Cocrystal form of selinexor

Abstract

To provide a selinexor cocrystal.SOLUTION: The present invention is intended for a selinexor cocrystal form, more specifically, two cocrystal forms having succinic acid as a coformer, and a cocrystal form having vanillin as a coformer. The present disclosure also relates to a process for preparing the selinexor cocrystal form. Further, the present invention also relates to a pharmaceutical composition including the selinexor cocrystal form, and a method for curing a disease by using the selinexor cocrystal form.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present disclosure is directed to co-crystalline forms of selinexor, particularly to co-crystalline forms of selinexor using succinic acid or vanillin as a co-crystal former (coformer). Additionally, the disclosure also relates to processes for preparing selinexor co-crystalline forms using succinic acid and vanillin. Furthermore, the disclosure also relates to pharmaceutical compositions containing these forms, and to methods for treating diseases using the forms. [Background technology]

[0002] Selinexor is an orally available small molecule inhibitor of CRM1 (also known as chromosome region maintenance 1 protein, exportin 1, or XPO1), which is overexpressed in various cancer cell types and is therefore useful for treating CRM1-related disorders, such as cancer. Selinexor irreversibly inactivates CRM1-mediated nuclear export of cargo proteins such as tumor suppressor proteins (TSPs), including p53, p21, BRCA1 / 2, pRB, FOXO, and other growth regulatory proteins. Thus, selinexor's activity as a selective inhibitor of SINEs restores endogenous tumor suppressor processes, selectively eliminating tumor cells while sparing normal cells. Selinexor has the chemical name (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-(pyrazin-2-yl)acrylohydrazide and the following structure: [ka]

[0003] Selinexor is sold under the trade name XPOVIO®. XPOVIO® is indicated in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies, and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

[0004] Selinexor is also expected to be useful in the treatment of acute myeloid leukemia, multiple myeloma, endometrial cancer, sarcoma, liposarcoma, glioma, diffuse large B-cell lymphoma, brain tumors, cervical cancer, ovarian cancer, head and neck cancer, foot ulcers, acute lymphoblastic leukemia, colorectal cancer, and Richter's transformation (SIRRT). Summary of the Invention [Problem to be solved by the invention]

[0005] Selinexor is described in U.S. Patent Nos. 8,999,996 and 9,714,226. Solid forms of selinexor are described in U.S. Patent No. 10,519,139 (four patterns A-D) and U.S. Patent Publication Nos. 2019 / 0023693 (amorphous and 14 patterns α-ξ), and 2019 / 0336499 (17 patterns T1-T17). None of the references describes any patterns resulting from reactions in the presence of succinic acid or vanillin. Furthermore, none of the references discloses cocrystals of selinexor, more specifically, cocrystals of selinexor with succinic acid or vanillin.

[0006] The present invention is directed to selinexor cocrystalline forms, and more particularly to two cocrystalline forms using succinic acid as a coformer and a cocrystalline form using vanillin as a coformer. The present disclosure also relates to processes for preparing the selinexor cocrystalline forms. Furthermore, the present invention also relates to pharmaceutical compositions containing the selinexor cocrystalline forms and methods for treating diseases using the selinexor cocrystalline forms. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 shows the XRPD pattern of Form I of selinexor cocrystal with succinic acid. [Figure 2] FIG. 2 shows a comparison of the XRPD patterns for Form I of selinexor co-crystal with succinic acid, succinic acid, and selinexol. [Figure 3] FIG. 3 is a DSC plot of Form I of selinexor co-crystal with succinic acid. [Figure 4] FIG. 4 is a TGA plot of Form I of selinexor co-crystal with succinic acid. [Figure 5] FIG. 5 is a DVS plot of Form I of selinexor co-crystal with succinic acid. [Figure 6] FIG. 6 is a 1H NMR spectrum of Form I of selinexor co-crystal with succinic acid. [Figure 7] FIG. 7 depicts the FT-IR spectrum of Form I of selinexor cocrystal with succinic acid. [Figure 8] FIG. 8 depicts the FT-IR spectrum of a physically unbound mixture of selinexol and succinic acid. [Figure 9] FIG. 9 depicts the XRPD pattern for Form II of selinexor co-crystal with succinic acid. [Figure 10] FIG. 10 shows a comparison of the XRPD patterns for Form II of selinexor co-crystal with succinic acid, succinic acid, and selinexol. [Figure 11] FIG. 11 shows the DSC and TGA plots for Form II of selinexor co-crystal with succinic acid. [Figure 12] FIG. 12 is a 1H NMR spectrum of Form II of selinexor co-crystal with succinic acid. [Figure 13] FIG. 13 is a DVS plot of Form II of selinexor co-crystal with succinic acid. [Figure 14]FIG. 14 depicts the FT-IR spectrum of Form II of selinexol co-crystal with succinic acid. [Figure 15] FIG. 15 depicts the XRPD pattern for Form I of selinexor co-crystal with vanillin. [Figure 16] FIG. 16 shows a comparison of XRPD patterns for Form I of the selinexor co-crystal with vanillin, vanillin, and selinexor. DETAILED DESCRIPTION OF THE INVENTION

[0008] The following description is presented to enable any person skilled in the art to make and use various embodiments. Descriptions of specific devices, techniques, and applications are presented only as examples. Various modifications to the examples described herein will be apparent to those skilled in the art, and the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Accordingly, the various embodiments are not intended to be limited to the examples described and shown herein, but are to be accorded the scope consistent with the claims.

[0009] As used herein, unless otherwise specified, the terms "about," "approximately," and "approximately," when used in connection with a numerical value or range of values ​​provided to characterize a particular solid form, such as, for example, a particular temperature or temperature range describing a DSC or TGA thermal event, including, for example, a melting, dehydration, desolvation, or glass transition event; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or moisture content, for example, in terms of mass or percentage; or a peak position, such as, for example, an analysis by IR spectroscopy or Raman spectroscopy or XRPD, indicate that the value or range of values ​​may deviate to an extent that would be considered reasonable by one of ordinary skill in the art while still describing the particular solid form.

[0010] As used herein, unless otherwise specified, "cocrystal" and "cocrystal system" refer to a solid material composed of two or more different coformer molecular compounds in a stoichiometric ratio that interact through non-covalent interactions, particularly those that can be designed using a supramolecular synthon approach. A cocrystal in which at least one of the components is selinexor and the coformer is a second pharmaceutically acceptable compound is referred to as a pharmaceutical selinexor cocrystal with coformer.

[0011] As used herein, unless otherwise specified, "pharmaceutical composition" is intended to encompass a pharmaceutically effective amount of selinexor in the cocrystal of the present invention and pharmaceutically acceptable excipients. As used herein, the term "pharmaceutical composition" includes pharmaceutical compositions such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injectable formulations.

[0012] As used herein, unless otherwise specified, the term "crystalline" and related terms, when used to describe a compound, substance, modification, material, component, or product, means that the compound, substance, modification, material, component, or product is substantially crystalline as determined by X-ray diffraction, unless otherwise specified. See, e.g., Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005); United States Pharmacopeia, 23rd edition, 1843-1844 (1995).

[0013] As used herein, unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable organic or inorganic carrier substance. Excipients can be natural or synthetic substances blended with the active ingredient of a pharmaceutical agent, either for the purpose of increasing the bulk of a formulation containing an active active ingredient (and thus often referred to as "bulking agents," "fillers," or "diluents"), or to impart a therapeutic enhancement to the active ingredient in the final dosage form, such as promoting drug absorption or solubility. Excipients can also be useful in manufacturing processes to aid in handling of the active agent, such as by promoting powder flow or non-stick properties, in addition to aiding in in vitro stability, such as preventing degradation over the expected shelf life.

[0014] As used herein, unless otherwise specified, the term "patient" refers to an animal, preferably a mammal, and most preferably a human, who has been the object of treatment, observation, or experiment. Preferably, the patient is experiencing and / or exhibiting at least one symptom of the disease or disorder being treated and / or prevented. In addition, the patient may not exhibit any symptoms of the disorder, disease, or condition being treated and / or prevented, but is considered by a physician, clinician, or other medical professional to be at risk for developing said disorder, disease, or condition.

[0015] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" refer to the eradication or amelioration of a disease or disorder, or the eradication or amelioration of one or more symptoms associated with a disease or disorder. In certain embodiments, these terms refer to minimizing the spread or worsening of a disease or disorder resulting from the administration of one or more therapeutic agents to a patient with such disease or disorder. In some embodiments, these terms refer to the administration of a compound provided herein, with or without other additional active agents, after the onset of disease symptoms.

[0016] Certain embodiments of the present invention are directed to forms of selinexor cocrystals with succinic acid, more particularly Forms I and II, respectively. Another particular embodiment of the present invention is directed to forms of selinexor cocrystals with vanillin, more particularly Form I, respectively. Forms I and II, respectively, of selinexor cocrystals with succinic acid, and Form I, respectively, of selinexor cocrystals with vanillin, are anhydrous.

[0017] The present invention also relates to a process for preparing Forms I and II of selinexor cocrystal with succinic acid.

[0018] Another embodiment according to the present invention for preparing Form I of selinexor cocrystal with succinic acid comprises: a) A saturated solution of selinexol in ethyl formate and a saturated solution of succinic acid in ethyl formate were added to approximately 1 ギ酸エチル中セリネクソール 1 vs. 1 ギ酸エチル中コハク酸 in a mL ratio of 1:1 to form a mixed solution of selinexol and succinic acid in ethyl formate; b) To a mixture of selinexol and succinic acid in ethyl formate, add approximately 1 mL ギ酸エチル中のセリネクソールとコハク酸との混合溶液 to 0.25 mmol 固体セリネクソール to 0.375 mmol 固体コハク酸 adding solid selinexol and solid succinic acid in a ratio of c) slurrying the mixed solution with the added selinexol and succinic acid; d) cooling the solution to obtain Form I of selinexor co-crystal with succinic acid.

[0019] In a further embodiment of the proceeding method for preparing Form I of selinexor co-crystal with succinic acid, the slurrying is carried out at about 60° C. for about 4 hours. In another embodiment, the cooling is carried out to about −5° C. to 10° C., more particularly to about 0° C. In yet another embodiment, the method further comprises isolating Form I of selinexor co-crystal with succinic acid by filtration and air-drying at about 45° C. for about 2-3 hours. In a further embodiment, in Form I of selinexor co-crystal with succinic acid, the molar ratio of selinexol to succinic acid is 1:1.

[0020] Yet another embodiment according to the present invention is for preparing Form II of selinexor co-crystal with succinic acid, a) mixing a selinexor solution with a succinic acid solution, wherein the solvent for the selinexor or succinic acid solution is selected from the group consisting of ethyl formate, methanol, 1-propanol, ethyl acetate, isopropanol, and acetone, or a mixture thereof, to form a mixed solution of selinexor and succinic acid, and the ratio of millimoles of selinexor to millimoles of succinic acid to mL of solvent for selinexor to mL of solvent for succinic acid is about 1 millimoles; セリネクソール 1 to 1.5 mmol コハク酸 For 3-4mL セリネクソールのための溶媒 For 3-4mL コハク酸のための溶媒 a mixing step, b) adding an anti-solvent to the mixture of selinexor and succinic acid, wherein the ratio of mL of the mixture of selinexor and succinic acid to mL of the anti-solvent is about 1 mL セリネクソールとコハク酸との混合溶液 1-3mL per 抗溶媒 and c) cooling the mixture of step b) to obtain Form II of selinexor co-crystal with succinic acid.

[0021] In a further embodiment of the process proceeding for preparing Form II of selinexor cocrystal with succinic acid, the solvent for dissolving selinexor or succinic acid is a single solvent or a mixture of solvents in a volume ratio of about 3:1 to 9:1. In yet another embodiment, the solvent is 1-propanol, a mixture of 1-propanol and methanol, a mixture of ethyl acetate and methanol, or a mixture of ethyl formate and methanol, more particularly a mixture of 1-propanol and methanol, and a mixture of ethyl acetate and methanol. In yet another embodiment, the selinexor solution is prepared by dissolving selinexol in the solvent at about 45-60°C, more particularly about 50-55°C. In yet another embodiment, the succinic acid solution is prepared by dissolving succinic acid in the solvent at about 45-60°C, more particularly about 50-55°C. In another embodiment, the anti-solvent is CH 12 ~C8H 18 Alkanes, more specifically, C7H 16 (heptane). In yet a further embodiment, the addition of the anti-solvent is carried out at about room temperature. In a further embodiment, the cooling step is carried out at about -5°C to 10°C, more particularly at about 0°C to 5°C. In yet another embodiment, the method further comprises isolating Form II of selinexol co-crystal with succinic acid by filtration and drying under vacuum at about 45°C for about 8 to 10 hours. In a further embodiment, Form II of selinexol co-crystal with succinic acid has a molar ratio of selinexol to succinic acid of 2:3.

[0022] Another embodiment according to the present invention for preparing Form I of selinexor cocrystal with vanillin comprises: a) A saturated solution of selinexol in tetrahydrofuran and a saturated solution of vanillin in tetrahydrofuran were added to approximately 1 テトラヒドロフラン中セリネクソール 1 vs. 1 テトラヒドロフラン中バニリン in a mL ratio to form a mixed solution of selinexol and vanillin in tetrahydrofuran; b) To the mixture of selinexol and vanillin in tetrahydrofuran, add approximately 1 mL テトラヒドロフラン中のセリネクソールとバニリンとの混合溶液 to 0.25 mmol 固体セリネクソール to 0.26 mmol固体バニリン adding solid selinexol and solid vanillin in a ratio of c) slurrying the mixed solution with the added selinexol and vanillin; d) cooling the solution to obtain Form I of selinexor co-crystal with vanillin.

[0023] In a further embodiment of the proceeding method for preparing Form I of selinexor co-crystals with vanillin, the slurrying is carried out at about 60° C. for about 4 hours. In another embodiment, the cooling is carried out to about −5° C. to 10° C., more particularly to about 0° C. In yet another embodiment, the method further comprises isolating Form I of selinexor co-crystals with vanillin by filtration and air-drying at about 45° C. for about 2-3 hours.

[0024] Additionally, the present invention also relates to pharmaceutical compositions containing Form I or II of selinexor cocrystal with succinic acid or Form I of selinexor cocrystal with vanillin, and methods for treating diseases using Form I or II of selinexor cocrystal with succinic acid or Form I of selinexor cocrystal with vanillin. Pharmaceutical compositions containing Form I or II of selinexor cocrystal with succinic acid or Form I of selinexor cocrystal with vanillin can be prepared according to U.S. Pat. No. 9,714,226, which is incorporated herein by reference in its entirety. XPOVIO® (selinexor) is currently available as a 20 mg tablet. The recommended starting dose of XPOVIO® is 80 mg in combination with dexamethasone, administered orally on days 1 and 3 of each week.

[0025] The disclosure provides methods of treating a disease comprising administering to a patient in need thereof a pharmaceutical composition comprising Form I or II of selinexor cocrystal with succinic acid or Form I of selinexor cocrystal with vanillin. XPOVIO® (selinexor) is indicated in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies, and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. [Example]

[0026] The examples that follow are directed to embodiments of the present invention. The examples are presented to enable those skilled in the art to make and use various embodiments. Descriptions of specific devices, techniques, and applications are presented only as examples. Various modifications to the examples described herein will be readily apparent to those skilled in the art, and the general principles described herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Accordingly, the various embodiments are illustrative of the present disclosure, and it is not intended that the disclosure be limited to the illustrated examples described herein.

[0027] analysis technology XRPD patterns are obtained using a Bruker D8 Advance equipped with a Cu Kα radiation source (λ=1.54 Å), a 9-position sample holder, and a LYNXEYE ultrafast detector. Samples are placed in a domed, background-free, air-sensitive silicon plate holder for analysis. Those skilled in the art will recognize that °2θ values ​​and relative intensity values ​​are generated by performing a peak search on the measured data, and d-spacing values ​​are calculated by the instrument from the °2θ values ​​using Bragg's equation. Those skilled in the art will further recognize that the relative intensities for the measured peaks may vary due to, for example, sample preparation, orientation, and the instrument used.

[0028] DSC data are collected using a TA Instruments Q10 DSC. Approximately, samples (2-8 mg) are placed in unsealed, but covered, hermetic alodine-treated aluminum sample pans and scanned from approximately 30 to approximately 300 °C at a rate of approximately 10 °C / min under a nitrogen purge of approximately 50 mL / min. Some DSC runs are performed on a TA Instruments Q2000 equipped with an autosampler and an RSC40. Sampling is performed in T4P (or T3) mode using Tzero hermetic sealed aluminum sample pans at a ramp rate of approximately 10 °C / min from 20 to 320 °C.

[0029] TGA measurements are recorded using a TA Q500 instrument. Approximately 2-5 mg of sample is placed in a sealed, airtight, alodine-treated aluminum DSC pan with a pinhole. The aluminum pan is pre-tared. TGA tests are performed over a temperature range of approximately 30 to approximately 300 °C at a heating rate of 10.0 °C / min, purged with nitrogen at a flow rate of 60 mL / min.

[0030] Sorption isotherms are obtained using a TA Instruments Q5000 SA DVS. Sample temperature is maintained at 25 °C by instrument control. Humidity is controlled by mixing dry and humid nitrogen streams at a total flow rate of 200 mL / min. Relative humidity is measured by a calibrated probe (operating range 1.0-100% RH) located near the sample. The weight change of the sample (mass relaxation) as a function of % RH is constantly monitored by a microbalance (accuracy ±0.0001 mg).

[0031] Typically, 3-10 mg of sample is placed in a tared mesh stainless steel basket under ambient conditions. Samples are loaded and unloaded at 50% RH and 25°C (typical room conditions). Moisture sorption isotherms are performed as outlined below (two scans per complete cycle). Standard isotherms are performed at 25°C in 10% RH intervals over the range of 0-90% RH. Three cycles are typically performed. Data analysis is performed using a TA Instruments Universal Analysis 2000.

[0032] [Table 1]

[0033] 1 H-NMR data are collected using a Bruker Avance 300 MHz NMR equipped with TopSpin software. Samples are prepared by dissolving the compound in deuterated dimethyl sulfoxide containing 0.05% (v / v) tetramethylsilane (TMS). The number of scans is 1 H-NMR gives 16.

[0034] IR analysis is performed by preparing solid samples for FTIR using KBr pellets. The pellets are prepared by mixing KBr and sample in a 1:150 ratio (approximately 2-5 mg of sample and 350 mg of KBr). Analysis is performed using Omnic software, and 32 scans of the sample are collected.

[0035] experiment The following examples provide embodiments for the preparation of co-crystalline forms of selinexol with succinic acid and vanillin.

[0036] Example 1 Preparation of Form I of selinexor cocrystal with succinic acid 2 mL of succinic acid-saturated ethyl formate was added to 2 mL of selinexol-saturated ethyl formate, and then 450 mg of selinexol and 180 mg of succinic acid were added to the mixture at room temperature to form a slurry. The slurry was stirred at 60°C for 4 hours and then cooled to 0°C overnight (approximately 8 hours). The thick slurry was vacuum filtered and then air-dried on a hot plate at 42°C for several hours (approximately 2-3 hours) to obtain Form I of selinexol cocrystal with succinic acid.

[0037] Figure 1 shows the experimental XRPD pattern of Form I of selinexor co-crystal with succinic acid obtained by the present method. Figure 2 shows the XRPD pattern of Form I of selinexor co-crystal with succinic acid compared to the XRPD patterns for selinexor and succinic acid. Form I of selinexor co-crystal with succinic acid is characterized by its XRPD pattern peaks and their corresponding intensities listed in Table I below.

[0038] [Table 2]

[0039] Angular measurements are ±0.2 degrees 2θ. Key defining peaks for Form I of solid selinexor co-crystal with succinic acid include 5.2, 16.7, 17.0, 17.6 and 19.7 degrees 2θ.

[0040] The DSC plot (Figure 3) shows three thermal events at about 121°C, 152°C, and 162°C for Form I of selinexol cocrystal with succinic acid. The TGA plot (Figure 4) shows a TGA weight loss of about 2.0% from about 100°C to about 135°C for Form I of selinexol cocrystal with succinic acid. Figure 5 shows the DVS for Form I of selinexol cocrystal with succinic acid, indicating that it is prone to adsorb water. Such adsorption aids the solubility of the cocrystal, in contrast to selinexol, which does not adsorb water and has low solubility. Figure 6 shows the DVS for Form I of selinexol cocrystal with succinic acid. 11 H NMR spectrum. Figure 7 is an FT-IR spectrum of Form I of selinexol cocrystal with succinic acid, while Figure 8 is an FT-IR spectrum of the unbound physical mixture of selinexol and succinic acid.

[0041] Example 2 Preparation of Form II of selinexor cocrystal with succinic acid Method 1 Selinexor (2.59 g, 5.85 mmol) is dissolved in 18 mL of ethyl formate and 2 mL of acetone at 55°C. Succinic acid (0.69 g, 5.84 mmol) is dissolved in 15 mL of ethyl formate and 5 mL of MeOH at 55°C or in 20 mL of 1-propanol. The selinexol and succinic acid solutions are mixed together in a flask, and then 100 mL of heptane is added at room temperature. The resulting mixture is cooled to 5°C and stirred overnight to obtain a precipitate. The precipitate is isolated by filtration and then dried in an oven at 45°C overnight (8-10 hours) to obtain Form II of selinexor cocrystals with succinic acid.

[0042] Method 2 Selinexor (2.59 g, 5.85 mmol) is dissolved in 14 mL of methanol and 4 mL of 1-propanol at 50° C. Succinic acid (0.69 g, 5.84 mmol) is dissolved in 14 mL of 1-propanol and 4 mL of MeOH at 50° C. The selinexol and succinic acid solutions are mixed together in a flask at 50° C., and then 120 mL of heptane is added. The resulting mixture is cooled to 5° C. and stirred for 2-3 hours to obtain a precipitate. The precipitate is isolated by filtration and then dried in an oven at 45° C. overnight (8-10 hours) to obtain Form II of selinexor cocrystal with succinic acid.

[0043] Figure 9 shows the experimental XRPD pattern of Form II of selinexor co-crystal with succinic acid obtained by this method. Figure 10 shows the XRPD pattern of Form II of selinexor co-crystal with succinic acid compared to the XRPD patterns for selinexol and succinic acid. Form II of selinexor co-crystal with succinic acid is characterized by its XRPD pattern peaks and their corresponding intensities listed in Table II below.

[0044] [Table 3]

[0045] Angular measurements are ±0.2 degrees 2θ. Key defining peaks for Form II of the solid selinexor co-crystal with succinic acid include 10.4, 16.6, 18.9 and 20.7 degrees 2θ.

[0046] Figure 11 shows both the DSC and TGA plots. The DSC plot shows one thermal event at about 156°C for Form II of selinexol co-crystal with succinic acid. Figure 12 shows the DSC plot for Form II of selinexol co-crystal with succinic acid. 1 Figure 13 shows the DVS for Form II of selinexor cocrystal with succinic acid, indicating that it is prone to adsorb water. Such adsorption aids in the solubility of the cocrystal, in contrast to selinexol, which does not adsorb water and has low solubility. Figure 14 shows the FT-IR spectrum of Form II of selinexor cocrystal with succinic acid.

[0047] Example 3 Preparation of Form I of selinexor cocrystal with vanillin 2 mL of vanillin-saturated tetrahydrofuran was added to 2 mL of selinexol-saturated tetrahydrofuran, and then 450 mg of selinexol and 160 mg of vanillin were added to the mixture at room temperature to form a slurry. The slurry was stirred at 60°C for 4 hours and then cooled to 0°C overnight (approximately 8 hours). The thick slurry was vacuum filtered and then air-dried on a hot plate at 42°C for several hours (approximately 2-3 hours) to obtain Form I of selinexol cocrystal with vanillin.

[0048] Figure 15 shows the experimental XRPD pattern of Form I of selinexor co-crystal with vanillin obtained by this method. Figure 16 shows the XRPD pattern of Form I of selinexor co-crystal with vanillin compared to the XRPD patterns for selinexor and vanillin. Form I of selinexor co-crystal with vanillin is characterized by its XRPD pattern peaks and their corresponding intensities listed in Table III below.

[0049] [Table 4]

[0050] Angular measurements are ±0.2°2θ. Key defining peaks for Form I of the solid selinexor co-crystal with vanillin include 12.6, 15.8, and 19.0°2θ.

[0051] The above examples are presented to aid in understanding the disclosure and to enable one of ordinary skill in the art to make and use various embodiments, and are not intended to, and should not be construed to, limit the disclosure as set forth in the claims that follow.

Claims

1. Selinexol cocrystal.

2. 2. The selinexor cocrystal of claim 1, which is a selinexor cocrystal with succinic acid.

3. 3. The selinexor co-crystal with succinic acid of claim 2, which is Form I of the selinexor co-crystal with succinic acid.

4. 4. The selinexor co-crystal with succinic acid of claim 3, having 1 to 3 thermal events occurring at about 121°C, 146°C, and 161°C as measured by differential scanning calorimetry.

5. 4. The selinexor cocrystal with succinic acid of claim 3, characterized in that it has one or more X-ray powder diffraction peaks selected from about 5.2, 16.7, 17.0, 17.6 and 19.7 degrees 2θ.

6. 4. The selinexor cocrystal with succinic acid of claim 3, characterized in that it has two or more X-ray powder diffraction peaks selected from about 5.2, 16.7, 17.0, 17.6 and 19.7 degrees 2θ.

7. 3. The selinexor co-crystal with succinic acid of claim 2, which is Form II of the selinexor co-crystal with succinic acid.

8. 8. The selinexol co-crystal with succinic acid of claim 7, having a thermal event occurring at about 155°C as measured by differential scanning calorimetry.

9. 8. The selinexor cocrystal with succinic acid of claim 7, characterized in that it has one or more X-ray powder diffraction peaks selected from about 10.4, 16.6, 18.9 and 20.7 degrees 2θ.

10. 8. The selinexor cocrystal with succinic acid according to claim 7, characterized in that it has two or more X-ray powder diffraction peaks selected from about 10.4, 16.6, 18.9 and 20.7 degrees 2θ.

11. 2. The selinexor cocrystal of claim 1, which is a selinexor cocrystal with vanillin.

12. 12. The selinexor cocrystal with vanillin according to claim 11, which is Form I of the selinexor cocrystal with vanillin.

13. 13. The selinexor cocrystal with vanillin according to claim 12, characterized in that it has one or more X-ray powder diffraction peaks selected from about 12.6, 15.8 and 19.0 degrees 2θ.

14. 12. A pharmaceutical composition comprising a pharmaceutically effective amount of the selinexor cocrystal of claim 2 or claim 11 and a pharmaceutically acceptable excipient.

15. 13. A pharmaceutical composition comprising a pharmaceutically effective amount of the selinexor cocrystal of claim 3, claim 7, or claim 12, and a pharmaceutically acceptable excipient.

16. 16. A method of treating a disease in a patient in need thereof, comprising administering to said patient the pharmaceutical composition of claim 15.

17. 1. A process for preparing Form I of selinexor co-crystal with succinic acid, comprising: a) A saturated solution of selinexol in ethyl formate and a saturated solution of succinic acid in ethyl formate were added to approximately 1 ギ酸エチル中セリネクソール 1 to 1 ギ酸エチル中コハク酸 to form a mixed solution of selinexol and succinic acid in ethyl formate; b) Add about 1 mL of the mixture of selinexol and succinic acid in ethyl formate. ギ酸エチル中のセリネクソールとコハク酸との混合溶液 to 0.25 mmol 固体セリネクソール to 0.375 mmol 固体コハク酸 adding solid selinexol and solid succinic acid in a ratio of c) slurrying the mixed solution with the added selinexol and succinic acid; d) cooling the solution to obtain Form I of selinexor co-crystal with succinic acid; The process includes:

18. 18. The process of claim 17, wherein the slurrying is carried out at about 60°C for about 4 hours.

19. 18. The process of claim 17, wherein the cooling is performed at about -5°C to 10°C.

20. 20. The process of claim 19, wherein the cooling is performed to about 0°C.

21. 18. The process of claim 17, further comprising isolating the selinexol co-crystals with succinic acid by filtration and air drying at about 45°C for about 2-3 hours.

22. 1. A process for preparing Form II of selinexor co-crystal with succinic acid, comprising: a) mixing a selinexor solution with a succinic acid solution, wherein the solvent for the selinexor or succinic acid solution is selected from the group consisting of ethyl formate, methanol, 1-propanol, ethyl acetate, isopropanol, and acetone, or a mixture thereof, to form a mixed solution of selinexor and succinic acid, wherein the ratio of millimoles of selinexor to millimoles of succinic acid to mL of solvent for selinexor to mL of solvent for succinic acid is about 1 millimoles; セリネクソール 1 to 1.5 mmol コハク酸 For 3-4 mL セリネクソールのための溶媒 For 3-4 mL コハク酸のための溶媒 a mixing step, b) adding an anti-solvent to the mixture of selinexol and succinic acid, wherein the ratio of mL of the mixture of selinexol and succinic acid to mL of anti-solvent is about 1 mL セリネクソールとコハク酸との混合溶液 For 2 to 4 mL 抗溶媒 and c) cooling the mixture of step b) to obtain Form II of selinexor co-crystal with succinic acid; The process includes:

23. 23. The process of claim 22, further comprising preparing the selinexor solution and the succinic acid solution by dissolving selinexor or succinic acid in a single solvent or a mixture of solvents in a volume ratio of about 3:1 to 9:

1.

24. 23. The process of claim 22, wherein the solvent is 1-propanol, a mixture of 1-propanol and methanol, a mixture of ethyl acetate and methanol, or a mixture of ethyl formate and methanol.

25. 24. The process of claim 23, wherein the selinexor solution is prepared by dissolving the selinexor in a mixture of 1-propanol and methanol or a mixture of ethyl acetate and methanol.

26. 24. The process of claim 23, wherein the succinic acid solution is prepared by dissolving the succinic acid in 1-propanol, or a mixture of 1-propanol and methanol, or a mixture of ethyl acetate and methanol.

27. The anti-solvent is C ５ H １２ ~C ８ H １８ 23. The process of claim 22, wherein the alkane is

28. The alkane is ７ H １６ 28. The process of claim 27, wherein the hexane is (heptane).

29. 23. The process of claim 22, wherein the addition of the anti-solvent occurs at about room temperature.

30. 23. The process of claim 22, wherein the cooling step is carried out at about -5°C to 10°C.

31. 31. The process of claim 30, wherein the cooling step is carried out at about 0°C to 5°C.

32. 23. The process of claim 22, further comprising isolating the selinexol co-crystals with succinic acid by filtration and drying under vacuum at about 45° C. for about 8 to 12 hours.

33. 1. A process for preparing Form I of selinexor co-crystal with vanillin, comprising: a) A solution of dissolved selinexol in tetrahydrofuran and a solution of dissolved vanillin in tetrahydrofuran were added to a solution of about 1 テトラヒドロフラン中セリネクソール 1 to 1 テトラヒドロフラン中バニリン to form a mixed solution of selinexol and vanillin in tetrahydrofuran; b) To the mixture of selinexol and vanillin in tetrahydrofuran, add about 1 mL テトラヒドロフラン中のセリネクソールとバニリンとの混合溶液 to 0.25 mmol 固体セリネクソール to 0.26 mmol 固体バニリン adding solid selinexol and solid vanillin in a ratio of c) slurrying the mixed solution with the added selinexol and vanillin; d) cooling the solution to obtain Form I of selinexor co-crystal with vanillin; The process includes:

34. 34. The process of claim 33, wherein the slurrying is carried out at about 60°C for about 4 hours.

35. 34. The process of claim 33, wherein the cooling is performed at about -5°C to 10°C.

36. 36. The process of claim 35, wherein the cooling is performed to about 0°C.

37. 34. The process of claim 33, further comprising isolating the selinexol co-crystals with vanillin by filtration and air drying at about 45° C. for about 2-3 hours.

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