BARICITINIB SALTS

The field of the invention

The subject of our invention relates to novel salts of the pharmaceutical active substance baricitinib, to a method for their production, to pharmaceutical preparations containing the novel salts as well as to the use of all these in medical therapy.

The state of the art

It is known that the formula (1) { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )- lH-pyrazol-l-yl]azetidin-3-yl}acetonitrile with international non-proprietary name baricitinib is a pharmacologically active substance developed for the treatment of rheumatoid arthritis belonging to the family of Janus kinase inhibitors.

The formula (1) baricitinib was first disclosed in international patent application number WO2009114512. The production of the baricitinib trifluoroacetate salt is described in example 1 of the patent application. The ^-NMR and LC-MS data are given. The baricitinib trifluoroacetate salt is obtained using a preparative HPLC method. It should be noted that due to the toxic nature of the trifluoracetate ion it cannot be used as the counter ion of basic pharmaceutical active substances. The same patent application also discloses the baricitinib dihydrogen phosphate salt (incorrectly called phosphate in the application), and its production is also described. The dihydrogen phosphate salt is characterised by melting point, element analysis and with FTIR, ¹³ C-NMR, ^ NMR and LC-MS data. The patent application number WO 2015145286 describes the production of the amorphous form of the baricitinib base. The amorphous form is characterised by XRPD, DSC, TG, IR data.

Patent application number WO 2015166434 describes the crystalline form of the baricitinib base containing 3% water. The crystalline form is characterised by XRPD, DSC, TG, IR data. A brief description of the invention

In the recent past a serious demand has arisen in the pharmaceutical industry to be able to reproducibly produce pure and morphologically homogenous products. This is a basic condition in order to be able to satisfy pharmaceutical formulation demands. It is well known that the various salts and polymorphs exhibit differences in important characteristics such as solubility, chemical stability, polymorph stability, dissolution rate, bioavailability, filterability, drying capability, and tabletability. Furthermore, from the point of view of production economy, it is exceptionally important to produce the product with a method that may be implemented on the industrial scale and that reproducibly results in a morphologically homogenous crystalline form that is free of impurities. We wished to produce a product that complies with the above conditions by producing salts.

We repeated the methods disclosed in patent application number WO 2009114512 for the production of baricitinib dihydrogen phosphate salt. Proceeding in accordance with example 61, the dihydrogen salt did not precipitate from the reaction mixture, therefore we reproduced the recipe described in example 71 as well, which is characterised by the phosphoric acid being added in two steps. The water sorption isotherms of the baricitinib dihydrogen phosphate salt produced in this way show that it is very susceptible to absorbing water, which limits its use in pharmaceutical preparations.

Therefore the objective of elaborating the invention was the production of high-purity, new baricitinib salt forms with a homogenous crystalline structure, the stability and physical- chemical characteristics of which are preferable to those of the known forms and which have chemical stability at least as good and that of the known forms, and also which may be reproducibly produced even on industrial scales.

The subject of the invention relates to new salts of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- <i]pirimidin-4-yl)-lH-pyrazol- l-yl]azetidin-3-yl}acetonitrile with international non- proprietary name baricitinib that may be used as pharmaceutical active substances and a method for their production. More specifically the subject of the invention relates to the salts of baricitinib formed with ethanesulfonic acid (2), methanesulfonic acid (3) and benzenesulfonic acid (4), hydrochloric acid, 4-toluenesulfonic acid, oxalic acid, 2- hydroxyethane sulfonic acid, fumaric acid, tartaric acid and cyclamic acid.

We produced the salts of baricitinib formed with hydrochloric acid, 4-toluenesulfonic acid, oxalic acid, 2-hydroxyethane sulfonic acid, fumaric acid, tartaric acid, cyclamic acid, ethanesulfonic acid (2), methanesulfonic acid (3) and benzenesulfonic acid (4).

In the case of baricitinib hydrochloride and bicyclamate salts, several polymorphic forms and their physical mixtures were produced, however, the production of neither of them could be upscaled and reproduced. Experience shows that the hydrochloride and bicyclamate salt forms and their crystalline forms exhibit a large degree of chemical instability.

In the case of the baricitinib oxalate, hydrogen fumarate and hydrogen tartrate salts, it was seen that from a crystallographic point of view these forms have a low degree of structural order and low thermodynamic stability.

The baricitinib tosylate salt form produced by us has a complex crystalline structure. The salt consists of several crystal forms, the thermodynamic stability of which may be very similar, as using the usual techniques it was not possible to achieve the desired solid phase inter- transformation and so the production of a homogenous, thermodynamically stable form. However, it was surprising to find that the salts of baricitinib produced with sulfonic acids, especially ethanesulfonic acid (2), methanesulfonic acid (3) and benzenesulfonic acid (4) are forms with homogenous crystalline structures and may be reproducibly produced.

Figures

Figure 1: The moisture sorption isotherms of baricitinib dihydrogen phosphate salt produced according to example 71 of international patent application number WO 2009114512 at 25 °C

Figure 2: The x-ray powder diffractogram of the baricitinib esylate (1: 1) salt form

Figure 3: The moisture sorption isotherms of the baricitinib esylate (1:1) salt form at 25 °C Figure 4: The x-ray powder diffractogram of the baricitinib mesylate (1: 1) salt form

Figure 5: The moisture sorption isotherms of the baricitinib mesylate (1: 1) salt form at 25 °C

Figure 6: The x-ray powder diffractogram of the baricitinib besylate (1: 1) salt form

Figure 7 The moisture sorption isotherms of the baricitinib besylate (1:1) salt form at 25 °C Figure 8: Baricitinib base and salts water adsorption isotherms at 25 °C

A detailed description of the invention

The subject of the invention relates to the salts of baricitinib formed with sulfonic acids. More specifically, the subject of the invention is: - the baricitinib esylate (1: 1) salt,

- the baricitinib mesylate (1: 1) salt,

- the baricitinib besylate (1: 1) salt.

More specifically the subject of the invention relates to the crystalline baricitinib esylate (1: 1) salt form the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 5.80; 9.10; 13.57; 15.30; 18.30. More specifically it may be characterised by the following x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 5.80; 9.10; 11.59; 13.57; 15.30; 15.93; 18.30; 19.02; 20.09; 22.05. Even more specifically it may be characterised by the following x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 5.80; 9.10; 9.95; 11.59; 13.24; 13.57; 15.30; 15.93; 17.46; 18.30; 19.02; 20.09; 21.06; 21.36; 22.05; 23.31; 23.57; 24.44; 24.69; 24.95; 25.37; 25.81; 26.37; 26.69; 26.88; 27.36; 28.27; 28.72; 29.32; 30.17; 30.78; 31.76; 32.22; 34.40. The characteristic x-ray powder diffractogram of this may be seen in figure 2, and the 2% or greater intensity signals are summarised in the following table 1.

Table 1: The x-ray powder diffraction data of the baricitinib esylate (1: 1) salt form

(relative intensities > 2%)

Peak 2Θ (°) d (A) Relative intensity (%)

1 5.80 15.23 13

2 9.10 9.71 56

3 9.95 8.88 5

4 11.59 7.63 8

5 13.24 6.68 5

6 13.57 6.52 18

7 15.30 5.79 45

8 15.93 5.56 32

9 17.46 5.07 4

10 18.30 4.84 100

11 19.02 4.66 20

12 20.09 4.42 25 Peak 2Θ (°) d (A) Relative intensity (%)

13 21.06 4.22 4

14 21.36 4.16 8

15 22.05 4.03 50

16 23.31 3.81 4

17 23.57 3.77 7

18 24.44 3.64 14

19 24.69 3.60 11

20 24.95 3.57 10

21 25.37 3.51 22

22 25.81 3.45 6

23 26.37 3.38 12

24 26.69 3.34 14

25 26.88 3.31 20

26 27.36 3.26 15

27 28.27 3.15 10

28 28.72 3.11 17

29 29.32 3.04 4

30 30.17 2.96 4

31 30.78 2.90 9

32 31.76 2.82 3

33 32.22 2.78 8

34 34.40 2.60 8

The moisture sorption isotherms of the baricitinib esylate (1: 1) salt form according to the invention recorded at 25 °C are presented in figure 3. It is visible that, preferably, the substance does not exhibit significant hygroscopicity. More specifically the subject of the invention also relates to the crystalline baricitinib mesylate (1: 1) salt form the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 5.84; 9.33; 13.92; 15.44; 18.59. More specifically it may be characterised by the following x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 5.84; 9.33; 11.70; 13.62; 15.44; 15.99; 18.59; 18.73; 19.23; 25.45. Even more specifically it may be characterised by the following x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 5.84; 9.33; 10.29; 11.70; 13.33; 13.62; 15.44; 15.99; 17.58; 18.59; 18.73; 19.23; 19.80; 20.23; 20.43; 20.66; 21.10; 21.52; 22.47; 22.54; 23.53; 23.91; 24.11; 24.50; 24.75; 25.05; 25.30; 25.45; 26.37; 26.50; 26.95; 27.45; 28.04; 28.50; 28.93; 29.53; 31.22; 31.65; 34.78. The characteristic x-ray powder diffractogram of this may be seen in figure 4, and the 1% or greater intensity signals are summarised in the following table 2.

Table 2: The x-ray powder diffraction data of the baricitinib mesylate (1: 1) salt form

(relative intensities > 1%)

Peak 2Θ (°) d (A) Relative intensity (%)

1 5.84 15.12 13

2 9.33 9.47 29

3 10.29 8.59 9

4 11.70 7.56 11

5 13.33 6.64 7

6 13.62 6.50 38

7 15.44 5.73 76

8 15.99 5.54 31

9 17.58 5.04 4

10 18.59 4.77 100

11 18.73 4.73 27

12 19.23 4.61 31

13 19.80 4.48 12

14 20.23 4.39 7 Peak 2Θ (°) d (A) Relative intensity (%)

15 20.43 4.34 10

16 20.66 4.30 6

17 21.10 4.21 4

18 21.52 4.13 6

19 22.47 3.95 23

20 22.54 3.94 21

21 23.53 3.78 3

22 23.91 3.72 12

23 24.11 3.69 2

24 24.50 3.63 12

25 24.75 3.59 32

26 25.05 3.55 12

27 25.30 3.52 20

28 25.45 3.50 65

29 26.37 3.38 9

30 26.50 3.36 19

31 26.95 3.31 38

32 27.45 3.25 42

33 28.04 3.18 5

34 28.50 3.13 9

35 28.93 3.08 32

36 29.53 3.02 3

37 31.22 2.86 12

38 31.65 2.82 6 Peak 2Θ (°) d (A) Relative intensity (%)

39 32.31 2.77 13

40 34.78 2.58 9

The moisture sorption isotherms of the baricitinib mesylate (1: 1) salt form according to the invention recorded at 25 °C are presented in figure 5. It is visible that, preferably, the substance does not exhibit significant hygroscopicity.

More specifically the subject of the invention also relates to the crystalline baricitinib besylate (1: 1) salt form the characteristic x-ray powder diffraction peaks of which are the following: 2Θ (±0.2 °2Θ): 7.19; 11.26; 12.63; 14.36; 16.51. More specifically it may be characterised by the following x-ray powder diffraction peaks: 2Θ (±0,2 °2Θ): 7.19; 11.26; 12.63; 14.36; 16.51; 16.61; 17.66; 18.48; 20.83; 24.64. Even more specifically it may be characterised by the following x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 7.19; 9.20; 11.26; 12.63; 14.36; 14.86; 16.51; 16.61; 16.92; 17.33; 17.66; 18.25; 18.48; 18.79; 20.15; 20.83; 21.17; 22.11; 22.39; 22.73; 24.10; 24.35; 24.64; 25.35; 25.77; 26.83; 26.99; 27.72; 27.92; 28.34; 28.99; 29.52; 29.98; 30.57; 31.32; 31.64. The characteristic x-ray powder diffractogram of this may be seen in figure 6, and the 2% or greater intensity signals are summarised in the following table 3.

Table 3: The x-ray powder diffraction data of the baricitinib besylate (1: 1) salt form

(relative intensities > 2%)

Peak 2Θ (°) d (A) Relative intensity (%)

1 7.19 12.29 70

2 9.20 9.61 8

3 11.26 7.85 40

4 12.63 7.00 45

5 14.36 6.17 55

6 14.86 5.96 10

7 16.51 5.37 89

8 16.61 5.33 35

9 16.92 5.24 11 Peak 2Θ (°) d (A) Relative intensity (%)

10 17.33 5.11 7

11 17.66 5.02 77

12 18.25 4.86 21

13 18.48 4.80 85

14 18.79 4.72 12

15 20.15 4.40 38

16 20.83 4.26 59

17 21.17 4.19 28

18 22.11 4.02 4

19 22.39 3.97 3

20 22.73 3.91 24

21 24.10 3.69 10

22 24.35 3.65 13

23 24.64 3.61 100

24 25.35 3.51 40

25 25.77 3.45 46

26 26.83 3.32 17

27 26.99 3.30 32

28 27.72 3.22 15

29 27.92 3.19 9

30 28.34 3.15 4

31 28.99 3.08 32

32 29.52 3.02 4

33 29.98 2.98 3 Peak 2Θ (°) d (A) Relative intensity (%)

34 30.57 2.92 3

35 31.32 2.85 13

36 31.64 2.83 9

The moisture sorption isotherms of the baricitinib besylate (1:1) salt form according to the invention recorded at 25 °C are presented in figure 7. It is visible that the substance is slightly more susceptible to absorbing water than the baricitinib esylate (1: 1) or the baricitinib mesylate (1: 1) salt forms according to the invention, however, from the point of view of use in a pharmaceutical preparation the hygroscopicity is still sufficiently low.

On the basis of toxicology data in the literature it can be determined that the 2.95 mg of ethanesulfonic acid, the 2.58 mg of methanesulfonic acid and the 4.25 mg of benzenesulfonic acid taken with the maximum daily dose of 10 mg of baricitinib is, preferably, just a fraction of the permitted daily amount of ethanesulfonic acid, methanesulfonic acid and benzenesulfonic acid, therefore toxicity concerns do not arise.

The thermal stress test and the forced stability test present an accelerated model of the degradation occurring in the pharmaceutical preparation during storage. The results of this forecast whether the new salts of baricitinib (1) according to the invention will be stable in pharmaceutical preparations under forced stability conditions. This preferable characteristic of the baricitinib salts according to the present invention is very important from the point of view of the formulation of the pharmaceutical preparation, its storage and the minimising of the damaging effects exerted on the human body.

The stability of the baricitinib esylate (1: 1), baricitinib mesylate (1: 1) and baricitinib besylate (1: 1) salts forming the subject of the present application was subjected to detailed tests. The baricitinib base was used as a reference.

The results of the accelerated stability test are presented in the following tables 4 to 7. The table includes the percentage amounts of the contaminants and their change, as well the water content of the samples and its change. Table 4 The stability test data of the baricitinib base (1) used as a reference

Initial 40 °C, 70%

Storage conditions 25 °C, 90% RH 70 °C, open sample RH

6 3 6 3 6

Storage time 3 weeks

weeks weeks weeks weeks weeks

Water content

0.2 0.2 0.1 0.2 0.2 0.2 0.2 [m/m%]

Known contaminant

1 0.10 0.10 0.11 0.10 0.11 0.11 0.11

RRT=0.90 (%)

Unknown

contaminant 0.11 0.14 0.09 0.14 0.09 0.14 0.08

RRT=0.92 (%)

Known contaminant

2 0.05 - 0.08 - 0.08 - 0.09

RRT=1.06 (%)

Total 0.26 0.24 0.28 0.24 0.28 0.25 0.28

Table 5. The stability test data of baricitinib esylate (2)

Initial 40 °C, 70%

Storage conditions 25 °C, 90% RH 70 °C, open sample RH

6 3 6 3 6

Storage time 3 weeks

weeks weeks weeks weeks weeks

Water content

0.3 0.2 0.1 0.2 0.1 0.2 0.2 [m/m%]

Known contaminant

1 0.11 0.12 0.14 0.12 0,15 0.12 0.14

RRT=0.90 (%)

Unknown - - - - - - - Initial 40 °C, 70%

Storage conditions 25 °C, 90% RH 70 °C, open sample RH

contaminant

RRT=0.92 (%)

Known contaminant

2 0.06 0.07 0.07 0.06 0.06 0.06 0.06

RRT=1.06 (%)

Total 0.17 0.19 0.21 0.18 0.21 0.18 0.20

Table 6. The stability test data of baricitinib mesylate (3)

Initial 40 °C, 70%

Storage conditions 25 °C, 90% RH 70 °C, open sample RH

6 3 6 3 6

Storage time 3 weeks

weeks weeks weeks weeks weeks

Water content

0.3 0.2 0.2 0.2 0.1 0.2 0.2 [m/m%]

Known contaminant

1 0.11 0.11 0.13 0.11 0.13 0.11 0.13

RRT=0.90 (%)

Unknown

contaminant - - - - - - -

RRT=0.92 (%)

Known contaminant

2 0.03 0.04 0.04 0.04 0.04 0.04 0.04

RRT=1.06 (%)

Total 0.14 0.15 0.17 0.15 0.17 0.15 0.17 Table 7. The stability test data of baricitinib besylate (4)

It was surprising to experience that the baricitinib salts according to the present invention were seen to be especially stable as compared to the baricitinib base (1) and the baricitinib dihydrogen phosphate salt during 3 and 6 weeks of storage under various forced conditions. An especially significant advantage of our new salts over the base (1) is that while the base contains a contaminant of unknown structure with retention of RRT=0.92, surprisingly this contaminant cannot be detected at all in the new salts (2-4) according to the invention. As a strict 0.10% limit relates to contaminants of unknown structure on the basis of pharmaceutical industry guidelines, the presence of the contaminant in this amount in the base is critical. From the data in the table it can be seen that the salts (2-4) according to the present invention can be preferably produced at a greater level of purity than the reference baricitinib base (1).

It can also be seen from the summary table of the results that the salt forms preferably did not display water absorption under various storage conditions, even when the humidity was high. Therefore the baricitinib esylate (1: 1), baricitinib mesylate (1: 1) and baricitinib besylate (1: 1) salts may be preferably used for the formulation of pharmaceutical preparations from the point of view of chemical stability and hygroscopicity as well.

In figure 8 the moisture sorption isotherms of all the baricitinib salts according to the invention have been compared with the moisture sorption isotherms of the baricitinib dihydrogen phosphate salt that may be produced according to example 71 of international patent application number WO 2009114512 and of the baricitinib base produced according to that described in the IP.com publication number 000244270 (publication date: 27.11.2015). From the comparison of figures 1, 3, 5, 7 and 8 it can be seen that all three baricitinib salt forms according to the invention are less disposed to absorb water than the baricitinib dihydrogen phosphate salt that may be produced according to example 71 of international patent application number WO 2009114512 between 5 and 95% RH. The dihydrogen phosphate salt is strongly hygroscopic, DVS tests have shown that at a humidity of 95% its water uptake reaches 3% at room temperature, which makes this salt unfavourable from the point of view of development. At the same time, it was surprising to determine that the moisture content of none of the baricitinib salts according to the present invention reaches 0.5% at a relative humidity between 5 and 95%. Even in the case of the besylate salt (4) this value is an order of magnitude lower than in the case of the dihydrogen phosphate salt, around 0.35%, due to which this salt is suitable for development purposes, without special storage conditions being prescribed. This mass increase in the case of the baricitinib esylate salt (2) is especially preferable, being even lower at about 0.08%, and very preferable in the case of the mesylate salt (3) at around 0.02%.

Formulation for oral administration demands that the active substance be bioavailable. In the case of a preparation taken orally, this bioavailability may be influenced by numerous factors, such as the solubility, stability and absorption of the given medicine in the gastrointestinal system.

The solubility of the baricitinib base in water strongly depends on the pH value of the aqueous medium. The normal pH value of the stomach varies between 1.2-1.8 [Remington: The Science and Practice of Pharmacy, 20 ^th issue (2000, editor: A.R. Gennaro); chapter 32; C.J. Perigard: Clinical Analysis]. The pH value of the oesophagus is 4.5 and the pH value of the small intestines is around 6.8. Therefore the solubility experiments were carried out at three different pH values in addition to distilled water (pH=l, pH=4.5 and pH=6.8). The solubility results are summarised in table 8. Table 8. Results of the solubility test

From the summary table of the results it can be seen that the solubility data of the new salts forming the subject of the invention, i.e. baricitinib esylate (1:1), baricitinib mesylate (1: 1) and baricitinib besylate (1: 1), at pH=l are similar to the solubility values of the reference baricitinib base, significantly better at pH=6.8, and in distilled water and at pH=4.5 they are surprisingly considerably and preferably better. Similarly, the solubility of the new salts forming the subject of the invention is preferably better than that of the dihydrogen phosphate salt known of from the patent literature.

The subject of the invention also relates to a pharmaceutical preparation containing a therapeutically effective amount of any baricitinib salt according to the invention and, optionally, one or more excipients used in pharmaceutical formulation. Furthermore, it also relates to a method for the production of a pharmaceutical preparation, characterised by that any baricitinib salt according to the invention is mixed with a pharmaceutically acceptable carrier and, optionally, pharmaceutically acceptable excipients and then placed in galenic form.

The subject of the invention also relates to a method for the production of the above pharmaceutical preparations, in such a way that a baricitinib salt according to the invention or a mixture of them is mixed with pharmaceutically acceptable solid or liquid diluents and/or excipients, and the mixture is placed in galenic form.

The advantage of the invention is that the compounds according to the present invention have preferable crystalline structures with homogenous morphology. Accordingly they have preferable and reproducible characteristics from the point of view of dissolution rate, bioavailability, chemical stability, hygroscopicity and processing characteristics (filterability, drying capability, tabletability, etc.).

The subject of the invention also relates to a method for the production of baricitinb salts, characterised by that the crystalline, anhydrous, hydrate or solvate form of formula (1) baricitinib is reacted in a suitable organic solvent with the desired organic or inorganic acid, then the salt formed is isolated.

The salts and salt polymorphs according to the invention may be produced in a way that the baricitinib free base (1) is suspended or dissolved in an organic solvent and then reacted with the desired acid at the appropriate temperature, the crystalized salt is isolated, washed with an organic solvent if necessary and then dried at the appropriate temperature.

Any method used in the pharmaceutical industry may be used for isolating the salt that serves for separating the solid phase and the liquid phase, for example, it may be filtered under atmospheric conditions, or by using vacuum filtering, or even under pressure, and a centrifuge may even be used. Inorganic or organic acids may be used to produce the salts according to the invention, which may be the following: ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, hydrochloric acid, 4-toluenesulfonic acid, oxalic acid, 2-hydroxyethane sulfonic acid, fumaric acid, cyclamic acid, tartaric acid.

The reaction may be carried out in organic solvents, such as in aliphatic alcohols with 1 to 6 carbon atoms, in straight chain or ring ethers with 1 to 5 carbon atoms, in esters with 1 to 6 carbon atoms, in open chain asymmetric or symmetric ketones, and in dipolar aprotic solvents, in addition mixtures of the listed solvents may be used, as well as mixtures and blends of the listed solvents containing water.

Preferably ethers, esters or alcohols with 1 to 4 carbon atoms, open chain ketones or dipolar aprotic solvents, or especially preferably diisopropyl ether, ethyl acetate, acetonitrile, methyl alcohol, 2-propanol or their mixtures, or the mixtures and blends of the listed solvents may be used in order to perform the reaction. The acid used to form the salts is used in a 1.0 to 3.0 mol equivalent amount, preferably in a 1.1 to 2.1 mol equivalent amount calculated for the amount of baricitinib (1).

A preferable procedure involves that the organic acid solution is used and the salt-formation reaction is carried out at a temperature between 0 °C and the boiling point of the solvent or at the boiling point of the solvent.

The new salts of baricitinib (1) according to the present invention may be produced by dissolving or suspending the baricitinib base (1) in a suitable solvent, preferably in a polar aprotic solvent, in an alcohol or ester with 1 to 6 carbon atoms, preferably in acetonitrile, methanol, 2-propanol or ethyl acetate, then between 0 °C and the reflux temperature of the solvent 1.0 to 3.0 mol, preferably 1.1 to 2.1 mol of acid is added, on its own or in the form of a solution. If the salt precipitates at the temperature of the addition of the acid or when cooled, after the required crystallization time the product is filtered, washed and dried. If the salt does not precipitate, the solvent is evaporated in a vacuum, and the residual material is crystalized with a suitable solvent or solvent mixture, finally the crystalline material is filtered, washed and dried.

The new salts according to the invention may be recrystallized in order to achieve the appropriate pharmaceutical active substance quality. The recrystallization is performed by dissolving the product obtained according to the above in a polar aprotic solvent, or in a mixture of a polar aprotic solvent and an alcohol with 1 to 6 carbon atoms, more preferably the dissolving is performed in acetonitrile or in a mixture of acetonitrile and methanol at boiling point, then by cooling the solution the desired salt is precipitated. The precipitated solid material is filtered, washed and dried.

The production of the baricitinib esylate (1: 1) salt form is carried out by suspending the baricitinib free base (1) in a polar aprotic, straight-chain alcohol, nitrile or ester-type solvent, preferably in acetonitrile, 2-propanol or ethyl acetate at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature, then a solution of 1.0 to 1.5 mol equivalent, preferably 1.1 mol equivalent ethanesulfonic acid made with a given solvent is added while stirring. The reaction mixture is stirred for 1 to 24 hours, preferably for 2 to 4 hours at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature. The precipitated crystals are filtered, washed and dried.

The production of the baricitinib mesylate (1: 1) salt form is carried out by suspending the baricitinib free base (1) in a polar aprotic, straight-chain alcohol, nitrile or ester-type solvent, preferably in acetonitrile, 2-propanol or ethyl acetate at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature, then a solution of 1.0 to 1.5 mol equivalent, preferably 1.1 mol equivalent methanesulfonic acid made with a given solvent is added while stirring. The reaction mixture is stirred for 1 to 24 hours, preferably for 2 to 4 hours at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature. The precipitated crystals are filtered, washed and dried.

The production of the baricitinib besylate (1: 1) salt form is carried out by suspending the baricitinib free base (1) in a polar aprotic, straight-chain alcohol, nitrile or ester-type solvent, preferably in acetonitrile, 2-propanol or ethyl acetate at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature, then a solution of 1.0 to 1.5 mol equivalent, preferably 1.1 mol equivalent benzenesulfonic acid made with a given solvent is added while stirring. The reaction mixture is stirred for 1 to 24 hours, preferably for 2 to 4 hours at a temperature between 0 °C and the boiling point of the solvent, preferably at room temperature. The precipitated crystals are filtered, washed and dried.

The invention is illustrated via the following examples, without limiting the invention to these examples.

EXAMPLES Measurement conditions used

NMR measurement conditions

The NMR spectra of the new salts according to the invention were recorded using the following device:

- VARIAN INOVA 500 (500 MHz)

- BRUKER AVANCE III 400 (400 MHz)

The NMR measurements of the new salts were in all cases performed in solution phase, the solvent used was deuterated dimethyl sulfoxide (DMSO-ifc).

Differential scanning calorimetry (DSC) measurement conditions

Device: TA Instruments Discovery DSC differential scanning

calorimeter

Atmosphere: N ₂ current (50 mL/min) Sampling intervals

Temperature program: Room temperature - melting point 10 °C/min

Standard Al open Example 2

Sample holder: Standard Al closed Examples 1, 4, 9

Hermetically closed Al: Examples 3, 5, 6, 7, 8 x-ray powder diffraction (XRPD) measurement conditions

Device: PANalytical Empyrean X-ray powder diffractometer

Measuring mode: Transmission

X-ray tube

Type: Empyrean Long Fine Focus High Resolution tube Anode: Cu

Wavelength Ka (1.541874 A)

Focussing: line focus

Radiation source side optics

Divergence slit: Fixed slit 1/2 °

Mirror: Elliptical focussing mirror

Soller slit: 0.04 rad

Diffusion inhibitor slit: Fixed slit 1/2 °

Detector side optics

Diffusion inhibitor slit: Programmable slit in fixed mode:

Soller slit: 0.04 rad

Sample holder

Type: Reflection-transmission spinner stage

Sample rotation speed: 1 rps

Sample knife: Transmission ray blocking used Detector

Type: PrXcel 3D 1 1 terdetektor

Detecting mode: Scanning line detector mode (ID)

Active length: 3.3473°

Sample preparation: The unpowdered samples are placed between Mylar sheets.

Measurement settings

Temperature: room temperature

Accelerating voltage: 45 kV

Anode heating current: 40 mA

Scanning: continuous gonio (Θ/Θ) scan

Measurement range: 2.0000 - 34.9964 °2Θ

Step gap: 0.0131° 2Θ

Step duration: 109.650 s

Measurement cycles: 1

Measurement time: -20 min

Dynamic vapour sorption analysis (DVS) measurement conditions

SMS DVS Advantage DVSAl-STD dynamic vapour sorption

Device:

analyser

Atmosphere: nitrogen

Total gas flow: 200 ml/min

Solvent: water

Temperature: 25 °C

Step size: 5% RH

Stability criterion: 0.002 %/min

Phases: DMDT Window: 5 min

Minimum stability time: 30 min

Maximum phase time: 360 min Data saving frequency: 1 min

Range 1 : current % RH→ 95% RH

Measurement ranges: Range 2: 95% RH→ 0% RH

Range 3 : 0% RH→ current % RH

Measurement conditions used during the stability test

Test name Baricitinib purity test

Device type: Waters Acquity H-Class UPLC

Column type: Waters Acquity CSH CI 8; 2,1 x50 mm; 1,7 μιη

Preparation of sample solution for solubility test

With analytical precision 500 mg salt form is measured into a 20.0 ml Erlenmeyer flask. 10 ml of medium is added, then shaken for 6 hours at a rate of 100 min ^"1 at 37 °C. After shaking the solution is left to settle for 18 hours at 37 °C. The settled solution is filtered through a 0.45 μιη filter. 1 ml of filtered solution is diluted to 100.0 ml. Example 1

The production of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )-lH-pyrazol-l- yl]azetidin-3-yl}acetonitrile besylate (baricitinib besylate)

Method "A "

6.0 g (16.15 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)-lH- pyrazol-l-yl]azetidin-3-yl}acetonitrile (baricitinib) is measured into 100 ml of acetonitrile at 20-22 °C, then while stirring a solution of 2.81 g (17.77 mmol; 1.1 equiv.) of benzenesulfonic acid made with 20 ml of acetonitrile is added to it drop by drop. The reaction mixture is stirred for 3 hours at 20-22 °C, then for 1 hour at 18-20 °C. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in a drying cabinet at 24 °C and at a pressure of 150-200 mbar for 24 hours. In this way 8.35 g (97.6%) of white coloured solid product is obtained.

Following this 7.6 g of raw product is dissolved in 700 ml of acetonitrile at boiling point, then the solution is left to cool to room temperature, and stirred for 1 hour. The precipitated solid material is filtered, then dried in a drying cabinet at 24 °C and at a pressure of 150-200 mbar for 24 hours. In this way 6.80 g (89.3%) of white coloured solid product is obtained.

Mp.: 179.2 °C (onset). IR (KBr): 3100, 2817, 2259, 1615, 1592, 1328.

^ NMR (DMSO-ifc, 400 MHz): 13.19 (b, 1H), 9.20 (s, 1H), 9.03 (s, 1H), 8.68 (s, 1H), 7.99

(m, 1H), 7.61 (m, 2H), 7.43 (m,lH), 7.31 (m, 3H), 4.60 (d, J=9.2 Hz, 2H), 4.30 (d, J=9.2 Hz, 2H), 3.73 (s, 3H), 3.24 (q, J=7.3 Hz, 2H), 1.25 (t, J=7.3Hz, 3H).

1 ³ C-NMR (DMSO-ifc, 100 MHz): 152.07, 148.46, 145.87, 140.54, 132.00, 130.97, 128.58, 127.81, 125.65, 116.64, 112.66, 102.87, 58.58,56.84, 43.72, 26.98, 7.61.

Element analysis calculated for the formula C22H23N7O5S2 (M 529.59):

C 49.90%; H 4.38%; N 18.51%; S 12.11%

Measured: C 50.01%; H 4.36%; N 18.47%; S 12.00%.

Method "B "

1.00 g (2.69 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)-lH- pyrazol-l-yl]azetidin-3-yl}acetonitrile (baricitinib) is suspended in 15 ml of 2-propanol at 20- 22 °C, then while stirring a solution of 470 mg (2.96 mmol; 1.1 equiv.) of benzenesulfonic acid made with 5 ml of 2-propanol is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 °C, then the precipitated solid material is filtered, washed with 2- propanol on the filter, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 1.40 g (98.2%) of a white coloured solid product is obtained.

The sample is spectroscopically and morphologically identical to the substance produced with method "A".

Method "C"

1.00 g (2.69 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)-lH- pyrazol-l-yl]azetidin-3-yl}acetonitrile (baricitinib) is suspended in 15 ml of ethyl acetate at 20-22 °C, then while stirring a solution of 470 mg (2.96 mmol; 1.1 equiv.) of benzenesulfonic acid made with 5 ml of ethyl acetate is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 °C, then the precipitated solid material is filtered, washed on the filter with ethyl acetate, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 1.43 g (100%) of a white coloured solid product is obtained.

The sample is spectroscopically and morphologically identical to the substance produced with method "A".

Example 2

The production of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )-lH-pyrazol-l- yl]azetidin-3-yl}acetonitrile esylate (baricitinib esylate) Method "A "

6.0 g (16.15 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-i/]pirimidin-4-yl)-l H- pyrazol- l-yl]azetidin-3-yl}acetonitrile (baricitinib) is measured into 100 ml of acetonitrile at 20-22 °C, then while stirring a solution of 1.96 g (17.77 mmol; 1.1 equiv.) of ethanesulfonic acid made with 20 ml of acetonitrile is added to it drop by drop. The reaction mixture is stirred for 3 hours at 20-22 °C, then for 1 hour at 18-20 °C. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in a drying cabinet at 24 °C and at a pressure of 150-200 mbar for 24 hours. In this way 7.36 g (94.6%) of white coloured solid product is obtained.

Following this 6.68 g of raw product is dissolved in 550 ml of acetonitrile at boiling point, then the solution is left to cool to room temperature, and stirred for 1 hour. The precipitated solid material is filtered, then dried in a drying cabinet at 24 °C and at a pressure of 150-200 mbar for 24 hours. In this way 5.78 g (86.5%) of white coloured solid product is obtained. Mp.: 171.2 °C (onset).

IR (KBr): 2775, 2245, 1623, 1317, 1208, 1140, 1033.

^ NMR (DMSO-ifc, 400 MHz): 13.24 (b, 1H), 9.23 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 8.01 (m, 1H), 7.44 (m, 1H), 4.60 (d, J=9.2 Hz, 2H), 4.31 (d, J=9.3 Hz, 2H), 3.74 (s, 2H), 3.25 (q, J=7.3 Hz, 2H), 2.46 (q, J=7.4 Hz, 2H), 1.25 (t, J=7.3 Hz, 3H), 1.09 (t, J=7.4 Hz, 3H).

1 ³ C-NMR (DMSO-ifc, 100 MHz): 152.07, 144.52, 140.58, 132.08, 131.08, 116.65, 115.73, 112.64, 102.93, 58.58, 56.85, 45.38, 43.67, 26.98, 10.00, 7.62.

Element analysis calculated for the formula C18H23N7O5S2 (M 481.55):

C 44.90%; H 4.82%; N 20.36%; S 13.32%

Measured: C 45.00%; H 4.84%; N 19.87%; S 13.06%.

Method "B "

1.00 g (2.69 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)-lH- pyrazol- l-yl]azetidin-3-yl}acetonitrile (baricitinib) is suspended in 15 ml of 2-propanol at 20- 22 °C, then while stirring a solution of 326.2 mg (2.96 mmol; 1.1 equiv.) of ethanesulfonic acid made with 5 ml of 2-propanol is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 °C, then the precipitated solid material is filtered, washed with 2- propanol on the filter, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 1.28 g (98.4%) of a white coloured solid product is obtained.

The sample is spectroscopic ally and morphologically identical to the substance produced with method "A". Method "C "

1.00 g (2.69 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-i/]pirimidin-4-yl)-l H- pyrazol- l-yl]azetidin-3-yl}acetonitrile (baricitinib) is suspended in 15 ml of ethyl acetate at 20-22 °C, then while stirring a solution of 326.2 mg (2.96 mmol; 1.1 equiv.) of ethanesulfonic acid made with 5 ml of ethyl acetate is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 °C, then the precipitated solid material is filtered, washed on the filter with ethyl acetate, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 1.28 g (98.8%) of a white coloured solid product is obtained.

The sample is spectroscopically and morphologically identical to the substance produced with method "A".

Example 3

The production of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )- lH-pyrazol-l- yl]azetidin-3-yl}acetonitrile mesylate (baricitinib mesylate)

Method "A "

8.45 g (22.75 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)-lH- pyrazol- l-yl]azetidin-3-yl}acetonitrile (baricitinib) is measured into 150 ml of acetonitrile at 20-22 °C, then while stirring 2.40 g (25.03 mmol; 1.1 equiv.) of methanesulfonic acid is added to it drop by drop. The reaction mixture is stirred for 3 hours at 20-22 °C. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in a drying cabinet at 24 °C and at a pressure of 150-200 mbar for 24 hours. In this way 10.51 g (99.6%) of white coloured solid product is obtained.

Following this 9.80 g of raw product is suspended in 300 ml of acetonitrile at boiling point, then 200 ml of methanol is added to it drop by drop. The solution is left to cool to room temperature, and stirred for 1 hour. The precipitated solid material is filtered, then dried in a drying cabinet at 24 °C and at a pressure of 150-200 mbar for 24 hours. In this way 5.26 g (53.7%) of white coloured solid product is obtained.

Mp.: 220.4 °C (onset).

IR (KBr): 2251, 1625, 1320, 1221, 1151, 1036.

HNMR (DMSO-ifc, 400 MHz): 13.18 (bs, 1H), 9.21 (s, 1H), 9.02 (s, 1H), 8.68 (s, 1H), 7.99

(m, 1H), 7.42 (m, 1H), 4.59 (d, J=9.2 Hz, 2H), 4.30 (d, J=9.3 Hz, 2H), 3.25 (q, J=7.3

Hz, 2H), 2.38 (s, 3H), 1.25 (t, J=7.3 Hz, 3H).

CNMR (DMSO-ifc, 100 MHz): 152.10, 146.02, 140.56, 131.98, 130.92, 116.67, 112.68,

102.82, 58.59, 56.83, 43.68, 26.99, 7.63. Element analysis calculated for the formula C17H21N7O5S2 (M 467.52):

C 43.67%; H 4.53%; N 20.97%; S 13.71%

Measured: C 43.77%; H 4.54%; N 20.44%; S 13.53%.

Method "B "

1.00 g (2.69 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)-lH- pyrazol-l-yl]azetidin-3-yl}acetonitrile (baricitinib) is suspended in 15 ml of 2-propanol at 20- 22 °C, then while stirring 191 μΐ (2.96 mmol; 1.1 equiv.) of methanesulfonic acid is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 °C, then the precipitated solid material is filtered, washed with 2-propanol on the filter, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 1.23 g (97.8%) of a white coloured solid product is obtained.

The sample is spectroscopically and morphologically identical to the substance produced with method "A".

Method "C"

1.00 g (2.69 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)-lH- pyrazol-l-yl]azetidin-3-yl}acetonitrile (baricitinib) is suspended in 15 ml of ethyl acetate at 20-22 °C, then while stirring 191 μΐ (2.96 mmol; 1.1 equiv.) methanesulfonic acid is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 °C, then the precipitated solid material is filtered, washed on the filter with ethyl acetate, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 1.23 g (97.8%) of a white coloured solid product is obtained.

The sample is spectroscopically and morphologically identical to the substance produced with method "A".

Example 4

The production of formula (I) { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )- lH-pyrazol-l-yl]azetidin-3-yl}acetonitrile hydrochloric acid salt (baricitinib hydrochloride)

1.00 g (2.69 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)-lH- pyrazol-l-yl]azetidin-3-yl}acetonitrile of formula (I) (baricitinib) is measured into 15 ml of methanol at 20-22 °C, then while stirring 2.86 ml (1.1 equiv.) of a 1 M methanolic HC1 solution is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 °C. The precipitated solid material is filtered, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 1.00 g (91.1%) of a white coloured solid product is obtained. Element analysis calculated for the formula C16H18CIN7O2S (M 407.88):

C 47.12%; H 4.45%; N 24.04%; S 7.86%; CI 8.69%.

Measured: C 47.03%; H 4.44%; N 23.22%; S 7.84%; CI 8.43%.

Following this 0.80 g of raw product is dissolved in 15 ml of acetonitrile at boiling point, then 7 ml of methanol is added to it drop by drop at this temperature. Following this the solution is left to cool to room temperature, and stirred for two hours. The precipitated solid material is filtered, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 0.32 g (40.6%) of white coloured solid product is obtained. Mp.: 240.8 °C (peak maximum)

IR (KBr): 2393, 1612, 1592, 1346, 1143.

^ NMR (DMSO-ifc, 400 MHz): 13.42 (b, 1H), 9.47 (s, 1H), 8.98 (s, 1H), 8.94 (s, 1H), 8.03

(m, 1H), 7.51 (m, 1H), 4.60 (d,J=9.3 Hz, 2H), 4.33 (d, J=9.3 Hz, 2H), 3.77 (s, 2H), 3.28 (q, J=7.3 Hz, 2H), 1.26 (t, J=7.3 Hz, 3H).

1 ³ C-NMR (DMSO-ifc, 100 MHz): 152.03, 145.02, 143.80, 141.04, 132.60, 131.35, 116.63, 115.09, 112.41, 103.22, 58.60, 56.88, 43.66, 26.97, 7.62.

Element analysis calculated for the formula C16H18CIN7O2S (M 407.88):

C 47.12%; H 4.45%; N 24.04%; S 7.86%; CI 8.69%.

Measured: C 47.25%; H 4.36%; N 23.68%; S 7.85%; CI 8.37%.

Example 5

The production of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )- lH-pyrazol-l- yl]azetidin-3-yl}acetonitrile oxalate (baricitinib oxalate) 1.00 g (2.69 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)-lH- pyrazol- l-yl]azetidin-3-yl}acetonitrile (baricitinib) is measured into 40 ml of acetonitrile at 20-22 °C, then while stirring a solution of 0.27 g (2.96 mmol; 1.1 equiv.) of oxalic acid made with 10 ml of acetonitrile is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 °C. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 0.70 g (56.36%) of a white coloured solid product is obtained.

Mp.: 184.1 °C (peak maximum).

IR (KBr): 3113, 2656, 2259, 1625, 1583, 1345, 1142. ^ NMR (DMSO-ifc, 400 MHz): 12.20 (bs, 1H), 8.95 (s, 1H), 8.74 (s, 1H), 8.50 (s, 1H), 7.65 (dd, Jl=2.4 Hz, J2=3.5 Hz, 1H), 7.11 (dd, Jl=1.5 Hz, J2=3.5 Hz, 1H), 4.62 (d, J=9.2 Hz, 2H), 4.27 (d, J=9.3 Hz, 2H), 3.71 (s, 2H), 3.25 (q, J=7.4 Hz, 2H), 1.26 (t, J=7.3 Hz, 3H).

1 ³ C-NMR (DMSO-ifc, 100 MHz): 161.27, 152.39, 150.95, 149.41, 140.13, 129.88, 127.26, 122.23, 116.86, 113.25, 100.23, 58.75, 56.30, 43.56, 27.04, 7.64.

Element analysis calculated for the formula C18H19N7O6S (M 461.45):

C 46.85%; H 4.15%; N 21.25%; S 6.95%

Measured: C 46.72%; H 4.17%; N 21.16%; S 6.97%.

Example 6

The production of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )- lH-pyrazol-l- yl]azetidin-3-yl}acetonitrile tosylate (baricitinib tosylate)

5.85 g (15.57 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)-lH- pyrazol- l-yl]azetidin-3-yl}acetonitrile (baricitinib) is measured into 150 ml of acetonitrile at 20-22 °C, then while stirring a mixture of 1.98 g (17.33 mmol; 1.1 equiv.) of p- toluenesulfonic acid made with 20 ml of acetonitrile is added to it drop by drop. The reaction mixture is stirred for 3 hours at 20-22 °C. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in a drying cabinet at 24 °C and at a pressure of 150- 200 mbar for 24 hours. In this way 8.28 g (96.7%) of a white coloured solid product is obtained.

Mp.: 221,2 °C (peak maximum).

IR (KBr): 3062, 2250, 2811, 1595, 1317, 1149.

^X H-NMR (DMSO-ifc, 400 MHz): 13.24 (b, 1H), 9.22 (s, 1H), 9.04 (s, 1H), 8.69 (s, 1H), 8.01

(m, 1H), 7.49 (~d, J=8.0 Hz, 2H), 7.45 (m, 1H), 7.12 (~d, J=7.9 Hz, 2H), 4.60 (d, J=9.2 Hz, 2H), 4.30 (d, J=9.2 Hz, 2H), 3.25 (q. J=7.3 Hz, 2H), 2.29 (s, 3H), 1.25 (t,

J=7.3 Hz, 3H).

¹³ C-NMR (DMSO-ife, 100 MHz): 152.09, 146.03, 140.55, 131.96, 130.89, 116.66, 112.68,

102.80, 58.59, 56.82, 43.69, 26.98, 7.62.

Element analysis calculated for the formula C23H25N7O5S2 (M 543.62):

C 50.82%; H 4.64%; N 18.04%; S 11.80%

Measured: C 50.83%; H 4.59%; N 17.96%; S 11.83%.

Example 7 The production of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )- lH-pyrazol-l- yl]azetidin-3-yl}acetonitrile 2-hydroxy- ethanesulfonic acid salt (baricitinib isethionate)

1.00 g (2,.69 mmol) { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )- lH-pyrazol- l-yl]azetidin-3-yl}acetonitrile (baricitinib) is suspended in 30 ml of acetonitrile at 20-22 °C, then while stirring a solution of 0.47 g (2.97 mmol; 1.1 mol equiv.) of 2-hydroxy- ethanesulfonic acid made with 5 ml of acetonitrile is added to it drop by drop. The reaction mixture is stirred for 4 hours at 20-22 °C. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 1.18 g (90.8%) of a white coloured solid product is obtained. Mp.: 142,9 °C (onset).

IR (KBr): 3455, 3111, 2671, 2249, 1628, 1595, 1158, 1029, 1322..

^ NMR (DMSO-ifc, 400 MHz): 13.31 (b, 1H), 9.25 (s, 1H), 9.06 (s, 1H), 8.72 (s, 1H), 8.04

(m, 1H), 7.47 (m, 1H), 4.60 (d, J=9.2 Hz, 2H), 4.32 (d, J=9.2 Hz, 2H), 3.74 (s, 2H), 3.66 (t, J=6.8 Hz, 2H), 3.26 (q, J=7.3 Hz, 2H), 2.69 (t, J=6.8 Hz, 2H), 1.26 (t, J=7.3

Hz, 3H).

¹³ C-NMR (DMSO-ifc, 100 MHz): 152.05, 145.31, 144.03, 140.62, 132.28, 131.42, 116.64,

115.13, 112.60, 103.18, 58.59, 57.88, 56.91, 53.87, 43.73, 26.98, 7.63

Element analysis calculated for the formula C18H23N7O6S2 (M 497.55):

C 43.45%; H 4.66%; N 19.71%; S 12.89%

Measured: C 43.36%; H 4.63%; N 19.48%; S 12.99%.

Example 8

The production of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )- lH-pyrazol-l- yl]azetidin-3-yl}acetonitrile fumarate (baricitinib hydrogen fumarate)

3.00 g (8.08 mmol) { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)- lH-pyrazol- l-yl]azetidin-3-yl}acetonitrile (baricitinib) is dissolved in 130 ml of acetonitrile at boiling point, then while stirring 1.03 g (8.89 mmol; 1.1 equiv.) of fumaric acid is added to it. The reaction mixture is stirred at this temperature for 30 minutes, then left to cool to room temperature, and stirred for a further 1 hour. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 3.81 g (96.7%) of a white coloured solid product is obtained. Mp.: 206,5 °C (peak maximum). IR (KBr): 3120, 2536, 1703, 1584, 1275, 1141.

^ NMR (DMSO-ifc, 400 MHz): 13.16 (b, 2H), 12.16 (bs, 1H), 8.94 (s, 1H), 8.72 (s, 1H),

8.48 (s, 1H), 7.63 (dd, Jl=2.5 Hz, J2=3.4 Hz, 1H), 7.09 (dd, Jl=1.6 Hz, J2=3.5 Hz, 1H), 6.64 (s, 2H), 4.61 (d, J=9.2 Hz, 2H), 4.24 (d, J=9.2 Hz, 2H), 3.70 (s, 2H), 3.23 (q, J=7.4 Hz, 2H), 1.25 (t, J=7.3 Hz, 3H).

1 ³ C-NMR (DMSO-ife, 100 MHz): 166.16, 152.39, 151.09, 149.55, 140.09, 134.17, 129.78,

127.12, 122.41, 116.83, 113.25, 100.12, 58.73, 56.25, 43.55, 27.07, 7.62.

Element analysis calculated for the formula C20H21N7O6S (M 487.49):

C 49.28%; H 4.34%; N 20.11%; S 6.58%

Measured: C 49.52%; H 4.32%; N 20.41%; S 6.61%.

Example 9

The production of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )- lH-pyrazol-l- yl]azetidin-3-yl}acetonitrile dicyclamate (baricitinib dicyclamate) 0.50 g (1.35 mmol) of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3- ]pirimidin-4-yl)-lH- pyrazol- l-yl]azetidin-3-yl}acetonitrile (baricitinib) is dissolved in 20 ml of acetonitrile at boiling point, then while stirring 0.27 g (1.48 mmol; 1.1 equiv.) of cyclamic acid is added to it. The reaction mixture is stirred at this temperature for 30 minutes, then left to cool to room temperature, and stirred for a further 2 hours. The precipitated solid material is filtered, then 20 ml of acetonitrile and 5 ml of methanol is added to it and heated to boiling point. The mixture is left to cool to room temperature and the precipitated solid material is filtered. The product is washed on the filter with acetonitrile, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 0.23 g (41.8%) of a white coloured solid product is obtained.

Mp.: 217,5 °C (peak maximum).

IR (KBr): 3422, 1628, 1599, 1329, 1137, 1063, 617.

^X H-NMR (DMSO-ifc, 400 MHz): 12.20 (bs, 1H), 8.95 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 7.69

(b), 7.64 (m, 1H), 7.10 (m, 1H), 4.60 (d, J=9.3 Hz, 2H), 4.25 (d, J=9.4 Hz, 2H), 3.70 (s, 2H), 3.26 (q, J=7.4 Hz, 2H), 2.95 (m, 2x lH), 1.87 (m, 2x2H), 1.62 (m, 2x2H), 1.59 (m, 2x lH), 1.23 (m, 3H + 2x4H), 1.10 (2x lH).

¹³ C-NMR (DMSO-ifc, 100 MHz): 152.37, 151.02, 149.48, 140.08, 129.82, 127.18, 122.33,

116.84, 113.23, 100.16, 58.72, 56.25, 49.51, 43.48, 30.52, 27.01, 24.72, 23.91, 7.62.

Element analysis calculated for the formula (M 729.89): C 46.08%; H 5.94%; N 17.27%.

Measured: C 44.29%; H 6.44%; N 15.88%.

Example 10

The production of { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )- lH-pyrazol-l- yl]azetidin-3-yl}acetonitrile tartarate (baricitinib hydrogen tartarate)

0.5 g (1.35 mmol) { l-(ethylsulphonyl)-3-[4-(7H-pyrrolo[2,3-<i]pirimidin-4-yl )- lH-pyrazol-l- yl]azetidin-3-yl}acetonitrile (baricitinib) is suspended in 22 ml of acetonitrile at 20-22 °C, then while stirring a solution of 0.22 g (1.48 mmol; 1.1 mol equiv.) of D,L-tartaric acid made with 3 ml of water is added to it drop by drop. The reaction mixture is stirred for 2 hours at 20-22 °C, then evaporated until dry. 25 ml of acetonitrile is added to the residue, and then stirred for 1 hour at 20-22 °C. The precipitated solid material is filtered, washed on the filter with acetonitrile, then dried in the air at atmospheric pressure until constant weight is achieved. In this way 0.1 mg (33.3%) of a white coloured solid product is obtained.

IR (KBr): 3142, 2258, 1694, 1631, 1599, 1350, 1328, 1137.

^ NMR (DMSO-ifc, 400 MHz): 12.57 (b, 1H), 12.15 (bs, 1H), 8.93 (s, 1H), 8.71 (s, 1H),

8.48 (s, 1H), 7.63 (dd, Jl=2.4 Hz, J2=3.5 Hz, 1H), 7.09 (dd, Jl=1.6 Hz, J2=3.5 Hz, 1H), 4.61 (d, J=9.2 Hz, 2H), 4.31 (s, 2H), 4.24 (d, J=9.2 Hz, 2H), 3.70 (s, 2H), 3.24 (q, J=7.4 Hz, 2H), 1.25 (t, J=7.3 Hz, 3H).

¹³ C-NMR (DMSO-ife, 100 MHz): 173.32, 152.38, 151.09, 149.55, 140.09, 129.80, 127.14,

122.41, 116.85, 113.24, 100.13, 72.33, 58.73, 56.25, 43.49, 27.02, 7.62.

Element analysis calculated for the formula C20H23N7O8S (M 521.51):

C 46.06%; H 4.45%; N 18.80%; S 6.15%

Measured: C 44.41%; H 4.56%; N 17.96%; S 6.21%.