Polymorphs of bis(fluoroalkyl)-1,4-benzodiazepinone compounds and their use

Abstract

This provides the crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound (1)). [Solution] A crystalline form of compound (1) represented by the following structure is provided, wherein the crystalline form has an N-2 crystalline form. JPEG2026048787000022.jpg4352

Description

[Technical Field]

[0001] The present invention relates to the crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide, represented by the structure of Compound 1 below.

[0002] [ka]

[0003] The process of its preparation, its composition, and its use are provided. [Background technology]

[0004] Benzodiazepinone compounds are useful as pharmaceutically active ingredients in the pharmaceutical and refinement chemical industries. For example, the following gamma-secretase inhibitor (GSI) (2R,3S)-N1-[(3S)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl]-2,3-bis(3,3,3-trifluoropropyl)-butanediamide

[0005] [ka]

[0006] This has shown promising results in current clinical trials for the treatment of various cancers (see U.S. Patent No. 8,629,136, incorporated herein by reference). Crystalline forms of pharmaceutically active drugs, such as those disclosed in U.S. 8,629,136, have been identified that possess desirable physiological and chemical properties, including high bioavailability, solubility, melting point, and crystallinity.

[0007] U.S. Patent No. 9,273,014, incorporated herein by reference, describes some of the preparations and uses of Compound 1. However, the crystalline structure of Compound 1 was not disclosed. Therefore, a crystalline form of Compound 1 with desirable physiological and chemical properties is needed to provide a form of Compound 1 with high bioavailability, solubility, melting point, and crystallinity. [Overview of the project] [Means for solving the problem]

[0008] In one embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide represented by the following structure of compound 1,

[0009] [ka]

[0010] The crystal morphology includes N-2 crystal morphology, IPA2-1 crystal morphology, M3-1 crystal morphology, P4 crystal morphology, P5 crystal morphology, P6 crystal morphology, or any combination thereof.

[0011] In another embodiment, the present invention provides the following crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide,

[0012] [ka]

[0013] The crystalline forms include the P1 crystalline form, which is crystallized by desolvation of the crystalline form IPA2-1 or M3-1, and IPA2-1 and M3-1 are additional crystalline forms of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl) succinimide.

[0014] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl) succinimide represented as follows,

[0015]

Chemical formula

[0016] The crystalline forms include the P2 crystalline form, which is crystallized from the crystalline form P1 described above and slurried in ethyl acetate.

[0017] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)-2,3-bis(3,3,3-trifluoropropyl) succinimide represented as follows,

[0018]

Chemical formula

[0019] The crystalline forms include the P3 crystalline form, which is crystallized from the crystalline form P1 described above and slurried in acetonitrile.

[0020] <, In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described crystalline form and a pharmaceutically acceptable carrier. [Brief explanation of the drawing]

[0021] [Figure 1] The PXRD patterns of the N-2 morphology are shown at room temperature (bottom), 165°C (middle), and 270°C (top). [Figure 2] The PXRD pattern in IPA2-1 form is shown. [Figure 3] The PXRD pattern of the M3-1 form is shown. [Figure 4] The PXRD pattern in P4 form is shown. [Figure 5] The PXRD pattern of the P5 form is shown. [Figure 6] The PXRD pattern of the P6 form is shown. [Figure 7] The PXRD pattern of the E2-1 form is shown. [Figure 8] The PXRD pattern of the P1 form is shown. [Figure 9] The PXRD pattern of the P2 form is shown. [Figure 10] The PXRD pattern of the P3 form is shown. [Figure 11A] The HTC solvent screen of compound 1 is shown, along with microscopic images and crystallization solvents for (A) the neutral morphology screen (i.e., a neutral plate) and (B) the neutral morphology screen in the presence of a weak acid (i.e., a co-crystal plate). [Figure 11B] The HTC solvent screen of compound 1 is shown, along with microscopic images and crystallization solvents for (A) the neutral morphology screen (i.e., a neutral plate) and (B) the neutral morphology screen in the presence of a weak acid (i.e., a co-crystal plate). [Figure 12A] (A) Selected intermolecular hydrogen bonds of compound 1 observed in the N-2 form, and (B) Packing of compound 1 molecules parallel to the bc plane in form N-2. [Figure 12B](A) Selected intermolecular hydrogen bonds of compound 1 observed in the N-2 form, and (B) Packing of compound 1 molecules parallel to the bc plane in form N-2. [Figure 13] The image shows the simulated N-2 pattern (lower pattern) in RT and the overlaid PXRD pattern (upper pattern) of the N-2 form as a dried powder. [Figure 14] The DSC / TGA thermogram of the P1 morphology is shown. [Figure 15] The PXRD patterns of the initial P1 morphology at room temperature (top), the P1 morphology after heating to 165°C and then cooling back to room temperature (center), and the N-2 morphology at room temperature (bottom) are shown. [Figure 16] The PXRD patterns of the P1 morphology after slurrying in FASIF (fasting-simulated intestinal fluid) (top), the P1 morphology after slurrying in HCl (pH=1) (middle), and the N-2 morphology (bottom) are shown. [Figure 17] The overlay of the N2 form PXRD pattern prepared according to the procedure described in Example 5 is shown, with the upper trace being the reference standard and the lower trace being the sample. [Figure 18] The overlay of the N2 form PXRD pattern prepared according to the procedure described in Example 5 is shown, with the top trace being the reference standard, the center trace being sample 1, and the bottom trace being sample 2. [Modes for carrying out the invention]

[0022] The following detailed description includes numerous specific details to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the invention can be carried out without these specific details. In other examples, well-known methods, procedures, and components are not described in detail so as not to obscure the invention.

[0023] Crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1)

[0024] In one embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1), represented by the following structure of compound 1.

[0025] [ka]

[0026] In one embodiment, the crystal morphology includes N-2 crystal morphology, IPA2-1 crystal morphology, M3-1 crystal morphology, E2-1 crystal morphology, P1 crystal morphology, P2 crystal morphology, P3 crystal morphology, P4 crystal morphology, P5 crystal morphology, P6 crystal morphology, or any combination thereof. In another embodiment, the crystal morphology includes N-2 crystal morphology, IPA2-1 crystal morphology, M3-1 crystal morphology, P4 crystal morphology, P5 crystal morphology, P6 crystal morphology, or any combination thereof. In yet another embodiment, the crystal morphology includes E2-1 crystal morphology, P1 crystal morphology, P2 crystal morphology, P3 crystal, or any combination thereof. Each possibility represents a distinct embodiment of the present invention.

[0027] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1), represented by the following structure of compound 1.

[0028] [ka]

[0029] The crystal morphology includes the N-2 crystal morphology.

[0030] In one embodiment, the N-2 crystalline form is crystallized from ethanol / water. In another embodiment, the N-2 crystalline form is characterized by an XRPD pattern with peaks at 14.92±0.3, 15.49±0.3, 19.3±0.3, 19.64±0.3, and 21.57±0.3 degrees 2-theta (2θ), or by unit cell parameters a=4.84±0.3Å, b=18.47±0.3Å, c=15.67±0.3Å, a=90°, b=91.62±0.5°, g=90°, with a unit cell volume of 1399.51±0.5Å. 3 The number of compounds per asymmetric unit is 1, and the space group is P21. In another embodiment, the XRPD pattern of crystalline morphology N-2 has additional peaks at 11.12±0.3 and 12.23±0.3 degrees 2-theta (2θ). In yet another embodiment, crystalline morphology N-2 is characterized by an XRPD pattern substantially as shown by Figure 1. Each possibility represents a distinct embodiment of the present invention.

[0031] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1), represented by the following structure of compound 1.

[0032] [ka]

[0033] The crystalline form includes the IPA2-1 crystalline form. In one embodiment, the IPA2-1 crystalline form is crystallized from isopropyl alcohol (IPA). In another embodiment, the IPA2-1 crystalline form is characterized by an XRPD pattern having peaks at 7.71±0.3, 12.96±0.3, 13.12±0.3, 14.84±0.3, and 19.35±0.3 degrees 2-theta (2θ), or by unit cell parameters a=11.93±0.3Å, b=8.57±0.3Å, c=17.42±0.3Å, a=90°, b=105.16±0.5°, g=90°, with a unit cell volume of 1718.67±0.5Å. 3 The number of compounds per asymmetric unit is 1, and the space group is P21. In another embodiment, the XRPD pattern of the IPA2-1 crystalline form has additional peaks at 21.62±0.3 and 21.83±0.3 degrees 2-theta (2θ). In yet another embodiment, the IPA2-1 crystalline form features an XRPD pattern substantially as shown by Figure 2. Each possibility represents a distinct embodiment of the present invention.

[0034] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1), represented by the following structure of compound 1.

[0035] [ka]

[0036] The crystalline form includes the M3-1 crystalline form. In one embodiment, the M3-1 crystalline form is crystallized from methanol. In another embodiment, the M3-1 crystalline form is characterized by an XRPD pattern having peaks at 7.96±0.3, 13.26±0.3, 19.19±0.3, and 21.56±0.3 degrees 2-theta (2θ), or by unit cell parameters a=11.72±0.3 Å, b=8.36±0.3 Å, c=17.41±0.3 Å, a=90°, b=108.62±0.5°, g=90°, with a unit cell volume of 1616.59±0.5 Å. 3 The number of compounds per asymmetric unit is 1, and the space group is P21. In another embodiment, the crystalline form M3-1 is characterized by an XRPD pattern substantially as shown in Figure 3. Each possibility represents a distinct embodiment of the present invention.

[0037] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1), represented by the following structure of compound 1.

[0038] [ka]

[0039] The crystalline form includes the P4 crystalline form. In one embodiment, the P4 crystalline form is crystallized from v / v 1:1 MeCN / MTBE, 1:2 DCM / heptane, 1:1 DCM / MTBE, or 1:1 MEK / cyclohexane. In another embodiment, the P4 crystalline form is characterized by an XRPD pattern having peaks at 7.16±0.3, 16.02±0.3, 18.62±0.3, 20.32±0.3, and 21.14±0.3 degrees 2-theta (2θ). In yet another embodiment, the XRPD pattern of the P4 crystalline form has additional peaks at 12.04±0.3 and 23.56±0.3 degrees 2-theta (2θ). In yet another embodiment, the P4 crystalline form is characterized by an XRPD pattern substantially as shown in Figure 4. Each possibility represents a distinct embodiment of the present invention.

[0040] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1), represented by the following structure of compound 1.

[0041] [ka]

[0042] The crystalline form includes the P5 crystalline form. In one embodiment, the P5 crystalline form is crystallized from acetone:water 1:1 v / v. In another embodiment, the P5 crystalline form is characterized by an XRPD pattern having peaks at 6.5±0.3, 10.99±0.3, 17.36±0.3, 19.49±0.3, and 21.84±0.3 degrees 2-theta (2θ). In yet another embodiment, the XRPD pattern of the P5 crystalline form has additional peaks at 14.78±0.3 and 20.26±0.3 degrees 2-theta (2θ). In yet another embodiment, the P5 crystalline form is characterized by an XRPD pattern substantially as shown by Figure 5. Each possibility represents a distinct embodiment of the present invention.

[0043] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1), represented by the following structure of compound 1.

[0044] [ka]

[0045] The crystalline form includes the P6 crystalline form. In one embodiment, the P6 crystalline form is crystallized from ethanol:water 1:1 v / v. In another embodiment, the P6 crystalline form is characterized by an XRPD pattern having peaks at 3.52±0.3, 10.00±0.3, 12.36±0.3, 19.32±0.3, and 20.40±0.3 degrees 2-theta (2θ). In yet another embodiment, the XRPD pattern of the P6 crystalline form has additional peaks at 14.2±0.3 and 16.04±0.3 degrees 2-theta (2θ). In yet another embodiment, the P6 crystalline form is characterized by an XRPD pattern substantially as shown by Figure 6. Each possibility represents a distinct embodiment of the present invention.

[0046] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1), represented by the following structure of compound 1.

[0047] [ka]

[0048] The crystalline form includes the E2-1 crystalline form. In one embodiment, the E2-1 crystalline form is crystallized from THF / heptane. In another embodiment, the E2-1 crystalline form is crystallized from acetone / heptane. In yet another embodiment, the E2-1 crystalline form is crystallized from propylene glycol. In yet another embodiment, the E2-1 crystalline form is crystallized from ethanol / water. Each possibility represents a distinct embodiment of the present invention. In yet another embodiment, the E2-1 crystalline form is crystallized from THF / heptane, acetone / heptane, or propylene glycol. In one embodiment, the crystal morphology E2-1 is characterized by an XRPD pattern having peaks at 37.87±0.3, 13.09±0.3, 18.88±0.3, 19.41±0.3, and 21.62±0.3 degrees 2-theta (2θ), or by unit cell parameters a=11.70±0.3Å, b=8.53±0.3Å, c=17.42±0.3Å, α=90°, β=106.03±0.5°, γ=90°, with a unit cell volume of 1672.01±0.5Å. 3 The number of compounds per asymmetric unit is 1, and the space group is P21. In another embodiment, the XRPD pattern of crystalline morphology E2-1 has additional peaks at 21.83±0.3 and 22.3±0.3 degrees 2-theta (2θ). In yet another embodiment, crystalline morphology E2-1 features an XRPD pattern substantially as shown by Figure 7. Each possibility represents a distinct embodiment of the present invention.

[0049] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1), represented by the following structure of compound 1.

[0050] [ka]

[0051] The crystalline form includes the P1 crystalline form. In one embodiment, the P1 crystalline form is crystallized by desolvation of crystalline form E2-1. In another embodiment, the P1 crystalline form is crystallized by desolvation of IPA2-1. In yet another embodiment, the P1 crystalline form is crystallized by desolvation of M3-1. Each possibility represents a distinct embodiment of the present invention. In one embodiment, crystalline form P1 is characterized by an XRPD pattern having peaks at 8.04±0.3, 14.64±0.3, 16.1±0.3, 19.52±0.3, and 21.94±0.3 degrees 2-theta (2θ). In another embodiment, the XRPD pattern of crystalline form P1 has additional peaks at 20.46±0.3 and 25.1±0.3 degrees 2-theta (2θ). In yet another embodiment, crystalline form P1 is characterized by an XRPD pattern substantially as shown in Figure 8. Each possibility represents a distinct embodiment of the present invention.

[0052] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1), represented by the following structure of compound 1.

[0053] [ka]

[0054] The crystalline form includes the P2 crystalline form. In one embodiment, the P2 crystalline form is crystallized from the above-described crystalline form P1, which is slurryed in ethyl acetate. In one embodiment, the crystalline form P2 is characterized by an XRPD pattern having peaks at 7.35±0.3, 14.61±0.3, 19.2±0.3, 23.15±0.3, and 26.4±0.3 degrees 2-theta (2θ). In another embodiment, the XRPD pattern of the crystalline form P2 has additional peaks at 11.04±0.3 and 23.71±0.3 degrees 2-theta (2θ). In yet another embodiment, the crystalline form P2 is characterized by an XRPD pattern substantially as shown by Figure 9. Each possibility represents a distinct embodiment of the present invention.

[0055] In another embodiment, the present invention provides a crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1), represented by the following structure of compound 1.

[0056] [ka]

[0057] The crystalline form includes the P3 crystalline form. In one embodiment, the P3 crystalline form is crystallized from the P1 crystalline form, which is slurryed in ethyl acetate as described above. In one embodiment, the P3 crystalline form is characterized by an XRPD pattern having peaks at 87.45±0.3, 14.76±0.3, 19.02±0.3, 19.44±0.3, and 21.41±0.3 degrees 2-theta (2θ). In another embodiment, the XRPD pattern of the P3 crystalline form has additional peaks at 11.11±0.3 and 22.15±0.3 degrees 2-theta (2θ). In yet another embodiment, the P3 crystalline form is characterized by an XRPD pattern substantially as shown by Figure 10. Each possibility represents a distinct embodiment of the present invention.

[0058] In another embodiment, the crystallization of a crystalline form formed in a particular solvent has a different crystal habit than the same crystalline form formed in a different solvent. In another embodiment, the crystallization of a crystalline form formed in a particular solvent has a different grain size than the same crystalline form formed in a different solvent.

[0059] Process for preparing the crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1)

[0060] In one embodiment, the present invention is a process for preparing the crystalline form of compound 1 of the present invention, - Dissolving compound 1 in a solvent, - The process of adding a reverse solvent to a solution to obtain a precipitate, - A process is provided which includes isolating the precipitate to provide the crystalline form of compound 1.

[0061] In another embodiment, the present invention is a process for preparing the crystalline form of compound 1 of the present invention, - Heating and dissolving compound 1 in a solvent, - Adding the reverse solvent to the heated solution, - Cooling a high-temperature solution to obtain a precipitate, - A process is provided which includes isolating the precipitate to provide the crystalline form of compound 1.

[0062] In one embodiment, the present invention is a process for preparing the crystalline form of compound 1 of the present invention, - Mixing and dissolving compound 1 in a solvent system to obtain a precipitate, - A process is provided which includes isolating the precipitate to provide the crystalline form of compound 1.

[0063] In another embodiment, the present invention is a process for preparing the crystalline form of compound 1 of the present invention, - Mixing, heating, and dissolving compound 1 in a solvent system, - Cooling a high-temperature solution to obtain a precipitate, - A process is provided which includes isolating the precipitate to provide the crystalline form of compound 1.

[0064] In another embodiment, the present invention is a process for preparing the crystalline form of compound 1 of the present invention, - Dissolve compound 1 in a solvent in a flask. - The contents of the flask are transferred through a filter to obtain filtrate A, - Adding the solvent to the flask, - The contents of the flask are transferred through a filter to obtain filtrate B, - Combine filtrates A and B in a flask, add the reverse solvent to provide a precipitate, - A process is provided which includes drying the precipitate to provide a crystalline form of compound 1.

[0065] In one embodiment, the solvent is acetic acid. In one embodiment, the reverse solvent is water. In one embodiment, the solvent is acetic acid and the reverse solvent is water. In one embodiment, the method further comprises adding the reverse solvent again to the dried precipitate, collecting the resulting wet precipitate ("cake"), filtering the wet precipitate, and drying the filtrate to obtain a crystalline form. In some embodiments, the latter step may be repeated one or more additional times as needed (to obtain the highest possible purity). In some embodiments, the latter step may be repeated two, three, four, or five additional times.

[0066] In one embodiment, the N-2 crystalline form is prepared by dissolving compound 1 in acetic acid and then adding water to bring about the crystallization of compound 1.

[0067] In some embodiments, non-limiting examples of solvents include MeOH, EtOH (including absolute EtOH), i-PrOH, i-PrOH / MeCN, n-BuOH, i-BuOH, i-BuOH / MeCN, acetone, MeCN, MEK (butanone), ethyl-formate, siRNA, i-BuOAc, n-PrOAc, MeOAc, i-PrOAc, n-BuOAc, i-BuOAc, MIBK, anisole, n-P Examples include rOH, n-PrOH / MeCN, n-BuOH, n-BuOH / MeCN, s-BuOH, n-AmOH, DMSO / TBME, acetone / water, MeCN / water, EtOH / water, i-PrOH / water, n-PrOH / water, EtOH / n-PrOAc, i-PrOH / n-PrOAc, n-PrOH / n-PrOAc, n-PrOH / heptane, n-BuOH / heptane, water, acetic acid, formic acid, and mixtures thereof. Each possibility represents a distinct embodiment of the present invention.

[0068] In some embodiments, non-limiting examples of the reverse solvent include water, æş, acetone, acetonitrile, and mixtures thereof. Each possibility represents a distinct embodiment of the present invention.

[0069] In some embodiments, the solvent system includes at least one solvent and / or inverse solvent as described above. In one embodiment, non-limiting examples of solvent systems include acetic acid / water, EtOH / water (e.g., 1:1, 1:2), EtOH, MeOH, IPA, THF / heptane, acetone / heptane, propylene glycol, MeCN / MTBE (e.g., 1:1), DCM / heptane (e.g., 1:2), DCM / MTBE (e.g., 1:1), MEK / cyclohexane (e.g., 1:1), acetone / water (e.g., 1:1), IPA / water (e.g., 1:2, 1:1), THF / n-heptane (e.g., 1:1), THF / water (e.g., 1:1), acetone / n-heptane (e.g., 1:1), water, ethyl acetate, DCM, acetonitrile, acetonitrile / water (e.g., 1:1), acetic acid / water (e.g., 1:1), and DMSO / water (e.g., 1:1). Each possibility represents a separate embodiment of the present invention.

[0070] In some embodiments, the compound 1 + solvent / solvent system mixture is heated to the reflux temperature of the medium (solvent / solvent system). In one embodiment, the mixture is heated to a temperature of 40–150°C. In another embodiment, the mixture is heated to a temperature of 40–100°C. In yet another embodiment, the mixture is heated to a temperature of 40–80°C. In yet another embodiment, the mixture is heated to a temperature of 40–60°C. In yet another embodiment, the mixture is heated to a temperature of 60–80°C. In yet another embodiment, the mixture is heated to a temperature of 80–100°C. In yet another embodiment, the mixture is heated to a temperature of 100–120°C. In yet another embodiment, the mixture is heated to a temperature of 120–150°C. In yet another embodiment, the mixture is heated to a temperature of 80°C. In yet another embodiment, the mixture is not heated. In yet another embodiment, the mixture is stirred at room temperature. Each possibility represents a distinct embodiment of the present invention.

[0071] In some embodiments, precipitate isolation is performed by vacuum filtration with optionally solvent washing and / or by any other method known in the art.

[0072] In some embodiments, the mixture is cooled to a temperature of 10–30°C. In one embodiment, the mixture is cooled to a temperature of -50–25°C. In another embodiment, the mixture is cooled to a temperature of -20–0°C. In yet another embodiment, the mixture is cooled to a temperature of 0–25°C. In one embodiment, the mixture is cooled to a temperature of 0–10°C. Each possibility represents a distinct embodiment of the present invention.

[0073] In some embodiments, heating and / or cooling are performed in one or more steps.

[0074] Pharmaceutical composition containing the crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1)

[0075] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described compound 1 in crystalline form and optionally at least one pharmaceutically acceptable carrier, diluent, vehicle, or excipient. In one embodiment, the form of the pharmaceutical composition comprises a sterile injection solution. In another embodiment, the form of the pharmaceutical composition is, as is well known in the art, tablets (e.g., including film-coated tablets), powders, granules, capsules (e.g., soft capsules), orally disintegrating tablets, pills, pellets, lozenges, sachets, caches, patches, elixirs, suspensions, dispersions, emulsions, solutions, syrups, aerosols, ointments, soft and hard gelatin capsules, suppositories, sterile packaging powders, and sustained-release preparations. In yet another embodiment, the composition is a solid-state composition (e.g., tablets, pills, capsules, pellets, granules, powders, etc.). Each possibility represents a distinct embodiment of the present invention.

[0076] In some embodiments, pharmaceutically acceptable carriers, diluents, vehicles, or excipients that may be used in the context of the present invention include, but are not limited to, surfactants, lubricants, binders, fillers, compression aids, disintegrants, water-soluble polymers, inorganic salts, preservatives, antioxidants, colorants, sweeteners, acidifiers, foaming agents, and flavorings. Each possibility represents a distinct embodiment of the present invention.

[0077] In some embodiments, specific non-limiting examples of preferred carriers, diluents, vehicles, or excipients within the present invention include, for example, lactose, D-mannitol, starch, corn starch, crystalline cellulose, soft anhydrous silicic acid, and titanium dioxide. Each possibility represents a distinct embodiment of the present invention. Suitable surfactants include, for example, lecithin and phosphatidylcholine. Each possibility represents a distinct embodiment of the present invention. Suitable lubricants include, for example, magnesium stearate, sucrose fatty acid esters, polyethylene glycol, talc, and stearic acid. Each possibility represents a distinct embodiment of the present invention. Suitable binders include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, crystalline cellulose, α-starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, and low-substituted hydroxypropyl cellulose. Each possibility represents a distinct embodiment of the present invention. Suitable disintegrants include, for example, cross-linked povidone (any cross-linked 1-ethenyl-2-pyrrolidinone homopolymer including polyvinylpyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone homopolymer), cross-linked carmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and corn starch. Each possibility represents a distinct embodiment of the present invention. Suitable water-soluble polymers include, for example, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, methylcellulose and carboxymethylcellulose sodium, sodium polyacrylate, polyvinyl alcohol, sodium alginate, and cellulose derivatives such as guar gum. Each possibility represents a distinct embodiment of the present invention. Suitable inorganic salts include, for example, basic inorganic salts of sodium, potassium, magnesium, and / or calcium. Each possibility represents a distinct embodiment of the present invention. Specific embodiments include basic inorganic salts of magnesium and / or calcium. Examples of basic inorganic salts of sodium include sodium carbonate, sodium bicarbonate, and disodium hydrogen phosphate. Each possibility represents a distinct embodiment of the present invention.Examples of basic inorganic salts of potassium include potassium carbonate and potassium bicarbonate. Each possibility represents a distinct embodiment of the present invention. Examples of basic inorganic salts of magnesium include heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium aluminometasilicate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite, and magnesium alumina hydroxide. Each possibility represents a distinct embodiment of the present invention. Examples of basic inorganic salts of calcium include precipitated calcium carbonate and calcium hydroxide. Each possibility represents a distinct embodiment of the present invention.

[0078] Suitable preservatives include, for example, sodium benzoate, benzoic acid, and sorbic acid. Each possibility represents a distinct embodiment of the present invention. Suitable antioxidants include, for example, sulfites, ascorbic acid, and α-tocopherol. Each possibility represents a distinct embodiment of the present invention. Suitable colorants include, for example, food colorants such as Yellow No. 5, Red No. 2, and Blue No. 2. Each possibility represents a distinct embodiment of the present invention. Suitable sweeteners include, for example, dipotassium glycyrrhetinate, aspartame, stevia, and thaumatin. Each possibility represents a distinct embodiment of the present invention. Suitable acidulants include, for example, citric acid (anhydrous citric acid), tartaric acid, and malic acid. Each possibility represents a distinct embodiment of the present invention. Suitable foaming agents include, for example, sodium bicarbonate. Suitable flavorings include, for example, synthetic or natural substances including lemon, lime, orange, menthol, and strawberry. Each possibility represents a distinct embodiment of the present invention.

[0079] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above-described compound 1 in crystalline form and a pharmaceutically acceptable carrier. In another embodiment, the composition is in solid, suspension, or emulsion form. In yet another embodiment, the composition is in solid form and is a tablet. In a further embodiment, the composition is a suspension. In one embodiment, the suspension comprises crystalline form and propylene glycol, which in one embodiment comprises solid crystals suspended in a solvent.

[0080] In one embodiment, the crystalline form of the present invention is useful as a pharmaceutical agent for medical purposes. Accordingly, in one embodiment, the present invention provides a pharmaceutical composition comprising the crystalline form of Compound 1 disclosed herein and at least one pharmaceutically acceptable carrier, diluent, vehicle, or excipient. The crystalline form of the present invention can be safely administered orally or parenterally. In one embodiment, the route of administration includes an intravenous route. Routes of administration also include, but are not limited to, oral, topical, subcutaneous, intraperitoneal, rectal, intravenous, intra-arterial, percutaneous, intramuscular, topical, and intranasal. Each possibility represents a distinct embodiment of the present invention. Additional routes of administration include, but are not limited to, mucosal, nasal, parenteral, gastrointestinal, intrathecal, intrauterine, intraocular, intradermal, intracranial, intratracheal, vaginal, intraventricular, intracerebral, ophthalmoscopy, oral cavity, epidural, and sublingual. Each possibility represents a distinct embodiment of the present invention.

[0081] In one embodiment, the crystalline form of the present invention is particularly suitable for oral administration in the form of tablets, capsules, pills, sugar-coated tablets, powders, granules, etc. Each possibility represents a separate embodiment of the present invention. Tablets may optionally be prepared by compression or molding using one or more excipients known in the art. Specifically, molded tablets may be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent using a suitable machine.

[0082] In another embodiment, tablets and other solid dosage forms of the pharmaceutical compositions described herein may optionally be stored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using varying proportions of hydroxypropyl methylcellulose to provide a desired release profile, other polymer matrices, etc. The active ingredient may also be in a microencapsulated form, optionally containing one or more of the excipients described above.

[0083] Use of the crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide (compound 1)

[0084] In one embodiment, the present invention provides a method for treating cancer, comprising administering the above-described composition to a target subject as needed. In another embodiment, the cancer is selected from bladder cancer, breast cancer, colorectal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, gallbladder cancer, prostate cancer, thyroid cancer, osteosarcoma, rhabdomyosarcoma, malignant fibrous histocytoma (MFH), fibrosarcoma, glioblastoma / astrocytoma, neuroblastoma, melanoma, T-cell acute lymphoblastic leukemia (T-ALL), and mesothelioma. Each possibility represents a distinct embodiment of the present invention.

[0085] definition

[0086] In one embodiment, the term “crystal” as used herein means a solid form of a material having a significant amount or degree of crystallinity (at least 1 wt%, at least 10 wt%, or at least 30 wt% of a crystalline phase). Accordingly, “crystal” in the context of the present invention includes highly crystalline materials, as well as semi-crystalline or partially crystalline materials, and / or any material having an amount or degree of crystallinity of more than 1 wt%, more than 10 wt%, or more than 30 wt%, and 100 wt% or less of a crystalline phase.

[0087] In one embodiment, the term “therapeutic dose” as used herein refers to the amount of drug that is effective to a subject in a single or multiple doses in providing a therapeutic benefit to that subject. In additional embodiments, the crystalline form of the present invention is used for the preparation of drugs to treat the aforementioned diseases or disorders.

[0088] In one embodiment, the term “room temperature” (or RT) as used herein refers to a temperature range of 12–35°C, 20–30°C, 20–25°C, or 23–27°C.

[0089] In one embodiment, the term “obtaining a precipitate” as used herein typically refers to a process or step in a process in which a precipitate is formed from a solution or slurry. In one embodiment, the precipitate formation process occurs immediately after a previous step (e.g., adding a reverse solvent to a solution of the dissolved compound, or mixing / dissolving the compound in a solvent system). In another embodiment, the precipitate formation process may take a few minutes, several minutes, several hours, or several days. Each possibility represents a distinct embodiment of the present invention.

[0090] In one embodiment, when a solvent ratio (e.g., "X:X") is disclosed, the ratio is measured by volume.

[0091] While certain features of the present invention have been illustrated and described herein, many modifications, substitutions, alterations, and equivalents will now be conceivable to those skilled in the art. It should be understood that the appended claims are intended to cover all such modifications and alterations that fall within the true spirit of the invention. [Examples]

[0092] Example 1: Morphological screening

[0093] For compound 1, a total of eight forms and patterns were identified: N-2, E2-1 / IPA2-1 / M3-1 (also referred to as the -1 structure), P1, P2, P3, P4, P5, and P6 (Figures 1-10).

[0094] [Table 1]

[0095] The N-2 form is, for example, a neat form crystallized from THF / heptane. Additional conditions for isolating N-2 are summarized in Table 1. E2-1 (diethanolate), IPA2-1 (diisopropanolate), and M3-1 (trimethanolate) are alcohol solvates identical in structure to N-2, and their isolation conditions are summarized in Table 1. Phase purity is unknown for patterns P1-P6. Of the patterns identified so far, only P1 and P4 were obtained from isolated solids and are presumably neat / desolvated phases. The remaining patterns (P2, P3, P5, and P6) were obtained from slurries and were never isolated as dry solids. P2 and P3 are presumed solvates identical in structure to N-2 and converted to N-2 after drying.

[0096] High-throughput crystallization (HTC) screening of free bases

[0097] HTC solvent screening was performed for compound 1 alone (i.e., on a neutral plate) and in the presence of a weak acid (i.e., on a co-crystal plate) in a 96-well format (Figures 11A-11B). For each plate, 100 mg of the material was dissolved in 5 mL of tetrahydrofuran at room temperature (RT), and for the neutral plate, it was evenly divided into 96 wells (Figure 11A), and for the co-crystal plate, it was evenly divided into eight vials containing 2 equivalents of each weak acid listed in Figure 11b. A standard full-plate solvent / reverse solvent array was loaded into the neutral plate (see Figure 11A), and the solvents listed in Figure 11B were loaded into the co-crystal plate. Based on microscopic images, crystallization was evident in many wells for both plates. Crystallized solids were analyzed by Raman, and selected wells were also evaluated by GADDS (General Area Detector Diffraction System) and PXRD (Powder X-ray Diffraction) analysis. A new PXRD pattern, P4, was obtained from HTC neutral plate screens using the solvent systems MeCN / MTBE, DCM / heptane, DCM / MTBE, and MEK / cyclohexane. PXRD analysis allowed for the crystallization of N-2, P1, -1 structures, P4, or mixtures of these forms / phases from neutral and co-crystal plates. Several solvent systems yielded PXRD patterns similar to IPA2-1 / E2-1 (e.g., acetone / water, acetone / MTBE, THF / water, IPAC / heptane), suggesting that other solvents besides isopropanol, methanol, and ethanol may be incorporated into the -1 structure. No evidence of co-crystal formation was found from the HTC co-crystal screens.

[0098] Manual crystallization of free bases

[0099] Manual solvent screening was performed using 50 mg per 1 mL of the solvents listed in Table 2. Two new, unknown patterns, P5 and P6, were identified from recrystallization in acetone:water 1:1 (slurry pattern P5) and ethanol-water 1:1 (slurry pattern P6). After drying, both P5 and P6 were converted to N-2. Similar to the HTC study, other solvent systems (e.g., THF / heptane, acetone / heptane) produced patterns similar to IPA2-1 / E2-1 / M3-1 in the slurry, suggesting that other solvents may be incorporated into the -1 structure. The N-2 form was observed from several solvent systems, including acetonitrile (slurry), water (slurry and wet cake), DCM (slurry), acetic acid / water (slurry and wet cake), and ethyl acetate (slurry and wet cake).

[0100] [Table 2]

[0101] Example 2: Characterization of free base morphology

[0102] Characterization of N-2 and P1

[0103] The crystal structure of compound 1 was determined by single-crystal X-ray diffraction studies of elongated columnar crystals grown from THF / heptane. The intermolecular hydrogen bonds in the N-2 structure are shown in Figures 12A-12B, and this structure is approximately 20 Å. 3 It contains small voids. The experimental PXRD pattern of N-2 matches the simulated pattern confirming the single-phase identity of bulk crystallized N-2 (Figure 13). The slurry and dry PXRD patterns of N-2 match, indicating that N-2 crystallizes directly from solution. Thermal analysis of the material representing N-2 (acetic acid: crystallized from water) shows molten decomposition at approximately 290°C, with a weight loss of 0.05% at 250°C consistent with the neat morphology and the absence of solvent in the structure (Figure 14). After heating N-2 to 270°C, no physical changes in morphology are observed (Figure 1).

[0104] The first free base lot crystallized by Discovery Chemistry was either P1 or a mixture of P1 and IPA2-1. P1 is a desolvated phase that has not been observed to crystallize directly from solution. IPA2-1, E2-1, and M3-1 all convert to P1 upon drying. To date, single crystal structures or ssNMR have not been collected to confirm that P1 is a single phase.

[0105] DSC / TGA data for P1 show an exothermic transition initiated at approximately 130°C (Figure 14). Heating beyond the exothermic transition to 165°C forms N-2, suggesting a monotropic relationship between P1 and N-2, with N-2 being a more stable form below 290°C (Figure 15). Additional experiments confirmed that heating beyond the endothermic transition at 165°C converts P1 to N-2. However, additional peaks not consistent with any known crystalline form / phase were observed during cooling. P1 is also converted to N-2 after slurrying in aqueous solution (Figure 16), and N-2 is confirmed to be more stable than P1 in RT. Therefore, based on thermal data in RT and slurry conversion studies, N-2 and P1 are monotropic, with N-2 being a more stable form below 290°C.

[0106] Solid-state stability of N-2 free base form:

[0107] Solid-state stability was tested for N-2 only at 5°C, 25°C, 40°C / 75%RH (open and closed), and 50°C for up to 4 weeks. N-2 was chemically and physically stable under all conditions for up to 4 weeks. N-2 was also chemically and physically stable after 7 days of exposure to high-intensity light (HIL) / ultraviolet (UV) light, indicating that its handling under ambient conditions is not a concern.

[0108] Example 3: Preparation of N-2

[0109] N-2 was initially scaled up (1.4 g) by recrystallization in acetone:water 1:1.5 with an 89% yield. However, in this solvent system, N-2 is produced by desolvation of P5, the presumed acetone solvate. Recrystallization in the ternary solvent system acetic acid:ethanol:water (1:1:3) yielded N-2 in slurry, while acetic acid:IPA:water (1:1:3) yielded IPA2-1 solvate. Both of these solvent systems were not ideal, as they both had the potential to form IPA2-1 / E2-1 solvate depending on the corresponding solvent activity. Based on manual screening studies that showed N-2 crystallizes directly from several solvent systems (e.g., acetonitrile / water, DCM, and acetic acid / water), direct crystallization methods were evaluated. Since several patterns were observed from acetonitrile / water, i.e., P3 and N-2, the development of crystallization methods focused on acetic acid:water as the recrystallization solvent.

[0110] For IND (Investigative Drug) toxicology and First Human (FIH) batches, the API (active pharmaceutical ingredient) is isolated from a reaction mixture consisting of DMF / water and recrystallized from acetic acid:water (1:2.5). The current crystallization procedure involves first completely dissolving the API in acetic acid (5 mL / g) and adding water (12.5 ml / g) as the reverse solvent. The resulting slurry is stirred at room temperature for 2 hours, filtered, washed with water (2 × 3 ml / g), and dried at 50°C. The obtained form was confirmed to be N-2 by GADDS / PXRD.

[0111] Alternatively, the API is isolated from a reaction mixture consisting of DMF / water and from recrystallization from acetic acid:water (1:1.1). The API is completely dissolved in acetic acid (5 mL / g), and water (5.5 mL / g) is added as the reverse solvent. The resulting slurry is stirred at 15–25°C for 10–20 minutes, filtered, washed with water (2 × 5 mL / g), and dried at 50°C. The obtained form was confirmed to be N-2 by GADDS / PXRD.

[0112] Example 4: Solubility and bioavailability

[0113] N-2 has a water solubility of less than 1 μg / mL in water. Of the solvents tested, the solubility of N-2 was highest in PEG400 (approximately 38 mg / mL) and high molecular weight PEG. Slurrying N-2 in propylene glycol yielded a PXRD pattern similar to the simulated pattern of the -1 type structure, suggesting that compound 1 forms a solvate containing propylene glycol that is structurally equivalent to E2-1 / IPA2-1 / M3-1.

[0114] The oral absorption of compound 1 was found to be affected by solubility, dissolution rate, content of precipitation inhibitors in the formulation, and efflux-mediated permeability. When administered as a solution in ethanol / TPGS / PEG300 (10 / 10 / 80 v / v / v), the oral bioavailability of compound 1 in mice (2 mg / kg), rats (5 mg / kg), dogs (0.1 mg / kg), and monkeys (0.2 mg / kg) was 51%, 18%, 62%, and 25%, respectively. However, when compound 1 was administered as a microsuspension containing 3 μm d90 in 2% polyvinylpyrrolidone and 0.15% docusate sodium in water, the oral bioavailability in rats (5 mg / kg) was approximately 1%. When administered as an amorphous solid containing hypromellose acetate succinate, the oral bioavailability of compound 1 in rats (5 mg / kg) was approximately 5%. Compound 1 is a substrate for efflux transporters (efflux ratio of approximately 9 in the Caco2 assay at 3.7 μM). The bioavailability of Compound 1 in rats administered 5 mg / kg is increased to 100% with co-administration of Elacridar.

[0115] Solubilized capsule formulations were used to support the FIH study because compound 1 has low endogenous water solubility, poor oral absorption when administered as a microsuspension, and is classified as a Band 5 Special.

[0116] Example 5: Alternative synthesis of N-2 form

[0117] Morphology N-2 was prepared as follows. - Compound 1 is added to the reactor under nitrogen conditions. -4.0 mL / g equivalent of acetic acid is added to the reactor. - Adjust the contents of the reactor to 20±5℃, - Stir the contents of the reactor at 20±5°C until all solids are dissolved. -Transfer the contents of the reactor through a polished filter, -1.0 mL / g equivalent of acetic acid is added to the reactor. -Transfer the contents of the reactor through a polished filter, - The combined polish filtrate is returned to the reactor and transferred, -5.5 g / g equivalent of water is added to the reactor at a rate that maintains the internal temperature below 25°C. -The products in the reactor were isolated by vacuum filtration. -8.74 g / g equivalent of water is added to the reactor. -Transfer the contents of the reactor to a filter, -8.74 g / g equivalent of water is added to the reactor. -Transfer the contents of the reactor to a filter, -Transfer the product from the filter to a drying tray, - Dry the product at 50±5℃ until a certain weight is obtained. -The product was sampled and tested for residual acetic acid and water content by HPLC. - The dried product was placed in a suitable container and labeled.

[0118] Crude AL102 dissolved in acetic acid was polish-filtered using a disk filter, a 0.45 μM PTFE disposable filter, and a 3-piece 1 μM Hydradyne membrane. Dried products obtained from several different batches were characterized by XRPD and had diffractograms corresponding to the N-2 form (Figures 17-18). NMR, MS, FTIR, and HPLC indicated that the obtained compound batches characterized in Figure 18 were compound 1. HPLC showed assay purity of 98.3–101.7% (corrected for water, total volatiles, and acetic acid content). The particle size distribution was X for the first batch.10 = 3.3 μm, X 50 = 11.3 μm, and X 90 = 45.7 μm, for the second batch X 10 = 3.2 μm, X 50 = 12.2 μm, and X 90 = 33.4 μm were shown. The data demonstrated high between-batch reproducibility.

Claims

1. The crystalline form of (2R,3S)-N-((3S)-5-(3-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepine-3-yl)-2,3-bis(3,3,3-trifluoropropyl)succinimide is represented by the structure of compound 1 below, 【Chemistry 1】 The aforementioned crystal form has an N-2 crystal form, The N-2 crystal morphology is characterized by an XRPD pattern having peaks at 14.92±0.3, 15.49±0.3, 19.3±0.3, 19.64±0.3, and 21.57±0.3 degrees 2-theta (2θ), or by a crystal morphology characterized by unit cell parameters a=4.84±0.3 Å, b=18.47±0.3 Å, c=15.67±0.3 Å, α=90°, β=91.62±0.5°, γ=90°, a unit cell volume of 1399.51±0.5 ų, a number of compounds per asymmetric unit of 1, and a space group of P²¹.

2. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form described in Claim 1 and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is in the form of a solid, a suspension, or an emulsion.

4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is in solid form.

5. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a suspension.

6. The crystal morphology according to claim 1, wherein the N-2 crystal morphology is characterized by an XRPD pattern having peaks at 14.92±0.3 degrees, 15.49±0.3 degrees, 19.3±0.3 degrees, 19.64±0.3 degrees, and 21.57±0.3 degrees 2-theta (2θ).

7. The crystal morphology according to claim 6, characterized by the XRPD pattern having additional peaks at 11.12 ± 0.3 degrees and 12.23 ± 0.3 degrees 2-theta (2θ).

8. A pharmaceutical composition for use in the treatment of cancer, A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form described in claim 1 and a pharmaceutically acceptable carrier.

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