2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide and crystalline forms thereof

Abstract

Disclosed are a free base hemihydrate and a free base anhydrate of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide and crystalline forms thereof.

Description

[0001] Cross-referencing

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 598,169, filed November 13, 2023, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to the free base hemihydrate of 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide and its crystal form. Background Technology

[0004] Compound 2-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)piperidin-1-yl)acetamide has the structure of formula (I): (I) And is referred to herein as "compound (I)". Compound (I) is disclosed as Example 15 in WO 2018 / 005586 A1, which has been assigned to the assignee. The common name of compound (I) is afimetoran.

[0005] Compound (I) is an inhibitor of Toll-like receptors 7 and 8 (TLR7 / 8) and is currently in clinical trials for the treatment of lupus.

[0006] In the synthesis of chemical compounds for pharmaceutical use, it is necessary to isolate and purify the compound upon completion of the synthetic process and before further processing to provide the compound in a pharmaceutical formulation. The isolation and purification steps (which may be combined or separate sequential steps) provide the compound in a purified solid form with minimal yield loss during separation from other components of the reaction mixture and / or during purification to remove impurities from the isolated compound sample.

[0007] In preparing pharmaceutical compositions, a balanced form of the active ingredient with desired properties is sought, such as dissolution rate, solubility, bioavailability, and / or storage stability. For example, a form of the active ingredient with sufficient stability, solubility, and bioavailability is sought to prevent that form from transforming into another form with undesirable solubility and / or bioavailability profiles during the manufacture, preparation, and / or storage of the pharmaceutical composition. A form that is stable under ambient temperature and humidity conditions and has low hygroscopicity is also sought.

[0008] It is desirable to isolate purified compounds in solid form that are physically and chemically stable under a range of storage conditions, such as different temperatures and humidity conditions.

[0009] The applicant has discovered the form of compound (I), which is physically and chemically stable under a range of storage conditions.

[0010] In addition, the applicant has discovered a crystal form of compound (I), which unexpectedly provides compound (I) in solid form, which is physically and chemically stable under a range of storage conditions.

[0011] This invention also relates to other important aspects. Summary of the Invention

[0012] This invention provides a compound (I) in the form of a free base. This invention also provides a compound (I) in the form of a free base hemihydrate of crystal form B and a compound (I) in the form of anhydrous free bases of crystal forms N, O, and P. Attached Figure Description

[0013] Figure 1 The powder X-ray diffraction pattern of the observed free base hemihydrate crystal form B of compound (I) is shown (CuKa, λ = 1.54178 Å, T = 25 ℃).

[0014] Figure 2 The differential scanning calorimetry (DSC) temperature spectrum of free base hemihydrate crystal form B is shown, with endothermic reaction at approximately 275 °C.

[0015] Figure 3 The thermogravimetric analysis (TGA) temperature spectrum of free base hemihydrate crystal form B is shown.

[0016] Figure 4 The water adsorption isotherm of the ionized alkali hemihydrate crystal form B is shown at a temperature of 25 °C.

[0017] Figure 5 The powder X-ray diffraction pattern of the free base anhydrous form N of the observed compound (I) is shown (CuKa, λ = 1.54178 Å, T = 25 ℃).

[0018] Figure 6 The powder X-ray diffraction pattern of the free base anhydrous form O of the observed compound (I) is shown (CuKa, λ = 1.54178 Å, T = 25 ℃).

[0019] Figure 7 The powder X-ray diffraction pattern of the free base anhydrous form P of the observed compound (I) is shown (CuKa, λ = 1.54178 Å, T = 25 ℃). Detailed Implementation

[0020] After reading the following detailed description, those skilled in the art will more readily understand the features and advantages of the present invention. It should be understood that, for clarity, certain features of the invention described above and below in the context of individual embodiments can also be combined to form a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment can also be combined to form sub-combinations thereof.

[0021] The names used in this article to characterize specific forms ( For example "Crystal form B, etc." are merely identifiers, which should be interpreted in accordance with the characterization information presented herein and should not be limited to excluding any other substances having similar or identical physical and chemical characteristics. A particular form of name should be understood as merely an identifier to be interpreted in accordance with the characterization information presented herein.

[0022] The definitions set forth herein take precedence over those set forth in any patent, patent application and / or patent application publication incorporated herein by reference.

[0023] All figures indicating the quantity of ingredients, weight percentages, temperatures, etc., preceded by the word "approximately" should be understood as approximate values; therefore, slight variations above and below these figures can be used to achieve substantially the same result. Thus, unless otherwise indicated, numerical parameters preceded by the word "approximately" are approximate values ​​that can vary depending on the desired characteristics sought. To a minimum and without attempting to limit the application of the doctrine of equivalence to the scope of the claims, each numerical parameter should be interpreted at least according to the number of significant figures reported and by applying ordinary rounding techniques.

[0024] All measurements have experimental errors, which are within the spirit of this invention.

[0025] As used in this article, "polymorph" refers to a crystal form that has the same chemical structure but different spatial arrangements of molecules and / or ions that form crystals.

[0026] As used herein, "amorphous" refers to a solid form of molecules and / or ions that are not crystalline. Amorphous solids do not exhibit definite X-ray diffraction patterns with sharp maxima.

[0027] As used herein, “substantially pure” when referring to a crystal form means a purity greater than 90% by weight, including greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% by weight, and comprising approximately 100% by weight of compound (I). The remaining material comprises other forms of the compound, and / or reactive impurities and / or processing impurities arising from its preparation. For example, a crystal form of compound (I) may be considered substantially pure if it has a purity greater than 90% by weight, as measured by methods currently known and generally accepted in the art, wherein the remaining less than 10% by weight of material comprises amorphous and / or other forms of compound (I) and / or reactive and / or processing impurities.

[0028] As used herein, a powder X-ray diffraction (PXRD) pattern “contains” a number of peaks selected from a particular set of peaks, intended to include additional peaks in the PXRD pattern that are not included in the particular set of peaks. For example, a PXRD pattern contains four or more, preferably five or more, 2θ values ​​selected from the following: A, B, C, D, E, F, G, and H, intended to include PXRD patterns that: (a) have four or more, preferably five or more, 2θ values ​​selected from the following: A, B, C, D, E, F, G, and H; and (b) have zero or more peaks that are not one of the following: A, B, C, D, E, F, G, and H.

[0029] The presence of reaction impurities and / or processing impurities can be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry and / or infrared spectroscopy.

[0030] As used in this article, the cell parameter “number of molecules per cell” refers to the number of molecules of compound (I) in the cell.

[0031] A first aspect of the invention provides a compound (I) in the form of a free base hemihydrate solid. This solid form has a stoichiometry of 0.5 molecules of water per molecule of compound (I).

[0032] In one embodiment, compound (I) is provided in the form of a free base hemihydrate as a crystalline material.

[0033] In one embodiment, compound (I) is provided in the form of a free base hemihydrate as a pure crystalline material.

[0034] Compound (I) in the form of free base hemihydrate B

[0035] In one embodiment, the free base hemihydrate of compound (I) is provided as a crystalline material comprising form B. Crystal form B of the free base hemihydrate of compound (I) is a hemihydrate crystal form. Crystal form B is also referred to herein as "form B".

[0036] In one embodiment, the crystal form B of the free base hemihydrate of compound (I) is characterized by a unit cell parameter approximately equal to the following: a = 39.16 ± 0.10 Å b = 7.50 ± 0.10 Å c = 16.77 ± 0.10 Å α = 90.0 ± 1.0° β = 93.2 ± 1.0° γ = 90.0 ± 1.0° Space Group: C 2 / c Number of molecules per unit cell (Z): 8 Unit cell volume = 4920 ± 20 Å 3 The calculated density is 1.225 g / cm³. 3 The cell parameters of the free base hemihydrate form B of compound (I) were measured at a temperature of approximately 296 K.

[0037] Table 1

[0038] Compound (I) in the form of free base hemihydrate B

[0039] The selected PXRD 2θ value measured at room temperature (CuKα λ = 1.5418 Å)

[0040] In one embodiment, the crystal form B of the free base hemihydrate of compound (I) is characterized by a powder X-ray diffraction pattern containing four or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2, and 21.3 ± 0.2, wherein the PXRD pattern of crystal form B is measured at a temperature of about 25 °C.

[0041] In one embodiment, the crystal form B of the free base hemihydrate of compound (I) is characterized by a powder X-ray diffraction pattern containing five or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2, and 21.3 ± 0.2, wherein the PXRD pattern of crystal form B is measured at a temperature of about 25 °C.

[0042] In one embodiment, the crystal form B of the free base hemihydrate of compound (I) is characterized by a powder X-ray diffraction pattern containing six or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2, and 21.3 ± 0.2, wherein the PXRD pattern of crystal form B is measured at a temperature of about 25 °C.

[0043] In one embodiment, the crystal form B of the free alkaline hemihydrate of compound (I) is characterized by an observed powder X-ray diffraction pattern that is substantially as follows: Figure 1 As shown in the image.

[0044] In one embodiment, the crystal form B of the free base hemihydrate of compound (I) is characterized by a differential scanning calorimetry (DSC) temperature spectrum that is substantially as follows: Figure 2 As shown in the image.

[0045] In one embodiment, the crystal form B of the free base hemihydrate of compound (I) is characterized by endothermic activity in the range of 273°C to 277°C.

[0046] In one embodiment, the crystal form B of the free base hemihydrate of compound (I) is characterized by (i) a powder X-ray diffraction pattern containing 2q values ​​(CuKa l = 1.5418 Å) measured at a temperature of about 25 °C at 16.1 ± 0.2 and 21.3 ± 0.2; and (ii) a differential scanning calorimetry (DSC) temperature spectrum substantially consistent with... Figure 2 Consistent with what is shown.

[0047] In one embodiment, the crystal form B of the free base hemihydrate of compound (I) is characterized by: (i) a powder X-ray diffraction pattern containing four or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2 and 21.3 ± 0.2, wherein the PXRD pattern of crystal form B is measured at a temperature of about 25 °C; and (ii) a melting point in the range of 273 °C to 275 °C.

[0048] In one embodiment, the thermogravimetric analysis (TGA) temperature spectrum of crystal form B of the free base hemihydrate of compound (I) is essentially as follows: Figure 3 As shown in the image.

[0049] In one embodiment, the free base hemihydrate of compound (I) is characterized in that when heated to a temperature of about 220°C, the weight loss of the thermogravimetric analysis (TGA) temperature spectrum is about 2.3 to 2.7 wt% based on the weight of the sample of form B.

[0050] In one embodiment, the water adsorption isotherm exhibited by crystal form B of the free alkaline hemihydrate of compound (I) is essentially as follows: Figure 4 As shown. In Figure 4 In the free base hemihydrate of compound (I) in crystal form B, a variation of approximately 0.3% by weight was observed between 5% and 95% relative humidity.

[0051] In yet another further embodiment, the crystal form B of the free base hemihydrate of compound (I) is substantially pure.

[0052] In another embodiment, the crystal form of the free base hemihydrate of compound (I) is substantially composed of form B. The crystal form of this embodiment may contain at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight of form B of the free base hemihydrate of compound (I) based on the crystal form.

[0053] One embodiment provides a composition comprising a free alkali hemihydrate of compound (I), wherein at least 95% by weight, preferably at least 97% by weight and more preferably at least 99% by weight of the free alkali hemihydrate of compound (I) is crystal form B.

[0054] Compound (I) in the form of free base anhydrous N

[0055] In one embodiment, the free base of compound (I) is provided in the form of a crystalline material comprising form N. The crystal form N of the free base of compound (I) is an anhydrous crystal form. Crystal form N is also referred to herein as "form N".

[0056] Table 2

[0057] Compound (I) in the form of free base anhydrous N

[0058] The selected PXRD 2θ value measured at room temperature (CuKα λ = 1.5418 Å)

[0059] In one embodiment, the crystalline form N of the free anhydrous base of compound (I) is characterized by a powder X-ray diffraction pattern containing four or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 8.7 ± 0.2, 10.0 ± 0.2, 10.6 ± 0.2, 11.2 ± 0.2, 13.2 ± 0.2, 14.0 ± 0.2, 14.6 ± 0.2, 15.9 ± 0.2, 17.1 ± 0.2, 19.2 ± 0.2, 20.0 ± 0.2, 23.1 ± 0.2, and 24.4 ± 0.2, wherein the PXRD pattern of crystalline form N is measured at a temperature of about 25 °C.

[0060] In one embodiment, the crystalline form N of the free anhydrous base of compound (I) is characterized by a powder X-ray diffraction pattern comprising five or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 8.7 ± 0.2, 10.0 ± 0.2, 10.6 ± 0.2, 11.2 ± 0.2, 13.2 ± 0.2, 14.0 ± 0.2, 14.6 ± 0.2, 15.9 ± 0.2, 17.1 ± 0.2, 19.2 ± 0.2, 20.0 ± 0.2, 23.1 ± 0.2, and 24.4 ± 0.2, wherein the PXRD pattern of crystalline form N is measured at a temperature of approximately 25 °C.

[0061] In one embodiment, the crystalline form N of the free anhydrous base of compound (I) is characterized by a powder X-ray diffraction pattern containing six or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 8.7 ± 0.2, 10.0 ± 0.2, 10.6 ± 0.2, 11.2 ± 0.2, 13.2 ± 0.2, 14.0 ± 0.2, 14.6 ± 0.2, 15.9 ± 0.2, 17.1 ± 0.2, 19.2 ± 0.2, 20.0 ± 0.2, 23.1 ± 0.2, and 24.4 ± 0.2, wherein the PXRD pattern of crystalline form N is measured at a temperature of about 25 °C.

[0062] In one embodiment, the crystal form N of the free anhydrous base of compound (I) is characterized by an observed powder X-ray diffraction pattern that is substantially as follows: Figure 5 As shown in the image.

[0063] In one embodiment, the crystal form N of the free base anhydrous compound (I) is substantially pure.

[0064] In another embodiment, the crystal form of the free anhydrous base of compound (I) is substantially composed of form N. The crystal form of this embodiment may contain at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight of form N of the free anhydrous base of compound (I), based on the crystal form.

[0065] One embodiment provides a composition comprising anhydrous form of compound (I) free alkali, wherein at least 95% by weight, preferably at least 97% by weight and more preferably at least 99% by weight of the anhydrous form of compound (I) free alkali is crystalline form N.

[0066] Compound (I) in the form of free base anhydrous O

[0067] In one embodiment, the free base of compound (I) is provided in the form of a crystalline material comprising form O. Crystal form O of the free base of compound (I) is an anhydrous crystalline form. Crystal form O is also referred to herein as "form O".

[0068] Table 3

[0069] Compound (I) in the form of free base anhydrous O

[0070] The selected PXRD 2θ value measured at room temperature (CuKα λ = 1.5418 Å)

[0071] In one embodiment, the crystalline form O of the free anhydrous base of compound (I) is characterized by a powder X-ray diffraction pattern comprising four or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 7.0 ± 0.2, 9.3 ± 0.2, 10.4 ± 0.2, 13.3 ± 0.2, 14.1 ± 0.2, 15.0 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.0 ± 0.2, 18.7 ± 0.2, 21.0 ± 0.2, 21.7 ± 0.2, and 22.2 ± 0.2, wherein the PXRD pattern of crystalline form O is measured at a temperature of approximately 25 °C.

[0072] In one embodiment, the crystalline form O of the free anhydrous base of compound (I) is characterized by a powder X-ray diffraction pattern comprising five or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 7.0 ± 0.2, 9.3 ± 0.2, 10.4 ± 0.2, 13.3 ± 0.2, 14.1 ± 0.2, 15.0 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.0 ± 0.2, 18.7 ± 0.2, 21.0 ± 0.2, 21.7 ± 0.2, and 22.2 ± 0.2, wherein the PXRD pattern of crystalline form O is measured at a temperature of about 25 °C.

[0073] In one embodiment, the crystalline form O of the free anhydrous base of compound (I) is characterized by a powder X-ray diffraction pattern comprising six or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 7.0 ± 0.2, 9.3 ± 0.2, 10.4 ± 0.2, 13.3 ± 0.2, 14.1 ± 0.2, 15.0 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.0 ± 0.2, 18.7 ± 0.2, 21.0 ± 0.2, 21.7 ± 0.2, and 22.2 ± 0.2, wherein the PXRD pattern of crystalline form O is measured at a temperature of about 25 °C.

[0074] In one embodiment, the crystal form O of the free anhydrous base of compound (I) is characterized by the observed powder X-ray diffraction pattern being substantially as follows: Figure 6 As shown in the image.

[0075] In one embodiment, the crystal form O of the free base anhydrous compound (I) is substantially pure.

[0076] In another embodiment, the crystal form of the free anhydrous base of compound (I) is substantially composed of form O. The crystal form of this embodiment may contain at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight of form O of the free anhydrous base of compound (I) based on the crystal form.

[0077] One embodiment provides a composition comprising anhydrous form of compound (I) free alkali, wherein at least 95% by weight, preferably at least 97% by weight and more preferably at least 99% by weight of the anhydrous form of compound (I) free alkali is crystalline form O.

[0078] Compound (I) in the form of free base anhydrous form P

[0079] In one embodiment, the free base of compound (I) is provided in the form of a crystalline material comprising form P. The crystal form P of the free base of compound (I) is an anhydrous crystal form. Crystal form P is also referred to herein as "form P".

[0080] Table 4

[0081] Compound (I) in the form of free base anhydrous form P

[0082] The selected PXRD 2θ value measured at room temperature (CuKα λ = 1.5418 Å)

[0083] In one embodiment, the crystalline form P of the free anhydrous base of compound (I) is characterized by a powder X-ray diffraction pattern comprising four or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 6.0 ± 0.2, 8.1 ± 0.2, 8.8 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 12.1 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 21.5 ± 0.2, 22.2 ± 0.2, and 23.8 ± 0.2, wherein the PXRD pattern of crystalline form P is measured at a temperature of approximately 25 °C.

[0084] In one embodiment, the crystalline form P of the free anhydrous base of compound (I) is characterized by a powder X-ray diffraction pattern comprising five or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 6.0 ± 0.2, 8.1 ± 0.2, 8.8 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 12.1 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 21.5 ± 0.2, 22.2 ± 0.2, and 23.8 ± 0.2, wherein the PXRD pattern of crystalline form P is measured at a temperature of about 25 °C.

[0085] In one embodiment, the crystalline form P of the free anhydrous base of compound (I) is characterized by a powder X-ray diffraction pattern comprising six or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 6.0 ± 0.2, 8.1 ± 0.2, 8.8 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 12.1 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 21.5 ± 0.2, 22.2 ± 0.2, and 23.8 ± 0.2, wherein the PXRD pattern of crystalline form P is measured at a temperature of about 25 °C.

[0086] In one embodiment, the crystal form P of the free anhydrous base of compound (I) is characterized by an observed powder X-ray diffraction pattern that is substantially as follows: Figure 6 As shown in the image.

[0087] In one embodiment, the crystal form P of the free base anhydrous compound (I) is substantially pure.

[0088] In another embodiment, the crystal form P of the free anhydrous base of compound (I) is substantially composed of form P. The crystal form P of this embodiment may contain at least about 90% by weight, preferably at least about 95% by weight, and more preferably at least about 99% by weight of the free anhydrous base of compound (I) based on the crystal form.

[0089] One embodiment provides a composition comprising anhydrous form of compound (I) free alkali, wherein at least 95% by weight, preferably at least 97% by weight and more preferably at least 99% by weight of the anhydrous form of compound (I) free alkali is crystalline form P.

[0090] Crystal forms can be prepared by a variety of methods, including, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid-state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallizing or recrystallizing crystal forms from solvent mixtures include, for example, evaporating the solvent, lowering the temperature of the solvent mixture, adding crystal seeds to a supersaturated solvent mixture of molecules and / or salts, freeze-drying the solvent mixture, and adding an anti-solvent (back-extraction solvent) to the solvent mixture. High-throughput crystallization techniques can be used to prepare crystal forms including polymorphs.

[0091] Drug crystals (including polymorphs), preparation methods, and characterization of drug crystals are discussed. Solid-State Chemistry of Drugs This is discussed in SR Byrn, RR Pfeiffer and JG Stowell, 2nd edition, SSCI, WestLafayette, Indiana (1999).

[0092] For solvent-based crystallization techniques, the choice of one or more solvents typically depends on one or more factors, such as the solubility of the compound, the crystallization technique, and the vapor pressure of the solvent. Combinations of solvents can be used; for example, the compound can be dissolved in a first solvent to provide a solution, followed by the addition of an antisolvent to reduce the compound's solubility in the solution and promote crystal formation. An antisolvent is a solvent in which the compound has low solubility.

[0093] In one method for preparing crystals, the compound is suspended and / or stirred in a suitable solvent to provide a slurry, which may be heated to promote dissolution. As used herein, the term "slurry" means a saturated solution of the compound, which may also contain additional amounts of the compound to provide a heterogeneous mixture of the compound and solvent at a given temperature.

[0094] Seeding can be added to any crystallization mixture to promote crystallization. Seeding can be used to control the growth of specific polymorphs or to control the particle size distribution of the crystalline product. Therefore, the required amount of seed crystals depends on the size of the available seed crystals and the desired average product particle size, as in, for example, "Programmed Cooling of Batch Crystallizers," JW Mullin and J. Nyvlt. Chemical Engineering Science As described in 1971, 26, 369-377. Generally, small-sized seed crystals are required to effectively control crystal growth in a batch. Small-sized seed crystals can be generated by sieving, grinding, or micronizing large crystals, or by microcrystallization of solution. It should be noted that grinding or micronizing crystals does not result in any change in the crystallinity of the desired crystal form (i.e., becoming amorphous or another polymorph).

[0095] The cooled crystallized mixture can be filtered under vacuum, and the separated solids can be washed with a suitable solvent (such as a cold recrystallization solvent) and dried under nitrogen purging to obtain the desired crystal form. The separated solids can be analyzed by suitable spectroscopic or analytical techniques, such as solid-state nuclear magnetic resonance, differential scanning calorimetry, powder X-ray diffraction, etc., to ensure the preferred crystal form of the product. Based on the weight of the compound initially used in the crystallization process, the resulting crystal form is typically produced in an amount greater than about 70% by weight, preferably greater than 90% by weight. If necessary, the product can be co-ground or passed through a mesh sieve to disperse the product.

[0096] The crystal form can be prepared directly from the reaction medium of the final method used to prepare compound (I). For example, this can be achieved by using a solvent or solvent mixture from which compound (I) can crystallize in the final process step. Alternatively, the crystal form can be obtained by distillation or solvent addition techniques. Suitable solvents for this purpose include, for example, the nonpolar and polar solvents described above, including protic polar solvents such as alcohols and nonpolar polar solvents such as ketones.

[0097] The presence of more than one polymorph in a sample can be determined using techniques such as powder X-ray diffraction (PXRD) or solid-state nuclear magnetic resonance spectroscopy. For example, the presence of additional peaks in a comparison of experimentally measured PXRD patterns with simulated PXRD patterns may indicate the presence of more than one polymorph in the sample. Simulated PXRD can be calculated from single-crystal X-ray data. See Smith, DK, “ A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns,” Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (April 1963).

[0098] Various techniques can be used to characterize the forms of compound (I), the operation of which is well known to those skilled in the art. These forms can be characterized and distinguished using single-crystal X-ray diffraction, which is based on unit cell measurements of a single crystal at a fixed analytical temperature. A detailed description of the unit cell is provided in Chapter 3 of Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), which is incorporated herein by reference. Alternatively, another means of characterizing crystalline structures is by powder X-ray diffraction analysis, in which diffraction patterns are compared with simulated patterns representing the pure powder material, both run at the same analytical temperature, and measurements are taken to characterize the subject form as a series of 2q values ​​(typically four or more).

[0099] Other methods for characterizing this form can be used, such as solid-state nuclear magnetic resonance (ssNMR), differential scanning calorimetry, thermal analysis, and vibrational spectroscopy. These parameters can also be used in combination to characterize the subject form.

[0100] practicality

[0101] The free base hemihydrate of compound (I) can be used to separate compound (I) from other components at the end of the synthesis process; and / or to purify compound (I) by one or a series of crystallization steps.

[0102] Crystal form B of the free base hemihydrate of compound (I) can be used to separate compound (I) from other components at the end of the synthesis process; and / or to purify compound (I) by one or a series of crystallization steps. The separation and purification steps can be combined or operated as separate process steps.

[0103] The free base hemihydrate of compound (I) can be formulated into a pharmaceutical composition for oral administration.

[0104] The free base hemihydrate of compound (I), crystal form B, can be formulated into a pharmaceutical composition for oral administration.

[0105] The free base hemihydrate of compound (I) and its form B can be used as sources of purified compound (I) for the preparation of salts of compound (I).

[0106] Example

[0107] The invention will now be further described through the following working examples, which are preferred embodiments of the invention. Unless otherwise indicated, all temperatures are in degrees Celsius (°C). These examples are illustrative and not restrictive, and it should be understood that other embodiments may fall within the spirit and scope of the invention as defined by the appended claims.

[0108] The synthesis of compound (I) is disclosed in WO 2018 / 005586 as Example 15.

[0109] Example 1: Preparation of free base hemihydrate crystal form B of compound (I)

[0110] Compound (I) (100 mg) was placed in 41... Dissolved in 1 mL DMF at temperature C. The sample was cooled to room temperature, and 0.2 mL of water was added to the slurry of crystal form B. The slurry was stirred at room temperature for 2 days. The solid in the slurry was free alkali hemihydrate crystal form B.

[0111] Example 2: Preparation of free base hemihydrate crystal form B of compound (I)

[0112] Compound (I) (1.15 g) was dissolved in a 95:5 THF:water (volume:volume) solution at room temperature. Next, 1 mL of the solution was transferred to a vial. The vials were placed in a vacuum concentrator to evaporate the solvent from each vial.

[0113] Add 1 mL of 90:10 DCM:MeOH (volume:volume) to a small vial and stir the slurry for 13 days. The solid in the slurry is free alkali hemihydrate crystal form B.

[0114] Add 1 mL of 1 mL MIBK to another vial and stir the slurry for 13 days. The solid in the slurry is free base hemihydrate crystal form B.

[0115] Example 3: Preparation of the anhydrous crystal form N of the free base of compound (I)

[0116] Compound (I) (31 g) was added to 420 mL of EtOH in a volumetric flask. The solution was heated until all solids dissolved, and then cooled to room temperature. The solids were separated by vacuum filtration and characterized by PXRD.

[0117] Example 4: Preparation of the anhydrous crystal form O of the free base of compound (I)

[0118] The sample of compound (I) in its free basic form N (Example 3) was heated to 200°C in a pan using differential scanning calorimetry. The solid was then separated from the pan and analyzed by PXRD.

[0119] Example 5: Preparation of the anhydrous crystal form P of the free base of compound (I)

[0120] A sample of compound (I) in its free base form N (Example 3) was added to a 95:5 v:v THF / water solution at a concentration of 5 mg / mL and stirred with a stir bar for 1 day in a vial. The slurry was then rapidly vacuum dried. Next, 1 mL of MeOH was added to the vial to bring the concentration back to 5 mg / mL. The slurry was stirred with a stir bar at room temperature for 14 days. The solids were separated using vacuum filtration and dried in a vacuum oven set to 50°C for 5 days. The solids were analyzed by PXRD.

[0121] The solid-state stability of compound (I) in its free base hemihydrate form B was investigated by storing the sample under the following conditions: (i) In a closed container at 5°C; (ii) In an open container at 25°C / 60% relative humidity (RH); (iii) In an open container at 40°C / 75% relative humidity; and (iv) In a closed container at 50°C.

[0122] Physical stability, characterized by DSC, TGA, and PXRD, and chemical stability, characterized by HPLC, were measured at 2 and 4 weeks.

[0123] Table 5

[0124] In Table 5, physical stability analyses (PXRD, DSC, and TGA) show that Form B is physically stable for at least 4 weeks under all stress conditions.

[0125] In Table 2, chemical stability analysis by HPLC indicates that compound (I) in its free base hemihydrate form B did not show significant degradation for at least 4 weeks under all stress conditions.

[0126] Figure 4 The moisture adsorption isotherm of compound (I) free base hemihydrate crystal form B at 25°C is shown. In this measurement, the weight change of compound (I) free base hemihydrate crystal form B was approximately 0.3% by weight between 5% and 95% relative humidity, indicating that crystal form B of compound (I) free base hemihydrate is non-hygroscopic.

[0127] Single crystal data

[0128] Single-crystal X-ray data for Form B were collected using a Bruker X8-Proteum diffractometer equipped with an APEX II CCD detector and monochromatic Cu Kα radiation (λ = 1.54178 Å). The single crystal was kept at room temperature (approximately 25 °C) during data collection.

[0129] The indexing and processing of the measured intensity data were performed using the APEX2 program group (Bruker AXS, Inc., 5465 EastCheryl Parkway, Madison, WI 53711 USA).

[0130] The final unit cell parameters were determined using the complete dataset. These structures were solved using direct methods and refined using the SHELXTL software package (GM Sheldrick, SHELXTL v6.14, Bruker AXS, Madison, WI USA.) via full matrix least squares. Structure refinement involved refining the structures by ∑ w (| F o | - | F c |) 2 The defined function finds the minimum parameter value, where w It is an appropriate weighting factor based on the error of the observed intensity. F o It is a structural factor based on measured reflection, and F c It is a calculation-based reflection structure factor. This is achieved by using the residual factor. R = ∑|| F o |-| F c || / ∑| F o | and wR = [∑ w (| F o |-| F c |) 2 / ∑ w | F o |] 1 / 2To evaluate the consistency between the refined crystal structure model and experimental X-ray diffraction data, differential Fourier maps were examined at all stages of refinement. All non-hydrogen atoms were refined using anisotropic thermal displacement parameters. Hydrogen atoms were introduced using an idealized geometry with an isotropic temperature factor and included in the structure factor calculation with fixed parameters.

[0131] Powder X-ray diffraction (PXRD)

[0132] Form B PXRD data were collected using a Bruker D8 Discover DaVinci X-ray generator with an XYZ stage. An 1 μS X-ray generator operated with a Cu target (CuKα radiation) at 50 kV and 1 mA. The incident beam optics consisted of a Montel mirror with a 0.3 mm collimator. Photons were counted using an Eiger 2 R 500K detector in a 2D, 2θ optimized mode. The sample-to-detector distance was set to 140 mm. The sample was run for 1000 seconds in transmission, snapshot mode with the incident beam at 0° and the detector at 17.5°.

[0133] PXRD data for N, O, and P were obtained using Bruker C2 GADDS. The radiation was Cu Kα (40 kV, 40 mA). The sample-detector distance was 15 cm. The sample was placed in a sealed glass capillary with a diameter ≤ 1 mm. The capillary was rotated during data collection. Data were collected at approximately 2 ≤ 2θ ≤ 32° with a sample exposure time of at least 1000 seconds. The resulting two-dimensional diffraction arc was integrated to produce a conventional one-dimensional PXRD pattern with a step size of 0.05 degrees 2θ in the approximate range of 2 to 32 degrees 2θ.

[0134] Differential scanning calorimetry (DSC)

[0135] Differential scanning calorimetry (DSC) experiments were performed using a TA Instruments Discovery DSC 2500. Samples (approximately 1–5 mg) were weighed in a Tzero aluminum pan. The sample weight was recorded to the nearest hundredth of a milligram before transfer to the DSC. The instrument was purged with nitrogen at 50 mL / min. Data were collected between room temperature and 350 °C at a heating rate of 10 °C / min. DSC curves were generated with the endothermic peak pointing downwards.

[0136] Thermogravimetric analysis (TGA)

[0137] Thermogravimetric analysis (TGA) experiments were performed using a TA Instruments Discovery TGA 5500. Samples (approximately 1–10 mg) were placed in pre-cleaned, tar-coated platinum dishes. The weight of the sample was measured precisely using the instrument and recorded to the nearest milligram. The furnace was purged with nitrogen at 25 mL / min. Data were collected between room temperature and 400°C at a heating rate of 10°C / min.

[0138] Moisture adsorption isotherm

[0139] Moisture adsorption isotherm data were collected using approximately 10 mg of sample on a VTI SGA-100 symmetric vapor analyzer. Samples were tested at 25°C, with decreases and increases of 5% RH from 95% RH to 5% RH and back to 95% RH. Equilibrium was reached at each RH level when a rate of 0.0010 wt% / min was achieved for 60 minutes or a maximum of 120 minutes.

Claims

1. A free base hemihydrate of a compound (I): (I)。 2. The free base hemihydrate of compound (I) according to claim 1, wherein the free base hemihydrate of compound (I) is crystalline.

3. The free base hemihydrate of compound (I) according to claim 2, wherein the free base hemihydrate of compound (I) is pure.

4. The free base hemihydrate of compound (I) according to claim 2, wherein the free base hemihydrate of compound (I) is crystal form B.

5. The free alkaline hemihydrate of compound (I) according to claim 4, wherein the crystal form B is characterized in that the powder X-ray diffraction pattern (PXRD) comprises four or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2, and 21.3 ± 0.2, wherein the PXRD pattern of crystal form B is measured at a temperature of about 25 °C.

6. The free alkali hemihydrate of compound (I) according to claim 4, wherein the crystal form B is characterized in that the powder X-ray diffraction pattern (PXRD) comprises five or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2 and 21.3 ± 0.2, wherein the PXRD pattern of crystal form B is measured at a temperature of about 25 °C.

7. The free alkali hemihydrate of compound (I) according to claim 4, wherein the crystal form B is characterized in that the powder X-ray diffraction pattern (PXRD) comprises six or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 4.5 ± 0.2, 11.3 ± 0.2, 11.8 ± 0.2, 13.1 ± 0.2, 13.6 ± 0.2, 14.5 ± 0.2, 14.8 ± 0.2, 16.1 ± 0.2, 19.9 ± 0.2, and 21.3 ± 0.2, wherein the PXRD pattern of crystal form B is measured at a temperature of about 25 °C.

8. The free basic hemihydrate of compound (I) according to claim 4, wherein the crystal form B is characterized by: (i) The powder X-ray diffraction pattern includes 2q values ​​(CuKa l = 1.5418 Å) measured at approximately 25 °C at 16.1 ± 0.2 and 21.3 ± 0.2 Å; and (ii) Melting point in the range of 273°C to 277°C.

9. The free basic hemihydrate of compound (I) according to claim 4, wherein the crystal form B is characterized by: (i) The powder X-ray diffraction pattern includes 2q values ​​(CuKa l = 1.5418 Å) measured at approximately 25 °C at 16.1 ± 0.2 and 21.3 ± 0.2 Å; and (ii) The differential scanning calorimetry (DSC) temperature spectrum is essentially consistent with that shown in Figure 2.

10. The free base hemihydrate of compound (I) according to claim 4, wherein the crystal form B is characterized by: (i) The powder X-ray diffraction pattern includes 2q values ​​(CuKa l = 1.5418 Å) measured at approximately 25 °C at 16.1 ± 0.2 and 21.3 ± 0.2 Å; and (ii) From 25 Heat to 220°C At C, the weight loss is 0.2 to 0.4 wt%.

11. The free base hemihydrate of compound (I) according to claim 4, which is essentially composed of crystal form B.

12. The free base hemihydrate of compound (I) according to claim 4, wherein form B is substantially pure.

13. A composition comprising the free base hemihydrate of the compound (I) according to claim 1.

14. The composition according to claim 13, wherein at least 95% by weight of the free base hemihydrate of said compound (I) is crystal form B.

15. The crystalline free base anhydrous form of compound (I): (I)。 16. The crystalline free alkali anhydrous form of compound (I) according to claim 15, wherein the crystalline free alkali anhydrous form of compound (I) is crystalline form N, characterized in that the powder X-ray diffraction pattern comprises four or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 8.7±0.2, 10.0±0.2, 10.6±0.2, 11.2±0.2, 13.2±0.2, 14.0±0.2, 14.6±0.2, 15.9±0.2, 17.1±0.2, 19.2±0.2, 20.0±0.2, 23.1±0.2, and 24.4±0.2, wherein the PXRD pattern of crystalline form N is measured at a temperature of about 25°C.

17. The crystalline free alkali anhydrous form of compound (I) according to claim 15, wherein the crystalline free alkali anhydrous form of compound (I) is crystal form O, wherein crystal form O is characterized in that its powder X-ray diffraction pattern comprises four or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 7.0 ± 0.2, 9.3 ± 0.2, 10.4 ± 0.2, 13.3 ± 0.2, 14.1 ± 0.2, 15.0 ± 0.2, 16.0 ± 0.2, 16.6 ± 0.2, 17.0 ± 0.2, 18.7 ± 0.2, 21.0 ± 0.2, 21.7 ± 0.2, and 22.2 ± 0.2, wherein the PXRD pattern of crystal form O is measured at a temperature of about 25°C.

18. The crystalline free alkali anhydrous form of compound (I) according to claim 15, wherein the crystalline free alkali anhydrous form of compound (I) is crystal form P, wherein crystal form P is characterized in that its powder X-ray diffraction pattern comprises four or more 2θ values ​​selected from the following (CuKα λ = 1.5418 Å): 6.0 ± 0.2, 8.1 ± 0.2, 8.8 ± 0.2, 9.5 ± 0.2, 11.4 ± 0.2, 12.1 ± 0.2, 13.2 ± 0.2, 14.5 ± 0.2, 16.7 ± 0.2, 17.2 ± 0.2, 21.5 ± 0.2, 22.2 ± 0.2 and 23.8 ± 0.2, wherein the PXRD pattern of crystal form P is measured at a temperature of about 25°C.

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