Crystalline forms of asciminib hydrochloride

Abstract

The present invention relates to crystalline Form 1S of asciminib hydrochloride, asciminib solvate Forms 1, 2, 3, 4 and 6, methods for their preparation, and compositions containing said forms. [Formula 1] JPEG2025536048000013.jpg44170

Description

[Technical Field]

[0001] Background of the Invention The present invention relates to solid crystalline form 1S of asciminib hydrochloride (a compound represented by formula (1)), a solid crystalline form of asciminib hydrochloride solvate, and a method for producing the same.

[0002] [ka]

[0003] N-[4-[chloro(difluoro)methoxy]phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide hydrochloride is an allosteric inhibitor of BCR-ABL kinase. Asciminib hydrochloride has been approved and launched for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (PH+CML) in chronic phase (CP) who have been previously treated with two or more tyrosine kinase inhibitors (TKIs), and adult patients with Ph+CML in CP with the T315I mutation. Asciminib hydrochloride is disclosed in WO 2013 / 171639. Solid forms of asciminib hydrochloride are disclosed in WO 2021 / 154980 or WO 2020 / 230099. It would be advantageous to develop a crystalline form of asciminib hydrochloride that exhibits good flowability, crystallinity, stability (including chemical stability, polymorphic stability or stability to water), crystalline shape and processability compared to prior art solid forms. Summary of the Invention

[0004] The present invention relates to a solid crystalline form 1S of asciminib hydrochloride (a compound represented by formula (1)), a solid crystalline form of asciminib hydrochloride solvate, and a method for preparing the same.

[0005] [ka]

[0006] Furthermore, the present invention relates to pharmaceutical compositions containing crystalline form IS of asciminib hydrochloride.

[0007] Crystalline Form 1S of asciminib hydrochloride of the present invention has improved flowability, crystallinity, stability (including chemical stability, polymorphic stability or aqueous stability), crystal shape and processability compared to prior art solid forms. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 1 shows the X-ray powder diffractogram (XRPD) of crystalline form 1S of asciminib hydrochloride prepared in Example 6. [Figure 2] FIG. 2 shows the X-ray powder diffractogram (XRPD) of crystalline Form 1 of the 2-butanol solvate of asciminib hydrochloride prepared in Example 1. [Figure 3] FIG. 3 shows the X-ray powder diffractogram (XRPD) of crystalline Form 3 of the tert-butanol solvate of asciminib hydrochloride prepared in Example 2. [Figure 4] FIG. 4 shows the X-ray powder diffractogram (XRPD) of crystalline Form 4 of the isobutanol solvate of asciminib hydrochloride prepared in Example 3. [Figure 5] FIG. 5 shows the X-ray powder diffractogram (XRPD) of crystalline Form 6 of the 2-methyltetrahydrofuran solvate of asciminib hydrochloride prepared in Example 4. [Figure 6] FIG. 6 shows the X-ray powder diffractogram (XRPD) of crystalline Form 2 of the cyclohexanol solvate of asciminib hydrochloride prepared in Example 5. [Figure 7] FIG. 7 shows the DSC pattern of crystalline form 1S of asciminib hydrochloride prepared in Example 6. [Figure 8] FIG. 8 shows the TGA pattern of crystalline form 1S of asciminib hydrochloride prepared in Example 6. [Figure 9] FIG. 9 shows the DSC pattern of crystalline Form 1 of the 2-butanol solvate of asciminib hydrochloride prepared in Example 1. [Figure 10] FIG. 10 shows the TGA pattern of crystalline Form 1 of the 2-butanol solvate of asciminib hydrochloride prepared in Example 1. [Figure 11] FIG. 11 shows the DSC pattern of crystalline Form 3 of the tert-butanol solvate of asciminib hydrochloride prepared in Example 2. [Figure 12] FIG. 12 shows the TGA pattern of crystalline Form 3 of the tert-butanol solvate of asciminib hydrochloride prepared in Example 2. [Figure 13] FIG. 13 shows the DSC pattern of crystalline Form 4 of the isobutanol solvate of asciminib hydrochloride prepared in Example 3. [Figure 14] FIG. 14 shows the TGA pattern of crystalline Form 4 of the isobutanol solvate of asciminib hydrochloride prepared in Example 3. [Figure 15] FIG. 15 shows the DSC pattern of crystalline Form 6 of the 2-methyltetrahydrofuran solvate of asciminib hydrochloride prepared in Example 4. [Figure 16] FIG. 16 shows the TGA pattern of crystalline Form 6 of the 2-methyltetrahydrofuran solvate of asciminib hydrochloride prepared in Example 4. [Figure 17] FIG. 17 shows the DSC pattern of crystalline Form 2 of the cyclohexanol solvate of asciminib hydrochloride prepared in Example 5. [Figure 18] FIG. 18 shows the TGA pattern of crystalline Form 2 of the cyclohexanol solvate of asciminib hydrochloride prepared in Example 5. [Figure 19] FIG. 19 shows the crystalline shape of solid form 1S of asciminib hydrochloride prepared in Example 6. [Figure 20] FIG. 20 shows the crystalline shape of solid form 1S of asciminib hydrochloride prepared in Example 6. [Figure 21] FIG. 21 shows the crystalline shape of solid form A of asciminib hydrochloride of the prior art. DETAILED DESCRIPTION OF THE INVENTION

[0009] Detailed Description of the Invention This invention relates to solid form 1S of asciminib hydrochloride, a compound of formula (1), its preparation method and formulations containing it.

[0010] [ka]

[0011] Solid Form 1S can be characterized by an XRPD pattern with 2θ values ​​of 5.9°, 16.7°, and 19.4° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). Solid Form 1S can also be characterized by an XRPD pattern with 2θ values ​​of 5.9°, 11.3°, 16.7°, 19.4°, 22.0°, and 23.6° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). Solid Form 1S can be further characterized by the XRPD pattern shown in the table below when measured with CuKα1 radiation (λ=1.54060 Å).

[0012] [Table 1]

[0013] Crystalline Form 1S may also be characterized by the XRPD pattern shown in FIG. 1, the DSC pattern shown in FIG. 7, or the TGA pattern shown in FIG.

[0014] Solid Form 1S can be prepared by a process comprising drying a solvate of asciminib hydrochloride, preferably with a solvent selected from 2-butanol, isobutanol, tert-butanol, 2-methyltetrahydrofuran, and cyclohexanol, at 55°C to 65°C for 48 to 72 hours, wherein the solvate of asciminib hydrochloride is defined as crystallizing in a triclinic system with two lattice constant axes of 8 to 9.5 Å and the remaining lattice constant axes of 17.5 to 19 Å. Profile fitting and indexing were performed using FOXgrid software. Unit cell indexing was performed using the first 15 peaks using a bisection algorithm. All possible crystal systems were investigated while limiting the unit cell volume. The solution showing the highest figure of merit was selected and subjected to LeBail refinement using JANA 2020 software. The PV profile function was used for refinement. Sample offsets, profile parameters, and background coefficients, other than the lattice constants, were refined. The solutions were then evaluated based on the GoF and R-factor, which represent the reliability of the refinement.

[0015] A solvate of asciminib hydrochloride, preferably a solvate with a solvent selected from 2-butanol, isobutanol, tert-butanol, 2-methyltetrahydrofuran or cyclohexanol, which is defined as crystallizing in a triclinic system with two axial lengths of 8 to 9.5 Å and the remaining axial length of 17.5 to 19 Å, is 1. suspending asciminib hydrochloride, preferably in its amorphous form, in a solvent; 2. Stirring the mixture at 20°C to 30°C for 20 to 120 minutes; 3. isolating the solvate of asciminib hydrochloride; It can be produced by a method comprising:

[0016] All of the asciminib hydrochloride solvates prepared, preferably those with a solvent selected from 2-butanol, isobutanol, tert-butanol, 2-methyltetrahydrofuran, and cyclohexanol, are isostructural compounds. Generally, isostructural compounds are compounds that have different chemical compositions but similar crystal structures and packing patterns in solid state. Therefore, compounds with similar / identical arrangements of components exhibit similar diffraction patterns. Because the positions of diffraction peaks are determined by lattice constants, isostructural compounds exhibiting similar diffraction patterns also have nearly identical lattice constants. The asciminib hydrochloride solvates prepared by this method are defined as crystallizing in a triclinic system with two lattice constant axis lengths of 8-9.5 Å and the remaining axis length of 17.5-19 Å.

[0017] The concentration of asciminib hydrochloride, preferably in its amorphous form, in the solvent can be 0.07 g / ml to 0.5 g / ml. Asciminib hydrochloride, preferably in its amorphous form, is suspended in the solvent, and the mixture is stirred at 20°C to 30°C for 20 to 120 minutes. The resulting solid can be isolated by an appropriate technique, such as filtration, to obtain a solvate of asciminib hydrochloride.

[0018] The solid form of asciminib hydrochloride and 2-butanol solvate, Form 1, can be characterized by an XRPD pattern with 2θ values ​​of 4.9°, 10.3°, and 16.6° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). The solid form can also be characterized by an XRPD pattern with 2θ values ​​of 4.9°, 10.3°, 15.0°, 16.6°, and 22.1° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). Solid Form 1 can be further characterized by the XRPD pattern shown in the table below when measured with CuKα1 radiation (λ=1.54060 Å).

[0019] [Table 2]

[0020] Crystalline Form 1 may also be characterized by the XRPD pattern shown in FIG. 2, the DSC pattern shown in FIG. 9, or the TGA pattern shown in FIG.

[0021] A solid form of asciminib hydrochloride and tert-butanol solvate, Form 3, can be characterized by an XRPD pattern at 2θ values ​​of 5.0°, 10.5°, and 21.8° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). The solid form can be characterized by an XRPD pattern at 2θ values ​​of 5.0°, 10.5°, 16.8°, 21.4°, and 21.8° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). Solid Form 3 can be further characterized by the XRPD pattern shown in the table below when measured with CuKα1 radiation (λ=1.54060 Å).

[0022] [Table 3]

[0023] Crystalline Form 3 may also be characterized by the XRPD pattern shown in FIG. 3, the DSC pattern shown in FIG. 11, or the TGA pattern shown in FIG.

[0024] The solid form of asciminib hydrochloride and isobutanol solvate, Form 4, can be characterized by an XRPD pattern with 2θ values ​​of 10.2°, 16.6°, and 22.1° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). The solid form can also be characterized by an XRPD pattern with 2θ values ​​of 4.9°, 10.2°, 16.6°, 21.2°, and 22.1° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). Solid Form 4 can be further characterized by the XRPD pattern shown in the table below when measured with CuKα1 radiation (λ=1.54060 Å).

[0025] [Table 4]

[0026] Crystalline Form 4 may also be characterized by the XRPD pattern shown in FIG. 4, the DSC pattern shown in FIG. 13, or the TGA pattern shown in FIG.

[0027] A solid form of asciminib hydrochloride and 2-methyltetrahydrofuran solvate, Form 6, can be characterized by an XRPD pattern at 2θ values ​​of 4.9°, 16.9°, and 21.9° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). The solid form can be characterized by an XRPD pattern at 2θ values ​​of 4.9°, 10.4°, 16.9°, 20.9°, and 21.9° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). Solid Form 6 can be further characterized by the XRPD pattern shown in the table below when measured with CuKα1 radiation (λ=1.54060 Å).

[0028] [Table 5]

[0029] Crystalline Form 6 may also be characterized by the XRPD pattern shown in FIG. 5, the DSC pattern shown in FIG. 15, or the TGA pattern shown in FIG.

[0030] A solid form of asciminib hydrochloride and cyclohexanol solvate, Form 2, can be characterized by an XRPD pattern at 2θ values ​​of 10.1°, 16.5°, and 21.5° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). The solid form can be characterized by an XRPD pattern at 2θ values ​​of 4.9°, 10.1°, 15.9°, 16.5°, and 21.5° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å). Solid Form 6 can be further characterized by the XRPD pattern shown in the table below when measured with CuKα1 radiation (λ=1.54060 Å).

[0031] [Table 6]

[0032] Crystalline Form 2 may also be characterized by the XRPD pattern shown in FIG. 6, the DSC pattern shown in FIG. 17, or the TGA pattern shown in FIG.

[0033] Amorphous asciminib hydrochloride is 1. dissolving asciminib in a C1-C4 alcohol, preferably methanol; 2. adding concentrated hydrochloric acid and water, wherein the volume ratio of alcohol to water is 8:1-12:1, preferably 9:1-10:1; 3. concentrating the mixture; It can be produced by a method comprising:

[0034] The C1 to C4 alcohol can be selected from methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, isobutanol or tert-butanol, and is preferably methanol.

[0035] The concentration of asciminib in the C1-C4 alcohol can be 0.07 g / ml to 0.15 g / ml, preferably 0.09 g / ml to 0.11 g / ml. The mixture is heated to 40°C to 60°C to obtain a solution. Concentrated hydrochloric acid (35% vol / vol) is added to the solution. The molar ratio of hydrochloric acid to asciminib can be 3:1 to 3.5:1. Water is added to the mixture, where the volume ratio of alcohol to water is 8:1 to 12:1, preferably 9:1 to 10:1. The resulting mixture is concentrated, preferably under vacuum, to obtain amorphous asciminib hydrochloride.

[0036] The crystalline form of asciminib hydrochloride or its solvates of the present invention, preferably Form 1S, can be processed into suitable pharmaceutical formulations. In pharmaceutical formulations, the solid form can be mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier. The amount of the crystalline form prepared by the present invention, preferably Form 1S, in the formulation depends on the condition being treated and the patient. The pharmaceutical formulation can be a solid oral formulation, such as a capsule, pill, powder, or granule. In the formulation, the crystalline form prepared by the present invention, preferably Form 1S, can be mixed with one or more additives, such as a filler, extender, binder, wetting agent, disintegrant, absorbent, lubricant, or buffer. Tablets, dragees, capsules, pills, or granules can be coated with a coating or shell, such as an enteric coating or other coating. The oral formulation can be an oral emulsion, solution, suspension, or syrup. The formulation can contain suitable additives, such as diluents, wetting agents, emulsifiers, suspending agents, sweeteners, and flavoring agents. Examples of suitable additives are known to those skilled in the art.

[0037] Suitable pharmaceutical formulations can be in parenteral form, such as injections, infusions, or injectable depots, or in the form of liposomes, including pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, or emulsions. Pharmaceutical formulations can also be in the form of powders to be reconstituted into injections or infusions. The formulations can further include additives such as preservatives, wetting agents, emulsifying agents, dispersing agents, antibacterial agents, or antifungal agents. Examples of suitable additives are known to those skilled in the art.

[0038] Suitable pharmaceutical formulations may be in a form suitable for rectal or vaginal administration, further comprising suitable additives, examples of which are known to those skilled in the art.

[0039] The crystalline form of asciminib hydrochloride or a solvate thereof of the present invention, preferably Form 1S, and pharmaceutical formulations containing said form can be used in the treatment of conditions treatable with asciminib or a salt thereof. [Example]

[0040] Asciminib hydrochloride can be prepared by the method disclosed in WO 2013 / 171639, and the amorphous form of asciminib hydrochloride can be prepared by the method described in Example 7.

[0041] DCS / TGA patterns were obtained at 10°C / min, ->260°C.

[0042] Photographs of the crystals were obtained by SEM Tescan Vega.

[0043] The conditions for measuring the XRPD spectrum were as follows: Panalytical Empyrean diffractometer in Θ / 2Θ geometry (transmission mode) with a PixCell 3D detector

[0044] [Table 7]

[0045] Example 1 Preparation of Crystalline Form 1 of Asciminib Hydrochloride 2-Butanol Solvate 500 mg of amorphous asciminib hydrochloride was suspended in 5 ml of 2-butanol at 25° C. The mixture was stirred for 30 minutes and filtered to obtain solid form 1 of asciminib hydrochloride 2-butanol solvate in nearly 100% yield.

[0046] The obtained crystalline Form 1 can be characterized by the XRPD pattern shown in FIG. 2, the DSC pattern shown in FIG. 9, or the TGA pattern shown in FIG.

[0047] Example 2 Preparation of Crystalline Form 3 of Asciminib Hydrochloride Tert-Butanol Solvate 500 mg of amorphous asciminib hydrochloride was suspended in 5 ml of tert-butanol at 25° C. The mixture was stirred for 30 minutes and filtered to obtain solid form 3 of asciminib hydrochloride tert-butanol solvate in nearly 100% yield.

[0048] The obtained crystalline Form 3 can be characterized by the XRPD pattern shown in FIG. 3, the DSC pattern shown in FIG. 11, or the TGA pattern shown in FIG.

[0049] Example 3 Preparation of Crystalline Form 4 of Asciminib Hydrochloride Isobutanol Solvate 500 mg of amorphous asciminib hydrochloride was suspended in 5 ml of isobutanol at 25° C. The mixture was stirred for 30 minutes and filtered to obtain asciminib hydrochloride isobutanol solvate solid form 4 in nearly 100% yield.

[0050] The obtained crystalline Form 4 can be characterized by the XRPD pattern shown in FIG. 4, the DSC pattern shown in FIG. 13, or the TGA pattern shown in FIG.

[0051] Example 4 Preparation of Crystalline Form 6 of Asciminib Hydrochloride 2-Methyltetrahydrofuran Solvate 500 mg of amorphous asciminib hydrochloride was suspended in 5 ml of 2-methyltetrahydrofuran at 25° C. The mixture was stirred for 30 minutes and filtered to give solid Form 6 of the 2-methyltetrahydrofuran solvate of asciminib hydrochloride in nearly 100% yield.

[0052] The obtained crystalline Form 6 can be characterized by the XRPD pattern shown in FIG. 5, the DSC pattern shown in FIG. 15, or the TGA pattern shown in FIG.

[0053] Example 5 Preparation of Crystalline Form 2 of Asciminib Hydrochloride Cyclohexanol Solvate 500 mg of amorphous asciminib hydrochloride was suspended in 5 ml of cyclohexanol at 25° C. The mixture was stirred for 30 minutes and filtered to obtain solid Form 2 of the cyclohexanol solvate of asciminib hydrochloride in nearly 100% yield.

[0054] The obtained crystalline Form 2 can also be characterized by the XRPD pattern shown in FIG. 6, the DSC pattern shown in FIG. 17, or the TGA pattern shown in FIG.

[0055] Example 6 Preparation of Crystalline Form 1S of Asciminib Hydrochloride The solid forms prepared in Examples 1-6 were air-dried at 25° C. for 15 hours and then dried at 60° C. for 90 hours to obtain asciminib hydrochloride Form 1S.

[0056] The prepared crystalline Form 1S can also be characterized by the XRPD pattern shown in Figure 1, the DSC pattern shown in Figure 7, or the TGA pattern shown in Figure 8. The crystalline shape of the prepared Form 1S is shown in Figures 19 and 20. The crystalline shape of prior art Form A is shown in Figure 21. It can be concluded that the crystalline shape of Form 1S (uniform crystals) compared to Form A (needle-like crystals) leads to better processability of Solid Form 1S, both in terms of the processability of the solid form 1S and the processability into final products containing it.

[0057] Example 7 Preparation of Amorphous Form of Asciminib Hydrochloride 5 g of asciminib was suspended in 50 ml of methanol at 20-25°C. The mixture was stirred and heated to 50°C to obtain a solution. To this solution was added 1.331 g of concentrated hydrochloric acid (35%) and 5 ml of water. The mixture was concentrated to dryness under vacuum (2-20 kPa / 60°C) to obtain an amorphous form of asciminib hydrochloride.

[0058] Example 8 Lattice constants of asciminib hydrochloride solvate The lattice constants of the asciminib hydrochloride solvates prepared in Examples 1 to 5 are summarized in the following table (Rwp factors are shown in %):

[0059] [Table 8]

Claims

1. 1. Solid Form IS of asciminib hydrochloride, characterized by an XRPD pattern with 2θ values ​​of 5.9°, 16.7°, and 19.4° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å).

2. 2. The solid form of claim 1, characterized by an XRPD pattern with 2θ values ​​of 5.9°, 11.3°, 16.7°, 19.4°, 22.0°, and 23.6° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å).

3. 3. A method for preparing the solid form of claim 1 or 2, comprising drying a solid form of a solvate of asciminib hydrochloride at 55°C to 65°C for 48 to 72 hours, wherein the solvate is defined as crystallizing in a triclinic system with two axial lengths of 8 to 9.5 Å and the remaining axial length of 17.5 to 19 Å.

4. 4. The method of claim 3, wherein the solvate is selected from 2-butanol, isobutanol, tert-butanol, 2-methyltetrahydrofuran, or cyclohexanol.

5. 3. A method for preparing the solid form of claim 1 or 2, comprising drying a solid form of a solvate of asciminib hydrochloride at 55°C to 65°C for 48 to 72 hours, wherein the solvate is selected from 2-butanol, isobutanol, tert-butanol, 2-methyltetrahydrofuran, or cyclohexanol.

6. 6. The method of claim 5, wherein the solid form of the 2-butanol solvate is characterized by an XRPD pattern with 2θ values ​​of 4.9°, 10.3°, and 16.6° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å).

7. 6. The method of claim 5, wherein the solid form of the isobutanol solvate is characterized by an XRPD pattern with 2θ values ​​of 10.2°, 16.6°, and 22.1° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å).

8. 6. The method of claim 5, wherein the solid form of the tert-butanol solvate is characterized by an XRPD pattern with 2θ values ​​of 5.0°, 10.5°, and 21.8° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å).

9. 6. The method of claim 5, wherein the solid form of 2-methyltetrahydrofuran solvate is characterized by an XRPD pattern with 2θ values ​​of 4.9°, 16.9°, and 21.9° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å).

10. 6. The method of claim 5, wherein the solid form of the cyclohexanol solvate is characterized by an XRPD pattern with 2θ values ​​of 10.1°, 16.5°, and 21.5° (±0.2°) when measured with CuKα1 radiation (λ=1.54060 Å).

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