CZ2018466A3 - Solid forms of ozanimod and their preparation - Google Patents

Abstract

Described are solid forms of ozanimod with acids, in particular citric acid, fumaric acid, oxalic acid, acetic acid, benzoic acid, L-malic acid, hydrobromic acid and phosphoric acid, a process for their preparation, their pharmaceutical use and a pharmaceutical preparation containing them.

Description

Prior art

Ozanimod, chemically 5- (3 - {(1S) -1 - [(2-hydroxyethyl) amino] -2,3-dihydro-1H-inden-4-yl} -1,2,4-oxadiazol-5-yl) -2-Isopropoxybenzonitrile of formula (1), an orally administered S1P1 and S1P5 sphingosine-1-phosphate receptor agonist, belongs to the group of immunotherapeutic agents and is being tested for the treatment of multiple sclerosis and ulcerative colitis.

The ozanimod molecule of formula (1) was first described in International Patent Application WO 2009151529.

formula (1)

The chemical synthesis of ozanimod was first described in patent application WO2011060392 and subsequently in patent applications WO 2015066515 and WO 2016164180. The described synthesis leads from commercially available raw materials in four steps to ozanimod hydrochloride, which is converted in the last step to ozanimod free base.

Solid crystalline forms of ozanimod have been described in WO2017215617, WO2018033149, WO 2018050091 and WO 2018049632. These are solid forms of ozanimod free base and ozanimod hydrochloride, including solvates thereof. However, the solid forms of the free base show polymorphism and also reversibly intersect. Polymorphic mixtures are formed which are difficult to define precisely. These mutual transitions, whether polymorphic or hydrate-anhydrous crystal, of the hitherto known solid forms of ozanimod cause considerable difficulties in the development of a stable dosage form, and can also alter the bioavailability of the active substance.

No other solid forms derived from ozanimod, such as salts of ozanimod with other acids or cocrystals with other substances, have been described so far. Thus, there is a need to find new solid forms of ozanimod which do not have the above-mentioned undesirable properties and exhibit advantageous physicochemical properties such as high stability, solubility, purity and bioavailability.

The essence of the invention

The invention relates to solid forms of ozanimod with inorganic (except HCl) or carboxylic acids, in particular salts with inorganic acids (excluding HCl), salts with polybasic carboxylic acids, and solvates and cocrystals with monobasic carboxylic acids. These forms are characterized by high purity - the HPLC purity of the ozanimod starting base was 99.5%, and all prepared solid forms increased this purity upon isolation without further purification. Solid forms derived from ozanimod, especially crystalline ones of high purity, are of extremely technical and economic importance, since they make it possible to obtain a substance suitable for pharmaceutical purposes.

CZ 2018 - 466 A3

Inorganic and carboxylic acids are in particular selected from the group consisting of hydrobromic acid, phosphoric acid, citric acid, fumaric acid, oxalic acid, malic acid, acetic acid, benzoic acid.

The term "solid form of ozanimod with an inorganic or polybasic carboxylic acid" in the context of the present invention means in particular a salt in solid form. Preferably, the ozanimod with the acid are in a molar ratio of 1: 1 to 3: 1, in a particularly preferred embodiment molar ratios of 1: 1 or 2: 1 are preferred.

Solid forms of ozanimod with an inorganic or polybasic carboxylic acid can be prepared in appropriate proportions and yields with high chemical purity in crystalline form, amorphous form or in a mixture of crystalline and amorphous solid form. Preferably, the solid forms of ozanimod with the inorganic or polybasic carboxylic acid are in crystalline form. The prepared solid forms of ozanimod with an inorganic or polybasic carboxylic acid may have different internal configurations (polymorphisms) with different physicochemical properties depending on the conditions of their preparation. The invention relates both to the individual crystalline or amorphous forms and to mixtures thereof.

In one preferred embodiment of the invention, the polybasic carboxylic acid is citric acid, preferably the solid form is in crystalline form. In a particularly preferred embodiment, the solid form contains ozanimod and citric acid in a 1: 1 ratio. In a most preferred embodiment, it is a solid form of ozanimod with citric acid exhibiting characteristic reflections in an X-ray powder record using CuKα radiation: 4.57; 12.49; 16.22; 21.21; 25.20 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKa radiation: 13.75; 14.52; 23.20; 29.45 ± 0.2 ° 2-theta. A complete list of X-ray powder record reflections for the solid form of ozanimod with citric acid is given in Table 1 in Example 1.

In another preferred embodiment of the invention, the polybasic carboxylic acid is fumaric acid, preferably the solid form is in crystalline form. In a particularly preferred embodiment, the solid form contains ozanimod and fumaric acid in a ratio of 1: 1. In a most preferred embodiment, it is a solid form of ozanimod with fumaric acid exhibiting characteristic reflections in an X-ray powder record using CuKa 3.89; 7.83; 13.27; 16.90; 20.02; 24.52 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKa radiation: 13.75; 18.16; 25.59 ± 0.2 ° 2-theta. A complete list of X-ray powder record reflections for the solid form of ozanimod with fumaric acid is given in Table 2 in Example 2.

In another preferred embodiment of the invention, the polybasic carboxylic acid is oxalic acid, preferably the solid form is in crystalline form.

In a particularly preferred embodiment, the solid form contains ozanimod and oxalic acid in a ratio of 1: 1. In a most preferred embodiment, it is a solid form of ozanimod with oxalic acid exhibiting characteristic reflections in an X-ray powder record using CuKα radiation: 3.19; 11.04; 12.73; 17.12; 24.60; 26.32 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKα radiation: 13.19; 13.95 ± 0.2 ° 2-theta. A complete list of X-ray powder record reflections for the solid form of ozanimod with oxalic acid is given in Table 3 in Example 3.

In another particularly preferred embodiment of the invention, the solid form comprises ozanimod and oxalic acid in a ratio of 2: 1. In a most preferred embodiment, it is a solid form of ozanimod with oxalic acid exhibiting characteristic reflections in an X-ray powder record using CuKα radiation: 6.16; 9.80; 11.97; 15.91; 24.45 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKa radiation: 3.25; 12.38; 14.53; 23.70 ± 0.2 ° 2-theta. Complete

-2GB 2018-466 The list of reflections in the X-ray powder record for the solid form of ozanimod with oxalic acid is given in Table 4 in Example 4.

In another preferred embodiment of the invention, the polybasic carboxylic acid is malic acid, preferably the solid form is in crystalline form. In a particularly preferred embodiment, the solid form contains ozanimod and L-malic acid in a 1: 1 ratio. In a most preferred embodiment, it is a solid form of ozanimod with L-malic acid exhibiting characteristic reflections in an X-ray powder record using CuKα radiation: 3.61; 11.95; 14.67; 22.13; 25.85 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKα radiation: 7.29; 13.25 ± 0.2 ° 2-theta. A complete list of X-ray powder record reflections for the solid form of ozanimod with L-malic acid is given in Table 7 in Example 7.

In another preferred embodiment of the invention, the inorganic acid is hydrobromic acid, preferably the solid form is in crystalline form. In a particularly preferred embodiment, the solid form contains ozanimod and hydrobromic acid in a 1: 1 ratio. In a most preferred embodiment, it is a solid form of ozanimod with hydrobromic acid exhibiting characteristic reflections in an X-ray powder record using CuKα radiation: 4.04; 12.23; 13.71; 19.60; 24.53 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKα radiation: 12.46; 19.60; 22.82; 26.82 ± 0.2 ° 2-theta. A complete list of X-ray powder record reflections for the solid form of ozanimod with hydrobromic acid is given in Table 8 in Example 8.

In another preferred embodiment of the invention, the inorganic acid is phosphoric acid, preferably the solid form is in crystalline form. In a particularly preferred embodiment, the solid form contains ozanimod and phosphoric acid in a 1: 1 ratio. In a most preferred embodiment, it is a solid form of ozanimod with phosphoric acid exhibiting characteristic reflections in an X-ray powder recording using CuKa radiation: 3.52; 11.39; 17.72; 21.33 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKa radiation: 3.82; 5.71 ± 0.2 ° 2theta. A complete list of X-ray powder record reflections for the solid form of ozanimod with phosphoric acid is given in Table 9 in Example 9.

The term "solid form of ozanimod with a monobasic carboxylic acid" in the context of the present invention means in particular a solvate or co-crystal in solid form. Preferably, the ozanimod with the acid are in a molar ratio of 1: 1 to 3: 1, in a particularly preferred embodiment molar ratios of 1: 1 or 2: 1 are preferred.

Solid forms of solvates and co-crystals of ozanimod can be prepared in appropriate proportions and yields with high chemical purity in crystalline form, amorphous form or in a mixture of crystalline and amorphous solid form. Preferably, the solid forms of the solvates or co-crystals of ozanimod are in crystalline form.

The prepared solid forms of solvates or co-crystals of ozanimod may have different internal configurations (polymorphisms) with different physicochemical properties depending on the conditions of their preparation. The invention relates both to the individual crystalline or amorphous forms and to mixtures thereof.

In one preferred embodiment of the invention, the monobasic carboxylic acid is acetic acid, preferably the solid form is in crystalline form. In a particularly preferred embodiment, the solid form contains ozanimod base and acetic acid in a ratio of 2: 1. In a most preferred embodiment, it is a solid form of ozanimod base with acetic acid exhibiting characteristic reflections in an X-ray powder record using CuKα radiation: 8.18; 11.66; 13.37; 20.08; 26.52 ± 0.2 ° 2theta. Other characteristic reflections in X-ray powder recording using CuKα radiation: 14.53; 18.95; 24.91 ± 0.2 ° 2-theta. A complete list of X-ray powder record reflections for the solid form of ozanimod base with acetic acid is given in Table 5 in Example 5.

In another preferred embodiment of the invention, the monobasic carboxylic acid is an acid

-3 CZ 2018 - 466 A3 benzoic, preferably the solid form is in crystalline form. In a particularly preferred embodiment, the solid form contains ozanimod base and benzoic acid in a 1: 1 ratio. In a most preferred embodiment, it is a solid form of ozanimod base with benzoic acid exhibiting characteristic reflections in an X-ray powder record using CuKα radiation: 8.60; 11.46; 16.24; 20.91; 25.51 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKα radiation: 9.47; 14.20; 21.72; 29.78 ± 0.2 ° 2-theta. A complete list of X-ray powder record reflections for the solid form of ozanimod base with benzoic acid is given in Table 6 in Example 6.

Another object of the invention is a process for the preparation of solid forms of ozanimod with an inorganic or carboxylic acid, which comprises at least the following steps:

(a) dissolving or suspending ozanimod and an inorganic or carboxylic acid in a solvent; and

b) removing the solvent to form a solid.

More preferably, the process for preparing solid forms of ozanimod with an inorganic or carboxylic acid comprises the following steps:

a1) dissolving ozanimod in a solvent, a2) mixing with a solution of an organic or inorganic acid and

b) removing the solvent to give a solid form, preferably by filtration.

A preferred embodiment of the preparation process leads more reliably to the preparation of well stoichiometrically defined, often crystalline, solid forms.

The molar ratio of ozanimod to inorganic or carboxylic acid is preferably 3: 1 to 1: 3.

In a preferred embodiment, the solution or suspension from step a), resp. a2), is stirred for 1 to 24 hours, at a temperature from -30 ° C to the boiling point of the solvent used, more preferably at a temperature of 0 to 130 ° C and most preferably at a temperature of 20 to 80 ° C.

The resulting solution is then cooled to a temperature in the range of 0 to 40 ° C, preferably to a temperature in the range of 0 to 20 ° C, or to a temperature in the range of 5 ° C to 10 ° C, or to a temperature in the range of 10 ° C to 25 ° C. ° C, and then the solvent is removed (step b)).

Alcohols, preferably methanol, ethanol or 2-propanol, can advantageously be used as solvent; ketones, preferably acetone or butanone; esters, preferably ethyl acetate; ethers, preferably tetrahydrofuran; aromatic hydrocarbons, preferably toluene or anisole; acetonitrile; water; or mixtures thereof.

In a particularly preferred embodiment, the solvent is an alcohol, ketone, ether or ester with a C 1 to C 4 aliphatic or cyclic chain. Particularly preferably, methanol, acetone, tetrahydrofuran, ethyl acetate or mixtures thereof.

The removal of the solvent in step b) is preferably carried out at a temperature in the range of -10 ° C to 30 ° C. Removal of the solvent is carried out in particular by filtration, or by concentrating the solution or suspension and subsequent filtration, or by adding another solvent acting as an antisolvent and removing the solvents, preferably by filtration.

A non-polar solvent with a Snyder Polarity Index (Modern Methods of Pharmaceutical Analysis, Second Edition, Volume 2, Roger E. Schirmer,

-4EN 2018 - 466 A3

CRC Press, 1990.) less than 4.0; such solvents include, for example, aliphatic and cyclic C6-C10 hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers.

The term "crystalline form of ozanimod" in the context of the present invention means a crystalline solid form of ozanimod free base with a monobasic carboxylic acid or a crystalline solid form, preferably a salt, of ozanimod with a polybasic carboxylic acid or an inorganic acid. The solid form may be hydrated or solvated. The term "ozanimod solvate" refers to a crystalline substance which, in addition to ozanimod, also contains solvent and / or monobasic carboxylic acid molecules (for example in a stoichiometric ratio of 2: 1, 1: 1 or 1: 2).

Finding well-crystallizing forms of any pharmaceutical substance has a fundamental effect on achieving the required quality, which is a condition for placing a drug on the market. In general, the chemical purity of an active pharmaceutical substance (API for short), Active Pharmaceutical Ingredient) produced on a production scale is one of the critical parameters for its commercialization. The US Food and Drug Administration (FDA), as well as the European Drug Control Authority, require that the API be stripped of impurities in accordance with ICH (International Conference on Harmonization) guidelines. to the maximum extent possible. The reason is to achieve maximum safety when using the drug in clinical practice. The impurities are covered by the ICH guidelines, which are indicated by codes Q3A to Q3D, namely the impurities in the pharmaceutical substances of the directive: Q3A (Impurities in New Drug Substances) and the residual solvents: Q3C (Guideline for Residual Solvents). Therefore, the solid forms according to the present invention are very suitable for use in the final pharmaceutical form, since they are obtained in an economically advantageous manner in a very chemically pure form.

Another aspect of the invention is a pharmaceutical composition comprising a solid form of ozanimod with an organic or inorganic acid of the present invention and at least one pharmaceutically acceptable excipient. The content of active substance in the pharmaceutical composition is 0.1 to 2 mg per unit dose, preferably an amount corresponding to 0.5 to 1.0 mg of ozanimod (free base) alone.

Ozanimod acts as an immunomodulatory agent and is in clinical trials for use in the treatment of multiple sclerosis and ulcerative colitis. The invention therefore also relates to the abovementioned solid forms of ozanimod with inorganic or carboxylic acids for use as medicaments, preferably for the treatment of multiple sclerosis and ulcerative colitis.

The present invention further provides a pharmaceutical composition comprising at least one solid form of ozanimod with an inorganic or carboxylic acid and at least one excipient. Excipients may be selected from solvents, carriers, lubricants, preservatives, disintegrants, binders, colorants, glidants, flavoring agents. The pharmaceutical preparation can be, for example, in the form of a capsule (hard or soft), a tablet, a suppository, a suspension or a solution, but also in other suitable forms. Methods of formulating and preparing pharmaceutical compositions are well known to those skilled in the art.

Explanation of drawings

Giant. 1: XRPD recording of the solid form of ozanimod with citric acid

Giant. 2: XRPD recording of the solid form of ozanimod with film-forming acid

Giant. 3: XRPD recording of the solid form of ozanimod with oxalic acid in a ratio of 1: 1

Giant. 4: XRPD recording of the solid form of ozanimod with oxalic acid in a ratio of 2: 1

-5 CZ 2018 - 466 A3

Giant. 5: XRPD recording of the solid form of ozanimod with acetic acid in a ratio of 2: 1

Giant. 6: XRPD recording of the solid form of ozanimod with benzoic acid

Giant. 7: XRPD recording of the solid form of ozanimod with L-malic acid

Giant. 8: XRPD recording of the solid form of ozanimod with hydrobromic acid

Giant. 9: XRPD recording of the solid form of ozanimod with phosphoric acid

Examples of embodiments of the invention

The invention is further elucidated in the following examples. These examples, which illustrate the preparation of solid forms of ozanimod, are purely illustrative and do not limit the scope of the invention in any way.

Example 1

Preparation of the crystalline form of ozanimod with citric acid

Ozanimod base (100 mg) and citric acid (50 mg) were stirred in methanol (3.5 ml) at 50 ° C. The resulting solution was stirred at room temperature for 12 h, during which time a solid precipitated. The suspension is cooled to 5 [deg.] C., the precipitate is filtered off with suction and washed with 0.5 ml of methanol. The product was dried for 12 h in a vacuum oven at 40 ° C. Yield 95.7%, HPLC 99.72%.

1 H NMR (500 MHz, dmso-δ / 6): the stoichiometric ratio of ozanimod: citric acid is approximately 1: 1.

1 H NMR (DMSO-D 6): 1.38 (d, J = 6.0, 6H); 2.10 (m, 1 H); 2.89 (m. 2H); 3.20 (m, overlap); 3.40 (m, overlap); 3.60 (t, J = 5.3, overlap); 4.62 (~ t, 1 H); 4.98 (septet, 1 H); 7.50 (t, J = 7.5, 1H); 7.56 (d, J = 9.0, 1 H); 7.74 (d, J = 7.6, 1H); 8.08 (d, J = 7.8, 1 H); 8.40 (dd, J = 8.9, 2.0, 1 H), 8.50 (d, J = 2.0, 1 H).

Citrate 2.50 (q, J = 15.0, 4H, overlay)

The crystalline form of ozanimod with citric acid is characterized by the reflections listed in Table 1. Table 1 includes reflections with a relative intensity value greater than 22%. Characteristic diffraction peaks of ozanimod with citric acid of the present invention using CuKα radiation: 4.57; 12.49; 16.22; 21.21; 25.20 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKa radiation: 13.75; 14.52; 23.20; 29.45 ± 0.2 ° 2theta. The X-ray powder record is shown in FIG. 1.

Table 1: Diffraction peaks of the crystalline form of ozanimod with citric acid

Location [° 2Th.] Interplanar distance [A] [Á] = 0.1 nm Rel. intensity [%] 4.57 19.33 100.00 12.49 7.08 44.37 13.75 6.43 51.58 14.18 6.24 61.69 14.52 6.10 84.48

-6EN 2018 - 466 A3

16.22 5.46 62.75 19.48 4.55 31.45 20.17 4.40 43.07 21.21 4.19 70.08 22.88 3.88 22.03 23.20 3.83 30.99 24.78 3.59 31.18 25.20 3.53 83.96 27.22 3.27 27.02 29.45 3.03 28.16

Example 2

Preparation of the crystalline form of ozanimod with fumaric acid

Ozanimod base (100 mg) and fumaric acid (30 mg) were stirred in tetrahydrofuran (3.5 ml) at 50 ° C. The resulting solution was stirred at room temperature for 12 h, during which time a solid precipitated. The suspension is cooled to 5 [deg.] C., the precipitate is filtered off with suction and washed with 0.5 ml of tetrahydrofuran. The product was dried for 12 h in a vacuum oven at 40 ° C. Yield 96.2%, HPLC 99.68%.

1 H NMR (500 MHz, dmso-r / 6): the stoichiometric ratio of ozanimod: fumaric acid is approximately 1: 1.

1 HNMR (DMSO-D 6): 1.38 (d, J = 5.6, 6H); 2.09 (m, 1 H); 2.89 (m. 2H); 3.20 (m, overlap); 3.43 (m, overlap); 3.62 (~ t, J = 5.3, overlap 1H); 4.64 (~ t, overlap 1H); 4.98 (m, overlap); 7.50 (t, J = 7.5, 1H); 7.56 (d, J = 9.0, 1 H); 7.78 (d, J = 7.1, 1 H); 8.08 (d, J = 7.1, 1 H); 8.41 (d, J = 8.6, 1 H), 8.52 (s, 1 H).

Fumarate 6.52 (s, 2H)

The crystalline form of ozanimod with fumaric acid is characterized by the reflections listed in Table 2. Table 2 includes reflections with a relative intensity value greater than 12%. Characteristic diffraction peaks of ozanimod with fumaric acid of the present invention using CuKα radiation: 3.89; 7.83; 13.27; 16.90; 20.02; 24.52 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKα radiation: 13.75; 18.16; 25.59 ± 0.2 ° 2-theta. The X-ray powder record is shown in FIG. 2.

Table 2: Diffraction peaks of the crystalline form of ozanimod with fumaric acid

Location [° 2Th.] Interplanar distance [Á] [Á] = 0, lnm Rel. intensity [%] 3.89 22.71 97.81 7.21 12.25 13.46 7.83 11.28 32.86 12.58 7.03 12.29 13.27 6.67 100.00 13.75 6.44 34.88 16.90 5.24 27.31

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18.16 4.88 17.29 18.76 4.73 16.70 20.02 4.43 28.54 23.30 3.82 21.66 24.52 3.63 28.87 25.59 3.48 26.53 28.53 3.13 12.30

Example 3

Preparation of the crystalline form of ozanimod with oxalic acid in a ratio of 1: 1

Ozanimod base (100 mg) and oxalic acid (25 mg) were stirred in tetrahydrofuran (3.5 ml) at 50 ° C. The resulting solution was stirred at room temperature for 12 h, during which time a solid precipitated. The suspension is cooled to 5 [deg.] C., the precipitate is filtered off with suction and washed with 0.5 ml of tetrahydrofuran. The product was dried for 12 h in a vacuum oven at 40 ° C. Yield 90.5%, HPLC 99.80%.

1 H NMR (500 MHz, dmso-δ / 6): the stoichiometric ratio of ozanimod: oxalic acid is approximately 1: 1.

1 HNMR (DMSO-D 6): 1.38 (d, J = 5.8, 6H); 2.28 (m, 1 H); 2.52 (m, 1 H); 2.98 (m, 1 H); 3.04 (m, 1 H); 3.25 (m, 1 H); 3.47 (m, 1 H); 3.70 (~ t, J = 5.0, 2H); 4.88 (m, 1 H); 4.98 (septet, J = 6.0, 1 H); 7.55 (t, J = 7.8, overlap, 1H); 7.55 (d, J = 8.6, overlap, 1H), 7.91 (d, J = 7.6 1H); 8.14 (d, J = 7.6, 1 H); 8.40 (~ dd, J = 8.9, 1.5; 1H); 8.51 (s, 1 H).

13 C NMR (DMSO-D 6): 21.5; 28.0; 31.6; 46.4; 56.8; 61.1; 72.5; 102.5; 114.9; 115.3; 115.9; 122.9; 127.5; 128.9; 129.2; 133.8; 134.6; 139.7; 144.6; 162.5; 168.0; 173.3.

Oxalate 164.6

The crystalline form of ozanimod with oxalic acid in a ratio of 1: 1 is characterized by the reflections listed in Table 3. Table 3 includes reflections whose relative intensity value is greater than 21%. Characteristic diffraction peaks of ozanimod with oxalic acid in a ratio of 1: 1 according to the present invention using CuKa radiation: 3.19; 11.04; 12.73; 17.12; 24.60; 26.32 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKα radiation: 13.19; 13.95 ± 0.2 ° 2-theta. The X-ray powder record is shown in FIG. 3.

Table 3: Diffraction peaks of the crystalline form of ozanimod with oxalic acid in a ratio of 1: 1

Location [° 2Th.] Interplanar distance [Á] [Á] = 0, lnm Rel. intensity [%] 3.19 27.66 52.04 11.04 8.01 100.00 12.73 6.95 34.64 13.19 6.71 28.13 13.95 6.34 32.69 17.12 5.18 26.31 19.03 4.66 26.01

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22.43 3.96 35.80 22.93 3.88 28.35 24.60 3.62 30.33 25.53 3.49 21.15 26.32 3.38 30.93

Example 4

Preparation of the crystalline form of ozanimod with oxalic acid in a ratio of 2: 1

Ozanimod base (100 mg) and oxalic acid (25 mg) were stirred in methanol (3.5 ml) at 50 ° C. The resulting solution was stirred at room temperature for 12 h, during which time a solid precipitated. The suspension is cooled to 5 [deg.] C., the precipitate is filtered off with suction and washed with 0.5 ml of methanol. The product was dried for 12 h in a vacuum oven at 40 ° C. Yield 85.3%, HPLC 99.70%.

Ή NMR (500 MHz, dmso- <76): the stoichiometric ratio of ozanimod: oxalic acid is approximately 2: 1.

1 HNMR (DMSO-D 6): 1.38 (d, J = 6.0, 6H); 2.10 (m, 1 H); 2.47 (m, 1 H); 2.89 (m. 2H); 3.18 (m, 1 H); 3.42 (m, 1 H); 3.68 (~ t, J = 5.0, 2H); 4.63 (m, 1 H); 5.0 (septet, J = 6.0, 1 H); 7.55 (t, J = 7.8, overlap, 1H); 7.56 (d, J = 8.6, 1 H), 7.75 (d, J = 7.6, 1 H); 8.09 (d, J = 7.6, 1 H); 8.41 (~ dd, J = 8.9, 1.5; 1H); 8.52 (s, 1 H).

13 C NMR (DMSO-D 6): 21.5; 29.8 (br); 31.5; 47.5; 57.4; 61.7; 72.6; 102.5; 114.9; 115.3; 115.9; 122.7; 127.3; 128.2; 128.5; 133.8; 134.6; 142.8 (br); 144.0; 162.5; 168.1; 173.2.

Oxalate 164.5

The crystalline form of ozanimod with oxalic acid in a ratio of 2: 1 is characterized by the reflections listed in Table 4. Table 4 includes reflections whose relative intensity value is greater than 11%. Characteristic diffraction peaks of ozanimod with oxalic acid in a ratio of 2: 1 according to the present invention using CuKa radiation: 6.16; 9.80; 11.97; 15.91; 24.45 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKa radiation: 3.25; 12.38; 14.53; 23.70 ± 0.2 ° 2-theta. The X-ray powder record is shown in FIG. 4.

Table 4: Diffraction peaks of the crystalline form of ozanimod with oxalic acid in a ratio of 2: 1

Location [° 2Th.] Interplanar distance [Á] [Á] = 0, lnm Rel. intensity [%] 3.25 27.19 11.29 6.16 14.34 100.00 9.80 9.01 21.68 10.12 8.73 15.91 11.47 7.71 17.78 11.97 7.39 92.12 12.38 7.14 59.16 14.53 6.09 21.75 15.91 5.56 13.85

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20.54 4.32 13.13 21.76 4.08 13.86 23.22 3.83 15.51 23.70 3.75 18.87 24.45 3.64 22.21 25.58 3.48 17.14

Example 5

Preparation of the crystalline form of ozanimod with acetic acid

Ozanimod free base (1.1 equivalents) was dissolved in cyclopentyl methyl ether at about 80 ° C. Subsequently, 0.95 to 1.05 equivalents of acetic acid were added in a mixture with cyclopentylmethyl ether. The resulting mixture was stirred at about 80 ° C until a solution was obtained. Subsequently, the solution was stirred under slow cooling to 20-30 ° C. The precipitated crystalline product was isolated by filtration, the filter cake was washed with cyclopentylmethyl ether and dried. Ozanimod free base was recovered as a solvate with acetic acid as described above. Yield 80.8%, HPLC 99.85%.

Ή NMR (500 MHz, dmso- <76): the stoichiometric ratio of ozanimod: acetic acid is approximately 2: 1.

1 HNMR (DMSO-D 6): 1.38 (d, J = 6.1, 6H); 1.83 (m, 1 H); 2.36 (m, 1 H); 2.69 (m. 2H); 3.06 (m, 1 H); 3.29 (m. 1H); 3.50 (m. 2H); 4.23 (t, J = 6.7, 1 H); 4.95 (septet, 1 H); 7.39 (t, J = 7.6, 1 H); 7.51 (d, J = 9.0, 1 H); 7.55 (d, J = 7.4, 1 H); 7.95 (d, J = 7.6, 1 H); 8.35 (dd, J = 8.9, 2.1, 1H), 8.43 (d, J = 2.1, 1 H).

Acetate 1.89 (s, 1.5H);

13 C NMR (DMSO-D 6): 21.5; 31.5; 32.5; 49.0; 60.7; 62.3; 72.5; 102.4; 114.8; 115.3; 116.0; 122.3; 126.8; 127.3; 133.7; 134.5; 143.0; 147.2; 162.4; 168.3; 173.0.

Acetate 21.3 172.3

The crystalline form of ozanimod with acetic acid is characterized by the reflections listed in Table 5. Table 5 includes reflections with a relative intensity value greater than 15%. Characteristic diffraction peaks of ozanimod with acetic acid of the present invention using CuKα radiation: 8.18; 11.66; 13.37; 20.08; 26.52 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKα radiation: 14.53; 18.95; 24.91 ± 0.2 ° 2-theta. The X-ray powder record is shown in FIG. 5.

Table 5: Diffraction peaks of the crystalline form of ozanimod with acetic acid

Location [° 2Th.] Interplanar distance [Á] [Á] = 0, lnm Rel. intensity [%] 4.06 21.72 15.06 8.18 10.81 22.84 11.66 7.58 77.95 12.86 6.88 30.32 13.37 6.62 100.00

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13.61 6.50 17.28 14.53 6.09 31.17 15.87 5.58 33.57 18.95 4.68 31.60 20.08 4.42 61.68 21.49 4.13 24.77 22.31 3.98 34.55 24.91 3.57 41.24 26.52 3.36 62.90

Example 6

Preparation of the crystalline form of ozanimod with benzoic acid

Ozanimod base (100 mg) and benzoic acid (35 mg) were stirred in ethyl acetate (3.5 mL) at 50 ° C. The resulting solution was stirred at room temperature for 12 h, during which time a solid precipitated. The suspension is cooled to 5 [deg.] C., the precipitate is filtered off with suction and washed with 0.5 ml of ethyl acetate. The product was dried for 12 h in a vacuum oven at 40 ° C. Ozanimod free base was isolated back as a cocrystal with benzoic acid as described above. Yield 82.7%, HPLC 99.88%.

1 H NMR (500 MHz, d 6 -δ / 6): the stoichiometric ratio of ozanimod: benzoic acid is approximately 1: 1.

1 HNMR (DMSO-D 6): 1.38 (d, J = 6.0, 6H); 2.04 (m, 1 H); 2.43 (m, 1 H); 2.83 (m. 2H); 3.12 (m, 1 H); 3.40 (m, 1 H); 3.60 (t, J = 5.6, 2 H); 4.51 (t, J = 6.7, 1 H); 4.95 (septet, J = 6.0, 1 H); 7.52 (overlap, 1H + 1H); 7.54 (t, overlap, 1H); 7.73 (d, J = 7.9, 1 H); 8.01 (d, J = 7.6, 1 H); 8.37 (dd, J = 8.9, 2.1, 1H); 8.46 (d, J = 2.1, 1 H).

Benzoate 7.43 (t, overlap, J = 7.6, 2H); 7.45 (t, overlap, 1H); 7.92 (d, J = 8.0, 2 H).

13 C NMR (DMSO-D 6): 21.5; 30.6; 31.6; 48.0; 59.2; 61.8; 72.5; 102.4; 114.8; 115.3; 115.9; 122.5; 128.0; 128.1; 131.8; 133.8; 134.6; 143.7; 144.2; 162.5; 168.2 173.1.

Benzoate 127.1, 128.2, 129.2, 133.3, 168.4.

The crystalline form of ozanimod with benzoic acid is characterized by the reflections listed in Table 6. Table 6 includes reflections with a relative intensity value greater than 21%. Characteristic diffraction peaks of ozanimod with benzoic acid of the present invention using CuKα radiation: 8.60; 11.46; 16.24; 20.91; 25.51 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKα radiation: 9.47; 14.20; 21.72; 29.78 ± 0.2 ° 2theta. The X-ray powder record is shown in FIG. 6.

Table 6: Diffraction peaks of the crystalline form of ozanimod with benzoic acid

Location [° 2Th.] Interplanar distance [Á] [Á] = 0, lnm Rel. intensity [%] 8.60 10.28 63.74 9.47 9.33 72.58 10.81 8.18 32.16

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11.46 7.72 50.03 14.20 6.23 41.05 16.24 5.45 60.61 17.31 5.12 32.81 18.88 4.70 31.74 19.41 4.57 30.30 20.91 4.24 70.92 21.72 4.09 87.02 23.08 3.85 21.53 24.55 3.62 27.06 25.51 3.49 100.00 29.78 3.00 21.67

Example 7

Preparation of the crystalline form of ozanimod with L-malic acid

Ozanimod base (100 mg) and malic acid (35 mg) were stirred in acetone (3.5 ml) at 50 ° C. The resulting solution was stirred at room temperature for 12 h, during which time a solid precipitated. The suspension was cooled to 5 [deg.] C., the precipitate was filtered off with suction and washed with 0.5 ml of acetone. The product was dried for 12 h in a vacuum oven at 40 ° C

1 H NMR (500 MHz, dmso-δ / 6): the stoichiometric ratio of ozanimod: L-malic acid is approximately 1: 1. Yield 97.7%, HPLC 99.59%.

1 HNMR (DMSO-D 6): 1.38 (d, J = 6.0, 6H); 2.22 (m, 1 H); 2.51 (overlap, 1H); 2.99 (m. 2H); 3.21 (m, 1 H); 3.44 (m, 1 H); 3.66 (t, J = 5.3, 2 H); 4.81 (dd, J = 7.6, J = 4.5, 1H); 4.97 (septet, J = 6.0, 1 H); 7.54 (t, overlap, 1H); 7.55 (d, overlap, 1H), 7.83 (d, J = 7.6, 1H); 8.11 (d, J = 7.6, 1 H); 8.38 (dd, J = 8.9, 2.1, 1H); 8.48 (d, J = 2.1, 1 H)

Malate 2.33 (dd, J = 15.5, J = 5.1, V2 CH2), 2.53 (dd, J = 15.5, J = 8.4, V2 CH2), 2.98 (dd, J = 8.4, J = 2.1, CH)

13 C NMR (DMSO-D 6): 21.5; 28.5; 31.7; 46.7; 57.3; 61.3; 72.6; 102.5; 114.9; 115.3; 115.9; 122.9; 127.5; 128.7; 129.1; 133.8; 134.6; 140.4; 144.5; 162.6; 168.0; 173.3.

Malate 41.1; 66.4; 172.2; 176.3

The crystalline form of ozanimod with L-malic acid is characterized by the reflections listed in Table 7. Table 7 includes reflections with a relative intensity value greater than 10%. Characteristic diffraction peaks of ozanimod with L-malic acid according to the present invention using CuKa radiation: 3.61; 11.95; 14.67; 22.13; 25.85 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKα radiation: 7.29; 13.25 ± 0.2 ° 2-theta. The X-ray powder record is shown in FIG. 7.

Table 7: Diffraction peaks of the crystalline form of ozanimod with L-malic acid

- 12 CZ 2018 - 466 A3

Location [° 2Th.] Interplanar distance [Á] [Á] = 0, lnm Rel. intensity [%] 3.61 24.43 100.00 7.29 12.12 15.30 11.95 7.40 48.45 13.25 6.67 46.68 14.67 6.03 57.08 18.40 4.82 20.53 21.52 4.13 25.28 22.13 4.01 84.53 24.94 3.57 13.32 25.85 3.44 25.98 36.67 2.45 10.66

Example 8

Preparation of the crystalline form of ozanimod with hydrobromic acid

Ozanimod base (100 mg) and hydrobromic acid (22 mg) were stirred in methanol (3.5 ml) at 50 ° C. The resulting solution was stirred at room temperature for 12 h, during which time a solid precipitated. The suspension is cooled to 5 [deg.] C., the precipitate is filtered off with suction and washed with 0.5 ml of methanol. The product was dried for 12 h in a vacuum oven at 40 ° C

Ή NMR (500 MHz, dmso-δ / 6): the stoichiometric ratio of ozanimod: hydrobromic acid is approximately 1: 1. Yield 98.6%, HPLC 99.84%.

1 HNMR (DMSO-D 6): 1.38 (d, J = 6.0, 6H); 2.23 (m, 1 H); 2.54 (m, 1 H); 3.02 (br. 1H); 3.08 (br, 1 H) 3.26 (m, 1 H); 3.48 (m, 1 H); 3.70 (quartet, J = 5.1, 2H); 4.93 (br. 1H); 4.98 (septet, J = 6.0, 1 H); 5.27 (t, J = 4.9, 1 H), 7.57 (d, overlap, 1 H); 7.58 (t, overlap, 1H), 7.91 (d, J = 7.6, 1H); 8.17 (d, J = 7.6, 1 H); 8.41 (dd, J = 8.9, 2.1, 1H); 8.52 (d, J = 2.1, 1 H), 8.98 (br, 2 H)

13 C NMR (DMSO-D 6): 21.5; 27.9; 31.7; 46.4; 56.6; 61.2; 72.6; 102.5; 114.9; 115.3; 115.9; 123.0; 127.6; 129.0; 129.5; 133.9; 134.7; 139.1; 144.7; 162.6; 167.9; 173.3.

The crystalline form of ozanimod with hydrobromic acid is characterized by the reflections listed in Table 8. Table 8 includes reflections with a relative intensity value greater than 6%. Characteristic diffraction peaks of ozanimod with hydrobromic acid of the present invention using CuKα radiation: 4.04; 12.23; 13.71; 19.60; 24.53 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKα radiation: 12.46; 19.60; 22.82; 26.82 ± 0.2 ° 2-theta. The X-ray powder record is shown in FIG. 8.

Table 8: Diffraction peaks of the crystalline form of ozanimod with hydrobromic acid

Location [° 2Th.] Interplanar distance [Á] [Á] = 0, lnm Rel. intensity [%] 4.04 21.83 100.00 12.23 7.23 26.78 12.46 7.10 10.77

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12.93 6.84 18.06 13.71 6.45 25.37 19.60 4.53 10.33 20.44 4.34 11.62 21.20 4.19 9.44 21.42 4.15 6.55 22.82 3.89 12.78 24.53 3.63 22.96 24.81 3.59 6.29 25.38 3.51 6.70

26.27 3.39 18.85 26.82 3.32 9.73

Example 9

Preparation of the crystalline form of ozanimod with phosphoric acid

Ozanimod base (100 mg) and phosphoric acid (25 mg) were stirred in methanol (3.5 ml) at 50 ° C. The resulting solution was stirred at room temperature for 12 h, during which time a solid precipitated. The suspension is cooled to 5 [deg.] C., the precipitate is filtered off with suction and washed with 0.5 ml of methanol. The product was dried for 12 h in a vacuum oven at 40 ° C

1 H NMR (500 MHz, d 6 -δ / 6): the stoichiometric ratio of ozanimod: phosphoric acid is approximately 1: 1. Yield 94.3%, HPLC 99.51%.

1 HNMR (DMSO-D 6): 1.38 (d, J = 5.8, 6H); 2.17 (m. 1H); 2.88 (m, 1 H); 2.93 (m, 1 H); 3.19 (m. 1H); 3.43 (m, 1 H); 3.65 (~ t, J = 5.0, 2H); 4.70 (~ t, J = 6.0, 1 H); 4.97 (m, J = 6.0, 1 H); 7.52 (t, J = 7.3, 1 H); 7.55 (d, J = 9.0, 1 H), 7.86 (d, J = 7.6 1 H); 8.10 (d, J = 7.6, 1 H); 8.40 (dd, J = 9.0, 2.2; 1H); 8.51 (d, J = 2.5, 1 H).

The crystalline form of ozanimod with phosphoric acid is characterized by the reflections listed in Table 9. Table 9 includes reflections with a relative intensity value greater than 3%. Characteristic diffraction peaks of ozanimod with phosphoric acid of the present invention using CuKa radiation: 3.52; 11.39; 17.72; 21.33 ± 0.2 ° 2-theta. Other characteristic reflections in X-ray powder recording using CuKa radiation: 3.82; 5.71 ± 0.2 ° 2-theta. The X-ray powder record is shown in FIG. 9.

Table 9: Diffraction peaks of the crystalline form of ozanimod with phosphoric acid

Location [° 2Th.] Interplanar distance [Á] [Á] = 0, lnm Rel. intensity [%] 3.52 25.05 100.00 3.82 23.10 15.24 5.71 15.46 12.41 7.61 11.61 5.82 11.39 7.76 3.56 12.69 6.97 3.62

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13.84 6.39 3.40 14.17 6.25 7.40 17.72 5.00 6.49 20.95 4.24 4.90 21.33 4.16 13.67 23.33 3.81 4.09 24.85 3.58 4.27

List of analytical methods

XRPD measurement parameters: Diffractograms were measured on an X'TERT PRO MPD PANalytical diffractometer, CuKa radiation used (λ = 1.542 Á), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40 ° 20, step size: 0.01 ° 20, the measurement was performed on a flat powder sample, which was applied to a Si plate. Programmable divergence apertures with an irradiated sample area of 10 mm, Soller apertures of 0.02 rad and an anti-scattering aperture of 'A °' were used to adjust the primary optics. An X'Celerator detector with a maximum aperture of the detection slit, a Soller aperture of 0.02 rad and an anti-scatter aperture of 5.0 mm was used to adjust the secondary optics.

Nuclear magnetic resonance (NMR) spectra were measured on a Bruker Avance 500. The spectra were measured at 500.13 MHz, ¹³ C at 125.8 MHz. The sample was measured in the deuterated solvent indicated for the specific analysis, standardly at 25 ° C (unless otherwise stated for the specific analysis). The chemical shift δ is expressed as ppm, the interaction constants J are given in Hz. The spectra were referenced by standard to the residual solvent signal.

Claims (13)

PATENT CLAIMS A solid form of ozanimod with an acid selected from the group consisting of inorganic acids except HCl and carboxylic acid. A solid form according to claim 1, selected from the group consisting of salts with inorganic acids other than HCl, salts with polybasic carboxylic acids, and solvates and cocrystals with monobasic carboxylic acids. The solid form according to claim 1 or 2, wherein the acid is selected from the group consisting of hydrobromic acid, phosphoric acid, citric acid, fumaric acid, oxalic acid, malic acid, acetic acid, benzoic acid. Solid form according to any one of the preceding claims, characterized in that the ozanimod and the acid are in a molar ratio of 1: 1 to 3: 1, preferably in a molar ratio of 1: 1 to 2: 1. A solid form of ozanimod according to any one of claims 1 to 4, selected from the group: (i) solid form of ozanimod with citric acid, which shows characteristic reflections in X-ray powder recording using CuKa radiation: 4.57; 12.49; 16.22; 21.21; 25.20 ± 0.2 ° 2-theta. (Ii) solid form of ozanimod with film-forming acid, which shows characteristic reflections in X-ray powder recording using CuKα radiation: 3.89; 7.83; 13.27; 16.90; 20.02; 24.52 ± 0.2 ° 2-theta. (iii) a solid form of ozanimod with oxalic acid in a ratio of 1: 1, which shows characteristic reflections in the X-ray powder recording using CuKa radiation: 3.19; 11.04; 12.73; 17.12; 24.60; 26.32 ± 0.2 ° 2-theta. (iv) a solid form of ozanimod with oxalic acid in a ratio of 2: 1, which shows characteristic reflections in the X-ray powder recording using CuKa radiation: 6.16; 9.80; 11.97; 15.91; 24.45 ± 0.2 ° 2-theta. (v) solid form of ozanimod with acetic acid, which characteristic reflections in X-ray powder recording using CuKa radiation: 8.18; 11.66; 13.37; 20.08; 26.52 ± 0.2 ° 2theta. (vi) solid form of ozanimod with benzoic acid, which shows characteristic reflections in X-ray powder recording using CuKa radiation: 8.60; 11.46; 16.24; 20.91; 25.51 ± 0.2 ° 2-theta. (vii) solid form of ozanimod with L-malic acid, which shows characteristic reflections in X-ray powder recording using CuKa radiation: 3.61; 11.95; 14.67; 22.13; 25.85 ± 0.2 ° 2-theta. (viii) solid form of ozanimod with hydrobromic acid, which shows characteristic reflections in X-ray powder recording using CuKa radiation: 4.04; 12.23; 13.71; 19.60; 24.53 ± 0.2 ° 2-theta. (ix) a solid form of ozanimod with phosphoric acid that shows characteristic reflections in an X-ray powder record using CuKα radiation: 3.52; 11.39; 17.72; 21.33 ± 0.2 ° 2theta. Process for the preparation of a solid form of ozanimod according to any one of claims 1 to 5, characterized in that it comprises at least the following steps: (a) dissolving or suspending ozanimod and an organic or inorganic acid in a solvent; and b) removing the solvent to form a solid. The method of claim 6, comprising at least the following steps: a1) dissolving ozanimod in a solvent, a2) mixing with a solution of an organic or inorganic acid and b) removing the solvent to form a solid. Process according to Claim 6 or 7, characterized in that the solution or suspension from step a) is stirred for 1 to 24 hours at a temperature of from -30 ° C to the boiling point of the solvent used, more preferably at a temperature of 0 to 130 ° C and most preferably at a temperature of 20 to 80 ° C; the resulting solution is then cooled to a temperature in the range of 0 to 40 ° C, preferably to a temperature in the range of 0 ° C to 25 ° C, and then the solvent is removed, preferably at a temperature in the range of -10 ° C to 30 ° C, and either by filtration, or by concentrating the solution or suspension and then filtering, or by adding an antisolvent and then filtering. - 16 CZ 2018 - 466 A3 Process according to any one of claims 6 to 8, characterized in that the solvent is selected from the group consisting of alcohols, preferably methanol, ethanol or 2-propanol; ketones, preferably acetone or butanone; esters, preferably ethyl acetate; ethers, preferably tetrahydrofuran; aromatic 5 hydrocarbons, preferably toluene or anisole; acetonitrile; water; or mixtures thereof. A solid form of ozanimod according to any one of claims 1 to 5 for use as a medicament. A solid form of ozanimod according to any one of claims 1 to 5 for use in the treatment of multiple sclerosis or ulcerative colitis. Pharmaceutical preparation, characterized in that it comprises at least one solid form of ozanimod with an inorganic or carboxylic acid according to any one of claims 1 to 5 and at least one excipient selected from solvents, carriers, lubricants, preservatives 15 agents, disintegrants, binders, dyes, glidants, flavoring agents; preferably the pharmaceutical preparation is in the form of a capsule, tablet, suppository, suspension or solution, but also in other suitable forms.