DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
SOLID FORMS OF SELINEXOR AND PROCESS FOR THEIR PREPARATION

INTRODUCTION
Aspects of the present application relate to solid forms of Selinexor, processes for their preparation and pharmaceutical compositions thereof. Specific aspects relate to crystalline forms and amorphous form of Selinexor.
The drug compound having the adopted name “Selinexor” has chemical name:(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-1-yl)-N'-(pyrazin-2-yl)acrylohydrazide as below.

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE™ compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. Over 1,200 patients have been treated with selinexor in company and investigator-sponsored Phase 1 and Phase 2 clinical trials in advanced hematologic malignancies and solid tumors. Karyopharm has initiated four later-phase clinical trials of selinexor, including one in older patients with acute myeloid leukemia (SOPRA), one in patients with Richter's transformation (SIRRT), one in patients with diffuse large B-cell lymphoma (SADAL) and a single-arm trial of selinexor and lose-dose dexamethasone in patients with multiple myeloma (STORM). Patients may receive a twice-weekly combination of selinexor in combination with low dose dexamethasone. Randomized 1:1, selinexor will be dosed either at 60mg + dexamethasone or at 100 mg + dexamethasone.
US 8999996 B2 discloses Selinexor and a pharmaceutically acceptable salt thereof, pharmaceutical compositions and use for treating disorders associated with CRM1 activity. Further, it discloses preparative methods for the preparation of compounds disclosed therein including Selinexor by reacting (Z)-3-(3- (3,5-bis(trifluoromethyl)phenyl)-lH-l,2,4-triazol-l-yl)acrylic acid in 1:1 CH2Cl2: AcOEt with 2-Hydrazinopyrazine at -40 °C followed by addition of T3P[Propylphosphonic anhydride] (50%) and DIPEA. After 30 minutes, the reaction mixture was concentrated and the crude oil was purified by preparative TLC using 5% MeOH in CH2Cl2 as mobile phase (under ammonia atmosphere) to afford 40 mg of Selinexor with purity: 95.78%. However, it is not disclosed about the nature of the compound obtained therein.
WO 2016025904 A1 discloses various crystalline forms of Selinexor namely Form A, Form B, Form C, Form D, compositions and MoU thereof for the treatment of disorder associated with CRM1 activity and their preparative processes.
In general, polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices. Thus, “polymorphs” refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. Different polymorphs may have different physical properties such as melting point, solubility, etc. The variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties may significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form.
For these reasons, the drug manufacturing companies put efforts into identifying all polymorphic forms of new drug substances e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers. The existence and possible numbers of polymorphic forms for a given compound may not be predicted, and there are no “standard” procedures that may be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, “Tricky Business,” Science News, Vol. 166(8), August 2004.
Hence, there remains a need for the identification of Selinexor in alternate solid form, specifically, a solid form with suitable physical properties, which may lead to its selection as the final drug substance for pharmaceutical dosage form development. Particularly, it is desirable to have an amorphous form or a crystalline form of drug to meet the needs of drug development and reproducible process for their preparation.

SUMMARY
In an aspect, the present application provides crystalline form of Selinexor.
In another aspect, the present application provides crystalline Form-Alpha of Selinexor, characterized by a PXRD pattern comprising the peaks at about 4.38, 12.45, 13.13, 15.85, 19.98 and 21.35 ±0.2° 2?. In an embodiment, the application provides crystalline form Alpha of Selinexor, characterized by a PXRD pattern having one or more additional peaks at about 14.51, 14.77, 20.30 and 27.32 ±0.2° 2?.
In another aspect, the present application provides crystalline Form-Beta of Selinexor, characterized by a PXRD pattern comprising the peaks at about 5.87, 11.73, 18.71, 20.53 and 24.05 ±0.2° 2?. In an embodiment, the application provides crystalline Form-Beta of Selinexor, characterized by a PXRD pattern having one or more additional peaks at about 16.28 and 21.28 ±0.2° 2?.
In another aspect, the present application provides crystalline Form-Gamma of Selinexor, characterized by a PXRD pattern comprising the peaks at about 3.28, 11.95, 14.62, 15.74 and 20.96 ±0.2° 2?. In an embodiment, the application provides crystalline Form-Gamma of Selinexor, characterized by a PXRD pattern having one or more additional peaks at about 16.95, 18.23, 20.01 and 22.13 ±0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline form of Selinexor or a solvate thereof, comprising the step of converting amorphous Selinexor to crystalline form of Selinexor or a solvate thereof.
In another aspect, the present application provides process for preparing a crystalline form of Selinexor, which comprises:
a) combining amorphous Selinexor with a solvent or a mixture thereof;
b) stirring the mixture of step a);
c) optionally adding an anti-solvent to the mixture of step a) or b)
d) isolating crystalline form of Selinexor.
In another aspect, the present application provides process for preparing a crystalline Form-Alpha of Selinexor, which comprises:
a) combining Selinexor with acetone: water mixture;
b) stirring the mixture of step a);
c) isolating crystalline Form-Alpha of Selinexor.
In another aspect, the present application provides an amorphous form of Selinexor.
In another aspect, the present application provides a process for the preparation of an amorphous form of Selinexor, comprising the steps of:
a) providing a solution of Selinexor in a solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous form of Selinexor.
d) optionally combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient.

In another aspect, the present application provides amorphous solid dispersion of Selinexor together with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of Selinexor, comprising the steps of:
a) providing a solution of Selinexor and atleast one pharmaceutically acceptable excipient in a solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and
c) isolating the amorphous solid dispersion of Selinexor.
d) optionally combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
In another aspect, the present application provides a pharmaceutical composition comprising the any of the solid forms of Selinexor described in the specification and atleast one pharmaceutically acceptable excipient. In embodiments, the present application provides a pharmaceutical composition comprising amorphous or crystalline forms of Selinexor and atleast one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Form-Alpha of Selinexor prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of crystalline Form-Beta of Selinexor prepared by the method of Example No 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of crystalline Form-Gamma of Selinexor prepared by the method of Example No 3.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous form of Selinexor prepared by the method of Example No 4.
Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Selinexor with povidone K-30 prepared by the method of Example No 6.
Figure 6 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Selinexor with HPMC phthalate prepared by the method of Example No 7.
Figure 7 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Selinexor with povidone K-30 and Syloid-244 FP NF prepared by the method of Example No 6.
Figure 8 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Selinexor with HPMC phthalate and Syloid-244 FP NF prepared by the method of Example No 7.
According to National Institute of Standards and Technology (NIST), for silica powder, one of the PXRD peak position is at 28.44°(2?). Silica powder was spiked to all the crystalline forms (Forms-Alpha, Beta and Gamma) of Selinexor in order to obtain accurate PXRD peak positions. In Figures (1, 2 and 3), peak at 28.44° (2?) corresponds to silica powder.

DETAILED DESCRIPTION
Aspects of the present application relate to solid forms of Selinexor, processes for their preparation and pharmaceutical compositions thereof. Specific aspects relate to crystalline forms and amorphous form of Selinexor.
In an aspect, the present application provides crystalline form of Selinexor. In embodiments, the crystalline form of Selinexor may be selected from the group comprising Form-Alpha, Form-Beta, and Form-Gamma of Selinexor or mixtures thereof.
In another aspect, the present application provides a crystalline Form-Alpha of Selinexor, characterized by a PXRD pattern comprising the peaks at about 4.38, 12.45, 13.13, 15.85, 19.98 and 21.35 ±0.2° 2?. In an embodiment, the application provides crystalline form Alpha of Selinexor, characterized by a PXRD pattern having one or more additional peaks at about 14.51, 14.77, 20.30 and 27.32 ±0.2° 2?.
In an embodiment, the present application provides a crystalline Form-Alpha of Selinexor, characterized by a PXRD pattern having peaks located substantially as shown in figure 1.
In another aspect, the present application provides crystalline Form-Beta of Selinexor, characterized by a PXRD pattern comprising the peaks at about 5.87, 11.73, 18.71, 20.53 and 24.05 ±0.2° 2?. In an embodiment, the application provides crystalline Form-Beta of Selinexor, characterized by a PXRD pattern having one or more additional peaks at about 16.28 and 21.28 ±0.2° 2?.
In an embodiment, the present application provides a crystalline Form-Beta of Selinexor, characterized by a PXRD pattern having peaks located substantially as shown in figure 2.
In another aspect, the present application provides crystalline Form-Gamma of Selinexor, characterized by a PXRD pattern comprising the peaks at about 3.28, 11.95, 14.62, 15.74 and 20.96 ±0.2° 2?. In an embodiment, the application provides crystalline Form-Gamma of Selinexor, characterized by a PXRD pattern having one or more additional peaks at about 16.95, 18.23, 20.01 and 22.13 ±0.2° 2?.
In an embodiment, the present application provides a crystalline Form-Gamma of Selinexor, characterized by a PXRD pattern having peaks located substantially as shown in figure 3.

In another aspect, the present application provides a process for the preparation of crystalline form of Selinexor or a solvate thereof, comprising the step of converting amorphous Selinexor to crystalline form of Selinexor or a solvate thereof.
In an embodiment, crystalline form of Selinexor may be selected from the group comprising of crystalline form A, Form B, Form C, Form D, Form-Alpha, Form-Beta, Form-Gamma or mixtures thereof.
In an embodiment, the step of converting amorphous Selinexor to crystalline form may be carried out by suspending or re-crystallizing amorphous Selinexor in a suitable solvent or mixture of solvents.
Re-crystallizing amorphous Selinexor may be carried out by according previous aspects or any of the methods or procedures described or exemplified in the present application. In an embodiment, amorphous Selinexor may be suspended in a suitable solvent or mixture of solvents under suitable conditions in which crystalline Form is stable.

In another aspect, the present application provides process for preparing a crystalline form of Selinexor, which comprises:
a) combining amorphous Selinexor with a solvent or a mixture thereof;
b) stirring the mixture of step a);
c) optionally adding an anti-solvent to the mixture of step a) or b)
d) isolating crystalline form of Selinexor.
In an embodiment, Selinexor that is used in step a) of this aspect may be either the amorphous form of Selinexor or by directly taking a synthetic reaction mixture comprising Selinexor and a solvent or mixture of solvents.
In an embodiment, Selinexor that is used in step a) may be purified by any methods known in the art such as column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
In an embodiment of step a), solvent may include, but not limited to water; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone; esters, such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate; alcohols, such as methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol; nitriles, such as acetonitrile and propionitrile; halogenated hydrocarbons, such as dichloromethane, chloroform and carbontetrachloride;, and dimethoxyethane; aprotic non-poplar solvents such as dimethylsulfoxide; formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl- 2-pyrrolidone; any mixtures of two or more thereof.
In an embodiment, amorphous Selinexor may be combined with solvent at any suitable temperatures, such as at about 0°C to about the reflux temperature of the solvent or mixture thereof. The mixture of Selinexor in solvent may be prepared preferably at about 0°C to 80°C.
In an embodiment the mixture of amorphous Selinexor and solvent may be either a heterogeneous or homogeneous phase.
In an embodiment, the mixture of amorphous Selinexor and solvent may be optionally filtered to make particle free solution when it is a homogeneous clear solution and treated with a decolorizing agent, such as carbon, before filtration.
In an embodiment, the mixture of amorphous Selinexor and solvent may be cooled to suitable temperature for the precipitation of crystalline Selinexor from the mixture. In an embodiment, the mixture of amorphous Selinexor and solvent may be cooled drastically or gradually with either constant rate of cooling or by step-wise cooling periodically to achieve desired nature of the crystalline Selinexor.

In an embodiment, the mixture of amorphous Selinexor and solvent may be stirred for sufficient time to complete formation of crystalline Selinexor. In an embodiment, the mixture of amorphous Selinexor and solvent may be stirred for atleast 1hour or more, preferably for atleast 24 hours or more and more preferably atleast 48 hours or more.
In an embodiment, the mixture of amorphous Selinexor and solvent may be stirred at suitable temperature for the formation of crystalline form of Selinexor. In an embodiment, the mixture of amorphous Selinexor and solvent may be stirred at 0°C and above, preferably between 0°C to reflux temperature of the solvent used, more preferably between 0°C and 50°C.
In an embodiment, optionally an anti-solvent may be added to the mixture of step a) or b). In an embodiment, anti-solvent may be added for sufficient time and at suitable temperature to complete the formation of crystalline Selinexor. Anti-solvents may include but not limited to water; aliphatic hydrocarbons, such as hexane, heptane, cyclohexane; aromatic hydrocarbons, such as toluene, xylene and chlorobenzene; ethers, such as diethyl ether, di-isopropyl ether, tetrahydrofuran, dioxane; or the like.
In an embodiment, isolation of crystalline form of Selinexor may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Selinexor may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment, isolated crystalline form of Selinexor may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In another aspect, the present application provides process for preparing a crystalline Form-Alpha of Selinexor, which comprises:
a) combining Selinexor with acetone: water mixture;
b) stirring the mixture of step a);
c) isolating crystalline Form-Alpha of Selinexor.
In an embodiment, Selinexor that is used in step a) may be purified by any methods known in the art such as column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
In an embodiment, Selinexor that is used in step a) of this aspect may be either the amorphous form or any other crystalline form of Selinexor or by directly taking a synthetic reaction mixture comprising Selinexor and acetone: water mixture.
In an embodiment, Selinexor may be combined with mixture of acetone and water at any suitable temperatures, such as at about 0°C to about the reflux temperature of the solvent mixture. The mixture of Selinexor and acetone-water solvent may be prepared preferably at about 0°C to 60°C.
In an embodiment the mixture of Selinexor and acetone-water may be either a heterogeneous or homogeneous phase.
The acetone to water ratio of the acetone-water mixture may be between about 1:1 to 20: 1, preferably between about 1:1 to 15:1
In an embodiment, the mixture of Selinexor and acetone-water may be optionally filtered to make particle free solution when it is a homogenous clear solution and treated with a decolorizing agent, such as carbon, before filtration.
In an embodiment, Selinexor that may be used in step a) of this aspect may be amorphous form of Selinexor.
In an embodiment, the mixture of Selinexor and acetone-water at step b) may be stirred for sufficient time to complete formation of crystalline Form-Alpha of Selinexor. In an embodiment, the mixture of Selinexor and acetone-water may be stirred for atleast 1hour or more, preferably for atleast 24 hours or more and more preferably atleast 48 hours or more.
In an embodiment, the mixture of Selinexor and acetone-water may be stirred at suitable temperature for the formation of crystalline Form-Alpha of Selinexor. In an embodiment, the mixture of Selinexor and acetone-water may be stirred at 0°C and above, preferably between 0°C to reflux temperature of the solvent used, more preferably between 0°C and 50°C.
In an embodiment, isolation of crystalline Form-Alpha of Selinexor may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Form-Alpha of Selinexor may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
Drying process for crystalline Form-Alpha of Selinexor may be carried out in the similar manner as described in the above aspect for crystalline Selinexor.

In another aspect, the present application provides process for preparing a crystalline Form-Beta of Selinexor, which comprises:
a) combining Selinexor with ethanol;
b) stirring the mixture of step a);
c) isolating crystalline Form-Beta of Selinexor.
In an embodiment, Selinexor that is used in step a) may be purified by any methods known in the art such as column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
In an embodiment, Selinexor that is used in step a) of this aspect may be either the amorphous form or any other crystalline form of Selinexor or by directly taking a synthetic reaction mixture comprising Selinexor and ethanol.
In an embodiment, Selinexor may be combined with ethanol at any suitable temperatures, such as at about 0°C to about the reflux temperature of the ethanol. The mixture of Selinexor and ethanol may be prepared preferably at about 0°C to 60°C.
In an embodiment the mixture of Selinexor and ethanol may be either a heterogeneous or homogeneous phase.
In an embodiment, the mixture of Selinexor and ethanol may be optionally filtered to make particle free solution when it is a homogenous clear solution and treated with a decolorizing agent, such as carbon, before filtration.
In an embodiment, Selinexor that may be used in step a) of this aspect may be amorphous form of Selinexor.
In an embodiment, the mixture of Selinexor and ethanol at step b) may be stirred for sufficient time to complete formation of crystalline Form-Beta of Selinexor. In an embodiment, the mixture of Selinexor and ethanol may be stirred for atleast 1hour or more, preferably for atleast 24 hours or more and more preferably atleast 48 hours or more.
In an embodiment, the mixture of Selinexor and ethanol may be stirred at suitable temperature for the formation of crystalline Form-Beta of Selinexor.
In an embodiment, the mixture of Selinexor and ethanol may be stirred at 0°C and above, preferably between 0°C to reflux temperature of the solvent used, more preferably between 0°C and 50°C.
In an embodiment, isolation of crystalline Form-Beta of Selinexor may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Form-Beta of Selinexor may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
Drying process for crystalline Form-Beta of Selinexor may be carried out in the similar manner as described in the above aspect for crystalline Selinexor.

In another aspect, the present application provides process for preparing a crystalline Form-Gamma of Selinexor, which comprises:
a) combining Selinexor with water;
b) stirring the mixture of step a);
c) isolating crystalline Form-Gamma of Selinexor.

In an embodiment, Selinexor that is used in step a) may be purified by any methods known in the art such as column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
In an embodiment, Selinexor that is used in step a) of this aspect may be either the amorphous form or any other crystalline form of Selinexor or by directly taking a synthetic reaction mixture comprising Selinexor and water.
In an embodiment, Selinexor may be combined with water at any suitable temperatures, such as at about 0°C to about the reflux temperature of water. The mixture of Selinexor and water may be prepared preferably at about 0°C to 60°C.
In an embodiment the mixture of Selinexor and water may be either a heterogeneous or homogeneous phase.
In an embodiment, the mixture of Selinexor and water may be optionally filtered to make particle free solution when it is a homogenous clear solution and treated with a decolorizing agent, such as carbon, before filtration.
In an embodiment, Selinexor that may be used in step a) of this aspect may be amorphous form of Selinexor.
In an embodiment, the mixture of Selinexor and water at step b) may be stirred for sufficient time to complete formation of crystalline Form-Gamma of Selinexor. In an embodiment, the mixture of Selinexor and water may be stirred for atleast 1hour or more, preferably for atleast 24 hours or more and more preferably atleast 48 hours or more.
In an embodiment, the mixture of Selinexor and water may be stirred at suitable temperature for the formation of crystalline Form-Beta of Selinexor. In an embodiment, the mixture of Selinexor and water may be stirred at 0°C and above, preferably between 0°C to reflux temperature of water, more preferably between 0°C and 50°C.
In an embodiment, isolation of crystalline Form-Gamma of Selinexor may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, crystalline Form-Gamma of Selinexor may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
Drying process for crystalline Form-Gamma of Selinexor may be carried out in the similar manner as described in the above aspect for crystalline Selinexor.

In another aspect, the present application provides an amorphous form of Selinexor.
In an embodiment, the present application provides an amorphous form of Selinexor characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 4.
In another aspect, the present application provides a process for the preparation of an amorphous form of Selinexor, comprising the steps of:
a) providing a solution of Selinexor in a solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous form of Selinexor.
d) optionally combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient
In an embodiment, Selinexor that is used in step a) may be purified by any methods known in the art such as column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
In an embodiment, Selinexor that is used in step a) of this aspect may be either a crystalline form of Selinexor or by directly taking a synthetic reaction mixture comprising Selinexor and a solvent or a mixture of solvents.
In an embodiment, solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
In preferred embodiment, the solvent may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate; water and mixtures thereof.
In an embodiment, suitable solvent at step a) may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; or mixtures thereof.
In an embodiment, providing a solution at step a) may be carried out by dissolving Selinexor in a solvent or by taking the reaction mixture containing Selinexor directly. In an embodiment, a solution of Selinexor can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Selinexor may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, thin film drying, agitated thin film drying and the like.
In preferred embodiment, the solvent may be removed under reduced pressures and at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
In an embodiment, the isolation of an amorphous form of Selinexor at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used. In an embodiment, the amorphous form of Selinexor obtained from step b) may be optionally dried before or after isolating it at step c).
Amorphous form of Selinexor obtained at step c) may be optionally combined with atleast one pharmaceutically acceptable excipient at step d).
In an embodiment, amorphous form of Selinexor may be combined with excipient using a technique known in art or by the procedures disclosed in the present application.
In preferred embodiment, amorphous form of Selinexor may be combined with excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous form of Selinexor and atleast one pharmaceutically acceptable excipient.
In an embodiment, amorphous form of Selinexor may be combined with the excipient by evaporating the suspension or solution of amorphous form of Selinexor and atleast one pharmaceutically acceptable excipient.
In an embodiment, pharmaceutically acceptable excipient may include, but not limited to an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.
In preferred embodiment, pharmaceutically acceptable excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica; copolymers, such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose.
Amorphous form of Selinexor isolated at step c) or d) may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In an aspect, the present application provides pharmaceutical composition comprising amorphous form of Selinexor and atleast one pharmaceutically acceptable excipient.
In an aspect, the present application provides amorphous solid dispersion of Selinexor together with atleast one pharmaceutically acceptable excipient.
In an embodiment, the present application provides amorphous solid dispersion of Selinexor together with atleast one pharmaceutically acceptable excipient characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 5,6, 7 & 8.
In another aspect, the present application provides a process for the preparation of an amorphous solid dispersion of Selinexor, comprising the steps of:
a) providing a solution of Selinexor and atleast one pharmaceutically acceptable excipient in a solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a), and
c) isolating the amorphous solid dispersion of Selinexor.
d) optionally combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.

In an embodiment, Selinexor that is used in step a) may be purified by any methods known in the art such as column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
In an embodiment, Selinexor that is used in step a) of this aspect may be either a crystalline form of Selinexor or by directly taking a synthetic reaction mixture comprising Selinexor and a solvent or a mixture of solvents.
In an embodiment, solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
In preferred embodiment, the solvent may be selected from the group consisting of alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate; water and mixtures thereof.
In an embodiment, suitable solvent at step a) may be selected from the group comprising of alcohol solvents such as methanol, ethanol, 2-propanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; or mixtures thereof.
In an embodiment, atleast one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl ellulose acetate succinate, hydroxypropylmethyl ellulose, hydroxypropyl cellulose SL, hydroxyethyl cellulose, gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.
In an embodiment, providing a solution at step a) may be carried out by dissolving Selinexor and atleast one pharmaceutically acceptable excipient in a solvent simultaneously or by dissolving components in a solvent separately to form individual solutions and combining those solutions later.
In an embodiment, a solution of Selinexor and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Selinexor and the excipient may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying, agitated thin film drying and the like.
In preferred embodiment, the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.
In an embodiment, the isolation of an amorphous solid dispersion of Selinexor and excipient at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
In an embodiment, the amorphous solid dispersion of Selinexor and excipient obtained from step b) may be optionally dried before or after isolating at step c).
Amorphous solid dispersion of Selinexor obtained at step c) may be optionally combined with atleast one additional pharmaceutically acceptable excipient at step d).
In an embodiment, amorphous solid dispersion of Selinexor may be combined with additional excipient using a technique known in art or by the procedures disclosed in the present application.
In preferred embodiment, amorphous solid dispersion of the present application may be combined with additional excipient either by physical blending of both the solid components or by suspending both the components in a solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous solid dispersion of Selinexor with pharmaceutically acceptable excipient and atleast one additional pharmaceutically acceptable excipient.
In an embodiment, amorphous solid dispersion of the present application may be combined with additional excipient by evaporating the suspension or solution of amorphous solid dispersion of Selinexor and additional excipient.
In an embodiment, pharmaceutically acceptable additional excipient may be same or different from the excipient used in the preparation of amorphous solid dispersion of Selinexor. Additional excipient may include, but not limited to an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.
In preferred embodiment, pharmaceutically acceptable additional excipient may be selected from the group consisting of silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous silica; copolymers, such as polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose, preferably microcrystalline cellulose.
Amorphous solid dispersion of Selinexor isolated at step c) or d) may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In an aspect, the present application provides pharmaceutical composition comprising amorphous solid dispersion of Selinexor with atleast one pharmaceutically acceptable excipient and atleast one additional pharmaceutically acceptable excipient.
In an aspect, the present application provides pharmaceutical compositions comprising amorphous Selinexor and atleast one pharmaceutically acceptable excipient, in particular in the form of solid dispersions and adsorbates, and a process for preparing the same. In embodiments, the pharmaceutically acceptable excipient is selected from the excipients at any aspect of present application.
In embodiments, the present application provides adsorbates, wherein Selinexor is associated with a substrate. Substrate may be a particulate and/or porous substrate, wherein this substrate has an outer and/or inner surface onto which the API may be adsorbed. This means that if the substrate has pores, these pores are filled by the Selinexor and the substrate remains unaffected, it does not, at least not essentially, change during and / or after the adsorption. In embodiments, the substrate is selected from the excipients at any aspect of present application.
Amorphous form of Selinexor or its solid dispersion may be obtained alternatively either by employing a melt-extrusion technique or by combining a solution of Selinexor as obtained any of the aspects of present application with a anti-solvent. In embodiment, amorphous product may be obtained by employing suitable melt-extrusion conditions or any of the procedures known in the art for obtaining amorphous product by melt-extrusion technique. In embodiment, solution of Selinexor may be combined with the anti-solvent at suitable temperature and for sufficient time to obtain amorphous product. Anti-solvent is a solvent, wherein Selinexor has low solubility and it may include, but not limited to aliphatic or cyclic ethers solvents, aliphatic or aromatic hydrocarbons or the like.
In an aspect, the present application provides pharmaceutical composition comprising Selinexor and atleast one pharmaceutically acceptable excipient, wherein Selinexor may be selected from group comprising of crystalline Form-Alpha, Form-Beta, Form-Gamma and amorphous form of Selinexor or mixtures thereof.
In another aspect, the present application provides crystalline form of Selinexor or its pharmaceutical composition comprising Selinexor having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
In another aspect, the present application provides amorphous form, its solid dispersion or its pharmaceutical composition comprising Selinexor having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
X-ray powder diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer or PANalytical X’pert pro X-ray diffractometer with a copper K-alpha radiation source. Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ±0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2?) ±0.2° of 6.3°" means "having a diffraction peak at a diffraction angle (2?) of 6.1° to 6.5°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peak relationships and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the PXRD peaks may vary somewhat, depending on factors such as the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrumental variation and other factors may slightly affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments may vary by plus or minus about 0.2°. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a filter is used or not).
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and
referring to it, is meant to designate any value which lies within the range of ±10%,
preferably within a range of ±5%, more preferably within a range of ±2%, still more
preferably within a range of ±1 % of its value. For example "about 10" should be
construed as meaning within the range of 9 to 11 , preferably within the range of 9.5
to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably
within the range of 9.9 to 10.1.
The term “solvent” when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
The terms “crystalline form of Selinexor” or “crystalline Selinexor” includes solvates, hydrates, and anhydrates of Selinexor. The percent crystallinity of any of the crystalline forms of Selinexor described herein can vary with respect to the total amount of Selinexor. In particular, certain embodiments provide for the percent crystallinity of a crystalline form of Selinexor being at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least, 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. In some embodiments, the percent crystallinity can be substantially 100%, where substantially 100% indicates that the entire amount of Selinexor appears to be crystalline as best can be determined using methods known in the art.
The terms “amorphous form of Selinexor" and “amorphous Selinexor” indicate that the Selinexor is present in substantially amorphous state in the composition (e.g. solid dispersion, adsorbate or pharmaceutical composition). "Substantially" amorphous denotes that 90 %, preferably 95 % or 99 %, more preferably all of the Selinexor being present in the solid dispersion, on the adsorbate or in the pharmaceutical composition is amorphous. In other words, an "amorphous" Selinexor composition denotes a Selinexor-containing composition, which does not contain substantial amounts, preferably does not contain noticeable amounts, of crystalline portions of Selinexor e.g. measurable upon X-ray powder diffraction analysis.
The term "solid dispersion" when used in the present application, denotes a state where most of the Selinexor, preferably 90%, 95% or all of the Selinexor of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a solvent at least at one time point during preparation of said solid dispersion.
The term "adsorbate" when used in the present application, specifies that the Selinexor is, preferably evenly, and preferably homogeneously, distributed on the inner and/or outer surface of the particulate substrate.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called“aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.
EXAMPLES
Example-1: Preparation of Form-Alpha of Selinexor
A mixture of amorphous Selinexor (0.2 g) and 9:1 acetone: water (1mL) was stirred at 25°C for 54 hours and filtered the solid and dried in air tray drier at 40°C for 1 hour 20 minutes to obtain the title compound.
Example-2: Preparation of Form-Beta of Selinexor.
A mixture of amorphous Selinexor (0.2 g) and ethanol (1mL) was stirred at 25°C for 54 hours and filtered the solid and dried in air tray drier at 40°C for 1 hour to obtain the title compound.
Example-3: Preparation of Form-Gamma of Selinexor
A mixture of amorphous Selinexor (0.2 g) and water (1mL) was stirred at 25°C for 55 hours and filtered the solid and dried in air tray drier at 40°C for 1 hour 10 minutes to obtain the title compound.
Example-4: Preparation of amorphous form of Selinexor
Selinexor (0.3 g) was dissolved in methanol (10 mL) at 50°C. The clear solution was evaporated in a rotavapour at 60°C under vacuum to obtain the title compound.
Example-5: Preparation of amorphous form of Selinexor
Selinexor (0.3 g) was dissolved in acetone (10 mL) at 50°C. The clear solution was evaporated in a rotavapour at 60°C under vacuum to obtain the title compound. XRD: Amorphous
Example-6: Preparation of amorphous solid dispersion of Selinexor and Povidone
Selinexor (0.3 g) and povidone K-30 (0.3 g) was dissolved in methanol (15 mL) at 60°C. The clear solution was evaporated in a rotavapour at 60°C under vacuum to obtain the amorphous solid dispersion. Above obtained solid dispersion (150 mg) was combined with Syloid (75 mg) by gently grinding the mixture in a mortar and pestle for 10 minutes. XRD: Amorphous
Example-7: Preparation of amorphous solid dispersion of Selinexor and HPMC phthalate
Selinexor (0.3 g) and HPMC phthalate (0.3 g) was dissolved in methanol (15 mL) at 60°C. The clear solution was evaporated in a rotavapour at 60°C under vacuum to obtain the amorphous solid dispersion. Above obtained solid dispersion (500 mg) was combined with Syloid (500 mg) by gently grinding the mixture in a mortar and pestle for 10 minutes. XRD: Amorphous
,CLAIMS:We Claim:
1. An amorphous form of Selinexor.
2. An amorphous solid dispersion of Selinexor together with atleast one pharmaceutically acceptable excipient.
3. An amorphous solid dispersion of claim 5, wherein the pharmaceutically acceptable excipient is selected from the group comprising of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose SL, hydroxyethyl cellulose, ethyl cellulose.
4. A process for the preparation of an amorphous form of Selinexor of clam 1, comprising the steps of:
a. providing a solution of Selinexor in a solvent or a mixture thereof;
b. removing the solvent from the solution obtained in step a); and
c. isolating the amorphous form of Selinexor.
d. optionally, combining amorphous form of step c) with atleast one pharmaceutically acceptable excipient.
5. A process of claim 6, wherein solvent at step a) is selected from the group comprising of methanol, ethanol, 2-propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof.
6. A process for the preparation of crystalline form of Selinexor or a solvate thereof, comprising the step of converting amorphous Selinexor to crystalline form of Selinexor or a solvate thereof.
7. A process for the preparation of an amorphous solid dispersion of Selinexor of claim 4, comprising the steps of:
a. providing a solution of Selinexor and atleast one pharmaceutically acceptable excipient in a solvent or a mixture thereof;
b. removing the solvent from the solution obtained in step a), and
c. isolating the amorphous solid dispersion of Selinexor.
d. optionally, combining amorphous solid dispersion of step c) with atleast one additional pharmaceutically acceptable excipient.
8. A process of claim 9, wherein solvent at step a) is selected from the group comprising of methanol, ethanol, 2-propanol, acetone, methyl ethyl ketone, methyl isobutyl ketone or mixtures thereof.
9. A pharmaceutical composition comprising amorphous form of Selinexor or amorphous solid dispersion of Selinexor together with atleast one pharmaceutically acceptable excipient and atleast one additional one pharmaceutically acceptable excipient.
10. A pharmaceutical composition comprising amorphous form or amorphous solid dispersion of Selinexor and atleast one additional pharmaceutically acceptable excipient, wherein the additional excipient is selected from the group comprising of colloidal silicon dioxide, fumed silicon dioxide, porous silica, polyethylene or polyvinyl alcohol copolymer, polyethylene or polyvinyl pyrrolidinone copolymer and microcrystalline cellulose.