WO2023175622A1

WO2023175622A1 - Crystalline forms of aspacytarabine

Info

Publication number: WO2023175622A1
Application number: PCT/IL2023/050280
Authority: WO
Inventors: Ramy Lidor-Hadas; Margarita Shumilov; Shoshi Tessler
Original assignee: Biosight Ltd.
Priority date: 2022-03-17
Filing date: 2023-03-16
Publication date: 2023-09-21

Abstract

The present invention relates to novel crystalline polymorphs, Form C and Form D, of (S)-2-amino-4-((1-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (also known as BST-236, Astarabine® or Aspacytarabine), processes of preparation thereof, and uses thereof for the treatment of neoplastic diseases.

Description

CRYSTALLINE FORMS OF ASPACYTARABINE

FIELD OF THE INVENTION

[001] The present invention relates to two novel crystalline polymorphs of (S)-2-amino-4-(( l - ((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (also known as BST-236, Astarabine® or Aspacytarabine), processes of preparation thereof, and uses thereof for the treatment of neoplastic diseases.

BACKGROUND OF THE INVENTION

[002] International Patent Application Publication No. WO/2017/093993 teaches prodrugs comprising cytarabine conjugated to a single amino acid selected from the group consisting of aspartic acid, glutamic acid, asparagine, and glutamine, for use in treating neoplastic diseases in medically compromised subjects. Aspacytarabine is a conjugate of cytarabine and aspartic acid wherein cytarabine is covalently attached to the carboxyl group of the side chain of aspartic acid. It is useful for treatment neoplastic diseases including hematological cancers such as leukemias thereby prolonging the survival of the patients in need of the treatment.

[003] Polymorphs, solvates, and salts of various drugs have been described in the literature as imparting novel properties to the drugs. Organic small drug molecules have a tendency to selfassemble into various polymorphic forms depending on the environment that drives the selfassembly.

[004] Identifying which polymorphic form is the most stable under each condition of interest and the processes that lead to changes in the polymorphic form is crucial to the design of the drug manufacturing process in order to ensure that the final product is in its preferred polymorphic form. Different polymorphic forms of an active pharmaceutical ingredient (API) can lead to changes in the drug’s solubility, dissolution rate, pharmacokinetics and ultimately its bioavailability and efficacy in patients.

[005] Solid materials can be in an amorphous form that lacks the long-range order that is characteristic of a crystal solid. Crystalline materials may have more than one form of crystal structure that differs in the arrangements or conformations of the molecules in the crystal lattice.

[006] The crystalline forms and amorphous form of drug molecules have similar chemical structures, molecular formulas, and molecular configurations, but differ in physicochemical properties like stability and solubility. Crystallization may increase the stability of amorphous drug substances. For example, amorphous penicillin G is less stable than crystalline salt and Amitriptyline is more stable in crystalline form than in amorphous form.

[007] One crystalline polymorph of Aspacytarabine (Form B) is disclosed in International Patent Application No. PCT/IL2021/051144.

[008] This invention provides two new crystalline polymorphs of Aspacytarabine and process of preparation thereof to ensure reproducible manufacturing of Aspacytarabine.

SUMMARY OF THE INVENTION

[009] In one aspect, this invention relates to crystalline polymorph (Form C) of (S)-2-amino- 4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine).

[0010] In some embodiments, the crystalline polymorph (Form C) of Aspacytarabine is characterized by X-Ray Powder diffraction pattern comprising unique peaks at °29 ±0.2 (d value A); 17.8 (5.0), 19.1 (4.6), 19.3 (4.6), 19.8 (4.5) and 21.5 (4.1), obtained with a Cu tube anode with Ka radiation. In other embodiments, the crystalline polymorph of Aspacytarabine is characterized by X-Ray Powder diffraction pattern comprising unique peaks at °29 ±0.2 (d value A); 16.9 (5.2), 17.8 (5.0), 19.1 (4.6), 19.3 (4.6), 19.8 (4.5), 21.0 (4.2), 21.5 (4.1), 25.4 (3.5) and 26.3 (3.4), obtained with a Cu tube anode with K- a radiation.

[0011] In one aspect, this invention relates to crystalline polymorph (Form D) of (S)-2-amino- 4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine).

[0012] In some embodiments, the crystalline polymorph (Form D) of Aspacytarabine is characterized by X-Ray Powder diffraction pattern comprising unique peaks at °29 ±0.2 (d value A); 17.1 (5.2), 19.3 (4.6), and 25.5 (3.5), obtained with a Cu tube anode with Ka radiation. In other embodiments, the crystalline polymorph of Aspacytarabine is characterized by X-Ray Powder diffraction pattern comprising unique peaks at °29 ±0.2 (d value A); 13.3 (6.7), 17.1 (5.2), 19.3 (4.6), 21.3 (4.2), 25.5 (3.5), 26.9 (3.3) and 27.2 (3.3), obtained with a Cu tube anode with K- a radiation.

[0013] In one aspect, this invention provides a composition comprising a crystalline polymorph (FormC) of (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5 (hydroxymethyl)tetrahydrofuran- 2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine) of the invention and a pharmaceutically acceptable carrier. [0014] In one aspect, this invention provides a composition comprising a crystalline polymorph (Form D) of (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5

(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine) of the invention and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE FIGURES

[0015] The subject matter regarded as the present invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The present invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:

[0016] Figure 1 depicts the XRPD pattern of amorphous Aspacytarabine form.

[0017] Figure 2 depicts the XRPD pattern of Aspacytarabine crystalline polymorph (Form C) measured by Bruker AXS D2 diffractometer using Cu Ka radiation (30 kV, 10 mA), 9-9 geometry, using a LynxEye detector from 5-42 °29.

[0018] Figure 3 depicts DSC of Aspacytarabine crystalline polymorph Form C that was measured by Mettler DSC 3+ equipped with a 34-position auto-sampler. The instrument was calibrated for energy and temperature using certified indium. 0.5-3 mg of each sample, in a pin- holed aluminum pan, was heated at 10 °C/min from 30 °C to 300 °C. (A nitrogen purge at 50 mL.min'¹ was maintained over the sample.)

[0019] Figure 4 depicts TGA of Aspacytarabine crystalline polymorph Form C that was measured by Mettler TGA 2 equipped with a 34position auto-sampler. The instrument was temperature calibrated using certified nickel and isotherm. Typically, 5-30 mg of each sample was loaded into a pin-holed aluminum pan and heated at 10°C/min from 30 °C to 400 °C (A nitrogen purge at 50 mL.min'¹ was maintained over the sample).

[0020] Figure 5 depicts SEM images of Aspacytarabine crystalline polymorph Form C that were acquired using a CamScan MX2600 Scanning Electron Microscope using an SEI or BSC detector. [0021] Figure 6 depicts the XRPD pattern of Aspacytarabine crystalline polymorph Form D measured by Bruker AXS D2 diffractometer using Cu Ka radiation (30 kV, 10 mA), 9-9 geometry, using a LynxEye detector from 5-42 °29.

[0022] Figure 7 depicts DSC experiment (see example 5.2) on Aspacytarabine crystalline polymorph Form B, which resulted in the formation of Aspacytarabine crystalline polymorph Form D. The upper curve refers to the heating of Aspacytarabine crystalline polymorph Form B to 155°C and the lower curve refers to the cooling from 155°C.

[0023] Figure 8 depicts DSC of Aspacytarabine crystalline polymorph Form D.

[0024] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.

DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention provides crystalline polymorph Form C and crystalline polymorph Form D of (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine).

[0026] The present invention provides a crystalline polymorph Form C of (S)-2-amino-4-(( l - ((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine).

[0027] In some embodiments, the crystalline polymorph Form C of Aspacytarabine is an anhydrous crystalline form. In another embodiment, the crystalline polymorph Form C of the compound is a hydrate crystalline form. In another embodiment, the crystalline polymorph Form C of the compound is a solvate crystalline form. In another embodiment, the crystalline polymorph Form C of the compound is a salt crystalline form.

[0028] In some embodiments, the crystalline polymorph Form C of Aspacytarabine is characterized by X-Ray Powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 17.8 (5.0), 19.3 (4.6), and 19.8 (4.5), obtained with a Cu tube anode with K- a radiation.

[0029] In some embodiments, the crystalline polymorph Form C of Aspacytarabine is characterized by X-Ray Powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 17.8 (5.0), 19.3 (4.6), 19.8 (4.5), and 21.5 (4.1), obtained with a Cu tube anode with K- a radiation.

[0030] In some embodiments, the crystalline polymorph Form C of Aspacytarabine is characterized by X-Ray Powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 17.8 (5.0), 19.1 (4.6), 19.3 (4.6), 19.8 (4.5) and 21.5 (4.1) obtained with a Cu tube anode with K- a radiation. [0031] In some embodiments, the crystalline polymorph Form C is characterized by X-Ray powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 17.8 (5.0), 19.1 (4.6),

19.3 (4.6), 19.8 (4.5), and 21.5 (4.1), obtained with a Cu tube anode with K- a radiation.

[0032] In some embodiments, the crystalline polymorph Form C is characterized by X-Ray powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 17.8 (5.0), 19.1 (4.6),

19.3 (4.6), 19.8 (4.5), 21.0 (4.2), 21.5 (4.1), 25.4 (3.5) and 26.3 (3.4), obtained with a Cu tube anode with K- a radiation.

[0033] In some embodiments, the crystalline polymorph Form C is characterized by X-Ray powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 16.9 (5.2), 17.8 (5.0), 19.1 (4.6), 19.3 (4.6), 19.8 (4.5), 21.0 (4.2), 21.5 (4.1), 25.4 (3.5) and 26.3 (3.4), obtained with a Cu tube anode with K- a radiation.

[0034] In other embodiments, the crystalline polymorph Form C of Aspacytarabine is characterized by an X-Ray Powder diffraction pattern as shown in Figure 2.

[0035] In some embodiments, the crystalline polymorph Form C of Aspacytarabine is characterized by DSC as shown in Figure 3.

[0036] In some embodiments, the crystalline polymorph Form C of Aspacytarabine is characterized by TGA as shown in Figure 4.

[0037] In some embodiments, the crystalline polymorph Form C of Aspacytarabine is characterized by SEM as shown in Figure 5.

[0038] The present invention provides a crystalline polymorph Form D of (S)-2-amino-4-(( l - ((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine).

[0039] In some embodiments, the crystalline polymorph Form D of Aspacytarabine is an anhydrous crystalline form. In another embodiment, the crystalline polymorph (Form D) of the compound is a hydrate crystalline form. In another embodiment, the crystalline polymorph (Form D) of the compound is a solvate crystalline form. In another embodiment, the crystalline polymorph (Form D) of the compound is a salt crystalline form.

[0040] In some embodiments, the crystalline polymorph Form D of Aspacytarabine is characterized by X-Ray Powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 17.1 (5.2), 19.3 (4.6), and 25.5 (3.5), obtained with a Cu tube anode with K- a radiation.

[0041] In some embodiments, the crystalline polymorph Form D is characterized by X-Ray powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 13.3 (6.7), 17.1 (5.2),

19.3 (4.6), 21.3 (4.2), and 25.5 (3.5), obtained with a Cu tube anode with K- a radiation. [0042] In some embodiments, the crystalline polymorph Form D is characterized by X-Ray powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 17.1 (5.2), 19.3 (4.6) and 25.5 (3.5), obtained with a Cu tube anode with K- a radiation.

[0043] In some embodiments, the crystalline polymorph Form D is characterized by X-Ray powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 17.1 (5.2), 19.3 (4.6), 21.3 (4.2), 25.5 (3.5), and 26.9 (3.3), obtained with a Cu tube anode with K- a radiation.

[0044] In some embodiments, the crystalline polymorph Form D of Aspacytarabine is characterized by X-Ray powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 13.3 (6.7), 17.1 (5.2), 19.3 (4.6), 21.3 (4.2), 25.5 (3.5), 26.9 (3.3) and 27.2 (3.3), obtained with a Cu tube anode with K- a radiation.

[0045] In other embodiments, the crystalline polymorph Form D of Aspacytarabine is characterized by an X-Ray Powder diffraction pattern as shown in Figure 6.

[0046] In some embodiments, the crystalline polymorph Form D of Aspacytarabine is characterized by DSC as shown in Figure 8.

[0047] In some embodiments, the chemical purity of the crystalline polymorphs of Aspacytarabine of this invention - Form C or Form D of the invention is more than 90%. In some embodiments, the chemical purity of the crystalline polymorphs of Aspacytarabine of this invention is more than 92%. In some embodiments, the chemical purity of the crystalline polymorphs of Aspacytarabine of this invention is more than 95%. In some embodiments, the chemical purity of the crystalline polymorphs of Aspacytarabine of this invention is more than 98%. In some embodiments, the chemical purity of the crystalline polymorphs of Aspacytarabine of this invention is more than 99%. In some embodiments, the chemical purity of the crystalline polymorphs of Aspacytarabine of this invention is from about 95% to about 100%. In some embodiments, the chemical purity of the crystalline polymorphs of Aspacytarabine of this invention is from about 96% to about 100%. In some embodiments, the chemical purity of the crystalline polymorphs of Aspacytarabine of this invention is from about 97% to about 100%. In some embodiments, the chemical purity of the crystalline polymorphs of Aspacytarabine of this invention is from about 98% to about 100%. In some embodiments, the chemical purity of the crystalline polymorphs of Aspacytarabine of this invention is from about 99% to about 100%. In some embodiments, the chemical purity of the crystalline polymorphs of Aspacytarabine of this invention is about 99%.

[0048] In some embodiments, the water solubility of the crystalline polymorph Form C of Aspacytarabine is at least 20mg per ImL. In some embodiments, the water solubility of the crystalline polymorph Form C of Aspacytarabine is about 25mg per ImL. In some embodiments, the water solubility of the crystalline polymorph Form C of Aspacytarabine is between 20-30 mg per 1 mL. In some embodiments, the water solubility of the crystalline polymorph Form C of Aspacytarabine is between 20- 25mg per ImL. In some embodiments, the water solubility of the crystalline polymorph Form C of Aspacytarabine is between 25- 30 mg per ImL.

[0049] In some embodiments, the water solubility of the crystalline polymorph Form D of Aspacytarabine is at least 20mg per ImL. In some embodiments, the water solubility of the crystalline polymorph Form D of Aspacytarabine is about 25mg per ImL. In some embodiments, the water solubility of the crystalline polymorph Form D of Aspacytarabine is between 20-30 mg per 1 mL. In some embodiments, the water solubility of the crystalline polymorph Form D of Aspacytarabine is between 20- 25mg per ImL. In some embodiments, the water solubility of the crystalline polymorph Form D of Aspacytarabine is between 25- 30 mg per ImL.

[0050] In some embodiments, the crystalline polymorph Form C of Aspacytarabine is stable (no changes in the form checked by XRPD) at room temperature for at least 7 days.

[0051] In some embodiments, the crystalline polymorph Form C of Aspacytarabine is stable (no changes in the form checked by XRPD) at 40 C and 75% relative humidity for at least 7 days. In some embodiments, the crystalline polymorph Form C of Aspacytarabine is stable (no changes in the form checked by XRPD) at 25 C and 96% relative humidity for at least 7 days.

[0052] In some embodiments, a slurry of a mixture of crystalline polymorph Form C of Aspacytarabine and crystalline polymorph Form B of Aspacytarabine in EtOH containing 20% water resulted in a conversion of Form C to Form B. In one embodiment, the crystalline polymorph Form B of Aspacytarabine is characterized by an X-Ray Powder diffraction pattern comprising unique peaks at 20° ±0.2 (d value A); 12.7 (7.0), 12.9 (6.9), 16.5 (5.4), 19.9 (4.5) and 20.9 (4.2) when obtained with a Cu tube anode with K- a radiation.

[0053] In some embodiments, a slurry of a mixture of crystalline polymorph Form C of Aspacytarabine and crystalline polymorph Form B of Aspacytarabine in EtOH containing 20% water resulted in a conversion of Form C to Form B after 5 days at 50 °C and after 6 weeks at room temperature.

[0054] In some embodiments, a slurry of a mixture of crystalline polymorph Form C of Aspacytarabine and crystalline polymorph Form B of Aspacytarabine in EtOAc saturated with water converted to Form B. [0055] In some embodiments, a slurry of a mixture of crystalline polymorph Form C of Aspacytarabine and crystalline polymorph Form B of Aspacytarabine in EtOAc saturated with water at 50 °C and room temperature converted to Form B after 6 weeks.

[0056] In some embodiments, crystalline polymorph Form C of Aspacytarabine is metastable to crystalline polymorph Form B of Aspacytarabine at 50 °C. In some embodiments, crystalline polymorph Form C of Aspacytarabine is metastable to crystalline polymorph Form B of Aspacytarabine at room temperature.

[0057] In some embodiments, the crystalline polymorph Form C of Aspacytarabine is converted into a crystalline polymorph Form B by mixing Form C in water or saline at room temperature to obtain Form B.

[0058] In some embodiments, the crystalline polymorph Form D of Aspacytarabine is converted to Form B at room temperature in about 12h.

[0059] In some embodiments, the crystalline polymorph Form C and/or Form D of f S)-2-amino- 4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine) of this invention is used for the preparation of (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid salt thereof (Aspacytarabine-salt).

[0060] In some embodiment, this invention provides a process for the preparation of (S)-2- amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid-salt (Aspacytarabine-salt), wherein the salt is prepared by reacting the crystalline polymorph of Aspacytarabine, Form C and/or Form D, of this invention with a strong acid.

[0061] In another embodiment the Aspacytarabine-salt comprises a strong acid salt. In another embodiment the salt is selected from the group consisting of, hydrochloride salt, hydrobromide salt, TFA salt, methanesulfonate salt, phosphate salt, toluenesulfonate salt, benzenesulfonate salt, bisulfate salt and sulfate salt. In one embodiment, the salt is a hydrochloride salt. In one embodiment, the salt is a hydrobromide salt. In one embodiment, the salt is a TFA salt. Each possibility represents a separate embodiment of the invention. In another embodiment, the Aspacytarabine-salt is soluble in water. Aspacytarabine Pharmaceutical Compositions

[0062] According to one aspect, the present invention provides a pharmaceutical composition comprising a crystalline polymorph, Form C and/or Form D, of (S)-2-amino-4-((l- ((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine) of the invention and a pharmaceutically acceptable carrier. In one embodiment, the present invention provides a pharmaceutical composition comprising a crystalline polymorph, Form C, of (S)-2-amino-4-((l- ((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine) of the invention and a pharmaceutically acceptable carrier. In another embodiment, the present invention provides a pharmaceutical composition comprising a crystalline polymorph, Form D, of (S)-2-amino-4-((l- ((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine) of the invention and a pharmaceutically acceptable carrier. In another embodiment, the present invention provides a pharmaceutical composition comprising a crystalline polymorphs, Form C and Form D, of (S)-2- amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine) of the invention and a pharmaceutically acceptable carrier.

[0063] In some embodiments, this invention provides a pharmaceutical composition comprising a combination of crystalline polymorph, Form C and/or Form D, of Aspacytarabine and an amorphous form of Aspacytarabine and a pharmaceutically acceptable carrier. Each possibility represents a separate embodiment of this invention. In other embodiments, the weight ratio between the crystalline polymorph and the amorphous form is in the range of between 10:1 to 1:10. In another embodiment the weight ratio between the crystalline polymorph and the amorphous form is 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3 or 1:2 or any ranges thereof. Each possibility represents a separate embodiment of this invention.

[0064] In some embodiments, this invention provides a pharmaceutical composition comprising a combination of crystalline polymorphs Form C and Form D of Aspacytarabine. In other embodiments, the weight ratio between the crystalline polymorphs Form C and Form D is in the range of between 10:1 to 1:10.

[0065] In some embodiments, this invention provides a pharmaceutical composition comprising a combination of crystalline polymorphs Form C and Form D of Aspacytarabine and an amorphous form of Aspacytarabine and a pharmaceutically acceptable carrier. In other embodiments, the weight ratio between the crystalline polymorphs and the amorphous form is in the range of between 10:1 to 1:10. In other embodiments, the weight ratio between the crystalline polymorphs Form C and Form D is in the range of between 10: 1 to 1:10.

[0066] In some embodiments, this invention provides a pharmaceutical composition comprising a combination of crystalline polymorph (Form C and/or Form D) of Aspacytarabine and an additional crystalline polymorph Form B and a pharmaceutically acceptable carrier. Each possibility represents a separate embodiment of this invention. In another embodiment, the crystalline polymorph Form B of Aspacytarabine is characterized by an X-Ray Powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 12.7 (7.0), 12.9 (6.9), 16.5 (5.4), 19.9 (4.5) and 20.9 (4.2) when obtained with a Cu tube anode with K- a radiation.

[0067] In some embodiments, this invention provides a pharmaceutical composition comprising a combination of crystalline polymorphs Form C and Form B of Aspacytarabine and an amorphous form of Aspacytarabine and a pharmaceutically acceptable carrier. In other embodiments, the weight ratio between the crystalline polymorphs and the amorphous form is in the range of between 10:1 to 1:10. In other embodiments, the weight ratio between the crystalline polymorphs Form C and Form B is in the range of between 10:1 to 1:10.

[0068] In some embodiments, this invention provides a pharmaceutical composition comprising a combination of crystalline polymorphs Form D and Form B of Aspacytarabine and an amorphous form of Aspacytarabine and a pharmaceutically acceptable carrier. In other embodiments, the weight ratio between the crystalline polymorphs and the amorphous form is in the range of between 10:1 to 1:10. In other embodiments, the weight ratio between the crystalline polymorphs Form D and Form B is in the range of between 10:1 to 1:10.

[0069] In other embodiments, the weight ratio between the crystalline polymorph of this invention and the additional crystalline polymorph Form B, is in the range of between 10: 1 to 1 : 10. In another embodiment the weight ratio between the crystalline polymorph and the amorphous form is 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3 or 1:2 or any ranges thereof. Each possibility represents a separate embodiment of this invention.

[0070] In some embodiments, this invention provides a pharmaceutical composition comprising a combination of crystalline polymorphs Form C, Form D, Form B of Aspacytarabine with or without the presence of an amorphous form of Aspacytarabine.

[0071] According to one aspect, the present invention provides a pharmaceutical composition comprising a crystalline polymorph, Form C or Form D, of (5)-2-amino-4-((l-((2R,3S,4S,5R)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4- oxobutanoic acid (Aspacytarabine) of the invention and at least one water-soluble stabilizer.

[0072] According to one aspect, the present invention provides a pharmaceutical composition comprising a crystalline polymorph, Form C or Form D, of (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4- oxobutanoic acid (Aspacytarabine) of the invention and at least one stabilizer and/or solubilizer selected from a linear polymer, cyclodextrin and combination thereof.

[0073] In one embodiment, the weight ratio between the Aspacytarabine within the pharmaceutical composition described herein and the stabilizer and/or solubilizer is between 99:1 and 1:10. In one embodiment, the ratio is between 99:1 to 99:9. In another embodiment, the ratio is between 99:9 to 99:49. In another embodiment, the ratio is between 99:49 to 1:1. In another embodiment, the ratio is between 1:2 to 1:5. In another embodiment, the ratio is between 1:5 to 1:10. Each possibility represents a separate embodiment of the present invention. In another embodiment, the weight ratio between the Aspacytarabine and the stabilizer and/or solubilizer is between 80:20 and 60:40. In another embodiment, the weight ratio is between 40:60 and 20:80. In another embodiment, the weight ratio is between 30:70 and 10:90.

[0074] In another embodiment, the weight percentage of Aspacytarabine within the pharmaceutical composition described herein is between 1% and 99%, relative to the total weight of the composition. In another embodiment, the weight percentage of Aspacytarabine within the pharmaceutical composition described herein is between 75% and 95%, relative to the total weight of the composition. In another embodiment, the weight percentage of Aspacytarabine within the pharmaceutical composition described herein is between 50% and 80%, relative to the total weight of the composition. In another embodiment, the weight percentage of Aspacytarabine within the pharmaceutical composition described herein is between 10% and 80%, relative to the total weight of the composition. In another embodiment, the weight percentage of Aspacytarabine within the pharmaceutical composition described herein is between 10% and 50%, relative to the total weight of the composition. In another embodiment, the weight percentage of Aspacytarabine within the pharmaceutical composition described herein is between 10% and 30%, relative to the total weight of the composition. In another embodiment, the weight percentage of Aspacytarabine within the pharmaceutical composition described herein is between 5% and 15%, relative to the total weight of the composition. In another embodiment, the weight percentage of Aspacytarabine within the pharmaceutical composition described herein is between 1% and 10%, relative to the total weight of the composition. Each possibility represents a separate embodiment of the invention. [0075] In some embodiments, the pharmaceutical composition comprising a crystalline polymorph (Form C or Form D) of (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine) of the invention and at least one linear polymer, and/or cyclodextrin. In one embodiment, the weight percentage of the at least one linear polymer and/or cyclodextrin is between 0.1 and 30% w/w relative to the total weight of the composition. In another embodiment, the weight percentage is between 0.1 and 0.5% w/w relative to the total weight of the composition. In another embodiment, the weight percentage is between 0.5 and 1% w/w relative to the total weight of the composition. In another embodiment, the weight percentage is between 1 and 2% w/w relative to the total weight of the composition. In another embodiment, the weight percentage is between 2 and 5% w/w relative to the total weight of the composition. In another embodiment, the weight percentage is between 5 and 10% w/w relative to the total weight of the composition. In another embodiment, the weight percentage is between 10 and 20% w/w relative to the total weight of the composition. In another embodiment, the weight percentage is 1 or 3% w/w relative to the total weight of the composition. Each possibility represents a separate embodiment of the invention.

[0076] According to one aspect, the present invention provides a pharmaceutical composition comprising a crystalline polymorph (Form C or Form D) of (S)-2-amino-4-((l-((2R,3S,4S,5R)- 3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4- yl)amino)-4-oxobutanoic acid (Aspacytarabine) of the invention and at least one stabilizer and/or solubilizer. In one embodiment, the at least one stabilizer and/or solubilizer is a water-soluble linear polymer. In another embodiment, the linear polymer is ionic or non-ionic. In some embodiments, non-ionic water soluble linear polymer comprise poly(vinyl alcohol), polyacrylamide, polyethylene glycol (polyethylene oxide) (PEG), polyethylene oxide (PEG) or polyoxyethylene (POE), triblock copolymers comprising polyoxypropylene (poly(propylene oxide)) two polyoxyethylene (poly(ethylene oxide)) (Poloxamer), polyvinyl pyrrolidone (PVP), derivative thereof or any combination thereof. In some embodiments, ionic water soluble linear polymer comprise ionic derivatives of poly(vinyl alcohol), polyacrylamide, polyethylene glycol (polyethylene oxide) (PEG), polyethylene oxide (PEO) or polyoxyethylene (POE), triblock copolymers comprising polyoxypropylene (poly(propylene oxide)) and two polyoxyethylene (poly (ethylene oxide)) (Poloxamer), polyvinyl pyrrolidone (PVP), polystyrene sulfonic acid, polystyrene sulfonates derivatives thereof or any combination thereof. [0077] In another embodiment, the at least one linear polymer is poloxamer. In another embodiment, the at least one water soluble linear polymer is combination of poloxamer and polyvinyl pyrrolidone (PVP). In another embodiment, the at least one water soluble linear polymer is cyclodextrin. In another embodiment, non-limiting examples of cyclodextrin (CD) include a- CD, P-CD, y-CD, HP-P-CD (hydroxypropylated), SBE-P-CD (sulfobutyl-ether - modified), RM- P-CD (randomly methylated) and any combination thereof. Each possibility represents a separate embodiment of the present invention.

[0078] In another embodiment, the compositions as described herein comprises Aspacytarabine and poloxamer. In another embodiment, the compositions comprise Aspacytarabine and a combination of poloxamer and polyvinyl pyrrolidone (PVP). In another embodiment, the compositions comprise Aspacytarabine and cyclodextrin. Each possibility represents a separate embodiment of the present invention.

[0079] The term “water-soluble stabilizer” refers to a chemical ingredient that stabilizes the Aspacytarabine or pharmaceutically acceptable salt thereof and prevents its decomposition. In some embodiments, the water-soluble stabilizer is also a solubilizer. In some embodiments, the water-soluble stabilizer is selected from a water-soluble linear polymer, a cyclodextrin or combination thereof.

[0080] In one embodiment, the composition as described herein is formulated as a parenteral, oral, intranasal or inhalation composition. In one embodiment, the parenteral composition is selected from a solution, a suspension, an emulsion for injection or infusion, particles for injection or infusion, liposomes as injectable delivery system, a powder for injection or infusion, and a gel for injection. In another embodiment, the parenteral composition is administered by intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intracerebral, intracerebroventricular, intrathecal or intradermal administration route. In another embodiment, the oral composition is selected from a tablet, a pill, a capsule, a drage, a gel, a syrup, a slurry, a suspension, a powder, or a liquid form. Each possibility represents a separate embodiment of the present invention.

[0081] In one embodiment, the composition as described herein further comprises a pharmaceutically acceptable carrier. In one embodiment, the carrier is water, saline solution, isotonic solution, aqueous dextrose, multiple electrolyte injection or aqueous glycerol solution. Each possibility represents a separate embodiment of the present invention.

[0082] In one embodiment, the composition as described herein is formulated for infusion or injection in a pharmaceutically acceptable carrier, wherein the carrier is selected from water, saline solution, isotonic solution, solutions accepted for infusion, aqueous dextrose or aqueous glycerol solution, wherein the composition having a pH range of between 2.2 and 8. In one embodiment, the pH range is between 4 and 8. In another embodiment, the pH range is between 7 and 8. In another embodiment, the pH range is between 4 and 5. In another embodiment, the pH is physiological.

[0083] In another embodiment, a buffer is used in order to maintain and/or adjust the required pH range. In another embodiment, the buffer can be a pharmaceutically acceptable mono-ionic buffer system or a poly-ionic buffer system having an ionization pK in the range of 2.2 - 8. In another embodiment, various buffers can be used, for example, ACES (N-(acetamido)-2- aminoethansulfonic acid); Acetate; N-(2-acetamido)-2-iminodiacetic acid; BES (N,N-bis[2- hydroxyethyl]-2-aminoethansulfonic acid); Bicine (2-(Bis(2-hydroxyethyl)amino)acetic acid); Bis-Tris methane (2-[Bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-l,3-diol); Bis-Tris propane (l,3-bis(tris(hydroxymethyl)methylamino)propane); Carbonate; Citrate; 3,3-dimethyl glutarate; DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxypropansulfonic acid); N- ethylmorpholine; Glycerol-2-phosphate; Glycine; Glycine-amid; HEPBS (N-(2- hydroxyethyl)piperazin-N’-4-buthanesulfonic acid); HEPES (N-(2-hydroxyethyl)piperazin-N’-2- ethanesulfonic acid); HEPPS (N-(2-hydroxyethyl)piperazin-N’-(3-propanesulfonic acid)); HEPPSO (N-(2-hydroxyethyl)piperazin-N’-(2-hydroxypropanesulfonic acid); Histidine; Hydrazine; Imidazole; Maleate; 2-methylimidazole; MES (2-(N-morpholino)ethanesulfonic acid); MOBS (4-(N-morpholino)-butansulfonic acid); MOPS (3-(N-morpholino)-propanesulfonic acid; MOPSO (3-(N-morpholino)-2-hydroypropanesulfonic acid); Oxalate; Phosphate; Piperazine; PIPES (1,4-Piperazine-diethanesulfonic acid); POPSO (Piperazine-N,N’-bis(2- hydroxypropanesulfonic acid)); Succinate; Sulfite; TAPS (3-[[l,3-dihydroxy-2- (hydroxymethyl)propan-2-yl]amino]propane-l-sulfonic acid); TAPSO (3-[[l,3-dihydroxy-2- (hydroxymethyl)propan-2-yl] amino] -2-hydroxypropane-l -sulfonic acid); Tartaric acid; TES (2- [[l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid); THAM (Tris) (2- Amino-2-hydroxymethyl-propane-l,3-diol); and Tricine (N-(2-Hydroxy-l,l- bis(hydroxymethyl)ethyl)glycine); a sulfonic acid derivative buffer including, but not limited to, ACES, BES, DIPSO, HEPBS, HEPES, HEPPS, HEPPSO, MES, MOBS, MOPS, MOPSO, PIPES, POPSO, Sulfite, TAPS, TAPSO, and TES buffer; a carboxylic acid derivative buffer including, but not limited to, Acetatate, N-(2-acetamido)-2-iminodiacetic acid, 2-(Bis(2- hydroxyethyl)amino)acetic acid, Carbonate, Citrate, 3,3-dimethyl glutarate, Lactate, Maleate, Oxalate, Succinate, and Tartaric acid buffer; an amino acid derivative buffer including, but not limited to, Bicine, Glycine, Glycine-amid, Histidine, and Tricine buffer; a phosphoric acid derivative buffer including, but not limited to, Glycerol-2-phosphate and phosphate buffer; and other buffer systems such as: Hank’s balanced salt solution, Earle’s balanced salt solution, Gey’s balanced salt solution, HEPES buffered saline, phosphate buffered saline, Plasma-lyte, Ringer’s solution, Ringer Acetate, Ringer lactate, Saline citrate, Tris buffered saline, acid-citrate-dextrose solution and Elliott’s B solution; and any combination thereof. Each possibility represents a separate embodiment of the present invention.

[0084] In other embodiments, pharmaceutical compositions for parenteral administration include aqueous solutions of the active ingredients in water-soluble form. Additionally, suspensions of the active compound may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes.

[0085] In other embodiments, the compositions as described herein may be formulated as a liquid formulation.

[0086] The compositions can be formulated as solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides, microcrystalline cellulose, gum tragacanth or gelatin. Each possibility represents a separate embodiment of the present invention.

[0087] The compositions can further comprise excipients including, but not limited to, sodium chloride, potassium chloride, magnesium chloride, sodium gluconate, sodium acetate, calcium chloride, sodium lactate, and the like. The compositions, if desired, can also contain minor amounts of sugar alcohols, wetting or emulsifying agents, and pH adjusting agents. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned. Each possibility represents a separate embodiment of the present invention.

[0088] For oral administration, the compositions as described herein can be formulated readily by combining Aspacytarabine and at least one stabilizer and/or solubilizer selected from a linear polymer, cyclodextrin or combination thereof with additional components as known in the art. Such components enable the composition as described herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a subject. Pharmacological preparations for oral use can be made using a solid component, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable components are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose. If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

[0089] In addition, enteric coating can be useful if it is desirable to prevent exposure of the compounds of the invention to the gastric environment.

[0090] Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.

[0091] In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

[0092] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0093] For administration by inhalation, the active compound for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e. g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e. g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the peptide and a suitable powder base such as lactose or starch.

[0094] An intranasal composition may be formulated as a powder, an aqueous solution or a nonaqueous solution. A preferred method of administering the solutions of the invention is using a spray device. Spray devices can be single (“unit”) dose or multiple dose systems. The powder formulation is preferably administered to the patient in aerosolized form whereby energy from patient inhalation (sniffing) is used to aerosolize the powder into the nasal cavity or where the device itself provides the aerosolization energy, such as via compressed air. Process of Preparing Aspacytarabine Solid Form - Form C and Form D

[0095] In some embodiments, provided herein is a process for the preparation of crystalline polymorph Form C of Aspacytarabine, wherein the process comprises: crystallization of the amorphous form of Aspacytarabine with solvent and antisolvent. In one embodiment, the solvent is water. In one embodiment, the anti-solvent is organic solvent.

[0096] In another embodiment, the process for the preparation of crystalline polymorph Form C of Aspacytarabine, comprises dissolving the amorphous form of Aspacytarabine with water followed by adding anti-solvent. In another embodiment, the addition of the anti-solvent is dropwise. In another embodiment, the anti-solvent is organic solvent. In one embodiment, the anti-solvent is water miscible organic solvent. In another embodiment, the anti-solvent is water immiscible solvent. In another embodiment, the anti-solvent is selected from ethanol, 2-propanol, or combination thereof. In one embodiment, the anti-solvent is ethanol. In another embodiment, the anti-solvent is 2-propanol.

[0097] In another embodiment, the ratio between the anti-solvent and water in the crystallization process is from about 1:10 to 10:1. In another embodiment, the ratio between the anti-solvent and water in the crystallization process is from about 1:1 to 10:1. In another embodiment, the ratio between the organic solvent and water is from about 1:1 to 5:1. In another embodiment, the ratio between the organic solvent and water is 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1 or any ranges thereof. In another embodiment, the ratio between the organic solvent and water is 7:3. In another embodiment, the ratio between the organic solvent and water is 7:4. In another embodiment, the ratio between the organic solvent and water is 7:2.

[0098] In some embodiments, provided herein is a process for the preparation of crystalline polymorph Form C of Aspacytarabine, wherein the process comprises mixing amorphous Aspacytarabine in organic solvent containing water (as a slurry). In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in organic solvent containing 2-50% of water. In another embodiment, the organic solvent contains 5% of water. In another embodiment, the organic solvent contains 10% of water. In another embodiment, the organic solvent contains 20% of water. In another embodiment, the organic solvent contains 30% of water. In another embodiment, the organic solvent contains 40% of water. In another embodiment, the organic solvent contains 50% of water. In another embodiment, the organic solvent is selected from, acetone, acetonitrile, methanol, ethanol, 2-propanol, or combination thereof. [0099] In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in acetonitrile containing 5% water. In another embodiment, crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in acetonitrile containing 10% water. In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in acetonitrile containing 20% water. In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in methanol containing 30% water. In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in methanol containing 40% water. In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in ethanol containing 30% water. In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in ethanol containing 40% water. In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in acetone containing 5% water. In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in acetone containing 20% water. In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in acetone containing 30% water. In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in acetone containing 40% water. In another embodiment, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in 2-propanol containing 5% water

[00100] In some embodiments, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in a mixture of organic solvent and water. In another embodiment, the ratio between the organic solvent and water in the mixture is from about 20:1 to 1:1. In another embodiment, the ratio between the organic solvent and water in the mixture is from about 19:1 to 1 : 1. In another embodiment, the ratio between the organic solvent and water in the mixture is from about 1:1 to 19:1. In another embodiment, the ratio between the organic solvent and water is 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1 or any ranges thereof. In another embodiment, the ratio between the organic solvent and water is 19:1, 9:1, 4:1, 7:3, 3:2 or any ranges thereof. In another embodiment, the ratio between the organic solvent and water is 7:3. In another embodiment, the ratio between the organic solvent and water is 19:1. In another embodiment, the ratio between the organic solvent and water is 9:1. In another embodiment, the ratio between the organic solvent and water is 4:1. In another embodiment, the ratio between the organic solvent and water is 7:4. In another embodiment, the ratio between the organic solvent and water is 7:2. In another embodiment, the ratio between the organic solvent and water is 3:2.

[00101] In some embodiments, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in a mixture of acetone and water. In another embodiment, the ratio between the acetone and water is 19:1, 4:1, 7:3, 3:2 or any ranges thereof. In another embodiment, the ratio between the acetone and water is 19:1. In another embodiment, the ratio between the acetone and water is 4:1. In another embodiment, the ratio between the acetone and water is 7:3. In another embodiment, the ratio between the acetone and water is 3:2.

[00102] In some embodiments, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in a mixture of acetonitrile and water. In another embodiment, the ratio between the acetonitrile and water is 20: 1 to 1 : 1 or any ranges thereof. In another embodiment, the ratio between the acetonitrile and water is 9:1. In another embodiment, the ratio between the acetonitrile and water is 4:1

[00103] In some embodiments, crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in a mixture of methanol and water. In another embodiment, the ratio in the mixture between the methanol and water is 20:1 to 1:1 or any ranges thereof. In another embodiment, the ratio in the mixture between the methanol and water is 7:3. In another embodiment, the ratio in the mixture between the methanol and water is 3:2.

[00104] In some embodiments, the crystalline polymorph C is obtained from a slurry of amorphous Aspacytarabine in a mixture of 2-propanol and water. In another embodiment, the ratio in the mixture between the 2-propanol and water is 20:1 to 1:1 or any ranges thereof. In another embodiment, the ratio in the mixture between the 2-propanol and water 19:1.

[00105] In some embodiments, the processes provided herein produce anhydrous crystalline polymorph of Aspacytarabine Form C. In some embodiments, the processes provided herein produce hydrate crystalline polymorph of Aspacytarabine Form C. In some embodiments, the processes provided herein produce solvate crystalline polymorph of Aspacytarabine Form C. In some embodiments, the processes provided herein produce salt crystalline polymorph of Aspacytarabine Form C.

[00106] In some embodiments, provided herein a process for the preparation of crystalline polymorph of Aspacytarabine Form D, wherein the process comprises: heating crystalline polymorph (From B) of Aspacytarabine to 140-170°C followed by rapid cooling to obtain crystalline polymorph of Aspacytarabine Form D. In another embodiment, the process provided herein for the preparation of crystalline polymorph of Aspacytarabine Form D is done without any solvent.

[00107] In some embodiments, this invention provides a crystalline polymorph Form C of compound (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine), which is prepared by the process of this invention.

[00108] In some embodiments, this invention provides a crystalline polymorph Form D of compound (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran- 2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine), which is prepared by the process of this invention.

[00109] In one embodiment, the crystalline Aspacytarabine polymorph Form C obtained by the process described in this invention possess high purity (above 90%). In another embodiment, the crystalline Aspacytarabine polymorph C obtained by the process described in this invention possess high purity - above 90%, above 91%, above 92%, above 93%, above 94%, above 95%, above 96%, above 97%, above 98%, above 99%, to any range thereof. Each possibility represents a different embodiment of this invention.

[00110] In one embodiment, the crystalline Aspacytarabine polymorph Form D obtained by the process described in this invention possess high purity (above 90%). In another embodiment, the crystalline Aspacytarabine polymorph D obtained by the process described in this invention possess high purity - above 90%, above 91%, above 92%, above 93%, above 94%, above 95%, above 96%, above 97%, above 98%, above 99%, to any range thereof. Each possibility represents a different embodiment of this invention.

Therapeutic use

[00111] In one aspect, the present invention provides a method of treating a neoplastic disease comprising administering to a subject in need thereof a crystalline polymorph Form C of (S)-2- amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine) of the invention.

[00112] In one aspect, the present invention provides a method of treating a neoplastic disease comprising administering to a subject in need thereof an Aspacytarabine acid salt, prepared from the crystalline polymorph Form C of Aspacytarabine of the invention or from the crystalline polymorph Form D of Aspacytarabine of the invention. In another embodiment, the salt is a strong acid salt. In another embodiment, the salt is a HC1 salt. [00113] According to some embodiments of the present invention, the neoplastic disease is selected from the group consisting of hematological cancers and non-hematological cancers. In another embodiment, the hematological cancer is selected from the group consisting of leukemias, lymphomas, myelomas and Myelodysplastic Syndromes (MDS).

[00114] The term "Myelodysplastic Syndromes" (MDS) refers to a heterogeneous group of hematopoietic malignancies characterized by blood cytopenias, ineffective hematopoiesis and a hypercellular bone marrow. The MDS is a preleukemic condition in which transformation into acute myeloid leukemia (AML) occurs in approximately 30-40% of cases. Unless allogenic stem cell transplantation can be offered, MDS is generally considered to be an uncurable condition.

[00115] According to some embodiments, the MDS is selected from MDS with multilineage dysplasia (MDS-MLD), MDS with single lineage dysplasia (MDS-SLD), MDS with ring sideroblasts (MDS-RS), MDS with excess blasts (MDS-EB), MDS with isolated del(5q) and MDS unclassifiable (MDS-U). Each possibility represents a separate embodiment of the invention.

[00116] In one embodiment, leukemia is selected from the group consisting of Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia (CML), and Chronic Lymphoblastic Leukemia (CLL). In another embodiment, the AML is selected from the group consisting of newly diagnosed AML, secondary AML, and relap sed/refractory AML. In another embodiment, the lymphoma is selected from the group consisting of Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. Each possibility represents a separate embodiment of the present invention.

[00117] Non-hematological cancers are malignant neoplasm that arises from a site other than the bone marrow and lymphoid tissue. Non-hematological cancers comprise and are not limited to, sarcoma, carcinoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, mesothelioma, Ewing's tumor sarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, astrocytoma, Kaposi's sarcoma, and melanoma. Each possibility represents a separate embodiment of the invention.

[00118] Non-hematological cancers include cancers of organs, wherein the cancer of an organ includes, but is not limited to, breast cancer, bladder cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, testicular cancer, thyroid cancer, ovarian cancer, brain cancer including ependymoma, glioma, glioblastoma, medulloblastoma, craniopharyngioma, pinealoma, acoustic neuroma, hemangioblastoma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, and their metastasis. Each possibility represents a separate embodiment of the invention. The present invention further provides a method for the treatment of an infection caused by a viral agent that is a cancer-causing virus. Thus, the invention provides a method for the treatment of a viral infection caused by a viral oncogene. Non-limiting examples of such viruses include human papillomavirus, Hepatitis B, Hepatitis C, Epstein-Barr virus, Human T-lymphotropic virus, Kaposi's sarcoma-associated herpesvirus, and Merkel cell polyomavirus. Each possibility represents a separate embodiment of the invention.

[00119] According to some embodiments of the present invention, the composition provided herein is administered parenterally, orally or by inhalation. In one embodiment, the composition provided herein is administered by intravenous (i.v.), intraarterial, intramuscular, subcutaneous, intraperitoneal (i.p.), intracerebral, intracerebroventricular, intrathecal or intradermal administration route. In another embodiment, the composition provided herein is administered at a daily dose wherein the Aspacytarabine dosage is ranging from about 0.3 g/m² to about 10 g/m² of the subject’s surface area, for a period of at least 3 days. In another embodiment, the dosage is ranging from about 0.3 g/m² to about 1 g/m². In another embodiment, the dosage is ranging from about 1 g/m² to about 2 g/m². In another embodiment, the dosage is ranging from about 2 g/m² to about 5 g/m². In another embodiment, the dosage is ranging from about 5 g/m² to about 10 g/m². In another embodiment, the dosage is ranging from about 0.3 g/m² to about 1 g/m². In another embodiment, the period is of at least 4 days. In another embodiment, the period is of at least 5 days. In another embodiment, the period is of at least 6 days. In another embodiment, the period is of at least 7 days. In another embodiment, the period is of at least 10 days. In another embodiment, the composition provided herein is administered by intravenous infusion for a period ranging from 15 minutes to 24 hours. In another embodiment, the composition provided herein is processed to enable administered by intravenous infusion for a period ranging from 30 minutes to 24 hours. In another embodiment, the composition provided herein is administered by intravenous infusion for a period ranging from 15 minutes to 0.5 hours. In another embodiment, the composition provided herein is administered by intravenous infusion for a period ranging from 0.5 hour to 1 hour. In another embodiment, the composition provided herein is administered by intravenous infusion for a period ranging from 1 hour to 3 hours. Each possibility represents a separate embodiment of the present invention. The composition provided herein may be administered locally and may further comprise an additional active agent and/or excipient.

[00120] According to further embodiments, the composition provided herein is administered in a daily dosage of at least 2, 3, 5, 10, 15, 20, 30 or at least 40 times greater than the standard of care dose of cytarabine. Each possibility represents a separate embodiment of the invention.

[00121] According to some embodiments, the composition provided herein is administered at least once a week. According to yet further embodiments, the composition provided herein is administered at least twice a week. According to still further embodiments, the composition provided herein is administered once a day for at least one week. According to still further embodiments, the composition provided herein is administered once a day for at least 6 days. According to still further embodiments, the composition provided herein is administered once a day for at least 6 days with at least 28 days apart. According to further embodiments, the composition provided herein is administered at least once a day for at least one week or until the subject reaches a remission.

[00122] According to some embodiments, the composition provided herein is administered once a day for at least 2, 3, 4, 5, 6, 8, 10, 12, or at least 14 consecutive days once a month. According to some embodiments, the composition provided herein is administered once a day for at least 4, 5, 6, or 8, consecutive days once a month. Alternatively, the composition provided herein is administered once a day for at least 2, 3, 4, 5, 6, or 12 days, or further alternatively the composition provided herein is administered every day or twice a week until the patient reaches a remission. [00123] The composition provided herein can also be delivered by slow-release delivery systems, pumps, and other known delivery systems for continuous infusion. Dosing regimens may be varied to provide the desired circulating levels of a particular compound based on its pharmacokinetics. Thus, doses are calculated so that the desired circulating level of a therapeutic agent is maintained. [00124] Typically, the effective dose is determined by the activity and efficacy of the compound and the condition of the subject as well as the body weight or surface area of the subject to be treated. The dose and the dosing regimen are also determined by the existence, nature, and extent of any adverse side effects that accompany the administration of the compounds in a particular subject.

Definitions

[00125] As used herein a "pharmaceutical composition" refers to a preparation of one or more of the compounds described herein, or physiologically acceptable salts or solvents thereof, with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to a subject.

[00126] The terms “standard of care dose” and “the recommended maximal dose” of cytarabine are used herein interchangeably and refer to the dosage, e.g., the daily dose, of cytarabine approved by the U.S. FDA for administration to a human subject, as described for example in https://www.nccn.org/patients/guidelines/content/PDF/aml-patient.pdf for AML.

[00127] The terms "treatment", "treat", "treating" and the like, are meant to include slowing, arresting or reversing the progression of a disease. These terms also include alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disease, even if the disease is not actually eliminated and even if progression of the disease is not itself slowed or reversed. A subject refers to a mammal, preferably a human being.

[00128] The term “about” in reference to a numerical value stated herein is to be understood as the stated value +/- 10%.

[00129] The term “pharmaceutically acceptable salt” of a drug refers to a salt according to IUPAC conventions. Pharmaceutically acceptable salt is an inactive ingredient in a salt form combined with a drug. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral, base, acid or salt. Acid salts are also known as acid addition salts (see herein below). Pharmaceutically acceptable salts are known in the art (Stahl and Wermuth, 2011, Handbook of pharmaceutical salts, Second edition). The acid is a strong acid and is selected from the group consisting of acetic acid, hydrochloric acid, hydrobromide acid, methanesulfonic acid, phosphoric acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, sulfuric acid, bisulfuric acid, and trifluoroacetic acid. In one embodiment, the salt is a hydrochloride salt. Each possibility represents a separate embodiment of the invention.

[00130] The term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[00131] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents.

[00132] The term “BST-236” refers to Aspacytarabine. [00133] The term “Form B” refer to a crystalline polymorph of Aspacytarabine (Form B) as represent in patent application PCT/IL2021/051144.

[00134] The following examples are to be considered merely as illustrative and non-limiting in nature. It will be apparent to one skilled in the art to which the present invention pertains that many modifications, permutations, and variations may be made without departing from the scope of the invention.

EXAMPLES

EXAMPLE 1

A process for preparing crystalline polymorph Form C from a slurry of amorphous Aspacytarabine with 30% water in acetone mixture

[00135] Example 1.1: Amorphous Aspacytarabine (50 mg) was treated with a mixture of water:acetone (3:7 v/v, 0.333ml) and the resultant gummy material was shaken overnight at ambient temperature . It gave a white solid which was isolated by filtration to give Form C (37.2 mg, 74% yield). UPLC purity 95.7%.

[00136] Example 1.2: To amorphous Aspacytarabine (941 mg) was added a mixture of water:acetone (3:7 v/v, 6.25 mL). The reaction mixture was stirred at ambient temperature for 48 hours after which a white solid was obtained. The solid was isolated by filtration and dried to give Form C as a white solid (787 mg, 84% yield). UPLC purity 93.5%.

[00137] Characterization of Form C (dried overnight at room temperature) from the Experiment 1.2:

EXAMPLE 2

A process for preparing crystalline polymorph Form C by crystallization of amorphous Aspacytarabine in water/ethanol mixture [00138] Amorphous Aspacytarabine (50mg) was dissolved in water (0.5 mL) at ambient temperature to give a clear solution. EtOH (0.875mL) was dropwise added until cloudy and was shaken at RT overnight. Further EtOH (0.1 mL) was added and shaking was continued for additional overnight. The solid was isolated by filtration and dried to give Form C as a white solid (14.9 mg, 30% yield). UPLC purity 93.7%.

EXAMPLE 3

[00139] As in Example 1, crystalline polymorph Form C was obtained from a slurry of amorphous Aspacytarabine (not shown) in: 1. Acetonitrile containing 5% water,

2. Acetonitrile containing 10% water,

3. Acetonitrile containing 20% water,

4. Methanol containing 30% water,

5. Methanol containing 40% water,

6. Ethanol containing 30% water,

7. Ethanol containing 40% water,

8. Acetone containing 5% water,

9. Acetone containing 20% water,

10. Acetone containing 30% water (Example 1), or

11. Acetone containing 40% water.

12. 2-propanol containing 5% water

EXAMPLE 4

[00140] XRPD of Aspacytarabine crystalline polymorph Form C

[00141] Figure 2 provides XRPD diffractogram of Aspacytarabine crystalline polymorph Form C prepared according to Example 2. X-Ray Powder Diffraction patterns were collected on a Bruker AXS D2 diffractometer using Cu Ka radiation (30 kV, 10 mA), 9-9 geometry, using a LynxEye detector from 5-42 °29.

[00142] The following Table provides the main XRPD peaks for Aspacytarabine polymorph, Form C.

EXAMPLE 5

A process for preparing crystalline polymorph Form D [00143] Example 5.1: A sample of Aspacytarabine Form B (3.44 mg) was heated to 155 °C at

10 °C/min, held at 155 °C for 2 minutes and then cooled at a rate of 50 °C/min to 30 °C. The DSC pan was quickly removed from the instrument and analyzed by XRPD (Figure 6). Example 5.2: Aspacytarabine Form B (9 mg) was heated in a DSC to 155°C at 10°C/min, held at 155°C for 2 minutes and then cooled at -50°C/min to 30°C. Figure 7 shows the DSC thermogram of this experiment.

[00144] The DSC pan was quickly removed from the instrument, opened and a portion of the residual material was rapidly analyzed by XRPD and DSC (heated 3O-3OO°C at 10°C/min.) These results suggested that only partial conversion to Form C had occurred. The DSC experiment repeated as above (heated to 155 °C at 10°C/min, held at 155 °C for 2 minutes and then cooled at a rate of 50°C/min to 30°C) on a portion of the material remaining from the initial experiment to give material that its XRPD of was consistent with pure Form D This material was also characterized by DSC showing a single endothermic event of onset 187°C (Figure 8).

[00145] UPLC was performed on the final material:

Airm D is converted spontaneously to Form B at ambient temperature after t several hours.

EXAMPLE 6

XRPD of Aspacytarabine crystalline polymorph Form D

[00146] Figure 6 provides XRPD diffractogram of Aspacytarabine crystalline polymorph prepared according to Example 4. X-Ray Powder Diffraction patterns were collected on a Bruker AXS D2 diffractometer using Cu Ka radiation (30 kV, 10 mA), 9-9 geometry, using a LynxEye detector from 5-42 °29.

The following Table provides the XRPD peaks for Aspacytarabine Polymorph, Form D.

[00147] It is appreciated by persons skilled in the art that the present invention is not limited by what has been particularly shown and described hereinabove. Rather the scope of the present invention includes both combinations and sub-combinations of various features described hereinabove as well as variations and modifications. Therefore, the invention is not to be constructed as restricted to the particularly described embodiments, and the scope and concept of the invention will be more readily understood by references to the claims, which follow.

Claims

What is claimed is:

1. A crystalline polymorph Form C of (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4- oxobutanoic acid (Aspacytarabine).

2. The crystalline polymorph of claim 1, wherein said crystalline polymorph is an anhydrous or hydrate or solvate or salt crystalline form.

3. The crystalline polymorph of claim 1, wherein said crystalline polymorph Form C is characterized by Powder X-Ray diffraction pattern comprising unique peaks at 29 ⁰ ±0.2 (d value A); 17.8 (5.0), 19.1 (4.6), 19.3 (4.6), 19.8 (4.5) and 21.5 (4.1) when obtained with a Cu tube anode with K- a radiation.

4. The crystalline polymorph of claim 1, wherein said crystalline polymorph is characterized by an X-Ray Powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 17.8 (5.0), 19.1 (4.6), 19.3 (4.6), 19.8 (4.5), 21.0 (4.2), 21.5 (4.1), 25.4 (3.5) and 26.3 (3.4) when obtained with a Cu tube anode with K- a radiation.

5. The crystalline polymorph of claim 1, wherein said crystalline polymorph is characterized by an x-ray diffraction pattern as depicted in Figure 2.

6. The crystalline polymorph of claim 1, wherein said crystalline polymorph of Aspacytarabine has a chemical purity of more than 90%.

7. The crystalline polymorph of claim 1, having water solubility of at least 20 mg in ImL.

8. A composition comprising a crystalline polymorph of compound (S)-2-amino-4-((l- ((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine) of any one of claims 1-7 and a pharmaceutically acceptable carrier.

9. The composition of claim 8, wherein the composition comprises a crystalline polymorph of Aspacytarabine and an amorphous form of Aspacytarabine.

10. The composition of claim 9, wherein the weight ratio between the crystalline polymorph and the amorphous form is in the range of between 10:1 to 1:10. 1. The composition of claim 8, wherein the composition comprises a crystalline polymorph of claim 1, and an additional crystalline Form B characterized by an X-Ray Powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 12.7 (7.0), 12.9 (6.9), 16.5 (5.4), 19.9 (4.5) and 20.9 (4.2) when obtained with a Cu tube anode with K- a radiation. The composition of claim 11, wherein the weight ratio between the crystalline polymorph of claim 1 and the additional crystalline polymorph of Aspacytarabine, Form B is in the range of between 10:1 to 1:10. A process for the preparation of Aspacytarabine polymorph Form C of any one of claims 1-7, wherein the process comprises crystallization of the amorphous form of Aspacytarabine in water and organic solvent. The process of claim 13, wherein the crystallization process comprises dissolving the amorphous form of Aspacytarabine with water followed by adding organic solvent. The process of claim 13, wherein the crystallization process comprises adding to the amorphous form of Aspacytarabine a mixture of organic solvent and water. The process of any one of claims 13-15, wherein the organic solvent is selected from methanol, ethanol, acetonitrile, acetone, isopropanol, or any combination thereof. A crystalline polymorph Form C of compound (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4- yl)amino)-4-oxobutanoic acid (Aspacytarabine), prepared by the process according to any one of claims 13-16. A process for the preparation of (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4- oxobutanoic acid-salt (Aspacytarabine- salt), wherein the salt is prepared by reacting the crystalline polymorph (Form C) of any one of claims 1-8 with a strong acid. A crystalline polymorph Form D of (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4- oxobutanoic acid (Aspacytarabine). The crystalline polymorph of claim 19, wherein said crystalline polymorph is an anhydrous or hydrate or solvate or salt crystalline form. The crystalline polymorph of claim 19, wherein said crystalline polymorph Form D is characterized by Powder X-Ray diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 17.1 (5.2), 19.3 (4.6), and 25.5 (3.5) when obtained with a Cu tube anode with K- a radiation. The crystalline polymorph of claim 19, wherein said crystalline polymorph is characterized by an X-Ray Powder diffraction pattern comprising unique peaks at °29 ±0.2 (d value A);

17.1 (5.2), 19.3 (4.6), 21.3 (4.2), 25.5 (3.5), and 26.9 (3.3) when obtained with a Cu tube anode with K- a radiation. The crystalline polymorph of claim 19, wherein said crystalline polymorph is characterized by an x-ray diffraction pattern as depicted in Figure 6. The crystalline polymorph of claim 19, wherein said crystalline polymorph of Aspacytarabine has a chemical purity of more than 90%. A composition comprising a crystalline polymorph of compound (S)-2-amino-4-((l- ((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid (Aspacytarabine) of any one of claims 19-24 and a pharmaceutically acceptable carrier. The composition of claim 25, wherein the composition comprises a crystalline polymorph of Aspacytarabine and an amorphous form of Aspacytarabine. The composition of claim 26, wherein the weight ratio between the crystalline polymorph and the amorphous form is in the range of between 10:1 to 1:10. The composition of claim 25, wherein the composition comprises a crystalline polymorph of claim 17, and an additional crystalline polymorph of Aspacytarabine Form B characterized by an X-Ray Powder diffraction pattern comprising unique peaks at 29° ±0.2 (d value A); 16.5 (5.4), 19.9 (4.5) and 20.9 (4.2) when obtained with a Cu tube anode with K- a radiation. The composition of claim 28, wherein the weight ratio between the crystalline polymorph of claim 19 and the additional crystalline polymorph Form B of Aspacytarabine is in the range of between 10:1 to 1:10. A process for the preparation of Aspacytarabine polymorph Form D of any one of claims 19-24, wherein the process comprises: heating crystalline polymorph (From B) of Aspacytarabine to 140-170 C followed by rapid cooling to obtain Form D of Aspacytarabine. A crystalline polymorph Form D of (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4- oxobutanoic acid (Aspacytarabine), prepared by the process of claim 30. A process for the preparation of (S)-2-amino-4-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-4- oxobutanoic acid-salt (Aspacytarabine- salt), wherein the salt is prepared by reacting the crystalline polymorph Form D of any one of claims 19-24 with a strong acid. A method of treating a neoplastic disease comprising administering to a subject in need thereof a crystalline polymorph of Aspacytarabine of any one of claims 1-7, and 19-24. The method of claim 33, wherein the neoplastic disease is selected from the group consisting of hematological cancers and non-hematological cancers. The method of claim 34, wherein the hematological cancer is selected from the group consisting of leukemias, lymphomas, myelomas and Myelodysplastic Syndromes (MDS). The method of claim 35, wherein the leukemia is selected from the group consisting of Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia (CML), and Chronic Lymphoblastic Leukemia (CLL). The method of claim 36, wherein the AML is selected from the group consisting of newly diagnosed AML, secondary AML, and relap sed/refractory AML. The method of claim 35, wherein the lymphoma is selected from the group consisting of Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. The method of any one of claims 33-38, wherein the crystalline polymorph of Aspacytarabine is administered parenterally, orally or by inhalation. The method of claim 39, wherein the crystalline polymorph of Aspacytarabine is administered by intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intracerebral, intracerebroventricular, intrathecal or intradermal administration route. The method of any one of claims 33-40, wherein the crystalline polymorph of Aspacytarabine is administered at a daily dose wherein the Aspacytarabine dosage is ranging from about 0.3 g/m²to about 10 g/m² of the subject’s surface area, for a period of at least 3 days. The method of claim 41, wherein the crystalline polymorph of Aspacytarabine is administered by intravenous infusion for a period ranging from 15 minutes to 24 hours.