FIELD OF THE INVENTION

[0001] The present disclosure relates to Ozanimod solid state forms, salts including hydrochloride and solid state thereof, processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

BACKGROUND

[0002] Ozanimod (RPC-1063) which has the chemical name 5-[3-[(l S)-l-(2- hydroxyethylamino)-2,3-dihydro-lH-inden-4-yl]-l,2,4-oxadiazo l-5-yl]-2-propan-2- yloxybenzonitrile is an investigational selective sphingosine 1 -phosphate (S IP) 1 and 5 receptor modulator in development for the treatment of patients with relapsing multiple sclerosis, and ulcerative colitis. As described in US patent No. 8,481,573 Ozanimod has the following chemical structure:

[0003] Ozanimod preparation is disclosed in US patent No. 8,481,573 and in US patent No. 9,388, 147. Ozanimod hydrochloride salt preparation is disclosed in US patent No. 9,388, 147 (compound 85). Polymorphs of Ozanimod are disclosed in PCT applications WO2017/215617, WO 2018/033149 and WO 2018/049632. Polymorphs of Ozanimod hydrochloride salt are disclosed in PCT applications WO2017/215617 and WO 2018/050091.

[0004] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Ozanimod, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state ( ¹ C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound. [0005] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf- life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0006] Discovering new salts and solid state forms of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New polymorphic forms and new salts of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms (including solvated forms) of Ozanimod.

SUMMARY OF THE INVENTION

[0007] The present disclosure relates to Ozanimod solid state forms, Ozanimod salts, including hydrochloride, and their solid state forms thereof, to processes for preparation thereof, and to pharmaceutical compositions comprising these salts and solid state forms.

[0008] In particular, the present disclosure provides crystalline forms of Ozanimod designated as Forms A and B (defined herein) and crystalline forms of Ozanimod

hydrochloride salt designated as Forms I, II and III (defined herein).

[0009] The present disclosure further provides process for preparing Ozanimod and Ozanimod hydrochloride solid state forms thereof.

[0010] The present disclosure also relates to the uses of any one or combination of the solid state forms of Ozanimod, Ozanimod salts, including hydrochloride and their solid state forms thereof of the present disclosure, for preparing other solid state forms of

Ozanimod and Ozanimod salts, such as hydrochloride salt, and their solid state forms thereof.

[0011] The present disclosure also relates to any one or a combination of the solid state forms of Ozanimod and Ozanimod salts, including hydrochloride and their solid state forms thereof of the present disclosure, for use in preparing other solid state forms of Ozanimod and Ozanimod salts, such as hydrochloride salt, and their solid state forms thereof.

[0012] In another aspect, the present disclosure encompasses the above described solid state forms of Ozanimod, Ozanimod salts, including hydrochloride and solid state forms thereof for use in the preparation of pharmaceutical compositions and/or formulations, preferably for use in medicine, preferably for treatment of relapsing multiple sclerosis (RMS), inflammatory bowel disorders, ulcerative colitis (US) and for the treatment of immune-mediated disorders.

[0013] In another aspect, the present disclosure encompasses the use of the above described solid state forms of Ozanimod, Ozanimod salts, including hydrochloride and solid state forms thereof for the preparation of pharmaceutical compositions and/or formulations, preferably for use in medicine, preferably for treatment of relapsing multiple sclerosis (RMS), inflammatory bowel disorders, ulcerative colitis (US) and for the treatment of immune-mediated disorders.

[0014] In yet another embodiment, the present disclosure encompasses

pharmaceutical compositions comprising any one or a mixture of the solid state forms of Ozanimod and Ozanimod salts, including hydrochloride, and solid state forms thereof.

[0015] In a specific embodiment, the present disclosure encompasses

pharmaceutical formulations comprising any one or a mixture of the solid state forms of Ozanimod and Ozanimod salts, such as hydrochloride, and solid state forms thereof, and at least one pharmaceutically acceptable excipient.

[0016] The present disclosure further encompasses processes to prepare said pharmaceutical formulations of Ozanimod and/or salts of Ozanimod, comprising combining any one or a mixture of the above described salts and solid state forms of Ozanimod, or pharmaceutical compositions comprising them, and at least one pharmaceutically acceptable excipient.

[0017] The solid state forms of Ozanimod, Ozanimod salts and their solid state forms thereof as defined herein as well as the pharmaceutical compositions or formulations comprising them can be used as medicaments, particularly for treating relapsing multiple sclerosis (RMS), inflammatory bowel disorders and ulcerative colitis (US), comprising administering a therapeutically effective amount of any of the solid state form and/or salt of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from immune-mediated disorders, or otherwise in need of the treatment.

[0018] The present disclosure also provides the uses of the solid state forms of Ozanimod, Ozanimod salts, including hydrochloride and their solid state forms thereof of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for treating immune-mediated disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 shows an X-ray powder diffraction (XRPD) pattern of Ozanimod hydrochloride Form I.

[0020] Figure 2 shows an XRPD pattern of Ozanimod hydrochloride Form II.

[0021] Figure 3 shows an XRPD pattern of Ozanimod hydrochloride Form III.

[0022] Figure 4 shows an XRPD pattern of Ozanimod Form A.

[0023] Figure 5 shows an XRPD pattern of Ozanimod Form B.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0024] The present disclosure relates to solid state forms of Ozanimod, salts of Ozanimod, including hydrochloride and solid state forms thereof , to processes for preparation thereof and to pharmaceutical compositions comprising solid state forms and salts and/or combinations thereof. The disclosure also relates to the conversion of the Ozanimod to other solid state form of Ozanimod and/or to Ozanimod salts and to the conversion of Ozanimod salt, such as hydrochloride to other solid state form of Ozanimod.

[0025] The Ozanimod solid state forms, Ozanimod salts, including hydrochloride and solid state thereof according to the present disclosure may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, dissolution rate, bioavailability, morphology or crystal habit, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents, adhesive tendencies and advantageous processing and handling characteristics such as compressibility, and bulk density.

[0026] A crystal form may be referred to herein as being characterized by graphical data "as depicted in" a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called "fingerprint") which can not necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to factors such as variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms.

[0027] A crystal form of Ozanimod or a solid state form of salt, including hydrochloride, referred to herein as being characterized by graphical data "as depicted in" a Figure will thus be understood to include any crystal forms of Ozanimod or a salt thereof, characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

[0028] A solid state form (or polymorph) may be referred to herein as

polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0%) (w/w) of any other forms of the subject compound as measured, for example, by XRPD. Thus, solid states of Ozanimod or a salt thereof described herein as substantially free of any other solid state forms including other solid state forms of salts would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject salts or solid state form of Ozanimod. Accordingly, in some embodiments of the disclosure, the described salts and solid state forms of Ozanimod may contain from about 1% to about 20%) (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more solid state forms of Ozanimod or salts thereof.

[0029] As used herein, unless stated otherwise, XRPD peaks reported herein are preferably measured using CuKa radiation, λ = 1.54187 A, preferably, XRPD peaks reported herein are measured using CuK a radiation, λ = 1.54187 A, at a temperature of 25 ± 3°C.

[0030] As used herein, the term "isolated" in reference to solid state forms and salts of Ozanimod of the present disclosure corresponds to salt and solid state form of Ozanimod that is physically separated from the reaction mixture in which it is formed.

[0031] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to "room temperature", often abbreviated "RT." This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0032] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10 to about 18 hours, typically about 16 hours.

[0033] As used herein, and unless stated otherwise, the term "anhydrous" in relation to crystalline Ozanimod or a salt thereof which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an

"anhydrous" form does not contain more than about 1% (w/w) of either water or organic solvents as measured for example by TGA, Karl Fischer or by other suitable technique.

[0034] The term "solvate", as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

[0035] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization may be referred to herein as a number of "volumes" or "vol" or "V." For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding (methyl tert-butyl ether) MTBE (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of MTBE was added.

[0036] As used herein the term non-hygroscopic in relation to crystalline Ozanimod or a salt thereof, refers to less than about 1.0% (w/w) absorption of water at about 25°C and about 80%) relative humidity (RH), as determined for example by TGA or other suitable technique.

[0037] As used herein, the term "reduced pressure" refers to a pressure of about 10 mbar to about 500 mbar.

[0038] As used herein, and unless indicated otherwise, the term "thermo-dynamical stability" in relation to solid state forms of Ozanimod and salts thereof refers to resistance of the solid state form to polymorphic conversion under certain conditions, for example, heating, melting or dissolving. In some embodiments, the term refers to less than about 20% (w/w), about 10%) (w/w), about 5% (w/w), about 1%> (w/w), about 0.5% (w/w), or about 0% (w/w) conversion of crystalline Ozanimod or a salt thereof to any other solid state form of Ozanimod or a salt thereof as measured by XRPD. In some embodiments, the conversion is about 1%) (w/w) to about 20% (w/w), about 1% (w/w) to about 10% (w/w) or about 1% (w/w) to about 5%> (w/w).

[0039] As used therein the term "Ozanimod hydrochloride Form I" relates to crystalline forms, having an XRPD pattern shown herein in figure 1, as described in IP.com Prior Art Database Technical Disclosure No. IPCOM000250546D (published in August 2, 2017). Alternatively, Ozanimod hydrochloride Form I refers to a crystalline form

characterized by XRPD peaks at 4.0, 12.6, 13.1, 13.8 and 16.6 degrees 2 theta ± 0.2 degrees 2 theta.

[0040] The present disclosure comprises Ozanimod salts, such as hydrochloride salt.

[0041] The salt can be isolated, preferably it is crystalline.

[0042] The present disclosure comprises a crystalline form of Ozanimod

hydrochloride designated as Form II. The crystalline Form II of Ozanimod hydrochloride can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 12.2, 13.4, 17.5, 17.7 and 27.7 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern substantially as depicted in figure 2; or combinations of these data.

[0043] Crystalline Ozanimod hydrochloride Form II may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 12.2, 13.4, 17.5, 17.7 and 27.7 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 4.0, 14.2, 21.2, 23.3 and 25.1 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0044] The present disclosure further comprises a crystalline form of Ozanimod hydrochloride designated as Form III. The crystalline Form III of Ozanimod hydrochloride can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.9, 7.8, 11.7, 23.6 and 24.7 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 3; or combinations of these data.

[0045] Crystalline Ozanimod hydrochloride form III may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.9,

7.8, 11.7, 23.6 and 24.7 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 4.0, 15.4, 17.3, 26.9 and 31.5 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0046] The present disclosure also comprises a crystalline form of Ozanimod designated as Form A. The crystalline Form A of Ozanimod can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.9, 11.3, 1 1.8, 12.4 and 15.1 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 4; or combinations of these data.

[0047] Crystalline Form A of Ozanimod may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.9, 11.3, 1 1.8, 12.4 and 15.1 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 13.1, 14.0, 14.6, 20.5 and 25.8 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0048] Crystalline Form A of Ozanimod may alternatively be characterized by XRPD pattern having peaks at 5.9, 11.3, 11.8, 12.4, 13.1, 14.0, 14.6, 15.1, 20.5 and 25.8 degrees two theta ± 0.2 degrees two theta.

[0049] Crystalline Form A of Ozanimod may be characterized by each of the above characteristics alone/or by all possible combinations, e.g. by XRPD pattern having peaks at

5.9, 11.3, 11.8, 12.4 and 15.1 degrees two theta ± 0.2 degrees two theta and an XRPD pattern as depicted in Figure 4, and combinations thereof.

[0050] In any aspect or embodiment of the present invention, the crystalline Ozanimod Form A described herein may be substantially free of any other solid state forms of Ozanimod. Preferably, crystalline Form A of Ozanimod according to any aspect or embodiment of the present invention contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w), about 0.2% (w/w) or less, or about 0% (w/w) of any other forms of Ozanimod as measured, for example, by XRPD. Thus, according to any aspect or embodiment of the present invention, the crystalline form comprises greater than about 80% (w/w), greater than about 90%) (w/w), greater than about 95%> (w/w), greater than about 98%> (w/w), greater than about 99% (w/w), or about 100% of Form A of Ozanimod. Preferably, the Form A of Ozanimod according to any aspect or embodiment of the present invention contains no detectable amounts of other solid state forms of Ozanimod (preferably as measured by XRPD).

[0051] According to a further aspect of the present invention, there is provided Ozanimod hemihydrate. Alternatively, in any aspect or embodiment of the present invention as described herein, crystalline Ozanimod Form A may be in the form of a hydrate, preferably in the form of a hemihydrate . In a further embodiment, the present invention provides crystalline Ozanimod Form A, which is preferably in the form of a hemihydrate, having an XRPD pattern with characteristic peaks at 5.9, 11.3, 11.8, 12.4 and 15.1 degrees two theta ± 0.2 degrees two theta; and optionally having one, two, three, four or five additional peaks selected from 13.1, 14.0, 14.6, 20.5 and 25.8 degrees two theta ± 0.2 degrees two theta. Alternatively, crystalline Form A may preferably be in the form of a hemihydrate having an XRPD pattern with characteristic peaks at 5.9, 11.3, 11.8, 12.4, 13.1, 14.0, 14.6, 15.1, 20.5 and 25.8 degrees two theta ± 0.2 degrees two theta. In any aspect or embodiment of the present invention, crystalline Ozanimod Form A which is in the form of a hydrate, and preferably which is in the form of a hemihydrate, may contain about 2% of water.

[0052] In another embodiment of the present disclosure, crystalline Ozanimod Form A is polymorphically pure. In a further embodiment, Ozanimod hemihydrate is

polymorphically pure.

[0053] In another embodiment of the present disclosure, crystalline Ozanimod Form A is isolated. In a further embodiment, Ozanimod hemihydrate is isolated.

[0054] As described above, depending on which other solid state it is compared with, Form A of Ozanimod according to the present disclosure may have advantageous properties as described above.

[0055] The above Ozanimod Form A can be prepared by a process comprising: suspending Ozanimod hydrochloride (preferably Ozanimod hydrochloride Form I) in water and adding sodium hydrogencarbonate to the suspension.

[0056] Typically, 3-10 vol of water, preferably 4-8 vol of water, preferably 4.5-7.5 vol and more preferably about 5 to about 7 vol of water is used for preparing Ozanimod hydrochloride suspension.

[0057] Typically, sodium hydrogencarbonate is added to the suspension. The sodium hydrogencarbonate may be added either as a suspension or as a solid. Preferably, the sodium hydrogencarbonate is added as a solid, and particularly as a powder. The addition of sodium hydrogen carbonate is preferably done gradually, e,g. portionwise. Water may also be added, preferably gradually.

[0058] The addition of sodium hydrogencarbonate and water is preferably conducted at room temperature.

[0059] Preferably the sodium hydrogencarbonate is added in an amount of at least 1 mol equivalents relative to the Ozanimod hydrochloride, more preferably the sodium hydrogencarbonate is added in an amount of: about 1 to about 1.4 mol equivalents, about 1 to about 1.2 mol equivalents, about 1.02 to about 1.15 mol equivalents, or about 1.04 to about 1.08 mol equivalents relative to Ozaminod hydrochloride.

[0060] After the addition, the suspension is preferably heated to temperature of about 60 to about 80°C, preferably about 65 to about 75°C, more preferably to about 70°C.

[0061] Typically, the suspension is kept under the above described heating temperatures, for about 10 to 60 min, preferably for about 10 to 30 min, and more preferably for about 15 minutes, optionally with stirring.

[0062] Typically, prior to isolating the Ozanimod Form A, the suspension is cooled to temperature of about 0 to about 25°C, about 4 to about 20°C, about 5 to about 15°C, and preferably about 5 to about 10°C, optionally with stirring.

[0063] Typically the suspension is cooled for about 20 to about 40 min, preferably for about 25 to about 35 min, more preferably for 30 min, optionally with stirring.

[0064] Optionally the suspension is held at the cooling temperature for additional 30 to about 120 min, preferably for 50 to about 70 min, more preferably for about 60 min, optionally under stirring.

[0065] Typically, isolation of the said crystalline form may be done for example by filtering the suspension and optionally drying. Preferably, drying is done by nitrogen or air. Preferably, drying is performed at a temperature of about 40- 60°C, preferably about 45- 55°C, and more preferably about 50°C, preferably wherein the drying is under nitrogen.

[0066] The present disclosure also relates to a crystalline form of Ozanimod Form A which is obtainable by any embodiment of the process as described above.

[0067] The present disclosure also relates to a pharmaceutical composition comprising Ozanimod Form A as described herein, or Ozanimod Form A which is obtainable by any embodiment of the process as described above.

[0068] The invention further comprises a process for preparing a pharmaceutical composition comprising Ozanimod Form A, wherein the process comprises combining the Ozanimod Form A with at least one pharmaceutically acceptable excipient. The invention further comprises a process for preparing Ozanimod Form A as described in any embodiment of the process as described above, and further comprising combining the Ozanimod Form A with at least one pharmaceutically acceptable excipient.

[0069] The present disclosure also comprises a crystalline form of Ozanimod designated as Form B. The crystalline Form B of Ozanimod can be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.5, 7.9, 15.9, 18.5 and 26.1 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as depicted in Figure 5; or combinations of these data.

[0070] Crystalline Form B of Ozanimod may be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.5, 7.9, 15.9, 18.5 and 26.1 degrees two theta ± 0.2 degrees two theta; and also having one, two, three, four or five additional peaks selected from 8.9, 13.1, 17.2, 24.3 and 28.6 degrees two theta ± 0.2 degrees two theta; or combinations of these data.

[0071] The present disclosure also provides for processes for the preparation of the solid state forms of Ozanimod or Ozanimod salts and their solid state forms thereof. The said process can include the process set out in the examples herein below.

[0072] The present disclosure also provides uses of the solid state form of

Ozanimod, Ozanimod salts and their solid state forms thereof of the present disclosure for preparing other solid state forms of Ozanimod, other Ozanimod salts and their solid state forms thereof.

[0073] The present disclosure also relates to the solid state forms of Ozanimod, Ozanimod salts, and their solid state forms thereof of the present disclosure, for use in preparing other solid state forms of Ozanimod and other salts of Ozanimod and their solid state thereof.

[0074] The present disclosure further encompasses processes for preparing other solid state forms of Ozanimod, other Ozanimod salts and their solid state forms thereof. The said process comprises preparing any one or a mixture of the Ozanimod solid state forms, or Ozanimod salts and their solid state forms thereof, according to the present disclosure, and converting it to Ozanimod or solid state forms thereof or to Ozanimod salt and solid state forms thereof. The conversion can be done, for example, by reacting the solid state form of Ozanimod hydrochloride described herein with a suitable base to obtain Ozanimod, and optionally reacting it with an acid to obtain the corresponding acid-addition salt.

Alternatively, the conversion to other Ozanimod salts may be carried out by reacting the solid state form of Ozanimod (e.g. Form A Ozanimod as described in any aspect or embodiment herein) with a suitable acid to obtain the desired Ozanimod acid addition salt. In a preferred embodiment, Form A of Ozanimod as described in any aspect or embodiment of the present invention may be used in the production of a pharmaceutically acceptable salt of Ozanimod (preferably Ozanimod hydrochloride) or a solid state form thereof, for example by reacting Form A of Ozanimod with an acid, preferably hydrochloric acid or hydrogen chloride, in an appropriate solvent.

[0075] The present invention encompasses a process for preparing a

pharmaceutically acceptable salt (preferably hydrochloride) of Ozanimod comprising reacting a solid state form of Ozanimod according to the present invention (preferably Form A), with an acid (preferably hydrochloric acid). The process may further comprise combining the resulting pharmaceutically acceptable salt of Ozanimod (preferably Ozanimod hydrochloride) with at least one pharmaceutically acceptable excipient to produce a pharmaceutical formulation or dosage form.

[0076] In another aspect, the present disclosure encompasses the above described solid state forms of Ozanimod, Ozanimod salts and solid state forms thereof for use in the preparation of pharmaceutical compositions and/or formulations, preferably for use in medicine, preferably for treatment of relapsing multiple sclerosis (RMS), inflammatory bowel disorders, ulcerative colitis (US) and for the treatment of immune-mediated disorders.

[0077] In another aspect, the present disclosure encompasses the use of the above described solid state forms of Ozanimod, Ozanimod salts and solid state forms thereof for the preparation of pharmaceutical compositions and/or formulations, preferably for use in medicine, preferably for treatment of relapsing multiple sclerosis (RMS), inflammatory bowel disorders, ulcerative colitis (US) and for the treatment of immune-mediated disorders.

[0078] In yet another embodiment, the present disclosure encompasses

pharmaceutical compositions comprising any one or a mixture of the solid state forms of Ozanimod and Ozanimod salts, including hydrochloride and solid state forms thereof.

[0079] In specific embodiment, the present disclosure encompasses pharmaceutical formulation comprising any one or a mixture of the solid state forms of Ozanimod and Ozanimod salts, including hydrochloride and solid state forms thereof, and at least one pharmaceutically acceptable excipient.

[0080] The present disclosure further encompasses processes to prepare said pharmaceutical formulations of Ozanimod and/or salts of Ozanimod, comprising combining any one or a mixture of the above described salts and solid state forms of Ozanimod, or pharmaceutical compositions comprising them, and at least one pharmaceutically acceptable excipient.

[0081] The present disclosure comprises processes for preparing the above mentioned pharmaceutical compositions. The processes comprise combining any one of the above crystalline polymorphs of Ozanimod, Ozanimod hydrochloride and/or combinations thereof of the present disclosure with at least one pharmaceutically acceptable excipient.

[0082] Pharmaceutical formulations of the present invention contain any one or a combination of the crystalline polymorphs of Ozanimod of the present invention, particularly crystalline Ozanimod Form A. In addition to the active ingredient, the pharmaceutical formulations of the present invention can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.

[0083] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.

[0084] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxy ethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.

[0085] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition.

Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab®), and starch. [0086] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.

[0087] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.

[0088] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[0089] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

[0090] In liquid pharmaceutical compositions of the present invention, Ozanimod and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.

[0091] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

[0092] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.

[0093] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.

[0094] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.

[0095] According to the present invention, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.

[0096] The solid compositions of the present invention include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.

[0097] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

[0098] The dosage form of the present invention can be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

[0099] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.

[00100] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, which causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.

[00101] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.

[00102] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

[00103] A capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.

[00104] A pharmaceutical formulation of Ozanimod can be administered.

Ozanimod is preferably formulated for administration to a mammal, preferably a human, by injection. Ozanimod can be formulated, for example, as a viscous liquid solution or suspension, preferably a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al, Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

[00105] The solid state forms of Ozanimod, Ozanimod salts, including

hydrochloride and their solid state forms thereof as defined herein as well as the

pharmaceutical compositions or formulations comprising them can be used as medicaments, particularly for treating relapsing multiple sclerosis (RMS), inflammatory bowel disorders and ulcerative colitis (US), comprising administering a therapeutically effective amount of any of the solid state form and/or salt of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from immune-mediated disorders, or otherwise in need of the treatment. [00106] The present disclosure also provides the uses of the solid state forms of Ozanimod, Ozanimod salts, including hydrochloride and their solid state forms thereof of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, for the manufacture of medicaments for treating immune-mediated disorders.

[00107] Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosure is further illustrated by reference to the following examples describing in detail the preparation of the composition and methods of use of the disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure.

ANALYTICAL METHODS

[00108] Powder X-ray Diffraction was performed on an X-Ray powder

diffractometer PanAlytical X'pert Pro; CuKa radiation (λ = 1.541874 A); X'Celerator detector with active length 2.122 degrees 2-theta; laboratory temperature 25 ± 3 °C; zero background sample holders. Prior to analysis, the samples were gently ground using a mortar and pestle to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed using a cover glass. The parameters for X-ray Powder diffraction pattern ("XRPD") method:

Scan range 3 - 40 degrees 2-theta

Scan mode continuous

Step size 0.0167 degrees

Step size 42 s

Sample spin 60 rpm

Sample holder zero background silicon plate

EXAMPLES

[00109] Ozanimod can be obtained by any procedure described in the literature, for example using the syntheses procedure reported in US patent No. 8,481,573 and in US patent No. 9,388,147. Ozanimod hydrochloride salt can be obtained by any procedure described in the literature, such as disclosed in US patent No. 9,388,147. Ozanimod hydrochloride form I, used in examples below can be prepared according to procedures described in IP.com Prior Art Database Technical Disclosure No. IPCOM000250546D (published in August 2, 2017). [00110] Example 1: Preparation of Ozanimod hydrochloride Form II Ozanimod hydrochloride form I (500 mg) was suspended to triethylamine (50 ml), the suspension was heated up to temperature 89°C during 1 hour, the suspension was stirred at this temperature for 30 minutes and then the suspension was cooled down to temperature (- 10)°C and stirred at this temperature for 30 minutes. The crystal was filtered off and dried for 15 min, under stream of N ₂ on the filter and then was further dried for 10 hours at 50 °C under stream of N ₂ in hot air drier. According to XRD, Ozanimod hydrochloride form II was obtained, PXRD pattern is shown in Figure 2.

[00111] Example 2: Preparation of Ozanimod hydrochloride Form III

Ozanimod hydrochloride form II (100 mg, obtained by example 1) was placed in a saturated atmosphere of water (100% RH) heated to 50 °C for 5 days. Sample was removed and placed on XRD sample holder open to atmosphere for further 3 days at RT, and then it was analyzed by PXRD. According to XRD, Ozanimod hydrochloride form III was obtained (Figure 3).

[00112] Example 3: Preparation of Ozanimod hydrochloride Form III

Ozanimod hydrochloride form I (1.0 g) was dissolved in water (30 ml) and dioxane (30 ml) was added. Solution was refrigerated at -20 °C and lyophilized at 300 Pa. Then, the sample was analyzed by PXRD. According to XRD, Ozanimod hydrochloride form III was obtained.

[00113] Example 4: Preparation of Ozanimod hydrochloride Form III

Ozanimod hydrochloride form I (1.0 g) was suspended in dioxane (100 ml) and heated to 100 °C. Further, water (9 ml) was added in order to prepare a clear solution. The solution was refrigerated at -20°C and lyophilized at 300 Pa. Then, the sample was analyzed by PXRD. According to XRD, Ozanimod hydrochloride form III was obtained.

[00114] Example 5: Preparation of Ozanimod Form A

Ozanimod hydrochloride form I (1 g) was suspended in water (5 ml), to this suspension was added suspension of NaHC0 (0.2 g) and water (1 ml). Then the combined suspensions were heated up to the temperature 70°C and stirred for 15 min. Afterwards, the suspension was cooled down to 5°C during 30 min, followed by additional stirring for 60 min at 5°C. The obtained powder was filtered off and dried on the filter under nitrogen (N ₂ ) for 30 min, and for additional 5 hours under nitrogen (N ₂ ) at 50°C in hot air dryer. Then, the sample was analyzed by PXRD. According to XRD, Ozanimod form A was obtained, PXRD pattern is shown in Figure 4.

[00115] Example 6: Preparation of Ozanimod Form B

Ozanimod hydrochloride, form I (1 g) was suspended in water (30 ml), followed by addition of Na ₂ C0 (0.25 g). Then the suspension was heated up to the temperature of 50°C, during 30 min., and stirred for 60 min at 50°C. It was further cooled down to 28°C during 30 min. At this temperature CH2CI2 (50 ml) was added and the suspension was stirred for 60 min., cooled down to temperature 5°C during 30 min. and stirred for additional 60 min. Then the suspension was given to the separatory funnel and two layers were separated, the lower phase, methylene chloride layer was evaporated until dryness at 50°C for 10 hours in hot air dryer. Then, the sample was analyzed by PXRD. According to XRD, Ozanimod form B was obtained, PXRD pattern is shown in Figure 5.

[00116] Example 7: Preparation of Ozanimod Form A

Ozanimod hydrochloride form I (1 g) was suspended in 7 ml of water. Then 0.2 g of NaHC0 powder and 1 ml of water were added at RT (gradually). The thick suspension was heated up to 70°C during 30 min and stirred for 15 min. Then the suspension was cooled down to 10°C during 30 min and it was further stirred for 60 min. at 10°C. The obtained powder was filtered off and dried on the filter under nitrogen (N2) for 30 min, and for additional 5 hours under nitrogen (N2) at 50°C in hot air dryer. The sample was analyzed by PXRD confirming Ozanimod base form A.