Crystalline forms

Abstract

Provided are crystalline forms of 5-chloro-N-((2S,3S)-1-(dideutero(phenyl)methyl)-2-methylpyrrolidin-3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide, compositions comprising the same, and methods of making and using such crystalline form.

Description

CRYSTALLINE FORMS

[0001] This application claims priority to International Application No. PCT / CN2024 / 103779 filed July 5, 2024, the contents of which is hereby incorporated by reference in its entirety.FIELD

[0002] Provided are crystalline forms of 5-chloro- / V-((2S,3S)-l-(dideutero(phenyl)methyl)-2- methylpyrrolidin-3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide (Formula I), compositions comprising the same, and methods of making and using such crystalline forms.BACKGROUND

[0003] 5 -chloro-A-((2S,3S)-l-(dideutero(phenyl)methyl)-2-methylpyrrolidin-3-yl)-2-methoxy-4- (trideuteromethylamino)benzamide is disclosed in International Publication No.WO 2023 / 130119. The compound may be used for prophylaxis or treatment of a central nervous system disorder (e.g., a brain disorder), for instance, a central nervous system disorder (e.g., a brain disorder) that benefits from modulating dopamine.

[0004] Active pharmaceutical ingredients can exist in different physical forms (e g., liquid or solid in different crystalline, amorphous, hydrate, or solvate forms), which can vary the processability, stability, solubility, bioavailability, or pharmacokinetics (absorption, distribution, metabolism, excretion, or the like) and / or bioequivalency of the active pharmaceutical ingredient and pharmaceutical compositions comprising it.

[0005] In addition, isolation of a crystalline solid form may have advantages over an amorphous solid in terms of purification, stability, and solid handling. Discovery of a crystalline solid may provide for more control over purity of intermediates or final products than an amorphous solid during manufacturing or for different physical properties, such as solubility, dissolution, tableting, etc. if used as an active pharmaceutical ingredient.

[0006] Thus, there is a need to identify advantageous physical forms of a compound.BRIEF SUMMARY

[0007] 5 -chloro-7V-((2S,3S)-l-(dideutero(phenyl)methyl)-2-methylpyrrolidin-3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide is shown as Formula I below:Formula I.

[0008] Provided herein is Formula I (5-chloro-A-((2S,3S)-l-(dideutero(phenyl)methyl)-2- methylpyrrolidin-3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide) in crystalline form. Crystalline forms of Formula 1 may be used as active ingredients in pharmaceutical compositions and in methods and syntheses described in International Publication No. WO 2023 / 130119, which is hereby incorporated by reference in its entirety.

[0009] Further provided are methods of preparing Formula I in crystalline form.

[0010] Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 depicts inter-relationships of crystalline forms of Formula I.

[0012] Figure 2 depicts an XRPD pattern of Crystalline Form 1 collected with Cu Kot radiation.

[0013] Figure 3 depicts a thermogravimetric analysis (TGA) thermogram of Crystalline Form 1.

[0014] Figure 4 depicts a differential scanning calorimetry (DSC) thermogram of Crystalline Form 1.

[0015] Figure 5 depicts an XRPD pattern of Crystalline Form 2 collected with Cu Kot radiation.

[0016] Figure 6 depicts a thermogravimetric analysis (TGA) thermogram of Crystalline Form 2.

[0017] Figure 7 depicts a differential scanning calorimetry (DSC) thermogram of Crystalline Form 2.

[0018] Figure 8 depicts an XRPD pattern of Crystalline Form 3 collected with Cu Ka radiation.

[0019] Figure 9 depicts an overlay of XRPD patterns of Crystalline Form 3 (top), Crystalline Form 2 (middle), and Crystalline Form 1 (bottom) collected with Cu Ka radiation.

[0020] Figure 10 depicts an overlay of XRPD patterns of Crystalline Form 3 (top), crystal form after vacuum drying Crystalline Form 3 overnight at room temperature (second from top), crystal form after vacuum drying Crystalline Form 3 for 2 days at room temperature (second from top), and Crystalline Form 1 (bottom) collected with Cu Ka radiation.

[0021] Figure 11 depicts a dynamic vapour sorption (DVS) isotherm plot of Crystalline Form 2.

[0022] Figure 12 depicts an overlay of XRPD patterns of Crystalline Form 2 before (top XRPD pattern) and after (bottom XRPD pattern) solubility test.

[0023] Figure 13 depicts an overlay of XRPD patterns of Crystalline Form 2 from solid-state stability test. In Figure 13, XRPD patterns are from top to bottom:60°C, 7 days (top)40°C / 75% RH, 7 days25°C / 60% RH, 7 days before solid-state stability test (bottom).

[0024] Figure 14 depicts an overlay of XRPD patterns of Crystalline Form 2 before DVS (top XRPD pattern) and after DVS (bottom XRPD pattern).DETAILED DESCRIPTION

[0025] The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.

[0026] In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.

[0027] Provided herein is Formula I (5-chloro-V-((2S,3S)-l-(dideutero(phenyl)methyl)-2- methylpyrrolidin-3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide) in crystalline form (e.g., Crystalline Form 1, Crystalline Form 2, or Crystalline Form 3 as described herein). Crystalline forms of Formula I may be used as active ingredients in pharmaceutical compositionsand in methods and syntheses described in International Publication No. WO 2023 / 130119, which is hereby incorporated by reference in its entirety.

[0028] The inter-relationships of Crystalline Forms 1-3 are shown in Figure 1.

[0029] Crystalline Form 3 converts to Crystalline Form 1 after vaccum drying at room temperature. In contrast, there is no change in Crystalline Form 2 after vacuum drying overnight at room temperature.

[0030] Experiments (see Examples) with Crystalline Form 2 also show that: 1) the equilibrium solubility of Crystalline Form 2 in water is < 0.2 pg / mL and no solid form change is observed post solubility test; 2) no solid form change or appreciable HPLC purity decrease is observed for Crystalline Form 2 after 7 days at long-term, accelerated, and high-temperature conditions; and 3) Crystalline Form 2 is determined to be non-hygroscopic by dynamic vapor sorption (DVS) analysis and no solid form change is observed after DVS. Crystalline Form 2 shows beneficial physicochemical and solid-state properties for pharmaceutical development.

[0031] In competitive slurry experiments between Crystalline Form 1 and Crystalline Form 2 at room temperature and 50°C in HEP / IPAc (20:1) and MCH / EtOH (20: 1), the solid mixture of Crystalline Form 1 and Crystalline Form 2 is almost converted to Crystalline Form 2 under all tested conditions, suggesting Crystalline Form 2 is more thermodynamically stable than Crystalline Form 1 from room temperature to 50°C.

[0032] However, in the absence of Crystalline Form 2, Crystalline Form 1 maintains its crystal form after slurrying in many various solvents at room temperature (see Examples). Owing to kinetic contraints, the thermodynamic transformation of Crystalline Form 1 to Crystalline Form 2 is hindered even under temperature conditions where it is thermodynamically metastable. Thus, Crystalline Form 1 may be synthesized on large scale easily, yet also, surprisingly, persists longterm in the solid state even under conditions in which it is thermodynamically metastable. In contrast, Crystalline Form 3 does not persist in the solid state, instead converting to Crystalline Form 1 after vaccum drying at room temperature.

[0033] Seeding with crystals of a particular form may ensure generation of that form. Crystalline Form 1 and Crystalline Form 2 may also be selectively generated by controlling supersaturation of the solution. For instance, Crystalline Form 1 may be favored under conditions of high supersaturation of a solution, while Crystalline Form 2 may be favored under conditions of lowersupersaturation of a solution (e.g., increased quantity of anti-solvent and / or initiating crystallization at higher temperature).

[0034] Provided is Formula I:Formula I. in Crystalline Form 1. Further provided is Crystalline Form 1 as follows:1.1 Crystalline Form 1, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, 2-theta (°) values selected from the group consisting of 7.7, 10.6, 12.5, 14.5, 15.5, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.8, 23.5, 23.8, 24.5, 26.0, and 28.2.1.2 Crystalline Form 1 or 1.1, wherein Crystalline Form 1 exhibits an XRPD pattern comprising 2-theta (°) values of 7.7, 10.6, 12.5, 14.5, 15.5, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.8, 23.5, 23.8, 24.5, 26.0, and 28.2.1.3 Any of Crystalline Form 1, 1.1, or 1.2, wherein Crystalline Form 1 exhibits anXRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, 2-theta (°) values selected from the group consisting of 7.7, 9.7, 10.6, 11.7, 12.5, 14.5, 14.8, 15.5, 16.0, 16.6, 17.3, 18.1,18.9, 20.0, 20.4, 21.5, 22.5, 22.8, 23.5, 23.8, 24.2, 24.5, 25.4, 26.0, 27.0, 28.2,28.9, 29.6, 30.0, 30.3, 30.8, 31.0, 31.6, 32.1, 32.8, 33.4, 35.7, and 36.7. Or, any ofCrystalline Form 1, 1.1, or 1.2, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, 2-theta (°) values selected from the group consisting of 7.7, 9.7, 10.6, 11.7, 12.5, 14.5, 14.8, 15.5, 16.0, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.5, 22.8, 23.5, 23.8, 24.2, 24.5, 25.4, 26.0, 27.0, 28.2, and 28.9.Any of Crystalline Form 1 or 1.1-1.3, wherein Crystalline Form 1 exhibits an XRPD pattern comprising 2-theta (°) values of 7.7, 9.7, 10.6, 11.7, 12.5, 14.5,14.8, 15.5, 16.0, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.5, 22.8, 23.5, 23.8, 24.2, 24.5, 25.4, 26.0, 27.0, 28.2, 28.9, 29.6, 30.0, 30.3, 30.8, 31.0, 31.6, 32.1,32.8, 33.4, 35.7, and 36.7. Or, any of Crystalline Form 1 or 1.1-1.3, wherein Crystalline Form 1 exhibits an XRPD pattern comprising 2-theta (°) values of 7.7, 9.7, 10.6, 11.7, 12.5, 14.5, 14.8, 15.5, 16.0, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.5, 22.8, 23.5, 23.8, 24.2, 24.5, 25.4, 26.0, 27.0, 28.2, and 28.9. Any of Crystalline Form 1 or 1.1-1.4, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, 2-theta (°) values selected from the group consisting of 7.73, 10.62,12.46, 14.46, 15.49, 16.60, 17.26, 18.14, 18.93, 20.05, 20.43, 21.48, 22.83, 23.45, 23.79, 24.49, 25.99, and 28.25. Any of Crystalline Form 1 or 1.1-1.5, wherein Crystalline Form 1 exhibits an XRPD pattern comprising 2-theta (°) values of 7.73, 10.62, 12.46, 14.46, 15.49, 16.60, 17.26, 18.14, 18.93, 20.05, 20.43, 21.48, 22.83, 23.45, 23.79, 24.49, 25.99, and 28.25. Any of Crystalline Form 1 or 1.1-1.6, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, 2-theta (°) values selected from the group consisting of 7.73, 9.66, 10.62, 11.74, 12.46, 14.46, 14.77, 15.49, 15.99, 16.60, 17.26, 18.14, 18.93, 20.05, 20.43, 21.48, 22.46, 22.83, 23.45, 23.79, 24.17, 24.49, 25.44, 25.99, 27.02, 28.25, 28.89, 29.59, 29.96, 30.28, 30.84, 31.01, 31.64, 32.11, 32.81, 33.41, 35.73, and 36.68. Or, any of Crystalline Form 1 or 1.1-1.6, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, 2-theta (°) values selected from the group consisting of 7.73, 9.66, 10.62, 11.74, 12.46,14.46, 14.77, 15.49, 15.99, 16.60, 17.26, 18.14, 18.93, 20.05, 20.43, 21.48, 22.46, 22.83, 23.45, 23.79, 24.17, 24.49, 25.44, 25.99, 27.02, 28.25, and 28.89. Any of Crystalline Form 1 or 1.1-1.7, wherein Crystalline Form 1 exhibits an XRPD pattern comprising 2-theta (°) values of 7.73, 9.66, 10.62, 11.74, 12.46,14.46, 14.77, 15.49, 15.99, 16.60, 17.26, 18.14, 18.93, 20.05, 20.43, 21.48, 22.46, 22.83, 23.45, 23.79, 24.17, 24.49, 25.44, 25.99, 27.02, 28.25, 28.89, 29.59, 29.96, 30.28, 30.84, 31.01, 31.64, 32.11, 32.81, 33.41, 35.73, and 36.68. Or, any of Crystalline Form 1 or 1.1-1.7, wherein Crystalline Form 1 exhibits an XRPD pattern comprising 2-theta (°) values of 7.73, 9.66, 10.62, 11.74, 12.46, 14.46, 14.77, 15.49, 15.99, 16.60, 17.26, 18.14, 18.93, 20.05, 20.43, 21.48, 22.46, 22.83, 23.45, 23.79, 24.17, 24.49, 25.44, 25.99, 27.02, 28.25, and 28.89. Any of Crystalline Form 1 or 1.1-1.8, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, 2-theta (°) values selected from the group consisting of 7.729, 10.62, 12.463, 14.455, 15.489, 16.596, 17.256, 18.141, 18.932, 20.045, 20.431, 21.484, 22.832, 23.453, 23.787, 24.49, 25.986, and 28.248. Any of Crystalline Form 1 or 1.1-1.9, wherein Crystalline Form 1 exhibits an XRPD pattern comprising 2-theta (°) values of 7.729, 10.62, 12.463, 14.455, 15.489, 16.596, 17.256, 18.141, 18.932, 20.045, 20.431, 21.484, 22.832, 23.453, 23.787, 24.49, 25.986, and 28.248. Any of Crystalline Form 1 or 1.1-1.10, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, 2-theta (°) values selected from those set forth in Table A:Table A.Any of Crystalline Form 1 or 1.1-1.11, wherein Crystalline Form 1 exhibits an XRPD pattern comprising the 2-theta (°) values set forth in Table A of Crystalline Form 1.11. Any of Crystalline Form 1 or 1.1-1.12, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, d-spacing (A) values selected from the group consisting of 11.4, 8.3, 7.1, 6.1, 5.7, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.4, and 3.2. Any of Crystalline Form 1 or 1.1-1.13, wherein Crystalline Form 1 exhibits an XRPD pattern comprising d-spacing (A) values of 11.4, 8.3, 7.1, 6.1, 5.7, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.4, and 3.2.Any of Crystalline Form 1 or 1.1-1.14, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, d-spacing (A) values selected from the group consisting of 11.4, 9.1, 8.3, 7.5, 7.1, 6.1, 6.0, 5.7, 5.5, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.5, and 2.4. Or, any of Crystalline Form 1 or 1.1-1.14, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, d-spacing (A) values selected from the group consisting of 11.4, 9.1, 8.3, 7.5, 7.1, 6.1, 6.0, 5.7, 5.5, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, and 3.1. Any of Crystalline Form 1 or 1.1-1.15, wherein Crystalline Form 1 exhibits an XRPD pattern comprising d-spacing (A) values of 11.4, 9.1, 8.3, 7.5, 7.1, 6.1, 6.0,5.7, 5.5, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.5, and 2.4. Or, any of Crystalline Form 1 or 1.1-1.15, wherein Crystalline Form 1 exhibits an XRPD pattern comprising d-spacing (A) values of 11.4, 9.1, 8.3, 7.5, 7.1, 6.1, 6.0, 5.7, 5.5, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 4.0, 3.9,3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, and 3.1. Any of Crystalline Form 1 or 1.1-1.16, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, d-spacing (A) values selected from the group consisting of 11.43, 8.32, 7.10, 6.12, 5.72, 5.34, 5.13, 4.89, 4.68, 4.43, 4.34, 4.13, 3.89, 3.79, 3.74, 3.63, 3.43, and 3.16. Any of Crystalline Form 1 or 1.1-1.17, wherein Crystalline Form 1 exhibits an XRPD pattern comprising d-spacing (A) values of 11.43, 8.32, 7.10, 6.12, 5.72, 5.34, 5.13, 4.89, 4.68, 4.43, 4.34, 4.13, 3.89, 3.79, 3.74, 3.63, 3.43, and 3.16. Any of Crystalline Form 1 or 1.1-1.18, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e g., at least fifteen, e.g., at least eighteen, d-spacing (A) values selected from the group consisting of 11.43, 9.15, 8.32, 7.53, 7.10, 6.12, 5.99, 5.72, 5.54, 5.34, 5.13, 4.89, 4.68, 4.43, 4.34, 4.13, 3.95, 3.89, 3.79, 3.74, 3.68, 3.63, 3.50, 3.43, 3.30, 3.16, 3.09, 3.02, 2.98, 2.95, 2.90, 2.88, 2.83, 2.79, 2.73, 2.68, 2.51, and 2.45. Or, any ofCrystalline Form 1 or 1.1-1.18, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, d-spacing (A) values selected from the group consisting of 11.43, 9.15, 8.32, 7.53, 7.10, 6.12, 5.99, 5.72, 5.54, 5.34, 5.13, 4.89, 4.68, 4.43, 4.34, 4.13, 3.95, 3.89, 3.79, 3.74, 3.68, 3.63, 3.50, 3.43, 3.30, 3.16, and 3.09. Any of Crystalline Form 1 or 1.1-1.19, wherein Crystalline Form 1 exhibits an XRPD pattern comprising d-spacing (A) values of 11.43, 9.15, 8.32, 7.53, 7.10, 6.12, 5.99, 5.72, 5.54, 5.34, 5.13, 4.89, 4.68, 4.43, 4.34, 4.13, 3.95, 3.89, 3.79, 3.74, 3.68, 3.63, 3.50, 3.43, 3.30, 3.16, 3.09, 3.02, 2.98, 2.95, 2.90, 2.88, 2.83, 2.79, 2.73, 2.68, 2.51, and 2.45. Or, any of Crystalline Form 1 or 1.1-1.19, wherein Crystalline Form 1 exhibits an XRPD pattern comprising d-spacing (A) values of 11.43, 9.15, 8.32, 7.53, 7.10, 6.12, 5.99, 5.72, 5.54, 5.34, 5.13, 4.89, 4.68, 4.43, 4.34, 4.13, 3.95, 3.89, 3.79, 3.74, 3.68, 3.63, 3.50, 3.43, 3.30, 3.16, and 3.09. Any of Crystalline Form 1 or 1.1-1.20, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e g., at least fifteen, d-spacing (A) values selected from the group consisting of 11.429, 8.324, 7.096, 6.123, 5.716, 5.337, 5.134, 4.886, 4.684, 4.426, 4.343, 4.133, 3.892, 3.790, 3.738, 3.632, 3.426, and 3.157. Any of Crystalline Form 1 or 1.1-1.21, wherein Crystalline Form 1 exhibits an XRPD pattern comprising d-spacing (A) values of 11.429, 8.324, 7.096, 6.123, 5.716, 5.337, 5.134, 4.886, 4.684, 4.426, 4.343, 4.133, 3.892, 3.790, 3.738, 3.632, 3.426, and 3.157. Any of Crystalline Form 1 or 1.1-1.22, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, d-spacing (A) values selected from the group consisting of 11.429, 9.145, 8.324, 7.530, 7.096, 6.123, 5.994, 5.716, 5.538, 5.337, 5.134, 4.886, 4.684, 4.426, 4.343, 4.133, 3.955, 3.892, 3.790, 3.738, 3.679, 3.632, 3.499, 3.426, 3.297, 3.157, 3.088, 3.016, 2.98, 2.950, 2.897, 2.881, 2.826, 2.786, 2.728, 2.680, 2.511, and 2.448. Or, any of Crystalline Form 1 or 1.1-1.22,wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, cispacing (A) values selected from the group consisting of 11.429, 9.145, 8.324, 7.530, 7.096, 6.123, 5.994, 5.716, 5.538, 5.337, 5.134, 4.886, 4.684, 4.426, 4.343, 4.133, 3.955, 3.892, 3.790, 3.738, 3.679, 3.632, 3.499, 3.426, 3.297, 3.157, and 3.088. Any of Crystalline Form 1 or 1.1-1.23, wherein Crystalline Form 1 exhibits an XRPD pattern comprising d-spacing (A) values of 11.429, 9.145, 8.324, 7.530, 7.096, 6.123, 5.994, 5.716, 5.538, 5.337, 5.134, 4.886, 4.684, 4.426, 4.343, 4.133, 3.955, 3.892, 3.790, 3.738, 3.679, 3.632, 3.499, 3.426, 3.297, 3.157, 3.088, 3.016, 2.98, 2.950, 2.897, 2.881, 2.826, 2.786, 2.728, 2.680, 2.511, and 2.448. Or, any of Crystalline Form 1 or 1.1-1.23, wherein Crystalline Form 1 exhibits an XRPD pattern comprising d-spacing (A) values of 11.429, 9.145, 8.324, 7.530, 7.096, 6.123, 5.994, 5.716, 5.538, 5.337, 5.134, 4.886, 4.684, 4.426, 4.343, 4.133, 3.955, 3.892, 3.790, 3.738, 3.679, 3.632, 3.499, 3.426, 3.297, 3.157, and 3.088. Any of Crystalline Form 1 or 1.1-1.24, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, d-spacing (A) values selected from the group consisting of 11.4286, 8.3235, 7.0964, 6.1226, 5.716, 5.3371, 5.1344, 4.886, 4.6836, 4.426, 4.3432, 4.1328, 3.8916, 3.7901, 3.7375, 3.6318, 3.426, and 3.1566. Any of Crystalline Form 1 or 1.1-1.25, wherein Crystalline Form 1 exhibits an XRPD pattern comprising d-spacing (A) values of 11.4286, 8.3235, 7.0964, 6.1226, 5.716, 5.3371, 5.1344, 4.886, 4.6836, 4.426, 4.3432, 4.1328, 3.8916, 3.7901, 3.7375, 3.6318, 3.426, and 3.1566. Any of Crystalline Form 1 or 1.1-1.26, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, d-spacing (A) values selected from the group consisting of those set forth in Table A of Crystalline Form 1.11. Any of Crystalline Form 1 or 1.1-1.27, wherein Crystalline Form 1 exhibits an XRPD pattern comprising the d-spacing (A) values set forth in Table A of Crystalline Form 1.11.Any of Crystalline Form 1 or 1.1-1.28, wherein Crystalline Form 1 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least eighteen, e.g., all of the peaks, of the XRPD pattern shown in Figure 2. Any of Crystalline Form 1 or 1.1-1.29, wherein Crystalline Form 1 exhibits an XRPD pattern comprising characteristic peaks of the XRPD pattern shown in Figure 2. Any of Crystalline Form 1 or 1.1-1.30, wherein Crystalline Form 1 exhibits an XRPD pattern comprising representative peaks of the XRPD pattern shown in Figure 2. Any of Crystalline Form 1 or 1.1-1.31, wherein Crystalline Form 1 exhibits an XRPD pattern corresponding to Figure 2. Any of Crystalline Form 1 or 1.1-1.32, wherein Crystalline Form 1 exhibits a thermogravimetric analysis (TGA) thermogram comprising weight loss between 30°C and 150°C, e.g., a weight loss of < 2 weight%, e.g., a weight loss of 1.5 weight%. Any of Crystalline Form 1 or 1.1-1.33, wherein Crystalline Form 1 exhibits a thermogravimetric analysis (TGA) thermogram corresponding to Figure 3. Any of Crystalline Form 1 or 1.1-1.34, wherein Crystalline Form 1 exhibits a differential scanning calorimetry thermogram comprising an endotherm, e.g., an endotherm at 118°C, e.g., an endotherm at 118°C with an onset at 116°C. Any of Crystalline Form 1 or 1.1-1.35, wherein Crystalline Form 1 exhibits a differential scanning calorimetry thermogram corresponding to Figure 4. Any of Crystalline Form 1 or 1.1-1.36, wherein polarized light microscopy of Crystalline Form 1 shows irregular particles. Any of Crystalline Form 1 or 1.1-1.37, wherein Crystalline Form 1 is an anhydrate. Any of Crystalline Form 1 or 1.1-1.38, wherein in aNMR spectrum no organic solvent residue is detected. Any of Crystalline Form 1 or 1.1-1.39, wherein Crystalline Form 1 is free or substantially free of any other form, e.g., comprises less than 20 weight %, e.g.,less than 15 weight %, e.g., less than 10 weight %, e.g., less than 5 weight %, e.g., less than 3 weight %, e.g., less than 2 weight %, e.g., less than 1 weight %, e.g., less than 0. 1 weight %, of the amorphous form. Any of Crystalline Form 1 or 1.1-1.40, wherein Crystalline Form 1 is free or substantially free of any other form, e.g., comprises less than 20 weight %, e.g., less than 15 weight %, e.g., less than 10 weight %, e.g., less than 5 weight %, e.g., less than 3 weight %, e.g., less than 2 weight %, e.g., less than 1 weight %, e.g., less than 0.1 weight %, of any other crystalline form. Any of Crystalline Form 1 or 1.1-1.41, wherein Crystalline Form 1 is free or substantially free of any other form, e.g., comprises less than 20 weight %, e.g., less than 15 weight %, e.g., less than 10 weight %, e.g., less than 5 weight %, e.g., less than 3 weight %, e.g., less than 2 weight %, e.g., less than 1 weight %, e.g., less than 0.1 weight %, of the amorphous form and any other crystalline form. Any of Crystalline Form 1 or 1.1-1.42, wherein preparation of Crystalline Form 1 comprises seeding with Crystalline Form 1 (e.g., any of Crystalline Form 1 et seq ). Any of Crystalline Form 1 or 1.1-1.43, wherein Crystalline Form 1 is made by any of Process 1 et seq. vide infra. Any of Crystalline Form 1 or 1.1-1.44, wherein Crystalline Form 1 is made by any of the examples that produce Crystalline Form 1. Any of Crystalline Form 1 or 1.1-1.45, wherein each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°. Any of Crystalline Form 1 or 1.1-1.46, wherein the XRPD is obtained using Cu radiation, e.g., Cu Koc radiation, e.g., Cu Koc radiation wavelength of 1.54 A, e.g., Cu Koc radiation wavelength of 1.5406 A. Any of Crystalline Form 1 or 1.1-1.47, wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance.Any of Crystalline Form 1 or 1.1-1.48, wherein Crystalline Form 1 has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. Any of Crystalline Form 1 or 1.1-1.49, wherein Crystalline Form 1 is substantially stereoisomerically pure. For instance, wherein Crystalline Form 1 has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%. For instance, Crystalline Form 1 is substantially diastereomerically and / or enantiomerically pure, e.g., wherein Crystalline Form 1 is substantially diastereomerically and enantiomerically pure. Any of Crystalline Form 1 or 1.1-1.50, wherein Crystalline Form 1 is substantially diastereomerically pure. For instance, wherein Crystalline Form 1 has a diastereomeric excess of greater than 90%, e.g., a diastereomeric excess equal to or greater than 95%, e.g., a diastereomeric excess equal to or greater than 96%, e.g., a diastereomeric excess equal to or greater than 97%, e.g., a diastereomeric excess equal to or greater than 98%, e.g., a diastereomeric excess equal to or greater than 99%. Any of Crystalline Form 1 or 1.1-1.51, wherein Crystalline Form 1 is substantially enantiomerically pure. For instance, wherein Crystalline Form 1 has an enantiomeric excess of greater than 90%, e.g., an enantiomeric excess equal to or greater than 95%, e.g., an enantiomeric excess equal to or greater than 96%, e.g., an enantiomeric excess equal to or greater than 97%, e.g., an enantiomeric excess equal to or greater than 98%, e.g., an enantiomeric excess equal to or greater than 99%. Any of Crystalline Form 1 or 1.1-1.52, wherein Crystalline Form 1 has the stereochemical configuration as shown in Formula I.1.54 Any of Crystalline Form 1 or 1.1-1.53, wherein Crystalline Form 1 is in a pharmaceutical composition with a pharmaceutically acceptable carrier. For instance, any of Crystalline Form 1 or 1. 1-1.53, wherein an effective amount of Crystalline Form 1 is in a pharmaceutical composition with a pharmaceutically acceptable carrier.

[0035] Further provided is Formula I:Formula I. in Crystalline Form 2. Further provided is Crystalline Form 2 as follows:2.1 Crystalline Form 2, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 15.1, 15.7, 16.3, 18.0, 19.9, 20.4, 22.1, 22.7, 26.1, 27.7, 28.9, 31.1, and 32.8. Or, Crystalline Form 2, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 15.1, 15.7, 16.3, 18.0, 19.9, 20.4, 22.1, 22.7, 26.1, 27.7, and 28.9.2.2 Crystalline Form 2 or 2.1, wherein Crystalline Form 2 exhibits an XRPD pattern comprising 2-theta (°) values of 6.9, 10.1, 13.2, 15.1, 15.7, 16.3, 18.0, 19.9, 20.4, 22.1, 22.7, 26.1, T1.7 , 28.9, 31.1, and 32.8. Or, Crystalline Form 2 or 2.1, wherein Crystalline Form 2 exhibits an XRPD pattern comprising 2-theta (°) values selected of 6.9, 10.1, 13.2, 15.1, 15.7, 16.3, 18.0, 19.9, 20.4, 22.1, 22.7, 26.1, 27.7, and 28.9.2.3 Any of Crystalline Form 2, 2.1, or 2.2, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e g., atleast fifteen, e.g., at least sixteen, 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 14.8, 15.1, 15.7, 16.3, 18.0, 18.2, 19.9, 20.4, 21.4, 22.1, 22.7, 26.1, 27.7, 28.9, 31.1, and 32.8. Or, any of Crystalline Form 2, 2.1, or 2.2, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least sixteen, 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 14.8, 15.1, 15.7, 16.3, 18.0, 18.2, 19.9, 20.4, 21.4, 22.1, 22.7, 26.1, 27.7, and 28.9. Any of Crystalline Form 2 or 2.1-2.3, wherein Crystalline Form 2 exhibits an XRPD pattern comprising 2-theta (°) values of 6.9, 10.1, 13.2, 14.8, 15.1, 15.7, 16.3, 18.0, 18.2, 19.9, 20.4, 21.4, 22.1, 22.7, 26.1, 27.7, 28.9, 31.1, and 32.8. Or, any of Crystalline Form 2 or 2.1-2.3, wherein Crystalline Form 2 exhibits an XRPD pattern comprising 2-theta (°) values of 6.9, 10.1, 13.2, 14.8, 15.1, 15.7, 16.3, 18.0, 18.2, 19.9, 20.4, 21.4, 22.1, 22.7, 26.1, 27.7, and 28.9. Any of Crystalline Form 2 or 2.1-2.4, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, 2-theta (°) values selected from the group consisting of 6.94, 10.15, 13.19, 15.12, 15.72, 16.34, 17.98, 19.93, 20.36, 22.13, 22.70, 26.14, 27.74, 28.95, 31.11, and 32.78. Or, any of Crystalline Form 2 or 2.1-2.4, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, 2-theta (°) values selected from the group consisting of 6.94, 10.15, 13.19, 15.12, 15.72, 16.34, 17.98, 19.93, 20.36, 22.13, 22.70, 26.14, 27.74, and 28.95. Any of Crystalline Form 2 or 2.1-2.5, wherein Crystalline Form 2 exhibits an XRPD pattern comprising 2-theta (°) values selected from the group consisting of 6.94, 10.15, 13.19, 15.12, 15.72, 16.34, 17.98, 19.93, 20.36, 22.13, 22.70, 26.14, 27.74, 28.95, 31.11, and 32.78. Or, any of Crystalline Form 2 or 2.1-2.5, wherein Crystalline Form 2 exhibits an XRPD pattern comprising 2-theta (°) values of 6.94, 10.15, 13.19, 15.12, 15.72, 16.34, 17.98, 19.93, 20.36, 22.13, 22.70, 26.14, 27.74, and 28.95. Any of Crystalline Form 2 or 2.1-2.6, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., atleast fifteen, e.g., at least sixteen, 2-theta (°) values selected from the group consisting of 6.94, 10.15, 13.19, 14.79, 15.12, 15.72, 16.34, 17.98, 18.23, 19.93, 20.36, 21.39, 22.13, 22.70, 26.14, 27.74, 28.95, 31.11, and 32.78. Or, any of Crystalline Form 2 or 2.1-2.6, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e g., at least fifteen, e.g., at least sixteen, 2-theta (°) values selected from the group consisting of 6.94, 10.15, 13.19, 14.79, 15.12, 15.72, 16.34, 17.98, 18.23, 19.93, 20.36, 21.39, 22.13, 22.70, 26.14, 27.74, and 28.95. Any of Crystalline Form 2 or 2.1-2.7, wherein Crystalline Form 2 exhibits an XRPD pattern comprising 2-theta (°) values of 6.94, 10.15, 13.19, 14.79, 15.12, 15.72, 16.34, 17.98, 18.23, 19.93, 20.36, 21.39, 22.13, 22.70, 26.14, 27.74, 28.95, 31.11, and 32.78. Or, any of Crystalline Form 2 or 2.1-2.7, wherein Crystalline Form 2 exhibits an XRPD pattern comprising 2-theta (°) values of 6.94, 10.15, 13.19, 14.79, 15.12, 15.72, 16.34, 17.98, 18.23, 19.93, 20.36, 21.39, 22.13, 22.70, 26.14, 27.74, and 28.95. Any of Crystalline Form 2 or 2.1-2.8, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, 2-theta (°) values selected from the group consisting of 6.935, 10.147, 13.188, 15.118, 15.724, 16.343, 17.98, 19.929, 20.355, 22.129, 22.696, 26.143, 27.74, 28.947, 31.11, and 32.784. Or, any of Crystalline Form 2 or 2.1- 2.8, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, 2-theta (°) values selected from the group consisting of 6.935, 10.147, 13.188, 15.118, 15.724, 16.343, 17.98, 19.929, 20.355, 22.129, 22.696, 26.143, 27.74, and 28.947. Any of Crystalline Form 2 or 2.1-2.9, wherein Crystalline Form 2 exhibits an XRPD pattern comprising 2-theta (°) values of 6.935, 10.147, 13.188, 15.118, 15.724, 16.343, 17.98, 19.929, 20.355, 22.129, 22.696, 26.143, 27.74, 28.947, 31.11, and 32.784. Or, any of Crystalline Form 2 or 2.1-2.9, wherein Crystalline Form 2 exhibits an XRPD pattern comprising 2-theta (°) values of 6.935, 10.147, 13.188, 15.118, 15.724, 16.343, 17.98, 19.929, 20.355, 22.129, 22.696, 26.143, 27.74, and 28.947.Any of Crystalline Form 2 or 2.1-2.10, wherein Crystalline Form 2 exhibits anXRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least sixteen, 2-theta (°) values selected from those set forth in Table B:Table B.Any of Crystalline Form 2 or 2.1-2.11, wherein Crystalline Form 2 exhibits an XRPD pattern comprising the 2-theta (°) values set forth in Table B of Crystalline Form 2.11. Any of Crystalline Form 2 or 2.1-2.12, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e g., at least fifteen, d-spacing (A) values selected from the group consisting of 12.7, 8.7, 6.7, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.0, 3.9, 3.4, 3.2, 3.1, 2.9, and 2.7. Or, any of Crystalline Form 2 or 2.1-2.12, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, d-spacing (A)values selected from the group consisting of 12.7, 8.7, 6.7, 5.9, 5.6, 5.4, 4.9, 4.5,4.4, 4.0, 3.9, 3.4, 3.2, and 3.1. Any of Crystalline Form 2 or 2.1-2.13, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.7, 8.7, 6.7, 5.9, 5.6, 5.4, 4.9,4.5, 4.4, 4.0, 3.9, 3.4, 3.2, 3.1, 2.9, and 2.7. Or, any of Crystalline Form 2 or 2.1- 2.13, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.7, 8.7, 6.7, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.0, 3.9, 3.4, 3.2, and 3.1. Any of Crystalline Form 2 or 2.1-2.14, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least sixteen, d-spacing (A) values selected from the group consisting of 12.7, 8.7, 6.7, 6.0, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.2, 4.0, 3.9, 3.4, 3.2,3.1, 2.9, and 2.7. Or, any of Crystalline Form 2 or 2.1-2.14, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least sixteen, d-spacing (A) values selected from the group consisting of 12.7, 8.7, 6.7, 6.0, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4,4.2, 4.0, 3.9, 3.4, 3.2, and 3.1. Any of Crystalline Form 2 or 2.1-2.15, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.7, 8.7, 6.7, 6.0, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.2, 4.0, 3.9, 3.4, 3.2, 3.1, 2.9, and 2.7. Or, any of Crystalline Form 2 or 2.1-2.15, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d- spacing (A) values of 12.7, 8.7, 6.7, 6.0, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.2, 4.0, 3.9, 3.4, 3.2, and 3.1. Any of Crystalline Form 2 or 2.1-2.16, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e g., at least fifteen, d-spacing (A) values selected from the group consisting of 12.74, 8.71, 6.71, 5.86, 5.63, 5.42, 4.93, 4.45, 4.36, 4.01, 3.91, 3.41, 3.21, 3.08, 2.87, and 2.73. Or, any of Crystalline Form 2 or 2.1-2.16, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e g., at least five, e.g., at least ten, d-spacing (A) values selected from the group consisting of 12.74, 8.71, 6.71, 5.86, 5.63, 5.42, 4.93, 4.45, 4.36, 4.01, 3.91, 3.41, 3.21, and 3.08.Any of Crystalline Form 2 or 2.1-2.17, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.74, 8.71, 6.71, 5.86, 5.63, 5.42, 4.93, 4.45, 4.36, 4.01, 3.91, 3.41, 3.21, 3.08, 2.87, and 2.73. Or, any of Crystalline Form 2 or 2.1-2.17, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.74, 8.71, 6.71, 5.86, 5.63, 5.42, 4.93, 4.45, 4.36, 4.01, 3.91, 3.41, 3.21, and 3.08. Any of Crystalline Form 2 or 2.1-2.18, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least sixteen, d-spacing (A) values selected from the group consisting of 12.74, 8.71, 6.71, 5.99, 5.86, 5.63, 5.42, 4.93, 4.86, 4.45, 4.36, 4.15, 4.01, 3.91, 3.41, 3.21, 3.08, 2.87, and 2.73. Or, any of Crystalline Form 2 or 2.1- 2.18, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least sixteen, d-spacing (A) values selected from the group consisting of 12.74, 8.71, 6.71, 5.99, 5.86, 5.63, 5.42, 4.93, 4.86, 4.45, 4.36, 4.15, 4.01, 3.91, 3.41, 3.21, and 3.08. Any of Crystalline Form 2 or 2.1-2.19, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.74, 8.71, 6.71, 5.99, 5.86, 5.63, 5.42, 4.93, 4.86, 4.45, 4.36, 4.15, 4.01, 3.91, 3.41, 3.21, 3.08, 2.87, and 2.73. Or, any of Crystalline Form 2 or 2.1-2.19, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.74, 8.71, 6.71, 5.99, 5.86, 5.63, 5.42, 4.93, 4.86, 4.45, 4.36, 4.15, 4.01, 3.91, 3.41, 3.21, and 3.08. Any of Crystalline Form 2 or 2.1-2.20, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, d-spacing (A) values selected from the group consisting of 12.735, 8.710, 6.708, 5.855, 5.631, 5.419, 4.929, 4.452, 4.359, 4.014, 3.915, 3.406, 3.213, 3.082, 2.872, and 2.729. Or, any of Crystalline Form 2 or 2.1-2.20, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e g., at least ten, d-spacing (A) values selected from the group consisting of 12.735, 8.710, 6.708, 5.855, 5.631, 5.419, 4.929, 4.452, 4.359, 4.014, 3.915, 3.406, 3.213, and 3.082.Any of Crystalline Form 2 or 2.1-2.21, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.735, 8.710, 6.708, 5.855, 5.631, 5.419, 4.929, 4.452, 4.359, 4.014, 3.915, 3.406, 3.213, 3.082, 2.872, and 2.729. Or, any of Crystalline Form 2 or 2.1-2.21, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.735, 8.710, 6.708, 5.855, 5.631, 5.419, 4.929, 4.452, 4.359, 4.014, 3.915, 3.406, 3.213, and 3.082. Any of Crystalline Form 2 or 2.1-2.22, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least sixteen, d-spacing (A) values selected from the group consisting of 12.735, 8.710, 6.708, 5.986, 5.855, 5.631, 5.419, 4.929, 4.862, 4.452, 4.359, 4.150, 4.014, 3.915, 3.406, 3.213, 3.082, 2.872, and 2.729. Or, any of Crystalline Form 2 or 2.1-2.22, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least sixteen, d-spacing (A) values selected from the group consisting of 12.735, 8.710, 6.708, 5.986, 5.855, 5.631, 5.419, 4.929, 4.862, 4.452, 4.359, 4.150, 4.014, 3.915, 3.406, 3.213, and 3.082. Any of Crystalline Form 2 or 2.1-2.23, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.735, 8.710, 6.708, 5.986, 5.855, 5.631, 5.419, 4.929, 4.862, 4.452, 4.359, 4.150, 4.014, 3.915, 3.406, 3.213, 3.082, 2.872, and 2.729. Or, any of Crystalline Form 2 or 2.1-2.23, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.735, 8.710, 6.708, 5.986, 5.855, 5.631, 5.419, 4.929, 4.862, 4.452, 4.359, 4.150, 4.014, 3.915, 3.406, 3.213, and 3.082. Any of Crystalline Form 2 or 2.1-2.24, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, d-spacing (A) values selected from the group consisting of 12.7352, 8.7104, 6.7076, 5.8554, 5.6312, 5.4193, 4.9293, 4.4515, 4.3593, 4.0137, 3.9147, 3.4058, 3.2132, 3.082, 2.8724, and 2.7294. Or, any of Crystalline Form 2 or 2.1- 2.24, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, d-spacing (A) valuesselected from the group consisting of 12.7352, 8.7104, 6.7076, 5.8554, 5.6312, 5.4193, 4.9293, 4.4515, 4.3593, 4.0137, 3.9147, 3.4058, 3.2132, and 3.082. Any of Crystalline Form 2 or 2.1-2.25, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.7352, 8.7104, 6.7076, 5.8554, 5.6312, 5.4193, 4.9293, 4.4515, 4.3593, 4.0137, 3.9147, 3.4058, 3.2132, 3.082, 2.8724, and 2.7294. Or, any of Crystalline Form 2 or 2.1-2.25, wherein Crystalline Form 2 exhibits an XRPD pattern comprising d-spacing (A) values of 12.7352, 8.7104, 6.7076, 5.8554, 5.6312, 5.4193, 4.9293, 4.4515, 4.3593, 4.0137, 3.9147, 3.4058, 3.2132, and 3.082. Any of Crystalline Form 2 or 2.1-2.26, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least sixteen, d-spacing (A) values selected from the group consisting of those set forth in Table B of Crystalline Form 2.11. Any of Crystalline Form 2 or 2.1-2.27, wherein Crystalline Form 2 exhibits an XRPD pattern comprising the d-spacing (A) values set forth in Table B of Crystalline Form 2.11. Any of Crystalline Form 2 or 2.1-2.28, wherein Crystalline Form 2 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least fifteen, e.g., at least sixteen, e.g., all of the peaks, of the XRPD pattern shown in Figure 5. Any of Crystalline Form 2 or 2.1-2.29, wherein Crystalline Form 2 exhibits an XRPD pattern comprising characteristic peaks of the XRPD pattern shown in Figure 5. Any of Crystalline Form 2 or 2.1-2.30, wherein Crystalline Form 2 exhibits an XRPD pattern comprising representative peaks of the XRPD pattern shown in Figure 5. Any of Crystalline Form 2 or 2.1-2.31, wherein Crystalline Form 2 exhibits an XRPD pattern corresponding to Figure 5. Any of Crystalline Form 2 or 2.1-2.32, wherein Crystalline Form 2 exhibits a thermogravimetric analysis (TGA) thermogram comprising weight loss between30°C and 150 °C, e.g., a weight loss of < 3 weight%, e.g., a weight loss of 2 weight%. Any of Crystalline Form 2 or 2.1-2.33, wherein Crystalline Form 2 exhibits a thermogravimetric analysis (TGA) thermogram corresponding to Figure 6. Any of Crystalline Form 2 or 2.1-2.34, wherein Crystalline Form 2 exhibits differential scanning calorimetry comprising an endotherm, e.g., an endotherm at 123°C, e.g., an endotherm at 123°C with an onset at 120°C. Any of Crystalline Form 2 or 2.1-2.35, wherein Crystalline Form 2 exhibits a differential scanning calorimetry thermogram corresponding to Figure 7. Any of Crystalline Form 2 or 2.1-2.36, wherein polarized light microscopy of Crystalline Form 2 shows fine particles. Any of Crystalline Form 2 or 2.1-2.37, wherein Crystalline Form 2 is an anhydrate. Any of Crystalline Form 2 or 2.1-2.38, wherein in aNMR spectrum no organic solvent residue is detected. Any of Crystalline Form 2 or 2.1-2.39, wherein Crystalline Form 2 exhibits a dynamic (water) vapor sorption (DVS) isotherm comprising less than 0.2% weight gain upon increasing the relative humidity (RH) from 0% to 90% (e.g., increasing the relative humidity (RH) from 0% to 80%), e.g., less than 0.1% weight gain, e.g., 0.08% weight gain. Any of Crystalline Form 2 or 2.1-2.40 exhibiting a dynamic (water) vapor sorption (DVS) isotherm as shown in Figure 11. Any of Crystalline Form 2 or 2.1-2.41, wherein Crystalline Form 2 comprises less than 20 weight %, e.g., less than 15 weight %, e.g., less than 10 weight %, e.g., less than 5 weight %, e.g. Jess than 3 weight %, e.g., less than 2 weight %, e.g., less than 1 weight %, e.g., less than 0.1 weight %, of the amorphous form. Any of Crystalline Form 2 or 2.1-2.42, wherein Crystalline Form 2 is free or substantially free of any other form, e.g., comprises less than 20 weight %, e.g., less than 15 weight %, e.g., less than 10 weight %, e.g., less than 5 weight %, e.g., less than 3 weight %, e.g., less than 2 weight %, e.g., less than 1 weight %, e.g., less than 0.1 weight %, of any other crystalline form.Any of Crystalline Form 2 or 2.1-2.43, wherein Crystalline Form 2 is free or substantially free of any other form, e.g., comprises less than 20 weight %, e.g., less than 15 weight %, e.g., less than 10 weight %, e.g., less than 5 weight %, e.g., less than 3 weight %, e.g., less than 2 weight %, e.g., less than 1 weight %, e.g., less than 0.1 weight %, of the amorphous form and any other crystalline form. Any of Crystalline Form 2 or 2.1-2.44, wherein preparation of Crystalline Form 2 comprises seeding with Crystalline Form 2 (e.g., any of Crystalline Form 2 et seq.). Any of Crystalline Form 2 or 2.1-2.45, wherein Crystalline Form 2 is made by any of Process 2 et seq. vide infra. Any of Crystalline Form 2 or 2.1-2.46, wherein Crystalline Form 2 is made by any of the examples that produce Crystalline Form 2. Any of Crystalline Form 2 or 2.1-2.47, wherein each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°. Any of Crystalline Form 2 or 2.1-2.48, wherein the XRPD is obtained using Cu radiation, e.g., Cu Koc radiation, e.g., Cu Koc radiation wavelength of 1.54 A, e.g., Cu Koc radiation wavelength of 1.5406 A. Any of Crystalline Form 2 or 2.1-2.49, wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance. Any of Crystalline Form 2 or 2.1-2.50, wherein Crystalline Form 2 has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. Any of Crystalline Form 2 or 2.1-2.51, wherein Crystalline Form 2 is substantially stereoisomerically pure. For instance, wherein Crystalline Form 2 has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%. For instance, Crystalline Form 2 is substantially diastereomerically and / or enantiomerically pure, e.g., wherein Crystalline Form 2 is substantially diastereomerically and enantiomerically pure.2.53 Any of Crystalline Form 2 or 2.1-2.52, wherein Crystalline Form 2 is substantially diastereomerically pure. For instance, wherein Crystalline Form 2 has a diastereomeric excess of greater than 90%, e.g., a diastereomeric excess equal to or greater than 95%, e.g., a diastereomeric excess equal to or greater than 96%, e.g., a diastereomeric excess equal to or greater than 97%, e.g., a diastereomeric excess equal to or greater than 98%, e.g., a diastereomeric excess equal to or greater than 99%.2.54 Any of Crystalline Form 2 or 2.1-2.53, wherein Crystalline Form 2 is substantially enantiomerically pure. For instance, wherein Crystalline Form 2 has an enantiomeric excess of greater than 90%, e.g., an enantiomeric excess equal to or greater than 95%, e.g., an enantiomeric excess equal to or greater than 96%, e.g., an enantiomeric excess equal to or greater than 97%, e.g., an enantiomeric excess equal to or greater than 98%, e.g., an enantiomeric excess equal to or greater than 99%.2.55 Any of Crystalline Form 2 or 2.1-2.54, wherein Crystalline Form 2 has the stereochemical configuration as shown in Formula I.2.56 Any of Crystalline Form 2 or 2.1-2.55, wherein Crystalline Form 2 is in a pharmaceutical composition with a pharmaceutically acceptable carrier. For instance, any of Crystalline Form 2 or 2.1-2.55, wherein an effective amount of Crystalline Form 2 is in a pharmaceutical composition with a pharmaceutically acceptable carrier.

[0036] Further provided is Formula I:Formula I. in Crystalline Form 3. Further provided is Crystalline Form 3 as follows:3.1 Crystalline Form 3, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, 2-theta (°) values selected from the group consisting of 6.1, 7.6, 11.1, 12.3, 18.5, 20.4, 21.4, 22.4, 24.8, 31.1, and 37.5. Or, Crystalline Form 3, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, 2-theta (°) values selected from the group consisting of 6.1, 7.6, 11.1, 12.3, 18.5, 20.4, 21.4, 22.4, and 24.8.3.2 Crystalline Form 3 or 3.1, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, 2-theta (°) values selected from the group consisting of 6.1, 7.6, 11.1, 12.3, 18.5, 20.4, 21.4, 22.4, 24.8, 31.1, 37.5, and 37.6.3.3 Any of Crystalline Form 3, 3.1, or 3.2, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.1, 7.6, 11.1, 12.3, 18.5, 20.4, 21.4, 22.4, 24.8, 31.1, and 37.5. Or, any of Crystalline Form 3, 3.1, or 3.2, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.1, 7.6, 11.1, 12.3, 18.5, 20.4, 21.4, 22.4, and 24.8.3.4 Any of Crystalline Form 3 or 3.1-3.3, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.1, 7.6, 11.1, 12.3, 18.5, 20.4, 21.4, 22.4, 24.8, 31.1, 37.5, and 37.6.3.5 Any of Crystalline Form 3 or 3.1-3.4, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, 2-theta (°) values selected from the groupconsisting of 6.1, 7.6, 11.1, 12.3, 13.4, 14.3, 15.4, 16.5, 18.0, 18.5, 18.8, 19.9,20.4, 21.4, 22.4, 23.8, 24.5, 24.8, 25.9, 31.1, 37.5, and 38.3. Or, any of Crystalline Form 3 or 3.1-3.4, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, 2-theta (°) values selected from the group consisting of 6.1, 7.6, 11.1, 12.3, 13.4, 14.3, 15.4, 16.5, 18.0, 18.5, 18.8, 19.9, 20.4, 21.4, 22.4, 23.8,24.5, 24.8, and 25.9. Any of Crystalline Form 3 or 3.1-3.5, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, 2-theta (°) values selected from the group consisting of 6.1, 7.6, 11.1, 12.3, 13.4, 14.3, 15.4, 16.5, 18.0, 18.5, 18.8, 19.9,20.4, 21.4, 22.4, 23.8, 24.5, 24.8, 25.9, 31.1, 37.5, 37.6, and 38.3. Any of Crystalline Form 3 or 3.1-3.6, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.1, 7.6, 11.1, 12.3, 13.4, 14.3,15.4, 16.5, 18.0, 18.5, 18.8, 19.9, 20.4, 21.4, 22.4, 23.8, 24.5, 24.8, 25.9, 31.1,37.5, and 38.3. Or, any of Crystalline Form 3 or 3.1-3.6, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.1, 7.6, 11.1,12.3, 13.4, 14.3, 15.4, 16.5, 18.0, 18.5, 18.8, 19.9, 20.4, 21.4, 22.4, 23.8, 24.5,24.8, and 25.9. Any of Crystalline Form 3 or 3.1-3.7, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.1, 7.6, 11.1, 12.3, 13.4, 14.3,15.4, 16.5, 18.0, 18.5, 18.8, 19.9, 20.4, 21.4, 22.4, 23.8, 24.5, 24.8, 25.9, 31.1,37.5, 37.6, and 38.3. Any of Crystalline Form 3 or 3.1-3.8, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, 2-theta (°) values selected from the group consisting of 6.12, 7.56, 11.1, 12.30, 18.51, 20.40, 21.41, 22.41, 24.76, 31.11, and 37.54. Or, any of Crystalline Form 3 or 3.1-3.8, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, 2-theta (°) values selected from the group consisting of 6.12, 7.56, 11.1, 12.30, 18.51, 20.40, 21.41, 22.41, and 24.76.Any of Crystalline Form 3 or 3.1-3.9, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, 2-theta (°) values selected from the group consisting of 6.12, 7.56, 11.1, 12.30, 18.51,20.40, 21.41, 22.41, 24.76, 31.11, 37.54, and 37.6. Any of Crystalline Form 3 or 3.1-3.10, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.12, 7.56, 11.1, 12.30, 18.51,20.40, 21.41, 22.41, 24.76, 31.11, and 37.54. Or, any of Crystalline Form 3 or 3.1- 3.10, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.12, 7.56, 11.1, 12.30, 18.51, 20.40, 21.41, 22.41, and 24.76. Any of Crystalline Form 3 or 3.1-3.11, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.12, 7.56, 11.1, 12.30, 18.51,20.40, 21.41, 22.41, 24.76, 31.11, 37.54, and 37.6. Any of Crystalline Form 3 or 3.1-3.12, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, 2-theta (°) values selected from the group consisting of 6.12, 7.56, 11.1, 12.30, 13.40, 14.32, 15.45, 16.45, 18.04, 18.51, 18.80, 19.95, 20.40, 21.41, 22.41, 23.79, 24.45, 24.76, 25.87, 31.11, 37.54, and38.31. Or, any of Crystalline Form 3 or 3.1-3.12, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, 2-theta (°) values selected from the group consisting of 6.12, 7.56, 11.1, 12.30, 13.40, 14.32, 15.45, 16.45, 18.04, 18.51, 18.80, 19.95, 20.40, 21.41, 22.41, 23.79, 24.45, 24.76, and 25.87. Any of Crystalline Form 3 or 3.1-3.13, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e g., at least eleven, e.g., at least twelve, 2-theta (°) values selected from the group consisting of 6.12, 7.56, 11.1, 12.30, 13.40, 14.32, 15.45, 16.45, 18.04, 18.51, 18.80, 19.95, 20.40, 21.41, 22.41, 23.79, 24.45, 24.76, 25.87, 31.11, 37.54, 37.6, and 38.31. Any of Crystalline Form 3 or 3.1-3.14, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.12, 7.56, 11.1, 12.30, 13.40,14.32, 15.45, 16.45, 18.04, 18.51, 18.80, 19.95, 20.40, 21.41, 22.41, 23.79, 24.45,24.76, 25.87, 31.11, 37.54, and 38.31. Or, any of Crystalline Form 3 or 3.1-3.14, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.12, 7.56, 11.1, 12.30, 13.40, 14.32, 15.45, 16.45, 18.04, 18.51, 18.80, 19.95, 20.40, 21.41, 22.41, 23.79, 24.45, 24.76, and 25.87. Any of Crystalline Form 3 or 3.1-3.15, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.12, 7.56, 11.1, 12.30, 13.40, 14.32, 15.45, 16.45, 18.04, 18.51, 18.80, 19.95, 20.40, 21.41, 22.41, 23.79, 24.45, 24.76, 25.87, 31.11, 37.54, 37.6, and 38.31. Any of Crystalline Form 3 or 3.1-3.16, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, 2-theta (°) values selected from the group consisting of 6.122, 7.558, 11.1, 12.298, 18.509, 20.396, 21.408, 22.405, 24.764, 31.107, and 37.543. Or, any of Crystalline Form 3 or 3.1-3.16, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, 2-theta (°) values selected from the group consisting of 6.122, 7.558, 11.1, 12.298, 18.509, 20.396, 21.408, 22.405, and 24.764. Any of Crystalline Form 3 or 3.1-3.17, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, 2-theta (°) values selected from the group consisting of 6.122, 7.558, 11.1, 12.298, 18.509, 20.396, 21.408, 22.405, 24.764, 31.107, 37.543, and 37.6. Any of Crystalline Form 3 or 3.1-3.18, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.122, 7.558, 11.1, 12.298, 18.509, 20.396, 21.408, 22.405, 24.764, 31.107, and 37.543. Or, any of Crystalline Form 3 or 3.1-3.18, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.122, 7.558, 11.1, 12.298, 18.509, 20.396, 21.408, 22.405, and 24.764. Any of Crystalline Form 3 or 3.1-3.19, wherein Crystalline Form 3 exhibits an XRPD pattern comprising 2-theta (°) values of 6.122, 7.558, 11.1, 12.298, 18.509, 20.396, 21.408, 22.405, 24.764, 31.107, 37.543, and 37.6. Any of Crystalline Form 3 or 3.1-3.20, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., atleast eleven, e.g., at least twelve, 2-theta (°) values selected from those set forth inTable C:Table C.Any of Crystalline Form 3 or 3.1-3.21, wherein Crystalline Form 3 exhibits an XRPD pattern comprising the 2-theta (°) values set forth in Table C of Crystalline Form 3.21 . Any of Crystalline Form 3 or 3.1-3.22, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, cispacing (A) values selected from the group consisting of 14.4, 11.7, 8.0, 7.2, 4.8, 4.4, 4.1, 4.0, 3.6, 2.9, and 2.4. Or, any of Crystalline Form 3 or 3.1-3.22, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, d-spacing (A) values selected from the group consisting of 14.4, 11.7, 8.0, 7.2, 4.8, 4.4, 4.1, 4.0, and 3.6.Any of Crystalline Form 3 or 3.1-3.23, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.4, 11.7, 8.0, 7.2, 4.8, 4.4, 4.1, 4.0, 3.6, 2.9, and 2.4. Or, any of Crystalline Form 3 or 3.1-3.23, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.4, 11.7, 8.0, 7.2, 4.8, 4.4, 4.1, 4.0, and 3.6. Any of Crystalline Form 3 or 3.1-3.24, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, d-spacing (A) values selected from the group consisting of 14.4, 11.7, 8.0, 7.2, 6.6, 6.2, 5.7, 5.4, 4.9, 4.8, 4.7, 4.4, 4.1, 4.0, 3.7,3.6, 3.4, 2.9, 2.4, and 2.3. Or, any of Crystalline Form 3 or 3.1-3.24, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, d-spacing (A) values selected from the group consisting of 14.4, 11.7, 8.0, 7.2, 6.6, 6.2, 5.7, 5.4, 4.9, 4.8, 4.7, 4.4, 4.1, 4.0, 3.7, 3.6, and 3.4. Any of Crystalline Form 3 or 3.1-3.25, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.4, 11.7, 8.0, 7.2, 6.6, 6.2,5.7, 5.4, 4.9, 4.8, 4.7, 4.4, 4.1, 4.0, 3.7, 3.6, 3.4, 2.9, 2.4, and 2.3. Or, any of Crystalline Form 3 or 3.1-3.25, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.4, 11.7, 8.0, 7.2, 6.6, 6.2, 5.7, 5.4, 4.9, 4.8, 4.7, 4.4, 4.1, 4.0, 3.7, 3.6, and 3.4. Any of Crystalline Form 3 or 3.1-3.26, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, d- spacing (A) values selected from the group consisting of 14.42, 11.69, 7.96, 7.19, 4.79, 4.35, 4.15, 3.96, 3.59, 2.87, and 2.39. Or, any of Crystalline Form 3 or 3.1- 3.26, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, d-spacing (A) values selected from the group consisting of 14.42, 11.69, 7.96, 7.19, 4.79, 4.35, 4.15, 3.96, and 3.59. Any of Crystalline Form 3 or 3.1-3.27, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.42, 11.69, 7.96, 7.19, 4.79, 4.35, 4.15, 3.96, 3.59, 2.87, and 2.39. Or, any of Crystalline Form 3 or 3.1-3.27,wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.42, 11.69, 7.96, 7.19, 4.79, 4.35, 4.15, 3.96, and 3.59. Any of Crystalline Form 3 or 3.1-3.28, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, d-spacing (A) values selected from the group consisting of 14.42, 11.69, 7.96, 7.19, 6.60, 6.18, 5.73, 5.38, 4.91, 4.79, 4.72, 4.45, 4.35, 4.15, 3.96, 3.74, 3.64, 3.59, 3.44, 2.87, 2.39, and 2.35. Or, any of Crystalline Form 3 or 3.1-3.28, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, d-spacing (A) values selected from the group consisting of 14.42, 11.69, 7.96, 7.19, 6.60, 6.18, 5.73, 5.38, 4.91, 4.79, 4.72, 4.45, 4.35, 4.15, 3.96, 3.74, 3.64, 3.59, and 3.44. Any of Crystalline Form 3 or 3.1-3.29, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.42, 11.69, 7.96, 7.19, 6.60, 6.18, 5.73, 5.38, 4.91, 4.79, 4.72, 4.45, 4.35, 4.15, 3.96, 3.74, 3.64, 3.59, 3.44, 2.87, 2.39, and 2.35. Or, any of Crystalline Form 3 or 3.1-3.29, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.42, 11.69, 7.96, 7.19, 6.60, 6.18, 5.73, 5.38, 4.91, 4.79, 4.72, 4.45, 4.35, 4.15, 3.96, 3.74, 3.64, 3.59, and 3.44. Any of Crystalline Form 3 or 3.1-3.30, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, d- spacing (A) values selected from the group consisting of 14.424, 11.687, 7.964, 7.192, 4.790, 4.351, 4.147, 3.965, 3.592, 2.873, and 2.394. Or, any of Crystalline Form 3 or 3.1-3.30, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, d-spacing (A) values selected from the group consisting of 14.424, 11.687, 7.964, 7.192, 4.790, 4.351, 4.147, 3.965, and 3.592. Any of Crystalline Form 3 or 3.1-3.30, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, d- spacing (A) values selected from the group consisting of 14.424, 11.687, 7.964, 7.192, 4.790, 4.351, 4.147, 3.965, 3.592, 2.873, 2.394, and 2.390.Any of Crystalline Form 3 or 3.1-3.32, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.424, 11.687, 7.964, 7.192,4.790, 4.351, 4.147, 3.965, 3.592, 2.873, and 2.394. Or, any of Crystalline Form 3 or 3.1-3.32, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d- spacing (A) values of 14.424, 11.687, 7.964, 7.192, 4.790, 4.351, 4.147, 3.965, and 3.592. Any of Crystalline Form 3 or 3.1-3.33, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.424, 11.687, 7.964, 7.192,4.790, 4.351, 4.147, 3.965, 3.592, 2.873, 2.394, and 2.390. Any of Crystalline Form 3 or 3.1-3.34, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, d-spacing (A) values selected from the group consisting of 14.424, 11.687, 7.964, 7.192, 6.603, 6.182, 5.732, 5.384, 4.913,4.790, 4.716, 4.447, 4.351, 4.147, 3.965, 3.738, 3.638, 3.592, 3.441, 2.873, 2.394, and 2.347. Or, any of Crystalline Form 3 or 3.1-3.34, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., at least twelve, d-spacing (A) values selected from the group consisting of 14.424, 11.687, 7.964, 7.192, 6.603, 6.182, 5.732, 5.384, 4.913, 4.790, 4.716, 4.447, 4.351, 4.147, 3.965, 3.738, 3.638, 3.592, and 3.441. Any of Crystalline Form 3 or 3.1-3.35, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e g., at least eleven, e.g., at least twelve, d-spacing (A) values selected from the group consisting of 14.424, 11.687, 7.964, 7.192, 6.603, 6.182, 5.732, 5.384, 4.913,4.790, 4.716, 4.447, 4.351, 4.147, 3.965, 3.738, 3.638, 3.592, 3.441, 2.873, 2.394, 2.390, and 2.347. Any of Crystalline Form 3 or 3.1-3.36, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.424, 11.687, 7.964, 7.192, 6.603, 6.182, 5.732, 5.384, 4.913, 4.790, 4.716, 4.447, 4.351, 4.147, 3.965, 3.738, 3.638, 3.592, 3.441, 2.873, 2.394, and 2.347. Or, any of Crystalline Form 3 or 3.1- 3.36, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing(A) values of 14.424, 11.687, 7.964, 7.192, 6.603, 6.182, 5.732, 5.384, 4.913, 4.790, 4.716, 4.447, 4.351, 4.147, 3.965, 3.738, 3.638, 3.592, and 3.441. Any of Crystalline Form 3 or 3.1-3.37, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.424, 11.687, 7.964, 7.192, 6.603, 6.182, 5.732, 5.384, 4.913, 4.790, 4.716, 4.447, 4.351, 4.147, 3.965, 3.738, 3.638, 3.592, 3.441, 2.873, 2.394, 2.390, and 2.347. Any of Crystalline Form 3 or 3.1-3.38, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, d- spacing (A) values selected from the group consisting of 14.4238, 11.6871, 7.9644, 7.1915, 4.7896, 4.3507, 4.1471, 3.9649, 3.5922, 2.8727, and 2.3937. Or, any of Crystalline Form 3 or 3.1-3.38, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, d-spacing (A) values selected from the group consisting of 14.4238, 11.6871, 7.9644, 7.1915, 4.7896, 4.3507, 4.1471, 3.9649, and 3.5922. Any of Crystalline Form 3 or 3.1-3.39, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, d- spacing (A) values selected from the group consisting of 14.4238, 11.6871, 7.9644, 7.1915, 4.7896, 4.3507, 4.1471, 3.9649, 3.5922, 2.8727, 2.3937, and 2.3903. Any of Crystalline Form 3 or 3.1-3.40, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.4238, 11.6871, 7.9644, 7.1915, 4.7896, 4.3507, 4.1471, 3.9649, 3.5922, 2.8727, and 2.3937. Or, any of Crystalline Form 3 or 3.1-3.40, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.4238, 11.6871, 7.9644, 7.1915, 4.7896, 4.3507, 4.1471, 3.9649, and 3.5922. Any of Crystalline Form 3 or 3.1-3.42, wherein Crystalline Form 3 exhibits an XRPD pattern comprising d-spacing (A) values of 14.4238, 11.6871, 7.9644, 7.1915, 4.7896, 4.3507, 4.1471, 3.9649, 3.5922, 2.8727, 2.3937, and 2.3903. Any of Crystalline Form 3 or 3.1-3.42, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., atleast eleven, d-spacing (A) values selected from the group consisting of those set forth in Table C of Crystalline Form 3.21. Any of Crystalline Form 3 or 3. 1-3.43, wherein Crystalline Form 3 exhibits an XRPD pattern comprising the d-spacing (A) values set forth in Table C of Crystalline Form 3.21. Any of Crystalline Form 3 or 3.1-3.44, wherein Crystalline Form 3 exhibits an XRPD pattern comprising at least three, e.g., at least five, e.g., at least ten, e.g., at least eleven, e.g., all of the peaks, of the XRPD pattern shown in Figure 8. Any of Crystalline Form 3 or 3.1-3.45, wherein Crystalline Form 3 exhibits an XRPD pattern comprising characteristic peaks of the XRPD pattern shown in Figure 8. Any of Crystalline Form 3 or 3.1-3.46, wherein Crystalline Form 3 exhibits an XRPD pattern comprising representative peaks of the XRPD pattern shown in Figure 8. Any of Crystalline Form 3 or 3.1-3.47, wherein Crystalline Form 3 exhibits an XRPD pattern corresponding to Figure 8. Any of Crystalline Form 3 or 3.1-3.48, wherein Crystalline Form 3 is free or substantially free of any other form, e.g., comprises less than 20 weight %, e.g., less than 15 weight %, e.g., less than 10 weight %, e.g., less than 5 weight %, e.g., less than 3 weight %, e.g., less than 2 weight %, e.g., less than 1 weight %, e.g., less than 0.1 weight %, of the amorphous form. Any of Crystalline Form 3 or 3.1-3.49, wherein Crystalline Form 3 is free or substantially free of any other form, e.g., comprises less than 20 weight %, e.g., less than 15 weight %, e.g., less than 10 weight %, e.g., less than 5 weight %, e.g., less than 3 weight %, e.g., less than 2 weight %, e.g., less than 1 weight %, e.g., less than 0.1 weight %, of any other crystalline form. Any of Crystalline Form 3 or 3.1-3.50, wherein Crystalline Form 3 is free or substantially free of any other form, e.g., comprises less than 20 weight %, e.g., less than 15 weight %, e.g., less than 10 weight %, e.g., less than 5 weight %, e.g., less than 3 weight %, e.g., less than 2 weight %, e.g., less than 1 weight %, e.g., less than 0.1 weight %, of the amorphous form and any other crystalline form.Any of Crystalline Form 3 or 3.1-3.51, wherein preparation of Crystalline Form 3 comprises seeding with Crystalline Form 3 (e.g., any of Crystalline Form 3 et seq.). Any of Crystalline Form 3 or 3.1-3.52, wherein Crystalline Form 3 is made by any of Process 3 et seq. vide infra. Any of Crystalline Form 3 or 3.1-3.53, wherein Crystalline Form 3 is made by any of the examples that produce Crystalline Form 3. Any of Crystalline Form 3 or 3.1-3.54, wherein each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°. Any of Crystalline Form 3 or 3.1-3.55, wherein the XRPD is obtained using Cu radiation, e.g., Cu Koc radiation, e.g., Cu Kot. radiation wavelength of 1.54 A, e.g., Cu Koc radiation wavelength of 1.5406 A. Any of Crystalline Form 3 or 3.1-3.56, wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance. Any of Crystalline Form 3 or 3.1-3.57, wherein Crystalline Form 3 has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. Any of Crystalline Form 3 or 3.1-3.58, wherein Crystalline Form 3 is substantially stereoisomerically pure. For instance, wherein Crystalline Form 3 has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e.g., a stereoisomeric excess equal to or greater than 99%. For instance, Crystalline Form 3 is substantially diastereomerically and / or enantiomerically pure, e.g., wherein Crystalline Form 3 is substantially diastereomerically and enantiomerically pure.3.60 Any of Crystalline Form 3 or 3.1-3.59, wherein Crystalline Form 3 is substantially diastereomerically pure. For instance, wherein Crystalline Form 3 has a diastereomeric excess of greater than 90%, e.g., a diastereomeric excess equal to or greater than 95%, e.g., a diastereomeric excess equal to or greater than 96%, e g., a diastereomeric excess equal to or greater than 97%, e.g., a diastereomeric excess equal to or greater than 98%, e.g., a diastereomeric excess equal to or greater than 99%.3.61 Any of Crystalline Form 3 or 3.1-3.60, wherein Crystalline Form 3 is substantially enantiomerically pure. For instance, wherein Crystalline Form 3 has an enantiomeric excess of greater than 90%, e.g., an enantiomeric excess equal to or greater than 95%, e.g., an enantiomeric excess equal to or greater than 96%, e.g., an enantiomeric excess equal to or greater than 97%, e.g., an enantiomeric excess equal to or greater than 98%, e g., an enantiomeric excess equal to or greater than 99%.3.62 Any of Crystalline Form 3 or 3.1-3.61, wherein Crystalline Form 3 has the stereochemical configuration as shown in Formula I.3.63 Any of Crystalline Form 3 or 3.1-3.62, wherein Crystalline Form 3 is in a pharmaceutical composition with a pharmaceutically acceptable carrier. For instance, any of Crystalline Form 3 or 3.1-3.62, wherein an effective amount of Crystalline Form 3 is in a pharmaceutical composition with a pharmaceutically acceptable carrier.

[0037] For processes described herein, refer to examples for definitions of abbreviations.

[0038] Further provided is a process (Process 1) for making Formula I in crystalline form, e.g., for making any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., e.g., Crystalline Form 1.

[0039] Further provided is Process 1 as follows:1.1 Process 1, wherein the process comprises dissolving Formula I in an organic solvent or a mixture of organic solvents in which it is soluble, e.g., an alcohol (e.g., ethanol, isopropanol), an amide (e g., A,A-dimethylformamide, l-Methyl-2- pyrrolidone), a ketone (e.g., methyl ethyl ketone, EtOAc, acetone), an ether (e.g., tetrahydrofuran, 1,4-dioxane, diethyl ether, 2-MeTHF), an alkyl halide (e.g.,CH2CI2), dimethylsulfoxide, acetonitrile, IP Ac, and / or an aromatic organic solvent (e.g., toluene). For instance, wherein the process comprises dissolving Formula I in a polar organic solvent (e.g., an alcohol (e.g., ethanol), an amide (e.g., A,A-dimethylformamide, l-Methyl-2-pyrrolidone), and / or dimethylsulfoxide. Process 1.1, wherein the process comprises evaporating the solvent or mixture of solvents at room temperature. Process 1.1 or 1.2, wherein the process comprises mixing with or exposing to an anti-solvent (e.g., H2O, an alkane (e.g., heptane, hexane, pentane), and / or MCH) (e.g., adding an amount of anti-solvent sufficient to precipitate Formula I. Any of Process 1 or 1.1-1.3, wherein the process comprises dissolving Formula I in an organic solvent or a mixture of organic solvents with heating (e.g., heating to 50°C or more, e.g., heating to between 50°C to 65°C, e.g., heating at 60-65°C), optionally filtering the mixture, optionally mixing with an anti-solvent (e.g., an alkane, e.g., heptane), and then cooling the mixture (e.g., cooling to room temperature, e g., cooling to 15-20°C, or cooling to 5°C). For instance, any of Process 1 or 1.1 -1.3, wherein the process comprises dissolving Formula I in IP Ac with heating (e.g., heating to 50°C or more, e.g., heating to between 50°C to 65°C, e.g., heating at 60-65°C), mixing with an anti-solvent (e.g., an alkane, e.g., heptane), and then cooling the mixture (e.g., cooling to 15-20°C). Any of Process 1 or 1.1 -1.4, wherein the process comprises adding a polymer (e.g., polyethylene glycol, copovidone, polyvinyl pyrrolidone, or a cellulose, e.g., hydroxypropyl methyl cellulose) to the mixture. Process 1, wherein the process comprises slurrying at room temperature, with cooling (e.g., to 5°C), or with heating (e.g., 50°C) and optionally stirring a suspension of Formula I in a solvent or mixture of solvents in which Formula I has poor solubility (e g., H2O, H2O / MeOH, H2O / IPAc, H2O / CH2C12, H2O / IPE, heptane / CH2Cl2, MCH / CPME, H2O / TFE, H2O / acetone, H2O / 2-BtOH, H2O / CHCh, hexane / acetone, HEP / IPAc, HEP, H2O / l,4-dioxane, H2O / EtOAc, or H2O / toluene).1.7 Process 1, wherein the process comprises grinding Formula I with a solvent or mixture of solvents (e.g., H2O, MIBK, hexane / EtOH) and mortar.1.8 Any of Process 1 or 1.1-1.7, wherein the process comprises seeding with Crystalline Form 1 (e.g., any of Crystalline Form 1 et seq.).1.9 Any of Process 1 or 1.1-1.8, wherein the process comprises isolating Crystalline Form 1.1.10 Process 1.9, wherein Crystalline Form 1 is isolated by filtration.1.11 Any of Process 1 or 1.1-1.10, wherein the process is as described in any of the examples that produce Crystalline Form 1.1.12 Any of Process 1 or 1.1 -1.11, wherein Crystalline Form 1 is dried under vacuum (e.g., -0.08 MPa to -0.09 MPa) optionally with heating (e.g., dried at 35-45°C). For instance, any of Process 1 or 1.1-1.11, wherein Crystalline Form 1 is dried under vacuum (e.g., -0.08 MPa to -0.09 MPa) optionally with heating (e.g., dried at 35-45°C) for at least 12 hours (e.g., for 14 hours).1.13 A crystalline form of Formula I made by any of Process 1 or 1.1-1.12.1.14 Any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., wherein the crystal is made by any of Process 1 et seq.

[0040] Further provided is a crystal made by any of Process 1 et seq.

[0041] Further provided is a process (Process 2) for making Formula I in crystalline form, e.g., for making any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., e.g., Crystalline Form 2.

[0042] Further provided is Process 2 as follows:2.1 Process 2, wherein the process comprises dissolving Formula I in an organic solvent or a mixture of organic solvents in which it is soluble, e.g., an ether (e.g., 2-MeTHF).2.2 Process 2.1, wherein the process comprises evaporating the solvent or mixture of solvents at room temperature.2.3 Any of Process 2, 2.1 or 2.2, wherein the process comprises mixing Formula I with or exposing Formula I to an anti-solvent (e.g., an alkane (e.g., hexane)).2.4 Any of Process 2 or 2.1-2.3, wherein the process comprises dissolving Formula I in an organic solvent or a mixture of organic solvents with heating (e.g., heatingto 50°C or more, e.g., heating to between 50°C to 65°C, e.g., heating at 60-65°C), optionally filtering the mixture, optionally mixing with an anti-solvent (e.g., an alkane, e.g., heptane), and then cooling the mixture (e.g., cooling to room temperature, e.g., cooling to 5-20°C, e.g., 5-10°C). For instance, any of Process 2 or 2.1-2.3, wherein the process comprises dissolving Formula I in IP Ac with heating (e.g., heating to 50°C or more, e.g., heating to between 50°C to 65°C, e.g., heating at 60-65°C), mixing with an anti-solvent (e.g., an alkane, e.g., heptane), and then cooling the mixture (e.g., cooling to 5-20°C, e.g., 5-10°C).2.5 Process 2, wherein the process comprises slurrying at room temperature and optionally stirring a suspension of Formula I in a solvent or mixture of solvents in which Formula I has poor solubility (e.g., MCH / H2O). Refer to examples below for definitions of abbreviations.2.6 Any of Process 2 or 2.1-2.5, wherein the process comprises seeding with Crystalline Form 2 (e.g., any of Crystalline Form 2 et seq.).2.7 Any of Process 2 or 2.1-2.6, wherein the process comprises isolating Crystalline Form 2.2.8 Process 2.7, wherein Crystalline Form 2 is isolated by filtration.2.9 Any of Process 2 or 2.1-2.8, wherein the process is as described in any of the examples that produce Crystalline Form 2.2.10 Any of Process 2 or 2.1-2.9, wherein Crystalline Form 2 is dried under vacuum (e.g., -0.08 MPa to -0.09 MPa) optionally with heating (e.g., dried at 35-45°C). For instance, any of Process 2 or 2.1-2.9, wherein Crystalline Form 2 is dried under vacuum (e.g., -0.08 MPa to -0.09 MPa) optionally with heating (e.g., dried at 35-45°C) for at least 12 hours (e.g., for 14 hours).2.11 Any of Process 2 or 2.1-2.10, wherein the solid is micronized by jet mill.2.12 A crystalline form of Formula I made by any of Process 2 or 2.1-2.11.2.13 Any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., wherein the crystal is made by any of Process 2 et seq.

[0043] Further provided is a crystal made by any of Process 2 et seq.

[0044] Further provided is a process (Process 3) for making Formula I in crystalline form, e.g., for making any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., e.g., Crystalline Form 3.

[0045] Further provided is Process 3 as follows:3.1 Process 3, wherein the process comprises dissolving Formula I in an organic solvent or a mixture of organic solvents in which it is soluble, e.g., a polar organic solvent (e.g., NMP).3.2 Process 3.1, wherein the process comprises evaporating the solvent or mixture of solvents at room temperature.3.3 Any of Process 3, 3.1 or 3.2, wherein the process comprises mixing Formula I with or exposing Formula I to an anti-solvent (e.g., an alkane (e.g., pentane) or H2O).3.4 Any of Process 3 or 3.1-3.3, wherein the process comprises adding a polymer (e.g., copovidone, polyvinyl pyrrolidone, or a cellulose, e.g., ethyl cellulose ether) to the mixture. For instance, any of Process 3 or 3.1-3.3, wherein the process comprises dissolving Formula I in FFO / EtOH and adding ethyl cellulose ether to the mixture.3.5 Any of Process 3 or 3.1-3.4, wherein the process comprises seeding with Crystalline Form 3 (e.g., any of Crystalline Form 3 et seq.).3.6 Any of Process 3 or 3.1-3.5, wherein the process comprises isolating Crystalline Form 3.3.7 Process 3.6, wherein Crystalline Form 3 is isolated by filtration.3.8 Any of Process 3 or 3.1-3.7, wherein the process is as described in any of the examples that produce Crystalline Form 3.3.9 A crystalline form of Formula I made by any of Process 3 or 3.1-3.8.3.10 Any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., wherein the crystal is made by any of Process 3 et seq.

[0046] Further provided is a crystal made by any of Process 3 et seq.

[0047] Further provided is a pharmaceutical composition (Composition 1) comprising a crystalline form of Formula I (e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq.):Formula I.

[0048] Further provided is Composition 1 as follows:1.1 Composition 1, wherein the composition comprises a pharmaceutically acceptable carrier.1.2 Composition 1 or 1.1, wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance.1.3 Any of Composition 1, 1.1, or 1.2, wherein the crystalline form of Formula I has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.1.4 Any of Composition 1 or 1.1 -1.3, wherein the composition is in oral or parenteral dosage form, e.g., oral dosage form, for instance, a tablet, capsule, solution, or suspension, for instance, a capsule or tablet.1.5 Any of Composition 1 or 1.1-1.4, wherein the composition comprises a therapeutically effective amount of the crystalline form of Formula I, e.g., a therapeutically effective amount of the crystalline form of Formula I, for the prophylaxis or treatment of a disorder disclosed herein, e.g., a therapeutically effective amount of the crystalline form of Formula I, for use in any of the methods disclosed herein.Any of Composition 1 or 1.1-1.5, wherein the composition is substantially free of any other stereoisomeric form of Formula I. For instance, any of Composition 1 or 1.1-1.5, wherein the composition is substantially free of any other diastereomeric and / or enantiomeric form of Formula I, e.g., wherein the composition is substantially free of any other diastereomeric and enantiomeric form of Formula I. Any of Composition 1 or 1.1-1.6, wherein the composition comprises less than 10% w / w (weight / weight) of any other stereoisomeric form of Formula I, e.g., less than 5% w / w of any other stereoisomeric form of Formula I, e.g., less than 4% w / w of any other stereoisomeric form of Formula I, e.g., less than 3% w / w of any other stereoisomeric form of Formula I, e.g., less than 2% w / w of any other stereoisomeric form of Formula I, e.g., less than 1% w / w of any other stereoisomeric form of Formula I. Any of Composition 1 or 1. 1-1.7, wherein the composition comprises less than 10% w / w of any other diastereomeric form of Formula I, e.g., less than 5% w / w of any other diastereomeric form of Formula I, e.g., less than 4% w / w of any other diastereomeric form of Formula I, e.g., less than 3% w / w of any other diastereomeric form of Formula I, e.g., less than 2% w / w of any other diastereomeric form of Formula I, e.g., less than 1% w / w of any other diastereomeric form of Formula I. Any of Composition 1 or 1.1-1.8, wherein the composition comprises less than 10% w / w of any other enantiomeric form of Formula I, e.g., less than 5% w / w of any other enantiomeric form of Formula I, e.g., less than 4% w / w of any other enantiomeric form of Formula I, e.g., less than 3% w / w of any other enantiomeric form of Formula I, e.g., less than 2% w / w of any other enantiomeric form of Formula I, e.g., less than 1% w / w of any other enantiomeric form of Formula I. Any of Composition 1 or 1.1 -1.9, wherein the compound has the stereochemical configuration as shown in Formula I. Any of Composition 1 or 1.1-1.10, wherein the composition comprises 1-60 mg of the compound of Formula I. For instance, any of Composition 1 or 1.1-1.10, wherein the composition comprises 1-10 mg, e.g., 1-9 mg (e.g., 1-8 mg) of thecompound of Formula I. For instance, any of Composition 1 or 1.1-1.10, wherein the composition comprises 3 mg or 10 mg of the compound of Formula I. For instance, any of Composition 1 or 1.1-1.10, wherein the composition comprises 1 mg to less than 3 mg (e.g., 2 mg) of the compound of Formula I.1.12 Any of Composition 1 or 1.1-1.11, wherein the composition comprises 1-60 mg of the crystalline form of Formula I. For instance, any of Composition 1 or 1.1-1.11 , wherein the composition comprises 1-10 mg, e.g., 1-9 mg (e.g., 1-8 mg) of the crystalline form ofFormula l. For instance, any of Composition 1 or 1.1-1.11, wherein the composition comprises 3 mg or 10 mg of the crystalline form of Formula I. For instance, any of Composition 1 or 1.1-1.11, wherein the composition comprises 1 mg to less than 3 mg (e.g., 2 mg) of the crystalline form of Formula I.1.13 Any of Composition 1 or 1.1-1.12, wherein the composition comprises any of Crystalline Form 1 et seq.1.14 Any of Composition 1 or 1.1-1.13, wherein the composition comprises any of Crystalline Form 2 et seq.1.15 Any of Composition 1 or 1.1-1.14, wherein the composition comprises any of Crystalline Form 3 et seq.1.16 Any of Composition 1 or 1.1-1.15, wherein the composition is for once, twice, or three times daily dosing. For instance, any of Composition 1 or 1.1-1.15, wherein the composition is for once daily dosing.

[0049] Further provided is a process (Process 4) for preparing a pharmaceutical composition comprising a crystalline form of Formula I (e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq.), wherein the process comprises mixing a crystalline form of Formula I as described herein, e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., and a pharmaceutically acceptable carrier or excipient. For instance, provided is a process for preparing a pharmaceutical composition comprising an effective amount of a crystalline form of Formula I (e g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq.), wherein the process comprises mixing a crystalline form of Formula I as described herein, e.g., any of Crystalline Form 1 et seq.,Crystalline Form 2 et seq., or Crystalline Form 3 et seq., and a pharmaceutically acceptable carrier or excipient.

[0050] Further provided are methods of prophylaxis or treatment of a central nervous system disorder (e.g., a brain disorder), for instance, a central nervous system disorder (e.g., a brain disorder) that benefits from modulating dopamine, in a patient (e.g., a human) in need thereof, wherein the method comprises administering to the patient a crystalline form of Formula I (e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq.) or a pharmaceutical composition comprising a crystalline form of Formula I (e.g., any of Formula 1.54, 2.56, or 3.63, or any of Composition 1 et seq ). Further provided are methods of prophylaxis or treatment of a central nervous system disorder (e g., a brain disorder) that benefits from D2 receptor antagonism, D3 receptor antagonism, and / or D4 receptor antagonism in a patient (e.g., a human) in need thereof, wherein the method comprises administering to the patient a crystalline form of Formula I (e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq.) or a pharmaceutical composition comprising a crystalline form of Formula I (e.g., any of Formula 1.54, 2.56, or 3.63, or any of Composition 1 et seq.). For instance, provided are methods as described below.

[0051] Provided is a method (Method 1) for treatment or prophylaxis of a disorder (e.g., a brain disorder) in a patient (e.g., a human) in need thereof, wherein the method comprises administering to the patient an effective amount of (or a pharmaceutical composition comprising) a crystalline form of Formula I (e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq. or any of Formula 1.54, 2.56, or 3.63 or any of Composition 1 et seq.):Formula I.

[0052] Further provided is Method 1 as follows:Method 1, wherein the effective amount of has a stereoisomeric excess of greater than 90%, e.g., a stereoisomeric excess equal to or greater than 95%, e.g., a stereoisomeric excess equal to or greater than 96%, e.g., a stereoisomeric excess equal to or greater than 97%, e.g., a stereoisomeric excess equal to or greater than 98%, e g., a stereoisomeric excess equal to or greater than 99%. For instance, wherein the effective amount is substantially diastereomerically and / or enantiomerically pure, e.g., wherein the effective amount is substantially diastereomerically and enantiomerically pure. For instance, wherein the effective amount of has a diastereomeric and / or enantiomeric excess of greater than 90%, e.g., a diastereomeric and / or enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and / or enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and / or enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and / or enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and / or enantiomeric excess equal to or greater than 99%. For instance, wherein the effective amount has a diastereomeric and enantiomeric excess of greater than 90%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 95%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 96%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 97%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 98%, e.g., a diastereomeric and enantiomeric excess equal to or greater than 99%. Any of Method 1 or 1.1, wherein the designation of deuterium (i.e., D) at a position means that position has a significantly greater than natural abundance of deuterium at that position (e.g., greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%). Any atom not designated as a particular isotope is present at natural isotopic abundance. Any of Method 1, 1.1, or 1.2, wherein the crystalline form of Formula I has greater than 50% incorporation of deuterium (i.e., D) at each position designated as deuterium (i.e., D), e.g., greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.Any of Method 1 or 1.1-1.3, wherein the disorder is a brain disorder. For instance, any of Method 1 or 1.1-1.3, wherein the disorder is a neuropsychiatric condition in which anhedonia is prominent. Any of Method 1 or 1.1-1.4, wherein the disorder is an affective (mood) disorder or an anxiety disorder. Any of Method 1 or 1.1-1.5, wherein the disorder is depression (e.g., depression associated with anhedonia), an anxiety disorder, psychosis (e.g., psychosis in neurodegenerative conditions, such as psychosis in Alzheimer’s disease, Parkinson’s disease, or dementia (e.g., dementia-related psychosis)), schizophrenia, schizoaffective disorder, post-traumatic stress disorder (PTSD), attention-deficit / hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder (including bipolar depression, bipolar mania, and bipolar disorder with mixed features), or a migraine. For instance, any of Method 1 or 1.1-1.5, wherein the anxiety disorder is panic disorder, social anxiety disorder, a phobia, or generalized anxiety disorder. Or, any of Method 1 or 1.1-1.5, wherein the method is prophylaxis or treatment of behavioral and psychological symptoms of dementia including agitation, depression, anxiety, apathy, and / or psychosis. Any of Method 1 or 1.1 -1.6, wherein the disorder is anhedonia or depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression. For instance, any of Method 1 or 1.1-1.6, wherein the disorder is depression associated with anhedonia. Or, for instance, wherein the disorder is anhedonia. Or, for instance, any of Method 1 or 1.1-1.6, wherein the disorder is melancholic depression. Any of Method 1 or 1.1-1.7, wherein the disorder is major depressive disorder. Any of Method 1 or 1.1-1.6, wherein the disorder is a substance use disorder. Any of Method 1 or 1.1-1.6, wherein the method is prophylaxis or treatment of negative symptoms of schizophrenia. Or, any of Method 1 or 1.1-1.6, wherein the method is improving cognition in schizophrenia.Any of Method 1 or 1.1-1.3, wherein Formula I is administered as an anti-emetic. Any of Method 1 or 1.1-1.11, wherein the method comprises administering 9-60 mg a day of Formula I (e.g., in crystalline form) (i.e., 9-60 mg total daily dose of Formula I). For instance, any of Method 1 or 1.1-1.11, wherein the method comprises administering 9-36 mg a day of Formula I (e.g., in crystalline form) (i.e., 9-36 mg total daily dose of Formula I). Any of Method 1 or 1.1-1.12, wherein the method comprises administering an amount of Formula I (e.g., in crystalline form) that provides 55%-80% D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography. For instance, wherein the method comprises administering an amount of Formula I that provides about 65% D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography. Or, for instance, wherein the method comprises administering an amount of Formula I (e.g., in crystalline form) that provides about 60% D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography. Method 1.12 or 1.13, wherein the disorder is psychosis (e.g., psychosis in neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease, and dementia (e.g., dementia-related psychosis)), schizophrenia, schizoaffective disorder, or bipolar disorder (e.g., bipolar mania). Method 1.12 or 1.13, wherein the method is prophylaxis or treatment of negative symptoms of schizophrenia. Or, Method 1.12 or 1.13, wherein the method is improving cognition in schizophrenia. Any of Method 1 or 1.1-1.11, wherein the method comprises administering 1 -9 mg (e.g., 1-8 mg, e.g., 1.5-6 mg) a day of Formula I (e.g., in crystalline form) (i.e., 1-9 mg total daily dose, e.g., 1-8 mg total daily dose, e.g., 1.5-6 mg total daily dose, of Formula I). For instance, any of Method 1 or 1.1-1.11, wherein the method comprises administering 1-8 mg a day of Formula I (e.g., in crystalline form) (i.e., 1-8 mg total daily dose of Formula I). For instance, any of Method 1 or 1.1-1.11, wherein the method comprises administering 1-3 mg a day of Formula I (e.g., in crystalline form) (i.e., 1-3 mg total daily dose of Formula I). For instance, any of Method 1 or 1.1-1.11, wherein the method comprisesadministering 1 mg to less than 3 mg a day (e.g., 2 mg a day) of Formula I (e.g., in crystalline form) (i.e., 1 mg to less than 3 mg total daily dose of Formula I). Any of Method 1 , 1.1-1.11, or 1.16, wherein the method comprises administering an amount of Formula I (e.g., in crystalline form) that provides 10%-60% (e.g., 40%-60% or, e.g., 10%-55%, e.g., 10%-50%, e.g., 30%-50% or, e.g., 15%-50%, e.g., 15%-45%, e.g., 20%-40%, e.g., 10%-30%) D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography. Or, for instance, any of Method 1, 1.1-1.11, or 1.16, wherein the method comprises administering an amount of Formula I (e.g., in crystalline form) that provides < 40% (e.g., about 40%), e.g., < 40%, D2 / D3 receptor occupancy, e.g., as measured by positron emission tomography. Method 1.16 or 1.17, wherein the disorder is depression (e.g., depression associated with anhedonia), an anxiety disorder, post-traumatic stress disorder (PTSD), attention-deficit / hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder, bipolar disorder with mixed features, or a migraine. For instance, Method 1.16 or 1.17, wherein the anxiety disorder is panic disorder, social anxiety disorder, a phobia, or generalized anxiety disorder. Any of Method 1.16-1.18, wherein the disorder is anhedonia or depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression. For instance, wherein the disorder is anhedonia or depression associated with anhedonia. Any of Method 1.16-1.19, wherein the disorder is major depressive disorder. Method 1.16 or 1.17, wherein the disorder is a substance use disorder. Any of Method 1 or 1.1-1.21, wherein the method comprises administering a pharmaceutical composition comprising a crystalline form of Formula I (e.g., a pharmaceutical composition comprising any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq.). For instance, any ofMethod 1 or 1.1-1.21, wherein the method comprises administering Formula 1.54, 2.56, or 3.63 or any of Composition 1 et seq.1.23 Any of Method 1 or 1.1-1.22, wherein the method comprises administering a crystalline form of Formula I (e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq.) once, twice, or three times a day, e.g., once a day. For instance, any of Method 1 or 1.1-1.22, wherein the method comprises administering a pharmaceutical composition comprising a crystalline form of Formula I (e.g., a pharmaceutical composition comprising any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., e.g., any of Formula 1.54, 2.56, or 3.63 or any of Composition 1 et seq.) once, twice, or three times a day, e.g., once a day.1.24 Any of Method 1 or 1.1-1.23, wherein the method comprises administering a crystalline form of Formula I (e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq.) once a day. For instance, any of Method 1 or 1.1-1.23, wherein the method comprises administering a pharmaceutical composition comprising a crystalline form of Formula I (e.g., a pharmaceutical composition comprising any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., e.g., any of Formula 1.54, 2.56, or 3.63 or any of Composition 1 et seq.) once a day.

[0053] Further provided is 5-chloro-7V-((2S,3S)-l-(dideutero(phenyl)methyl)-2- methylpyrrolidin-3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide (Formula I), e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., wherein the purity by HPLC is > 98%, e.g., > 99%.

[0054] Further provided is 5-chloro-A-((2S,3S)-l-(dideutero(phenyl)methyl)-2- methylpyrrolidin-3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide (Formula I), e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., comprising < 1% of any of the following:

[0055] Further provided is 5-chloro-7V-((2S,3S)-l-(dideutero(phenyl)methyl)-2- methylpyrrolidin-3-yl)-2-methoxy-4-(trideuteromethylamino)benzamide (Formula I), e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., comprising < 2% total impurities, e.g., < 1.5% total impurities.

[0056] Further provided is a crystalline form of Formula I as described herein, e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., or a pharmaceutical composition disclosed herein (e.g., any of Formula 1.54, 2.56, or 3.63 or any of Composition 1 et seq.) for use in any method or in the treatment of any disease or condition as described herein, e.g., for use in any of Method 1 or 1.1-1.24 vide supra.

[0057] Further provided is use of a crystalline form of Formula I as described herein, e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., or a pharmaceutical composition disclosed herein (e.g., any of Formula 1.54, 2.56, or 3.63 or any of Composition 1 et seq.) in any method or in the treatment of any disease or condition as described herein, e.g., for use in any of Method 1 or 1.1-1.24 vide supra.

[0058] Further provided is use of a crystalline form of Formula I as described herein, e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., or a pharmaceutical composition disclosed herein (e.g., any of Formula 1.54, 2.56, or 3.63 or any of Composition 1 et seq.) in the manufacture of a medicament for use any method or in the treatment of any disease or condition as described herein, e.g., for use in any of Method 1 or 1.1- 1.24 vide supra.

[0059] Further provided is a pharmaceutical composition comprising a crystalline form of Formula I as described herein, e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq.,or Crystalline Form 3 et seq., in combination or association with a pharmaceutically acceptable diluent or carrier, e.g., Formula 1.54, 2.56, or 3.63 or any of Composition 1 et seq.

[0060] Further provided is a pharmaceutical composition comprising a crystalline form of Formula I as described herein, e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., in combination or association with a pharmaceutically acceptable diluent or carrier, e.g., any of Formula 1.54, 2.56, or 3.63 or any of Composition 1 et seq. for use in the treatment of any disease or condition as described herein, e.g., for use in any of Method 1 or 1.1-1.24 vide supra.

[0061] For crystalline forms disclosed herein, a hydrogen atom position of a structure is considered substituted with deuterium when the abundance of deuterium at that position is enriched. The natural abundance of deuterium is about 0.02%, so a compound is “enriched” with deuterium at a specific position when the frequency of incorporation of deuterium at that position exceeds 0.02%. Therefore, for deuterated crystalline forms disclosed herein, any position designated as deuterium (i.e., D) may be enriched with deuterium at a level of greater than 0.1%, or greater than 0.5%, or greater than 1%, or greater than 5%, such as, greater than 50%, or greater than 60%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%. For crystalline forms disclosed herein, any atom not designated as a particular isotope is present at natural isotopic abundance.

[0062] Pure stereoisomeric forms of the compounds, crystalline forms, and intermediates disclosed herein are isomers substantially free of other enantiomeric and diastereomeric forms of the same basic molecular structure of said compounds or intermediates. “Substantially stereoisomerically pure” includes compounds, crystalline forms, and intermediates having a stereoisomeric excess of greater than 90% (i.e., more than 90% of one isomer and less than 10% of any other possible isomer). The terms “substantially diastereomerically pure” and “substantially enantiomerically pure” should be understood in a similar way, but then having regard to the diastereomeric excess and enantiomeric excess, respectively, of the material in question.

[0063] For methods of treatment, the word “effective amount” is intended to encompass a therapeutically effective amount to treat a specific disease or disorder.

[0064] Dosages employed in practicing the present invention will of course vary depending, e.g. on the particular disease or condition to be treated, the particular compound used, the mode of administration, and the therapy desired.

[0065] The crystallinity, morphology, and properties of the crystals described herein, e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., may be determined by a number of methods, including, but not limited to single crystal X-ray diffraction, X-ray powder diffraction, polarizing optical microscopy, thermal microscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic (water) vapor sorption, infared absorption spectroscopy, and Raman spectroscopy.

[0066] It is to be understood that an XRPD pattern of a given sample may vary (standard deviation) depending on the instrument used, the time and temperature of the sample when measured, and standard experimental errors. Therefore, the 2-theta values (°20), d-spacing values, heights, and relative intensity of the peaks will have an acceptable level of deviation. For example, the values may have an acceptable deviation of e.g., 20%, 15%, 10%, 5%, 3%, 2%, or 1%. In a particular embodiment, the 2-theta (°) values or the d-spacing (A) values of the XRPD patterns of the crystalline forms described herein may have an acceptable deviation of ± 0.2° and / or ± 0.2 A. Further, the XRPD patterns of the crystalline forms described herein may be identified by characteristic peak(s) as recognized by one skilled in the art. For example, the crystalline forms disclosed herein, e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq., may be identified by, e.g., two characteristic peaks, in some instances, three characteristic peaks, in another instance, five characteristic peaks. Therefore, the term “corresponding to” shown in a particular figure refers to any crystal which has an XRPD that is identified as a particular form by one skilled in the art, e.g., an XRPD comprising major and / or characteristic and / or representative peaks as recognized by one skilled in the art.

[0067] It is also to be understood that the differential scanning calorimetry and thermogravimetric analysis thermograms of a given sample may vary (standard deviation) depending on the instrument used, the time and temperature of the sample when measured, and standard experimental errors. The temperature value itself may deviate by ± 10 °C, preferably ± 5 °C, preferably ± 3 °C of the reference temperature.

[0068] If multiple diffraction patterns are available, then assessments of particle statistics (PS) and / or preferred orientation (PO) are possible. Reproducibility among XRPD patterns frommultiple samples analyzed on a single diffractometer may indicate that the particle statistics are adequate. Consistency of relative intensity among XRPD patterns from multiple diffractometers may indicate good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a single crystal structure, if available. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS / PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as “representative peaks.”

[0069] “ Characteristic peaks,” to the extent they exist, are a subset of representative peaks and may be used to differentiate one crystalline polymorph from another crystalline polymorph (polymorphs being crystalline forms having the same chemical composition). Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within ± 0.2 °26. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.

[0070] As used herein, “XRPD” means X-ray powder diffraction.

[0071] As used herein, the term “amorphous” refers to solids of disordered arrangements of molecules and do not possess a distinguishable crystal lattice.

[0072] As used herein, “soluble” means the dissolution of Formula I is > 10 mg / ml, e.g., > 30 mg / ml.

[0073] As used herein, “poorly soluble” means the dissolution of Formula I is < 10 mg / ml.

[0074] As used herein, “anti-solvent” means a solvent in which Formula I has low solubility or is insoluble. For instance, an anti-solvent includes a solvent in which Formula I has a solubility of less than 10 mg / ml.

[0075] The terms “pharmaceutical” or “pharmaceutically acceptable” when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to the receipient.

[0076] By “pharmaceutical composition” it is further meant that the carrier, solvent, and / or excipient must be compatible with Formula I. It is understood by those of ordinary skill in this art that the terms “pharmaceutical composition” and “pharmaceutical formulation” are generally interchangeable, and they are so used for the purposes of this application.

[0077] As used herein, “patient” includes human and non-human. In one embodiment, the patient is a human. In another embodiment, the patient is a non-human.

[0078] Formula I (e.g., Formula I in any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq. or in a pharmaceutical composition as in Formula 1.54, 2.56, or 3.63 or any of Composition 1 et seq.) may be administered by any suitable route, including orally, parenterally, or transdermally, but are preferably administered orally.

[0079] Pharmaceutical compositions comprising a crystalline form of Formula I as disclosed herein, e.g., any of Crystalline Form 1 et seq., Crystalline Form 2 et seq., or Crystalline Form 3 et seq. or Composition 1 et seq., may be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, oral dosage forms may include tablets, capsules, solutions, suspensions, and the like.

[0080] If not commercially available, starting materials for processes described herein may be made by procedures which are selected from the chemical art using techniques that are similar to or analogous to the synthesis of known compounds.EXAMPLESAbbreviations h = hour(s) min = minutes rt (or RT or r.t.) = room temperature RH = relative humidityAbbreviations for solventsGeneral ProceduresX-ray Powder Diffraction (XRPD)Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC)Dynamic Vapor Sorption (DVS)Example 1Synthesis of Crystalline Form 1Compound 8: (2S,3R)-l-(dideutero(phenyl)methyl)-2-methylpyrrolidin-3-ol7 8

[0081] A solution of compound 7 (3.7 kg) in dry THF (33 kg) is added dropwise to a stirring solution of LiAlD4 (l. l kg) in dry THF (16.5 kg) at 0-10°C under N2 atomsphere. After stirring at 0-10°C for 20 minutes, the reaction mixture is allowed to warm to 40-45°C and is then stirred at 40-45°C for 14 hours. The reaction mixture is cooled to 0-10°C and quenched with 20% aqueous KOH solution (2 kg) and H2O (3.4 kg). The suspension is extracted with di chloromethane (55.7 kg x 1) to yield compound 8 (3.8 kg) as a yellow oil.Compound 9: (2S,3S)-3-azido-l-(dideutero(phenyl)methyl)-2-methylpyrrolidine8 9

[0082] Dichloromethane (50.4 kg) is added to a 100 L reactor and stirred. Compound 8 (3.8 kg) and triethylamine (4 kg) is added in turn. The inner temperature is adjusted to 0-5°C, then methanesulfonyl chloride (3.4 kg) is added to the reactor at 0-5°C. The inner temperature is adjusted to 15-25°C after addition and the reaction mixture is stirred at 15-25°C for 2 hours. The reaction mixture is quenched with 5% (w / w) NaHCOi solution (25.2 kg), stirred, and separated. The organic phase is stirred with 5% (w / w) NaHCCh solution (25 kg) again and then separated. The aqueous phase is extracted with di chloromethane (30.2 kg x 1), stirred, and separated. The combined di chloromethane phases are washed with H2O (22.8 kg), stand, and separate. The organic phase is concentrated at 35-45°C in vacuum to yield product as an oil (5.3 kg), which is used directly in the next step.

[0083] N,N-Dimethylformamide (50.2 kg) and the product from above (5.3 kg) are added to a 100 L reactor in turn and the temperature is adjusted to 10-30°C. Then sodium azide (3.8 kg) is added to the solution at 10-30°C. The reaction mixture is stirred for 16.5 hours at 80-85°C. Thereaction mixture is cooled to 10-20°C and quenched with H2O (58 kg), stirred, and it becomes a clear solution. The reaction solution is extracted with ethyl acetate twice (26.7 kg x 2), stirred, and separated. The organic phase is concentrated at 35-45°C in vacuum to 4-5V and methanol is added (15.8 kg), concentrated to 4-5V. Methanol (15.8 kg) is added to the solution again and concentrated to 4-5V. The solution of compound 9 in methanol (18.6 kg) is used directly in the next step.Compound 10: (2S,3S)-l-(dideutero(phenyl)methyl)-2-methylpyrrolidin-3-amine9 10

[0084] Four batches of parallel reactions:To a solution of compound 9 in methanol (4.7 kg) is added 10% Pd / C (107 g). The mixture is replaced with N2 for three times and stirred under hydrogen (balloon) at 20-30°C for 23 hours.

[0085] The reaction mixtures are combined and filtered. The filtrate is concentrated at 35-45°C in vacuum to dryness. The solid is transferred to a 100 L reactor by ethyl acetate (20 kg). To the solution is added 4 mol / L HC1 ethyl acetate solution (5 L) at 20-30°C and the mixture is stirred for 2 hours (solid precipitate). The mixture is filtered and the filter cake is dried under vacuum at 45-55°C (vacuum: 0.07 MPa-0. 10 MPa) for 24 hours to yield compound 10 as the hydrochloride salt (3.3 kg).Compound 13: 4-(tert-Butoxycarbonyl(trideuteromethyl)amino)-5-chloro-2- methoxybenzoic acid12 13

[0086] To a 100 L reactor is added THF (20 kg), compound 12 (4.3 kg), and H2O (21.7 kg) in turn and the mixture is stirred. The temperature is then adjusted to 15-25°C. Lithium hydroxidemonohydrate (1.1 kg) is added to the reaction and stirred for 2-3 hours. The pH of the reaction mixture is adjusted to 2-3 with 1 mol / L HC1 aqueous solution. Ethyl acetate (19.4 kg) is added to the mixture, stirred, and separated. The aqueous phase is extracted with ethyl acetate twice (19.2 kg + 19.2 kg), stand, and separate. The organic phases are combined and washed with saturated NaCl solution (64.6 kg), stand, and separate. The organic phase is concentrated in vacuum at 35- 45°C to dryness to yield compound 13 (4.1 kg).Compound 14:

[0087] To a 100 L reactor is added N,N-dimethylacetamide (28.1 kg), compound 10 as the hydrochloride salt (3 kg), and tri ethylamine (4 kg) in turn and the temperature is adjusted to 10- 20°C. Compound 13 (4 kg), HOBt (1.8 kg), and l-ethyl-3-(3-dimethylaminopropyl)carbodiimideEDCI (2.6 kg) are added in turn at 10-20°C. The reaction mixture is stirred under N2 at 10-20°C for 4 hours. The reaction mixture is added to pre-cooled H2O (0-5°C, 60 kg), the inner temperature is controlled below 30°C. The mixture is extracted with ethyl acetate 3 times (27.1 kg x 3), stirred, and separated. The organic phases are combined and washed sequentially with saturated NaCl solution (40.8 kg x 1), 1 mol / L NaOH solution (31.2 kg x 1), saturated NaCl solution (40.8 kg x 1), stand, and separate. The organic phase is concentrated in vacuum at 35- 45°C to dryness to yield compound 14 (5.6 kg).Compound 15: 5-chloro- / V-((2S,3S)-l-(dideutero(phenyl)methyl)-2-methylpyrrolidin-3-yl)- 2-methoxy-4-(trideuteromethylamino)benzamide (Crystalline Form 1)

[0088] A 100 L reactor is charged with 4 mol / L HC1 ethyl acetate solution (50.5 kg) at 15-25°C.Ethyl acetate (22.5 kg) and compound 14 (5 kg) are added to the 100 L reactor. The reaction mixture is stirred at 15-25°C for 12 hours. The temperature of the mixture is adjusted to 0-10°C.The mixture is extracted with H2O (40.1 kg) and stirred until oil is dissolved. Aqueous phase is separated. Organic phase is extracted with H2O again (40.1 kg) and aqueous phase is separated. The aqueous phases are combined. The aqueous phase is adjusted to pH > 10 at 15-25°C with 5% (w / w) sodium hydroxide solution (38.4 kg) and then extracted with ethyl acetate twice (36.4 kg + 36 kg). The organic phases are combined and concentrated at 35-45°C under -0.09 MPa to yield crude compound 15.

[0089] The crude product is dissolved in isopropyl acetate (32.1 kg) at 30-35°C. H2O (10.8 kg) is added to the solution and stirred and then allowed to stand and separate. The aqueous phase is extracted with isopropyl acetate (3.2 kg) again. The organic phases are combined and decolored with activated carbon (0.7 kg) at 30-35°C for 1 hour. Then the mixture is filtered and washed with isopropyl acetate. The filtrate is concentrated in vacuum to about 3X at 35-45°C. The mixture is heated to 60-65°C until solid dissolves to a clear solution. n-Heptane (5.1 kg) is added to the solution, then the mixture is cooled to 15-20°C over 1.5 hours. The mixture is stirred at 15- 20°C for 1 hour and filtered. The filter cake is rinsed with n-heptane (2.5 kg). The wet filter cake is dried at 35-45°C under -0.09 MPa for 18 hours.

[0090] The solid is dissolved in isopropyl acetate (4.5 kg) at 60-65°C. n-Heptane (3.5 kg) is added to the solution, then the mixture is cooled to 15-20°C over 1.5 hours. The mixture is stirred at 15-20°C for 1 hour and then filtered and washed with n-heptane. The wet filter cake is dried at 35-45°C under -0.09 MPa for 14 hours to yield compound 15 (2.2 kg). HPLC: > 98%. XRPD shows the product is Crystalline Form 1 (see Figure 2 for XRPD, see Figure 3 for TGA, and see Figure 4 for DSC).Example 2 - Synthesis of Crystalline Form 1

[0091] About 20 mg of Crystalline Form 1 from Example 1 is suspended in 0.5 mb of the solvent listed in Table 1. The suspension is stirred magnetically for about 3 days at 5°C. The remaining solid is isolated. As shown in Table 1, Crystalline Form 1 is obtained.Table 1.Example 3 - Synthesis of Crystalline Form 1 and Crystalline Form 2

[0092] About 20 mg of Crystalline Form 1 from Example 1 is suspended in 0.5 mL of the solvent listed in Table 2. The suspension is stirred magnetically for about 3 days at room temperature. The remaining solid is isolated. As shown in Table 2, Crystalline Form 1 and Crystalline Form 2 is obtained.Table 2.Example 4 - Synthesis of Crystalline Form 1

[0093] About 20 mg of Crystalline Form 1 from Example 1 is suspended in 0.5 mL of the solvent listed in Table 3. The suspension is stirred magnetically for about 3 days at 50°C. The remaining solid is isolated. As shown in Table 3, Crystalline Form 1 is obtained.Table 3.Example 5 - Synthesis of Crystalline Form 1 and Mixture of Crystalline Form 1 and Crystalline Form 2

[0094] About 20 mg of Crystalline Form 1 from Example 1 is suspended in 0.5 mL of the solvent listed in Table 4. The suspension is stirred magnetically with temperature cycling as follows:50°C: 120 minutesTemperature is lowered by 0.1°C / minute to 5 °C.5 °C: 120 minutesTemperature is increased by 0.1°C / minute to 50°C.50°C: 120 minutesTemperature is lowered by 0.1°C / minute to 5°C.5 °C: 120 minutesThe remaining solid is isolated. As shown in Table 4, Crystalline Form 1 and a mixture of Crystalline Form 1 and Crystalline Form 2 is obtained.Table 4.Example 6 - Synthesis of Crystalline Form 1 and Mixture of Crystalline Form 1 andCrystalline Form 2

[0095] About 20 mg of Crystalline Form 1 from Example 1 is added to an appropriate amount of the solvent listed in Table 5 at 50°C for ultrasonic solubilization, filtered to a new vial using apolytetrafluoroethylene (PTFE) membrane filter, and the filtrate is stirred overnight at 5°C. Precipitate is isolated. As shown in Table 5, Crystalline Form 1 and a mixture of Crystalline Form 1 and Crystalline Form 2 is obtained.Table 5.Example 7 - Synthesis of Crystalline Form 1 and Mixture of Crystalline Form 1 and Crystalline Form 2

[0096] About 20 mg of Crystalline Form 1 from Example 1 is weighed into a 3 mL vial, which is placed into a 20 mL vial with 3 mL of the volative solvent listed in Table 6. The 20 mL vial is sealed with a cap and kept at room temperature for 7 days. Precipitate is isolated. As shown in Table 6, Crystalline Form 1 and a mixture of Crystalline Form 1 and Crystalline Form 2 is obtained.Table 6.Example 8 - Synthesis of Crystalline Form 1 and Mixture of Crystalline Form 1 and Crystalline Form 3

[0097] About 20 mg of Crystalline Form 1 from Example 1 is dissolved in 0.3 -0.4 mL of the solvent listed in Table 7 and then filtered to obtain a clear solution. The clear solution is placed into a 20 mL vial with 3 mL of the volatile anti-solvent listed in Table 7. The 20 mL vial is sealed with a cap and kept at room temperature. Precipitate is isolated. As shown in Table 7, Crystalline Form 1 and a mixture of Crystalline Form 1 and Crystalline Form 3 is obtained.Table 7.Example 9 - Synthesis of Crystalline Form 1

[0098] About 20 mg of Crystalline Form 1 from Example 1 is dissolved in 0.3 mL of the solvent listed in Table 8. If not dissolved completely, suspension is filtered using a polytetrafluoroethylene (PTFE) membrane filter. Filtrate is exposed to evaporate at room temperature. Precipitate is isolated. As shown in Table 8, Crystalline Form 1 is obtained.Table 8.Example 10 - Synthesis of Crystalline Form 1, Crystaline Form 3, and Mixture ofCrystalline Form 1 and Crystalline Form 3

[0099] About 20 mg of Crystalline Form 1 from Example 1 is dissolved in 3.0 mL of the solvent listed in Table 9. If not dissolved completely, the suspension is fdtered using a polytetrafluoroethylene (PTFE) membrane filter and the filtrate is used for the following steps.About 1-2 mg of polymer is added to each vial. The visually clear solution is evaporated at room temperature. Precipitate is isolated. As shown in Table 9, Crystalline Form 1, Crystalline Form 3, and a mixture of Crystalline Form 1 and Crystalline Form 3 is obtained.Table 9.Example 11 - Synthesis of Crystalline Form 1 and Mixture of Crystalline Form 1 andCrystalline Form 3

[0100] About 20 mg of Crystalline Form 1 from Example 1 is dissolved in 0.3 mL of the solvent listed in Table 10 and then filtered to obtain a clear solution. The solution is magnetically stirred followed by addition of the anti-solvent listed in Table 10 until precipitate appears.Precipitate is isolated after stirring for 5 minutes. If no solid precipitates, then the mixture is stirred overnight. As shown in Table 10, Crystalline Form 1 and a mixture of Crystalline Form 1 and Crystalline Form 3 is obtained.Table 10.Example 12 - Synthesis of Crystalline Form 1

[0101] About 20 mg of Crystalline Form 1 from Example 1 is dissolved in 0.3 mL of the solvent listed in Table 11 and then filtered to obtain a clear solution. The solution is added into a vial with 3 mL of the anti-sovent listed in Table 11. Precipitate is isolated after stirring for 5 minutes. If no solid precipitates, mixture is stirred overnight. As shown in Table 11, Crystalline Form 1 is obtained.Table 11.Example 13 - Synthesis of Crystalline Form 1

[0102] About 20 mg of Crystalline Form 1 from Example 1 is grinded with with the solvent listed in Table 12 in a mortar. 50 pL solvent is added three times for grinding and mixture is ginded for 3 minutes each time. Solid is isolated. As shown in Table 12, Crystalline Form 1 is obtained.Table 12.Example 14 - Synthesis of Crystalline Form 1

[0103] About 20 mg of Crystalline Form 1 from Example 1 is dissolved in 0.3 mL of the solvent listed in Table 13 and then filtered using a polytetrafluoroethylene (PTFE) membrane filter to obtain a clear solution. Solution is evaporated with rotary evaporation at room temperature. Solid is isolated. As shown in Table 13, Crystalline Form 1 is obtained.Table 13.Example 15 - Synthesis of Crystalline Form 1

[0104] About 20 mg of Crystalline Form 1 from Example 1 is weighed into a 3mL vial, which is placed at RT-75%RH, RT-85%RH, and RT-97%RH conditions for 7 days. Solid is isolated. As shown in Table 14, Crystalline Form 1 is obtained.Table 14.Example 16 - Synthesis of Crystalline Form 2

[0105] To about 200 mg of Crystalline Form 1 from Example 1 is added 5 mL MCH saturated H2O solution. The mixture is stirred for about 6 days at RT, then vacuum fdtered to isolate the solid. The obtained solid is dried with air-blowing overnight at 50°C. Crystalline Form 2 is obtained (see Figure 5 for XPRD, see Figure 6 for TGA, and see Figure 7 for DSC).Example 17 - Synthesis of Crystalline Form 2

[0106] 8 g of Crystalline Form 1 from Example 1 is added to 20 mL of isopropyl acetate and dissolved clearly at 60°C. Then 40 mL of n-heptane is added dropwise. 80 mg of Crystalline Form 2 seed is added. Mixture is cooled to 5-10°C and filtered. The wet solid is dried at 45°C under vacuum to provide Crystalline Form 2.Example 18 - Synthesis of Crystalline Form 3

[0107] To about 20 mg of Crystalline Form 1 from Example 1 is added 3 mL of FfO / EtOH (1 : 1 v:v). Solid is dissolved by ultrasonic. Mixture is filtered. 1-2 mg of ethyl cellulose ether is added to filtrate. Mixture is exposed to evaporate at room temperature. Solid is isolated. Crystalline Form 3 is obtained (see Figure 8 for XRPD).Example 19 - Conversion of Crystalline Form 3 to Crystalline Form 1

[0108] Crystalline Form 3 from Example 18 is mainly converted to Crystalline Form 1 after vacuum drying under 20-30 Pa for 2 days at room temperature. Figure 10 depicts an overlay of the XRPD patterns. Figure 10 shows Crystalline Form 3 (top), crystal form after vacuum drying Crystalline Form 3 overnight at room temperature (second from top), crystal form after vacuum drying Crystalline Form 3 for 2 days at room temperature (second from top), and Crystalline Form 1 (bottom) collected with Cu Ka radiation.Example 20 - Competitive Slurry

[0109] Crystalline Form 1 / 2 competitive slurry experiments are carried out at room temperature and 50°C in HEP / IPAc (20:1) and MCH / EtOH (20:1). Saturated solutions of 5- chloro-7V-((2S,3S)-l-(dideutero(phenyl)methyl)-2-methylpyrrolidin-3-yl)-2-methoxy-4- (trideuteromethylamino)benzamide at desired temperature and solvent are prepared by fdtering suspensions of Crystalline Form 1 after equilibrating for 2 hours. Then solid mixtures of Crystalline Form 1 from Example 1 and Crystalline Form 2 from Example 16 are added to the filtrates. The solid mixture of Crystalline Form 1 and Crystalline Form 2 is almost converted to Crystalline Form 2 under all tested conditions, suggesting Crystalline Form 2 is thermodynamically more stable than Crystalline Form 1 from room temperature to 50°C.Table 15.Example 21 - Equilibrium Solubility of Crystalline Form 2

[0110] Equilibrium solubility of Crystalline Form 2 from Example 16 is measured in FEO. Crystalline Form 2 is suspended in H2O with an initial loading of about 10 mg / mL and mixed at 37±2°C. The suspension is sampled at 24 hour time points to obtain solubility from supernatant and check crystal form for the residual solids. The equilibrium solubility in water is < 0.2 pg / mL. No solid form change is observed after 24 hours (see XRPD patterns in Figure 12 in which top XRPD pattern is before solubility test and bottom XRPD pattern is after solubility test).Example 22 - Solid-State Stability of Crystalline Form 2

[0111] Crystalline Form 2 from Example 16 is stored at long-term (25°C / 60%RH), accelerated (40°C / 75%RH), and high-temperature (60°C, RH<30%) conditions. After 7 days of storage, all samples are characterized by XRPD and HPLC.

[0112] HPLC: No appreciable HPLC purity decrase is observed after 7 days under all conditions (see Table 16).

[0113] XRPD: No solid form change is observed after 7 days under all conditions (see Table 16 and Figure 13).

[0114] No form change is observed under long-term, accelerated, and high-temperature conditions.Table 16.

[0115] In Figure 13, XRPD patterns are from top to bottom:60°C, 7 days (top)40°C / 75% RH, 7 days 25°C / 60% RH, 7 days before solid-state stability test (bottom).Example 23 - Hygroscopicity

[0116] A DVS isotherm of Crystalline Form 2 from Example 16 is collected at 25°C (Figure 11). For the 0-90% RH adsorption curve, Crystalline Form 2 absorbs 0.08% moisture at 80% RH. Crystalline Form 2 is non-hygroscopic (Chinese Pharmacopoeia 2020: water uptake under the condition of 25°C / 80%RH: <0.2% for non-hygroscopic) with no solid change post DVS (see see XRPD patterns in Figure 14 in which top XRPD pattern is before DVS and bottom XRPD pattern is after DVS).Example 24 - Synthesis of Crystalline Form 2

[0117] A 30 L reactor is charged with isopropyl acetate (3.9 kg) and Crystalline Form 1 from Example 1 (1.8 kg). The mixture is stirred at 60-65°C to obtain a clear solution. n-Heptane (4.7 kg) is added to the solution at 60-65°C, then the mixture is seeded with Crystalline Form 2 (28 g) and cooled to 5-10°C over 1 hour. The mixture is stirred at 5-10°C for 1 hour. The mixture is concentrated in vacuum and dried at 35-45°C under -0.08 MPa for 18 hours. The solid is micronized by jet mill 8 times to yield Crystalline Form 2 (1.5 kg).Example 25Synthesis of Crystalline Form 2Compound 8: (2S,3R)-l-(dideutero(phenyl)methyl)-2-methylpyrrolidin-3-ol7 8

[0118] To a 100 L reactor is added THF (12.6 kg) and stirred under N2. The solution is cooled to 0-10°C. IJAID4 (0.9 kg) is added in portions under N2 at 0-10°C. Then a solution of compound 7 (2.8 kg) in THF (24.9 kg) is added dropwise at 0-10°C. After addition, the mixture is heated to 40-45°C and stirred at 40-45°C for 15 hours. The reaction mixture is cooled to 0- 10°C and quenched by addition of 20% aqueous KOH solution (1.5 kg) and H2O (2.6 kg) in turn. The suspension is adjusted to 10-20°C and stirred for 24 minutes, then the mixture is filtered and the filtrate is concentrated in vacuum (-0.09 MPa) at 45-55°C to yield compound 8 (2.5 kg).Compound 9: (2S,3S)-3-azido-l-(dideutero(phenyl)methyl)-2-methylpyrrolidine8 9

[0119] Di chloromethane (32.5 kg) is added to a 100 L reactor and stirred. Compound 8(2.5 kg) and triethylamine (2.6 kg) is added in turn. The inner temperature is adjusted to 0-5°C, then methanesulfonyl chloride (2.2 kg) is added to the reactor at 0-5°C. The inner temperature is adjusted to 15-25°C after addition and the reaction mixture is stirred at 15-25°C for 2 hours. The reaction mixture is adjusted to 10-20°C and quenched with 5% (w / w) NaHCCh solution (16.3 kg), stirred, and separated. The organic phase is stirred with 5% (w / w) NaHCO? solution (16.4 kg) again and then separated. The combined aqueous phases are extracted with dichloromethane (20 kg x 1), stirred, and separated. The combined dichloromethane phases are washed with H2O (15.1 kg x 1), stand, and separate. The organic phase is concentrated at 35-45°C in vacuum (- 0.09 MPa) to yield product as an oil (3.4 kg), which is used directly in the next step.

[0120] N,N-Dimethylformamide (33 kg) and the product from above (3.4 kg) are added to a 100 L reactor in turn and the temperature is adjusted to 10-30°C. Then sodium azide (2.5 kg)is added to the solution at 10-30°C. The reaction mixture is stirred for 18 hours at 80-85°C. The reaction mixture is cooled to 10-20°C, quenched with H2O (76.6 kg), and stirred until it becomes a clear solution. The reaction solution is extracted with ethyl acetate twice (34.6 kg + 34.7 kg), stirred, and separated. The organic phase is concentrated at 35-45°C in vacuum to 4-5 V and methanol is added (10 kg), concentrated to 4-5V. Methanol (9.9 kg) is added to the solution again and concentrated to 4-5 V. The solution of compound 9 in methanol (8.5 kg) is used directly in the next step.Compound 10: (2S,3S)-l-(dideutero(phenyl)methyl)-2-methylpyrrolidin-3-amine9 10

[0121] To the solution of compound 9 in methanol (8.5 kg) is added 10% Pd / C (275 g). The mixture is replaced with N2 for three times and stirred under hydrogen (balloon) at 20-30°C for 24 hours. The reaction mixture is filtered and the filtrate is concentrated at 35-45°C in vacuum to dryness. The concentrate is transferred to a 100 L reactor by ethyl acetate (13.6 kg). To the solution is added 4 mol / L HC1 ethyl acetate solution (2.9 kg) at 20-30°C and the mixture is stirred for 2 hours (solid precipitate). The mixture is filtered. The filter cake is rinsed with ethyl acetate (2.2 kg) and the filter cake is dried under vacuum at 45-55°C for 24 hours. The solid (2 kg) and ethyl acetate (18.2 kg) are added to a reactor and heated to 45-50°C under N2. The mixture is stirred at 45-55°C for 1 hour, then adjusted to 10-20°C and stirred for 0.5 hour. The mixture is filtered, then the filter cake is rinsed with ethyl acetate (1.8 kg) and dried in vacuum at 45-50°C for 16 hours to yield compound 10 as the hydrochloride salt (2 kg).Compound 13: 4-(tert-Butoxycarbonyl(trideuteromethyl)amino)-5-chloro-2- methoxybenzoic acid

[0122] To a 100 L reactor is added THF (15.6 kg), compound 12 (3.5 kg), and H2O (17.4 kg) in turn and the mixture is stirred. The temperature is then adjusted to 15-25°C. Lithium hydroxide monohydrate (875 g) is added to the reaction and stirred for 2-3 hours. The pH of the reaction mixture is adjusted to 3 with 1 mol / L HC1 aqueous solution. Ethyl acetate (15.9 kg) is added to the mixture, stirred, and separated. The aqueous phase is extracted with ethyl acetate twice (16 kg + 16 kg), stand, and separate. The organic phases are combined, washed with saturated sodium chloride solution (52.6 kg x 1), stand, and separate. The organic phase is concentrated in vacuum (-0.09 MPa) at 35-45°C to dryness to yield compound 13 (3.3 kg).Compound 14:

[0123] To a 100 L reactor is added N,N-dimethylacetamide (9.2 kg). Compound 13 (2.7 kg), HOBt (1.4 kg), and l-ethyl-3-(3-dimethylaminopropyl)carbodiimide EDCI (2 kg) are added in turn at 10-20°C and stirred for 0.5 hours. Then compound 10 as the hydrochloride salt (2 kg) and triethylamine (2.6 kg) are added to the reaction mixture in turn and stirred at 10-20°C under N2 for 4 hours. The reaction mixture is added to pre-cooled H2O (0-5°C, 39.2 kg), the inner temperature is controlled below 30°C. The mixture is extracted with ethyl acetate 3 times (35.5 kg + 8.9 kg + 9 kg), stirred, and separated. The organic phases are combined and washed sequentially with saturated NaCl solution (26.2 kg), 1 mol / L NaOH solution (20.4 kg), saturated NaCl solution (26.3 kg), stand, and separate. The organic phase is concentrated in vacuum to 1- 2V at 35-45°C. Then n-heptane (2.7 kg) is added to the mixture and concentrated to 1-2V. n- Heptane (2.7 kg) is added to the mixture and concentrated to dryness. Then n-heptane (6.8 kg) isadded to the concentrate and stirred at 20-30°C for 2 hours. The mixture is filtered and the filter cake is rinsed with n-heptane (1.4 kg).

[0124] The filter cake and tert-butyl methyl ether (2.2 kg) are added to the reactor and heated to 40-45°C, then n-heptane (5.3 kg) is added dropwise to the reactor over 1 hour. The mixture is cooled to 10-20°C and stirred for 1 hour. The mixture is filtered and the filter cake is rinsed with n-heptane (1.4 kg).

[0125] The filter cake and tert-butyl methyl ether (2.2 kg) are added to the reactor and heated to 40-45°C, then n-heptane (5.3 kg) is added dropwise to the reactor over 3.5 hours. The mixture is cooled to 10-20°C and stirred for 1 hour. The mixture is filtered, then the filter cake is rinsed with n-heptane (1.3 kg). The filter cake is dried at 35-45°C under -0.09 MPa for 1 hours to yield compound 14 (3.3 kg).Compound 15: 5-chloro-A-((2S,3S)-l-(dideutero(phenyl)methyl)-2-methylpyrrolidin-3-yl)- 2-methoxy-4-(trideuteromethylamino)benzamide (Crystalline Form 2)Boc1415

[0126] A 100 L reactor is charged with ethyl acetate (14.5 kg) and compound 14 (3.2 kg). The mixture is stirred to obtain a clear solution. The solution is added to 4 mol / L hydrochloride ethyl acetate solution (30 kg) at 15-25°C. The reaction mixture is stirred at 15-25°C for 12 hours. The temperature of the mixture is adjusted to 0-10°C. The mixture is extracted with H2O twice (25.6 kg + 25.1 kg) to dissolve oil phase. The aqueous phases are combined and cooled to 5- 10°C. Then 10% (w / w) NaOH solution (15.8 kg) is added to the aqueous phase and stirred at 5- 10°C for 8 hours. A solid precipitates. The mixture is filtered and washed with H2O (3.2 kg). The filter cake and dichloromethane (33.9 kg) are added to a reactor and adjusted to pH >10 with 5% (w / w) NaOH solution at 15-25°C, stirred, and separated. The alkaline aqueous phase is extracted with dichloromethane (33.7 kg) again, stand, and separate. The combined organic phases are concentrated at 35-45°C under -0.09 MPa to yield crude compound 15.

[0127] The crude product is dissolved in isopropyl acetate (22.2 kg) at 30-35°C and stirred until the mixture becomes a clear solution. H2O (3.4 kg) is added to the solution, stirred,and separated. The aqueous phase is extracted with isopropyl acetate (2.3 kg) again, stirred, and separated. The organic phases are combined and decolored with activated carbon (0.2 kg) at 30- 35°C for 1 hour. Then the mixture is filtered and the filtrate is concentrated under vacuum to dryness at 35-45°C. Isopropyl acetate (3.4 kg) is added to the concentrate and heated to 60-65° until solid dissolves to a clear solution. n-Heptane (5.4 kg) is added to the solution, then the mixture is cooled to 5-10°C over 1.5 hours and then stirred at 5-10°C for 2 hours. The mixture is filtered and washed with n-heptane (1.2 kg). The wet filter cake is dried at 35-45°C under -0.09 MPa for 18 hours. The solid is micronized by jet mill for nine times to yield compound 15 (1.2 kg). XRPD shows the product is Crystalline Form 2.

Claims

1. CLAIMSWhat is claimed:

1. A crystalline form of Formula I:Formula I, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising at least three 2-theta (°) values selected from the group consisting of 7.7, 10.6, 12.5, 14.5, 15.5, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.8, 23.5, 23.8, 24.5, 26.0, and 28.2, wherein the XRPD is obtained using Cu Ka radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; an XRPD pattern comprising at least three d-spacing (A) values selected from the group consisting of 11.4, 8.3, 7.1, 6.1, 5.7, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.4, and 3.2; an XRPD pattern comprising at least three 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 15.1, 15.7, 16.3, 18.0, 19.9, 20.4, 22.1, 22.7, 26.1, 27.7, and 28.9, wherein the XRPD is obtained using Cu Ka radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least three d-spacing (A) values selected from the group consisting of 12.7, 8.7, 6.7, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.0, 3.9, 3.4, 3.2, and 3.1.

2. The crystalline form of Formula I according to claim 1, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising at least three 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 15.1, 15.7, 16.3, 18.0, 19.9, 20.4, 22.1, 22.7, 26.1, 27.7, 28.9, 31.1, and 32.8, wherein the XRPD is obtained using Cu Ka radiation wavelength of1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least three d-spacing (A) values selected from the group consisting of 12.7, 8.7, 6.7, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.0, 3.9, 3.4, 3.2, 3.1, 2.9, and 2.7.

3. The crystalline form of Formula I according to claim 1, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising at least five 2-theta (°) values selected from the group consisting of 7.7, 10.6, 12.5, 14.5, 15.5, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.8, 23.5, 23.8, 24.5, 26.0, and 28.2, wherein the XRPD is obtained using Cu Koc radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least five d-spacing (A) values selected from the group consisting of 11.4, 8.3, 7.1, 6.1, 5.7, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.4, and 3.2.

4. The crystalline form of Formula I according to claim 1 or 3, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising at least ten 2-theta (°) values selected from the group consisting of 7.7, 10.6, 12.5, 14.5, 15.5, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.8, 23.5, 23.8, 24.5, 26.0, and 28.2, wherein the XRPD is obtained using Cu Koc radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least ten d-spacing (A) values selected from the group consisting of 11.4, 8.3, 7.1, 6.1, 5.7, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.4, and 3.2.

5. The crystalline form of Formula I according to any one of claims 1, 3, or 4, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising 2-theta (°) values of 7.7, 10.6, 12.5, 14.5, 15.5, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.8, 23.5, 23.8, 24.5, 26.0, and 28.2, wherein the XRPD is obtained using Cu Koc radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; andan XRPD pattern comprising d-spacing (A) values of 11.4, 8.3, 7.1, 6.1, 5.7, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 3.9, 3.8, 3.7, 3.6, 3.4, and 3.2.

6. The crystalline form of Formula I according to claim 1, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising at least five 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 15.1, 15.7, 16.3, 18.0, 19.9, 20.4, 22.1, 22.7, 26.1, 27.7, and28.9, wherein the XRPD is obtained using Cu Ka radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least five d-spacing (A) values selected from the group consisting of 12.7, 8.7, 6.7, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.0, 3.9, 3.4, 3.2, and 3.1.

7. The crystalline form of Formula I according to claim 1 or 6, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising at least ten 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 15.1, 15.7, 16.3, 18.0, 19.9, 20.4, 22.1, 22.7, 26.1, 27.7, and28.9, wherein the XRPD is obtained using Cu Ka radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least ten d-spacing (A) values selected from the group consisting of 12.7, 8.7, 6.7, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.0, 3.9, 3.4, 3.2, and 3.1.

8. The crystalline form of Formula I according to any one of claims 1, 6, or 7, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising 2-theta (°) values of 6.9, 10.1, 13.2, 15.1, 15.7, 16.3, 18.0,19.9, 20.4, 22.1, 22.7, 26.1, 27.7, and 28.9, wherein the XRPD is obtained using Cu Ka radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising d-spacing (A) values of 12.7, 8.7, 6.7, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.0, 3.9, 3.4, 3.2, and 3.1.

9. The crystalline form of Formula I according to claim 1, wherein the crystalline form exhibits at least one of:an XRPD pattern comprising at least three 2-th eta (°) values selected from the group consisting of 7.7, 9.7, 10.6, 11.7, 12.5, 14.5, 14.8, 15.5, 16.0, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.5, 22.8, 23.5, 23.8, 24.2, 24.5, 25.4, 26.0, 27.0, 28.2, 28.9, 29.6, 30.0, 30.3, 30.8, 31.0, 31.6, 32.1, 32.8, 33.4, 35.7, and 36.7, wherein the XRPD is obtained using Cu Kot radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; an XRPD pattern comprising at least three d-spacing (A) values selected from the group consisting of 11.4, 9.1, 8.3, 7.5, 7.1, 6.1, 6.0, 5.7, 5.5, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.5, and 2.4; an XRPD pattern comprising at least three 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 14.8, 15.1, 15.7, 16.3, 18.0, 18.2, 19.9, 20.4, 21.4, 22.1,22.7, 26.1, 27.7, 28.9, 31.1, and 32.8, wherein the XRPD is obtained using Cu Koc radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least three d-spacing (A) values selected from the group consisting of 12.7, 8.7, 6.7, 6.0, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.2, 4.0, 3.9, 3.4, 3.2, 3.1, 2.9, and 2.7.

10. The crystalline form of Formula I according to claim 9, wherein the crystalline form exhibits at least one of an XRPD pattern comprising at least five 2-theta (°) values selected from the group consisting of 7.7, 9.7, 10.6, 11.7, 12.5, 14.5, 14.8, 15.5, 16.0, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.5, 22.8, 23.5, 23.8, 24.2, 24.5, 25.4, 26.0, 27.0, 28.2, 28.9, 29.6, 30.0, 30.3,30.8, 31.0, 31.6, 32.1, 32.8, 33.4, 35.7, and 36.7, wherein the XRPD is obtained using Cu Koc radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least five d-spacing (A) values selected from the group consisting of 11.4, 9.1, 8.3, 7.5, 7.1, 6.1, 6.0, 5.7, 5.5, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.5, and 2.4.

11. The crystalline form of Formula I according to claim 9 or 10, wherein the crystalline form exhibits at least one of:an XRPD pattern comprising at least ten 2-theta (°) values selected from the group consisting of 7.7, 9.7, 10.6, 11.7, 12.5, 14.5, 14.8, 15.5, 16.0, 16.6, 17.3, 18.1, 18.9, 20.0,20.4, 21.5, 22.5, 22.8, 23.5, 23.8, 24.2, 24.5, 25.4, 26.0, 27.0, 28.2, 28.9, 29.6, 30.0, 30.3,30.8, 31.0, 31.6, 32.1, 32.8, 33.4, 35.7, and 36.7, wherein the XRPD is obtained using Cu Kot radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least ten d-spacing (A) values selected from the group consisting of 11.4, 9.1, 8.3, 7.5, 7.1, 6.1, 6.0, 5.7, 5.5, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.5, and 2.

412. The crystalline form of Formula I according to any one of claims 9-11, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising 2-theta (°) values of 7.7, 9.7, 10.6, 11.7, 12.5, 14.5, 14.8,15.5, 16.0, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.5, 22.8, 23.5, 23.8, 24.2, 24.5, 25.4, 26.0, 27.0, 28.2, 28.9, 29.6, 30.0, 30.3, 30.8, 31.0, 31.6, 32.1, 32.8, 33.4, 35.7, and 36.7, wherein the XRPD is obtained using Cu Koc radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising d-spacing (A) values of 11.4, 9.1, 8.3, 7.5, 7.1, 6.1, 6.0, 5.7,5.5, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9,2.8, 2.7, 2.5, and 2.4.

13. The crystalline form of Formula I according to claim 9, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising at least five 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 14.8, 15.1, 15.7, 16.3, 18.0, 18.2, 19.9, 20.4, 21.4, 22.1, 22.7, 26.1, 27.7, 28.9, 31.1, and 32.8, wherein the XRPD is obtained using Cu Koc radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least five d-spacing (A) values selected from the group consisting of 12.7, 8.7, 6.7, 6.0, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.2, 4.0, 3.9, 3.4, 3.2, 3.1, 2.9, and 2.7.

14. The crystalline form of Formula I according to claim 9 or 13, wherein the crystalline form exhibits at least one of:an XRPD pattern comprising at least ten 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 14.8, 15.1, 15.7, 16.3, 18.0, 18.2, 19.9, 20.4, 21.4, 22.1, 22.7, 26.1, 27.7, 28.9, 31.1, and 32.8, wherein the XRPD is obtained using Cu Ka radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least ten d-spacing (A) values selected from the group consisting of 12.7, 8.7, 6.7, 6.0, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.2, 4.0, 3.9, 3.4, 3.2, 3.1, 2.9, and 2.7.

15. The crystalline form of Formula I according to any one of claims 8, 13, or 14, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising 2-theta (°) values of 6.9, 10.1, 13.2, 14.8, 15.1, 15.7, 16.3, 18.0, 18.2, 19.9, 20.4, 21.4, 22.1, 22.7, 26.1, 27.7, 28.9, 31.1, and 32.8, wherein the XRPD is obtained using Cu Ko. radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising ten d-spacing (A) values of 12.7, 8.7, 6.7, 6.0, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.2, 4.0, 3.9, 3.4, 3.2, 3.1, 2.9, and 2.7.

16. The crystalline form of Formula I according to claim 1, wherein the crystalline form exhibits at least one of: an XRPD pattern comprising at least three or at least five or at least ten or all 2-theta (°) values selected from the group consisting of 7.7, 9.7, 10.6, 11.7, 12.5, 14.5, 14.8, 15.5, 16.0, 16.6, 17.3, 18.1, 18.9, 20.0, 20.4, 21.5, 22.5, 22.8, 23.5, 23.8, 24.2, 24.5, 25.4, 26.0, 27.0, 28.2, and 28.9, wherein the XRPD is obtained using Cu Ka radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; an XRPD pattern comprising at least three or at least five or at least ten or all d-spacing (A) values selected from the group consisting of 11.4, 9.1, 8.3, 7.5, 7.1, 6.1, 6.0, 5.7, 5.5, 5.3, 5.1, 4.9, 4.7, 4.4, 4.3, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, and 3.1; an XRPD pattern comprising at least three or at least five or at least ten or all 2-theta (°) values selected from the group consisting of 6.9, 10.1, 13.2, 14.8, 15.1, 15.7, 16.3, 18.0, 18.2, 19.9, 20.4, 21.4, 22.1, 22.7, 26.1, 27.7, and 28.9, wherein the XRPD is obtainedusing Cu Kot radiation wavelength of 1.54 A and each of the 2-theta (°) values of the XRPD pattern have an acceptable deviation of ± 0.2°; and an XRPD pattern comprising at least three or at least five or at least ten or all d-spacing (A) values selected from the group consisting of 12.7, 8.7, 6.7, 6.0, 5.9, 5.6, 5.4, 4.9, 4.5, 4.4, 4.2, 4.0, 3.9, 3.4, 3.2, and 3.1.

17. A crystalline form of Formula I, wherein the crystalline form exhibits an XRPD pattern corresponding to Figure 2.

18. A crystalline form of Formula I, wherein the crystalline form exhibits an XRPD pattern corresponding to Figure 5.

19. A pharmaceutical composition, wherein the pharmaceutical composition comprises a crystalline form of Formula I according to any one of claims 1-18 and a pharmaceutically acceptable carrier.

20. A method for treatment of a brain disorder in a patient in need thereof, wherein the method comprises administering to the patient the crystalline form of Formula I according to any one of claims 1-18 or the pharmaceutical composition according to claim 19.

21. The method according to claim 20, wherein the disorder is an affective disorder or an anxiety disorder.

22. The method according to claim 20, wherein the disorder is depression, an anxiety disorder, psychosis, schizophrenia, schizoaffective disorder, post-traumatic stress disorder (PTSD), attention-deficit / hyperactivity disorder (ADHD), Tourette syndrome, anorexia nervosa, bulimia nervosa, binge-eating disorder, body dysmorphic disorder, obsessive compulsive disorder, addiction, bipolar disorder, or a migraine.

23. The method according to claim 22, wherein the anxiety disorder is panic disorder, social anxiety disorder, a phobia, or generalized anxiety disorder.

24. The method according to claim 20, wherein the disorder is anhedonia, depression associated with anhedonia, suicidal ideation, anxious depression, inflammatory depression, treatment-resistant depression, dysthymia, bipolar depression, psychotic depression, or post-psychotic depression.

25. The method according to claim 20, wherein the disorder is depression associated with anhedonia.

26. The method according to claim 20, wherein the disorder is anhedonia.

27. The method according to claim 20, wherein the disorder is melancholic depression.

28. The method according to claim 20, wherein the disorder is major depressive disorder.

29. The method according to claim 20, wherein the disorder is a substance use disorder.

30. The crystalline form of Formula I according to any one of claims 1-18 or a pharmaceutical composition according to claim 19, for use in the treatment of a brain disorder.

31. Use of a crystalline form of Formula I according to any one of claims 1-18 in the manufacture of a medicament for treatment of a brain disorder.

32. The use according to claim 30 or 31, wherein the brain disorder is as recited in any of claims 21-20.

33. A process for preparing the pharmaceutical composition according to claim 19, wherein the process comprises mixing the crystalline form of Formula I according to any one of claims 1-18 and a pharmaceutically acceptable carrier.

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