Amorphous and crystalline form of ozanimod hydrochloride

Abstract

There are described novel solid forms of ozanimod hydrochloride, having the formula (I). Also described are the processes for the preparation of said solid forms, as well as pharmaceutical compositions comprising them.

Description

[0001] Amorphous and crystalline form of ozanimod hydrochloride

[0002] This application claims the benefit of European Patent Application EP23382526.4 filed on May 31, 2023.

[0003] Technical Field

[0004] The present invention relates to a new crystalline form and to an amorphous solid form of Ozanimod hydrochloride, to processes for their preparation, to their use in medicine, e.g. in the treatment of multiple sclerosis and ulcerative colitis, and to pharmaceutical compositions comprising said forms.

[0005] Background Art

[0006] Ozanimod hydrochloride, whose complete chemical name is 5-[3-[(1S)-1-(2- hydroxyethylamino)-2,3-dihydro-1 H-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-propan-2- yloxybenzonitrile hydrochloride, is the active pharmaceutical ingredient present in the medicament ZEPOSIA® (registered trademark of Celgene Corporation), approved by regulatory authorities in Europe and USA for the treatment of relapsing multiple sclerosis and ulcerative colitis. Its chemical structure is reported below as Formula (I):

[0007] Formula (I)

[0008] It is a sphingosine-1-phosphate receptor agonist which acts as an immunomodulatory agent by sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.

[0009] The family of compounds to which Ozanimod belongs is disclosed in patent application WO 2009 / 151529, while patent application WO 2011 / 060392 and WO 2011 / 060389 are directed to processes for the preparation of these compounds.

[0010] As generally known, any active pharmaceutical ingredient may exist different crystalline forms (polymorphs), either as pure compound or in forms in which, in the structure of the crystal, are present molecules of water (hydrates) or of another solvent (solvates); besides, in case of hydrates and solvates, the ratio between the number of molecules of active principle and molecules of water or solvent may vary, giving rise to different solid forms of the compound. Any active pharmaceutical ingredient may also exist as amorphous solid, which consists of disordered arrangement of molecules and does not possess a distinguishable crystal lattice.

[0011] Different salts and solid-state forms, including amorphous forms, of an active pharmaceutical ingredient may possess properties that are different and advantageous over those of other solid forms. Such variations in the properties of different salts and solid-state forms may provide a basis for improving manufacturing or formulation, for example, by facilitating better processing or handling characteristics thanks to different morphology or particle size distribution, changing the dissolution profile in a favorable direction, or improving stability (polymorphic and / or chemical) and shelf-life. These variations in the properties of different salts and solid-state forms may also offer improvements to the final dosage form, for instance, if they serve to improve formulation processes or bioavailability.

[0012] The first mention of a solid form of Ozanimod hydrochloride appears in patent application WO 2011 / 060392, wherein the product is obtained after re- crystallization in MeOH. Despite no characterization of the crystalline form obtained is given, the reproduction of this example using common re-crystallization conditions in MeOH, leads to a crystalline form that match with the form named CS1, that was later described and characterized in patent application WO 2017 / 215617. Therein, the reported experiments are carried out on an extremely small scale (5 to 10 mg), using very diluted solutions (6 to 20 g / L) and procedures not conveniently amenable to industrial production (spontaneous evaporation over 1 week or rapid cooling to -20 °C).

[0013] Other crystalline forms of Ozanimod hydrochloride are characterized in later documents, such as WO 2018 / 050091 (Form CS3), CN 107840830 (described as “anhydrous”), WO 2019 / 042219, WO 2018 / 184185, WO 2019 / 094409, WO / 2020 / 152718, and WO / 2021 / 197852. CN108245487A discloses a solid dispersion of amorphous Ozanimod or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant. The pharmaceutically acceptable adjuvant can be a polymer such as hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymer, polyacetic acid ethylene, carboxymethylethylcellulose, carboxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin , carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, and chitosan. Particularly, it discloses an amorphous solid dispersion of Ozanimod hydrochloride in povidone in a weigh ration of 1 :2. No amorphous form of free Ozanimod hydrochloride has been described in the literature. Object of this invention is to provide a new stable and useful crystal form CH and a stable and useful free amorphous form of Ozanimod hydrochloride, and processes for their preparation.

[0014] Summary of Invention

[0015] This and other objects are achieved with the present invention, that in a first aspect thereof provides a free amorphous form of Ozanimod hydrochloride characterized by an XRPD profile comprising a halo pattern between 6 and 40° 20, with essentially no discernible definite peaks, when collected with the Ka radiation of copper (A = 1.5418 A) at room temperature.

[0016] In its second aspect, the invention relates to a process for the production of the above mentioned amorphous form, carried out by spray-drying an Ozanimod hydrochloride solution.

[0017] In its third aspect, the present invention relates to a crystalline form of Ozanimod hydrochloride characterized by an XRPD profile comprising peaks at 4.7 ± 0.2, 7.1 ± 0.2, 11.3 ± 0.2, 16.4 ± 0.2, 17.6 ± 0.2, 22.8 ± 0.2, 23.2 ± 0.2, 25.5 ± 0.2° 20, when collected with the Ka radiation of copper (A = 1.5418 A) at room temperature.

[0018] In its fourth aspect, the invention relates to the preparation of the above mentioned crystalline form of Ozanimod hydrochloride by thermal treatment of the amorphous form at a temperature above 100 °C, preferably in a range from 110 to 130 °C.

[0019] Brief description of the drawings

[0020] Fig. 1 depicts the X-ray powder diffractogram of the free amorphous form of Ozanimod hydrochloride.

[0021] Fig. 2 depicts the X-ray powder diffractogram of the crystalline form of the invention of Ozanimod hydrochloride.

[0022] Fig. 3 depicts the differential scanning calorimetry trace of a sample of the free amorphous form of Ozanimod hydrochloride obtained in Example 1, after drying.

[0023] Fig. 4 depicts the thermogravimetric trace of a sample of the free amorphous form of Ozanimod hydrochloride obtained in Example 1, after drying.

[0024] Fig. 5 depicts the differential scanning calorimetry trace of a sample of the crystalline form of Ozanimod hydrochloride of the invention obtained in Example 4.

[0025] Fig. 6 depicts the thermogravimetric trace of a sample of the crystalline form of Ozanimod hydrochloride of the invention obtained in Example 4. Fig. 7 depicts the X-ray powder diffractogram of a sample of the free amorphous form of Ozanimod hydrochloride obtained in Example 1 , before drying.

[0026] Fig. 8 depicts the differential scanning calorimetry trace of a sample of the free amorphous form of Ozanimod hydrochloride obtained in Example 1 , before drying.

[0027] Fig. 9 depicts the X-ray powder diffractogram of a sample of the free amorphous form of Ozanimod hydrochloride obtained in Example 2.

[0028] Fig. 10 depicts the differential scanning calorimetry trace of a sample of the free amorphous form of Ozanimod hydrochloride obtained in Example 2.

[0029] Fig. 11 depicts the X-ray powder diffractogram of a sample of the crystalline form of Ozanimod hydrochloride of the invention obtained in Example 4.

[0030] Fig. 12 depicts a scanning electron microscope image of free amorphous form of Ozanimod hydrochloride.

[0031] Fig. 13 depicts an optical microscope image of the free amorphous form of Ozanimod hydrochloride.

[0032] Fig. 14 depicts an optical microscope image of the crystalline form of Ozanimod hydrochloride of the invention.

[0033] Fig. 15 depicts the particle size distribution profile and data of the free amorphous form of Ozanimod hydrochloride.

[0034] Fig. 16 depicts the particle size distribution profile and data of the crystalline form of Ozanimod hydrochloride of the invention.

[0035] Detailed description of the invention

[0036] All terms used in this application, unless otherwise specified, are to be understood in their ordinary meaning as known in the relevant technical field.

[0037] For brevity, the crystalline form of Ozanimod hydrochloride of the invention is referred to in the description that follows as “form CH”.

[0038] X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) were used to characterize the polymorphs of Ozanimod hydrochloride obtained by the processes described in this application. The DSC and TGA measurements, referred to in the description and in the claims, were carried out in a nitrogen atmosphere; in addition, the value of the temperature ranges in which the thermal phenomena and / or weight losses take place should be considered with a ± 0.5 °C accuracy.

[0039] In the description that follows, all XRPD spectra and data are collected with the Ka radiation of copper (A = 1.5418 A) at room temperature.

[0040] Unless otherwise indicated, the data relative to the peaks in the XRPD pattern are meant within the common uncertainty due to the instrument measurement, typically ± 0.2 degrees 20.

[0041] The term “solvent”, unless otherwise indicated, means a liquid medium in which a compound is at least partially soluble, and may refer to a single substance or a mixture of two or more substances, e g., water or organic solvents.

[0042] The term “about” includes the range of experimental errors, which can normally occur performing a measurement, e.g., ± 5% or ± 2% or ± 1%. Sometimes, such a range can lie within the experimental error, typical of standard methods used for the measurement and / or determination of a given value or range.

[0043] The term "mass" defines the combination of substrates, reagents, solvents, and products on which a physical or chemical transformation is carried out.

[0044] The term “room temperature” as used herein refers to a temperature in the range from about 18 °C to about 25 °C.

[0045] The term “any solid form” as used herein refers to Ozanimod as hydrochloride salt or as free base in any crystalline or amorphous forms.

[0046] The term “amorphous” refers to a solid form of a compound that is not crystalline. An amorphous compound possesses no long-range order and possesses an X-ray diffraction pattern showing a halo usually without defined peaks.

[0047] In the context of the present disclosure, the term "amorphous form of Ozanimod hydrochloride" refers to the free amorphous form of Ozanimod hydrochloride, as can be derived from the preparation process disclosed herein below.

[0048] The term "free amorphous form of Ozanimod hydrochloride" refers to Ozanimod hydrochloride in free amorphous form, that is, to an amorphous form of Ozanimod hydrochloride that is free of any pharmaceutically acceptable adjuvant such as a polymeric material. Particularly, the term does not include amorphous solid dispersions of Ozanimod hydrochloride in a polymeric material.

[0049] The terms “spray drying” or “spray drying technique” refer to a common industrial processing technique consisting in forming an essentially dry and / or free flowing powder by rapidly removing the solvent from a solution or slurry, sprayed through a nozzle, by means of a hot gas.

[0050] By “polymorphically stable” it is here meant that a crystalline solid form does not change its solid form when stored at 60 °C in a closed container, and / or when stored at room temperature in a closed container protected from humidity.

[0051] By “chemically stable” it is meant that a solid form shows no degradation when stored between room temperature and 60 °C in a closed container protected from humidity.

[0052] Unless otherwise indicated, in the context of the present invention the percentage and amount of a certain component in a composition are to be referred to the weight of said component with respect to the total weight of the composition.

[0053] Unless otherwise indicated, in the context of the present invention a range of values indicated for a certain parameter, for example the weight or the volume of a component in a mixture, includes the upper and the lower limits of the range, e.g., if the content in weight, or in volume, of a component A in a mixture is indicated as “X to Y” or “between X and Y”, the content of A can be X, Y or any of the intermediate values.

[0054] The term “excipient” means any substance contained in the final pharmaceutical form other than the active ingredient and which generally may not be therapeutically effective by itself. Excipients are essential for the administration of the active substance, as they allow to deliver the drug to the target site. Excipients are commonly referred to as raw materials entering into the composition of a pharmaceutical preparation with the aim of giving a shape, to facilitate administration and preserve the active ingredient.

[0055] Furthermore, they contribute to characterize the pharmaceutical preparation from the point of view of appearance, stability, biopharmaceutical profile and acceptability by the patient.

[0056] In its first aspect, the present invention relates to a free amorphous form of Ozanimod hydrochloride characterized by an XRPD profile comprising a halo pattern between 6° and 40° 20, with essentially no discernible definite peaks.

[0057] Such amorphous form of Ozanimod hydrochloride can be further characterized by having a weak diffraction peak at 5.1 ± 0.2 °20 and / or a very faint peak at 7.8 ± 0.2 °20 in the XRPD profile.

[0058] Such amorphous form of Ozanimod hydrochloride can be also characterized by an XRPD profile essentially similar to the one in Figure 1 or Figure 9.

[0059] Such amorphous form of Ozanimod hydrochloride can additionally be characterized by a DSC trace comprising an exothermic peak at 115 ± 5 °C, when recorded at 10 °C / min under nitrogen atmosphere. It can be further characterized by a DSC profile essentially similar to the one in Figure 3, when recorded at 10 °C / min under nitrogen atmosphere. Such amorphous can additionally be characterized by a TGA trace essentially similar to the one in Figure 4, when recorded at 2 °C / min under nitrogen atmosphere.

[0060] In its second aspect, the invention relates to the preparation of the above mentioned amorphous form from an Ozanimod hydrochloride solution by the spray-drying technique.

[0061] The spray-drying operation is preferably carried out using an outlet temperature in the atomization chamber in a range between 35 °C and 100 °C, more preferably between 40 °C and 55 °C.

[0062] Ozanimod hydrochloride can be prepared according to the procedure reported in the literature, e.g. in WO 2010 / 053471 or WO 2011 / 133751.

[0063] The Ozanimod hydrochloride solution is a clear mixture of Ozanimod hydrochloride dissolved in a solvent. Such solvent may be water or an organic solvent or any mixture thereof, preferably a mixture of water and one or more organic solvents, most preferably a mixture of water and tetrahydrofuran in any volume ratio.

[0064] The solution may be provided by dissolving Ozanimod hydrochloride in any solid form in the solvent or mixture of solvents, or by mixing a solution of Ozanimod free base in the solvent or mixture of solvents and adding aqueous hydrochloric acid or hydrogen chloride as gas or dissolved in a solvent or mixture of solvents.

[0065] The concentration of the solution, expressed as weight of Ozanimod hydrochloride over volume of the solution, may be from 1 to 200 g / L, preferably from 10 to 100 g / L, more preferably from 20 to 60 g / L.

[0066] As an illustrative but not limiting example, the solution may be an about 50 g / L solution of Ozanimod hydrochloride in a 1 :1 water / tetrahydrofuran solvent mixture.

[0067] The above-mentioned solution can be fed into a spray-drying apparatus in which it is sprayed through a nozzle and subjected to a hot gas flow to obtain an essentially dry and / or free flowing powder by rapidly removing the solvent. The equipment should be set so that the temperature of the gas at the outlet of the atomization nozzle is preferably in a range between 35 °C and 110 °C, more preferably between 40 °C and 55 °C.

[0068] As an illustrative but not limiting example, the parameters on a ProCepT 4M8 TriX spraydrying apparatus can be set in the following way: drying gas flowrate between 10 and 50 kg / h, feed solution flowrate between 2 and 10 g / min, atomization gas flowrate 5 to 20 g / min, atomization pressure 0.5 to 0.95 bar, nozzle tip 0.6 to 2 mm, cyclone gas 0.05 to 0.2 m3 / min.

[0069] After collecting the obtained amorphous Ozanimod hydrochloride, this can optionally be further dried to remove residual solvents and / or water, e.g., under atmospheric pressure or reduced pressure between room temperature and 65 °C.

[0070] The amorphous Ozanimod hydrochloride obtained by this procedure shows a peculiar particle morphology when observed under a microscope, consisting in mostly rounded particles with an average diameter lower than about 20 pm, as depicted in Fig. 12 (scanning electron microscope image), and Fig. 13 (optical microscope image). The particle size distribution is illustrated by the graph in Fig. 15, as obtained by laser diffraction technique. This morphology confers to the powder advantageous physical behavior such as improved flowability and homogeneity when mixed with other powders such as excipients.

[0071] The obtained amorphous Ozanimod hydrochloride is chemically and polymorphically stable, e.g. when stored at room temperature in a closed container, protected from humidity.

[0072] The amorphous Ozanimod hydrochloride obtainable by the process disclosed above also forms part of the invention.

[0073] The obtained amorphous Ozanimod hydrochloride may be used in combination with excipients to manufacture a drug product.

[0074] The obtained amorphous Ozanimod hydrochloride may be used to produce other polymorphic forms.

[0075] It is a third aspect of the present invention to provide a crystalline form CH of Ozanimod hydrochloride characterized by an XRPD profile comprising peaks at 4.7 ± 0.2, 7.1 ± 0.2, 11.3 ± 0.2, 16.4 ± 0.2, 17.6 ± 0.2, 22.8 ± 0.2, 23.2 ± 0.2, 25.5 ± 0.2° 20.

[0076] Such form CH can be further characterized by an XRPD profile comprising additional peaks at 9.4 ± 0.2, 11.8 ± 0.2, 15.8 ± 0.2, 18.7 ± 0.2, 24.6 ± 0.2, 26.7 ± 0.2, 31.1 ± 0.2° 20.

[0077] Such form CH can be even further characterized by an XRPD profile comprising additional peaks at 14.2 ± 0.2, 20.1 ± 0.2, 23.8 ± 0.2, 28.1 ± 0.2, 28.9 ± 0.2, 32.7 ± 0.2° 20.

[0078] Such form CH can also be characterized by an XRPD profile comprising the peaks reported in Table 1.

[0079] Form CH of Ozanimod hydrochloride can also be characterized by an XRPD profile essentially similar to the one in Figure 2.

[0080] Form CH of Ozanimod hydrochloride can additionally be characterized by a DSC trace comprising an exothermic peak at 192 ± 10 °C, when recorded at 10 °C / min under nitrogen atmosphere. It can be further characterized by a DSC profile essentially similar to the one in Figure 5, when recorded at 10 °C / min under nitrogen atmosphere.

[0081] Form CH of Ozanimod hydrochloride can additionally be characterized by a TGA trace essentially similar to the one in Figure 6, when recorded at 2 °C / min under nitrogen atmosphere. In a fourth aspect, the above mentioned form CH is obtained by thermal treatment of the amorphous form at a temperature above 100 °C, preferably in a range from 110 to 130 °C. Such thermal treatment can be carried out at atmospheric pressure or under vacuum.

[0082] The crystalline form CH of Ozanimod hydrochloride has an excellent chemical and polymorphic stability, e.g., when stored between room temperature and 60 °C in a closed container protected from humidity.

[0083] The crystalline form CH of Ozanimod hydrochloride obtained by the described procedure shows a peculiar particle morphology when observed under a microscope, consisting in mostly rounded particles with an average diameter lower than about 20 pm, as depicted Fig.14 (optical microscope image). The particle size distribution is illustrated by the graph in Fig. 16, as obtained by laser diffraction technique. This morphology confers to the powder advantageous physical behavior such as improved flowability and homogeneity when mixed with other powders such as excipients.

[0084] Crystalline form CH of Ozanimod hydrochloride may be used in combination with excipients to manufacture a drug product.

[0085] Crystalline form CH of Ozanimod hydrochloride may be used to produce other polymorphic forms.

[0086] Experimental examples

[0087] XRPD analyses were performed at room temperature by means of a theta / theta vertical scan Bruker 15 AXS D8 Advance high-performance diffractometer. The instrument was equipped with a Cu-Ka X-ray tube operating at 40 kV / 40 mA and generating radiation having A = 1.5418 A. The detector was a linear Lynxeye XE-T position sensitive set at 250 mm from the sample. Powder samples were deposited in the 20 mm x 0.5 mm hollow of the sample holder, consisting of a quartz monocrystal zero background plate. A mild grinding of the sample in 20 an agate mortar was generally carried out if needed to obtain a suitable fine powder. Diffraction data were collected applying the following conditions: angular range 2-40° 2-theta, 0.027step scan and 1 second acquisition time. The instrument calibration was verified by means of a NIST SRM 1976b. Data acquisition was performed by means of Bruker Diffraction Measurement Center software. Data elaboration was performed by means of Crystal Impact Match! Software.

[0088] DSC analysis was carried out with a Mettler DSC-1 Star System, using 40 pL standard Aluminum crucibles loaded with about 4-6 mg of sample and sealed with a specific crucible sealing press. A void crucible of the same kind was placed in the reference location of the DSC furnace. Indium reference material was used to calibrate the apparatus with regard to the temperature scale and the enthalpy response. The samples were analyzed under nitrogen flow at a heating rate of 10 °C / min after making a pinhole on the crucible lid. The explored thermal range was between 30 °C and 300 °C. TGA analysis was carried out with a Mettler TGA-DSC 3+ Star System, using 100 plstandard Aluminum crucibles loaded with about 15 mg of sample and sealed with a specific crucible sealing press. A void crucible of the same kind was placed in the reference location of the TGA furnace. Indium reference material was used to calibrate the apparatus for temperature and enthalpy measurement. Samples were analyzed under nitrogen flow (80 mL / min) at a heating rate of 2 °C / min after making a pinhole on the crucible lid. The explored thermal range was between 30 °C and 300 °C.

[0089] PSD analysis was performed using a Malvern Mastersizer 3000 equipment based on laser diffraction technique; a wet dispersion method was applied using isoparaffin fluid as dispersant.

[0090] Example 1 - spray drying of Ozanimod hydrochloride solution

[0091] Ozanimod hydrochloride (20 g) was dissolved in a mixture of water (200 g) and tetrahydrofuran (200 g) by stirring and gentle heating to 40 / 50 °C until completely clear.

[0092] The solution was fed into a ProCepT 4M8 TriX spray-drying apparatus set with an outlet temperature in the atomization chamber of 45 °C and the following other instrumental settings:

[0093] Solid amorphous Ozanimod Hydrochloride was obtained in a 77% yield with respect to the amount of compound in the portion of solution fed into the apparatus.

[0094] The XRPD profile of the obtained amorphous hydrochloride is reported in Figure 7. The DSC trace of the obtained amorphous hydrochloride is reported in Figure 8. The water content was 2.3% w / w by Karl Fischer analysis.

[0095] The solid was further dried in a vacuum oven at 65 °C for 16 hours.

[0096] The XRPD profile of the obtained amorphous Ozanimod hydrochloride after drying is reported in Figure 1. The DSC trace of the obtained amorphous Ozanimod hydrochloride is reported in Figure 3. The TGA trace of the obtained amorphous Ozanimod hydrochloride is reported in Figure 4. The water content was 1 .2% w / w by Karl Fischer analysis. Example 2 - spray drying of Ozanimod hydrochloride solution

[0097] Ozanimod hydrochloride (20 g) was dissolved in a mixture of water (200 g) and tetrahydrofuran (200 g) by stirring and gentle heating to 40 / 50 °C until completely clear.

[0098] The solution was fed into a ProCepT 4M8 TriX spray-drying apparatus set with an outlet temperature in the atomization chamber of 100 °C and these other instrumental settings:

[0099] Solid amorphous Ozanimod Hydrochloride was obtained in a 75% yield with respect to the amount of compound in the portion of solution fed into the apparatus.

[0100] The XRPD profile of the obtained amorphous Ozanimod hydrochloride is reported in Figure 9. The DSC trace of the obtained amorphous Ozanimod hydrochloride is reported in Figure 10. The water content was 1.1% w / w by Karl Fischer analysis.

[0101] Example 3 - preparation of Ozanimod hydrochloride Form CH

[0102] About 5 mg of amorphous Ozanimod hydrochloride powder in a non-hermetic aluminum pan were heated from 30 °C up to 120 °C at 10 °C / min in a DSC instrument (the DSC thermogram recorded during the experiment showed the presence of a broad endotherm and a subsequent exothermic transition before 120 °C).

[0103] The sample was then let to spontaneously cool down to room temperature and recovered from the DSC pan. The subsequent XRPD analysis confirmed the conversion from amorphous to Form CH.

[0104] The XRPD profile of the obtained form CH of Ozanimod hydrochloride is reported in Figure 2.

[0105] Example 4 - preparation of Ozanimod hydrochloride Form CH

[0106] Amorphous Ozanimod hydrochloride powder (5 g) was placed in a glass crystallizer and heated at 120 °C in a pre-heated vacuum oven for 1 hour. The sample was then then let to spontaneously cool down to room temperature. The subsequent XRPD analysis confirmed the conversion from amorphous to Form CH.

[0107] The XRPD profile of the obtained form CH of Ozanimod hydrochloride is reported in Figure 11 . The DSC trace of the obtained form CH of Ozanimod hydrochloride is reported in Figure 5. The TGA trace of the obtained form CH of Ozanimod hydrochloride is reported in Figure 6. The water content was 0.3% w / w by Karl Fischer analysis.

Claims

CLAIMS1. A crystalline form of Ozanimod hydrochloride characterized by an XRPD profile comprising peaks at 4.7 ± 0.2, 7.1 ± 0.2, 11 .3 ± 0.2, 16.4 ± 0.2, 17.6 ± 0.2, 22.8 ± 0.2, 23.2 ± 0.2, 25.5 ± 0.2° 20, when collected with the Ka radiation of copper of wavelength A = 1.5418 A at room temperature.

2. The crystalline form of Ozanimod hydrochloride according to claim 1 , characterized by an XRPD profile further comprising peaks at 9.4 ± 0.2, 11.8 ± 0.2, 15.8 ± 0.2, 18.7 ± 0.2, 24.6 ± 0.2, 26.7 ± 0.2, 31.1 ± 0.2° 20, when collected with the Ka radiation of copper of wavelength A = 1.5418 A at room temperature.

3. The crystalline form of Ozanimod hydrochloride according to claim 1 , characterized by an XRPD profile further comprising peaks at 14.2 ± 0.2, 20.1 ± 0.2, 23.8 ± 0.2, 28.1 ± 0.2, 28.9 ± 0.2, 32.7 ± 0.2° 20, when collected with the Ka radiation of copper of wavelength A = 1.5418 A at room temperature.

4. A process for the production of the crystalline form of Ozanimod hydrochloride of any one of claims 1 to 3, by thermal treatment of the amorphous form of Ozanimod hydrochloride at a temperature above 100 °C.

5. A pharmaceutical composition comprising the crystalline form of Ozanimod hydrochloride of any one of claims 1 to 3, and at least one pharmaceutically acceptable excipient, carrier, or diluent.

6. Free amorphous form of Ozanimod hydrochloride characterized by an XRPD profile comprising a halo pattern between 6 and 40° 20, when collected with the Ka radiation of copper of wavelength A = 1.5418 A at room temperature.

7. The free amorphous form of Ozanimod hydrochloride according to claim 6, further characterized by a DSC trace comprising an exothermic peak at 115 ± 5 °C, when recorded at 10 °C / min under nitrogen atmosphere.

8. A process for the production of the free amorphous form of Ozanimod hydrochloride of any one of claims 6 to 7, comprising the use of the spray-drying technique on an Ozanimod hydrochloride solution.

9. The process according to claim 8, wherein said solution has a concentration of Ozanimod hydrochloride from 1 to 200 g / L and is obtained by dissolving Ozanimod hydrochloride in a solvent selected from water, an organic solvent or a mixture thereof, or by mixing a solution of Ozanimod free base in a solvent selected from water, an organic solvent or a mixture thereof and adding aqueous hydrochloric acid or hydrogen chloride as a gas or dissolved in one of said solvents or mixture of solvents.

10. The process according to claim 9, wherein the solvent of the Ozanimod hydrochloride solution is a mixture of water and one or more organic solvents.

11. The process according to any one of claims 9 to 10, wherein the solvent of the Ozanimod hydrochloride solution is a mixture of water and tetrahydrofuran in any volume ratio.

12. The process according to any one of claims 8 to 11 , wherein said solution has a concentration of Ozanimod hydrochloride from 10 to 100 g / L.

13. The process according to any one of claims 8 to 12, wherein spray-drying is carried out using an atomization chamber with an outlet temperature in the range between 40 °C and 55 °C.

14. The process according to any one of claims 8 to 13, further comprising a step of further drying the obtained amorphous Ozanimod hydrochloride to remove residual solvents, carried out under atmospheric pressure or reduced pressure between room temperature and 65 °C.

15. A pharmaceutical composition comprising the amorphous form of Ozanimod hydrochloride of any one of claims 6 to 7, and at least one pharmaceutically acceptable excipient, carrier, or diluent.

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