Crystalline forms of ozanimod hydrochloride

Abstract

The present invention provides novel crystalline forms of ozanimod hydrochloride. Specific crystalline forms provided by the invention include crystalline forms of ozanimod hydrochloride comprising zinc chloride. Particular crystalline forms may have different dissolution rates, thereby providing different pharmacokinetic parameters, which allow for specific forms to be used in order to achieve specific pharmacokinetic targets. Different crystalline forms may also have different stability properties. Also provided are pharmaceutical compositions comprising the ozanimod hydrochloride crystalline forms and the use of these forms in the treatment of multiple sclerosis (MS) and / or ulcerative colitis (UC). (Formula 1)

Description

CRYSTALLINE FORMS OF OZANIMOD HYDROCHLORIDETECHNICAL FIELD

[0001] The present invention is directed to crystalline forms of ozanimod hydrochloride, pharmaceutical compositions containing these forms, and their use in the treatment of multiple sclerosis (MS) and ulcerative colitis (UC).BACKGROUND

[0002] Ozanimod (1 ), or 5-(3 (1 S)-H(24^yd^oxyethyl)amino]-2,3-dihyd^o-1 / - / - inden-4-yl}-1 ,2,4-oxadiazol-5-yl)-2[(propan-2-yl)oxy]benzonitrile, in the form of the hydrochloride salt, is the active pharmaceutical ingredient (API) in ZEPOSIA®, a prescription medication for use in the treatment of moderately to severely active ulcerative colitis (UC) in adults and relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

[0003] Crystalline solid forms of ozanimod hydrochloride are reported in, for example, US 11 ,680,050 B2, US 10,882,830 B2, US 11 ,117,876 B2 CN107840830 A, WO 2019 / 094409 A1 , US 2020 / 0031784 A1 and WO 2021 / 197852 A1 , WO 2023 / 152767 A1 and IN 202241025388 A.

[0004] One consideration in the provision of a crystalline form of ozanimod hydrochloride and drug products thereof is associated with the high potency of thedrug substance. The dose of ozanimod hydrochloride in the marketed ZEPOVIA® capsules ranges from 0.25 mg to 1 mg. There are several challenges in manufacturing high potency drug substances that are related to, for example, safe handling practices to avoid inadvertent exposures, achieving content uniformity or homogeneity within formulated products containing the drug substance and accurate determination of the drug content in unit doses.

[0005] Different crystalline forms of the same compound, including crystalline forms incorporating another chemical entity such as a coformer, may have different packing, thermodynamic, spectroscopic, kinetic, surface, and mechanical properties. Particular crystalline forms may also have different dissolution rates, thereby providing different pharmacokinetic parameters, which allow for specific forms to be used in order to achieve specific pharmacokinetic targets. Different crystalline forms may have different stability properties. A particular crystalline form may be more sensitive to heat, relative humidity (RH), and / or light. Alternatively, or additionally, a particular crystalline form may have different compressibility and / or density properties thereby providing more desirable characteristics for formulation and / or product manufacturing. Additionally, the particular solubility characteristics of a given crystalline form in relation to undesired impurities can result in differences in the chemical purity of different forms upon isolation. Differences in stability may result from changes in chemical reactivity, such as differential oxidation. Such properties may provide for more suitable product qualities, such as a dosage form that is more resistant to discolouration when comprised of a specific crystalline form. Additionally, the particle size of a given crystalline form upon isolation from a suitable crystallisation system may be finer than a different crystalline form, corresponding with increased surface area. Particle size can be particularly critical for high potency substances to ensure content uniformity in the dosage form.

[0006] There exists a need for novel crystalline forms of ozanimod hydrochloride having improved properties for use in providing drug products containing ozanimod hydrochloride.SUMMARY

[0007] The present invention provides ozanimod hydrochloride crystalline forms. The crystalline forms of ozanimod hydrochloride of the present invention are prepared in the presence of zinc chloride. Zinc is an essential nutritional requirement serving as a cofactor for more than 70 enzymes in the human body. Zinc chloride is also used as a pharmaceutical excipient in drug products, including oral dosage forms. As such, it is expected that the zinc chloride of the present invention can be safely used in materials intended for use in the preparation of pharmaceutical compositions intended for administration to humans or animals.

[0008] Accordingly, in a first aspect of the present invention, there is provided a crystalline form of ozanimod hydrochloride comprising ozanimod hydrochloride and zinc chloride. In a preferred embodiment of the first aspect, the molar ratio of ozanimod hydrochloride to zinc chloride is from about 1 :0.2 to about 1 :1. In a further preferred embodiment of the first aspect, the molar ratio of ozanimod hydrochloride to zinc chloride is about 1 :0.5. In a further preferred embodiment of the first aspect, the molar ratio of ozanimod hydrochloride to zinc chloride is about 1 :0.25. In another embodiment of the first aspect, the water content of the crystalline form is from about 0.5 wt% to about 5 wt%. In a further preferred embodiment of the first aspect, the crystalline form is a hydrate. In another embodiment of the first aspect, the crystalline form is a monohydrate.

[0009] In a second aspect of the present invention, there is provided a crystalline form of ozanimod hydrochloride characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 3.6°, 6.5°, and 7.2°. More preferably, the crystalline form of the second aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of: 7.7°, 12.1 °, 13.0°, 20.3°, 21.8°, and 25.2°. More preferably, the PXRD diffractogram of this aspect further comprises peaks, expressed in degrees 29 (± 0.2°), at 7.7°, 12.1 °, 13.0°, 20.3°, 21.8°, and 25.2°. Preferably, the crystalline form of the second aspect provides a PXRDdiffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 1 . In a further preferred embodiment of the second aspect, the crystalline form comprises zinc chloride. Preferably, the molar ratio of ozanimod hydrochloride to zinc chloride is about 1 :0.5.

[0010] In a third aspect of the present invention, there is provided a crystalline form of ozanimod hydrochloride characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 3.1 °, 6.2°, and 10.7°. More preferably, the crystalline form of the third aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 8.3°, 8.9°, 9.6°, 17.7°, 18.5°, and 28.0°. More preferably, the PXRD diffractogram of this aspect further comprises peaks, expressed in degrees 20 (± 0.2°), at 8.3°, 8.9°, 9.6°, 17.7°, 18.5°, and 28.0°. Preferably, the crystalline form of the third aspect provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 2. In a further preferred embodiment of the third aspect, the crystalline form comprises zinc chloride. Preferably, the molar ratio of ozanimod hydrochloride to zinc chloride is about 1 :0.5. In a further preferred embodiment of the third aspect, the crystalline form is a hydrate, preferably a monohydrate.

[0011] In a fourth aspect of the present invention, there is provided a crystalline form of ozanimod hydrochloride characterized by a PXRD diffractogram comprising peaks, expressed in degrees 20 (± 0.2°), at 3.9°, 9.6°, and 11 .6°. More preferably, the crystalline form of the fourth aspect is characterized by a PXRD diffractogram further comprising at least three peaks, expressed in degrees 20 (± 0.2°), selected from the group consisting of: 5.8°, 7.7°, 19.3°, 21.2°, 23.8°, and 24.6°. More preferably, the PXRD diffractogram of this aspect further comprises peaks, expressed in degrees 20 (± 0.2°), at 5.8°, 7.7°, 19.3°, 21.2°, 23.8°, and 24.6°. Preferably, the crystalline form of the fourth aspect provides a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 20) as those shown in Figure 3. In a further preferred embodiment of the fourth aspect,the crystalline form comprises zinc chloride. Preferably, the molar ratio of ozanimod hydrochloride to zinc chloride is about 1 :0.25.

[0012] In a fifth aspect of the present invention, there is provided a pharmaceutical composition comprising a crystalline form of ozanimod hydrochloride according to the first, second, third or fourth aspects of the invention, and one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition is in the form of a capsule or a tablet. Preferably, the pharmaceutical composition of the fifth aspect is a capsule that comprises an amount of the ozanimod hydrochloride crystalline form of the first, second, third, or fourth aspects, that is equivalent to 0.25, 0.5 or 1 mg of anhydrous ozanimod hydrochloride.

[0013] In a sixth aspect of the present invention, there is provided the use of a crystalline form of ozanimod hydrochloride according to the first, second, third or fourth aspects in the treatment of multiple sclerosis (MS) and / or ulcerative colitis (UC).

[0014] In a seventh aspect of the present invention, there is provided a method of treating multiple sclerosis (MS) or ulcerative colitis, comprising administering to a human subject in need thereof a therapeutically effective amount of crystalline form according to the first, second, third or fourth aspects, or a combination thereof, or the pharmaceutical composition of the fifth aspect of the invention.

[0015] Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying figures.BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Embodiments of the present invention are described, by way of example only, with reference to the attached Figures.

[0017] Figure 1 is a representative PXRD diffractogram of ozanimod hydrochloride Form APO-I as prepared in Example 1.

[0018] Figure 2 is a representative PXRD diffractogram of ozanimod hydrochloride Form APO-II as prepared in Example 2.

[0019] Figure 3 is a representative PXRD diffractogram of ozanimod hydrochloride Form APO-I II as prepared in Example 4.DETAILED DESCRIPTION

[0020] The present invention provides ozanimod hydrochloride crystalline forms. The crystalline forms of ozanimod hydrochloride of the present invention are prepared in the presence of zinc chloride. Zinc is an essential element that is involved in a wide range of biological processes such as biosynthesis, immune function and metabolism. Zinc chloride is used as a nutritional supplement and is also included in both the U.S. Food & Drug Administration’s (FDA’s) Substances Added to Food inventory (formerly Everything Added to Food in the United States (EAFUS)) list and the Inactive Ingredient Database (HD). The Substances Added to Food inventory contains approximately 4,000 substances, and includes information on food additives, colour additives, Generally Recognized As Safe (GRAS) substances, and prior-sanctioned substances. The HD list provides information on inactive ingredients present in FDA-approved drug products. Once an inactive ingredient has appeared in an approved drug product, the inactive ingredient is not considered new, and may require a less extensive review the next time it is included in a new drug product.

[0021] The ozanimod hydrochloride crystalline forms of the present invention exhibit differences in properties when compared to the known crystalline forms of ozanimod hydrochloride. Properties that differ between the invention and known crystalline forms of ozanimod hydrochloride include crystal packing properties such as molar volume, density and hygroscopicity; thermodynamic properties such as melting point and solubility; kinetic properties such as dissolution rate andchemical / polymorphic stability; surface properties such as crystal habit / particle morphology; and / or mechanical properties such as hardness, tensile strength, compactibility, tabletting, handling, flow, and blending.

[0022] Depending on the manner in which the crystalline forms of the present invention are prepared, and the methodology and instrument used for PXRD analysis, the intensity of a given peak observed in a PXRD diffractogram of the crystalline form may vary when compared to the same peak in the representative PXRD diffractograms provided in Figures 1 to 3. Thus, differences in relative peak intensities between peaks in a PXRD diffractogram for a given crystalline form may be observed when compared to the relative peak intensities of the peaks in the representative PXRD diffractograms of Figures 1 to 3. Any such differences may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, the preparation of the sample for analysis, and the methodology applied for the analysis. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.

[0023] In addition to the differences in relative peak intensities that may be observed in comparison to the representative PXRD diffractograms provided in Figures 1 to 3, it is understood that individual peak positions may vary between ±0.2° 29 from the values observed in the representative PXRD diffractograms provided in Figures 1 to 3 for the crystalline forms of the invention or listed in Tables 1 to 3. Such variations are known and understood by a person of skill in the art, and any such variations do not depart from the invention disclosed herein.

[0024] Further, depending on the instrument used for X-ray analysis and its calibration, uniform offsets in the peak position of each peak in a PXRD diffractogram of greater that 0.2° 26 may be observed when compared to the representative PXRD diffractograms provided in Figures 1 to 3. Thus, PXRD diffractograms of the crystalline forms of the present invention may, in some circumstances, display the same relative peak positions as observed in therepresentative PXRD diffractograms provided in Figures 1 to 3, with the exception that each peak is offset in the same direction, and by approximately the same amount, such that the overall PXRD diffractogram is substantially the same in appearance as the PXRD diffractograms of Figures 1 to 3, with the exception of the uniform offset in peak positions. The observation of any such uniform peak shift in a PXRD diffractogram does not depart from the invention disclosed herein given that the relative peak positions of the individual peaks within the PXRD diffractogram remain consistent with the relative peak positions observed in the PXRD diffractograms of Figures 1 to 3.

[0025] As used herein, the term “crystalline form” is intended to include singlecomponent and multiple-component crystalline forms. Single-component crystalline forms of ozanimod hydrochloride consist solely of ozanimod hydrochloride in the repeating unit of the crystal lattice. Multiple-component crystalline forms of ozanimod hydrochloride include crystalline forms of ozanimod hydrochloride wherein one or more other molecules, including solvent, water, and / or a coformer, are also incorporated into the crystal lattice with ozanimod hydrochloride. Crystalline forms can be identified by characterization methods as described herein, such as PXRD, NMR, and / or Karl Fischer titration.

[0026] Multi-component crystalline forms comprising more than one type of molecule in the crystalline lattice may have some variability in the exact molar ratio of their components depending on the conditions used for their preparation. For example, a molar ratio of components within a multi-component crystalline form provides a person of skill in the art information as to the general relative quantities of the components of the crystalline form. In many cases, the molar ratio may vary by ±20% from a stated range. With respect to the present invention, a molar ratio of 1 :0.5 should be understood to include the ratios 1 :0.4 and 1 :0.6, as well as all of the individual ratios in between.

[0027] As used herein, the term “weight percentage” (wt%) refers to the ratio of the weight of a subject component to the weight of the subject mixture, using the same weight unit, expressed as a percentage.

[0028] As used herein, the term “room temperature” refers to a temperature of from about 20°C to about 25°C.

[0029] As used herein, the term “about” means “close to” and that variation from the exact value that follows the term is within amounts that a person of skill in the art would understand to be reasonable. For example, depending on the context, when the term “about” is used with respect to a numerical value, the value may vary within a reasonable range, such as within + / -10%, + / -5%, or + / -1 % of the stated value.

[0030] As used herein, the term “ozanimod hydrochloride” refers to the hydrochloric acid salt of the compound (1 ) having a molar ratio of ozanimod to hydrochloric acid of 1 : 1 .

[0031] As used herein, the phrase “therapeutically effective amount” means that amount of crystalline form of ozanimod hydrochloride that will elicit a biological or medical response of a tissue, system, or patient that is being sought by the administrator (such as a researcher, doctor, or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing, or halting of progression of the condition or disease, including but not limited to multiple sclerosis and ulcerative colitis. In some examples, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. For convenience, the total daily dosage may be divided and administered in portions during the day as required. In some examples, the dosage can range from about 0.01 mg / kg to about 0.1 mg / kg of body weight / day of crystalline form of ozanimod hydrochloride. It should be understood that any numerical range recited herein is intended to include all sub-ranges subsumed therein.

[0032] When describing the embodiments of the present invention there may be a common variance to a given temperature or time that would be understood or expected by the person skilled in the art to provide substantially the same result. For example, when reference is made to a particular temperature, it is to be understood by the person skilled in the art that there is an allowable variance of ±5°C associated with that temperature. When reference is made to a particular time, it is to be understood that there is an allowable variance of ±10 minutes when the time is one or two hours, and ±1 hour when longer periods of time are referenced.

[0033] In one embodiment of the present invention, there is provided a new crystalline form of ozanimod hydrochloride, ozanimod hydrochloride Form APO-I. Ozanimod hydrochloride Form APO-I is prepared in the presence of zinc chloride. In a certain embodiment, ozanimod hydrochloride Form APO-I comprises zinc chloride, wherein the molar ratio of ozanimod hydrochloride to zinc chloride is preferably about 1 :0.5.

[0034] Ozanimod hydrochloride Form APO-I can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 3.6°, 6.5°, and 7.2°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 7.7°, 12.1 °, 13.0°, 20.3°, 21.8°, and 25.2°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 26 (± 0.2°), at 7.7°, 12.1 °, 13.0°, 20.3°, 21.8°, and 25.2°.

[0035] An illustrative PXRD diffractogram of ozanimod hydrochloride Form APO-I, as prepared in Example 1 , is shown in Figure 1. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 1 , and their relative intensities, is provided in Table 1. Although illustrative of the PXRD diffractogram that is provided for the ozanimod hydrochloride Form APO-I of the present invention, the relative intensities of the peaks are variable. Thus, depending on aparticular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0036] As described in Example 1 , ozanimod hydrochloride Form APO-I can be prepared by combining ozanimod hydrochloride with zinc chloride (ZnCl2), preferably about equimolar amounts, in a solvent, preferably methanol, which allows complete dissolution of the solids, typically with heating in the range of about 40°C to about 60°C. Preferably, a suspension is then formed by substantially replacing the methanol with a suitable anti-solvent, preferably 1 -propanol, and stirring for a suitable time and temperature, preferably in the range of about 40°C to about 60°C. After cooling, if necessary, the resulting suspension is isolated,washed with a suitable solvent and dried, if necessary, preferably in vacuo, to afford ozanimod hydrochloride Form APO-I having a PXRD diffractogram consistent with Figure 1.

[0037] In a second embodiment of the present invention, there is provided a new crystalline form of ozanimod hydrochloride, ozanimod hydrochloride Form APO-II. Ozanimod hydrochloride Form APO-II is prepared in the presence of zinc chloride. In a certain embodiment, ozanimod hydrochloride Form APO-II comprises zinc chloride, wherein the molar ratio of ozanimod hydrochloride to zinc chloride is preferably about 1 :0.5. Ozanimod hydrochloride Form APO-II can be characterized as having a water content of from about 2.5 wt% to about 3.5 wt%.

[0038] Ozanimod hydrochloride Form APO-II can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 3.1 °, 6.2°, and 10.7°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 8.3°, 8.9°, 9.6°, 17.7°, 18.5°, and 28.0°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 26 (± 0.2°), at 8.3°, 8.9°, 9.6°, 17.7°, 18.5°, and 28.0°.

[0039] An illustrative PXRD diffractogram of ozanimod hydrochloride Form APO-II, as prepared in Example 2, is shown in Figure 2. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 2, and their relative intensities, is provided in Table 2. Although illustrative of the PXRD diffractogram that is provided for the ozanimod hydrochloride Form APO-II of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0040] As described in Examples 2 and 3, ozanimod hydrochloride Form APO- II can be prepared by combining ozanimod hydrochloride with zinc chloride (ZnCl2), preferably about equimolar amounts, in a solvent, preferably methanol or a mixture thereof with 2,2,2-trifluoroethanol, which allows complete dissolution of the solids, typically with heating in the range of about 40°C to about 60°C.Preferably, a suspension is then formed by substantially replacing the methanol with a suitable anti-solvent, preferably 2-butanol, and applying methods, if necessary, such as sonication, stirring, and / or heat cycling between about 0°C and about 60°C for a suitable time. After cooling, if necessary, the resulting suspension is isolated, washed with a suitable solvent and dried, if necessary, preferably in vacuo, to afford a solid. The solid is treated with an anti-solvent, preferably methyl f-butyl ether, comprising a minor amount (e.g. about 1 to about 3 wt%) of water and the resulting suspension is isolated, washed with a suitable solvent and dried, if necessary, preferably in vacuo to afford ozanimod hydrochloride Form APO-II having a PXRD diffractogram consistent with Figure 2. Alternatively, the solid isexposed to a humid atmosphere, preferably at least about 75% relative humidity (RH) for a suitable time, preferably one or more days, to afford ozanimod hydrochloride Form APO-II.

[0041] In a third embodiment of the present invention, there is provided a new crystalline form of ozanimod hydrochloride, ozanimod hydrochloride Form APO-III. In a certain embodiment, ozanimod hydrochloride Form APO-III comprises zinc chloride, wherein the molar ratio of ozanimod hydrochloride to zinc chloride is preferably about 1 :0.25.

[0042] Ozanimod hydrochloride Form APO-III can be characterized by a PXRD diffractogram comprising, among other peaks, characteristic peaks, expressed in degrees 29 (± 0.2°), at 3.9°, 9.6°, and 11 .6°. Preferably, the PXRD diffractogram further comprises at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of 5.8°, 7.7°, 19.3°, 21.2°, 23.8°, and 24.6°. More preferably, the PXRD diffractogram further comprises peaks, expressed in degrees 26 (± 0.2°), at 5.8°, 7.7°, 19.3°, 21 .2°, 23.8°, and 24.6°.

[0043] An illustrative PXRD diffractogram of ozanimod hydrochloride Form APO-III, as prepared in Example 4, is shown in Figure 3. A peak listing, comprising representative peaks from the PXRD diffractogram in Figure 3, and their relative intensities, is provided in Table 3. Although illustrative of the PXRD diffractogram that is provided for the ozanimod hydrochloride Form APO-III of the present invention, the relative intensities of the peaks are variable. Thus, depending on a particular sample, the prominence or relative intensity of the peaks observed may differ from those in the illustrative PXRD diffractogram and peak listing.

[0044] As described in Examples 4 and 5, ozanimod hydrochloride Form APO- III can be prepared by combining ozanimod hydrochloride with zinc chloride (ZnCl2), preferably about equimolar amounts, in a solvent, preferably methanol, which allows complete dissolution of the solids, typically with heating in the range of about 40°C to about 60°C. Preferably, a suspension is then formed by substantially replacing the methanol with a suitable anti-solvent, preferably 1- propanol, comprising an amount of water (e.g. about 10 to about 20 wt%) and applying methods, if necessary, such as sonication, stirring, and / or heat cycling between about 0°C and about 60°C for a suitable time. After cooling, if necessary, the resulting suspension is isolated, washed with a suitable solvent and dried, if necessary, preferably in vacuo, to afford ozanimod hydrochloride Form APO-III having a PXRD diffractogram consistent with Figure 3.

[0045] In a further embodiment of the invention, there is provided a pharmaceutical composition comprising a crystalline form of ozanimod hydrochloride comprising ozanimod hydrochloride and zinc chloride, with one or more pharmaceutically acceptable excipients. In another embodiment of theinvention, there is provided a pharmaceutical composition comprising a crystalline form of ozanimod hydrochloride selected from the group consisting of ozanimod hydrochloride Form APO-I, Form APO-II, Form APO-HI and mixtures thereof. The amount of crystalline form(s) present in the composition, expressed as the equivalent anhydrous ozanimod hydrochloride, is preferably from about 0.1 wt% to about 5 wt%, the remainder comprising pharmaceutically acceptable excipients including, for example, from about 50 wt% to about 95 wt% diluent, from about 1 wt% to about 10 wt% disintegrant, and from about 0.5 wt% to about 5 wt% lubricant. Preferably, the pharmaceutical composition is a solid dosage form suitable for oral administration, such as a capsule, tablet, pill, powder, or granulate. Preferably, the pharmaceutical composition is a capsule. Preferably, the pharmaceutical composition provides a dose of the ozanimod hydrochloride crystalline form that is equivalent to the 0.25, 0.5, and 1 mg of ozanimod hydrochloride found in ZEPOSIA® drug products.

[0046] Suitable pharmaceutically acceptable excipients are preferably inert with respect to the crystalline form of ozanimod hydrochloride of the present invention, and may include, for example, one or more excipients selected from binders such as lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatine, polyvinylpyrrolidone (PVP) and sodium alginate; fillers or diluents such as lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, cellulose), calcium sulphate, xylitol and lactitol; disintegrants such as croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycollate, com starch, microcrystalline cellulose, silicon dioxide, hydroxypropyl methylcellulose and hydroxypropyl cellulose; lubricants such as magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palmitic acid, mineral oil, hydrogenated castor oil, medium-chaintriglycerides, poloxamer, polyethylene glycol and talc; and dispersants or solubility enhancing agents, such cyclodextrins, glyceryl monostearate, hypromellose, meglumine, poloxamer, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyoxylglycerides, povidone, and stearic acid. Other excipients including preservatives, stabilisers, anti-oxidants, silica flow conditioners, antiadherents, pH modifiers or glidants may be added as required. Other suitable excipients and the preparation of solid oral dosage forms is well known to person of skill in the art, and is described generally, for example, in Remington The Science and Practice of Pharmacy 21stEdition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 45).

[0047] Optionally, when the pharmaceutical compositions are solid dosage forms, the solid dosage forms may be prepared with coatings, such as enteric coatings and extended-release coatings, using standard pharmaceutical coatings. Such coatings, and their application, are well known to persons skilled in the art, and are described, for example, in Remington The Science and Practice of Pharmacy 21stEdition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 46).EXAMPLES

[0048] The following non-limiting examples are illustrative of some of the aspects and embodiments of the invention described herein.

[0049] The ozanimod hydrochloride used as a starting material in the following examples exhibited a PXRD consistent with Form I as depicted in WO 2019 / 094409 A1 . However, it is expected that other polymorphic forms are equally suitable as starting material, provided dissolution of the form occurs when preparing the novel crystalline forms of ozanimod hydrochloride of the present invention.

[0050] PXRD diffractograms were recorded on a Broker D8 Discover powder X-ray diffractometer (Broker AXS LLC, Karlsrohe, Germany). The generator was a Incoatec Microfocos Soorce (IpS) Co tobe (A = 1 .5406 A) with a voltage of 50 kV and corrent of 1.00 mA, osing a divergence slit of 0.1 mm and collimator of 2.0 mm. For each sample, two frames were collected osing a still scan with a PILATUS3 R 100K-A detector at the distance of 294.9 mm from the sample. Raw data were evaloated osing the program DIFFRAC.EVA (Broker AXS LLC, Karlsrohe, Germany).Example 1 : Preparation of Ozanimod hydrochloride Form APO-I

[0051] A solotion of ZnCL (302.7 mg) in methanol (15 mL) was added to ozanimod hydrochloride (978.4 mg) and the resolting sospension was sonicated and heated with stirring at 50°C ontil complete dissolotion, then allowed to cool to room temperatore. 1 -Propanol (6.25 mL) was then added, and the solvent was redoced in vacuo (40-50 Torr, 30°C) to about 6.25 mL. To this clear, colourless solution was added additional 1 -propanol (6.25 mL), which resulted in some white precipitate. The solvent was again reduced in vacuo to 6.25 mL, at which point some oily precipitate was observed. The reaction mixture was then stirred at 50°C for two hours and left to cool slowly at room temperature overnight. The resulting solid reaction mixture was stirred in 1 -propanol (6 mL) to afford a white suspension, which was isolated by vacuum filtration, washed with methyl f-butyl ether (2 x 6 mL, 1 x 3 mL) and dried overnight in vacuo (1 Torr) to afford ozanimod hydrochloride Form APO-I as a white powder (1.031 g). The PXRD diffractogram of the sample is shown in Figure 1.1H NMR analysis of the sample showed presence of about 0.25 wt% 1 -propanol. Karl Fischer (KF) analysis of the sample showed a water content of 0.73 wt%, consistent with about 0.25 mole equivalents of water. The PXRD of a sample of Form APO-I was substantially unchanged following storage in an uncapped vial at 40°C / 75% RH (relative humidity) for 7 days. EDTA (0.02 N solution) complexometric titration was used to measure thezinc present in a sample. A solution of Form APO-I (200 mg) in acetonitrile (35 mL) and aqueous NH4OH / NH4CI (25 mL, 0.3M / 0.1 M) containing Eriochrome Black T indicator (0.02 mM) and hydroxylamine hydrochloride (0.001 M) was titrated until a blue transparent solution was formed, corresponding to a 7.1 wt% zinc content.

[0052] 1H N MR (300 MHz, DMSO-d6): 9.14 (br. s, 2H), 8.52 (d, J = 2.2 Hz, 1 H), 8.41 (d of d, J = 2.2, 9.0 Hz, 1 H), 8.17 (d, J = 7.4 Hz, 1 H), 7.95 (d, J = 7.6 Hz, 1 H), 7.58 (m, 2H), 5.28 (t, J = 5.0 Hz, 1 H), 4.99 (septet, J = 6.0 Hz, 1 H), 4.92 (q, J = 4.0 Hz, 1 H), 3.72 (q, J = 5.0 Hz, 2H), 3.49 (m, 1 H), 3.27 (m, 1 H), 3.04 (m, 2H), 2.54 (m, 1 H), 2.30 (m, 1 H), 1 .39 (d, J = 6.1 Hz, 6H).Example 2: Preparation of Ozanimod Hydrochloride Form APO-

[0053] A solution of ZnCL (314.3 mg) in methanol (18 mL) was added to ozanimod hydrochloride (1015.5 mg), and the resulting suspension was sonicated and heated with stirring at 45°C until complete dissolution, then allowed to cool to room temperature. 2-Butanol (6.25 mL) was then added, and the solvent was reduced in vacuo (40-50 Torr, 30°C) to 6.25 mL. To this clear, colourless solution with some oily precipitate was added an additional amount (6.25 mL) of 2-butanol, which resulted in some white precipitate. The solvent was again reduced in vacuo to 6.25 mL, at which point an oily precipitate was observed. The reaction mixture was stirred at 50°C for two hours and left to cool slowly to room temperature to afford a very thick white suspension. Addition of methyl f-butyl ether (10 mL) and stirring afforded a flowable white suspension, which was isolated by vacuum filtration and washed with methyl f-butyl ether (2 x 5 mL). The sample was dried overnight in vacuo (1 Torr) to afford a white powder (1 .165 g). A portion (0.653 g) of the powder was suspended in wet (1 .3 wt% water) methyl f-butyl ether (13 mL) and stirred for 3.5 hours. The resulting solid was isolated by vacuum filtration, washed with wet (1 .3 wt% water) methyl f-butyl ether (2 x 5 mL) and dried in vacuo (1 Torr) overnight to afford ozanimod hydrochloride Form APO-II as a white powder (0.580 g). The PXRD diffractogram of the sample is shown in Figure 2.1H NMR analysis of the sample showed less than 0.1 wt% residual solvent. Karl Fischer(KF) analysis of the sample showed a water content of 3.13 wt%, consistent with about 1 mole equivalents of water. The PXRD of a sample of Form APO-II was substantially unchanged following storage in an uncapped vial at 40°C / 75% RH (relative humidity) for 15 days. EDTA (0.02 N solution) titration according to the method of Example 1 revealed the sample of Form APO-II had a 6.2 wt% zinc content.

[0054] 1H NMR (300 MHz, DMSO-d6): 9.17 (br. s, 2H), 8.52 (d, J = 2.2 Hz, 1 H),8.41 (d of d, J = 2.2, 9.0 Hz, 1 H), 8.16 (d, J = 7.3 Hz, 1 H), 7.95 (d, J = 7.6 Hz, 1 H), 7.58 (m, 2H), 5.28 (t, J = 5.0 Hz, 1 H), 4.99 (septet, J = 6.0 Hz, 1 H), 4.92 (q, J = 4.0 Hz, 1 H), 3.72 (q, J = 5.0 Hz, 2H), 3.49 (m, 1 H), 3.27 (m, 1 H), 3.04 (m, 2H), 2.54 (m, 1 H), 2.30 (m, 1 H), 1 .39 (d, J = 6.1 Hz, 6H).Example 3: Preparation of Ozanimod hydrochloride Form APO-

[0055] A solution of ZnCl2 in methanol (0.04 mL, 22 mg / mL) was combined with a solution of ozanimod hydrochloride in 2,2,2-trifluoroethanol (0.06 mL, 47 mg / mL), and the resulting solution was dried using a nitrogen flow overnight to afford a waxy solid. 2-Butanol (0.04 mL) was added, and the reaction mixture was then subjected to the following temperature regime with stirring: 50°C, 2h; 40°C, 1 h; 30°C, 1 h; 20°C, 1 h; 10°C, 1 h; 5°C, 1 h; 40°C, 1 h; 30°C, 1 h; 20°C, 1 h; 10°C, 1 h; 5°C, 1 h; 30°C, 1 h; 20°C, 1 h; 10°C, 1 h; 5°C, 1 h. The mother liquor was removed using a wick, and the resulting white powder was exposed to humid atmosphere (75 % RH) at 40°C for 12 days to afford ozanimod hydrochloride Form APO-II as a white powder.Example 4: Preparation of Ozanimod hydrochloride Form APO-HI

[0056] A solution of ZnCL (148.2 mg) in methanol (15 mL) was added to ozanimod hydrochloride (477.0 mg) and the resulting suspension was sonicated and heated with stirring at 40°C until complete dissolution, then allowed to cool to room temperature. The solvent was allowed to evaporate under a flow of nitrogen overnight to yield a white powder (0.657 g). 1 -Propanol (6.7 mL) and water(0.9 mL) were added to the solid, and the resulting translucent reaction mixture was heated to 50°C at which point it became a clear, colourless solution. The reaction mixture was then subjected to the following temperature regime with stirring: 50°C, 2h; 40°C, 1 h; 30°C (at this point, a substantial amount of white solid precipitated), 1 h; 20°C, 1 h; 10°C, 1 h; 5°C, 1 h; 40°C, 1 h; 30°C, 1 h; 20°C, 1 h; 10°C, 1 h; 5°C, 1 h; 30°C, 1 h; 20°C, 1 h; 10°C, 1 h; 5°C, 1 h. The solid was isolated by vacuum filtration, washed with wet (1.2 wt% water) methyl f-butyl ether (2 x 2 mL, 1 x 4 mL) and dried overnight in vacuo (1 Torr) to afford ozanimod hydrochloride Form APO-III as a white powder (403.5 mg). The PXRD diffractogram of the sample is shown in Figure 3.1H NMR analysis of the sample showed less than 0.15 wt% residual solvent. Karl Fischer (KF) analysis of the sample showed a water content of 0.79%, consistent with about 0.25 mole equivalents of water. The PXRD of a sample of Form APO-III was substantially unchanged following storage in a capped vial at 40°C / 75% RH (relative humidity) for 13 days. EDTA (0.02 N solution) titration according to the method of Example 1 revealed the sample of Form APO-III had a 2.7 wt% zinc content.

[0057] 1H NMR (300 MHz, DMSO-d6): 9.23 (br. s, 2H), 8.52 (d, J = 2.2 Hz, 1 H),8.41 (d of d, J = 2.2, 9.0 Hz, 1 H), 8.16 (d, J = 7.3 Hz, 1 H), 7.97 (d, J = 7.6 Hz, 1 H), 7.58 (m, 2H), 5.27 (t, J = 5.0 Hz, 1 H), 4.99 (septet, J = 6.0 Hz, 1 H), 4.91 (q, J = 3.9 Hz, 1 H), 3.72 (q, J = 5.0 Hz, 2H), 3.49 (m, 1 H), 3.27 (m, 1 H), 3.03 (m, 2H), 2.54 (m, 1 H), 2.30 (m, 1 H), 1 .39 (d, J = 6.1 Hz, 6H).Example 5: Preparation of Ozanimod hydrochloride Form APO-III

[0058] A solution of ZnCL (29.6 mg) in methanol (1.35 mL) was added to ozanimod hydrochloride (95.1 mg), and the resulting suspension was sonicated and heated with stirring at 50°C until complete dissolution, then allowed to cool to room temperature. 1 -Propanol (1.5 mL) was then added, and the solvent was reduced in vacuo (40-50 Torr, 30°C) to 1.5 mL. To this clear, colourless solution was added an additional amount (1.5 mL) of 1 -propanol. The solvent was again reduced in vacuo to 1.35 mL, at which point some oily precipitate was observed.Water (0.180 mL) was added, and the solution was heated to 50°C, at which point complete dissolution was observed. The reaction mixture was then subjected to the following temperature regime with stirring: 50°C, 2h; 40°C, 1 h; 30°C (at this point, a substantial amount of white solid precipitated), 1 h; 20°C, 1 h; 10°C, 1 h; 5°C, 1 h; 40°C, 1 h; 30°C, 1 h; 20°C, 1 h; 10°C, 1 h; 5°C, 1 h; 30°C, 1 h; 20°C, 1 h;10°C, 1 h; 5°C, 1 h. The solid was isolated by vacuum filtration, washed with methyl f-butyl ether (1 mL) and dried overnight in vacuo (1 Torr) to afford ozanimod hydrochloride Form APO-HI as a white powder (65.3 mg).

Claims

What is claimed is:

1. A crystalline form of ozanimod hydrochloride comprising ozanimod hydrochloride and zinc chloride.

2. The crystalline form of claim 1 , wherein the molar ratio of ozanimod hydrochloride to zinc chloride is from about 1 :0.2 to about 1 :1.

3. The crystalline form of claim 1 or 2, wherein the molar ratio of ozanimod hydrochloride to zinc chloride is about 1 :0.5.

4. The crystalline form of any one of claims 1 to 3, wherein the water content is from about 0.5 wt% to about 5 wt %.

5. The crystalline form of any one of claims 1 to 4, wherein the crystalline form is a hydrate.

6. The crystalline form of claim 5, wherein the hydrate is a monohydrate.

7. A crystalline form of ozanimod hydrochloride characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 3.6°, 6.5°, and 7.2°.

8. The crystalline form of claim 7, further comprising at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of: 7.7°, 12.1 °, 13.0°, 20.3°, 21.8°, and 25.2°.

9. The crystalline form of claim 7, further comprising peaks, expressed in degrees 26 (± 0.2°), at 7.7°, 12.1 °, 13.0°, 20.3°, 21.8°, and 25.2°.

10. The crystalline form of any one of claims 7 to 9 providing a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 1 .

11. The crystalline form of any one of claims 7 to 10, wherein the crystalline form comprises zinc chloride.

12. The crystalline form of claim 11 , wherein the molar ratio of ozanimod hydrochloride to zinc chloride is about 1 :0.5.

13. A crystalline form of ozanimod hydrochloride characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 3.1 °, 6.2°, and 10.7°.

14. The crystalline form of claim 13, further comprising at least three peaks, expressed in degrees 26 (± 0.2°), selected from the group consisting of: 8.3°, 8.9°, 9.6°, 17.7°, 18.5°, and 28.0°.

15. The crystalline form of claim 13, further comprising peaks, expressed in degrees 26 (± 0.2°), at 8.3°, 8.9°, 9.6°, 17.7°, 18.5°, and 28.0°.

16. The crystalline form of any one of claims 13 to 15 providing a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 2.

17. The crystalline form of any one of claims 13 to 16, wherein the crystalline form comprises zinc chloride.

18. The crystalline form of claim 17, wherein the molar ratio of ozanimod hydrochloride to zinc chloride is about 1 :0.5.

19. The crystalline form of any one of claims 13 to 18, wherein the crystalline form is a hydrate.

20. A crystalline form of ozanimod hydrochloride characterized by a PXRD diffractogram comprising peaks, expressed in degrees 29 (± 0.2°), at 3.9°, 9.6°, and 11.6°.

21. The crystalline form of claim 20, further comprising at least three peaks, expressed in degrees 29 (± 0.2°), selected from the group consisting of: 5.8°, 7.7°, 19.3°, 21.2°, 23.8°, and 24.6°.

22. The crystalline form of claim 20, further comprising peaks, expressed in degrees 29 (± 0.2°), at 5.8°, 7.7°, 19.3°, 21 .2°, 23.8°, and 24.6°.

23. The crystalline form of any one of claims 20 to 22 providing a PXRD diffractogram comprising peaks in substantially the same positions (± 0.2° 29) as those shown in Figure 3.

24. The crystalline form of any one of claims 20 to 23, wherein the crystalline form comprises zinc chloride.

25. The crystalline form of claim 24, wherein the molar ratio of ozanimod hydrochloride to zinc chloride is about 1 :0.25.

26. A pharmaceutical composition comprising a crystalline form of ozanimod hydrochloride of any one of claims 1 to 25, and one or more pharmaceutically acceptable excipients.

27. The pharmaceutical composition of claim 26, wherein the composition is in the form of a capsule or a tablet.

28. The pharmaceutical composition of claim 27, wherein the composition is in the form of capsule.

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