WO2017012773A1

WO2017012773A1 - Solid forms of filgotinib free base

Info

Publication number: WO2017012773A1
Application number: PCT/EP2016/063164
Authority: WO
Inventors: Wolfgang Albrecht; Richard Guserle; Annemarie MAIER; Roland SELIG; Nadine RUH; Jens Geier
Original assignee: Ratiopharm Gmbh
Priority date: 2015-07-23
Filing date: 2016-06-09
Publication date: 2017-01-26

Abstract

The present invention relates to crystalline filgotinib free base, a method of its preparation and a pharmaceutical composition comprising the same.

Description

Solid Forms of Filgotinib Free Base

The present invention relates to solid forms of filgotinib free base, a method of preparing the same as well as a pharmaceutical composition comprising the same.

The IUPAC name of filgotinib is N-[5-[4-[( 1 , 1 -dioxo-1 ,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 -dioxothio- morpholino)methyl)phenyl)-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl] cyclopropane- carboxamide) is an orally available, selective inhibitor of JAKl (Janus kinase 1 ), which is 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 JAKl and JAK2 inhibitors, and tofacitinib, which is a specific JAK3 inhibitor, filgotinib was developed to specifically target JAKl .

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 . However, when following the proposed route of synthesis the obtained filgotinib shows certain disadvantages, e.g. with regard to its purity and/or crystallinity. In particular, it was noted that the column chromatography step for purification of the final product described in the prior art seems to be not enabled since recovering of the desired product was not achieved.

Filgotinib in form of the free base is practically insoluble. The solvents best suitable for dissolving the compound are for example dichloromethane and dioxane. A further, but less suitable solvent, in which Filgotinib shows lower solubility, is for example ethanol. Such solvents have to be removed nearly completely from potential pharmaceutical formulations, since such solvents are only acceptable in low or very low concentrations. 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 filgotinib obtained in known preparation processes often showed a higher content of residual solvents and employing conventional drying methods like drying at elevated temperatures with and without vacuum did not lead to a pharmaceutically acceptable solvent levels and/or drug purity levels. Consequently, there is still a need for solid forms of filgotinib having a pharmaceutically acceptable purity.

Hence, it was an object of the present invention to overcome the drawbacks of the above-mentioned prior art.

Additionally filgotinib should be provided in a form which is easy to handle and/or stable over a long period.

Summary of the invention

According to the present invention, the above objectives are unexpectedly achieved. Crystalline filgotinib in form of its free base, a process for its preparation and pharmaceutical compositions comprising crystalline filgotinib free base is provided.

Thus, the subject of the present invention is crystalline filgotinib free base, preferably crystalline filgotinib free base having a residual solvent content within pharmaceutically acceptable limits. In the present application the term "residual solvent content within pharmaceutically acceptable limits" refers to a concentration limit (in ppm) of the corresponding solvent, which is regarded as pharmaceutically acceptable in the art. Respective 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 Bioligics Evaluation and Research (CBER), February 2012, ICH, Revision 2. According to the above-mentioned guideline the solvents are categorized into three classes.

Class 1 relates to solvents that should be avoided in pharmaceutical products.

Solvent C oncentration Limit Concern

(ppm)

Benzene 2 Carcinogen

Carbon tetrachloride 4 Toxic and environmental hazard i,2-Mdd<w0eAane 5 Toxic

U-DicMoroettme 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/da?) C oncentration Limit

Aeeteffltele 4 1 410

Chkxcbenss 3 6 360

CMorof ott 0 6 60

38 8 3.880

Cameo* 0.7 70

lJ!- tdiior -itheoe 18 ? 1,870

I¾cMorometfeaB* 6.0 600

1.0 100

NJ NDunethy!acetanude 109 1 090

Ν,Ν-Dimetkylfiamamide 8 8 380

1.4-Dicaune 3 8 380

2-Etfa Hsyefiia2oI 1 6 160

EthyleneeJycol 62 620

Fomianude 2.2 220

2.9 290

Methanol 30.0 3.000

2-Mettosyetiaa0l 0.5 50

Metby!batyi ketone 0.5 50

MetfaykycloteiGtae 11.8 1,180

N-Met ip roiidk>ffie 5.3 530

Nitroaietfaa§&e 05 50

Pyndtoe 2.0 200

Sxilfolame 1 6 160

Tebafaydroferm 7.2 720

Tetralm 1 0 100

Toiaene 8.9 890

Xylene¹ 21.7 2,170

Usually 60% m-x>1eie, 14% p-xylese, 9% o-xyfetK with 17*4 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. Acetic add Heptane

Acetone Isobutyl acetate

Anisole Isopropyi acetate

1-Butanol Methyl acetate

2-Butanol 3-MethyH-btrtanoi

Butyl acetate MethySethyl ketone tert-Bntylm tfcyl ether Methylisobutyl ketone

Dimethyl solfoxide 2-Methyl-l -propanol

Ethanol Peotane

Ethyl acetate l-Pentanol

Ethyl ether 1-Propaool

Ethyl f annate 2-Propaool

Formic acid Propyl scetste

Table 3: Class 3 solvents having a concentration limit of 5000 ppm.

The term "crystalline" can be used in the context of this invention to designate the state of solid substances in which the components (atoms, ions or molecules, i.e. in the case of crystalline filgotinib the filgotinib molecules) are arranged in an orderly repeating pattern, extending in all three spatial dimensions and thus exhibit a periodic arrangement over a great range (= long-range order). In a preferred embodiment the filgotinib composition may consist of purely crystalline filgotinib. Alternatively, it may also contain small amounts of noncrystalline filgotinib components, provided that a defined melting point of crystalline filgotinib can be detected in DSC. It is preferred that filgotinib contained in the inventive dosage form can be a mixture containing 85 to 99.999% by weight crystalline filgotinib and 0.001 to 15% by weight non-crystalline filgotinib, more preferably 90 to 99.99% by weight crystalline filgotinib and 0.01 to 10% non-crystalline filgotinib, particularly preferably 95 to 99.9% by weight crystalline filgotinib and 0.1 to 5% non-crystalline filgotinib. Crystalline filgotinib free base might be present in different crystal forms. Thus, crystalline filgotinib might be present in different polymorphic forms or mixtures thereof. 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 peaks 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 K< i/ Ka₂ radiation with a wavelength 1 .5406 A (weighted mean of Cu KGC I and Cu Kot₂). Further, unless indicated otherwise, XRPD peaks are reported as degrees 2Θ (2- theta) values with a standard error of ± 0.2 degrees 2Θ (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 are characterizing the same crystal form or two different crystal forms. Filgotinib in form of the free base can be illustrated by Formula (I). This means that the free form does not encompass a salt form. Thus, filgotinib as free form preferably corresponds to filgotinib free base. Further, filgotinib free base can encompass filgotinib in form of hydrate and/or solvate.

According to a first aspect of the invention crystalline filgotinib free base relates to the crystal form I of filgotinib free base. This form can be considered as polymorphic form I of filgotinib. Filgotinib free base form I can preferably be characterized by XRP diffraction peaks at 7.1 , 8.1 , 10.8, 18.4 and 27.3 degrees 2Θ (± 0.2 degrees 2Θ).

In a further preferred embodiment of the present invention filgotinib free base form I can be characterized by one or more further XRPD diffraction peak(s) at 14.2, 16.2, 17.2, 19.8 and/or 25.2 degrees 2Θ (± 0.2 degrees 2Θ).

In alternative further preferred embodiment of the present invention filgotinib free base form I can be characterized by the XRPD diffraction peak(s) at degrees 2Θ ± 0.2 degrees 2Θ (Intensity %): 7.1 (34), 8.1 (20), 10.8 (47), 14.2 ( 14), 16.2 (20), 16.9 (12), 17.2 (50), 18.3 (57), 18.4 (86), 18.7 (73), 19.1 (18), 19.8 (53), 20.0 (47), 20.4 (40), 20.6 ( 13), 21 .7 ( 14), 22.3 ( 1 1 ), 22.5 (24), 23.2 (2), 24.1 (6), 24.6 ( 12), 25.0 (31 ), 25.2 (100), 25.5 (32), 26.3 (7), 27.3 (88), 27.9 (21 ), 28.5 ( 12), 28.7 (5), 30.6 ( 18), 30.8 ( 1 1 ), 31.5 (4), 32.4 (22), 32.8 ( 15), 33.9 (3), 34.5 (5), 34.7 (3), 35.9 (4), 36.2 (6), 36.7 (2), 37.6 (2), 38.2 (3), 38.8 (3), 40.0 (9), 41.4 (6), 41.9 ( 1 1 ), 43.4 (17), 43.7 (13), 44.1 (5), 45.1 (4), 45.4 (3), 46.1 (4), 47.5 (5), 48.1 (6), 48.4 (4), 49.4 (2), 50.0 (3), 50.8 (3), 51 .1 (4), 53.6 (6), and 54.5 (2).

An XRPD diffraction pattern of filgotinib free base form I is shown in Figure 1.

Alternatively preferred filgotinib free base form I can be characterized by an FT- IR-spectrum showing peaks at the following wave numbers: 3288, 3230, 3 188, 3088, 3057, 3003, 2935, 2843, 2820, 1699, 1635, 1576, 1552, 1525, 1495, 1398, 1369, 1333, 1321 , 1298, 1269, 1215, 1 186, 1 1 57, 1 126, 1 1 13, 1084, 1053, 1038, 1020, 978, 962, 941 , 891 , 862, 854, 822, 779, 729, 677, 656, 63 1 , 625 and 615. It unexpectedly turned out that filgotinib free base form I exhibits an advantageous solubility in organic solvents.

Further, filgotinib free base form I is easily available from the synthesis without the need of a time-consuming and cost-intensive purification step. Moreover, it turned out that filgotinib free base form I exhibits an advantageously low hygroscopicity.

Additionally, filgotinib free base form I can be preferably used to prepare salts of filgotinib.

Due to the easy access and/or the good solubility in organic solvents filgotinib free base form I can advantageously be used to prepare pharmaceutically acceptable acid addition salts of filgotinib.

The acids which can be used to prepare the pharmaceutically acceptable acid addition salts are preferably those which form addition salts. Acid salts are for example hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, oxalic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, mandelic acid, gluconic acid, saccharic acid, glutamic acid, asparaginic acid, benzoic acid, 2,4,6- trimethylbenzoic acid, acetylsalicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ethane di sulfonic acid and pamoic acid, , hippuric acid and nicotinic acid

Preferably, the filgotinib free base form I is prepared by reacting cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l ,2,4]triazolo[l ,5a]pyri- dine-2yl] -amide with thiomorpholine dioxide until the completion of the reaction and the evaporation of the solvent. Up to this point the reactions 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 solvent. Subsequently, the product was filtered off and dried.

Examples of organic solvents are methanol, ethanol, isopropanol, acetone, ethyl acetate, dichloromethane, trichloromethane, dioxane, tetrahydrofurane, acetonitrile, diethylether and tert.butylmethylether.

In a preferred embodiment the suspending of the substance is carried out in a mixture of organic solvents, in particular in a mixture of ethyl acetate and methanol, more specifically in a volume ratio from 2: 1 to 15: 1.

It is further preferred that the suspension is subjected to a mechanical movement such as stirring. The step of 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 from 1 to 500 mbar, in particular 10 to 100 mbar.

According to a second aspect of the invention crystalline filgotinib free base relates to the crystal form II of filgotinib free base. This form can be considered as polymorphic form II of filgotinib. Filgotinib free base form II can preferably be characterized by XRP diffraction peaks at 9.2, 10.2, 21 .0, 22.9 and 29.5 degrees 2Θ (± 0.2 degrees 2Θ).

In a further preferred embodiment of the present invention filgotinib free base form II can be characterized by one or more further XRPD diffraction peak(s) at 12.9, 14.1 , 16.5, 18.8 and/or 24.3 degrees 2Θ (± 0.2 degrees 2Θ).

In alternative further preferred embodiment of the present invention filgotinib free base form II can be characterized by the XRPD diffraction peak(s) at degrees 2Θ ± 0.2 degrees 2Θ (Intensity %): 9.2 (24), 9.3 (9), 10.2 (4), 10.5 (2), 12.9 (24), 14.1 (1 1 ), 14.5 ( 1 ), 16.5 (100), 17.1 (21 ), 18.2 (45), 18.5 (3 1 ), 18.8 ( 100), 20.5 (29), 20.7 (62), 21.0 (50), 21.6 (20), 22.9 (14), 23.3 (39), 23.5 (29), 24.3 (79), 24.9 (3 1 ), 25.9 (10), 26.4 (13), 27.0 (1 ), 28.1 (6), 28.6 (16), 29.5 (18), 30.2 (3), 30.8 (4), 3 1.4 (2), 32.2 (8), 32.7 (8), 33.2 (16), 33.5 (23), 34.3 (4), 34.7 (1 1 ), 35.0 (5), 35.8 (2), 36.1 (4), 36.4 (3), 37.0 (3), 37.6 (8), 38.4 (2), 38.9 (2), 39.7 (6), 40.1 (4), 40.9 (7), 42.0 (10), 43.2 (9), 44.0 (3), 44.6 (4), 45.6 (2), 46.1 (6), 46.7 (5), 47.3 (3), 49.7 (2), 51.3 (4), 53. 1 (5) and 54.4 (3).

An XRPD diffraction pattern of filgotinib free base form II is shown in Figure 2.

Alternatively preferred filgotinib free base form II can be characterized by an FT- IR-spectrum showing peaks at the following wave numbers: 3228, 3 132, 3082, 3003, 291 8, 2829, 1666, 1637, 1556, 1525, 1510, 1466, 1444, 1414, 1381 , 1356, 1342, 1319, 1290, 1267, 1248, 1 190, 1 167, 1 155, 1 128, 1 107, 1076, 1047, 1022, 953, 924, 852, 795, 727, 687, 661 and 634. It unexpectedly turned out that filgotinib free base form II exhibits an advantageously low hygroscopicity.

Further, independent of the further processing conditions for the preparation of pharmaceutical formulations or dosage forms, such as dry or wet granulation and (direct compression), filgotinib free base form I I turned out to be stable and not to convert into other polymorphs.

Further, filgotinib free base form II is easily available from synthesis without the need of a time-consuming and cost-intensive purification step.

Preferably, the filgotinib free base form II is prepared by reacting cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[ 1 ,2,4]triazolo[ 1 ,5a]pyri- dine-2yl]-amide with thiomorpholine dioxide until the completion of the reaction and the evaporation of the solvent. Up to this point the reactions 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.

Examples of organic solvents are methanol, ethanol, isopropanol, acetone, ethylacetate, dichloromethane, trichloromethane, dioxane, tetrahydrofurane, acetonitrile, diethyl ether and tert.butylmethylether.

In a preferred embodiment the first and second suspending step of the substance is 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 .

It is further preferred that the suspension is subjected to a mechanical movement such as stirring.

Further, in the first optional heating and cooling step 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 from 1 to 500mbar, in particular 10 to 100 mbar.

According to a third aspect of the invention crystalline filgotinib free base relates to the crystal form III of filgotinib free base. This form can be considered as polymorphic form III of filgotinib. Filgotinib free base form III can preferably be characterized by XRP diffraction peaks at 7.6, 8.9, 1 1.1 , 1 1.4 and 26.6 degrees 2Θ (± 0.2 degrees 2Θ).

In a further preferred embodiment of the present invention filgotinib free base form III can be characterized by one or more further XRPD diffraction peak(s) at 14.1 , 17.3, 18.2, 19.8 and/or 22.3 degrees 2Θ (± 0.2 degrees 2Θ).

In alternative further preferred embodiment of the present invention filgotinib free base form III can be characterized by the XRPD diffraction peak(s) at degrees 2Θ ± 0.2 degrees 2Θ (Intensity %): 7.6 (26), 8.3 (1 ), 8.9 ( 13), 1 1.1 (21 ), 1 1.4 (23), 14.1 (21 ), 15.3 (9), 15.5 (4), 15.9 (14), 16.1 (15), 16.5 (23), 17.3 (48), 18.2 (63), 19.6 (67), 19.8 ( 100), 20.9 (20), 22.3 (66), 23.0 (34), 23.8 (50), 24.6 (38), 25.1 ( 1 1 ), 26.6 (32), 27.7 (7), 28.2 (6), 28.9 (17), 30.8 (8), 31.2 ( 15), 31.5 (8), 32.6 (7), 33.2 ( 10), 33.8 (9), 34.7 (10), 36.2 (6), 36.5 (6), 37.5 (5), 38.0 (6), 39.1 (5), 39.8 (6), 40.9 (1 ), 41.7 (3), 42.6 (5), 43.5 (3), 44.3 (4), 45.9 (8), 46.9 (5), 49.6 (4) and 51.2 (4).

An XRPD diffraction pattern of filgotinib free base form III is shown in Figure 3.

Alternatively preferred filgotinib free base form III can be characterized by an FT- IR-spectrum showing peaks at the following wave numbers: 3014, 2916, 2835, 1666, 1632, 1554, 1537, 1522, 1504, 1470, 1444, 1408, 1348, 1315, 1296, 1282, 1271 , 1232, 1219, 1 190, 1 1 19, 1 103, 1074, 1043, 1020, 951 , 924, 897, 883, 856, 827, 783, 760, 742, 725, 663, 650 and 625.

It unexpectedly turned out that filgotinib free base form III shows an enhanced solubility in water and organic solvents.

Further, filgotinib free base form III exhibits an advantageously low hygroscopicity. In addition filgotinib free base form III exhibits a good solubility in organic solvents, comparable to form I and highest solubility in aqueous solvent systems, compared to form I and II. Moreover, filgotinib free base form III unexpectedly shows an amount of residual organic solvent(s) so small that the compound meets the requirements of the FDA regulations. A subject of the present invention is a process for preparing crystalline filgotinib free base, in particular crystalline filgotinib free base form III as described above, comprising the following steps: a) providing filgotinib in form of an acid addition salt

b) adding the filgotinib from step a) to alkaline aqueous solution

c) isolating crystalline filgotinib free base.

In step a) filgotinib in form of an acid addition salt is provided. Examples of acids for the formation of the corresponding filgotinib acid addition salt are aspartic acid, fumaric acid, phosphoric acid, maleic acid, oxalic acid, hydrochloric acid, sulfuric acid, benzene sulfonic acid, toluene sulfonic acid, methane sulfonic acid and ethane sulfonic acid. More preferred are hydrochloric acid, sulfuric acid, benzene sulfonic acid, toluene sulfonic acid, methane sulfonic acid and ethane sulfonic acid, in particular hydrochloric acid.

In preferred embodiment filgotinib acid addition salt can be prepared by aj₎ suspending or dissolving filgotinib in a solvent,

an) adding an acid, and

¾ϋ) isolating the corresponding filgotinib acid addition salt

In step an filgotinib, such as filgotinib free base form I, can be suspended or dissolved in a solvent or a mixture of solvents. The solvent can be water, an organic solvent or a mixture thereof.

Examples of organic solvents are methanol, ethanol, isopropanol, acetone, ethylacetate, dichloromethane, trichloromethane, dioxane, tetrahydrofurane, acetonitrile, diethylether and tert.butylmethylether, preferably dichloromethane, methanol and a mixture of dichloromethane and methanol.

It is preferred that step ¾) is conducted with mechanical movement such as stirring. Further, step a,) can preferably be conducted under heating. In this application heating corresponds to elevating the temperature of the suspension/solution above 23 °C. In a preferred embodiment the temperature of the suspension/solution can be raised to the boiling point of the solvent or the mixture of solvents. After the heating, the suspension/solution can be cooled to 23 °C again.

In step an) an acid is added to the suspension/solution of step ¾). It is preferred that he acid can be present in form of a solution, either in water or in an organic solvent.

Step an) can be conducted under similar conditions as indicated above, i.e. under stirring and/or under heating/cooling. It is preferred that at the end of step au) the temperature of the mixture does not exceed 25 °C, more preferably the temperature can be from 0°C to 23 °C, in particular from 5° to 20°C.

In step a„ isolating the corresponding filgotinib acid addition salt can be carried out by filtering off the solid. Further, the filgotinib salt can preferably be washed. Subsequently, the filgotinib salt 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 10 to l OOmbar.

In an alternative preferred embodiment filgotinib acid addition salt can be provided in an aqueous solution/suspension. Such an aqueous solution/suspension can be prepared by suspending filgotinib in water, preferably under stirring and adding an acid in water to said suspension/solution. The preparation can be conducted under heating/cooling as described above.

In step b) filgotinib acid addition salt or an aqueous suspension/solution of filgotinib addition salt is added to a mixture of an alkaline substance in water.

Alkaline substances are amines such as ammonia, diethylamine, trimethylamine, triethylamine and bases hydroxides, phosphates, hydrogen phosphates, carbonates and hydrogen carbonates of alkali and earth alkali metal. Preferred are carbonates and hydrogen carbonates of alkali metal, more preferred carbonates and hydrogen carbonates of sodium and potassium, in particular sodium carbonate and sodium hydrogen carbonate, especially sodium hydrogen carbonate. Thus, the aqueous alkaline mixture can preferably contain 1 to 10 base equivalents, more preferably 1 .2 to 8 base equivalents, in particular 1.5 to 5 base equivalents based on the equivalents of acid contained in filgotinib acid addition salt or in the suspension/solution containing the filgotinib acid addition salt.

The addition of filgotinib acid addition salt or the aqueous suspension/solution of filgotinib acid addition salt to the aqueous alkaline mixture is preferably conducted under stirring.

Step c) of isolating crystalline filgotinib free base, preferably crystalline filgotinib free base form III, can be preferably carried out by filtering off the solid. Further, the crystalline filgotinib free base can preferably be washed. Subsequently, the crystalline filgotinib free base 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 10 to 100 mbar.

According to a fourth aspect of the invention crystalline filgotinib free base relates to the crystal form IV of filgotinib free base. This form can be considered as polymorphic form IV of filgotinib. Filgotinib free base form IV can preferably be characterized by XRP diffraction peaks at 8.6, 9.7, 10.6, 15.2 and 17.7 degrees 2Θ (± 0.2 degrees 2Θ).

In a further preferred embodiment of the present invention filgotinib free base form IV can be characterized by one or more further XRPD diffraction peak(s) at 6.5, 13.0, 1 6.9, 19.8 and/or 23.9 degrees 2Θ (± 0.2 degrees 2Θ).

In alternative further preferred embodiment of the present invention filgotinib free base form IV can be characterized by the XRPD diffraction peak(s) at degrees 2Θ ± 0.2 degrees 2Θ (Intensity %): 6.5 (4), 8.6 ( 100), 9.7 ( 19), 10.6 (35), 13.0 (46), 13.7 (8), 1 5.2 (72), 16.1 (5), 16.9 (56), 17.2 (42), 17.7 (25), 17.8 (22), 1 8.3 (2), 1 8.9 (55), 1 9.2 ( 1 1 ), 19.5 ( 15), 19.8 (60), 19.9 (36), 20.2 (6), 20.7 (35), 21.3 (4), 21 .5 (3), 22.1 (8), 22.6 ( 15), 22.9 (38), 23.5 (16), 23.9 (58), 24.4 (26), 24.8 ( 17), 25.9 (9), 26.1 ( 12), 26.4 (6), 27.7 ( 13), 28.1 (3), 28.7 (2), 29.0 ( 12), 30.0 (2), 30.3 (5), 30.7 (6), 31.0 (9), 3 1.4 ( 10), 31 .8 (4), 32.2 (9), 32.6 (8), 33.4 ( 14), 33.8 (6), 34.3 ( 1 1 ), 34.8 (4), 35.6 (3), 35.9 (6), 36.2 (2), 36.9 (2), 37.8 (5), 38.0 (3), 39.8 (3), 40.2 (3), 40.6 (4), 41.0 (7), 41 .8 (3 ), 42.1 (3), 43.1 (4), 43.5 (7), 43.9 (4). 44.7 (2), 45.0 (2), 45.5 (2), 46.2 (3), 46.5 (5), 47.9 (4), 48.7 (2), 49.6 (4), and 49.8 (6).

An XRPD diffraction pattern of filgotinib free base form IV is shown in Figure 4. Alternatively preferred filgotinib free base form IV can be characterized by an FT- IR-spectrum showing peaks at the following wave numbers: 3130, 3082, 3005, 2993, 2958, 2902, 283 1 , 1664, 1635, 1552, 1510, 1495, 1470, 1414, 1381 , 1369, 1352, 1340, 13 19, 1249, 1284, 1269, 1244, 1219, 1 192, 1 173, 1 128, 1 105, 1068, 1049, 1038, 1024, 1005, 976, 962, 953, 922, 881 , 854, 824, 810, 795, 760, 741 , 727, 687, 665, 646, 63 1.

It unexpectedly turned out that filgotinib free base form IV can be free of critical solvents according to the above-mentioned class 1 and class 2.

Moreover, filgotinib free base form IV unexpectedly shows an amount of residual organic solvent(s) so small that the compound meets the requirements of the FDA regulations. A subject of the present invention is a process for preparing crystalline filgotinib free base, in particular crystalline filgotinib free base form IV as described above, comprising the following steps: g) dissolving filgotinib in an organic solvent under elevated temperature h) cooling the solution of step g)

i) isolating crystalline filgotinib free base

In step g) filgotinib, such as filgotinib free base form I, can be dissolved, preferably completely dissolved, in an organic solvent at elevated temperature.

Examples of suitable organic solvents are alcohols with 2 to 5 carbon atoms such as ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, tert. butanol, n-pentanol, 2-pentanol, 3-pentanol, 2 -methyl- 1 -butanol, 2-methyl-2- butanol, 3-methyl- 1 -butanol, 3-methyl-2-butanol and, 2,2-dimethyl- l propanol, in particular n-butanol.

Further, step g) can be conducted under elevated temperature. In this application elevated temperature corresponds to a temperature which is above 23 °C (room temperature). In a preferred embodiment the temperature can be raised to the boiling point of the organic solvent.

It is preferred that step g) is conducted with mechanical movement such as stirring.

It is further preferred that the solution of step g) is filtered at elevated temperature. In step h) the solution, preferably the filtered solution of step g) can be cooled. It is preferred that the solution of step g) is cooled to a temperature of between 0°C to 35°C, more preferably between 3°C to 30°C, in particular between 5°C and 27°C, especially to 23°C.

It is preferred that also step h) is conducted with mechanical movement such as stirring.

Step i) of isolating crystalline filgotinib free base, preferably crystalline filgotinib free base form IV, can be preferably carried out by filtering off the solid. Further, the crystalline filgotinib free base can preferably be washed. Subsequently, the crystalline filgotinib free base can preferably be dried. Drying can preferably be carried out at a temperature of 23 °C to 90°C, preferably 35°C to 80°C, more preferably 45° to 75°C. Alternatively or additionally the drying can preferably be carried out under reduced pressure of from 0.1 to 500 mbar, preferably 0.5 to 100 mbar, in particular 1 to 25 mbar.

The present invention furthermore relates to pharmaceutical compositions comprising crystalline filgotinib free base according to the present invention. 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. ibbe, 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, hydroxy- propyl 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 μιτι 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 relates further to the use of a crystalline filgotinib free base form I, filgotinib free base form II and filgotinib free base form III for preparing a pharmaceutical preparation for the treatment of patients with rheumatoid arthritis and other inflammatory diseases.

A further subject of the present invention is a 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 the present invention or the pharmaceutical composition according to the present invention.

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 μ1

Solvent A: acetonitrile

Solvent B: 0.01 M H₂P0₄ pH Flow: 1.5 ml/min

Temperature: RT

Column: Supelco C I 8, 150 * 4.6 mm, 5 μιη 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 2μ1 and the following solvent gradient profile. time [min] solvent B [%]

0.00 75

8.00 50

13.00 40

14.00 75

17.00 75

Method C:

Method C corresponds to Method A, wherein the flow is amended to be I 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 Ka!_fl (λ- 1.5406 A)

Source 38 kV / 40 mA

Detector Vantec

detector slit Variable

divergence slit v6

antiscattering slit v6

2Θ range / ⁰ 2 < 2Θ < 55

step size / ° 0.017

Fourier Transform (FT) Infrared (IR) Spectroscopy nstrument: Thermo Nicolet, Avatar 330 FT-IR. Smart Endurance Diamond-ATR.

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

Differential Scanning Calorimetry (DSC)

Thermogravimetric Analysis (TGA)

Solubility Determination in Organic Solvents

Materials: HPLC-vials

0.2 μηι PTFE filter

solvents

Vortex mixer

ultrasonic bath

Calibration 5 concentration/peak area data points between 0.01 and 1.0 mg ml

(HPLC/UV) each calibration standard will be analyzed in duplicate;

Procedure Approx. 40 mg substance was weighed into a HPLC vial, in 100 μΐ portions the solvent was added followed by 1 s vortex mixing; the total amount added was at least 300 μΐ, the maximum amount was 1 ,000 μΐ. A sample was withdrawn from the suspension and filtered through a 0.2 PTFE filter directly into a fresh HPLC vial and diluted with an appropriate solvent. Quantification was done by HPLC in a duplicate

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 μηι 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- Ι μ (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 residua! solvents by Headspace GC

Sample preparation

Samples were dissolved 1 ml dimethylsulfoxide to 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, 5000ppm for ethanol and 3000ppm 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 μηι

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°C

MS Quadrupole: 150°C

Ionization: EI+

Detection mode: Scan (m/z 20 - 300) 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:

Filgotinib base was synthesized in six linear steps. The reaction scheme is given in the following scheme:

Scheme 1: Route of Synthesis for preparation of Filgotinib

Steps 1 to 5 are substantially known from the prior art. Step 6 was initially prepared in analogy to WO 2010/010190, but later modified.

Reference Example 1

In analogy to page 98 of WO 2010/010190, the starting material, [5-(4- bromomethyl-phenyl)-l ,2,4]triazolo[ l ,5-a]pyridine-2-yl]amide (1.5 g), was dissolved in a methanol (12.5 mL) dichloromethane (1.4 mL) mixture and diisopropylamine (1.37 mL) was added. Thiomorpholine dioxide (0.6 g) was added. The mixture was stirred at room temperature for 24 hours. After completion of the reaction the solvent was evaporated to yield a white solid. The compound was dissolved in dichloromethane ( 120 mL), dried over MgS0 , filtered and the solvent was evaporated. In analogy to the above patent literature the product was purified via chromatography with 100% ethylacetate on silica. The crude product was dry loaded on a silica column (40 g, 15-40 μηι). No elution of the product was observed with ethylacetate (after 3 L of eluent), even ethylacetate/methanol 9/1 was used as solvent system.

Reference Example 2

The starting material [5-(4-bromomethyl-phenyl)- 1 ,2,4]triazolo[ 1 ,5-a]pyridine-2- yl] amide and diisopropylamine were dissolved in a methanol/ dichloromethane mixture and stirred under nitrogen atmosphere at room temperature. Thiomorpholine dioxide was added. The yellow solution was stirred at room temperature for 16 hours. The solvent was evaporated. The compound was dissolved in dichlormethane, washed with water, dried over MgS0₄ (~5min) and the solvent was evaporated after filtration. The obtained white solid was dry loaded on a silica column (*Chromabond flash BT 40 SiOH 15-40 μηι, LOT: 01 14/2, Volume 71 ml, Ref.: 732999). No elution of the product was observed with ethylacetate ( 1.6 L of eluent).

Reference Example 3

The starting material [5-(4-bromomethyl-phenyl)- l ,2,4]triazolo[l ,5-a]pyridine-2- yl] amide (1 g; 2.7 mmol leq) and diisopropylamine (0.92 raL; 5.4 mmol 2eq) were dissolved in a methanol/ dichloromethane mixture (1 :5; 1.7 mL/8.5 mL) and stirred under N₂ at room temperature for 10 minutes. Thiomorpholine dioxide (0.4 g; 3 mmol 1.1 eq) was added. The yellow solution was stirred at room temperature for 16 hours. The solvent was evaporated. The compound was dissolved in dichloromethane (80 mL), washed with water (30 mL) and dried over MgS0₄ (~5min). MgS0₄ was filtrated off and the product solution was evaporated, yielding a white solid raw product (1.09 g, 95% oftheory). purity: 94.4 area-% at 254 nm

solid state: Polymorph IV

Reference example 4

The starting material (1 g; 2.7 mmol) was dissolved in a methanol/ dichloromethane (1 :5; 1.7 mL/8.4 mL) mixture, diisopropylamine (0.92 mL; 5.4 mmol) was added and the mixture was stirred under N₂ at room temperature for 10 minutes. Thiomorpholine dioxide (0.4 g; 3 mmol) was added. The yellow solution was stirred at room temperature for 16 hours. The solvent was evaporated and the obtained solid was dissolved in dichloromethane (50 mL), washed with water (30 mL) and dried over Na₂S0₄. After filtration the solution was evaporated, yielding a white solid raw product (1.09 g, 95% of theory). purity: 92.9 area-% at 254 nra

solid state: Polymorph IV

Example 1 : -[5-[4-[(l,l-dioxido-4-thiomorpholinyl)mcthyl] phenyl] [l,2,4]triazolo[ l,5- a|pyridin-2-yl]-cyclopropanecarboxamide (filgotinib free base form I)

[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 off and 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):

Ή-NMR (400 MHz, DMSO- 0.74 - 0.86 (m, 4 H) 2.01 (br. s., 1 H) 2.91 (s, 4 H) d₆) 3.10 - 3.15 (m, 4 H) 3.75 (s, 2 H) 7.27 (dd, J=6.26,

[δ ppm] 1.56 Hz, 1 H)7.50 (d, J=8.21 Hz, 2 H) 7.65 - 7.71 (m,

2 H) 7.97 (d, J=8.21 Hz, 2 H) 1 1.02 (br. s., 1 H)

FT-IPv (ATR) [cm ¹] 3288, 3230, 3 188, 3088, 3057, 3003, 2935, 2843,

2820, 1699, 1635, 1576, 1552, 1525, 1495, 1398, 1369, 1333, 1321 , 1298, 1269, 1215, 1 186, 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 (Figure 1 )

DSC endotherms (onset T):214°C; 319°C (br.)

residual solvent content 0.5.-2% (dichloromethane)

Example 2

N-[5-[4-[(l,l-dioxido-4-thiomorpholinyl)methyl] phenyl] [l,2,4]triazolo[l,5- a]pyridin-2-yl]-cyclopropanecarboxamide (filgotinib free base form II)

[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 overnight 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 overnight. The product was filtered off and washed with 50 ml dichloromethane and dried over night at 40°C and 7 mbar (crop 1; 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 overnight 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, 3 132, 3082, 3003, 2918, 2829, 1666, 1 637, 1556, 1525, 1510, 1466, 1444, 1414, 1381 , 1356,

1342, 13 19, 1290, 1267, 1248, 1 190, 1 167, 1 155, 1 128, 1 107, 1076, 1047, 1022, 953, 924, 852, 795, 727, 687, 661 , 634

XRPD (crop I same as crop II) 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 (Figure 2)

DSC (crop I) endotherms (onset T): 235°C; 327°C (br.)

residual solvent content 0.5-2% (dichloromethane)

Example 3:

N-|5-|4-|(l,l-dioxido-4-thiomorpholinyl)methyl] phenyl] | l ,2,4]triazolo| l ,5- a]pyridin-2-yl]-cyclopropanecarboxamide (filgotinib free base form III)

NaHC0₃ (79.72 g; 0.95 mol) was dissolved in water (3.2 1) and filgotinib hydrochloride, prepared according to Example 7 ( 109.6 g; 0.24 mol) was added portion wise. The reaction mixture was stirred for one hour at 23°C. The product was filtered off, washed with water (500 ml) and dried in an oven at 50°C/20 mbar to yield the product as white solid.

Yield: 89.2 g (88%)

purity (HPLC/UV, method 99.8%

A, t_r= 2.4 min, λ=230 nm):

FT-IR (ATR) [cm^"1] : 3014, 2916, 2835, 1666, 1632, 1554, 1537, 1522,

1504, 1470, 1444, 1408, 1348, 1315, 1296, 1282, 1271 , 1232, 1219, 1 190, 1 1 19, 1 103, 1074, 1043, 1020, 951 , 924, 897, 883, 856, 827, 783, 760, 742, 725, 663, 650, 625

XRPD 1^st priority reflections 7.6, 8.9, 1 1.1 , 1 1.4, 26.6°2Θ

2^nd priority reflections 14.1 , 17.3, 18.2, 19.8, 22.3°2Θ (Figure 3)

DSC endotherms (onset T): 230°C; 280°C (br.) residual solvent content 0- 1 10 ppm (dichloromethane)

Example 4:

N-[5-[4-[(l,l -dioxido-4-thiomorpholinyl)methyll phenyl] | l ,2,4|triazolo[I,5- a]pyridin-2-ylj-cyclopropanecarboxamide (filgotinib free base form IV)

Filgotinib (form I 1000 mg) was dissolved in n-butanol (60 mL) at reflux temperature. The solution was filtered hot through a folded filter and cooled to 23°C under ambient conditions. Crystallization of a colorless solid started within a few minutes. The solution was stored overnight at room temperature. The solid was then isolated by filtration and dried 40 h at 70°C / 2 mbar.

Yield: 0.7 g (73 % of theory)

Ή NMR (400 MHz, DMSO- 0.77 - 0.82 (m, 4H), 2.00 (br. s, 1 H), 2.92 (m, 4H), d ) 3.13 (m, 4H), 3.76 (s, 2H), 7.28 (dd, = 6.8 Hz, J₂

[δ ppm] = 1.8 Hz, 1 H), 7.51 (d, J = 8.2 Hz, 2H), 7.65 - 7.72

(m, 2H), 7.98 (d, J = 8.2 Hz, 2H), 1 1 .01 (s, 1H)

FT-IR (ATR) [cm^"1] : 3 130, 3082, 3005, 2993, 2958, 2902, 283 1 , 1664,

1635, 1552, 1510, 1495, 1470, 1414, 1381 , 1369, 1352, 1340, 13 19, 1249, 1284, 1269, 1244, 1219, 1 192, 1 173, 1 128, 1 105, 1068, 1049, 1038, 1024, 1005. 976, 962, 953, 922, 881 , 854, 824, 810, 795, 760, 741 , 727, 687, 665, 646, 631

XRPD 1 ^st priority reflections: 8.6, 9.7, 10.6, 15.2, 17.7° 2Θ

2^nd priority reflections: 6.5, 13.0, 16.9, 19.8, 23.9° 2Θ

DSC endotherm: onset 217.7°C / peak 220.2°C

exotherm: onset 221.8°C / peak 222.9°C

endotherm: onset 236.3°C / peak 237°C

Example 5: Conversion of filgotinib solid state I form to solid state II form

Filgotinib solid state I form (0.5 g) was stirred at room temperature over two nights in a mixture of methanol (0.8 mL) and dichloromethane (4.2 mL). The substance was filtrated off, washed with dichloromethane and dried under vacuum at 50°C and 6 mbar for 2 days to obtain solid state form II of filgotinib free base with a residual content of ~0.3% dichloromethane.

Example 6: Conversion of filgotinib solid state III form to solid state II form in pharmaceutical quality

Filgotinib Form III (5 g) and Form II (100 mg) were suspended in ethanol (65 mL) and stirred at 70°C for two days. The product was filtrated off and washed with ethanol (4 mL), dried at 50°C/ 6mbar overnight to obtain the polymorphic form II (residual solvent content 2710 ppm (ethanol)) in 97% yield (4.94 g).

Example 7 Preparation of filgotinib hydrochloride Form A

0.5 g ( 1 .18 mmol) Filgotinib base prepared according to Example 1 was dissolved in 40 ml dichloromethane and the solution was stirred at room temperature. 0.13 ml (1.3 mmol) 32% aqueous HQ was added in one portion and the reaction mixture was stirred over night at 23 °C. The white product was filtered off, washed with 10 ml dichloromethanr and dried for 2.5 h at 50°C / 20 mbar.

Name Filgotinib hydrochloride, solid Form A

Yield: 0.47 g (87 % of theory)

purity (HPLC/UV, method A, 98.6 %

t_r= 2.2 min, λ=230 nm:

Ή NMR (400 MHz, DMSO- 0.77 - 0.90 (m, 4 H) 2.01 (br. s., 1 H) 3.67 (br. s., 7 de) H) 4.57 (s, 2 H) 6.26 (br. s., 2 H) 7.43 (dd, J=7.04,

[δ ppm] 1.17 Hz, 1 H) 7.65 - 7.94 (m, 4 H) 8.10 (d, J=8.60

Hz, 2 H) 1 1.47 (br. s., 1 H)

FT-IR (ATR) [cm^"1] : 3092, 3036, 2985, 2943, 2847, 2609, 2434, 2378,

1693, 1647, 1597, 1572, 1524, 1502, 1454, 1396, 1348, 1335, 1302, 1284, 121 1 , 1 167, 1 128, 1067, 1030, 95 1 , 916, 870, 845, 781 , 764, 735, 721 , 631 , 606

XRPD 1^st priority reflections 14.9, 19.4, 19.9, 24.8,

28.3°2Θ

2^nd priority reflections 7.1 , 9.6, 14.3, 18.6, 26.2°20

DSC endotherms: 33 °C (br.), 188°C (br.), 250°C (br.) Example 8: Physical properties of filgotinib free base Forms I, II and III TGA measurements

Filgotinib free base (solid forms I-III)

Hygroscopicity (Dynamic Vapor Sorption Analysis (DVS))

It can be see that there is a low water-uptake in the range of 45% to 75% relative humidity, which may become relevant upon storage, which is 0.06% form Filgotinib free base form I, 0.33% for Filgotinib free base form II and 1.5% for Filgotinib free base form III.

Solubility in organic solvents

As it can be seen, dioxane and dichloromethane show the highest solubility among the tested solvents with forms I and III as superior forms, compared to form II with a less solubility of 1/5 to 1/6 of I or III

Aqueous solubility of free base form

As it can be seen, Filgotinib free base form III shows a significant better solubility in aqueous system, in particular in 0.01 M HC1.

Stability on long term storage:

Samples were stored in vials, opened and closed at 40°C and 75% humidity. The samples were analyzed after 12 weeks by XRD and HPLC.

storage stabilities of polymorph I and III after 12 weeks

*initial purity 97.6%: **initial purity 99.2%

Filgotinib free base form I and form III show an excellent stability over the period of 12 weeks even under stress condition (storage of the opened vial) Residual Solvents Filgotinib base solid forms I -IV

Claims

Claims:

1 . Crystalline filgotinib free base.

2. Crystalline filgotinib according to claim 1 having a residual solvent content within pharmaceutically acceptable limits.

3. Crystalline filgotinib free base according to claim 1 and 2, having characteristic X-ray powder diffraction peaks at 7.1 , 8.1 , 10.8, 1 8.4 and 27.3 degrees 2Θ (± 0.2 degrees 2Θ).

4. Crystalline filgotinib free base according to claim 1 , 2 and 3, having one or more further characteristic X-ray powder diffraction peak(s) at 14.2, 16.2, 17.2, 1 9.8 and/or 25.2 degrees 2Θ (± 0.2 degrees 2Θ).

5. Crystalline filgotinib free base according to claim 1 and 2, having characteristic X-ray powder diffraction peaks at 9.2, 10.2, 21 .0, 22.9 and 29.5 degrees 2Θ (± 0.2 degrees 2Θ).

6. Crystal line filgotinib free base according to claim 1 , 2 and 5, having one or more further characteristic X-ray powder diffraction peak(s) at 12.9, 14.1 , 16.5, 1 8.8 and/or 24.3 degrees 2Θ (± 0.2 degrees 2Θ).

7. Crystal line filgotinib free base according to claim 1 and 2, hav ing characteristic X-ray powder diffraction peaks at 7.6, 8.9, 1 1.1 , 1 1.4 and 26.6 degrees 2Θ (± 0.2 degrees 2Θ).

8. Crystalline filgotinib free base according to claim 1 , 2 and 7, having one or m re further characteristic X-ray powder diffraction peak(s) at 14. 1 , 17.3, 18.2, 19.8 and/or 22.3 degrees 2Θ (± 0.2 degrees 20).

9. Process for preparing crystalline filgoti nib free base according to claims 1 , 2, 7 and 8, characterized by the following steps: a) providing filgotinib in form of an acid addition salt

b) adding the filgotinib from step a) to alkaline aqueous solution

c) isolating crystalline filgotinib free base.

10. Process according to claim 9, wherein the acid for the filgotinib in form of an acid addition salt is selected from the group comprising hydrochloric acid, sulfuric acid, benzene sulfonic acid, toluene sulfonic acid, methane sulfonic acid and ethane sulfonic acid, preferably hydrochloric acid.

1 1 . Pharmaceutical composition comprising filgotinib free base according to any one o claims 1 to 8.

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

13. 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.