Crystalline melanocortin subtype 2 receptor (MC2R) antagonists

Abstract

Described herein are crystalline forms of N-[(3S)-1-azabicyclo [2.2. 2] oct-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)-cyclobutane carbonyl] piperazin-1-yl] pyridine-2-carboxamide and methods of making the same. N-[(3S)-1-azabicyclo [2.2. 2] oct-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)-cyclobutane carbonyl] piperazin-1-yl] pyridine-2-carboxamide in this form can be used for the preparation of a pharmaceutical composition for the treatment of a disease or condition, the disease or condition may benefit from the administration of a melanocortin subtype 2 receptor (MC2R) antagonist compound.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 387,884, filed on Dec. 16, 2022, the entire content of which is incorporated herein by reference. TECHNICAL FIELD

[0003] Described herein are crystalline forms of a melanocortin subtype-2 receptor (MC2R) antagonist compound, as well as pharmaceutical compositions thereof, methods of preparation thereof, and methods of use thereof in treating diseases or disorders that would benefit from treatment with an MC2R antagonist compound. BACKGROUND OF THE INVENTION

[0004] The melanocortin receptors form a family of G-protein coupled receptors (GPCRs) (MC1R, MC2R, MC3R, MC4R, and MC5R) that are selectively activated by different melanocortin peptides, adrenocorticotropic hormone (ACTH), and the melanocortin peptides α-, β-, and γ-melanocyte stimulating hormones (α-MSH, β-MSH, and γ-MSH), all of which are proteolytically derived from the proopiomelanocortin hormone or POMC protein. ACTH is a 39-amino acid peptide that is the main regulator of adrenal glucocorticoid synthesis and secretion and has an affinity only for MC2R. As a central actor in the hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted by the pituitary in response to stress stimuli and acts on the adrenals to stimulate cortisol synthesis and secretion. Modulation of MC2R is attractive for treating conditions, diseases, or disorders that would benefit from modulating melanocortin receptor activity. SUMMARY OF THE INVENTION

[0005] The present invention relates to various solid forms of the MC2R receptor antagonist N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide and methods for its preparation. This form of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide can be used to modulate the activity of the MC2R receptor in mammals that would benefit from such activity.

[0006] On the one hand, the present text describes the maleate of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I). In some embodiments, the maleate of Compound I is crystalline.

[0007] In some embodiments, the present text discloses a crystalline form of the maleate of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I).

[0008] In some embodiments, the crystalline maleate of Compound I is crystalline Form D. In some embodiments, the present text discloses a crystalline form of the maleate of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I),

[0009] wherein the crystalline maleate of Compound I is crystalline Form D and is characterized as having:

[0010] - an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown when measured using Cu(Kα) radiation; or Figure 1 an XRPD pattern that, when measured using Cu(Kα) radiation, has reflections at approximately 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ; or

[0011] - a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown; or

[0012] - a synchronous thermogravimetric analysis (TGA) / DSC thermogram that is substantially the same as that shown; or Figure 2 - a DSC thermogram having an endothermic peak onset temperature of 161.6 °C and a peak temperature of 168.4 °C; or an endothermic peak with an onset temperature of 158.1 °C and a peak temperature of 167.6 °C; or

[0013] - a TGA plot having a weight loss of 0.48% up to 180 °C; or Figure 3

[0014] - a DSC thermogram having an endothermic peak onset temperature of 161.6 °C and a peak temperature of 168.4 °C; or an endothermic peak with an onset temperature of 158.1 °C and a peak temperature of 167.6 °C; or

[0015] - a TGA plot having a weight loss of 0.48% up to 180 °C; or

[0016] At 100 K, the unit cell parameters are substantially equal to the following:

[0017]

[0018] ; or

[0020] - substantially the same dynamic vapor sorption (DVS) isotherm as shown in Figure 4 ; or

[0021] - a reversible mass increase of 1.14 wt% at 2% to 95% relative humidity (RH), no change in XRPD after DVS analysis at 2% to 95% RH, no change in XRPD after storage at 40 °C and 75% RH for at least one week, or a combination thereof;

[0022] or a combination thereof.

[0023] In some embodiments, crystalline form D of Compound I maleate is characterized as having an XRPD pattern measured using Cu(Kα) radiation that is substantially the same as that shown in Figure 1 . In some embodiments, the crystalline form is characterized as having an XRPD pattern with reflections at approximately 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ, measured using Cu(Kα) radiation. In some embodiments, the crystalline form is characterized as having: a DSC thermogram substantially the same as that shown in Figure 2 ; or a DSC thermogram with an endothermic peak having a start temperature of 161.6 °C and a peak temperature of 168.4 °C. In some embodiments, the crystalline form is characterized as having: a synchronous TGA / DSC thermogram substantially the same as that shown in Figure 3 ; or a DSC thermogram with an endothermic peak having a start temperature of 158.1 °C and a peak temperature of 167.6 °C; or a TGA with a weight loss of 0.48% up to 180 °C. In some embodiments, the crystalline form is characterized as having unit cell parameters at 100 K that are substantially equal to the following:

[0024]

[0025]

[0026] In some embodiments, crystalline form D of Compound I maleate is characterized as having: an X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 1 as measured using Cu(Kα) radiation; and a differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 2 ; orFigure 3 Substantially the same synchronous thermogravimetric analysis (TGA) / DSC thermogram as shown.

[0027] In some embodiments, crystalline form D of Compound I maleate is characterized as having: an XRPD pattern having reflections at about 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ when measured using Cu(Kα) radiation; and a DSC thermogram having an endothermic peak with a start temperature of 161.6 °C and a peak temperature of 168.4 °C; or an endothermic peak with a start temperature of 158.1 °C and a peak temperature of 167.6 °C; or a TGA pattern having a weight loss of 0.48% at up to 180 °C.

[0028] In some embodiments, crystalline form D of Compound I maleate is anhydrous.

[0029] In some embodiments, the crystalline maleate of Compound I is crystalline form C. In some embodiments, disclosed herein is a crystalline form of the maleate of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), wherein the crystalline maleate of Compound I is crystalline form C and is characterized as having:

[0030] - an X-ray powder diffraction (XRPD) pattern substantially the same as that shown Figure 5 when measured using Cu(Kα) radiation; or

[0031] - an XRPD pattern having reflections at about 4.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, and 18.4 ± 0.2° 2θ when measured using Cu(Kα) radiation; or

[0032] - a differential scanning calorimetry (DSC) thermogram substantially the same as that shown Figure 6 when measured using Cu(Kα) radiation; or

[0033] - a synchronous thermogravimetric analysis (TGA) / DSC thermogram substantially the same as that shown Figure 7 when measured using Cu(Kα) radiation; or

[0034] - a DSC thermogram having an endothermic peak with a start temperature of 144.1 °C and a peak temperature of 150.7 °C; or an endothermic peak with a start temperature of 141.7 °C and a peak temperature of 152.1 °C; or

[0035] - a TGA pattern having a weight loss of 0.45% at up to 170 °C; or

[0036] - identical to Figure 8 the dynamic vapor sorption (DVS) isotherm curve shown; or

[0037] - a reversible mass increase of 9.18 wt% at 2% to 95% relative humidity (RH), with a slight change in XRPD after DVS analysis at 2% to 95% RH, showing some conversion to the amorphous maleate of Compound I, and no change in XRPD after storage at 40 °C and 75% RH for at least one week, or a combination thereof;

[0038] or a combination thereof.

[0039] In some embodiments, crystalline Form C of Compound I maleate is characterized as having: an X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation that is substantially the same as that Figure 5 shown; and a differential scanning calorimetry (DSC) thermogram that is substantially the same as that Figure 6 shown; or a thermogravimetric analysis (TGA) / DSC thermogram that is substantially the same as that Figure 7 shown; or a dynamic vapor sorption (DVS) isotherm curve that is substantially the same as that Figure 8 shown.

[0040] In some embodiments, crystalline Form C of Compound I maleate is characterized as having: an XRPD pattern with reflections at approximately 4.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, and 18.4 ± 0.2° 2θ when measured using Cu(Kα) radiation; or a DSC thermogram that is substantially the same as that Figure 6 shown; and a DSC thermogram with an endothermic peak having a start temperature of 144.1 °C and a peak temperature of 150.7 °C; or an endothermic peak with a start temperature of 141.7 °C and a peak temperature of 152.1 °C; or a TGA profile with a weight loss of 0.45% up to 170 °C.

[0041] In some embodiments, the crystalline maleate of Compound I is crystalline Form B. The present invention discloses a crystalline form of the maleate of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), wherein the crystalline maleate of Compound I is crystalline Form B and is characterized as having:

[0042] - an X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation that is substantially the same as that Figure 9 shown; or

[0043] - An XRPD pattern measured using Cu(Kα) radiation having reflections at about 4.1 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, and 16.4 ± 0.2° 2θ; or

[0044] - Identical to Figure 10 the differential scanning calorimetry (DSC) thermogram shown; or

[0045] - Identical to Figure 11 the simultaneous thermogravimetric analysis (TGA) / DSC thermogram shown; or

[0046] - The onset temperature of the endothermic peak in the DSC thermogram is 141.4 °C and the peak temperature is 150.5 °C; or the onset temperature of the endothermic peak is 120.2 °C and the peak temperature is 131.4 °C; or

[0047] - Or a TGA profile having >4.7% weight loss up to 200 °C; or

[0048] - XRPD that converts to Form C after being placed for one week under ambient conditions;

[0049] Or a combination thereof.

[0050] In some embodiments, crystalline Form B of Compound I maleate is characterized as having: an X-ray powder diffraction (XRPD) pattern identical to that shown in Figure 9 when measured using Cu(Kα) radiation; and a differential scanning calorimetry (DSC) thermogram identical to that shown in Figure 10 or a simultaneous thermogravimetric analysis (TGA) / DSC thermogram identical to that shown in Figure 11 shown.

[0051] In some embodiments, crystalline Form B of Compound I maleate is characterized as having: an XRPD pattern having reflections at about 4.1 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, and 16.4 ± 0.2° 2θ when measured using Cu(Kα) radiation; and the onset temperature of the endothermic peak in the DSC thermogram is 141.4 °C and the peak temperature is 150.5 °C; or the onset temperature of the endothermic peak is 120.2 °C and the peak temperature is 131.4 °C; or a TGA profile having >4.7% weight loss up to 200 °C.

[0052] In some embodiments, the crystalline maleate of Compound I is crystalline Form A. Disclosed herein is a crystalline form of the maleate of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), wherein the crystalline maleate of Compound I is crystalline Form A and is characterized as having:

[0053] - an X-ray powder diffraction pattern (XRPD) measured using Cu(Kα) radiation that is substantially the same as that shown in Figure 12 ; or

[0054] - an XRPD pattern measured using Cu(Kα) radiation having reflections at approximately 4.2 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, and 12.5 ± 0.2° 2θ; or

[0055] - an XRPD that converts to Form C after being placed under ambient conditions for about three days; or

[0056] - an XRPD that converts to Form C after drying in a vacuum oven at 50 °C, 10 -2 - 10 -1 torr for 20 hours;

[0057] or a combination thereof.

[0058] In some embodiments, crystalline Form A of the maleate of Compound I is characterized as having an X-ray powder diffraction pattern (XRPD) measured using Cu(Kα) radiation that is substantially the same as that shown in Figure 12 .

[0059] In some embodiments, crystalline Form A of the maleate of Compound I is characterized as having an XRPD pattern measured using Cu(Kα) radiation having reflections at approximately 4.2 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, and 12.5 ± 0.2° 2θ.

[0060] In some embodiments, disclosed herein is a crystalline form of the maleate of Compound I, which is crystalline Form D, and optionally further comprises: crystalline Form C, crystalline Form B, crystalline Form A, or an amorphous form of the maleate of Compound I, or a combination thereof.

[0061] On the other hand, this text describes the mandelate salt of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I). In some embodiments, the mandelate salt of Compound I is crystalline. In some embodiments, this text discloses a crystalline form of the mandelate salt of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I). In some embodiments, the crystalline mandelate salt of Compound I is crystalline Form E. In some embodiments, what is disclosed herein is a crystalline form of the mandelate salt of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), wherein the crystalline mandelate salt of Compound I is crystalline Form E and is characterized as having:

[0062] - An X-ray powder diffraction pattern (XRPD) that is substantially the same as that shown Figure 13 when measured using Cu(Kα) radiation; or

[0063] - An XRPD that has X-ray diffraction pattern reflections at about 5.6 ± 0.2° 2θ, 10.5 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, and 16.5 ± 0.2° 2θ when measured using Cu(Kα) radiation; or

[0064] - A differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown Figure 14 ; or

[0065] - A simultaneous thermogravimetric analysis (TGA) / DSC thermogram that is substantially the same as that shown Figure 15 ; or

[0066] - The onset temperature of the endothermic peak in the DSC thermogram is 141.0 °C and the peak temperature is 152.8 °C; or the onset temperature of the endothermic peak is 139.8 °C and the peak temperature is 154.2 °C; or

[0067] - A TGA profile with a weight loss of 1.92% up to 170 °C; or

[0068] - A dynamic vapor sorption (DVS) isotherm that is substantially the same as that shown Figure 16 ; or

[0069] -A reversible mass increase of 5.68 wt% at 2% to 95% relative humidity (RH), no change in XRPD after DVS analysis at 2% to 95% RH, no change in XRPD after storage at 40 °C and 75% RH for at least one week, or a combination thereof;

[0070] or a combination thereof.

[0071] In some embodiments, crystalline form E of Compound I mandelate is characterized as having: an X-ray powder diffraction pattern (XRPD) measured using Cu(Kα) radiation that is substantially the same as that shown in Figure 13 ; and a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 14 ; or a thermogravimetric analysis (TGA) / DSC thermogram that is substantially the same as that shown in Figure 15 ; or a dynamic vapor sorption (DVS) isotherm that is substantially the same as that shown in Figure 16 .

[0072] In some embodiments, crystalline form E of Compound I mandelate is characterized as having: an XRPD with X-ray diffraction pattern reflections at approximately 5.6 ± 0.2° 2θ, 10.5 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, and 16.5 ± 0.2° 2θ measured using Cu(Kα) radiation; and the onset temperature of the endothermic peak in the DSC thermogram is 141.0 °C and the peak temperature is 152.8 °C; or the onset temperature of the endothermic peak is 139.8 °C and the peak temperature is 154.2 °C; or a TGA profile with a weight loss of 1.92% at up to 170 °C.

[0073] In another aspect, the present disclosure describes a pharmaceutical composition comprising a compound or solid form described herein. In some embodiments, described herein is a pharmaceutical composition comprising a maleate or solid form described herein and at least one pharmaceutically acceptable excipient. In some embodiments, described herein is a pharmaceutical composition comprising a mandelate or solid form described herein and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in the form of a solid form pharmaceutical composition. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, or capsule.

[0074] On the other hand, the present disclosure describes a method for preparing crystalline form D of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I) maleate:

[0075]

[0076] Comprising:

[0077] (1) Contacting Compound I with maleic acid in a suitable solvent to form a mixture;

[0078] (2) Adding a suitable antisolvent to the mixture and seeding the mixture with D-form crystals of Compound I maleate;

[0079] (3) Heating the mixture at a suitable temperature for a sufficient time to obtain a slurry;

[0080] (4) Cooling the slurry at a suitable cooling rate; and

[0081] (5) Filtering the slurry to obtain crystalline Form D of Compound I maleate.

[0082] In some embodiments, the suitable solvent in step (1) is ethanol, isopropanol, acetone, acetonitrile, methyl acetate, ethyl acetate, methyl isobutyl ketone (MIBK), water, or a combination thereof. In some embodiments, the suitable solvent in step (1) is a mixture of isopropanol and MIBK. In some embodiments, the mixture in step (1) is heated to about 50 °C. In some embodiments, relative to the amount of Compound I in the mixture, the mixture in step (1) contains about 1.1 equivalents of maleic acid and about 6 volumes of a 5:1 mixture of isopropanol and MIBK.

[0083] In some embodiments, the antisolvent in step (2) is methyl tert-butyl ether (MtBE), MIBK, water, heptane, or a combination thereof. In some embodiments, the antisolvent in step (2) is heptane. In some embodiments, about 4 to about 10 volumes of heptane are added to the mixture in step (2) relative to the amount of Compound I. In some embodiments, the amount of D-form seed crystals added to the mixture in step (2) relative to the amount of Compound I in the mixture is about 0.05%, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.5%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, or about 1.00%.

[0084] In some embodiments, the mixture is heated to a temperature of about 40 °C to about 50 °C in step (3). In some embodiments, the mixture is heated to a temperature of about 50 °C in step (3) for at least 8 h, at least 12 h, at least 18 h, or longer. In some embodiments, the mixture is heated to a temperature of about 50 °C in step (3) for about 18 hours.

[0085] In some embodiments, in step (4), the slurry is cooled to a temperature of about 20 °C at a rate of up to 2.5 °C / min. In some embodiments, in step (4), the slurry is cooled to a temperature of about 20 °C in about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes or longer. In some embodiments, in step (4), the slurry is cooled to a temperature of about 20 °C in about 45 minutes.

[0086] In some embodiments, the crystalline form D of Compound I maleate obtained in step (5) after filtration is dried under vacuum.

[0087] In some embodiments, the method further comprises recrystallizing the crystalline form D of Compound I maleate obtained in step (5). In some embodiments, recrystallizing the crystalline form D of Compound I maleate comprises:

[0088] i. contacting the D-form of Compound I maleate with a suitable solvent to obtain a mixture;

[0089] ii. heating the mixture of step (i) to obtain a solution;

[0090] iii. seeding the solution with crystals of the D-form of Compound I maleate to obtain a mixture;

[0091] iv. adding a suitable anti-solvent to the mixture at a suitable time;

[0092] v. heating the mixture for a suitable time to obtain a slurry;

[0093] vi. cooling the slurry at a suitable cooling rate; and

[0094] vii. filtering the slurry to obtain the crystalline form D of Compound I maleate.

[0095] In some embodiments, the suitable solvent in step (i) is ethanol, isopropanol, acetone, methyl acetate, or a combination thereof; and wherein about 4 to about 10 volumes of the solvent are used in step (i) relative to the amount of Compound I in the mixture. In some embodiments, about 4 volumes of isopropanol are used in step (i) relative to the amount of Compound I in the mixture.

[0096] In some embodiments, the mixture is heated to a temperature of about 30 °C to about 50 °C in step (ii). In some embodiments, the recrystallization further comprises cooling the solution obtained in step (ii) to a temperature of about 30 °C in about 2 hours before seeding in step (iii).

[0097] In some embodiments, the amount of D-form seed crystals added to the mixture in step (iii) is about 0.25%, about 0.50%, about 0.75%, about 1.0%, about 1.25%, about 1.50%, about 1.75%, about 2.0%, about 2.25%, about 2.5%, about 2.75%, about 3.0%, about 3.25%, about 3.5%, about 3.75%, about 4.0%, about 4.25%, about 4.5%, about 4.75%, or about 5.0% relative to the amount of Compound I in the mixture.

[0098] In some embodiments, a suitable anti-solvent for step (iv) is MtBE, heptane, or a combination thereof; and wherein about 3 volumes to about 10 volumes of the solvent are used in step (iv) relative to the amount of Compound I in the mixture. In some embodiments, a suitable anti-solvent for step (iv) is MtBE; and wherein the MtBE is added over at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, or longer.

[0099] In some embodiments, in step (v), the mixture is heated to about 40 °C and held for about 1 h, about 2 h, or about 3 h. In some embodiments, in step (vi), the slurry obtained in step (v) is cooled to a temperature of about 20 °C at a maximum rate of 2.5 °C / min. In some embodiments, in step (vi), the slurry obtained in step (v) is cooled to a temperature of about 20 °C over about 30 minutes, about 60 minutes, about 90 minutes, about 120 minutes, or longer. In some embodiments, in step (vi), the slurry obtained in step (v) is cooled to a temperature of about 20 °C within about 120 minutes.

[0100] In some embodiments, before step (vii), the cooled slurry from step (vi) is held at about 20 °C for at least 2 hours, at least 3 hours, at least 4 hours, or longer. In some embodiments, before step (vii), the cooled slurry from step (vi) is held at about 20 °C for about 4 hours. In some embodiments, the crystalline form D of Compound I maleate obtained in step (vii) after filtration is vacuum dried at a temperature of about 50 °C.

[0101] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples are given by way of illustration only, since various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0102] Figure 1Shows the X-ray powder diffraction pattern of crystalline form D of Compound I maleate measured using Cu(Kα) radiation.

[0103] Figure 2 Shows the DSC thermogram of crystalline form D of Compound I maleate.

[0104] Figure 3 Shows the simultaneous TGA / DSC thermogram of crystalline form D of Compound I maleate.

[0105] Figure 4 Shows the DVS isothermal curve of crystalline form D of Compound I maleate.

[0106] Figure 5 Shows the X-ray powder diffraction pattern of crystalline form C of Compound I maleate measured using Cu(Kα) radiation.

[0107] Figure 6 Shows the DSC thermogram of crystalline form C of Compound I maleate.

[0108] Figure 7 Shows the simultaneous TGA / DSC thermogram of crystalline form C of Compound I maleate.

[0109] Figure 8 Shows the DVS isothermal curve of crystalline form C of Compound I maleate.

[0110] Figure 9 Shows the X-ray powder diffraction pattern of crystalline form B of Compound I maleate measured using Cu(Kα) radiation.

[0111] Figure 10 Shows the DSC thermogram of crystalline form B of Compound I maleate.

[0112] Figure 11 Shows the simultaneous TGA / DSC thermogram of crystalline form B of Compound I maleate.

[0113] Figure 12 Shows the X-ray powder diffraction pattern of crystalline form A of Compound I maleate measured using Cu(Kα) radiation.

[0114] Figure 13 Shows the X-ray powder diffraction pattern of crystalline form E of Compound I mandelate measured using Cu(Kα) radiation.

[0115] Figure 14 Shows the DSC thermogram of crystalline form E of Compound I mandelate.

[0116] Figure 15Show the synchronous TGA / DSC thermogram of crystalline form E of compound I mandelate.

[0117] Figure 16 Show the DVS isothermal curve of crystalline form E of compound I mandelate.

[0118] Figure 17 Show the comparison of X-ray powder diffraction patterns of crystalline forms B, C, and D of compound I maleate measured using Cu(Kα) radiation.

[0119] Figure 18 Show the X-ray powder diffraction pattern of amorphous compound I measured using Cu(Kα) radiation.

[0120] Figure 19 Show the DSC thermogram of amorphous compound I.

[0121] Figure 20 Show the synchronous TGA / DSC thermogram of amorphous compound I.

[0122] Figure 21 Show the thermal ellipsoid representation of all atoms in the asymmetric unit of the structure of compound I maleate determined by single-crystal X-ray diffraction at the 50% probability level.

[0123] Figure 22 Show the overlay of the predicted XRPD pattern (2) and the actual XRPD pattern of compound I maleate, pattern D(1).

[0124] Figure 23 Show the disorder of trifluoromethyl-cyclobutyl in the structure of compound I maleate determined by single-crystal X-ray diffraction. Detailed Description

[0125] N-[(3S)-1-Azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)-cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I) is an effective and selective MC2R antagonist. MC2R is a highly selective receptor for adrenocorticotropic hormone (ACTH). The main function of MC2R is to stimulate the synthesis and secretion of cortisol by the fasciculata cells of the adrenal cortex. MC2R antagonists can be used to treat diseases or disorders in which abnormal ACTH signaling plays a role, such as Cushing's disease, Cushing's syndrome, ectopic ACTH syndrome (EAS), and congenital adrenal hyperplasia (CAH).

[0126] Compound I

[0127] Compound I is an effective, selective, and orally available MC2R antagonist that can be used to treat a variety of diseases or conditions described herein, such as Cushing's disease, Cushing's syndrome, ectopic ACTH syndrome (EAS), and congenital adrenal hyperplasia (CAH).

[0128] The preparation and use of Compound I have been previously described (see WO 2019 / 236699, US 10,562,884, US10,604,507, US10,766,877, US10,981,894, USSN 17 / 170,396, PCT / US2022 / 020543, and USSN 17 / 696,279, the entire content of each document is incorporated herein by reference).

[0129] Compound I is N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide, and its chemical structure is as follows:

[0130]

[0131] In some embodiments provided herein, Compound I is crystalline.

[0132] In some embodiments, salts of Compound I are disclosed herein. In some embodiments disclosed herein, the salts of Compound I are maleate or mandelate. In some embodiments disclosed herein, the salt of Compound I is maleate. In some embodiments disclosed herein, the salt of Compound I is mandelate.

[0133] In some embodiments disclosed herein, the salts of Compound I are crystalline. In some embodiments, crystalline maleate or crystalline mandelate of Compound I are disclosed herein. In some embodiments, crystalline maleate of Compound I is disclosed herein. In some embodiments, crystalline mandelate of Compound I is disclosed herein.

[0134] In some embodiments provided herein, Compound I or a salt thereof is in single crystal form. In some embodiments provided herein, Compound I or a salt thereof is in single crystal form that is substantially free of any other crystalline forms. In some embodiments, the crystalline solid form is a single solid form, such as crystalline Form D. In some embodiments, "substantially free of" means less than about 10% w / w, less than about 9% w / w, less than about 8% w / w, less than about 7% w / w, less than about 6% w / w, less than about 5% w / w, less than about 4% w / w, less than about 3% w / w, less than about 2.5% w / w, less than about 2% w / w, less than about 1.5% w / w, less than about 1% w / w, less than about 0.75% w / w, less than about 0.50% w / w, less than about 0.25% w / w, less than about 0.10% w / w or less than about 0.05% w / w of any other crystalline form (e.g., Form C) in a sample of crystalline Form D. In some embodiments, "substantially free of" means an undetectable amount (e.g., by XRPD analysis).

[0135] In some embodiments, the crystallinity of the solid form is determined by X-ray powder diffraction (XRPD).

[0136] Crystalline Form D of Compound I maleate

[0137] In some embodiments, provided herein is the maleate or solvate of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), which is in crystalline Form D. Some embodiments provide a composition comprising crystalline Form D of Compound I maleate. In some embodiments, crystalline Form D of Compound I maleate is characterized as having:

[0138] · an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown Figure 1 using Cu(Kα) radiation; or

[0139] · an XRPD pattern that has reflections at about 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ and 14.0 ± 0.2° 2θ when measured using Cu(Kα) radiation; or

[0140] · a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown Figure 2 using Cu(Kα) radiation; or

[0141] · a thermogravimetric analysis (TGA) / DSC thermogram that is substantially the same as that shown Figure 3 using Cu(Kα) radiation; or

[0142] ·The onset temperature of the endothermic peak in the DSC thermogram is 161.6 °C and the peak temperature is 168.4 °C; or the onset temperature of the endothermic peak is 158.1 °C and the peak temperature is 167.6 °C; or

[0143] ·A TGA thermogram with a weight loss of 0.48% up to 180 °C; or

[0144] ·At 100 K, the unit cell parameters are substantially equal to the following:

[0145] ; or

[0147] ·A dynamic vapor sorption (DVS) isotherm curve substantially the same as that shown in Figure 4 ; or

[0148] ·A reversible mass increase of 1.14 wt% at 2% to 95% relative humidity (RH), no change in XRPD after DVS analysis at 2% to 95% RH, no change in XRPD after storage at 40 °C and 75% RH for at least one week, or a combination thereof;

[0149] or a combination thereof.

[0150] In some embodiments, crystalline form D of Compound I maleate is characterized as having an XRPD pattern with reflections at approximately 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ measured using Cu(Kα) radiation.

[0151] In some embodiments, crystalline form D of Compound I maleate is characterized as having an XRPD pattern with reflections at approximately 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ measured using Cu(Kα) radiation; and an endothermic peak in the DSC thermogram with an onset temperature of 161.6 °C and a peak temperature of 168.4 °C; or an onset temperature of the endothermic peak of 158.1 °C and a peak temperature of 167.6 °C.

[0152] In some embodiments, crystalline form D of Compound I maleate is characterized as having an XRPD pattern with reflections at approximately 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ measured using Cu(Kα) radiation; and a TGA thermogram with a weight loss of 0.48% up to 180 °C.

[0153] In some embodiments, crystalline form D of Compound I maleate is characterized as having an XRPD pattern with reflections at approximately 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ measured using Cu(Kα) radiation; a DSC thermogram with an endothermic peak having an onset temperature of 161.6 °C and a peak temperature of 168.4 °C; or an endothermic peak having an onset temperature of 158.1 °C and a peak temperature of 167.6 °C; and a TGA profile with a weight loss of 0.48% up to 180 °C.

[0154] In some embodiments, crystalline form D of Compound I maleate is characterized as having an Figure 1 XRPD pattern measured using Cu(Kα) radiation that is substantially the same as that shown.

[0155] In some embodiments, crystalline form D of Compound I maleate is characterized as having an Figure 1 XRPD pattern measured using Cu(Kα) radiation that is substantially the same as that shown; and a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 2 In some embodiments, crystalline form D of Compound I maleate is characterized as having an

[0156] XRPD pattern measured using Cu(Kα) radiation that is substantially the same as that shown; and a synchronous TGA / DSC thermogram that is substantially the same as that shown in Figure 1 In some embodiments, crystalline form D of Compound I maleate is characterized as having an Figure 3 XRPD pattern measured using Cu(Kα) radiation that is substantially the same as that shown; a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in

[0157] In some embodiments, crystalline form D of Compound I maleate is characterized as having an Figure 1 XRPD pattern that is substantially the same as that shown, said XRPD pattern being measured using Cu(Kα) radiation; a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 2 and a synchronous TGA / DSC thermogram that is substantially the same as that shown in Figure 4 In some embodiments, crystalline form D of Compound I maleate is characterized as having an

[0158] In some embodiments, crystalline form D of Compound I maleate is characterized as having a Figure 2 DSC thermogram that is substantially the same as that shown. In some embodiments, crystalline form D of Compound I maleate is characterized as having a DSC thermogram with an endothermic peak having an onset temperature of 161.6 °C and a peak temperature of 168.4 °C. In some embodiments, crystalline form D of Compound I maleate is characterized as having an Figure 3Substantially identical synchronous TGA / DSC thermograms are shown. In some embodiments, crystalline form D of Compound I maleate is characterized by a DSC thermogram having an endothermic peak with a start temperature of 158.1 °C and a peak temperature of 167.6 °C. In some embodiments, crystalline form D of Compound I maleate is characterized by a TGA profile having a weight loss of 0.48% at up to 180 °C. In some embodiments, crystalline form D of Compound I maleate is characterized by a DSC thermogram having an endothermic peak with a start temperature of 158.1 °C and a peak temperature of 167.6 °C; and a TGA profile having a weight loss of 0.48% at up to 180 °C.

[0159] In some embodiments, crystalline form D of Compound I maleate is characterized by a reversible mass increase of 1.14 wt% at 2% to 95% relative humidity (RH). In some embodiments, crystalline form D of Compound I maleate is characterized by a reversible water uptake of 1.14 wt% at 2% to 95% relative humidity (RH). In some embodiments, crystalline form D of Compound I maleate is characterized by a reversible water uptake of about 1% at 2% to 95% relative humidity (RH).

[0160] In some embodiments, crystalline form D of Compound I maleate is characterized by an unchanged XRPD after DVS analysis at 2% to 95% RH.

[0161] In some embodiments, crystalline form D of Compound I maleate is characterized by an unchanged XRPD after storage at 40 °C and 75% RH for at least one week.

[0162] In some embodiments, crystalline form D of Compound I maleate is characterized by a reversible mass increase of 1.14 wt% at 2% to 95% relative humidity (RH); an unchanged XRPD after DVS analysis at 2% to 95% RH; no change in XRPD after storage at 40 °C and 75% RH for at least one week; or a combination thereof.

[0163] In some embodiments, crystalline form D of Compound I maleate is characterized by having unit cell parameters at 100K substantially equal to:

[0164]

[0165] In some embodiments, crystalline form D of Compound I maleate is characterized by having: a crystal structure characterized by the atomic coordinates substantially as in Table 16; wherein the measurement of the crystal structure is carried out at 100K. In some embodiments, the crystal structure of crystalline form D is characterized by unit cell parameters substantially equal to: α = 90°; β =

[0166] 97.109(3)°; γ = 90°; and has a monoclinic space group = C2; wherein the crystal structure was measured at 100 K. In some embodiments, the crystal structure of crystalline form D is characterized as having unit cell parameters substantially equal to: α = 90°; β = 97.109(3)°; γ = 90°; and has a monoclinic space group = C2; wherein the crystal structure was measured at 100 K and is characterized as having atomic coordinates substantially as shown in Table 16.

[0167] In some embodiments, crystalline form D of Compound I maleate is anhydrous.

[0168] In certain embodiments, described herein is the crystalline maleate of Compound I or a solvate thereof, i.e., crystalline form D, and optionally further comprises: crystalline form C, crystalline form B, crystalline form A, or the amorphous maleate of Compound I or a solvate thereof, or a combination thereof.

[0169] Crystalline form C of Compound I maleate

[0170] In some embodiments, provided herein is the maleate or a solvate thereof of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), which is crystalline form C. Some embodiments provide a composition comprising crystalline form C of Compound I maleate. In some embodiments, crystalline form C of Compound I maleate is characterized as having:

[0171] · Substantially the same X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation as Figure 5 shown; or

[0172] · An XRPD pattern measured using Cu(Kα) radiation having reflections at approximately 4.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, and 18.4 ± 0.2° 2θ; or

[0173] · Substantially the same differential scanning calorimetry (DSC) thermogram as Figure 6 shown; or

[0174] · Substantially the same simultaneous thermogravimetric analysis (TGA) / DSC thermogram as Figure 7 shown; or

[0175] ·The onset temperature of the endothermic peak in the DSC thermogram is 144.1 °C and the peak temperature is 150.7 °C; or the onset temperature of the endothermic peak is 141.7 °C and the peak temperature is 152.1 °C; or

[0176] ·A TGA thermogram with a weight loss of 0.45% up to 170 °C; or

[0177] ·Identical to Figure 8 The dynamic vapor sorption (DVS) isotherm curve shown; or

[0178] ·A reversible mass increase of 9.18 wt% at 2% to 95% relative humidity (RH), XRPD with slight changes after DVS analysis at 2% to 95% RH showing some conversion to amorphous maleate of Compound I, XRPD unchanged after storage at 40 °C and 75% RH for at least one week, or a combination thereof;

[0179] Or a combination thereof.

[0180] In some embodiments, crystalline Form C of Compound I maleate is characterized as having an XRPD pattern with reflections at approximately 4.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, and 18.4 ± 0.2° 2θ measured using Cu(Kα) radiation.

[0181] In some embodiments, crystalline Form C of Compound I maleate is characterized as having an XRPD pattern with reflections at approximately 4.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, and 18.4 ± 0.2° 2θ measured using Cu(Kα) radiation; and the onset temperature of the endothermic peak in the DSC thermogram is 144.1 °C and the peak temperature is 150.7 °C; or the onset temperature of the endothermic peak is 141.7 °C and the peak temperature is 152.1 °C.

[0182] In some embodiments, crystalline Form C of Compound I maleate is characterized as having an XRPD pattern with reflections at approximately 4.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, and 18.4 ± 0.2° 2θ measured using Cu(Kα) radiation; and a TGA thermogram with a 0.45% weight loss up to 170 °C.

[0183] In some embodiments, crystalline Form C of Compound I maleate is characterized as having an XRPD pattern with reflections at about 4.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, and 18.4 ± 0.2° 2θ measured using Cu(Kα) radiation; a DSC thermogram with an onset temperature of the endothermic peak at 144.1 °C and a peak temperature at 150.7 °C; or an onset temperature of the endothermic peak at 141.7 °C and a peak temperature at 152.1 °C; and a TGA profile with a weight loss of 0.45% up to 170 °C.

[0184] In some embodiments, crystalline Form C of Compound I maleate is characterized as having an Figure 5 XRPD pattern measured using Cu(Kα) radiation that is substantially the same as that shown.

[0185] In some embodiments, crystalline Form C of Compound I maleate is characterized as having an Figure 5 XRPD pattern that is substantially the same as that shown, the XRPD pattern being measured using Cu(Kα) radiation; and a Figure 6 differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown.

[0186] In some embodiments, crystalline Form C of Compound I maleate is characterized as having an Figure 5 XRPD pattern that is substantially the same as that shown, the XRPD pattern being measured using Cu(Kα) radiation; and a Figure 7 synchronous TGA / DSC thermogram that is substantially the same as that shown.

[0187] In some embodiments, crystalline Form C of Compound I maleate is characterized as having an Figure 5 XRPD pattern that is substantially the same as that shown, the XRPD pattern being measured using Cu(Kα) radiation; a Figure 6 differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown; and a Figure 7 synchronous TGA / DSC thermogram that is substantially the same as that shown.

[0188] In some embodiments, crystalline Form C of Compound I maleate is characterized as having a Figure 6 DSC thermogram that is substantially the same as that shown. In some embodiments, crystalline Form C of Compound I maleate is characterized as having a DSC thermogram with an endothermic peak having an onset temperature of 144.1 °C and a peak temperature of 150.7 °C. In some embodiments, crystalline Form C of Compound I maleate is characterized as having an Figure 7Substantially identical synchronous TGA / DSC thermograms as shown. In some embodiments, crystalline form C of Compound I maleate is characterized by a DSC thermogram having an endothermic peak with an onset temperature of 141.7 °C and a peak temperature of 152.1 °C. In some embodiments, crystalline form C of Compound I maleate is characterized by a TGA profile having a weight loss of 0.45% up to 170 °C. In some embodiments, crystalline form C of Compound I maleate is characterized by a DSC thermogram having an endothermic peak with an onset temperature of 141.7 °C and a peak temperature of 152.1 °C; and a TGA profile having a 0.45% weight loss up to 170 °C.

[0189] In some embodiments, crystalline form C of Compound I maleate is characterized by having a reversible mass increase of 9.18 wt% at 2% to 95% relative humidity (RH). In some embodiments, crystalline form C of Compound I maleate is characterized by having a reversible water uptake of 9.18 wt% at 2% to 95% relative humidity (RH). In some embodiments, crystalline form C of Compound I maleate is characterized by having a reversible water uptake of about 10% at 2% to 95% relative humidity (RH).

[0190] In some embodiments, crystalline form C of Compound I maleate is characterized by having slightly changed XRPD, which shows some conversion to the amorphous maleate of Compound I after DVS analysis at 2% to 95% RH.

[0191] In some embodiments, crystalline form C of Compound I maleate is characterized by having unchanged XRPD after storage at 40 °C and 75% RH for at least one week.

[0192] In some embodiments, crystalline form C of Compound I maleate is characterized by having a reversible mass increase of 9.18 wt% at 2% to 95% relative humidity (RH); having slightly changed XRPD showing some conversion to the amorphous maleate of Compound I after DVS analysis at 2% to 95% RH; having unchanged XRPD after storage at 40 °C and 75% RH for at least one week; or a combination thereof.

[0193] In some embodiments, crystalline form C of Compound I maleate is anhydrous.

[0194] Crystalline form B of Compound I maleate

[0195] In some embodiments, provided herein is the maleate salt or solvate of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), which is in crystalline Form B. Some embodiments provide a composition comprising crystalline Form B of the maleate salt of Compound I. In some embodiments, crystalline Form B of the maleate salt of Compound I is characterized by having:

[0196] · an X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation that is substantially the same as that shown in; or Figure 9

[0197] · an XRPD pattern measured using Cu(Kα) radiation having reflections at about 4.1 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, and 16.4 ± 0.2° 2θ; or

[0198] · a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in; or Figure 10

[0199] Figure 11 · a simultaneous thermogravimetric analysis (TGA) / DSC thermogram that is substantially the same as that shown in; or Figure 11

[0200] · the onset temperature of the endothermic peak in the DSC thermogram is 141.4 °C and the peak temperature is 150.5 °C; or the onset temperature of the endothermic peak is 120.2 °C and the peak temperature is 131.4 °C; or

[0201] · a TGA profile having a weight loss of >4.7% up to 200 °C; or

[0202] · an XRPD that converts to Form C after being placed at ambient conditions for one week;

[0203] or a combination thereof.

[0204] In some embodiments, crystalline Form B of the maleate salt of Compound I is characterized by having: an XRPD pattern measured using Cu(Kα) radiation having reflections at about 4.1 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, and 16.4 ± 0.2° 2θ.

[0205] In some embodiments, crystalline Form B of Compound I maleate is characterized as having an XRPD pattern with reflections at about 4.1 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, and 16.4 ± 0.2° 2θ measured using Cu(Kα) radiation; and a DSC thermogram having an endotherm onset temperature of 141.4 °C and a peak temperature of 150.5 °C; or an endotherm onset temperature of 120.2 °C and a peak temperature of 131.4 °C.

[0206] In some embodiments, crystalline Form B of Compound I maleate is characterized as having an XRPD pattern with reflections at about 4.1 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, and 16.4 ± 0.2° 2θ measured using Cu(Kα) radiation; and a TGA profile with a weight loss > 4.7% up to 200 °C.

[0207] In some embodiments, crystalline Form B of Compound I maleate is characterized as having an XRPD pattern with reflections at about 4.1 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, and 16.4 ± 0.2° 2θ measured using Cu(Kα) radiation; a DSC thermogram having an endotherm onset temperature of 141.4 °C and a peak temperature of 150.5 °C; or an endotherm onset temperature of 120.2 °C and a peak temperature of 131.4 °C; and a TGA profile with a weight loss > 4.7% up to 200 °C.

[0208] In some embodiments, crystalline Form B of Compound I maleate is characterized as having an XRPD pattern Figure 9 substantially the same as that shown, measured using Cu(Kα) radiation.

[0209] In some embodiments, crystalline Form B of Compound I maleate is characterized as having an XRPD pattern Figure 9 substantially the same as that shown, measured using Cu(Kα) radiation; and a differential scanning calorimetry (DSC) thermogram Figure 10 substantially the same as that shown.

[0210] In some embodiments, crystalline Form B of Compound I maleate is characterized as having an XRPD pattern Figure 9 substantially the same as that shown, measured using Cu(Kα) radiation; and a synchronous TGA / DSC thermogram Figure 11 substantially the same as that shown.

[0211] In some embodiments, crystalline Form B of Compound I maleate is characterized as having an XRPD pattern Figure 9substantially the same XRPD pattern as shown, measured using Cu(Kα) radiation; and Figure 10 substantially the same differential scanning calorimetry (DSC) thermogram as shown; and Figure 11 substantially the same synchronous TGA / DSC thermogram as shown.

[0212] In some embodiments, crystalline form B of Compound I maleate is characterized as having Figure 10 substantially the same DSC thermogram as shown. In some embodiments, crystalline form B of Compound I maleate is characterized as having a DSC thermogram with an endothermic peak having an onset temperature of 141.4 °C and a peak temperature of 150.5 °C. In some embodiments, crystalline form B of Compound I maleate is characterized as having Figure 11 substantially the same synchronous TGA / DSC thermogram as shown. In some embodiments, crystalline form B of Compound I maleate is characterized as having a DSC thermogram with an endothermic peak having an onset temperature of 120.2 °C and a peak temperature of 131.4 °C. In some embodiments, crystalline form B of Compound I maleate is characterized as having a TGA profile with a weight loss > 4.7% at up to 200 °C. In some embodiments, crystalline form B of Compound I maleate is characterized as having a DSC thermogram with an endothermic peak having an onset temperature of 120.2 °C and a peak temperature of 131.4 °C; and a TGA profile with a weight loss > 4.7% at up to 200 °C.

[0213] In some embodiments, crystalline form B of Compound I maleate is characterized as having an XRPD that converts to crystalline form C after being placed under ambient conditions for one week.

[0214] In some embodiments, crystalline form B of Compound I maleate is anhydrous.

[0215] Crystalline form A of Compound I maleate

[0216] In some embodiments, provided herein is a maleate or solvate of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), which is crystalline form A. Some embodiments provide a composition comprising crystalline form A of Compound I maleate. In some embodiments, crystalline form A of Compound I maleate is characterized as having:

[0217] · an X-ray powder diffraction pattern (XRPD) substantially the same as that shown Figure 12 measured using Cu(Kα) radiation; or

[0218] · An XRPD pattern having reflections at about 4.2 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, and 12.5 ± 0.2° 2θ measured using Cu(Kα) radiation; or

[0219] · An XRPD that converts to Form C after being placed under ambient conditions for about three days; or

[0220] · An XRPD that converts to Form C after drying in a vacuum oven at 50 °C, 10 -2 -10 -1 torr for 20 hours;

[0221] or a combination thereof

[0222] In some embodiments, crystalline Form A of Compound I maleate is characterized as having: an XRPD pattern having reflections at about 4.2 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, and 12.5 ± 0.2° 2θ measured using Cu(Kα) radiation.

[0223] In some embodiments, crystalline Form A of Compound I maleate is characterized as having an XRPD that is substantially the same as that Figure 12 shown and measured using Cu(Kα) radiation.

[0224] In some embodiments, crystalline Form A of Compound I maleate is characterized as having an XRPD that converts to Form C after being placed under ambient conditions for about three days.

[0225] In some embodiments, crystalline Form A of Compound I maleate is characterized as having an XRPD that converts to Form C after drying in a vacuum oven at 50 °C, 10 -2 -10 -1 torr for 20 hours.

[0226] Crystalline Form E of Compound I mandelate

[0227] In some embodiments, provided herein is the mandelate or solvate of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), which is Crystalline Form E. Some embodiments provide a composition comprising Crystalline Form E of Compound I mandelate. In some embodiments, Crystalline Form E of Compound I mandelate is characterized as having:

[0228] · An X-ray powder diffraction pattern (XRPD) that is substantially the same as that Figure 13 shown and measured using Cu(Kα) radiation; or

[0229] · XRPD having X-ray diffraction pattern reflections at about 5.6 ± 0.2° 2θ, 10.5 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, and 16.5 ± 0.2° 2θ measured using Cu(Kα) radiation; or

[0230] · And Figure 14 a differential scanning calorimetry (DSC) thermogram substantially the same as that shown; or

[0231] · And Figure 15 a synchronous thermogravimetric analysis (TGA) / DSC thermogram substantially the same as that shown; or

[0232] · The onset temperature of the endothermic peak of the DSC thermogram is 141.0 °C and the peak temperature is 152.8 °C; or the onset temperature of the endothermic peak is 139.8 °C and the peak temperature is 154.2 °C; or

[0233] · A TGA profile having a weight loss of 1.92% up to 170 °C; or

[0234] · And Figure 16 a dynamic vapor sorption (DVS) isotherm curve substantially the same as that shown; or

[0235] · A reversible mass increase of 5.68 wt% at 2% to 95% relative humidity (RH), XRPD that does not change after DVS analysis at 2% to 95% RH, XRPD that does not change after storage at 40 °C and 75% RH for at least one week, or a combination thereof;

[0236] Or a combination thereof.

[0237] In some embodiments, crystalline form E of Compound I mandelate is characterized as having: an XRPD pattern having reflections at about 5.6 ± 0.2° 2θ, 10.5 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, and 16.5 ± 0.2° 2θ measured using Cu(Kα) radiation.

[0238] In some embodiments, crystalline form E of Compound I mandelate is characterized as having: an XRPD pattern having reflections at about 5.6 ± 0.2° 2θ, 10.5 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, and 16.5 ± 0.2° 2θ measured using Cu(Kα) radiation; and the onset temperature of the endothermic peak of the DSC thermogram is 141.0 °C and the peak temperature is 152.8 °C; or the onset temperature of the endothermic peak is 139.8 °C and the peak temperature is 154.2 °C.

[0239] In some embodiments, crystalline form E of Compound I mandelate is characterized as having an XRPD pattern with reflections at about 5.6 ± 0.2° 2θ, 10.5 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, and 16.5 ± 0.2° 2θ measured using Cu(Kα) radiation; and a TGA profile with a weight loss of 1.92% up to 170 °C.

[0240] In some embodiments, crystalline form E of Compound I mandelate is characterized as having: an XRPD pattern with reflections at about 5.6 ± 0.2° 2θ, 10.5 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, and 16.5 ± 0.2° 2θ measured using Cu(Kα) radiation; a DSC thermogram with an onset temperature of the endothermic peak at 141.0 °C and a peak temperature at 152.8 °C; or an onset temperature of the endothermic peak at 139.8 °C and a peak temperature at 154.2 °C; and a TGA profile with a weight loss of 1.92% up to 170 °C.

[0241] In some embodiments, crystalline form E of Compound I mandelate is characterized as having an Figure 13 XRPD pattern measured using Cu(Kα) radiation that is substantially the same as that shown.

[0242] In some embodiments, crystalline form E of Compound I mandelate is characterized as having an Figure 13 XRPD pattern that is substantially the same as that shown, the XRPD pattern being measured using Cu(Kα) radiation; and a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown. Figure 14

[0243] In some embodiments, crystalline form E of Compound I mandelate is characterized as having an Figure 13 XRPD pattern that is substantially the same as that shown, the XRPD pattern being measured using Cu(Kα) radiation; and a synchronous TGA / DSC thermogram that is substantially the same as that shown. Figure 15

[0244] In some embodiments, crystalline form E of Compound I mandelate is characterized as having an Figure 13 XRPD pattern that is substantially the same as that shown, the XRPD pattern being measured using Cu(Kα) radiation; a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown; and a synchronous TGA / DSC thermogram that is substantially the same as that shown. Figure 14 Figure 15

[0245] In some embodiments, crystalline form E of Compound I mandelate is characterized as having an Figure 14 ​​​​Substantially the same DSC thermograms shown. In some embodiments, crystalline form E of Compound I mandelate is characterized by a DSC thermogram having an endothermic peak with an onset temperature of 141.0 °C and a peak temperature of 152.8 °C. In some embodiments, crystalline form E of Compound I mandelate is characterized by having Figure 15 substantially the same synchronous TGA / DSC thermogram shown. In some embodiments, crystalline form E of Compound I mandelate is characterized by a DSC thermogram having an endothermic peak with an onset temperature of 139.8 °C and a peak temperature of 154.2 °C. In some embodiments, crystalline form E of Compound I mandelate is characterized by a TGA profile having a weight loss of 1.92% at up to 170 °C. In some embodiments, crystalline form E of Compound I mandelate is characterized by a DSC thermogram having an endothermic peak with an onset temperature of 139.8 °C and a peak temperature of 154.2 °C; and a TGA profile having a weight loss of 1.92% at up to 170 °C.

[0246] In some embodiments, crystalline form E of Compound I mandelate is characterized by having a reversible mass increase of 5.68 wt% at 2% to 95% relative humidity (RH). In some embodiments, crystalline form E of Compound I mandelate is characterized by having a reversible water uptake of 5.68 wt% at 2% to 95% relative humidity (RH). In some embodiments, crystalline form E of Compound I mandelate is characterized by having a reversible water uptake of about 5% at 2% to 95% relative humidity (RH).

[0247] In some embodiments, crystalline form E of Compound I mandelate is characterized by having an unchanged XRPD after DVS analysis at 2% to 95% RH.

[0248] In some embodiments, crystalline form E of Compound I mandelate is characterized by having an unchanged XRPD after storage at 40 °C and 75% RH for at least one week.

[0249] In some embodiments, crystalline form E of Compound I mandelate is characterized by having a reversible mass increase of 95.68 wt% at 2% to 95% relative humidity (RH); an unchanged XRPD after DVS analysis at 2% to 95% RH; an unchanged XRPD after storage at 40 °C and 75% RH for at least one week; or a combination thereof.

[0250] In some embodiments, crystalline form E of Compound I mandelate is anhydrous.

[0251] Synthesis of Compound I

[0252] The preparation of Compound I has been previously described (for example, see Example 31 of WO 2019 / 236699 and US 10,562,884, which are incorporated herein by reference as methods for preparing Compound I).

[0253] Preparation of Crystalline Form D of Compound I Maleate

[0254] In some embodiments, described herein is a method for preparing crystalline Form D of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I) maleate:

[0255]

[0256] Comprising:

[0257] (1) Contacting Compound I with maleic acid in a suitable solvent to form a mixture;

[0258] (2) Adding a suitable anti-solvent to the mixture and seeding the mixture with D-form crystals of Compound I maleate;

[0259] (3) Heating the mixture at a suitable temperature for a sufficient time to obtain a slurry;

[0260] (4) Cooling the slurry at a suitable cooling rate; and

[0261] (5) Filtering the slurry to obtain crystalline Form D of Compound I maleate.

[0262] In some embodiments, the suitable solvent in step (1) is ethanol, isopropanol, acetone, acetonitrile, methyl acetate, ethyl acetate, methyl isobutyl ketone (MIBK), water, or a combination thereof. In some embodiments, the suitable solvent in step (1) is a mixture of isopropanol and MIBK. In some embodiments, the suitable solvent in step (1) is a mixture of isopropanol and MIBK, and the ratio of isopropanol to MIBK is about 9:1, 5:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:5, or 1:9.

[0263] In some embodiments, relative to the amount of Compound I in the mixture, the mixture in step (1) contains about 1 to about 10 volumes of solvent. In some embodiments, relative to the amount of Compound I in the mixture, the mixture in step (1) contains about 5 to about 10 volumes of solvent. In some embodiments, relative to the amount of Compound I in the mixture, the mixture in step (1) contains about 5, about 6, about 7, about 8, about 9, or about 10 volumes of solvent.

[0264] In some embodiments, the mixture of step (1) is heated to about 50 °C. In other embodiments, the mixture of step (1) is maintained at ambient temperature.

[0265] In some embodiments, the mixture of step (1) comprises about 1.0 to 1.5 equivalents of maleic acid relative to the amount of Compound I in the mixture. In some embodiments, the mixture of step (1) comprises about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, or about 1.5 equivalents of maleic acid relative to the amount of Compound I in the mixture.

[0266] In some embodiments, the mixture of step (1) comprises about 1.1 equivalents of maleic acid and about 6 volumes of a 5:1 mixture of isopropanol and MIBK relative to the amount of Compound I in the mixture.

[0267] In some embodiments, the anti-solvent in step (2) is methyl tert-butyl ether (MtBE), MIBK, water, heptane, or a combination thereof. In some embodiments, the anti-solvent in step (2) is heptane. In some embodiments, about 2 volumes to about 20 volumes of the anti-solvent are added to the mixture of step (2) relative to the amount of Compound I. In some embodiments, about 4 volumes to about 10 volumes of the anti-solvent are added to the mixture of step (2) relative to the amount of Compound I. In some embodiments, the anti-solvent is added in one portion. In other embodiments, the anti-solvent is added in two or more portions.

[0268] In some embodiments, about 4 volumes to about 10 volumes of heptane are added to the mixture of step (2) relative to the amount of Compound I. In some embodiments, about 4 volumes to about 10 volumes of heptane are added to the mixture of step (2) in two portions relative to the amount of Compound I.

[0269] In some embodiments, the amount of Type D seed crystals added to the mixture in step (2) is about 0.05%, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, or about 1.00% relative to the amount of Compound I in the mixture. In some embodiments, the seed crystals are added in one portion. In other embodiments, the seed crystals are added in two or more portions.

[0270] In some embodiments, the mixture is heated to a temperature of about 40°C to about 50°C in step (3). In some embodiments, the mixture is heated to a temperature of about 40°C, about 41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C or about 50°C in step (3).

[0271] In some embodiments, the mixture is heated for at least 8 hours in step (3). In some embodiments, the mixture is heated for at least 8 h, at least 12 h, at least 18 h or longer in step (3). In some embodiments, the mixture is heated to a temperature of about 50°C and maintained for about 8 h, about 12 h or about 18 h in step (3).

[0272] In some embodiments, the mixture is heated to a temperature of about 50°C and maintained for about 18 hours in step (3).

[0273] In some embodiments, the slurry is cooled to ambient temperature in step (4). In some embodiments, the slurry is cooled to a temperature below ambient temperature in step (4). In some embodiments, the slurry is cooled to a temperature not exceeding 25°C in step (4). In some embodiments, the slurry is cooled to a temperature of about 0°C to about 20°C in step (4). In some embodiments, the slurry is cooled to a temperature of about 20°C in step (4).

[0274] In some embodiments, the slurry is cooled at a rate of at most 10°C / min in step (4). In some embodiments, the slurry is cooled at a rate of at most 2.5, 5.0, 7.5 or 10°C / min in step (4). In some embodiments, the slurry is cooled at a rate of at most 2.5°C / min in step (4). In some embodiments, the slurry is cooled at a rate of about 2.5°C / min in step (4).

[0275] In some embodiments, the slurry is cooled for at least 15 minutes in step (4). In some embodiments, in step (4), the slurry is cooled for about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes or longer. In some embodiments, in step (4), the slurry is cooled for about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes or about 120 minutes. In some embodiments, the slurry is cooled for about 45 minutes in step (4).

[0276] In some embodiments, in step (4), the slurry is cooled to a temperature of about 20 °C at a rate of up to 2.5 °C / min. In some embodiments, in step (4), the slurry is cooled to a temperature of about 20 °C over about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes or longer. In some embodiments, in step (4), the slurry is cooled to a temperature of about 20 °C within about 45 minutes.

[0277] In some embodiments, the solid obtained after filtration in step (5) is further dried. In some embodiments, the solid obtained after filtration in step (5) is dried under vacuum. In some embodiments, the solid obtained after filtration in step (5) is dried in a vacuum oven. In some embodiments, the solid obtained after filtration in step (5) is dried under vacuum at ambient temperature. In some embodiments, the solid obtained after filtration in step (5) is dried under vacuum at about 50 °C. In some embodiments, the solid obtained after filtration in step (5) is the crystalline form D of Compound I maleate.

[0278] Recrystallization of Crystalline Form D of Compound I Maleate

[0279] In some embodiments, crystalline form D of Compound I maleate crystallizes directly from the reaction mixture before separation.

[0280] In other embodiments, crystalline form D of Compound I maleate is recrystallized. In some embodiments, crystalline form D of Compound I maleate is separated and recrystallized.

[0281] In some embodiments, recrystallization of crystalline form D of Compound I maleate comprises:

[0282] i. contacting crystalline form D of Compound I maleate with a suitable solvent to obtain a mixture;

[0283] ii. heating the mixture of step (i) to obtain a solution;

[0284] iii. seeding the solution with D-form crystals of Compound I maleate to obtain a mixture;

[0285] iv. adding a suitable anti-solvent to the mixture at a suitable time;

[0286] v. heating the mixture for a suitable time to obtain a slurry;

[0287] vi. cooling the slurry at a suitable cooling rate; and

[0288] vii. filtering the slurry to obtain crystalline form D of Compound I maleate.

[0289] In some embodiments, the suitable solvent in step (i) is ethanol, isopropanol, acetone, methyl acetate, or a combination thereof. In some embodiments, the suitable solvent in step (i) is ethanol, isopropanol, or methyl acetate, or a combination thereof. In some embodiments, the suitable solvent in step (i) is isopropanol.

[0290] In some embodiments, about 2 to about 20 volumes of solvent are used in step (i) relative to the amount of Compound I in the mixture. In some embodiments, about 4 to about 10 volumes of solvent are used in step (i) relative to the amount of Compound I in the mixture. In some embodiments, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 volumes of solvent are used in step (i) relative to the amount of Compound I in the mixture.

[0291] In some embodiments, the suitable solvent in step (i) is ethanol, isopropanol, acetone, methyl acetate, or a combination thereof; and wherein about 4 to about 10 volumes of solvent are used in step (i) relative to the amount of Compound I in the mixture. The method of claim 46, wherein about 4 volumes of isopropanol are used in step (i) relative to the amount of Compound I in the mixture.

[0292] In some embodiments, the mixture is heated to a temperature of about 30°C to about 50°C in step (ii). In some embodiments, the mixture is heated to a temperature of about 30°C, about 35°C, about 40°C, about 45°C, or about 50°C in step (ii). In some embodiments, the method further comprises cooling the solution obtained in step (ii) to a temperature of about 30°C prior to seeding in step (iii). In some embodiments, the method further comprises cooling the solution obtained in step (ii) to a temperature of about 30°C within about 2 hours prior to seeding in step (iii).

[0293] In some embodiments, the amount of D-form seed crystals added to the mixture in step (iii) is about 0.25%, about 0.50%, about 0.75%, about 1.0%, about 1.25%, about 1.50%, about 1.75%, about 2.0%, about 2.25%, about 2.5%, about 2.75%, about 3.0%, about 3.2%, about 3.5%, about 3.75%, about 4.0%, 4.25%, about 4.5%, about 4.75%, or about 5.0% relative to the amount of Compound I in the mixture. In some embodiments, the seed crystals used in step (iii) are dry.

[0294] In some embodiments, suitable anti-solvents for step (iv) are MtBE, heptane, or a combination thereof. In some embodiments, a suitable anti-solvent for step (iv) is heptane. In other embodiments, a suitable anti-solvent for step (iv) is MtBE. In some embodiments, the anti-solvent (e.g., MtBE) is slowly added to the reaction mixture in step (iv). In some embodiments, the anti-solvent (e.g., MtBE) is added in step (iv) over at least 1 hour, 2 hours, at least 4 hours, at least 6 hours, or longer. In some embodiments, the anti-solvent is added in portions. In other embodiments, the anti-solvent is added in two or more portions.

[0295] In some embodiments, suitable anti-solvents for step (iv) are MtBE, heptane, or a combination thereof; and wherein about 3 volumes to about 10 volumes of solvent are used in step (iii) relative to the amount of Compound I in the mixture. In some embodiments, a suitable anti-solvent for step (iv) is MtBE; and wherein the MtBE is added over at least 2 hours, at least 4 hours, at least 6 hours, or longer.

[0296] In some embodiments, in step (v), the mixture is heated to about 40 °C, about 45 °C, or about 50 °C to obtain a slurry. In some embodiments, the mixture is heated for about 1 hour, about 2 hours, about 3 hours, or longer to obtain a slurry. In some embodiments, in step (v), the mixture is heated to about 40 °C and held for about 1 h, about 2 h, or about 3 h.

[0297] In some embodiments, in step (vi), the slurry obtained in step (v) is cooled to ambient temperature. In some embodiments, in step (vi), the slurry is cooled to below ambient temperature. In some embodiments, in step (vi), the slurry is cooled to a temperature not exceeding 25 °C. In some embodiments, in step (vi), the slurry is cooled to a temperature of about 0 °C to about 20 °C. In some embodiments, in step (vi), the slurry is cooled to a temperature of about 20 °C.

[0298] In some embodiments, in step (vi), the slurry obtained in step (v) is cooled at a rate of up to 10 °C / min. In some embodiments, in step (vi), the slurry is cooled at a rate of up to 2.5, 5.0, 7.5, or 10 °C / min. In some embodiments, in step (vi), the slurry is cooled at a rate of up to 2.5 °C / min. In some embodiments, in step (vi), the slurry is cooled at a rate of about 2.5 °C / min.

[0299] In some embodiments, the slurry obtained in step (v) is cooled in step (vi) for at least 15 minutes. In some embodiments, the slurry is cooled in step (vi) for about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, about 120 minutes or longer. In some embodiments, the slurry is cooled in step (vi) for about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes or about 120 minutes. In some embodiments, the slurry is cooled in step (vi) for about 120 minutes.

[0300] In some embodiments, in step (vi), the slurry obtained in step (v) is cooled to a temperature of about 20 °C at a rate of at most 2.5 °C / min. In some embodiments, in step (vi), the slurry obtained in step (v) is cooled to a temperature of about 20 °C over a period of about 30 minutes, about 60 minutes, about 90 minutes, about 120 minutes or longer. In some embodiments, in step (vi), the slurry obtained in step (v) is cooled to a temperature of about 20 °C over a period of about 120 minutes.

[0301] In some embodiments, prior to step (vii), the cooled slurry of step (vi) is held at the cooling temperature for at least 2 hours, at least 3 hours, at least 4 hours or longer. In some embodiments, prior to step (vii), the cooled slurry of step (vi) is held at about 20 °C for at least 2 hours, at least 3 hours, at least 4 hours or longer. In some embodiments, prior to step (vii), the cooled slurry of step (vi) is held at about 20 °C for about 4 hours.

[0302] In some embodiments, the solid obtained after filtration in step (vii) is further dried. In some embodiments, the solid obtained after filtration in step (vii) is dried under vacuum. In some embodiments, the solid obtained after filtration in step (vii) is dried in a vacuum oven. In some embodiments, the solid obtained after filtration in step (vii) is vacuum dried at ambient temperature. In some embodiments, the solid obtained after filtration in step (vii) is dried under vacuum at about 50 °C. In some embodiments, the solid obtained after filtration in step (vii) is crystalline Form D of Compound I maleate.

[0303] In some embodiments, the crystalline Form D of the isolated Compound I maleate shows no evidence of other forms, as determined by, for example, XRPD.

[0304] As used herein, "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of the composition in which it is contained.

[0305] The term "pharmaceutically acceptable salt" refers to a form of a therapeutic agent that is formed by the combination of a therapeutically active agent in its cationic form with a suitable anion or, in an alternative embodiment, by the combination of a therapeutically active agent in its anionic form with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection, and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are generally more soluble and dissolve more rapidly in gastric and intestinal fluids than the non-ionic substances and can therefore be used in solid dosage forms. In addition, because their solubility is generally a function of pH, selective dissolution in one part or another of the digestive tract is possible, and this ability can be manipulated as an aspect of sustained release and extended release behavior. In addition, since the salt-forming molecules can be in equilibrium with the neutral form, the passage through biological membranes can be modulated.

[0306] In some embodiments, Compound I is prepared as a salt with maleic acid or mandelic acid. In some embodiments, Compound I is prepared in the form of maleate or mandelate. In some embodiments, Compound I is prepared as maleate. In other embodiments, Compound I is prepared as mandelate.

[0307] It should be understood that reference to pharmaceutically acceptable salts includes solvate addition forms. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of solvent and is formed with a pharmaceutically acceptable solvent such as water, ethanol, etc. during the crystallization process. A hydrate is formed when the solvent is water or an alcoholate is formed when the solvent is an alcohol. The solvates of the compounds described herein can be conveniently prepared or formed in the methods described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0308] Therapeutic agents that can be administered to mammals (such as humans) must be prepared in accordance with regulatory guidelines. Such government-regulated guidelines are known as Good Manufacturing Practice (GMP). GMP guidelines outline the acceptable levels of contamination of active therapeutic agents, such as the amount of residual solvent in the final product. Preferred solvents are those that are suitable for GMP equipment and comply with industrial safety requirements. For example, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has defined categories of solvents in the "Impurities: Guidance on Residual Solvents" (Q3C(R3)) (November 2005).

[0309] Solvents are divided into three classes. Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents that are restricted in the manufacture of therapeutic agents. Class 3 solvents are solvents with low potential toxicity and lower risk to human health. Data on Class 3 solvents indicate that they are less toxic in acute or short-term studies and are negative in genotoxicity studies.

[0310] Class 1 solvents to be avoided include: benzene; carbon tetrachloride; 1,2-dichloroethane; 1,1-dichloroethylene; and 1,1,1-trichloroethane.

[0311] Examples of Class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethylene, and xylene.

[0312] Class 3 solvents with low toxicity include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0313] Residual solvents in the active pharmaceutical ingredient (API) originate from the production of the API. In some cases, solvents cannot be completely removed by actual production techniques. The appropriate selection of solvents for the synthesis of the API can increase the yield or determine properties such as crystal form, purity, and solubility. Therefore, solvents are key parameters in the synthesis process.

[0314] In some embodiments, the composition comprising Compound I comprises an organic solvent. In some embodiments, the composition comprising Compound I includes a residual amount of an organic solvent. In some embodiments, the composition comprising Compound I comprises a residual amount of a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, heptane, isopropanol, and ethanol.

[0315] In some embodiments, the composition comprising Compound I includes a detectable amount of an organic solvent. In some embodiments, the organic solvent is a Class 3 solvent.

[0316] In other embodiments, there is provided a composition comprising Compound I, wherein the composition comprises less than about 1% of a detectable amount of a solvent selected from acetone, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, heptane, and 2-propanol. In another embodiment, there is provided a composition comprising Compound I, wherein the composition comprises less than about 5000 ppm of a detectable amount of a solvent. In another embodiment, there is provided a composition comprising Compound I, wherein the detectable amount of the solvent is less than about 5000 ppm, less than about 4000 ppm, less than about 3000 ppm, less than about 2000 ppm, less than about 1000 ppm, less than about 500 ppm, or less than about 100 ppm.

[0317] Unless otherwise indicated, the following terms used in this application have the definitions given below. The term "comprising" and other forms such as "comprises" and "comprising" are not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0318] The term "about" with respect to a number means that number plus or minus 10% of that number. The term "about" with respect to a range means that range minus 10% of its lowest value and plus 10% of its highest value.

[0319] The term "moiety" refers to a particular fragment or functional group of a molecule. A chemical moiety is generally considered to be a chemical entity embedded within or attached to a molecule.

[0320] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that it has no lasting adverse effect on the overall health of the subject being treated.

[0321] As used herein, the term "modulate" means to interact directly or indirectly with a target to alter the activity of the target, including, by way of example only, to enhance the activity of the target, inhibit the activity of the target, limit the activity of the target, or prolong the activity of the target.

[0322] As used herein, the term "modulator" means a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions of agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.

[0323] As used herein, the terms "administer", "administering", "administration", etc. refer to methods that can be used to deliver a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral route, duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial, or infusion), topical, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used for the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0324] As used herein, the term "effective amount" or "therapeutically effective amount" means administering a sufficient amount of an agent or compound that will, to some extent, relieve one or more symptoms of the disease or disorder being treated. Outcomes include reducing and / or alleviating the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in the symptoms of the disease. In any individual case, the appropriate "effective" amount is optionally determined using techniques such as dose escalation studies.

[0325] As used herein, the terms "enhance" or "augment" mean to increase or prolong the potency or duration of a desired effect. Thus, with respect to enhancing the action of a therapeutic agent, the term "enhance" means the ability to increase or prolong the action of another therapeutic agent on a system in terms of potency or duration. An "enhancing-effective amount" as used herein is an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0326] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; experimental animals, including rodents such as rats, mice, and guinea pigs, etc. In one aspect, the mammal is a human.

[0327] As used herein, the terms "treat", "treats", or "treating" include alleviating, reducing, or ameliorating at least one symptom of a disease or disorder, preventing additional symptoms, inhibiting the disease or disorder, e.g., arresting the development of the disease or disorder, alleviating the disease or disorder, causing regression of the disease or disorder, alleviating the condition caused by the disease or disorder, or prophylactically and / or therapeutically halting the symptoms of the disease or disorder.

[0328] Pharmaceutical composition

[0329] In some embodiments, the compounds and solid forms described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compound into a pharmaceutically useful formulation. Suitable formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0330] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. Administration of the compounds and compositions described herein can be accomplished by any method capable of delivering the compound to the site of action.

[0331] Methods of administration and treatment regimens

[0332] Cushing's syndrome is a rare disorder characterized by chronic, excessive glucocorticoid exposure. Clinical symptoms of Cushing's syndrome include growth of fat pads (clavicular, posterior neck, face, and trunk), excessive sweating, telangiectasia, thinning of the skin, muscle weakness, hirsutism, depression / anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease, and a range of other metabolic disorders leading to high morbidity. If severe Cushing's syndrome is not adequately controlled, it results in high mortality. Although glucocorticoid excess may sometimes be ACTH-independent, such as cortisol autonomous hypersecretion caused by a hyperfunctioning adrenal adenoma, carcinoma, or steroid abuse, approximately 60 - 80% of all cases are ACTH-dependent Cushing's syndrome, i.e., Cushing's disease. Cushing's disease is caused by a microadenoma of pituitary corticotroph cells that secrete excessive ACTH. Corticotroph adenomas are small, usually slow-growing, benign tumors that typically come to clinical attention due to the effects of glucocorticoid excess rather than the physical effects of tumor expansion. The first-line treatment for Cushing's disease is surgery, including resection of the ACTH-secreting tumor in the pituitary or adrenal gland. Due to surgery often being unsuccessful, contraindicated, or delayed, medical treatment is necessary for these patients. Current treatment regimens include steroid synthesis inhibitors, which can block cortisol production and improve symptoms, but these treatments also cause many unwanted side effects due to the accumulation of other steroid products. On the one hand, MC2R antagonists are used to treat Cushing's syndrome. In some embodiments, MC2R antagonists are used to treat Cushing's disease. In some embodiments, glucocorticoid excess is ACTH-independent. In some embodiments, glucocorticoid excess is ACTH-dependent.

[0333] Ectopic ACTH syndrome, or ectopic Cushing's syndrome or disease, is essentially the same as Cushing's disease except that the underlying tumor expressing ACTH is located outside the pituitary gland. In some embodiments, the tumor is a small carcinoid tumor occurring anywhere in the lung or gastrointestinal tract. In some embodiments, MC2R antagonists are used to treat ectopic ACTH syndrome.

[0334] Congenital adrenal hyperplasia (CAH) is characterized by reduced or absent cortisol synthesis, with excessive ACTH and corticotropin-releasing hormone (CRH). Multiple genetic defects in the adrenal steroid biosynthesis pathway can lead to CAH. In some embodiments, CAH is due to a mutation in 21β-hydroxylase. The lack of cortisol eliminates negative feedback on the pituitary, which results in excessive ACTH secretion. The resulting overstimulation of the adrenal glands leads to overproduction of steroid precursors, which also have negative consequences (e.g., hyperandrogenism). Administration of replacement glucocorticoids usually does not adequately suppress ACTH without causing Cushingoid symptoms. In some embodiments, MC2R antagonists are used to treat CAH.

[0335] In addition to Cushing's disease and CAH, it is also hypothesized that MC2R antagonists may play a role in the treatment of depressive disorders and septic shock. In some embodiments, MC2R antagonist compounds are used to treat depressive disorders. In some embodiments, MC2R antagonists are used to treat septic shock.

[0336] In one embodiment, the compounds and solid forms described herein are used to prepare a medicament for treating a disease or disorder in a mammal, the disease or disorder that would benefit from modulation of MC2R receptor activity, the disease or disorder including but not limited to Cushing's disease, Cushing's syndrome, ectopic ACTH syndrome (EAS), and congenital adrenal hyperplasia (CAH). A method of treating any disease or disorder described herein in a mammal in need of such treatment includes administering to the mammal a therapeutically effective amount of a pharmaceutical composition, the pharmaceutical composition including at least one compound disclosed herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0337] In any of the above aspects, in a further embodiment, an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal.

[0338] Examples

[0339] Abbreviations:

[0340] ACN or MeCN: Acetonitrile;

[0341] Am.: Amorphous;

[0342] Aq or aq: Aqueous;

[0343] Compound I: N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide;

[0344] DEE: Diethyl ether;

[0345] DMSO: Dimethyl sulfoxide;

[0346] DSC: Differential scanning calorimetry;

[0347] DVS: Dynamic vapor sorption;

[0348] Et: Ethyl;

[0349] EtOAc: Ethyl acetate;

[0350] EtOH: Ethanol;

[0351] equiv or eq.: Equivalent;

[0352] h or hr: Hour;

[0353] hrs: Hours;

[0354] HPLC: High Performance Liquid Chromatography;

[0355] IPA: Isopropyl Alcohol;

[0356] IPAc: Isopropyl Acetate;

[0357] M: Mole;

[0358] MEK: Methyl Ethyl Ketone;

[0359] Me: Methyl;

[0360] MeOAC: Methyl Acetate;

[0361] MeOH: Methanol;

[0362] MIBK: Methyl Isobutyl Ketone;

[0363] mins or min: Minute;

[0364] MtBE: Methyl Tert-Butyl Ether;

[0365] NMR: Nuclear Magnetic Resonance;

[0366] RH: Relative Humidity;

[0367] rt or RT: Room Temperature;

[0368] SCXRD: Single Crystal X-ray Diffraction;

[0369] TGA: Thermogravimetric Analysis;

[0370] THF: Tetrahydrofuran;

[0371] vol: Volume, usually used for reaction volume or solvent ratio;

[0372] w / w: Weight ratio; and

[0373] XRPD: X-ray Powder Diffraction The following examples are for illustrative purposes only and do not limit the scope of the claims provided herein.

[0374] Example 1. Preparation of N - [(3S) - 1 - azabicyclo[2.2.2]octan - 3 - yl] - 6 - (2 - ethoxyphenyl) - 3 - [(2R) - 2 - ethyl - 4 - [1 - (trifluoromethyl) - cyclobutanecarbonyl]piperazin - 1 - yl]pyridine - 2 - carboxamide (Compound I)

[0375] The preparation of Compound I has been previously described (e.g., see Example 31 of WO 2019 / 236699 and US 10,562,884, which are incorporated herein by reference as methods for preparing Compound I).

[0376] Example 2. Salt screening

[0377] Except for sulfuric acid (using 0.55 equivalents), 1.1 equivalents of counterion were used in all cases to establish a salt screen of Compound I with 19 counterions. In addition, 2.2 equivalents of HCl were also explored.

[0378] Experiments for the salt screening process were established in 2 mL vials containing a 5 mm stir bar. A stock solution of Compound I (50 mg / mL) was prepared in anhydrous EtOH. Stock solutions of counterions were also prepared in EtOH. At room temperature, Compound I (20 mg, approximately 380 μL of the stock solution) and 1.1 equivalents of the counterion were added to each vial. Upon addition, a color change from colorless or pale yellow to bright yellow solution was observed for the following counterions: hydrobromic acid, nitric acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, and toluenesulfonic acid. Each of these counterions has a negative pKa. The vials were then sealed and allowed to stir briefly (< 2 hours). The solvent was evaporated at room temperature under a steady nitrogen stream and then left under vacuum at room temperature overnight to dry thoroughly. In most cases, the resulting solids were beige to yellow gels, and some vials appeared to have a solid film on the vial walls.

[0379] Approximately 10 volumes of solvent (200 μL) were added to each vial for screening. The first two solvents selected were MtBE and MIBK. After adding the solvent, the mixture (or solution) was stirred overnight (400 RPM). In vials where the gel did not break upon addition of the solvent, sonication and vortexing of the vials achieved some success.

[0380] Most experiments in MIBK produced solutions, while experiments in MtBE generally produced gums or gels. However, two experiments formed slurries suitable for sampling. A free-flowing yellow powder was isolated from the experiments using 2 equivalents of HCl. After sampling, the first-round solvent was evaporated under a steady nitrogen stream and dried under vacuum over the weekend. Diethyl ether and IPA∶heptane (2∶8 volume) were selected as the second-round solvents, and 10 volumes of the respective solvents were allotted to each experiment.

[0381] In the second round of counterion screening, the first two solvent systems studied were diethyl ether and IPA∶heptane (2∶8 by volume). Twenty volumes of diethyl ether and ten volumes of the IPA:heptane mixture were used. Through the first round of solvent screening with these counterions, most experiments produced gums or gels. However, five slurries suitable for filtration were observed. After sampling, the first-round solvents were evaporated under nitrogen and dried overnight under vacuum. The second-round solvents selected were EtOH∶DEE (2∶8 by volume) and ACN∶MtBE (1∶9 by volume). After adding ten volumes of the solvent, sonication was used to achieve free stirring, and the mixture was stirred overnight at room temperature. Most experiments resulted in gels or gelling, and only one slurry was suitable for filtration.

[0382] XRPD analysis is generally carried out in three stages: 1) Wet state: XRPD of the wet filter cake was performed on all samples as long as solids suitable for sampling were observed. 2) Dry state: The unique solids were then left on the XRPD plate and dried under vacuum at 50 °C for at least 3 hours. Then the XRPD of the unique dried solids was collected. 3) Humid state: The solids were subsequently exposed to >95% relative humidity overnight, and the XRPD of the resulting solids was collected. A humid environment was generated by placing a beaker of saturated potassium sulfate in water in a sealed container. This procedure was not performed for any amorphous solids obtained. All XRPD patterns were compared with the counterion XRPD patterns and known free molecule patterns.

[0383] No solids were collected under the following counterions: oxalic acid, methanesulfonic acid, sulfuric acid, succinic acid, toluenesulfonic acid; no solids were collected under the following solvents: tert-butyl methyl ether (MtBE), diethyl ether. Methyl isobutyl ketone (MIBK) and 2-propanol (IPA)∶heptane (2∶8).

[0384] No solids were collected under the following counterions: hydrobromic acid, nitric acid, tartaric acid; no solids were collected under the following solvents: tert-butyl methyl ether (MtBE), methyl isobutyl ketone (MIBK) and 2-propanol (IPA):heptane (2:8).

[0385] No solids were collected under the following counterions: hydrochloric acid (1.1 and 2.2 equivalents); no solids were collected under the following solvents: methyl isobutyl ketone (MIBK) and 2-propanol (IPA)∶heptane (2∶8).

[0386] No solids were collected under the following counterions: benzenesulfonic acid, gentisic acid; no solids were collected under the following solvents: diethyl ether, IPA:diethyl ether, IPA:heptane (2:8), ACN:MtBE (1:9).

[0387] No solid was collected with the following counterions: malic acid; no solid was collected with the following solvents: diethyl ether, EtOH:diethyl ether, IPA:heptane (2:8), ACN:MtBE (1:9).

[0388] No solid was collected with the following counterions: citric acid, fumaric acid, phosphoric acid, glucuronic acid; no solid was collected with the following solvents: IPA:diethyl ether, IPA:heptane (2:8), ACN:MtBE (1:9).

[0389] The salt screening experiments resulted in gelling in most experiments, but experiments with HBr, nitric acid, HCl (both 1 and 2 equivalents), tartaric acid, maleic acid, citric acid, fumaric acid, phosphoric acid, mandelic acid, glucuronic acid, and aspartic acid provided slurries suitable for filtration.

[0390] Further results of the salt screening experiments are listed in the table below.

[0391] Table 1. Salt screening of Compound I

[0392]

[0393]

[0394] Note: Blank cells indicate that no solid was collected.

[0395] Amorphous solids were recovered from the experiments with HBr, nitric acid, HCl (both 1 and 2 equivalents), tartaric acid, citric acid, fumaric acid, phosphoric acid, and glucuronic acid. Only the counterion itself was recovered from the experiment with aspartic acid.

[0396] In the experiment with maleic acid, a low-crystalline viscous solid was isolated from diethyl ether and named Form A. Also in the experiment with maleic acid, a free-flowing white crystalline powder was isolated from IPA∶heptane (2∶8 v / v) and appears to be a mixture of forms named Form B+C.

[0397] Most of Form B of the maleate converts to Form C upon drying (a small amount of residual Form B was found by XRPD). Form C is also stable and no deliquescence was observed after overnight exposure to >95% relative humidity.

[0398] After filtering the maleate, a small amount of beige gel remained in the vial. Another 10 volumes of IPA∶heptane (2∶8 v / v) were added to the vial and it was stirred for a weekend to give a free-flowing white slurry with no visible gel. After filtration and drying, Form C of the free-flowing white crystalline powder was isolated again. NMR of Form C of the maleate showed reasonable consistency with the parent structure.

[0399] For the experiments with mandelic acid, the crystalline form, designated as Form E, was confirmed by XRPD. The solid had a slightly sticky texture immediately after filtration. The mandelate salt was shown to be stable to drying and no deliquescence or loss of crystallinity was observed after overnight exposure to >90% relative humidity.

[0400] Example 3. Small - scale preparation of N - [(3S) - 1 - azabicyclo[2.2.2]octan - 3 - yl] - 6 - (2 - ethoxyphenyl) - 3 - [(2R) - 2 - ethyl - 4 - [1 - (trifluoromethyl) - cyclobutanecarbonyl]piperazin - 1 - yl]pyridine - 2 - carboxamide mandelate (Compound I mandelate salt)

[0401] Weigh approximately 60 mg of Compound I into a 4 ml vial with a 10 mm stir bar. Add the stock solution of mandelic acid in EtOH (20 mg / ml) and stir for 1 hour. Evaporate the solvent under a nitrogen stream and dry the off-white gel in vacuo at room temperature overnight.

[0402] After drying the off-white gel, add 10 volumes of IPA∶heptane (2∶8 v / v) to the vial. Sonicate and vortex the mixture to allow for free stirring. Add a small amount of crystalline Compound I mandelate (from Example 2) as a seed. After several hours, only a small amount of free-flowing solid was observed, which was confirmed by XRPD to be amorphous. Most of the solid was an off-white gel. Add an additional 10 volumes of IPA∶heptane (2∶8 v / v), then sonicate and vortex. After approximately 1 hour, a flowable slurry was observed and stirred overnight. The slurry was sampled the next day for XRPD, which confirmed the previously observed crystalline Form E.

[0403] Example 4. Small - scale preparation of N - [(3S) - 1 - azabicyclo[2.2.2]octan - 3 - yl] - 6 - (2 - ethoxyphenyl) - 3 - [(2R) - 2 - ethyl - 4 - [1 - (trifluoromethyl) - cyclobutanecarbonyl]piperazin - 1 - yl]pyridine - 2 - carboxamide maleate (Compound I maleate salt)

[0404] Weigh approximately 60 mg of Compound I into a 4 ml vial with a 10 mm stir bar. Add the stock solution of maleic acid in EtOH (20 mg / ml) and stir for 1 hour. Evaporate the solvent under a nitrogen stream and dry the off-white gel in vacuo at room temperature overnight.

[0405] After drying the beige gel, 10 volumes of IPA∶heptane (2∶8 v / v) were added to the vial. The mixture was sonicated and vortexed to enable free stirring. A small amount of crystalline Compound I maleate (from Example 2) was added as a seed. After several hours, no free-flowing solid was observed and a beige oily gel was visible on the vial walls. The mixture was sonicated periodically and stirred overnight at room temperature. No change was observed. At this stage, 50 μL of MIBK was added and then briefly sonicated. A slurry was observed within 2 hours and was stirred overnight at room temperature. After filtration, the crystalline morphology observed was a mixture of two morphologies designated as Morph B and C. While the solid isolated from the screening experiment of Example 2 mainly contained Morph C, the solid isolated in this scale-up experiment mainly originated from Morph B.

[0406] Example 5. Preparation of N - [(3S) - 1 - azabicyclo[2.2.2]octan - 3 - yl] - 6 - (2 - ethoxyphenyl) - 3 - [(2R) - 2 - ethyl - 4 - [1 - (trifluoromethyl) - cyclobutanecarbonyl]piperazin - 1 - yl]pyridine - 2 - carboxamide mandelate (Compound I mandelate salt)

[0407] Approximately 200 mg of Compound I and 55 mg (1.1 eq) of mandelic acid were mixed in a 20 mL vial with a stir bar. Initially, 5 volumes of IPA were added with stirring at room temperature, which rapidly resulted in dissolution and a pale yellow solution. This solution was seeded with crystalline Morph E of Compound I mandelate (from Example 2), resulting in a turbid solution. The seed appeared to be retained. Heptane was slowly added dropwise with stirring until a mixture of IPA∶heptane (1∶1 v / v; total 10 volumes) was obtained. During the addition of heptane, the turbid solution gradually thickened into a white slurry. One hour after addition, a viscous gel-like slurry was observed. The slurry was sonicated and stirred at room temperature throughout the weekend, resulting in a viscous white slurry that was no longer gel-like. The slurry was filtered and the vial was washed with 3 volumes of IPA∶heptane (2∶8 v / v). The white solid was dried overnight at room temperature under vacuum (-30 in Hg).

[0408] The yield of mandelate was 78 mg (31% w / w). X-ray powder diffraction (XRPD) confirmed that the mandelate was Morph E. NMR spectra indicated the presence of 1.1 wt% residual IPA, 0.13 wt% heptane, and a Compound I∶counterion ratio of 1.00∶1.07.

[0409] Example 6. Preparation of N - [(3S) - 1 - azabicyclo[2.2.2]octan - 3 - yl] - 6 - (2 - ethoxyphenyl) - 3 - [(2R) - 2 - ethyl - 4 - [1 - (trifluoromethyl) - cyclobutanecarbonyl]piperazin - 1 - yl]pyridine - 2 - carboxamide maleate (Compound I maleate salt)

[0410] Approximately 200 mg of Compound I and 42 mg (1.1 equivalents) of maleic acid were mixed in a 20 mL vial with a stir bar. Initially, 5 volumes of IPA and 25 μL of MIBK were added with stirring at room temperature. This caused the gel to gradually dissolve, yielding a pale yellow solution. The solution was seeded with crystalline Form B + C Compound I maleate (from Example 2), but the seed crystal was not retained. Heptane was slowly added dropwise with stirring until a mixture of IPA:heptane (5:7 volume) was obtained, which caused the solid to precipitate as a gel. To address the gelling issue, 1 volume of MIBK was added in 7 additional portions of 25 μL each. The final solvent composition was IPA:heptane:MIBK (5:7:1 volume; total 13 volumes). The gel was sonicated for approximately 5 minutes and appeared to break up, producing some flowable solid. After 1 hour, a flowable white slurry was observed. The slurry was stirred at room temperature throughout the weekend, which did not result in a change in the slurry rheology. The slurry was filtered and the vial was washed with 3 volumes of IPA:heptane (2:8 volume). The white solid was dried under vacuum (-30 inches of mercury) at room temperature overnight.

[0411] The yield of the maleate was 126 mg (52% w / w). The wet filter cake of the maleate was confirmed by XRPD to be a mixture of Form B and Form C. After drying, a conversion to Form C was observed with no residual Form B. The NMR spectrum indicated the presence of 0.08 wt% residual heptane and a ratio of Compound I:counterion of 1.00:0.87. A qualitative humidity exposure test was conducted by exposing approximately 10 mg of the maleate to 80% RH overnight. No detectable mass increase was observed.

[0412] Example 7. Preparation of crystalline form C of N - [(3S) - 1 - azabicyclo[2.2.2]octan - 3 - yl] - 6 - (2 - ethoxyphenyl) - 3 - [(2R) - 2 - ethyl - 4 - [1 - (trifluoromethyl) - cyclobutanecarbonyl]piperazin - 1 - yl]pyridine - 2 - carboxamide maleate (Compound I maleate salt)

[0413] Weigh amorphous compound I (49.9 mg) into a 2 mL vial. Weigh maleic acid (1.1 equivalents, 11.5 mg) into the vial. Add approximately 250 μL (5 volumes) of MIBK and a 5 mm stir bar to the vial. Stir the materials into solution at room temperature. Seed the solution with the tip of a spatula of crystalline form C. The solution becomes slightly turbid, indicating that the seed has been retained. Slowly add three volumes of heptane antisolvent, 30 μL every 5 minutes until a total of 150 μL has been added, with vortexing between each addition of 30 μL. Some gelling was observed during the addition of heptane, manifested as pale yellow spots sticking to the vial wall. After adding 3 volumes of heptane, transfer the resulting slurry to a hot plate and stir at 50 °C, and break up the pale yellow gel with a spatula. Stir the slurry at 50 °C for 30 minutes. Add an additional 6 volumes of heptane dropwise (50 μL every 5 minutes for 30 minutes, or a total of 300 μL), with vortexing between each addition. Then stir the slurry at 50 °C for 1 hour, at which point a small amount of yellow gel was observed on the vial wall and the slurry had poor flowability. Ultrasonication was also used at this stage but did not result in an improvement in the slurry rheology. Add an additional 5 volumes (250 μL) of heptane (for a total of 14 volumes added), and stir the slurry at 50 °C overnight. The next day, transfer the slurry to room temperature and stir for 1 hour, but the rheology and flowability remained poor. Small pieces of orange gel were observed on the vial wall. Filter a small sample of the slurry and plate it for XRPD, which indicates form C.

[0414] Example 8. N-[(3S)-1-Azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2- ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide maleate (Compound I maleate salt), another preparation method of crystalline form C

[0415] Compound I free base (6.15 g; 5.72 g considering solvent content) and maleic acid (1.20 g, 1.1 molar equivalents (eq.)) were dissolved in 6 volumes (34.2 mL) of IPA:MIBK (5:1 volume) while stirring and heating to 30 °C. The reddish-brown solution was cooled to 25 °C and heptane was started to be added at a rate of 0.35 mL / min. After adding 4 volumes (22.5 mL) of heptane, the solution was seeded with maleate polymorph B+C (15 mg, 0.26 wt%). The seed was retained and as heptane was continued to be added, the mixture started to precipitate oily-gel-like brown solids. After adding 6 volumes of heptane, the mixture continued to thicken and precipitated oily-gummy-gel-like solids. After adding all 10 volumes (57.2 ml) of heptane, the rheology of the mixture seemed to improve and some suspended solid particles were visible in addition to the gummy-jelly brown mixture and the crust layer. Samples were taken for analysis by microscopy, showing some irregular small particles and gel-gum. The mixture was sonicated for 3 - 5 minutes to further improve the rheology of the mixture and another sample of the slurry was analyzed by microscopy. The mixture was heated to 50 °C and stirred overnight.

[0416] The next day, the resulting light brown slurry was sampled for microscopy and cooled to 15 °C. Samples were taken at this time for XRPD analysis, which showed a mixture of polymorph B and polymorph C. The solid was collected by filtration and washed three times with 1 volume of IPA:heptane (2:8 volume). The filter cake retained the mother liquor and was thus manually mixed with a spatula. Additional volumes of heptane were added twice to mix with the clay-like brown solid and produce a powdery solid. The powder sample was analyzed by XRPD and showed polymorph C. The residue was transferred to a vial and dried in a vacuum oven at 50 °C, 10 -2 -10 -1 torr for 18 hours. Polymorph C (5.8 g, 84% yield) was re-obtained.

[0417] Polymorph C of Compound I maleate was used as the input material for subsequent polymorph screening experiments.

[0418] Example 9. Preparation of crystalline form D of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2- ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide maleate (Compound I maleate salt)

[0419] Weigh approximately 50.1 mg of amorphous Compound I into a 4 mL vial. Weigh 11.7 mg (1.1 equivalents) of maleic acid onto weighing paper and add it to the vial. Add IPA∶MIBK (5∶1 by volume) (300 μL, 6 volumes) and a 10 mm stir bar, and stir the materials into a solution. Add heptane (50 μL, 1 volume) dropwise every 5 minutes for 15 minutes until 150 μL (3 volumes) is added. Then seed the solution with crystalline Form B. The solution becomes slightly turbid, indicating that the seed is retained. Immediately after seeding, add heptane and continue to add 1 volume every 5 minutes until 9 volumes (450 μL) are added. After 6 volumes of heptane, some gelling is observed on the vial wall. A viscous slurry forms after adding 9 volumes, and a gelatinous substance is visible on the vial wall. After sonication of the slurry for 5 minutes and stirring at 50 °C for 1 hour, the gelatinous substance decreases slightly. Filter a small sample of the slurry and prepare a tablet for XRPD. At this point, Form B is observed.

[0420] Stir the slurry at 50 °C for an additional 1 hour, after which most of the gelatinous substance breaks up and the slurry appears more fluid. Filter a small sample of the slurry and prepare a tablet for XRPD. At this point, Form B is observed again. Stir the slurry at 50 °C overnight, after which no visible gelatinous substance remains and the fluidity of the slurry seems to have improved. Filter a small sample of the slurry and prepare a tablet for XRPD, which indicates a new form, designated as Form D.

[0421] Example 10. Another preparation method of crystalline form D of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)- 2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide maleate (Compound I male ate salt)

[0422] Charge approximately 200 mg of Compound I maleate Form C (from Example 8) into a 4 mL vial. Add two volumes of solvent (IPA or MeOAc), and stir the mixture at 50 °C to dissolve it. Cool the solution to 40 °C and seed it with Form D. The seed seems to be retained and disperses as a fine silty - haze in the reddish - brown solution. Cool the mixture 2.5 °C every 10 minutes until 25 °C is reached, then stop all heating (RT ~ 22 - 24 °C), and stir the mixture overnight (18 hours). The next day, take samples of both slurries for microscopy and XRPD.

[0423] The slurry in IPA is thinner than that in MeOAc, showing a mixture of needle - shaped and flake - shaped crystals, and shows Form D by XRPD. Collect the solid and rinse the vial once with 1 volume of IPA to collect all the remaining solid and rinse the filter cake. Dry the solid in a vacuum oven at 50 °C, 10 -2 -10 -1 torr for 6 hours, then weigh it to obtain the yield (26 mg, 13%).

[0424] The slurry in MeOAc was more viscous than that in IPA, showing plate-like crystals and form D by XRPD. The solid was collected and the vial was rinsed once with 1 volume of MeOAc to collect all the remaining solid and rinse the filter cake. The solid was dried in a vacuum oven at 50 °C and 10 -2 -10 -1 torr for 6 hours and then weighed to obtain the yield (74 mg, 37%). The dried solid was analyzed by DSC and TGA / DSC.

[0425] Example 11. Large-scale preparation of crystalline form D of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)- 2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide maleate (Compound I male ate salt)

[0426] A method adapted from a previous experiment was carried out to convert the free base of compound I to the maleate, form D, according to the following procedure:

[0427] 1. 12.03 g of the free base (11.19 g considering the solvent content) was weighed into a 400 mL EasyMax container.

[0428] 2. Maleic acid (2.35 g, 1.1 equivalents (eq.)) was added to the container.

[0429] 3. IPA (about 5 volumes, 60 mL) and 1 volume of methyl isobutyl ketone (MIBK, 12 mL) were added at room temperature (RT), yielding a dark brown solution.

[0430] 4. The stirring was set to 150 rpm.

[0431] 5. Heptane (4 volumes, 48 mL) was added over 1.5 hours.

[0432] 6. Seeded with 30 mg of form D.

[0433] a. The seed crystals were retained.

[0434] 7. Heptane (2 volumes, 24 mL) was added over 45 minutes.

[0435] a. A thin slurry with a dark precipitate collected at the bottom of the container, and oil separation may occur.

[0436] b. Inoculated with an additional 15 mg of form D.

[0437] c. Some gelling was observed at this stage.

[0438] d. Increase the stirring to 300 rpm.

[0439] 8. Heptane (4 volumes, 48 mL) was added over 1.5 hours.

[0440] a. Obvious gelling was observed during and after the addition process.

[0441] b. The container was sonicated briefly (about 3 minutes).

[0442] 9. Heat to 50 °C within 30 minutes.

[0443] 10. Hold at 50 °C overnight.

[0444] 11. A flowable light brown slurry was obtained, with minimal gelling or solids on the container walls.

[0445] a. XRPD sampling confirmed the presence of only Form D.

[0446] 12. Cool to 20 °C within 45 minutes.

[0447] 13. Hold at 20 °C for 1 hour.

[0448] 14. Filter, wash with 5 ml of heptane (twice), and dry under vacuum (-27.5 inches of mercury) at room temperature for at least 2 days.

[0449] 15. A flowable light brown powder was obtained (yield = 10.9 g, 81% mol / mol).

[0450] XRPD confirmed the presence of only Form D in the product.

[0451] Example 12. Recrystallization of crystalline form D of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2- ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide maleate (Compound I maleate salt)

[0452] Solubility measurements (Example 13) identified the favorable characteristics of four solvents (EtOH, IPA, acetone, and MeOAc) and two anti-solvents (MtBE and heptane) for small-scale recrystallization experiments. During small-scale anti-solvent recrystallization, problems such as gelling, oil precipitation, or form transformation were observed in all experiments using heptane. EtOH:MtBE and IPA:MtBE were identified as the best solvent systems for the 2 - 3 g scale.

[0453] Compound I maleate Form D requires a long induction period. By ensuring sufficient holding time combined with slow and controlled anti-solvent addition, problems such as gelling, oil precipitation, and amorphous solid precipitation can be alleviated. Additionally, when the RH is high (>55%), filtration in the atmosphere causes the wet filter cake to dissolve on the filtration device. Despite these unpredictable challenges, a suitable and reliable process for the recrystallization of Compound I maleate Form D has been developed:

[0454] 1. Add the solid to a container.

[0455] 2. Add IPA (4 volumes) at room temperature.

[0456] 3. Set stirring to accommodate a mixing energy of approximately 0.7 W / kg based on the final process volume.

[0457] 4. Heat to 50 °C or until dissolved.

[0458] 5. Cool to 30 °C within 2 hours.

[0459] 6. Seed with approximately 2% seed loading (dry Form D crystals).

[0460] 7. Hold for 30 minutes.

[0461] 8. Add MtBE (3 volumes) within 1.5 hours.

[0462] 9. Hold for 3 hours.

[0463] 10. Add MtBE (7 volumes) within 6 hours.

[0464] 11. Hold for 1 hour.

[0465] 12. Heat to 40 °C within 30 minutes.

[0466] a. Set stirring to accommodate a mixing energy of approximately 0.18 W / kg based on the final process volume.

[0467] 13. Hold for 2.5 hours.

[0468] 14. Cool to 20 °C within 2 hours.

[0469] 15. Hold for 4 hours.

[0470] 16. Filter under nitrogen, ensuring that the filter cake is dehydrated.

[0471] 17. Wash with 2 x 2 volumes of IPA:MtBE (3:7 volumes).

[0472] 18. Ensure appropriate drying conditions (-30 inHg vacuum at 50 °C, nitrogen purge).

[0473] The purity of the process in this solvent system (IPA:MtBE) has always been high. The most representative process has a purity of 99.68% a / a. The yield of this process is approximately 90% w / w. The separated solid shows high crystallinity. Increasing the temperature cycling step after the anti-solvent addition improves the crystallinity. A controlled filtration procedure is crucial and should be carried out under an inert atmosphere to ensure that the filter cake is completely dehydrated before drying.

[0474] Example 13. Solubility evaluation of Compound I in solid form

[0475] The solubility of certain solid forms of Compound I in various solvents was determined by gravimetric solubility or solvent addition.

[0476] Gravimetric solubility determination

[0477] Weigh approximately 25 mg of the compound into a vial. Add approximately 5 volumes (0.125 mL) of solvent to the solid and stir the mixture at the specified temperature (RT or 50 °C). Record the solution and add an additional 0.125 mL of solvent to the slurry. If a thin slurry is noted at this stage, no additional solvent is added. If a thick slurry is noted, add 0.25 mL of solvent (total volume 0.5 mL). If a thick slurry is noted again, add an additional 0.25 mL of solvent (total volume 0.75 mL). After stirring for 2 days, centrifuge the slurry, collect the supernatant into a pre-weighed vial, and evaporate the solvent without stirring at 50 °C (ambient pressure). Dry the vial containing the solid residue in a vacuum oven at 50 °C, 10 -2 -10 -1 torr for 3 hours and then weigh again to determine the mass of the solid dissolved in the supernatant (i.e., mg solid / mL solvent).

[0478] Solvent addition solubility determination

[0479] Weigh approximately 20 mg of the compound into a vial. Add the solvent in aliquots and stir at the specified temperature until complete dissolution is observed. This measurement gives the solubility range. The results of the solubility experiments are shown in the following table.

[0480] Table 2. Solubility of solid forms of Compound I at room temperature and 50 °C

[0481]

[0482] a The compound is freely soluble at the test concentration; b Oil is produced upon addition of solvent, and the solubility is determined as the volume at which the mixture becomes homogeneous; c XRPD of the solid after separation indicates that the compound retains Form D; d XRPD of the solid after separation indicates that the compound is converted to Form C

[0483] Results:

[0484] Experiments with Compound I (amorphous free base) resulted in complete dissolution in all test solvents except heptane and IPA: water (1:1 volume), indicating that the compound is freely soluble. Oiling out was observed after adding two volumes of IPA: water (1∶1 volume), which cleared upon addition of more solvent. Due to the low solubility in heptane, the solid was stirred overnight in approximately 35 - 40 volumes of solvent. However, at this point, the compound adhered to the walls of the vial.

[0485] Experiments carried out with polymorph C of Compound I maleate showed that the solid was freely soluble in MeOH, EtOH, acetone, THF, ACN, MEK, DMSO and in an aqueous system of 8:2 volume water: organic component. Gels / gellies were formed in water and in a 95:5 volume water: organic system.

[0486] At room temperature and 50 °C, polymorph D of Compound I maleate was freely soluble and soluble in EtOAc and MIBK. At room temperature, polymorph D was soluble in IP and could not maintain a slurry at 50 °C. Polymorph D was insoluble in heptane, diethyl ether and MtBE. Solids obtained from experiments with polymorph D were also sampled for XRPD. All experiments maintained polymorph D, except for the experiment in EtOAc which was polymorph C, present at room temperature and becoming the major polymorph at 50 °C. Solubility tests for polymorph D were also carried out in mixtures of selected solvents (EtOH, IPA and MeOAc with MtBE as co-solvent).

[0487] Example 14. Polymorph screening 2: Short-term slurry

[0488] Example 14a. Slurries of polymorph C in various solvents

[0489] Short-term slurries with polymorph C of Compound I maleate were carried out in nine solvents at two temperatures (RT and 50 °C). The slurries were stirred for 2 days at a specific temperature and then the solids were analyzed by XRPD. The results of the short-term slurry experiments are summarized in the table below.

[0490] Table 3. Results of short-term slurry experiments of polymorph C at room temperature and 50 °C

[0491]

[0492] A set of slurries in an organic: water (5:95 volume) mixture were prepared at room temperature. The organic solvents tested were EtOH, IPA, THF, acetone and ACN. All five co-solvent samples produced brown gels and oils. After stirring for 5 h, the temperature was raised to 40 °C and stirring was continued overnight. No changes were observed in these mixtures and a pale yellow solution and brown gellies persisted.

[0493] Example 14b. Additional slurries of polymorphs C and D

[0494] Additional slurries were prepared with polymorph C and polymorph D of Compound I maleate in selected solvents. The conditions (solvent, volume, temperature) and results are shown in the table below.

[0495] Table 4. Results of additional slurry experiments of polymorphs C and D

[0496]

[0497] Result: In 5 volumes of pure MeOAc, Form C completely dissolved and then Form D precipitated after 3 days of stirring. In 4 volumes of water-saturated MeOAc, Form C dissolved and remained as a solution. After standing for 1 hour under ambient conditions and then after exposure to >95% RH for 16 hours, the solid recovered from MeOAc at 10 °C was analyzed as a wet filter cake. The solid transformed to Form C and no evidence of reversion to Form B was observed.

[0498] Example 14c. Amorphous slurry

[0499] The vitreous amorphous solid was prepared by evaporating a solution of crystalline Form C of Compound I maleate in 5 volumes of MeOH. The solution was evenly distributed in 10 vials and then evaporated overnight at 50 °C without stirring. The gel was dried in a vacuum oven at 50 °C, 10 -2 -10 -1 torr for 3 hours and then the slurry solvent was added and the mixture was stirred at room temperature. The results are summarized in the table below.

[0500] 5. Results of short-term slurry experiments on amorphous Compound I maleate

[0501]

[0502] *L.C. indicates low crystallinity. A hyphen indicates insufficient solid for XRPD analysis after 5 days.

[0503] Result: Most samples where the solid did not completely dissolve started to precipitate a very small amount of solid suspended in the solution at the 4-hour mark, but there was not enough at that time for analysis. All mixtures were stirred overnight at room temperature. After 24 hours of stirring, the fine haze in EtOAc had become a moderately dilute slurry and was collected for analysis, showing Form C. The remaining samples remained as solutions (water-saturated EtOAc and MIBK) or mostly glassy solids with a very small amount of suspended solid in the slurry and were continuously stirred at room temperature. The mixtures were monitored over the next 5 days and the slurry solids were collected and analyzed by XRPD when there was enough for analysis.

[0504] A mixture of Forms A and B collected from MIBK: heptane (1:1 volume) was placed on a bench under ambient conditions for 3 days and then analyzed by XRPD. The diffractogram showed an increase in peaks associated with Form C and a distinct loss of crystallinity. In a vacuum oven at 50 °C, 10 -2 -10 -1After further drying for 20 hours under reduced pressure, the peak corresponding to Form C became the main feature of the XRPD diffractogram.

[0505] Example 15. Polymorph screening 3: Evaporative crystallization

[0506] After stirring for 2 days, the compound I maleate slurry (Example 12) produced for weight solubility determination was centrifuged, and the supernatant was collected in a pre-weighed vial. The solvent was evaporated without stirring at 50 °C (ambient pressure). The vial containing the solid residue was dried in a vacuum oven at 50 °C under 10 -2 -10 -1 Torr for 3 hours. Most of the solids recovered from the evaporation were dry and powdery. A minimal amount of gel / glassy solid was obtained from the evaporation of the anti-solvent. The results of the evaporation crystallization studies are summarized in the table below.

[0507] Table 6. Results of evaporation crystallization experiments

[0508]

[0509] *L.C. indicates low crystallinity. A hyphen indicates insufficient solid for XRPD analysis after 5 days.

[0510] Results: Although the vial caps were sealed with paraffin film, the solutions produced in THF at room temperature slowly evaporated under stirring. This left an opaque brown residue for XRPD analysis. The solutions produced in MeOH, EtOH, acetone, and MEK at room temperature were placed in a -20 °C refrigerator for 1.5 weeks. When no solid precipitated, the lids were removed, and the reddish-brown solutions were placed at 50 °C to evaporate the solvent without stirring. The resulting reddish-brown gels were dried in a vacuum oven at 50 °C under 10 -2 -10 -1 Torr for 3 hours. The solids were probed with a needle, and the solids from the evaporation in MeOH were observed to be the most brittle and glassy. The solid sample from the evaporation in MeOH showed an amorphous pattern by XRPD.

[0511] Example 16. Polymorph screening 4: Cooling crystallization

[0512] Example 16a. Cooling in pure solvents

[0513] Approximately 23 mg of compound I maleate Form C was weighed into a 2 ml vial and dissolved in the selected solvent at 50 °C. Cooling was carried out using two protocols. Rapid cooling was carried out by immersing the vial containing the 50 °C solution in an ice bath and leaving the vial undisturbed. Slow cooling was carried out at a rate of 5 °C / h from 50 °C to room temperature under stirring. The results of the cooling crystallization studies are summarized in the table below.

[0514] Table 7. Results of cooling crystallization experiments in pure solvents

[0515] Solvent Quantity [volume] Procedure XRPD* MIBK 14 Rapid cooling L.C.; Broad peak EtOAc 40 Rapid cooling - MeOAc 2 Rapid cooling L.C.; Broad peak IPA 2 Rapid cooling Amorphous MeOH 5 Rapid cooling - EtOH 5 Rapid cooling - Acetone 5 Rapid cooling - ACN 5 Rapid cooling - MIBK 14 Slow cooling B + D EtOAc 40 Slow cooling - MeOAc 2 Slow cooling D IPA 2 Slow cooling D

[0516] *L.C. indicates low crystallinity. A hyphen indicates insufficient solid for XRPD analysis.

[0517] Results: Except in EtOAc, the rapid cooling experiments produced a gelatinous slurry within hours in an ice bath. The XRPD patterns shown by these gelatinous solids had broad peaks and very low crystallinity. Some extremely small fine brown solids suspended in the EtOAc solution were observed, but not enough to collect and analyze. Therefore, the mixture was moved to -20 °C to attempt to increase the amount of precipitated solid.

[0518] During the slow cooling experiments, a homogeneous slurry was produced only in MeOAc. Precipitation occurred around 40 °C and became thick upon further cooling. Morphology D was collected from MeOAc. Significant crusting was observed in the EtOAc and MIBK samples, and the seeding effect caused by evaporation and the crust layer may affect the results of these experiments. XRPD analysis was not feasible because the amount of the crust layer and the misty suspension in EtOAc was extremely small. After stirring at room temperature for some time, some gelatinous solids began to stick to the vial below the solvent level in MIBK. All the solids were mixed and collected, and the XRPD showed a mixture of Morphology D and Morphology B. The IPA solution was initially cooled into a viscous brownish-red solution. A small amount of Morphology D precipitated from the IPA solution after stirring at room temperature for 2 days.

[0519] Example 16b. Cooling in a solvent / antisolvent mixture

[0520] Approximately 20 mg of Compound I maleate Form C was loaded into a vial. A solvent mixture was prepared with a 1:1 volume composition. While stirring at 50 °C, the solvent was added in aliquots until the solid dissolved. When the solid dissolved, cooling was carried out at a rate of 5 °C / h. Except for the MIBK mixture, they were moved to another hot plate and continued to be stirred at 50 °C (see Example 14b). The results of the cooling crystallization experiments are summarized in the following table.

[0521] Table 8. Results of cooling crystallization experiments in a solvent / antisolvent mixture

[0522] Solvent mixture (1:1 volume) Quantity [volume] XRPD* MeOAc: IPAc 27 C + B IPA: MtBE 28 Amorphous MIBK: MtBE 67 - Acetone: Heptane 32 - IPA: Heptane 62 - MIBK: Heptane 67 -

[0523] *A hyphen indicates insufficient solid for XRPD analysis.

[0524] Results: At the end of cooling, some crusting was observed in the vial containing the MeOAc / IPAC solution. A brown gel / gelatinous material was observed in the acetone / heptane mixture. When reaching room temperature, none of the samples were slurries and they were stirred overnight. The MeOAc / IPAC mixture produced some gelatinous solids in solution in addition to the gel. It was mixed and collected for analysis, showing morphology C+B. The IPA / heptane mixture produced some very fine brown solids suspended in the solution, and an attempt was made to collect these solids for XRPD analysis, but the solids were trapped in the filter paper and no material could be recovered for analysis. The acetone / heptane and IPA / MtBE mixtures were transferred to 10 °C and stirred. The IPA / MtBE sample produced a gelatinous slurry, but the combination of poor filtration and heating of the sample during separation produced very little material for analysis. No peaks were observed.

[0525] Example 17. Polymorph screening 5: Anti-solvent crystallization

[0526] Weighed approximately 23 mg of Compound I maleate form C into a vial. The solid was dissolved in the selected solvent at room temperature. The anti-solvent addition was carried out by one of two methods, namely the reverse or direct addition method.

[0527] For reverse anti-solvent addition, the solution was transferred all at once to four times the solvent volume of the anti-solvent under rapid stirring. For example, if the solid was dissolved in 0.5 mL of solvent, the solution was immediately added to 2.0 mL of anti-solvent under vigorous stirring.

[0528] For direct anti-solvent addition, twice the volume of the solvent was used for the anti-solvent and it was added dropwise in four portions over 1 hour. The mixture was stirred during the anti-solvent addition. For example, if the solid was dissolved in 0.5 mL of solvent, 1.0 mL of anti-solvent was added over 60 minutes. The mixture was heated to 40 °C and stirred for 16 hours, then cooled to room temperature and stirred for another 24 hours, and then the sample was collected.

[0529] The results of the anti-solvent crystallization experiments are shown in the table below.

[0530] Table 9. Results of reverse anti-solvent crystallization

[0531]

[0532] *L.C. indicates low crystallinity. A hyphen indicates insufficient solid for XRPD analysis.

[0533] Table 10. Results of direct anti-solvent crystallization

[0534]

[0535] *L.C. indicates low crystallinity. A hyphen indicates insufficient solid for XRPD analysis.

[0536] Results: All samples that produced a slurry when the solution was mixed with the antisolvent in the reverse antisolvent mode produced crystalline solids with very low crystallinity with broad peaks and remained unchanged upon drying.

[0537] It was noted that the results at the completion of direct antisolvent addition were very similar to those of the reverse antisolvent addition experiment, which produced gel-like crystalline solids with very low crystallinity.

[0538] Some of the samples produced in the antisolvent crystallization experiment were mixtures of Form B, Form C, and Form D. These samples were left at ambient conditions for one week and then analyzed again by XRPD. Form B converted to Form C. However, no conversion between C and D was observed.

[0539] Example 18. Polymorph screening 6: Grinding

[0540] Approximately 30 mg of Compound I maleate Form C was loaded into a grinding capsule and 1 volume of solvent (if any) and 1 / 4” steel balls as a grinding medium were added. The solid was ground with a Wig-L-Bug at 3500 rpm for 30 seconds and then collected and analyzed by XRPD. The following table gives a summary of the results.

[0541] Table 11. Results of grinding experiments

[0542]

[0543] Example 19. One-week stability of crystalline form

[0544] Approximately 10 mg of crystalline Form D of Compound I maleate, 20 mg of crystalline Form C of Compound I maleate, and 10 mg of crystalline Form E of Compound I mandelate were weighed into an open 4 ml vial, and the vial was placed in a 20 ml vial containing saturated NaCl solution. The vial was sealed and kept at 40 °C for 7 days to create an atmosphere of 75% relative humidity in the system. After 7 days, the material was sampled and prepared for XRPD analysis. After one week under those conditions, no visible changes were observed by XRPD for any of the three tested crystalline forms. HPLC purity analysis confirmed that no degradation of the compound was observed for any crystalline form.

[0545] The stability test was repeated for 11 days on Forms C and D of Compound I maleate. After 11 days, no visible changes were observed by XRPD for either form, and HPLC purity analysis confirmed that no degradation of the compound was observed.

[0546] Example 20. Stability of form B and transformation to form C

[0547] Pure Form B is produced in the antisolvent crystallization with MIBK and heptane. After the sample was left at ambient conditions for one week, the sample was analyzed again by XRPD, showing the presence of some low-intensity peaks associated with Form C. The solid was scraped from the XRPD plate and used for simultaneous TGA / DSC analysis. The DSC thermogram shows an endothermic melting peak with an onset temperature of 120 °C, which seems to be consistent with the stepwise mass loss of 1.55% in the TGA thermogram. The TGA thermogram has many weight loss events (separated by analyzing the derivative of the TGA curve). After transferring the solid required for TGA / DSC analysis to the pan, the remaining solid was repressed onto the XRPD sample plate and analyzed again. After scraping and replating, the solid changed significantly, showing that the intensity of the peaks associated with Form C was greater than that of the peaks associated with Form B.

[0548] Example 21. Competitive slurry with Compound I maleate

[0549] Example 21a. Competitive slurries in IPA: heptane, MIBK, and EtOAc

[0550] At room temperature and 50 °C, saturated solutions were prepared in IPA: heptane (1:1 v / v), MIBK, and EtOAc, using Compound I maleate Form C as input. At 37 °C, a saturated solution was also produced in IPA: MIBK: heptane (5:1:10 v / v). In separate vials, approximately 12 mg of Form C and 6 mg of Form D were mixed. The saturated solution (supernatant separated from the slurry solid) was added to the vials, and stirring was continued at the same temperature as that at which the saturated solution was formed. The slurries were checked to ensure homogeneity. After stirring for 30 minutes, the slurries were sampled, and the solids were analyzed by XRPD. Although Form B was not added, all slurries except those in EtOAc showed a significant amount of Form B.

[0551] After stirring for 3 days, the slurries were sampled again. Those stirred at 50 °C converged to Form D (IPA: heptane (1:1 v / v) and MIBK) or Form C (EtOAc). Those at the lower temperature remained a mixture of all three forms (IPA: heptane (1:1 v / v) and IPA: MIBK: heptane (5:1:10 v / v)) or a mixture of Form C and Form D (MIBK and EtOAc).

[0552] The slurry was sampled again after 6 days of stirring. Starting from the 3-day time point, the slurry showing a single pattern did not change, but the mixtures of D, C, and B continued to change. In IPA:MIBK:heptane (5:1:10 by volume) at 35 °C, the trend seemed to favor forms B and C as the relative proportion of B gradually increased over time. The slurries were stirred at their respective temperatures.

[0553] The competing slurries were sampled again after 13 days. The EtOAc samples at room temperature were absorbed with filter paper, the IPA:MIBK:heptane (5:1:10 by volume) at 35 °C was crusted from the solvent, and the EtOAc at 50 °C was completely dried. Slight crusting was shown in other experiments. The results did not change compared to the 6-day time point, and the only significant change occurred in the slurry of IPA∶heptane (1∶1 by volume), where form C was no longer present. The following table summarizes the data from the competing slurries.

[0554] Table 12. Experimental results of competing slurries of form C and D of Compound I maleate

[0555]

[0556] *The hyphen indicates that data was not collected; a decrease; b increase.

[0557] Results: The results of the competing slurries showed that when seeds of form D were present, the conversion to form D occurred at elevated temperatures. However, at lower temperatures and in some solvent systems, the conversion seemed to be slow. In the competing slurries at room temperature, the relative amount of D seemed to remain stable over time, but B / C did not easily convert to D during the sampling period.

[0558] Example 21b. Competing slurries in IPA:MIBK, MIBK, and IPAc

[0559] Competing slurries were established with maleate forms B, C, and D. At two temperatures (22 - 25 °C and 50 °C), vials (4 mL) were set up with a 10 mm stir bar and 700 μL of three solvent systems. Maleate form D was added to all experimental vials (about 3 - 5 mg) with the tip of a spatula until a dilute slurry was formed. The slurries were stirred at their respective temperatures for 1 hour. Then the slurries were filtered through a syringe (0.45 μm filter) into new 4 mL vials. These new vials contained a pre-weighed amount of seed material with a mixture of maleate forms B / C and D. Since forms B and C showed an equal distribution in the dry solid, a material equivalent to twice the amount of form D was pre-weighed to obtain relatively similar proportions of each form in the resulting slurries. These slurries were stirred at their respective temperatures for 1 hour and then sampled for XRPD analysis.

[0560] When some crusting was observed, the vial was vortexed and positioned in such a way as to prevent crusting from forming above the liquid level on the heated vial wall. Then the slurry was sampled at the 4-day and 7-day marks for XRPD analysis. The following table summarizes the data from the competing slurries.

[0561] Table 13. Results of competing slurry experiments for forms B, C, and D of Compound I maleate

[0562]

[0563] *Hyphen indicates data not collected; a trace; b decreased.

[0564] Results: Form D was observed at all time points at 50 °C in MIBK:IPA:heptane (0.2:1.0:3.0 v / v) and pure MIBK. In MIBK at room temperature, form D was only observed at the 4-day and 7-day marks. In IPAc at room temperature, an initial conversion from form D to form C was observed, but approximately the same relative amount of form D was still observed at the 4-day and 7-day marks. However, in IPAc at 50 °C, form D was not observed at day 4, and a mixture of B and C was observed at days 4 and 7. MIBK:IPA:heptane at room temperature also appeared to remain as a mixture of B, C, and D, but the conversion was slower.

[0565] Example 22. Solubility in simulated fluid and water

[0566] Calibration samples of the solubility of the free base Compound I were prepared in the simulated fluids.

[0567] The solubility of the mandelate and maleate solids in the simulated fluids was studied. The simulated fluids FaSSIF (fasting state simulated intestinal fluid), FaSSGF (fasting state simulated gastric fluid), and FeSSIF (fed state simulated intestinal fluid) were removed from the refrigerator, heated to room temperature, and the pH of each fluid was measured. 1.9 - 2.0 mg of each salt was weighed into four vials, and 1 ml of each fluid including water was added. A stir bar (10 mm) was added to the vials, and the vials were stirred at 37 °C. After 30 minutes (mandelate samples) or 1 hour (maleate samples), the pH of each solution was measured, then 400 μL was removed from each solution and syringe filtered through a 0.45 μm syringe filter. Approximately 300 μL of the recovered filtrate was diluted 5-fold with diluent and injected for HPLC analysis. The samples remaining in the vials were stirred overnight. After stirring at 37 °C for 24 hours, the samples were filtered and diluted as described above and injected for analysis. The resulting data are shown in the following table.

[0568] Table 14 Solubility in simulated fluids

[0569]

[0570] *Solubility is greater than the listed value because the material has completely dissolved. Hyphens indicate data not collected. a Mandelate samples were taken at 30 minutes; maleate samples were taken after 1 hour.

[0571] There are minor differences in the solubility of the crystalline forms of maleate in FaSSIF. After 1 hour, the solubility of Form D was determined to be 1.50 mg / mL in FaSSIF, and the solubility of Form C was 1.24 mg / mL. The solids recovered from these experiments after 24 hours were oily and showed as amorphous by XRPD.

[0572] Example 23: X-ray powder diffraction (XRPD)

[0573] Although the diffractometer below was used, other types of diffractometers can also be used. Additionally, other wavelengths can be used and converted to Cu Kα.

[0574] "Characteristic peaks", to the extent of their existence, are a subset of the observed peaks and are used to distinguish one crystalline polymorph from another (polymorphs are crystalline forms with the same chemical composition). The determination of characteristic peaks is by evaluating the presence of observed peaks in one crystalline polymorph of a compound and, if any, comparing them with the peaks of all other known crystalline polymorphs of that compound, within an error range of ±0.2° 2θ.

[0575] XRPD was performed using a Bruker D8 Advance equipped with a LYNXEYE detector in reflection mode (i.e., Bragg - Brentano geometry). The samples were prepared on a silicon zero - recovery wafer. The parameters of the XRPD method used are shown below:

[0576]

[0577] The 2θ peaks provided for XRPD are in the range of ±0.2° 2θ.

[0578] Characterization of the solid forms of Compound I

[0579] The X - ray powder diffraction pattern of crystalline Form A of Compound I maleate is shown in Figure 12 . The X - ray powder diffraction pattern of crystalline Form B of Compound I maleate is shown in Figure 9 . The X - ray powder diffraction pattern of crystalline Form C of Compound I maleate is shown in Figure 5 . The X - ray powder diffraction pattern of crystalline Form D of Compound I maleate is shown in Figure 1 . The X - ray powder diffraction pattern of crystalline Form E of Compound I maleate is shown inFigure 13 In. The X-ray powder diffraction pattern of amorphous Compound I shows at Figure 18 In.

[0580] Comparison of the X-ray powder diffraction patterns of crystalline Forms B, C, and D of Compound I maleate measured during the competitive slurry experiment in Example 21, which is shown at Figure 17 In. Lines (1) and (2) are a mixture of Forms C+D; line (3) is a mixture of Forms B+C+D. Characteristic Form B peaks (orange arrows; 8.2 ± 0.2° 2θ; 12.3 ± 0.2° 2θ); characteristic Form C peaks (black arrows; 9.0 ± 0.2° 2θ; 13.5 ± 0.2° 2θ); characteristic Form D peaks (green arrows; 9.4 ± 0.2° 2θ; 14.0 ± 0.2° 2θ).

[0581] Characterization of crystalline Form A of Compound I maleate

[0582] The X-ray powder diffraction pattern of crystalline Form A of Compound I maleate is as shown at Figure 12 shown. Characteristic XRPD peaks include: 4.2 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, and 12.5 ± 0.2° 2θ. The list of XRPD peaks is shown in the following table:

[0583]

[0584] Characterization of crystalline Form B of Compound I maleate

[0585] The X-ray powder diffraction pattern of crystalline Form B of Compound I maleate is as shown at Figure 9 shown. Characteristic XRPD peaks include: 4.1 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, and 16.4 ± 0.2° 2θ. The list of XRPD peaks is shown in the following table:

[0586]

[0587] Characterization of crystalline Form C of Compound I maleate

[0588] The X-ray powder diffraction pattern of crystalline Form C of Compound I maleate is as shown at Figure 5 shown. Characteristic XRPD peaks include: 4.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, and 18.4 ± 0.2° 2θ. The list of XRPD peaks is shown in the following table:

[0589]

[0590] Characterization of crystalline Form D of Compound I maleate

[0591] The X-ray powder diffraction pattern of crystalline form D of Compound I maleate is as Figure 1 shown. The characteristic XRPD peaks include: 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ. The list of XRPD peaks is shown in the following table:

[0592]

[0593] Characterization of crystalline form E of Compound I mandelate

[0594] The X-ray powder diffraction pattern of crystalline form E of Compound I mandelate is as Figure 13 shown. The characteristic XRPD peaks include: 5.6 ± 0.2° 2θ, 10.5 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, and 16.5 ± 0.2° 2θ. The list of XRPD peaks is shown in the following table:

[0595]

[0596] In some embodiments, measurements on independently prepared samples on different instruments may result in variability greater than ±0.2° 2θ.

[0597] Example 24: Differential Scanning Calorimetry (DSC)

[0598] Using Mettler Toledo DSC 3+ Differential scanning calorimetry was performed. Samples (1 - 5 mg) were directly weighed into 40 μL sealed aluminum pans with pinholes and analyzed according to the following parameters:

[0599] Method Ramp method Sample size 1 - 5 mg Heating rate 5.0 to 10.0 °C / min Temperature range 30 to 200 °C Method gas <![CDATA[N2, 60.00 mL / min]]>

[0600] Characterization of solid forms of Compound I

[0601] The DSC thermogram of crystalline form B of Compound I maleate is shown in Figure 10 The DSC thermogram of crystalline form C of Compound I maleate is shown in Figure 6 The DSC thermogram of crystalline form D of Compound I maleate is shown in Figure 2 The DSC thermogram of crystalline form E of Compound I mandelate is shown in Figure 14 The DSC thermogram of amorphous Compound I is shown in Figure 19 The differential scanning calorimetry (DSC) thermogram thermal events of the solid forms are described in the following table:

[0602] The differential scanning calorimetry (DSC) thermogram thermal events of the solid forms are as described in the following table:

[0603]

[0604] Example 25: Simultaneous Thermogravimetric Analysis and Differential Scanning Calorimetry (TGA / DSC)

[0605] Using Mettler Toledo TGA / DSC 3+ Thermogravimetric analysis and differential scanning calorimetry were performed simultaneously on the same sample. The protective gas and purge gas were nitrogen at flow rates of 20 - 30 mL / min and 50 - 100 mL / min, respectively. The required amount of the sample (5 - 10 mg) was directly weighed in a sealed aluminum pan with a pinhole and analyzed according to the following parameters:

[0606] Method Ramp method Sample size 5 - 10 mg Heating rate 10.0 °C / min Temperature range 30 to 200 °C

[0607] Characterization of the solid forms of Compound I

[0608] The synchronous TGA / DSC thermogram of crystalline form B of Compound I maleate is as Figure 11 shown. The synchronous TGA / DSC thermogram of crystalline form C of Compound I maleate is as Figure 7 shown. The synchronous TGA / DSC thermogram of crystalline form D of Compound I maleate is as Figure 3 shown. The synchronous TGA / DSC thermogram of crystalline form E of Compound I mandelate is as Figure 15 shown. The synchronous TGA / DSC thermogram of amorphous Compound I is as Figure 20 shown.

[0609] The synchronous TGA / DSC spectra of the solid forms are as described in the following table:

[0610]

[0611] Results: The TGA spectrum of amorphous Compound I is consistent with an amorphous solid having approximately 1.52 wt% surface water and 5.48 wt% residual solvent. Crystalline Compound I maleate form C shows a 0.45% mass loss and form D shows a 0.48% mass loss, both of which are consistent with the non-solvated form. Crystalline Compound I mandelate form E shows a 1.92% mass loss, indicating that it retains more residual solvent under the same drying conditions. NMR analysis also shows 1.1 wt% IPA in mandelate form E.

[0612] Example 26: Dynamic Vapor Sorption (DVS)

[0613] DVS was performed using DVS Intrinsic 1. The sample (20 - 25 mg) was loaded into the sample pan, suspended on a microbalance, and exposed to a humid nitrogen stream. The sample was held at each humidity level for at least 5 minutes and progressed to the next humidity level only when the weight change was < 0.002% between measurements (at 60 - second intervals) or after 240 minutes. The following program was used:

[0614] 1. Equilibrium at 50% RH

[0615] 2. 50% to 2%. (50%, 40%, 30%, 20%, 10% and 2%)

[0616] 3. 2% to 95% (2%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 95%)

[0617] 4. 95% to 2% (95%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% and 2%)

[0618] 5. 2% to 50% (2%, 10%, 20%, 30%, 40% and 50%)

[0619] Characterization of the solid forms of Compound I

[0620] The DVS isotherm curves of crystalline Form C of Compound I maleate are as Figure 8 shown. The DVS isotherm curves of crystalline Form D of Compound I maleate are as Figure 4 shown. The DVS isotherm curves of crystalline Form E of Compound I mandelate are as Figure 16 shown.

[0621] Results:

[0622] For crystalline Form C of Compound I maleate, DVS analysis showed a reversible mass increase of 9.18 wt% from 2 to 95% relative humidity. After DVS analysis, a slight change was observed by XRPD, indicating some conversion to amorphous material.

[0623] For crystalline Form D of Compound I maleate, DVS analysis showed a reversible mass increase of 1.14 wt% from 2 to 95% relative humidity. No change was observed by XRPD after DVS analysis.

[0624] For crystalline Form E of Compound I mandelate, DVS analysis showed a reversible mass increase of 5.68 wt% from 2 to 95% relative humidity. No change was observed by XRPD after DVS analysis.

[0625] Maleate D has slight hygroscopicity and stability at high humidity. Maleate Form C and mandelate Form E have moderate hygroscopicity and start to transform into amorphous at high humidity. At 40 °C and 75% RH, Forms C and D and mandelate Form E can all be stable for more than one week.

[0626] Example 27: Nuclear Magnetic Resonance (NMR) Spectroscopy

[0627] Proton NMR was performed on a Bruker Avance 300 MHz spectrometer. The solid was dissolved in 0.75 ml of deuterated solvent in a 4 ml vial, transferred to an NMR tube (Wilmad 5 mm thin-walled 8″ 200 MHz, 506-PP-8), and analyzed according to the following parameters:

[0628] Instrument Bruker Avance 300 MHz spectrometer Temperature 300K Probe 5 mm PABBO BB - 1H / DZ - GRD Z104275 / 0170 Number of scans 16-64 Relaxation delay 1.000s Pulse width 14.2500 μs Acquisition time 2.9999s Spectrometer frequency 300.15 Hz Nucleus <![CDATA 1 H]]>

[0629] Example 28: High Performance Liquid Chromatography (HPLC)

[0630] High performance liquid chromatography (HPLC) was performed using an Agilent 1220 Infinity LC. The flow rate ranged from 0.2 - 5.0 mL / min, the operating pressure ranged from 0 - 600 bar, the temperature ranged from 5 °C above ambient temperature to 60 °C, and the wavelength range was from 190 - 600 nm.

[0631] The HPLC method used in this study is shown below:

[0632]

[0633] Example 29: Single Crystal X - ray Diffraction (SCXRD) of Crystal Form D of Compound I Maleate

[0634] Sample preparation

[0635] Using 32.2 mg of Compound I maleate dissolved in 0.25 mL of IPA, at 60 °C, using IPA as the solvent and MIBK as the anti-solvent, single crystals of suitable quality for the determination of the single crystal structure of Compound I maleate were obtained from a vapor diffusion experiment. Approximately 3 mL of MIBK was used as the anti-solvent.

[0636] Data collection and data reduction

[0637] Cu Kα radiation from an Iμs microsource was used Diffraction data were collected at 100 K on a Bruker-AXS X8 Kappa diffractometer coupled to a Bruker Photon2CPAD detector ( - and ω-scans). The data were reduced using the SAINT program and semi-empirical absorption correction based on equivalents was performed using the SADABS program.

[0638] Structure solution and refinement

[0639] The structure was solved using the dual space method with the program SHELXD and refined using established refinement techniques with SHELXL for all data of F 2Refinement was carried out. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms attached to carbon were placed in geometrically calculated positions and refined using the riding model, with their U iso constrained to 1.2 times that of the atoms to which they are attached (1.5 times for CH3 groups). The coordinates of hydrogen atoms attached to nitrogen and oxygen were taken from a difference Fourier synthesis and then refined semi-freely with distance restraints on the O-H and N-H distances (target value for OH is eq target value for amide NH is target value for amine NH is ). )

[0640] Crystal structure

[0641] It was found that Compound I maleate crystallizes in the monoclinic chiral space group C2, with two molecules of Compound I and two maleate ions in the asymmetric unit. The compound crystallizes in the monoclinic chiral space group C2, and the final R indices are R1 = 0.0661 (I > 2σ(I)) and wR2 = 0.1794 (all reflections).

[0642] The thermal ellipsoid representation of all atoms in the asymmetric unit of the structure of Compound I maleate at the 50% probability level is shown as Figure 21 shown, and the corresponding crystal data are shown in Table 15. The predicted XRPD pattern (2) and the actual XRPD pattern of maleate (1) are shown as Figure 22 shown, and the two are in good agreement (with a small additional peak at 15.88° 2θ).

[0643] During the structure refinement process, it was found that the trifluoromethyl-cyclobutyl in one of the crystallographically independent molecules was refined to be disordered at two positions. The disorder corresponds to a rotation of approximately 180° around the C78—C79 bond ( Figure 23 ). The disorder ratio converged to 0.860(7) after free refinement.

[0644] The molecule at hand is chiral, and the absolute structure can be determined based on resonant scattering data: the Flack-x parameter calculated by the Parsons method was refined to -0.06(14). Analyzing the anomalous signal using the method proposed by Hooft & Spek, the probability that the absolute structure is correct was calculated to be 1, and the probability that the structure is a racemic twin is 0.2×10 -3, the probability of an incorrect absolute structure is 0. This method also yields an absolute structure parameter, Hooft-y, which can be directly compared with Flack-x. Hooft-y is calculated to be 0.00(12). Thus, with a fairly high degree of confidence, it can be determined that the chiral atoms of compound I molecules have the configurations C15:S and C25:R in one independent molecule and the configurations C65:S / C65:R (the two molecules have the same configuration) in another molecule.

[0645] The crystal structure of crystalline form D of compound I maleate was determined at 100 K, and a summary of the structure data and refinement can be found in the table below.

[0646] Table 15. Compound I maleate, form D - Crystal data and structure refinement

[0647]

[0648]

[0649] Table 16. Compound I maleate, form D, atomic coordinates (×10 4 ) and equivalent isotropic displacement parameters

[0650]

[0651]

[0652]

[0653]

[0654] *U(eq) is defined as one-third of the trace of the orthogonalized Uij tensor.

[0655] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art will be included within the spirit and scope of this application and the scope of the appended claims.

Claims

1. The maleate salt of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I).

2. The maleate salt according to claim 1, wherein the maleate salt of Compound I is crystalline.

3. N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl The crystalline form of the maleate of [[1-(trifluoromethyl)cyclobutyl]carbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), wherein the crystalline maleate of Compound I is crystalline form D and is characterized by having: - an X-ray powder diffraction (XRPD) pattern that is substantially the same as that shown in Figure 1 measured using Cu(Kα) radiation; or - an XRPD pattern measured using Cu(Kα) radiation having reflections at about 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ; or - a differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 2; or - a simultaneous thermogravimetric analysis (TGA) / DSC thermogram that is substantially the same as that shown in Figure 3; or - the onset temperature of the endothermic peak in the DSC thermogram is 161.6 °C and the peak temperature is 168.4 °C; or the onset temperature of the endothermic peak is 158.1 °C and the peak temperature is 167.6 °C; or - a TGA pattern with a weight loss of 0.48% up to 180 °C; or At 100 K, the unit cell parameters are substantially equal to the following: or - a dynamic vapor sorption (DVS) isotherm that is substantially the same as that shown in Figure 4; or - a reversible mass increase of 1.14 wt% at 2% to 95% relative humidity (RH), no change in XRPD after DVS analysis at 2% to 95% RH, no change in XRPD after storage at 40 °C and 75% RH for at least one week, or a combination thereof; or a combination thereof.

4. The crystalline form of the maleate salt of Compound I according to claim 3, wherein the crystalline form is characterized as having an XRPD pattern measured using Cu(Kα) radiation that is substantially the same as that shown in Figure 1.

5. The crystalline form of the maleate salt of Compound I according to claim 3, wherein the crystalline form is characterized as having: an XRPD pattern measured using Cu(Kα) radiation having reflections at about 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ.

6. The crystalline form of the maleate salt of Compound I according to any one of claims 3-5, wherein the crystalline form is characterized as having: a DSC thermogram that is substantially the same as that shown in Figure 2; or the onset temperature of the endothermic peak in the DSC thermogram is 161.6 °C and the peak temperature is 168.4 °C.

7. The crystalline form of the maleate salt of Compound I according to any one of claims 3-5, wherein the crystalline form is characterized as having: a simultaneous TGA / DSC thermogram that is substantially the same as that shown in Figure 3; or the onset temperature of the endothermic peak in the DSC thermogram is 158.1 °C and the peak temperature is 167.6 °C; or The weight loss of TGA is 0.48% at up to 180 °C.

8. The crystalline form of the maleate salt of Compound I according to claim 3, wherein the crystalline form is characterized as having unit cell parameters substantially equal to the following at 100 K:

9. The crystalline form of the maleate salt of Compound I according to claim 3, wherein the crystalline form is characterized as having: - An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 1 measured using Cu(Kα) radiation; and - A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 2; or - A synchronous thermogravimetric analysis (TGA) / DSC thermogram substantially the same as that shown in Figure 3.

10. The crystalline form of the maleate salt of Compound I according to claim 3, wherein the crystalline form is characterized as having: - An XRPD pattern having reflections at approximately 4.7 ± 0.2° 2θ, 9.4 ± 0.2° 2θ, 11.0 ± 0.2° 2θ, and 14.0 ± 0.2° 2θ measured using Cu(Kα) radiation; and - The onset temperature of the endothermic peak of the DSC thermogram is 161.6 °C and the peak temperature is 168.4 °C; or the onset temperature of the endothermic peak is 158.1 °C and the peak temperature is 167.6 °C; or - The TGA pattern shows a weight loss of 0.48% at up to 180 °C.

11. The crystalline form of the maleate salt of Compound I according to claim 3, wherein the crystalline form is anhydrous.

12. N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl The crystalline form of the maleate of [[1-(trifluoromethyl)cyclobutyl]carbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), wherein the crystalline maleate of Compound I is crystalline form C and is characterized by having: - An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 5 measured using Cu(Kα) radiation; or - An XRPD pattern having reflections at approximately 4.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, and 18.4 ± 0.2° 2θ measured using Cu(Kα) radiation; or - A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 6; or - A synchronous thermogravimetric analysis (TGA) / DSC thermogram substantially the same as that shown in Figure 7; or - The onset temperature of the endothermic peak of the DSC thermogram is 144.1 °C and the peak temperature is 150.7 °C; or the onset temperature of the endothermic peak is 141.7 °C and the peak temperature is 152.1 °C; or - The TGA pattern shows a weight loss of 0.45% at up to 170 °C; or - A dynamic vapor sorption (DVS) isotherm substantially the same as that shown in Figure 8; or - A reversible mass increase of 9.18 wt% at 2% to 95% relative humidity (RH), XRPD after DVS analysis at 2% to 95% RH shows slight transformation to the amorphous maleate salt of Compound I, and XRPD does not change after storage at 40 °C and 75% RH for at least one week, or a combination thereof; or a combination thereof.

13. The crystalline form of the maleate salt of Compound I according to claim 12, wherein the crystalline form is characterized as having: - An X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation that is substantially the same as that shown in Figure 5; and - A differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 6; or - A simultaneous thermogravimetric analysis (TGA) / DSC thermogram that is substantially the same as that shown in Figure 7; or - A dynamic vapor sorption (DVS) isotherm curve that is substantially the same as that shown in Figure 8.

14. The crystalline form of the maleate salt of compound I according to claim 12, wherein the crystalline form is characterized as having: - An XRPD pattern measured using Cu(Kα) radiation having reflections at approximately 4.5 ± 0.2° 2θ, 9.0 ± 0.2° 2θ, 13.5 ± 0.2° 2θ, and 18.4 ± 0.2° 2θ; or - A differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 6; and - The onset temperature of the endothermic peak in the DSC thermogram is 144.1 °C and the peak temperature is 150.7 °C; or the onset temperature of the endothermic peak is 141.7 °C and the peak temperature is 152.1 °C; or - The weight loss in the TGA profile is 0.45% up to 170 °C.

15. N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl The crystalline form of the maleate of [[1-(trifluoromethyl)cyclobutyl]carbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), wherein the crystalline maleate of Compound I is crystalline Form B and is characterized by having: - An X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation that is substantially the same as that shown in Figure 9; or - An XRPD pattern measured using Cu(Kα) radiation having reflections at approximately 4.1 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, and 16.4 ± 0.2° 2θ; or - A differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 10; or - A simultaneous thermogravimetric analysis (TGA) / DSC thermogram that is substantially the same as that shown in Figure 11; or - The onset temperature of the endothermic peak in the DSC thermogram is 141.4 °C and the peak temperature is 150.5 °C; or the onset temperature of the endothermic peak is 120.2 °C and the peak temperature is 131.4 °C; or - The weight loss in the TGA profile is > 4.7% up to 200 °C; or - The XRPD that converts to Form C after being placed under ambient conditions for one week; or a combination thereof.

16. The crystalline form of the maleate salt of compound I according to claim 15, wherein the crystalline maleate salt of compound I is characterized as having: - An X-ray powder diffraction (XRPD) pattern measured using Cu(Kα) radiation that is substantially the same as that shown in Figure 9; and - A differential scanning calorimetry (DSC) thermogram that is substantially the same as that shown in Figure 10; or - A simultaneous thermogravimetric analysis (TGA) / DSC thermogram that is substantially the same as that shown in Figure 11.

17. The crystalline form of the maleate salt of compound I according to claim 15, wherein the crystalline maleate salt of compound I is characterized as having: - An XRPD pattern measured using Cu(Kα) radiation with reflections at approximately 4.1 ± 0.2° 2θ, 8.2 ± 0.2° 2θ, 12.3 ± 0.2° 2θ, and 16.4 ± 0.2° 2θ; and - The onset temperature of the endothermic peak in the DSC thermogram is 141.4 °C and the peak temperature is 150.5 °C; or the onset temperature of the endothermic peak is 120.2 °C and the peak temperature is 131.4 °C; or - The TGA pattern shows a weight loss > 4.7% up to 200 °C.

18. N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl Crystalline form of the maleate of [[1-(trifluoromethyl)cyclobutyl]carbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), wherein the crystalline maleate of Compound I is crystalline Form A and is characterized by Having: - An X-ray powder diffraction pattern (XRPD) that is substantially the same as that shown in Figure 12, measured using Cu(Kα) radiation; or - An XRPD pattern measured using Cu(Kα) radiation with reflections at approximately 4.2 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, and 12.5 ± 0.2° 2θ; or - An XRPD that converts to Form C after being placed under ambient conditions for approximately three days; or - In a vacuum oven at 50 °C, 10 -2 - 10 -1 Torr, after drying for 20 hours, it is converted to the XRPD of Form C; Or a combination thereof.

19. A crystalline form of the maleate salt of compound I according to claim 18, wherein the crystalline maleate salt of compound I is characterized as having: - An X-ray powder diffraction pattern (XRPD) that is substantially the same as that shown in Figure 12, measured using Cu(Kα) radiation.

20. A crystalline form of the maleate salt of compound I according to claim 18, wherein the crystalline maleate salt of compound I is characterized as having: - An XRPD pattern measured using Cu(Kα) radiation with reflections at approximately 4.2 ± 0.2° 2θ, 8.3 ± 0.2° 2θ, and 12.5 ± 0.2° 2θ.

21. A crystalline form of the maleate salt of compound I according to any one of claims 3-11, wherein the crystalline maleate salt of compound I is crystalline Form D and optionally further comprises: crystalline Form C according to any one of claims 12-14, crystalline Form B according to any one of claims 15-17, crystalline Form A according to any one of claims 18-20, or the amorphous maleate salt of compound I, or a combination thereof.

22. The mandelate salt of N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)-cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (compound I), wherein the mandelate salt of compound I is crystalline.

23. N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl The crystalline form of the mandelate salt of 4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I), wherein the crystalline mandelate salt of Compound I is crystalline Form E and is characterized by Having: - An X-ray powder diffraction pattern (XRPD) that is substantially the same as that shown in Figure 13, measured using Cu(Kα) radiation; or - XRPD with X-ray diffraction pattern reflections at approximately 5.6 ± 0.2° 2θ, 10.5 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, and 16.5 ± 0.2° 2θ measured using Cu(Kα) radiation; or - A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 14; or - A synchronous thermogravimetric analysis (TGA) / DSC thermogram substantially the same as that shown in Figure 15; or - The onset temperature of the endothermic peak in the DSC thermogram is 141.0 °C and the peak temperature is 152.8 °C; or the onset temperature of the endothermic peak is 139.8 °C and the peak temperature is 154.2 °C; or - The weight loss in the TGA profile is 1.92% up to 170 °C; or - A dynamic vapor sorption (DVS) isotherm substantially the same as that shown in Figure 16; or - A reversible mass increase of 5.68 wt% at 2% to 95% relative humidity (RH), no change in XRPD after DVS analysis at 2% to 95% RH, no change in XRPD after storage at 40 °C and 75% RH for at least one week, or a combination thereof; or a combination thereof.

24. The crystalline form of the mandelate salt of compound I according to claim 23, wherein the crystalline mandelate salt of compound I is characterized as having: - An X-ray powder diffraction pattern (XRPD) substantially the same as that shown in Figure 13 measured using Cu(Kα) radiation; and - A differential scanning calorimetry (DSC) thermogram substantially the same as that shown in Figure 14; or - A synchronous thermogravimetric analysis (TGA) / DSC thermogram substantially the same as that shown in Figure 15; or - A dynamic vapor sorption (DVS) isotherm curve substantially the same as that shown in Figure 16.

25. The crystalline form of the mandelate salt of compound I according to claim 23, wherein the crystalline mandelate salt of compound I is characterized as having: - XRPD with X-ray diffraction pattern reflections at approximately 5.6 ± 0.2° 2θ, 10.5 ± 0.2° 2θ, 14.9 ± 0.2° 2θ, and 16.5 ± 0.2° 2θ measured using Cu(Kα) radiation; and - The onset temperature of the endothermic peak in the DSC thermogram is 141.0 °C and the peak temperature is 152.8 °C; or the onset temperature of the endothermic peak is 139.8 °C and the peak temperature is 154.2 °C; or - The weight loss in the TGA profile is 1.92% up to 170 °C.

26. A pharmaceutical composition comprising the maleate salt according to any one of claims 1 to 21; and at least one pharmaceutically acceptable excipient.

27. A pharmaceutical composition comprising the mandelate salt according to any one of claims 22 to 25; and at least one pharmaceutically acceptable excipient.

28. The pharmaceutical composition according to claim 26 or 27, wherein the pharmaceutical composition is in the form of a solid-form pharmaceutical composition.

29. The pharmaceutical composition according to claim 28, wherein the pharmaceutical composition is in the form of a tablet, pill, or capsule.

30. Process for preparing crystalline form D of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide (Compound I) maleate: Comprising: (6) contacting Compound I with maleic acid in a suitable solvent to form a mixture; (7) adding a suitable antisolvent to the mixture and seeding the mixture with D-form crystals of Compound I maleate; (8) heating the mixture at a suitable temperature for a sufficient time to obtain a slurry; (9) cooling the slurry at a suitable cooling rate; and (10) filtering the slurry to obtain crystalline form D of Compound I maleate.

31. The method according to claim 30, wherein the suitable solvent in step (1) is ethanol, isopropanol, acetone, acetonitrile, methyl acetate, ethyl acetate, methyl isobutyl ketone (MIBK), water, or a combination thereof.

32. The method according to claim 30, wherein the suitable solvent in step (1) is a mixture of isopropanol and MIBK.

33. The method according to any one of claims 30 to 32, wherein the mixture in step (1) is heated to about 50 °C.

34. The method according to any one of claims 30 to 33, wherein, relative to the amount of Compound I in the mixture, the mixture in step (1) comprises about 1.1 equivalents of maleic acid and about 6 volumes of a 5:1 mixture of isopropanol and MIBK.

35. The method according to any one of claims 30 to 33, wherein the antisolvent in step (2) is methyl tert-butyl ether (MtBE), MIBK, water, heptane, or a combination thereof.

36. The method according to any one of claims 30 to 33, wherein the antisolvent in step (2) is heptane.

37. The method according to claim 35, wherein about 4 to about 10 volumes of heptane relative to the amount of Compound I are added to the mixture in step (2).

38. The method according to any one of claims 30 to 37, wherein the amount of D-form seed crystals added to the mixture in step (2) is about 0.05%, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.5%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, or about 1.0% relative to the amount of Compound I in the mixture.

39. The method according to any one of claims 30 to 38, wherein the mixture in step (3) is heated to a temperature of about 40 °C to about 50 °C.

40. The method according to any one of claims 30 to 39, wherein the mixture in step (3) is heated to a temperature of about 50 °C for at least 8 hours, at least 12 hours, at least 18 hours, or longer.

41. The method according to any one of claims 30 to 40, wherein in step (3), the mixture is heated to a temperature of about 50 °C for about 18 hours.

42. The method according to any one of claims 30 to 41, wherein in step (4), the slurry is cooled to a temperature of about 20 °C at a rate of at most 2.5 °C / min.

43. The method according to any one of claims 30 to 41, wherein in step (4), the slurry is cooled to a temperature of about 20 °C in about 15 min, about 30 min, about 45 min, about 60 min or longer.

44. The method according to any one of claims 30 to 41, wherein in step (4), the slurry is cooled to a temperature of about 20 °C in about 45 min.

45. The method according to any one of claims 30 to 44, wherein the crystalline form D of compound I maleate obtained in step (5) is dried under vacuum after filtration.

46. The method according to any one of claims 30 to 45, further comprising recrystallizing the crystalline form D of compound I maleate obtained in step (5).

47. The method according to claim 46, wherein recrystallizing the crystalline form D of compound I maleate comprises: viii. contacting the crystalline form D of compound I maleate with a suitable solvent to obtain a mixture; ix. heating the mixture of step (i) to obtain a solution; x. seeding the solution with D-form crystals of compound I maleate to obtain a mixture; xi. adding a suitable anti-solvent to the mixture at a suitable time; xii. heating the mixture for a suitable time to obtain a slurry; xiii. cooling the slurry at a suitable cooling rate; and xiv. filtering the slurry to obtain the crystalline form D of compound I maleate.

48. The method according to claim 47, wherein the suitable solvent in step (i) is ethanol, isopropanol, acetone, methyl acetate or a combination thereof; and wherein about 4 to about 10 volumes of the solvent are used in step (i) relative to the amount of compound I in the mixture.

49. The method according to claim 47, wherein about 4 volumes of isopropanol are used in step (i) relative to the amount of compound I in the mixture.

50. The method according to any one of claims 47 to 49, wherein in step (ii), the mixture is heated to a temperature of about 30 °C to about 50 °C.

51. The method according to any one of claims 47 to 50, further comprising cooling the solution obtained in step (ii) to a temperature of about 30 °C in about 2 hours before the seeding in step (iii).

52. The method according to any one of claims 47 to 51, wherein the amount of the D-form seed crystal added to the mixture in step (iii) is about 0.25%, about 0.50%, about 0.75%, about 1.0%, about 1.25%, about 1.50%, about 1.75%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5% or about 5.0% relative to the amount of compound I in the mixture.

53. The method according to any one of claims 47 to 52, wherein a suitable anti-solvent for step (iv) is MtBE, heptane or a combination thereof; and wherein about 3 volumes to about 10 volumes of the solvent are used in step (iv) relative to the amount of compound I in the mixture.

54. The method according to any one of claims 47 to 53, wherein a suitable anti-solvent for step (iv) is MtBE; and wherein the MtBE is added over at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours or longer.

55. The method according to any one of claims 47 to 54, wherein the mixture is heated to about 40 °C in step (v) and maintained for about 1 hour, about 2 hours or about 3 hours.

56. The method according to any one of claims 47 to 55, wherein in step (vi) the slurry obtained in step (v) is cooled to a temperature of about 20 °C at a rate of at most 2.5 °C / min.

57. The method according to any one of claims 47 to 55, wherein in step (vi) the slurry obtained in step (v) is cooled to a temperature of about 20 °C over about 30 min, about 60 min, about 90 min, about 120 min or longer.

58. The method according to any one of claims 47 to 57, wherein in step (vi) the slurry obtained in step (v) is cooled to a temperature of about 20 °C within about 120 min.

59. The method according to any one of claims 56 to 58, wherein before step (vii), the cooled slurry of step (vi) is maintained at about 20 °C for at least 2 hours, at least 3 hours, at least 4 hours or longer.

60. The method according to any one of claims 56 to 59, wherein before step (vii) the cooled slurry of step (vi) is maintained at about 20 °C for about 4 hours.

61. The method according to any one of claims 47 to 60, wherein the crystalline form D of compound I maleate obtained in step (vii) is vacuum dried at a temperature of about 50 °C after filtration.

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