 (4), 27.8 (2), 28.6 (8), 29.2 (3), 29.6 (1), 30.2 (2), 30.4 (3), 30.9 (15), 32.6 (5), 33.4 (4), 33.7 (5), 34.7 (8), 36.1 (2), 37.0 (1), 38.0 (3), 38.4 (2),

39.0 (2), 40.0 (2), 40.7 (1), 41.9 (2), 42.6 (2), 43.0 (1), 43.8 (1), 45.0 (1), 45.9 (2),

47.1 (2) and 48.3 (2).

Alternatively preferred filgotinib diesylate Form DEI can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 3257, 2983, 2931, 2879, 2565, 1714, 1647, 1601, 1572, 1543, 1527, 1506, 1462, 1421, 1402, 1342, 1311, 1277, 1244, 1230, 1192, 1182, 1 149, 1 132, 1066, 1055, 1028, 985, 957, 910, 866, 833, 779, 768, 737, 714, 677, 652, 633, 623.

Filgotinib diesylate Form DEI can be for example be prepared by the following steps: a_DEi) dissolving filgotinib in an organic solvent

b_DEi) heating

CDE I) adding ethanesulfo ic acid

d_DEi ) isolating filgotinib diesylate Form DEI In an alternatively preferred embodiment filgotinib diesylate Form DEI can for example be prepared by the following steps: a_DEi dissolving filgotinib in an organic solvent

b_DEr) heating

c_{DE1 '}) adding ethanesulfonic acid

do_Ei cooling to room temperature

e_DEr) isolating filgotinib diesylate Form DEI

Filgotinib and organic solvents can correspond to the ones described above.

Another possible embodiment of the present invention is filgotinib diesylate having characteristic X-ray powder diffraction peaks at 7.9, 9.5, 19.5, 21.3 and 23.2 degrees 2Θ (± 0.2 degrees 2Θ). This filgotinib diesylate can be considered as polymorphic Form DE2 of filgotinib diesylate.

In a preferred embodiment the filgotinib diesylate Form DE2 can be characterized by one or more further XRPD diffraction peak(s) at 11.3, 15.9, 18.3, 20.8 and/or

22.4 degrees 2Θ (± 0.2 degrees 2Θ).

In an alternatively further preferred embodiment of the present invention filgotinib diesylate Form DE2 can be characterized by the XRPD diffraction peak(s) at degrees 2Θ + 0.2 degrees 2Θ (intensity %): 7.9 (91), 8.4 (11), 9.5 (9), 9.7 (6), 11.3 (13), 12.2 (2), 13.2 (3), 14.3 (4), 15.9 (74), 16.8 (15), 17.4 (7), 18.3 (71), 18.9 (8),

19.5 (24), 20.3 (4), 20.8 (32), 21.3 (53), 21.6 (20), 22.4 (100), 23.2 (60), 23.9 (3), 24.7 (16), 25.0 (21), 26.7 (9), 27.4 (11), 27,9 (9), 29.2 (14), 29.5 (10), 30.8 (22), 31.1 (18), 32.2 (3), 32.9 (6), 33.5 (5), 34.6 (4), 36.0 (7), 36.5 (3), 37.8 (3), 38.3 (4), 39.0 (7), 39.7 (5), 40.2 (5) and 40.7 (4).

Alternatively preferred, filgotinib diesylate Form DE2 can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 2983, 2933, 1713, 1647, 1597, 1570, 1527, 1504, 1458, 1419, 1398, 1346, 1311, 1275, 1246, 1190, 1176, 1128, 1066, 1026, 978, 955, 910, 866, 839, 822, 796, 783, 766, 737, 714, 675, 650, 633, 625, 607. Filgotinib diesylate Form DE2 can be for example be prepared by the following steps:

¾>E2) dissolving filgotinib in an organic solvent and heating the mixture b_DE2) slowly adding ethanesulfonic acid

CDE2 precipitating filgotinib diesylate at room temperature

DE2) isolating filgotinib diesylate Form DE2

Filgotinib and organic solvents can correspond to the ones described above.

In a preferred embodiment of the invention the sulfonic acid is selected from toluenesulfonic acid, preferably p-toluenesulfonic acid, benzenesulfonic acid and ethanesdisulfonic acid, preferably 1 ,2-ethanedisulfonic acid. Particularly preferred is 1 ,2-ethanedisulfonic acid.

Thus, a preferred embodiment of the present invention is filgotinib dibesylate having characteristic X-ray powder diffraction peaks at 8.7, 15.2, 18.2, 19.7 and 24.8 degrees 2Θ (± 0.2 degrees 2Θ). This filgotinib dibesylate can be considered as polymorphic Form DB 1 of filgotinib dibesylate.

In a preferred embodiment the filgotinib dibesylate Form DB 1 can be characterized by one or more further XRPD diffraction peak(s) at 7.2, 9.9, 18.4, 19.4 and/or 24.0 degrees 2Θ (± 0.2 degrees 2Θ). In an alternatively further preferred embodiment of the present invention filgotinib dibesylate Form DB 1 can be characterized by the XRPD diffraction peak(s) at degrees 2Θ ± 0.2 degrees 2Θ (intensity %): 7.2 (25), 8.7 (11), 9.9 (26), 10.2 (2), 11.3 (4), 12.3 (8), 12.5 (2), 14.1 (3), 14.5 (8), 15.2 (44), 15.7 (3), 16.7 (2), 17.0 (2), 17.4 (9), 18.2 (70), 18.4 (27), 18.8 (12), 19.4 (45), 19.7 (100), 20.4 (28), 20.5 (28), 21.1 (12), 21.7 (23), 21.8 (16), 22.4 (14), 22.7 (27), 23.1 (21), 23.6 (19), 24.0 (30), 24.8 (22), 25.1 (15), 25.7 (23), 26.8 (7), 27.0 (5), 28.1 (14), 28.4 (9), 28.9 (12), 29.3 (6), 29.8 (13), 30.4 (2), 31.0 (5), 31.4 (6), 32.0 (2), 32.7 (3), 33.4 (3), 33.9 (5), 34.2 (6), 34.6 (7), 36.3 (8), 37.4 (2), 38.4 (4), 39.2 (2), 40.1 (2), 40.7 (2), 41.9 (3), 43.3 (3), 43.9 (3), 45.1 (3), 46.4 (5) and 48.3 (3).

An XRPD-diffraction pattern of filgotinib Form DB 1 is shown in Figure 1.

Alternatively preferred filgotinib dibesylate Form DB 1 can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 3338, 3014, 2983, 2933, 1703, 1653, 1605, 1574, 1543, 1529, 1502, 1460, 1444, 1402, 1356, 1342, 1315, 1290, 1275, 1228, 1161, 1122, 1070, 1063, 1034, 1014, 995, 951, 931, 906, 870, 862, 839, 823, 795, 760, 727, 692, 636, 609.

Filgotinib dibesylate Form DB 1 can be for example be prepared by the following steps: aoB i ) dissolving filgotinib in an organic solvent and heating the solution oBi) adding benzenesulfonic acid in organic solvent to the solution of step ao_Bi CDB I ) isolating filgotinib dibesylate Form DB1

In step a_DB i ) filgotinib and organic solvent can correspond to the ones described above. A preferred organic solvent is 1 ,4-dioxane.

Further, the solution is heated from 23 °C (ambient temperature) to an elevated temperature. An elevated temperature can be from 23 °C to the boiling point of the solvent. In case that dioxane is used as solvent the solution can be preferably heated to a temperature of 40°C to 100°C, more preferably 50°C to 95°C , in particular to about 80°C.

In step boBi) benzenesulfonic acid dissolved in an organic solvent is added to the solution of step aoBi)- The organic solvent can preferably be 1,4 dioxane.

Both steps aoBi) and boBi) can preferably be conducted under mechanical movement such as stirring.

I In step c_DB i) isolating of filgotinib dibesylate Form DB 1 can comprise cooling the mixture of step b_DB i), preferably to 23°C (room temperature). Further the step can be carried out by filtering off the solid. Further, the solid can preferably be washed, preferably with 1,4-dioxane. Subsequently, filgotinib dibesylate Form DB 1 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. In an alternative preferred embodiment filgotinib dibesylate Form DB l can be prepared by the following steps:

¾>Β Γ) dissolving filgotinib in an organic solvent and heating the solution bo_Bi adding benzenesulfonic acid in organic solvent to the solution of step aDB i CDB T) cooling to room temperature

do_Br) isolating filgotinib dibesylate Form DB 1

With regard to steps ΟΒ Γ) and b_DBr) the explanation given above in view of steps a_DB i) and b_DB i ) apply.

In step CDB T) the mixture of b_DB i is cooled, preferably cooled to 23°C (room temperature).

Step doBi ') can preferably be carried out by filtering off the solid. Further, the solid can preferably be washed, preferably with 1,4-dioxane. Subsequently, filgotinib dibesylate Form DB1 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.

Another preferred embodiment of the present invention is filgotinib dibesylate having characteristic X-ray powder diffraction peaks at 3.6, 7.4, 13.3, 15.0 and 17.6 degrees 2Θ (± 0.2 degrees 2Θ). This filgotinib dibesylate can be considered as polymorphic Form DB2 of filgotinib dibesylate.

In a preferred embodiment the filgotinib dibesylate Form DB2 can be characterized by one or more further XRPD diffraction peak(s) at 7.2, 11.4, 15.9, 19.5 and/or 25.8 degrees 2Θ (± 0.2 degrees 2Θ).

In an alternatively further preferred embodiment of the present invention filgotinib dibesylate Form DB2 can be characterized by the XRPD diffraction peak(s) at degrees 2Θ ± 0.2 degrees 2Θ (intensity %): 3.6 (9), 7.2 (29), 7.4 (9), 10.0 (2), 11.4 (52), 1 1.8 (13), 12.4 (14), 12.6 (16), 13.3 (15), 14.2 (3), 15.0 (67), 15.9 (36), 17.1 (9), 17.6 (37), 19.5 (100), 20.7 (21), 20.9 (20), 21.6 (31), 23.0 (84), 24.1 (9), 25.2 (49), 25.8 (95), 27.1 (25), 28.4 (6), 29.4 (5), 29.7 (7), 30.2 (8), 31.5 (9), 32.2 (10), 32.9 (7), 34.2 (17) and 35.6 (5).

An XRPD-diffraction pattern of filgotinib dibesylate Form DB2 is shown in Figure 2.

Alternatively preferred, filgotinib dibesylate Form DB2 can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 2982, 2933, 1701, 1651, 1597, 1574, 1525, 1504, 1444, 1398, 1387, 1360, 1309, 1282, 1240, 1217, 1180, 1142, 1120, 1066, 1032, 1014, 995, 951, 910, 883, 866, 837, 791, 760, 725, 714, 692, 607. Filgotinib dibesylate Form DB2 can for example be prepared by the following steps: aoB2) dissolving filgotinib in an organic solvent and heating the solution boB₂) slowly adding benzenesulfonic acid in organic solvent

c_DB₂) precipitating filgotinib dibesylate

d_DB₂) isolating filgotinib dibesylate Form DB2 Step _∑i ) can preferably correspond to above step aoB i). In step bo ) benzenesulfonic acid dissolved in organic solvent, preferably 1 ,4-dioxane, is added dropwise. Step c_DB2) includes cooling the mixture of step b_DB2) , preferably to a temperature of 0°C to 35°C, more preferably 5°C to 30°C, in particular 10°C to 27°C. Step doB₂) can preferably correspond to above step doB i) -

In an alternative preferred embodiment filgotinib dibesylate Form DB2 can be prepared by the following steps: aoB2_') dissolving filgotinib in an organic solvent and heating the solution bDB2') slowly adding benzenesulfonic acid in organic solvent

CDB2') precipitating filgotinib dibesylate

d_DB? isolating filgotinib dibesylate Form DB2

eDB2') storing under humid conditions.

With regard to steps aD_B2') to doB ') the explanation given above in view of steps a_DB2) to d_DB2) apply.

In step e_DB2 ') the filgotinib dibesylate Form DB2 is stored under humid conditions. Storing can preferably last from 12 hours to 7 days, more preferably from 1 day to 5 days, in particular from 2 to 4 days, especially 3 days. Further storing can be conducted under elevated temperature of 25° to 75°C, preferably of 30°C to 60°C, in particular 50°C. Humid conditions refer to a relative humidity of 60% to 100%, preferably of 80% to 100%, in particular 100%.

Further εοΒ2·) can comprise drying the product. 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 50 mbar.

An alternatively preferred embodiment of the present invention is filgotinib ditosylate having characteristic X-ray powder diffraction peaks at 6,3, 6.5, 9.7, 14.8 and 17.6 degrees 2Θ (± 0.2 degrees 2Θ). This filgotinib ditosylate can be considered as polymorphic Form DTI of filgotinib ditosylate.

In a preferred embodiment the filgotinib ditosylate Form DTI can be characterized by one or more further XRPD diffraction peak(s) at 11.2, 12.8, 16.1 , 18.4 and/or 21.0 degrees 2Θ (+ 0.2 degrees 2Θ).

In an alternatively further preferred embodiment of the present invention filgotinib ditosylate Form DTI can be characterized by the XRPD diffraction peak(s) at degrees 2Θ ± 0.2 degrees 2Θ (intensity %): 5.8 (4), 6.3 (30), 6.5 (46), 7.3 (2), 7.8 (3), 9.7 (17), 10.3 (2), 1 1.2 (8), 12.1 (1), 12.8 (7), 13.3 (3), 14.5 (1), 14.8 (3), 16.1 (10), 16.3 (5), 16.7 (6), 17.6 (41), 17.7 (36), 18.4 (38), 19.5 (12), 20.2 (12), 20.4 (16), 21.0 (100), 22.1 (12), 22.5 (6), 23.0 (9), 23.4 (12), 23.6 (12), 24.2 (5), 25.0 (6), 26.0 (4), 26.9 (12), 27.4 (4), 28.5 (4), 28.9 (8), 29.4 (13), 30.2 (4), 31.2 (4), 32.2 (4), 33.2 (5), 34.0 (3), 35.1 (1), 35.8 (2) and 37.0 (4).

An XRPD-diffraction pattern of filgotinib ditosylate Form DTI is shown in Figure J . Alternatively preferred, filgotinib ditosylate Form DTI can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 2928, 1707, 1649, 1599, 1504, 1497, 1452, 1396, 1348, 1309, 1288, 1277, 1219, 1147, 1134, 1117, 1065, 1030, 1005, 958, 931, 912, 868, 800, 735, 712, 677, 633, 606. Filgotinib ditosylate Form DTI can for example be prepared by the following steps: a_DTi) dissolving filgotinib in an organic solvent and heating the solution boTi) adding toluenesulfonic acid in organic solvent to the solution of step a_DTi) CDTI) isolating filgotinib ditosylate Form DTI Steps a_DTi ), b_DT1) and c_DT1) can preferably correspond to steps a_DBi), b_DBi) and CDB I)_> wherein in step boTi) toluenesulfonic acid is used instead of benzenesulfonic acid as in boB i) - Another alternatively preferred embodiment of the present invention is filgotinib ditosylate having characteristic X-ray powder diffraction peaks at 7.3, 11.4, 19.0, 21.9 and 25.3 degrees 2Θ (± 0.2 degrees 2Θ). This filgotinib ditosylate can be considered as polymorphic Form DT2 of filgotinib ditosylate. In a preferred embodiment the filgotinib ditosylate Form DT2 can be characterized by one or more further XRPD diffraction peak(s) at 10.9, 13.2, 15.7, 17.9 and/or 20.2 degrees 2Θ (+ 0.2 degrees 2Θ).

In an alternatively further preferred embodiment of the present invention filgotmib ditosylate Form DT2 can be characterized by the XRPD diffraction peak(s) at degrees 2Θ ± 0.2 degrees 2Θ (intensity %): 7.3 (100), 10.1 (9), 10.9 (20), 11.1 (9), 11.4 (25), 11.9 (12), 12.9 (20), 13.2 (33), 13.4 (19), 14.5 (8), 15.2 (8), 15.7 (28),

16.1 (16), 16.3 (4), 17.9 (36), 18.2 (6), 19.0 (53), 19.2 (42), 19.4 (3 1), 19.7 (27),

20.2 (48), 20.8 ( 16), 21.1 (23), 21.9 (53), 22.3 (47), 22.6 (54), 23.0 (18), 23.4 (16), 23.9 (19), 24.2 (28), 24.6 (17), 24.9 (19), 25.3 (58), 25.8 (11), 26.0 (12), 26.7 (7),

27.4 (20), 28.1 (3), 28.8 (6), 29.3 ( 15), 29.4 (15), 30.0 (12), 30.8 (26), 31.1 (15),

31.5 (7), 32.3 (5), 33.1 (12), 33.8 (3), 34.7 (8), 35.9 (7), 36.5 (4), 37.2 (3), 38.3 (15), 38.7 (5), 39.3 (6), 40.1 (5), 40.5 (4), 41.7 (6), 43.0 (4), 45.7 (6), 46.2 (4) and 46.8 (3).

An XRPD-diffraction pattern of filgotinib ditosylate Form DT2 is shown in Figure 4.

Alternatively preferred filgotinib ditosylate Form DT2 can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 3417, 2982, 2924, 1701, 1651, 1597, 1572, 1529, 506, 1497, 1448, 1423, 1390, 1358, 1340, 1308, 1288, 1217, 1184, 1157, 1 122, 1072, 1034, 1009, 949, 933, 914, 883, 860, 841 , 816, 800, 789, 771 , 739, 714, 679, 658, 634, 623, 604.

Filgotinib ditosylate Form DT2 can for example be prepared by the following steps: ao_T2) suspending filgotinib ditosylate form DTI in water

boT₂) isolating filgotinib ditosylate Form DT2 In step ami) filgotinib ditosylate form DTI is suspended in water. The step is preferably carried out under mechanical movement such as stirring. Further, it is preferred that the stirring is conducted for 2 to 96 hours, preferably 4 to 72 hours, in particular 6 to 48 hours. Further, step a_DT2) can be carried out at a temperature of 10° to 40°C, preferably 15°C to 35°C, in particular at 23°C.

In step boT2) isolating of filgotinib ditosylate Form DT2 can preferably be carried out by filtering off the solid. Additionally the solid can preferably be washed, preferably with water. Subsequently, filgotinib ditosylate Form DT2 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.

A particularly preferred embodiment of the present invention is filgotinib edisylate (filgotinib ethanedisulfonate) having characteristic X-ray powder diffraction peaks at 6.7, 10.0, 17.9, 23.7 and 25.0 degrees 2Θ (± 0.2 degrees 2Θ). This filgotinib edisylate can be considered as polymorphic Form EDS 1 of filgotinib edisylate.

In a preferred embodiment the filgotinib edisylate Form EDS 1 can be characterized by one or more further XRPD diffraction peak(s) at 14.3, 14.8, 16.8, 20.9 and/or 21.6 degrees 2Θ (± 0.2 degrees 2Θ) . In an alternatively further preferred embodiment of the present invention filgotinib edisylate EDSl can be characterized by the XRPD diffraction peak(s) at degrees 2Θ ± 0.2 degrees 2Θ (intensity %) : 6.7 (60), 7.4 (3), 10.0 (17), 12.1 (6), 12.8 (5), 14.3 (16), 14.8 (9), 15.3 (3), 16.2 (7), 16.8 (27), 17.9 (36), 18.4 (100), 18.9 (31), 19.3 (39), 19.6 (50), 20.0 (9), 20.3 (6), 20.5 (18), 20.9 (73), 21.4 (19), 21.6 (63), 22.0 (31), 22.2 ( 15), 22.4 (24), 22.6 (14), 23.3 (3), 23.7 (47), 23.9 (24), 24.4 (49), 25.0 (74), 25.3 (42), 25.7 (18), 26.3 (17), 26.9 (24), 27.1 (30), 27.6 (4), 28.1 (21), 28.8 (16), 29.7 (6), 29.9 (7), 30.6 (15), 31.4 (20), 32.0 (28), 32.8 (19), 33.9 (7), 34.1 (10), 34.5 (8), 35.0 (5), 35.7 (12), 36.3 (8), 37.3 (10), 37.8 (5), 38.1 (2), 38.3 (2), 39.0 (2), 39.3 (4), 39.8 (11), 40.6 (4), 41.2 (3), 41.6 (1), 42.3 (6), 43.1 (4), 43.5 (4), 43.8 (3), 44.2 (3), 44.7 (2), 45.3 (5), 45.7 (13), 46.4 (9), 46.6 (12), 48.6 (5), 48.8 (5), 49.9 (7), 52.0 (4) and 53.6 (5).

An XRPD-diffraction pattern of filgotinib edisylate Form EDSl is shown in Figure 5.

Alternatively preferred filgotinib edisylate EDS l can be characterized by an FT-IR spectrum showing peaks at the following wave numbers: 3543 , 3425, 3282, 2974, 2929, 1699, 1651 , 1603, 1566, 1551 , 1529, 1504, 1458, 1441 , 1419, 1402, 1342, 131 1 , 1275, 1244, 1153, 1130, 1111, 1068, 1055, 1024, 955, 914, 883, 870, 852, 839, 814, 787, 762, 735, 719, 708, 675, 650, 623, 606.

Filgotinib edisylate EDS l can be for example be prepared by the following steps: SLEDS I ) dissolving filgotinib in an organic solvent

bEDSi) adding ethanedisulfonic acid

CEDSI) isolating filgotinib ethanedisulfonate Form EDS l

In step a_EDS i) filgotinib and organic solvent correspond to the ones mentioned above. Further, filgotinib is dissolved, preferably completely dissolved, in an organic solvent, wherein the organic solvent is preferably dichloromethane.

It is further preferred that the step a_EDSi is conducted under a mechanical movement such as stirring.

In step bEDsi) ethanedisulfonic acid is added to the solution, preferably the complete solution. It is preferred that the mixture is further subjected to a mechanical movement such as stirring. In a preferred embodiment, step b_EDs i) includes stirring for 1 hour to 7 days, preferably 2 hours to 6 days, in particular 3 to 5 days. 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.

It is further preferred that the molar ratio of filgotinib free base and ethanedisulfonic acid is from 1 : 1 to 1 : 1.5, more preferably from 1 : 1.1 to 1 :1.4.

Step CEDS I) of isolating filgotinib ethanedisulfonate Form EDSl can preferably comprise cooling the mixture of step bEDsi)- Further isolating filgotinib ethanedisulfonate Form EDS l can preferably be carried out by filtering off the solid. Further, the isolated solid can preferably be washed, preferably with dichloromethane. Subsequently, filgotinib ethanedisulfonate Form EDS l 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.

Additionally, filgotinib ethanedisulfonate Form EDS 1 obtained as described above can be suspended in water. Further, the suspension can be subjected first to a warming step to an elevated temperature, preferably 50°C to 75°C, and then to a cooling step to a reduced temperature, preferably 0°C to 10°C. The solid can preferably be filtered and 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.

In an alternatively preferred embodiment filgotinib edisylate EDS 1 can for example be prepared by the following steps: aEDsr) dissolving filgotinib in an organic solvent

bEDs r) adding ethanedisulfonic acid

CEDS I isolating filgotinib ethanedisulfonate Form EDS 1

d£_Dsr) exposing to humid conditions

With regard to steps aEDs r ) to c_EDS r) the explanation given above in view of steps a_EDsi) to CEDS I) apply. In step d_EDsi the product of step CEDS I is exposed to humid conditions. In a preferred embodiment exposing the product of step CEDS I O to humid conditions can comprise suspending the product of C DS I in water. Further, the suspension can preferably be subjected to a warming step to an elevated temperature, preferably 50°C to 75°C. In a preferred embodiment the suspension can be hold on the elevated temperature for 1 to 12 hours, preferably for 2 to 6 hours, in particular for 4 hours. Subsequently, the suspension can be subjected to a cooling step to a reduced temperature, preferably 0°C to 10°C.

Further, step d_EDS i can preferably be filtering off the solid. Further, the product 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.

It unexpectedly turned out that filgotinib sulfonates, in particular filgotinib ditosylate, filgotinib dibesylate and filgotinib edisylate can contain an amount of residual organic solvent(s) so small that the compound meets the requirements of the FDA regulations. Further, filgotinib sulfonates, in particular filgotinib ditosylate, filgotinib dibesylate and filgotinib edisylate are present in a stable form. Additionally, filgotinib ditosylate, filgotinib dibesylate and filgotinib edisylate, in particular filgotinib edisylate Form EDS l show a significantly reduced polymorphism, i.e. it does not easily convert into other polymorphic forms. The possibility to convert to other polymorphic forms often bears the disadvantage of uncertain dissolution/bioavailability which is undesired due to the formulation regulations.

Further, filgotinib ethanedisulfonate Form EDS l is easily available from the synthesis without the need of a time-consuming and cost-intensive purification step.

Additionally, ethanedisulfonate Form EDS l contains an amount of residual organic solvent(s) so small that the compound meets the requirements of the FDA regulations.

Moreover, filgotinib ditosylate, filgotinib dibesylate and filgotinib edisylate Form EDS l show an advantageously reduced hygroscopy compared to other filgotinib acid addition salts, wherein the acid is a strong acid. Strong acids are considered to have a Ka < 2.

Finally, filgotinib edisylate Form EDS l shows an advantageously low molecular weight compared to the further filgotinib disulfonates such as filgotinib dibesylate and filgotinib ditosylate. Thus, it is especially suitable to be processed into tablets.

The present invention furthermore relates to pharmaceutical compositions comprising the compound of the invention, in particaular filgotinib diesylate Form DES 1. 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 Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", 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.

The term 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. Examples of 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 crosscarmelose sodium, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone (crosspovidone), 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.

It is further preferred that 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.

In the present invention, the following three types of film coatings are possible: film coating without affecting the release of the active ingredient,

- gastric juice-resistant film coatings,

retard film coatings. Generally, 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. It is preferred that the present tablet is coated with a gastric juice-resistant film coating. Alternatively, 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).

The coating is preferably free of active ingredient. It is further preferred that the thickness of the coating is usually 10 μπι to 2 mm, preferably from 50 to 500 μπι.

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.

In a preferred embodiment 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 edisylate Form EDS 1 , for preparing a pharmaceutical preparation for the treatment of patients with rheumatoid arthritis and other inflammatory diseases.

Experimental part Analytical Methods 1H-NMR Spectroscopy

Instrument: Varian Mercury 400 Plus NMR Spectrometer, Oxford AS, 400 MHz.

HPLC/UV

Method A:

Instrument: HP1200

Injection volume 5 μΐ

Solvent A: acetonitrile

Solvent B: O.OIM KH2PO4, pH = 2.3

Flow: 1.5 ml/min

Temperature: RT

Column: Supelco C18, 150 * 4.6 mm, 5 urn P T/EP2016/063157

time [min] solvent B [%]

0.00 75

8.00 40

13.00 40

14.00 75

17.00 75

Method B:

Method B corresponds to Method A, wherein the injection volume is amended to be 2 μΐ and the following solvent gradient profile time [min] solvent B [%]

0.00 75

8.00 500

13.00 40

14.00 75

17,00 75

Method C:

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 [%]

0.00 85

4.00 60

8.00 50

10.00 30

12.00 30

13.00 85

17.00 85 X-Ray Powder Diffraction (XRPD)

The sample was analyzed on a D8 Advance X-ray powder diffractometer (Bruker- AXS, Karlsruhe, Germany). The sample holder was rotated in a plane parallel to its surface at 20 rpm during the measurement. Further conditions for the measurements are summarized in the table below. The raw data were analyzed with the program EVA (Bruker-AXS, Germany). The samples were layered onto a silicon specimen holder. standard measurement

Radiation Cu Kai/2 (λ= 1.5406 A)

Source 38 kV / 40 mA

Detector Vantec

detector slit Variable

divergence slit v6

antiscattering slit v6

2Θ range / ° 2 < 2Θ < 55

step size / ° 0.017

Fourier Transform (FT) Infrared (IR) Spectroscopy

Instrument: Thermo Nicolet, Avatar 330 FT-IR. Smart Endurance Diamond- ATR.

Software: Omnic Vers. 6.1a. The sample was measured in solid form by placin_, the sample in the sample holder and directly carrying out the measurement.

Differential Scanning Calorimetry (DSC)

Solubility Determination in Aqueous Solvents

75 mg (exactly weighed) test substance was weighed into a glass vial, followed by addition of 3 ml solvent (a 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 μπι disposable filter, 50 μΐ of the clear filtrate were diluted with 950 μΐ DMSO and 2 μΐ thereof were analyzed by HPLC/UV. Hygroscopicity

Vapour sorption experiments were performed in the instrument SPSx-Ιμ (Projekt Messtechnik, Ulm, Germany) at a temperature of 25 °C and the humidity cycles as shown below.

Humidity cycle conditions

kept constant for 24 hours

Determination of residual solvents by Headspace GC

Sample preparation

Samples were dissolved in 1 ml dimethyl sulfoxide to a final concentration of 50 mg/ml. Calibration was realized with samples containing the solvent of interest in the concentration recommended by ICH guidelines (380 ppm for 1,4-dioxane, 600 ppm dichloromethane, 5000 ppm for ethanol and 3000 ppm for methanol). Instrument settings

Instrument: G1888 Network Headspace Sampler coupled with a 7890A GC- System from Agilent Technologies

Column settings

Column: HP-624

Column length (i.d.): 30 m ( 0.25 mm)

Film thickness 1.4 μπι

Carrier gas (flow): He (1.0 ml/min)

Injector settings

Injector temp.: 220°C

Split: 10:1

Detector settings:

transfer line 280°C

MS source: 230^CC

MS Quadrupole: 150°C

Ionization: EI+

Detection mode: Scan (m/z 20 - Identification by EI spectrum and retention time:

1,4-dioxane: 14.3 min

dichloromethane: 6.8 min

ethanol: 5.2 min

methanol: 4.0 min Temperature program:

Initial: 35°C (5 min isotherm)

Rate: 5°C/min

Final: 190°C (9.4 min isotherm)

Total run time: 45.4 min

Headspace settings:

Oven temp.:

Loop temp.:

Transfer temp.:

Injection loop:

vial pressure:

vial equilibration time:

pressurize time:

loop fill time:

loop equilibration time

injection time:

sequence purge time: EXAMPLES

Example 1: -t5-[4-[(l,1 -dioxido-4-thiomorpholin l)meth\ ] phenyl] [l,2,4]triazoIo[l,5-a]pyridin-2-yl]-cyclopropanecarboxamide (filgotinib free base )

[5-(4-bromomethyl-phenyl)-l,2,4]triazolo[l,5-a]pyridine-2-yl] amide (9 g;

24 mmol) was dissolved in a mixture of methanol (15 ml) and dichloromethane (75 ml). Diisopropylethylamine (8.25 ml; 48.5 mmol) was added. Thiomorpholine dioxide (3.61 g; 26.7 mmol) was added in one portion. The mixture was stirred over night at 23°C. After completion of the reaction the solvent was evaporated. The grey compound was suspended in a mixture of ethyl acetate (100 ml) and methanol (10 ml) and stirred for 2 hours at 23°C. The product was filtered

dried under vacuum at 17 mbar and 50°C for 3 hours.

Yield: 9.53 g (92% of theory)

purity (HPLC/UV, method A, 98.6%

t_r= 2.2 min, λ=230 nm):

1H-NMR (400 MHz, DMSO-rf₆) 0.74 - 0.86 (m, 4 H) 2.01 (br. s„ 1 H) 2.91 (s, 4 H) [δ ppm] 3.10 - 3.15 (m, 4 H) 3.75 (s, 2 H) 7.27 (dd, J=6.26,

1.56 Hz, 1 H)7.50 (d, J=8.21 Hz, 2 H) 7.65 - 7.71 (ni, 2 H) 7.97 (d, J=8.21 Hz, 2 H) 11.02 (br. s., 1 H)

FT-IR (ATR) [cm^{" 1}] 3288, 3230, 3188, 3088, 3057, 3003 , 2935, 2843,

2820, 1699, 1635 , 1576, 1552, 1525 , 1495, 1398, 1369, 1333, 1321 , 1298, 1269, 1215, 1186, 1 157 , 1 126, 1 1 13, 1084, 1053, 1038, 1020, 978, 962, 941 , 891 , 862, 854, 822, 779, 729, 677, 656, 631 , 625, 615

XRPD 1 ^st priority reflections 7. 1 , 8.1 , 10.8, 18.4, 27.3°2Θ

2^nd priority reflections 14.2, 16.2, 17.2, 19.8 , 25.2°2Θ DSC endotherms (onset T) :214°C; 319°C (br.)

residual solvent content 0.5.-2% (dichloromethane) Example 1 ' : N-[5-[4-[( l,l-dioxido-4-thiomorpholinyl)methylJ phenyl ] [ l,2,4]triazolo[ l ,5-a]pyridin-2-yl]-cyclopropanecarboxamide (filgotinib free base)

[5-(4-bromomethyl-phenyl)-l ,2,4]triazolo[l ,5-a]pyridine-2-yl]amide (25 g; 67.3 mmol) was dissolved in a mixture of methanol (52 ml) and dichloromethane (260 ml). Diisopropylethylamine (23 ml) was added. Thiomorpholine dioxide (10.1 g; 74.1 mmol) was added in one portion. The mixture was stirred over night at 23°C. After completion of the reaction the solvent was evaporated. The grey compound was suspended in a mixture of dichloromethane (180 ml) and methanol (80 ml) and stirred under reflux and nitrogen atmosphere for 30 minutes. The reaction mixture was slowly cooled to 23 °C under stirring. At about 40°C the product began to precipitate. After about one hour at 23 °C, a white to off-white thick suspension was formed. Stirring was continued over night under nitrogen atmosphere at 23°C. The solvent was evaporated at 43°C and to the grey solid was added a mixture of dichloromethane (200 ml) and methanol (80 ml). The suspension was heated to reflux and kept at this temperature for 1.5 hours (suspension became solution), then heating was turned off and the flask was left in the cooling oil bath and stirring was continued over night. The product was filtered off and washed with 50 ml dichloromethane and dried over night at 40°C and 7 mbar (crop I; 18.07 g).

The mother liquor was evaporated and the remaining grey solid was suspended in ethanol (100 ml) and water (20 ml), heated to reflux and cooled slowly to room temperature. The product was filtered off and suspended in acetone (50 ml), stirring was performed for 30 minutes, then the product was filtered off and dried at 40°C at 7 mbar over night to yield the product as a brownish solid (7.05 g)

Yield: 25.12 g (64%)

purity (HPLC/UV, method B 99.0% (crop I), 98.8% (crop II)

t_r= 2.2 min, λ=230 nm):

FT-IR (ATR) [cm^"1] (crop I): 3228, 3132, 3082, 3003, 2918, 2829, 1666, 1637,

1556, 1525, 1510, 1466, 1444, 1414, 1381 , 1356, 1342, 1319, 1290, 1267, 1248, 1190, 1167, 1155, 1128, 1107, 1076, 1047, 1022, 953, 924, 852, 795, 727, 687, 661, 634

XRPD (crop I same as crop 1^st priority reflections 9.2, 10.2, 21.0, 22.9, 29.5°2Θ

2^nd priority reflections 12.9, 14.1, 16.5, 18.8, 24.3°2Θ

DSC (crop I) endofherms (onset T): 235°C; 327°C (br.) residual solvent content 0.5-2% (dichloromethane) Example 2: Filgotinib dimesylate Form DM1

2.0 g (4.7 mmol) filgotinib base were mixed with 160 ml dichloromethane and heated to reflux (35°C). A solution of 0.5 g (5.2 mmol) methanesulfonic acid in 18 ml dichloromethane was added dropwise. Precipitation of a solid was observed. The reaction mixture was stirred for another 30 min at reflux, then slowly cooled down to 23°C and stirred over night. The product was filtered off, washed with 40 ml dichloromethane and dried for two days at 50°C / 8 mbar.

Name Filgotinib dimesylate, Form DM1

Yield: 2.34 g (81 % of theory)

purity (HPLC/UV, method B, 98.6 %

t_r= 2.4 min, λ=200 nm):

1H NMR (400 MHz, DMSO- 0.78 - 0.87 (m, 4 H) 1.94 - 2.08 (m, 1 H) 2.39 (s, 6 d₆) H) 3.55 (br. s., 4 H) 3.64 (br. s., 4 H) 4.52 (br. s., 2

[δ ppm] H) 5.71 - 5.76 (m, 1 H) 7.40 (dd, J=7.04, 1.56 Hz,

1 H) 7.67 - 7.84 (m, 4 H) 8.12 (d, J=8.21 Hz, 2 H) 9.45 - 10.36 (m, 2 H) 1 1.32 (br. s, 1 H)

FT-IR (ATR) [cm^{" 1}] : 3007, 2931 , 1711 , 1647, 1595, 1568, 1504, 1471,

1458, 1421, 1400, 1344, 1313, 1277, 1228, 1219,

1194, 1169, 1126, 1072, 1036, 953, 912, 866, 841,

822, 785, 771, 731, 715, 675, 650, 634, 625, 607

XRPD 1^st priority reflections 8.6, 16.6, 17.2, 20.1, 22.8

2^nd priority reflections 10.2, 10.5, 18.6, 20.7, 21.1

DSC endotherms: 34°C (br.), 200°C, 258°C, 332°C (br.)

TGA Two small endotherms (peaks at 53.5°C and

208.6°C); large endotherm with peak at 262.7°C; broad endotherm (320-400°C) Example 3: Filgolinib diesylate Form DEI

0.5 g (1.18 mmol) filgotinib base were dissolved in 50 ml 1,4-dioxane and heated to 80°C. 0.28 g (2.6 mmol) ethanesulfonic acid were added dropwise over 5 min. During addition, the formation of a white/brownish precipitate was observed. The reaction mixture was stirred for another 60 min at 80°C, then slowly cooled down to 23 °C and stirred over night. The product was filtered off, washed with 20 ml 1,4-dioxane and dried for 5 h at 50°C / 8 mbar.

Name Filgotinib diesylate, Form DEI

Yield: 0.63 g (84 % of theory)

purity (HPLC/UV, method B, 97.4 %

t_r= 2.2 min, λ=230 nm:

1H NMR (400 MHz, DMSO- ) 0.78 - 0.90 (m, 4 H) 1.09 (t, 7=7.43 Hz, 6 H) 2.01

[δ ppm] (br. s., 1 H) 2.45 - 2.54 (m, 5 H) 3.55 (s, 3 H

(dioxane)) 3.59 (br. s., 4 H) 3.67 (br. s., 4 H) 4.56 (br. s., 2 H) 7.40 - 7.45 (m, 1 H) 7.75 (t, 7=7.62 Hz, 3 H) 7.79 - 7.85 (m, 1 H) 8.1 1 (d, 7=8.21 Hz, 2 H) 8.25 - 9.52 (m, 2 H) 1 1.42 (br. s., 1 H)

FT-IR (ATR) [cm^"1]: 3257, 2983, 2931 , 2879, 2565, 1714, 1647, 1601,

1572, 1543, 1527, 1506, 1462, 1421, 1402, 1342, 1311, 1277, 1244, 1230, 1192, 1182, 1149, 1132, 1066, 1055, 1028, 985, 957, 910, 866, 833, 779, 768, 737, 714, 677, 652, 633, 623

XRPD 1^st priority reflections 8.1 , 10.3, 16.2, 19.9, 21.1

2^M priority reflections 11.2, 18.2, 18.9, 23.4. 23.7

Example 4: Filgotinib diesylate Form DE2

2.0 g (4.7 mmol) filgotinib base were dissolved in 200 ml 1,4-dioxane and heated to 80°C. 1.14 g (10.3 mmol) ethanesulfonic acid were added dropwise over 40 min. After completion, the reaction mixture was stirred for another 60 min at 80°C, then slowly cooled down to 23°C and stirred over night. The product was filtered off, washed with 80 ml 1,4-dioxane and dried for 3 weeks at 35°C / 7 mbar.

Name Filgotinib diesylate, Form DE2

Yield: 2.87 g (95 % of theory)

purity (HPLC/UV, method B, 99.0 %

t_r= 2.2 min, λ=230 nm:

¹H NMR (400 MHz, DMSO-rf₆) 0.81 - 0.87 (m, 4 H) 1.08 (t, 7=7.43 Hz, 6 H) 2.00 [5 ppm] (br. s„ 1 H) 2.46 - 2.52 (m, 6 H) 3.55 (s, 1 H

(dioxane)) 3.57 (br. s., 4 H) 3.65 (br. s., 4 H) 4.54 (br. s., 2 H) 7.41 (dd, 7=7.04, 1.56 Hz, 1 H) 7.71 - 7.77 (m, 3 H) 7.79 - 7.83 (m, 1 H) 8.11 (d, 7=8.21 Hz, 2 H) 11.35 (br. s., 1 H)

FT-IR (ATR) [cm^"1] : 2983, 2933, 1713, 1647, 1597, 1570, 1527, 1504,

1458, 1419, 1398, 1346, 1311 , 1275, 1246, 1190, 1176, 1128, 1066, 1026, 978, 955, 910, 866, 839, 822, 796, 783, 766, 737, 714, 675, 650, 633, 625, 607

XRPD 1^st priority reflections 7.9, 9.5, 19.5, 21.3, 23.2

2^nd priority reflections 11.3, 15.9, 18.3, 20.8, 22.4

DSC endotherms: 140-180°C (br. with peak at

172°C),210-230°C (br. with peak at 218), 20-

400°C (br. with peak at 341 °C)

exotherms: 175-210°C (br. with peak at 180°C) Example 5: Filgotinib dibesylate Form DB1

0.5 g (1.2 mmol) filgotinib base were dissolved in 1 ,4-dioxane (50 ml) and heated to 80°C. A solution of 0.4 g (2.6 mmol) benzenesulfonic acid in 1 ,4-dioxane (10 ml) was added dropwise into the solution. The mixture was stirred for 1 hour at 80°C, then slowly cooled down to 23 °C and stirred over night. The white precipitate was filtered off, washed with 20 ml dioxane and dried over night at 50°C / 8 mbar.

Name Filgotinib dibesylate, Form DB 1

Yield: 0.61 g (89 % of theory)

purity (HPLC/UV, method B, 99.2 %

t_r= 2.3 rain, λ=230 nm):

H NMR (400 MHz, DMSO-dg) 0.82 - 0.89 (m, 4 H), 2.00 (br. s., 1 H), 3.55 (s, 8 H [5 ppm] (2xCH₂ dioxane)), 3.67 (br. s., 4 H), 4.56 (br. s., 2

H), 7.27 - 7.35 (m, 5 H), 7.41 - 7.44 (m, 1 H), 7.61 (m, J=7.40, 2.00 Hz, 3 H), 7.71 (d, J=8.21 Hz, 2 H), 7.74 - 7.79 (m, 1 H), 7.80 - 7.86 (m, 1 H), 8.11 (d, J=8.21 Hz, 2 H), 8.23 - 10.36 (m, 2 H), 11.43 (br. s., 1 H)

FT-IR (ATR) [cm^'1] : 3338, 3014, 2983, 2933, 1703, 1653, 1605, 1574,

1543, 1529, 1502, 1460, 1444, 1402, 1356, 1342, 1315, 1290, 1275, 1228, 1161 , 1122, 1070, 1063, 1034, 1014, 995, 951 , 931 , 906, 870, 862, 839, 823, 795, 760, 727, 692, 636, 609

XRPD 1^st priority reflections 8.7, 15.2, 18.2, 19.7, 24.8

2^nd priority reflections 7.2, 9.9, 18.4, 19.4, 24.0 Example 6: Filgotinib dibesylate Form DB2

2.0 g (4.7 mmol) filgotinib base were dissolved in 1,4-dioxane (200 ml) and heated to 80°C. A solution of 1.64 g (10.3 mmol) benzenesulfonic acid in 1,4-dioxane (40 ml) was added dropwise. The reaction mixture was stirred for 1 hour at 80°C, then slowly cooled down to 23 °C and stirred over night. The product was filtered off, washed with 50 ml 1,4-dioxane and dried over night at 50°C / 7 mbar. After storage for three days at 50°C and 100% relative humidity, the product was dried over night at 50°C / 8 mbar. Name Filgotinib dibesylate, Form DB2 (monohydrate)

Yield: 2.84 g (100 % of theory)

purity (HPLC/UV, method B, 98.6 %

t_r= 2.3 min, λ=230 nm):

*H NMR (400 MHz, DMSO-<¾ 0.81 - 0.90 (m, 4 H) 2.00 (br. s, 1 H) 3.57 (br. s., 4 [δ ppm] H) 3.69 (br. s., 4 H) 4.58 (s, 2 H) 7.28 - 7.36 (m, 5

H) 7.45 (dd, J=7.23, 1.37 Hz, 1 H) 7.59 - 7.64 (m, 3 H) 7.72 (d, J=8.21 Hz, 2 H) 7.75 - 7.80 (m, 1 H) 7.83 - 7.89 (m, 1 H) 8.10 (d, J=8.21 Hz, 2 H) 1 1.53 (br. s., 1 H)

FT-IR (ATR) [cm^{" 1}] : 2982, 2933 , 1701 , 1651 , 1597, 1574, 1525, 1504,

1444, 1398, 1387, 1360, 1309, 1282, 1240, 1217, 1180, 1142, 1 120, 1066, 1032, 1014, 995, 951 , 910, 883, 866, 837, 791 , 760, 725, 714, 692, 607

XRPD 1^st priority reflections 3.6, 7.4, 13.3, 15.0, 17.6

2^nd priority reflections 7.2, 1 1.4, 15.9, 19.5, 25.8

DSC two br. endotherm (40- 120°C, 160-250°C with peak at 240°C) ; br. endotherm (290-400°C)

Residual solvent (dioxane) content of filgotinib dibesylate Form DB2 was below the detection limit of dioxane. Example 7: Filgotinib ditos late Form DTI

2.0 g (4.7 mmol) filgotinib base were dissolved in 1 ,4-dioxane (200 ml) and heated to 73°C. A solution of 1.97 g (10.3 mmol) toluene sulfonic acid mono hydrate in 1 ,4-dioxane (40 ml) was added dropwise. The reaction mixture was stirred for 1 hour at 76°C, then slowly cooled, down to 23°C and stirred over night. A white product was filtered off, washed with 100 ml 1 ,4-dioxane and dried over night at 50°C / 6 mbar. Name Filgotinib ditosylate, Form DTI

Yield: 3.44 g (95 % of theory)

purity (HPLC/UV, method B, 99.4 %

t_r= 2.4 min, λ=200 nm):

1H NMR (400 MHz, DMSO-d₆) 0.80 - 0.86 (m, 4 H) 2.00 (br. s., 1 H) 2.27 (s, 6 H)

[δ ppm] 3.47 - 3.49 (m, 1 H) 3.52 (br. s., 4 H) 3.55 (s, 1 H)

3.62 (br. s., 4 H) 4.50 (br. s., 2 H) 7.09 - 7.12 (m, 4 H) 7.38 (dd, J=7.04, 1.56 Hz, 1 H) 7.45 - 7.49 (m, 4 H) 7.69 (d, J=8.21 Hz, 2 H) 7.73 - 7.82 (m, 2 H) 8.11 (d, J=8.21 Hz, 2 H) 11.28 (br. s., 1 H)

FT-IR (ATR) [cm^" 2928, 1707, 1649, 1599, 1504, 1497, 1452, 1396,

1348, 1309, 1288, 1277, 1219, 1147, 1134, 1117, 1065, 1030, 1005, 958, 931, 912, 868, 800, 735, 712, 677, 633, 606

XRPD 1^st priority reflections 6.3, 6.5, 9.7, 14.8, 17.6

2^nd priority reflections 1 1.2, 12.8, 16.1 , 18.4, 21.0

DSC endotherms: 33°C (br.); 137°C (br.), 175°C,

240°C294°C (br.) exotherms: 188°C

Example 8: Filgotinib ditosylate Form DT2

1.72 g filgotinib ditosylate Form DTI from Example 7 and 9 ml water were mixed and the suspension was stirred for two days at room temperature. The product was filtered off and dried over night at 50°C / 7 mbar.

Name Filgotinib ditosylate, Form DT2

Yield: 1.18 g (68 % of theory)

purity (HPLC/UV, method B, 97.8 %

tr= 2.4 min, λ=200 nm:

1H NMR (400 MHz, DMSO-d₆) 0.81 - 0.87 (m, 4 H) 2.00 (br. s., 1 H) 2.27 (s, 6 H)

[5 ppm] 3.54 (br. s., 4 H) 3.65 (br. s., 4 H) 4.53 (br. s., 2 H)

7.09 - 7.13 (m, 4 H) 7.40 (dd, 7=7.23, 1.37 Hz, 1 H) 7.46 - 7.50 (m, 4 H) 7.70 (d, 7=8.21 Hz, 2 H)

7.72 - 7.84 (m, 2 H) 8.11 (d, .7=8.21 Hz, 2 H) 11.35 (br. s., 1 H)

3417, 2982, 2924, 1701, 1651 , 1597, 1572, 1529, 506, 1497, 1448, 1423, 1390, 1358, 1340, 1308, 1288, 1217, 1184, 1157, 1122, 1072, 1034, 1009, 949, 933, 914, 883, 860, 841, 816, 800, 789, 771, 739, 714, 679, 658, 634, 623,

1^st priority reflections 7.3, 11.4, 19.0, 21.9, 25.3 2^nd priority reflections 10.9, 13.2, 15.7, 17.9, 20.2 br. endotherm (30-140°C); br. endotherm (140- 170°C) with peak at 160°C, br. endotherm (210- 230°C) with peak at 220°C, br. endotherm (230- 245°C) with peak at 240°C, br. endotherm (240- 400°C) with peaks at 310 and 340°C

Residual solvent (dioxane) content of the obtained filgotinib ditosylate Form DT2 was below the detection limit of dioxane. Example 9: Preparation of filgotinib ethanedisulfonate form EDS1

3.0 g (7.05 mmol) filgotinib base were dissolved in 240 ml dichloromethane and the solution was stirred at 23°C. 1.65 g (8.5 mmol) ethanedisulfonic acid were added in one portion and the reaction mixture was stirred for another four days at 23°C. The product was filtered off, washed with 60 ml dichloromethane and dried over night at 50°C/8 mbar (yield: 3.6 g).

Example 9': Further processing of filgotinib ethanedisulfonate Form EDS1 To the obtained ethandisulfonate salt from Example 9 (0.5 g) water (10 ml) was added and heated to 64°C for 4 hours. The reaction mixture was cooled to 23 °C, stirring was continued over night. The reaction mixture was cooled to 5°C and stirred for 2 hours. The product was filtrated off and dried at 50°C / 8 mbar over night (yield: 0.34 g).

Name Filgotinib ethanedisulfonate, Form EDS 1 purity (HPLC/UV, method B, 97.9 %

t_r= 2.3 min, λ= 230 nm:

^!H NMR (400 MHz, DMSO-d₆) 0.80 - 0.92 (m, 4 H) 1.98 - 2.09 (m, 1 H) 2.75 (s, 4 [δ ppm] H) 3.58 (br. s., 4 H) 3.66 (br. s., 4 H) 4.55 (br. s., 2

H)7.48 (dd, 7=7.23, 1.37 Hz, 1 H) 7.71 - 7.79 (m, 3 H) 7.81 - 7.88 (m, 1 H) 8.13 (d, 7=8.60 Hz, 2 H) 11.54 (br. s., 1 H)

FT-IR (ATR) [cm^"1]: 3543, 3425, 3282, 2974, 2929, 1699, 1651 , 1603,

1566, 1551, 1529, 1504, 1458, 1441 , 1419, 1402, 1342, 1311, 1275, 1244, 1153, 1130, 111 1, 1068, 1055, 1024, 955, 914, 883, 870, 852, 839, 814, 787, 762, 735, 719, 708, 675, 650, 623, 606

XRPD 1^st priority reflections 6.7, 10.0, 17.9, 23.7, 25.0

2^nd priority reflections 14.3, 14.8, 16.8, 20.9, 21.6

DSC endotherms: 165°C, 216°C, 307°C (br.)

e otherms: 176°C

Residual solvent (dichloromethane) content of the obtained filgotinib ethanedisulfonate Form EDS 1 was 8 ppm and, thus, well below the pharmaceutically acceptable concentration limit of 600 ppm.

7

Reference Examples

Reference Example 1: Filgotinib fumarate

Filgotinib free base (0.5 g) was dissolved in dichloromethane (13 ml) and methanol (2 ml) at room temperature and heated to reflux. Fumaric acid (0.15 g) was dissolved in dichloromethane (17 ml) and methanol (3 ml). The acid solution was dropped into the solution of filgotinib and stirred for 1 hour at reflux temperature, then cooled to 23°C. The reaction mixture was stirred over night, no salt formation could be observed.

Reference Example 2: Filgotinib tartrate

Filgotinib free base (0.5 g) was dissolved in dichloromethane (13 ml) and methanol (2 ml), D-tartaric acid (0.19 g) was dissolved in dichloromethane (17 ml) and methanol (3 ml). The acid solution was dropped into the solution of filgotinib at 50°C. The reaction mixture was stirred for 1 hour and then slowly cooled to 23°C. The reaction mixture was stirred for 3 days, no salt formation could be observed. Reference Example 3: Filgotinib maleate:

Filgotinib free base (0.5 g) was dissolved at room temperature in dichloromethane (18 ml) and methanol (2 ml) and heated to reflux. Maleic acid (0.47 g) was dissolved in dichloromethane (12 ml) and methanol (2 ml). The acid solution was dropped into the solution of the starting material; stirring was continued for 1 hour at reflux temperature. The reaction mixture was cooled to 23°C. The reaction mixture was left stirring over night, no salt formation could be observed.

Reference Example 4: Filgotmib oxalate

Filgotinib free base (0.5 g) was dissolved in dichloromethane (18 ml) and methanol (2 ml), the reaction mixture was heated to reflux. Oxalic acid (0.12 g) was dissolved in dichloromethane (4.5 ml) and methanol (0.5 ml), the acid solution was dropped into the solution of the starting material and stirred for 1 hour at reflux temperature, then cooled to 23°C. The reaction mixture was stirred over night. No salt formation could be observed. Reference Example 5: Filgotinib phosphate

a) Filgotinib free base (0.5 g) was dissolved in dichloromethane (40 ml). Phosphoric acid (85%, 0.1 ml) was dropped into this solution at room temperature. The reaction mixture was stirred over night. A syrupy residue was formed, the solvent was decanted off and the substance was dried by evaporating (0.32 g). The solid was milled in a mortar. After storage for 4 days in a closed vial, the solid substance transformed into a syrupy substance by water uptake. In the present case the salt formation was successful, but the corresponding salt was highly instable due to its high hygroscopy and thus not applicable for a pharmaceutical formulation. b) Filgotinib free base (0.5 g) was dissolved in dioxane (250 ml) at 73°C. Phosphoric acid (anhydrous) (0.254 g) was dissolved in dioxane (20 ml) and added dropwise within 10 min into the solution of the starting material. The reaction mixture was stirred for 45 minutes at 80°C, slowly cooled to 23°C. After stirring over night, the beige product was filtered off and washed with dioxane (20 ml). The solid, filtrated product transformed into a syrupy substance shortly after filtration. Again, in the present case the salt formation was successful, but the corresponding salt was highly instable due to its high hygroscopy and thus not applicable for a pharmaceutical formulation.

Claims

Claims

1. Filgotinib sulfonic acid addition salt having a residual solvent content within pharmaceutically acceptable limits.

2. Filgotinib sulfonic acid addition salt according to claim 1, wherein the sulfonic acid is benzenesulfonic acid, toluenesulfonic acid and ethanedisulfonic acid.

3. Filgotinib sulfonic acid addition salt according to claim 1 or 2, wherein the sulfonic acid is benzenesulfonic acid and wherein the filgotinib sulfonic acid addition salt has characteristic X-ray powder diffraction peaks at 8.7, 15.2, 18.2, 19.7 and 24.8 degrees 2Θ (± 0.2 degrees 2Θ).

4. Filgotinib sulfonic acid addition salt according to claim 1 or 2, wherein the sulfonic acid is benzenesulfonic acid and wherein the filgotinib sulfonic acid addition salt has characteristic X-ray powder diffraction peaks at 3.6, 7.4, 13.3, 15.0 and 17.6 degrees 2Θ (± 0.2 degrees 2Θ).

5. Filgotinib sulfonic acid addition salt according to claim 1 or 2, wherein the sulfonic acid is toluenesulfonic acid and wherein the filgotinib sulfonic acid addition salt has characteristic X-ray powder diffraction peaks at 6.3, 6.5, 9.7, 14.8 and 17.6 degrees 2Θ (+ 0.2 degrees 2Θ).

6. Filgotinib sulfonic acid addition salt according to claim 1 or 2, wherein the sulfonic acid is toluenesulfonic acid and wherein the filgotinib sulfonic acid addition salt has characteristic X-ray powder diffraction peaks at 7.3, 11.4, 19.0, 21.9 and 25.3 degrees 2Θ (± 0.2 degrees 2Θ).

7. Filgotinib sulfonic acid addition salt according to claim 1 or 2, wherein the sulfonic acid is ethanedisulfonic acid and wherein the filgotinib sulfonic acid addition salt has characteristic X-ray powder diffraction peaks at 6.7, 10.0, 17.9, 23.7 and 25.0 degrees 2Θ (± 0.2 degrees 2Θ).

8. Filgotinib sulfonic acid addition salt according to claim 7 having one or more further characteristic X-ray powder diffraction peak(s) at 14.3, 14.8, 16.8, 20.9 and/or 21.6 degrees 2Θ (± 0.2 degrees 2Θ).

9. Process for preparing filgotinib sulfonic acid addition salt according to any one of claims 7 or 8, characterized by the following steps:

SEDS) dissolving filgotinib in an organic solvent

be_Ds) adding ethanedisulfonic acid

CEDS) isolating filgotinib ethanedisulfonate.

10. Pharmaceutical composition comprising filgotinib sulfonic acid addition salt according to any one of claims 1 to 8.

1 1. Pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is a solid oral dosage form.

12. Compound according to any one of claims 1 to 8 for use in the treatment of systemic diseases, autoimmune diseases or inflammatory diseases, preferably for the use in the treatment of multiple sclerosis, rheumatoid arthritis or psoriasis.

13. Method for treating and/or preventing systemic diseases, autoimmune diseases and/or inflammatory diseases, preferably multiple sclerosis, rheumatoid arthritis, or psoriasis, in particular multiple sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claims 10 or 11.