TW202434570A - Solid and co-crystal forms of a pyrimidine triazole compound - Google Patents

Abstract

The present disclosure relates to crystalline and amorphous forms of N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, cocrystals, pharmaceutical compositions, and preparations thereof.

Description

Solid and co-crystal forms of pyrimidinetriazole compounds

The present disclosure relates to crystalline polymorphs and amorphous forms of N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and co-crystals thereof for use in the treatment of peripheral and neurodegenerative diseases, including Parkinson's disease.

Cross-reference to related applications

This application claims the benefit of U.S. Provisional Application No. 63/422,339, filed on November 3, 2022, pursuant to 35 U.S.C. §119(e), which is incorporated by reference in its entirety.

Combined genetic and biochemical evidence suggests that certain kinases function in the pathogenesis of neurodegenerative diseases (Christensen, K.V. (2017) Progress in medicinal chemistry 56:37-80; Fuji, R.N. et al. (2015) Science Translational Medicine 7(273):273ra15; Taymans, J.M. et al. (2016) Current Neuropharmacology 14(3):214-225). Kinase inhibitors are being studied for the treatment of Alzheimer’s disease, Parkinson’s disease, ALS, and other diseases (Estrada, A.A. et al. (2015) J. Med. Chem. 58(17): 6733-6746; Estrada, A.A. et al. (2013) J. Med. Chem. 57:921-936; Chen, H. et al. (2012) J. Med. Chem. 55:5536-5545; Estrada, A.A. et al. (2015) J. Med. Chem. 58:6733-6746; Chan, B.K. et al. (2013) ACS Med. Chem. Lett. 4:85-90; US 8354420; US 8569281; US8791130; US 8796296; US 8802674; US 8809331; US 8815882; US 9145402; US 9212173; US 9212186; US 9932325; US 10590114; US 11111235; and WO 2012/062783.

Multiple crystalline forms of a drug substance with different solid-state properties may show differences in bioavailability, shelf life, physicochemical properties including melting point, crystal morphology, intrinsic dissolution rate, solubility and stability, and properties during processing. X-ray powder diffraction (XRPD) is a powerful tool for identifying different crystalline phases through unique diffraction patterns. Other techniques such as solid-state nuclear magnetic resonance NMR spectroscopy, Raman spectroscopy, DSC (differential scanning calorimetry) can also be used.

The pharmaceutical industry is often faced with the phenomenon of multiple polymorphs of the same crystalline chemical entity. Polymorphism is generally characterized by the ability of a drug substance (i.e., active pharmaceutical ingredient (API)) to exist in two or more crystalline phases with different molecular arrangements and/or configurations in the crystal lattice, thereby imparting different physicochemical properties to the crystal. The ability to reliably produce selected polymorphic forms is a key factor in consistent drug product performance.

Regulatory agencies around the world require that reasonable measures be taken to identify polymorphs of APIs and to check for polymorphic interconversion. Because polymorphs often behave in unpredictable ways and have different physical and chemical properties, it is important to demonstrate consistent manufacturing between batches of the same product. A proper understanding of the polymorphic state and properties of pharmaceutical polymorphs will aid in consistent manufacturing.

Atomic-level crystal structure determination and intermolecular interactions provide important information for establishing absolute configuration (mirror isomers), phase identification, quality control, and process development control and optimization. X-ray diffraction is widely regarded as a reliable tool for pharmaceutical solid crystal structure analysis and crystal form identification.

Single crystals of the API are preferred due to the speed and accuracy of structure determination. However, it is not always possible to obtain crystals of a size suitable for data collection. Synchrotron X-ray powder diffraction is a useful technique. In these cases, the crystal structure can be solved from X-ray powder diffraction data obtained by measurements under ambient conditions and/or at varying temperature or humidity.

There is a need in the industry to develop new polymorphic forms and co-crystals of drug substances and methods for their preparation.

The present disclosure relates to crystalline, amorphous and co-crystal forms of the LRRK2 inhibitor N ² -(3-(2-( 2H -1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl- 1H -pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, which is referred to herein as a compound of Formula I and has the following structure: I.

In one embodiment, a crystalline compound of Formula I is provided, which is selected from: Form A polymorph, which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 12.3, 13.8, 15.7, 18.7, 22.1 and 22.6; and Form B polymorph, which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 8.0, 9.9, 16.1, 19.9 and 23.2.

In some embodiments, a Form A polymorph of Formula I is provided that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 12.3, 13.8, 15.7, 18.7, 22.1, and 22.6. In other embodiments, the Form A polymorph further comprises peaks at approximately 5.4 and 7.4 degrees 2θ.

In some embodiments, differential scanning calorimetry (DSC) of the Form A polymorph shows a melting endotherm with an onset at about 107.1 °C.

In some embodiments, the Form A polymorph is an anhydrate.

In some embodiments, the Form A polymorph is characterized by the X-ray powder diffraction pattern shown in FIG. 2 .

In other embodiments, a Form B polymorph of Formula I is provided which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 8.0, 9.9, 16.1, 19.9 and 23.2.

In some embodiments, a crystalline compound of Formula I is provided in substantially pure form. In other embodiments, a co-crystal thereof of Formula I is provided in substantially pure form.

In some embodiments, the X-ray powder diffraction pattern of the crystalline compound or co-crystal of Formula I is obtained using CuKα1 irradiation.

In some embodiments, a crystalline compound of N ² -(3-(2-( 2H- 1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl- 1H -pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine is provided which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed as ± 0.3 degrees 2θ at approximately 12.3, 13.8, 15.7, 18.7, 22.1 and 22.6.

In some embodiments, a pharmaceutical composition is provided, comprising a crystalline polymorph of Formula I and a pharmaceutically acceptable carrier, glidant, diluent or excipient. In some embodiments, the crystalline polymorph is Form A.

In some embodiments, an amorphous compound, an amorphous form of ^CN2- (3-(2-( 2H- 1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl- 1H -pyrazol-5-yl) ^-N4 -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine is provided.

In some embodiments, a pharmaceutical composition is provided, which comprises an amorphous compound of Formula I and a pharmaceutically acceptable carrier, glidant, diluent or excipient.

In some embodiments, a process is provided for preparing amorphous Form C of compound N ² -(3-(2-( 2H- 1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl- 1H -pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine, comprising heating a crystalline form of the compound until dissolved, followed by cooling to form an amorphous compound.

In some embodiments, provided are co-crystals comprising N ² -(3-(2-(2 H -1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1 H -pyrazol-5-yl)- N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and co-constructs, and hydrates thereof.

In some embodiments, a pharmaceutical composition is provided, comprising a co-crystal of Formula I and a pharmaceutically acceptable carrier, glidant, diluent or excipient.

In some embodiments, a process for preparing a co-crystal of any one of Formula I is provided, comprising contacting N ² -(3-(2-(2 H -1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1 H -pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine with a co-construct.

In some embodiments, the co-construct is selected from 4-acetamidobenzoic acid, acetylsalicylic acid, trans-aconic acid, adipic acid, benzoic acid, butyric acid, cholic acid, gallic acid, glutaric acid, fumaric acid, 4-hydroxybenzoic acid, isobutyric acid, malonic acid, D,L-mandelic acid, propionic acid, salicylic acid, succinic acid, terephthalic acid, and vanillic acid. Definition

Unless otherwise defined, technical and scientific terms used herein have the same meanings as those commonly understood by persons skilled in the art to which the present invention belongs, and are consistent with the following:

When used in this specification and the patent application, the terms "comprise", "comprising", "include", "including" and "includes" are intended to specify the existence of stated features, integers, components or steps, but they do not exclude the existence or addition of one or more other features, integers, components, steps or groups thereof.

As used herein, the terms "about" or "approximately" when used in reference to X-ray powder diffraction pattern peak positions refer to the inherent variability of the instrument used, such as the calibration of the equipment used, the process used to produce the polymorph, the age of the crystallized material, and the like. In this case, the measurement variability of the instrument is about plus/minus ± 0.3 degrees 2θ (θ). Unless otherwise stated, those skilled in the art who have the benefit of this disclosure will understand the use of "about" or "approximately" herein (e.g., ± 0.05 degrees 2θ). The terms "about" or "approximately" when referring to other defined parameters (e.g., water content, _Cmax , _tmax , AUC, intrinsic dissolution rate, temperature, and time) indicate the inherent variability in, for example, measuring the parameter or arriving at the parameter. Those skilled in the art having the benefit of this disclosure will appreciate the variability of parameters as implied by the use of the terms about or approximately.

As used herein, "polymorph" refers to the occurrence of different crystalline forms of a compound with different packing or configuration/configuration but the same chemical composition. Crystalline forms have different molecular arrangements and/or configurations in the crystal lattice. Solvosomes are crystalline forms containing stoichiometric or non-stoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is usually called a hydrate. For compounds with the same solvent content but different lattice packing or configuration, hydrates/solvosomes can exist as polymorphs. Therefore, a single compound can produce multiple polymorphic forms, each of which has different and distinct physical properties, such as solubility profile, melting point temperature, hygroscopicity, particle shape, morphology, density, fluidity, compressibility and/or X-ray diffraction peaks. Each polymorph may differ in solubility, therefore, identifying the presence of drug polymorphs is critical to providing a drug with a predictable solubility profile. It is desirable to characterize and study all solid forms of a drug, including all polymorphs, and to determine the stability, dissolution, and flow properties of each polymorph. Polymorphic forms of a compound can be distinguished in the laboratory by X-ray diffraction and other methods such as infrared or Raman or solid state NMR spectroscopy. For a general overview of polymorphs and their pharmaceutical applications, see G. M. Wall, Pharm Manuf. 3:33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58:911 (1969); "Polymorphism in Pharmaceutical Solids, 2nd ed. (Drugs and the Pharmaceutical Sciences)", edited by Harry G. Brittain (2011) CRC Press (2009); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.

The acronym "XRPD" refers to X-ray powder diffraction, an analytical technique that measures X-ray diffraction in the presence of solid components and displays the X-ray diffraction pattern. X-ray diffraction patterns can be produced using CuKα1 radiation. Materials that are crystalline and have a regularly repeating array of atoms produce a unique powder pattern. Materials with similar unit cells will produce X-ray diffraction patterns that are similar in position (measured in °2θ (θ)). Solvates that exhibit this property are called isostructural or isomorphous solventates. The intensity of the reflections varies depending on the electron density causing the diffraction as well as the sample, sample preparation and instrument parameters. Analysis of XRPD data is based on the overall appearance of the measured powder pattern relative to the known reactivity of the X-ray diffraction system used to collect the data. The position, shape, width, and relative intensity distribution of diffraction peaks that may be present in the powder pattern can be used to characterize the type of solid-state order in the powder sample. The position, shape, and intensity of any extensive diffuse scattering (halo) on top of the instrumental background can be used to characterize the level and type of solid-state disorder. The combined interpretation of the solid-state order and disorder present in a powder sample provides a qualitative measure of the sample’s macrostructure.

The term "co-crystal" refers to a crystalline molecular complex composed of two or more different molecular compounds, usually in stoichiometric ratios, which are neither solvates nor pure salts. Co-crystals consist of hydrogen-bonded complexes with "pharmaceutically acceptable" co-structures (Aitipamula, S. et al. (2012) Cryst. Growth Des. 12(5):2147–2152). Coconstructs include, but are not limited to, acetylsalicylic acid, trans-aconic acid, adipic acid, L-ascorbic acid, benzoic acid, citric acid, fructose, fumaric acid, gallic acid, glucose, glutaric acid, hippuric acid, 4-hydroxybenzoic acid, maleic acid, malonic acid, mannitol, niacinamide, niacin, phenylalanine, riboflavin, salicylic acid, succinic acid, and vanillic acid.

The term "hydrate" refers to a complex in which the solvent molecule is water. The abbreviation "RH" refers to relative humidity Compounds of Formula I

The present disclosure includes polymorphs, co-crystals and amorphous forms of the compound of Formula I (CAS Reg. No. 2170179-24-3), which has the following structure: I and named: N ² -(3-(2-(2 H -1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1 H -pyrazol-5-yl)-N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (WO 2017/218843, US 9932325, each of which is incorporated by reference). Preparation of compounds of formula I

2- Methyl -2-( 2H- 1,2,3- triazol -2- yl ) propionic acid methyl ester: To a mixture of 2H -1,2,3-triazole (190 g, 2.75 mol) in THF (800 mL) was added t -BuOK (339.54 g, 3.03 mol) at 0 °C and then stirred for 1 h. Then 2-bromo-2-methyl-propionic acid methyl ester (547.62 g, 3.03 mol) was added dropwise at 0 °C within 1 h and then the mixture was stirred at 25 °C for 2 h. The mixture was poured into ice water (2 L) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 × 800 mL). The combined organic phases were washed with brine (4 × 500 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO ₂ , PE:EtOAc = 100:1 to 1:1) to give methyl 2-methyl-2-(2 H -1,2,3-triazol-2-yl)propanoate (245 g, 26.3%) as a yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ): δ 7.69 (s, 2 H), 3.74 (s, 3 H), 1.99 (s, 6 H).

4- Methyl -3- oxo -4-( 2H- 1,2,3- triazol -2- yl ) pentanenitrile : To a mixture of MeCN (36.9 g, 898.5 mmol) in THF (1.00 L) at -78 °C under N2 was added n-BuLi (2.5 M in THF, 359.4 mL) dropwise and stirred for 1 h. Then methyl ₂ -methyl-2-( 2H- 1,2,3-triazol-2-yl)propanoate (76 g, 449.2 mmol) in THF (500 mL) was added dropwise at -78 °C over 1 h and the reaction was then stirred at -78 °C for 1.5 h. The mixture was poured into ice water (1 L) and stirred for 5 min. The pH of the mixture was adjusted to 4-5 by aqueous HCl (2 M), and the aqueous phase was extracted with EtOAc (3 × 800 mL). The combined organic phases were washed with brine (800 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude product, which was washed with MTBE (500 mL) and filtered to give 4-methyl-3-oxo-4-(2 H -1,2,3-triazol-2-yl)pentanenitrile (130 g, 81.2%) as a purple solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.38 (s, 2 H), 3.11 (s, 2 H), 1.90 (s, 6 H).

3-(2-( 2H -1,2,3 - triazol - 2- yl ) propan - 2- yl )-1- cyclopropyl - 1H - pyrazol - 5- amine: To a mixture of 4-methyl-3-oxo-4-( 2H- 1,2,3-triazol-2-yl)pentanenitrile (45 g, 252.5 mmol) and cyclopropylhydrazine dihydrochloride (54.9 g, 378.8 mmol) in EtOH (1 L) at 25 °C under N2 was added concentrated HCl (12 M, 9.03 mL) in one portion. The mixture was stirred at 90 °C for 10 h. _Aqueous NaHCO3 solution was added to the mixture and the pH was adjusted to 7-8. The aqueous phase was extracted with EtOAc (3 × 300 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (SiO ₂ , PE:EtOAc = 100:1 to 1:1) to give 3-(2-(2 H -1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1 H -pyrazol-5-amine (42 g, 71.6%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.6 (s, 2 H), 5.05 (s, 1 H), 3.72 (br s, 2 H), 3.14-3.09 (m, 1 H), 2.05 (s, 6 H), 1.14-1.12 (m, 2 H), 1.04-1.01 (m, 2H).

N ² -(3-(2-( 2H- 1,2,3 - triazol - 2-yl)propan-2- yl ) -1 - cyclopropyl - 1H - pyrazol - 5- yl )- N ⁴ -ethyl -5-( trifluoromethyl ) pyrimidine -2,4- diamine: To a mixture of 3-(2-( 2H- 1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl- 1H -pyrazol-5-amine (42 g, 180.8 mmol) and 2-chloro- N -ethyl-5-(trifluoromethyl)pyrimidin-4-amine (40.8 g, 180.8 mmol) in 1,4-dioxane (840 mL) was added TsOH.H ₂ O (4.1 g, 21.7 mmol) in one portion at 25 °C under N 2. The mixture was stirred at 90 °C for 10 h. The mixture was poured into an aqueous NaHCO ₃ solution (1500 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (3 × 600 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purification by silica gel chromatography (SiO ₂ , PE:EtOAc=100:1 to 3:1) and washed with MTBE gave a crude product (72 g). 70 g of the product was suspended in n-heptane (250 mL) and heated to 70°C with stirring. MTBE (210 mL) was added to the solution in portions at 70°C until the solid dissolved. The hot solution was filtered. The filtrate was cooled to room temperature and allowed to stand for 16 h. The obtained crystals were filtered and washed with a small amount of n-heptane to obtain

N ² -(3-( 2- (2 H -1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1 H -pyrazol-5-yl)- N ⁴ -ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (64 g, 47.03%) was obtained as a yellow solid. ¹ H NMR (400 MHz, CDCl3): δ ppm 8.13 (s, 1 H), 7.62 (s, 2 H), 7.29 (br s, 1 H), 6.12 (s, 1 H), 5.18 (br s, 1 H), 3.37 - 3.47 (m, 2 H), 3.23 (tt, J=6.95, 3.59 Hz, 1 H), 2.10 (s, 6 H), 1.17 - 1.26 (m, 5 H), 1.08 - 1.16 (m, 2 H). MS: (M+H ⁺ ) m/z : 422.2. Polymorph Screening of Compound I

Polymorph screening experiments were performed using a variety of crystallization or solid transformation methods, including: anti-solvent addition, slow evaporation, slow cooling, room temperature slurrying, slurry cycling, solid vapor diffusion, liquid vapor diffusion, polymer-induced crystallization, and melt/cooling. By these methods, Form A, Form B, and Form C were identified.

As shown in Figure 1, Form A was found to be a stable crystalline form and could be converted to a mixture of Form A and Form B by crystallization from cyclohexane and methyl isobutyl ketone (MIBK). After one month at room temperature, the mixture reverted to Form A. Form A was heated to 110 ^° C and then cooled to -20 ^° C to form amorphous Form C, which converted back to Form A when warmed to room temperature.

The 24-hour solubility assessment showed that Form A has a solubility of 29.9 μg/mL in water. DVS (dynamic vapor sorption) results showed that Form A is not hygroscopic, as defined by a reversible water uptake of less than 0.2% (Table 1). Table 1. form TGA (wt loss%) DSC ( starting) Crystal form Hygroscopicity Enthalpy (J/g) Form A 0.05% (to 100 ºC) 107.1 ºC Anhydrous Non-hygroscopic 95.2 Polymorph Screening

A total of 70 polymorph screening experiments were performed using different crystallization or solid state transformation methods. The methods used and the crystal forms identified are summarized in Table 2 below. Table 2. method Number of experiments Identified crystal form Antisolvent addition 14 Form A, Form A + Form B Slow evaporation 8 Form A Slow cooling 5 Form A, gel Pulping at room temperature 15 Form A Circulation pulping 8 Form A Solid vapor diffusion 7 Form A, gel Liquid vapor diffusion 9 Form A Polymer Induced Crystallization 4 Form A Total 70 Form A, Form A + Form B, Gel Antisolvent addition

A total of 14 anti-solvent addition experiments were performed. About 20 mg of the compound of formula I was dissolved in 0.1-0.7 mL of solvent to obtain a clear solution, and the solution was stirred magnetically, and then 0.1 mL of anti-solvent was added at each step until precipitation occurred or the total amount of anti-solvent reached 10.0 mL. The precipitate was separated for XRPD analysis. The results in Table 3 below show that Form A and Form A+Form B were generated. Table 3. Solvent Antisolvent Solid form EtOH n-Heptane Form A* MEK Form A IPA Form A MTBE Form A Toluene Form A MeOH _H2O Form A acetone Form A THF Form A ACN Form A DMSO Form A IPA Cyclohexane Form A* MIBK Form A+Form B* Butyl acetate Form A* CPME Form A* *10 mL of antisolvent was added to the corresponding solution, but a clear solution was obtained and then transferred to evaporate at room temperature. Slow evaporation

Slow evaporation experiments were performed under eight conditions. Approximately 20 mg of the compound of formula I was dissolved in 0.5 mL of solvent in a 3 mL glass vial. If dissolution was not complete, the compound was filtered using a PTFE membrane (pore size 0.45 μm) and the filtrate was used in the subsequent step instead. The visually clear solution was evaporated at room temperature in a vial sealed with ^Parafilm® . The isolated solid was used for XRPD analysis, and the results summarized in Table 4 show that only Form A was found. Table 4. Solvent Solid form EtOH Form A acetone Form A EtOAc Form A 2-MeTHF Form A DCM Form A Toluene Form A ACN/ _H2O (1:1) Form A THF/n-heptane (1:1) Form A Slow cooling

Slow cooling experiments were performed in five different solvent systems. About 20 mg of the compound of formula I was suspended in 0.4-1.0 mL of solvent in a 5 mL vial. The suspension was then heated to 50°C and equilibrated for about 2 hr. If it was not completely dissolved, the compound was filtered using a PTFE membrane (pore size of 0.45 μm). The clear solution was slowly cooled from 50°C to 5°C at a rate of 0.1°C/min. The resulting solid was collected for XRPD analysis. The results summarized in Table 5A show that Form A and a gel were generated. Table 5A. Solvent (v/v) Solid form EtOH/ _H2O (1:4) Gel* MIBK/n-heptane (1:4) Form A IPAc/cyclohexane (1:4) Form A MTBE/n-heptane (1:4) Form A Toluene/cyclohexane (1:4) Form A *After cooling, a clear solution was obtained and then transferred to evaporate at room temperature.

Slurry conversion experiments were performed at room temperature in 15 different solvent systems. Approximately 20 mg of the compound of formula I was suspended in 0.2-0.3 mL of solvent in a 1.5 mL glass vial. After the suspension was magnetically stirred at room temperature for four days, the remaining solid was separated for XRPD analysis. From all experiments, only Form A was generated. Table 5B. Solvent (v/v) Solid form _H2O Form A n-Heptane Form A Cyclohexane Form A EtOH/n-heptane (1:4) Form A MEK/cyclohexane (1:4) Form A EtOAc/cyclohexane (1:9) Form A MTBE/n-heptane (1:4) Form A DCM/cyclohexane (1:4) Form A Toluene/n-heptane (1:4) Form A THF/DMAc/ _H2O (1:1:8) Form A IPAc/1,4-dioxane/n-heptane (1:1:8) Form A IPA/H ₂ O (a _w ~0.2, 98:2) Form A IPA/H ₂ O (a _w ~0.4, 96:4) Form A IPA/H ₂ O (a _w ~0.6, 92:8) Form A* IPA/H ₂ O (a _w ~0.8 85:15) Form A * A clear solution is obtained and then transferred to pulp at 5 °C. Pulping cycle

Slurry cycle experiments were performed in eight different solvent systems. Approximately 25 mg of the compound of Formula I was suspended in 0.2-0.3 mL of solvent in a 1.5 mL glass vial. After magnetic stirring (approximately 1000 rpm) at 70°C for one day, the suspension was transferred to a slurry at 50°C and maintained for three days. The results summarized in Table 5C below show that only Form A was generated. Table 5C. Solvent (v/v) Solid form _H2O Form A n-Heptane Form A Cyclohexane Form A n-BuOH/n-heptane (1:9) Form A MIBK/cyclohexane (1:9) Form A Butyl acetate/n-heptane (1:9) Form A 2-MeTHF/cyclohexane (1:9) Form A ACN/DMSO/H ₂ O (1:1:18) Form A Solid vapor diffusion

Solid vapor diffusion experiments were performed using seven different solvents. Approximately 10 mg of the compound of Formula I was weighed into a 3 mL vial and placed in a 20 mL vial with 4 mL of volatile solvent. The 20 mL vial was sealed with a cap and stored at room temperature for nine days to allow the solvent vapor to interact with the sample. The solid was tested by XRPD and the results summarized in Table 6 below show that Form A and a gel were generated. Table 6. Solvent Solid form _H2O Form A EtOH Form A* acetone Gel* EtOAc Form A* THF Form A* DCM Form A* Cyclohexane Form A * A clear solution was obtained and then transferred to evaporate at room temperature. Liquid vapor diffusion

Nine liquid vapor diffusion experiments were performed. Approximately 20 mg of the compound of Formula I was dissolved in 0.1-0.7 mL of an appropriate solvent to obtain a clear solution in a 3 mL vial. If it was not completely dissolved, the compound was filtered into a new vial. The solution was then placed in a 20 mL vial with 4 mL of a volatile solvent (antisolvent). The 20 mL vial was sealed with a cap and stored at room temperature to allow sufficient time for the antisolvent vapor to interact with the solution. The precipitate was separated for XRPD analysis. The results summarized in Table 7A below show that only Form A was observed. Table 7A Solvent Antisolvent Solid form IPA n-Heptane Form A* acetone Form A EtOAc Form A EtOH _H2O Form A ACN Form A DMSO Form A IPA Cyclohexane Form A 2-MeTHF Form A* Toluene Form A * A clear solution was obtained and then transferred to evaporate the polymer at room temperature to induce crystallization

Polymer induced crystallization experiments were performed using two sets of polymer mixtures in four different solvent systems. Approximately 20 mg of the compound of Formula I was dissolved in 1.0-2.0 mL of the appropriate solvent in a 3 mL glass vial containing approximately 2 mg of the polymer mixture. The clear solution was transferred for evaporation at room temperature. The resulting solid was collected for XRPD characterization. The results summarized in Table 7B below show that only Form A was generated. Table 7B. Solvent polymer Solid form EtOH Mixture A Form A MIBK/n-heptane (1:4) Form A CHCl ₃ Mixture B Form A IPAc/ACN (1:1) Form A

Polymer mixture A: polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyvinyl chloride (PVC), polyvinyl acetate (PVAC), hydroxypropyl methylcellulose (HPMC), methylcellulose (MC) (mass ratio is 1:1:1:1:1:1). Polymer mixture B: polycaprolactone (PCL), polyethylene glycol (PEG), poly(methyl methacrylate) (PMMA), sodium alginate (SA) and hydroxyethyl cellulose (HEC) (mass ratio is 1:1:1:1:1). General method XRPD

XRPD patterns were collected using a PANalytical Empyrean X-ray powder diffraction instrument. The X-ray source was a Cu tube operated at 45 kV and 40 mA. The scan mode was continuous and the divergence slit was automatic. Each sample was analyzed from 3° to 40° 2θ with a step size of 0.0167° 2θ and a scan step time of 18 sec. Table 8. Parameters of XRPD test Parameters Empyrean X-ray wavelength Cu, kα; Kα1 (Å): 1.540598 Kα2 (Å): 1.544426 Intensity ratio Kα2/Kα1: 0.50 X-ray tube settings 45 kV, 40 mA Divergent Slits Automatic Scan Mode Continuous Scanning range (°2θ) 3° ~ 40° Step size (°2θ) 0.0167 Scanning step time(s) 18 Test time(s) 5 min 30 s DSC/TGA

DSC analysis was performed on a TA Instruments Q2000 DSC. The DSC cell was kept under nitrogen purge. The samples were placed in an aluminum curled rim pan and heated from 25°C to 300°C at a rate of 10°C/min.

TGA data were collected using a TA Q500/Q5000 TGA from TA Instruments. TGA was performed using a nitrogen purge gas. Each sample was placed in an open aluminum pan and heated from room temperature to 350°C at a rate of 10°C/min. DSC analysis was performed on a TA Instruments Q200/Q2000 DSC. The DSC cell was maintained under a nitrogen purge. The samples were placed in an aluminum curled rim pan and heated from 25°C to 300°C at a rate of 10°C/min. Table 9. Parameters for TGA and DSC testing Parameters TGA DSC method Ramp Slope method Sample Plate Aluminum, open Aluminum, rolled edge temperature Room temperature -350℃ 25-300 °C Heating rate 10 °C/min 10 °C/min Purge gas N ₂ N ₂ DVS

DVS analysis was performed using an SMS (Surface Measurement Systems) DVS Intrinsic analyzer. Relative humidity at 25°C was calibrated to the deliquesce points of LiCl, Mg(NO3)2, and KCl. Approximately 15-20 mg of sample was loaded into the pan for analysis. A nitrogen flow rate of 200 mL/min was used. Samples were analyzed at 25°C and in the relative humidity (RH) range of 0 to 95% in steps of 10% RH from 0 to 90% RH and 5% RH from 90% to 95% RH. Progression from one step to the next occurred after an equilibrium criterion of 0.002 %/min weight change (dm/dt) was met, or after 180 min if the equilibrium criterion was not met. The minimum dm/dt stability duration for each step is 10 min. Form A Characterization

Form A was characterized by XRPD, TGA, DSC, DVS, and polarized light microscopy (PLM). XRPD (Figure 2, Table 10) showed a highly crystalline structure. TGA indicated low weight loss, and DSC indicated a single sharp melt at around 107°C (Figure 4). DVS showed that Form A was not hygroscopic and did not change form after exposure to humidity. PLM inspection indicated irregular plate-like particles. Based on the characterization results, Form A is an anhydrate form. Table 10. Form A Position [°2θ] Height [cts] FWHM left [°2θ] Lattice spacing [Å] Relative strength [%] 5.421079 292.616100 0.100368 16.30226 9.68 7.417347 224.926700 0.083640 11.91863 7.44 9.212257 464.539300 0.100368 9.60005 15.37 9.714739 699.811200 0.083640 9.10460 23.15 10.529370 592.539400 0.083640 8.40196 19.60 10.851660 541.991200 0.100368 8.15313 17.93 11.138000 268.499100 0.066912 7.94417 8.88 12.422050 1855.240000 0.066912 7.12573 61.38 13.894790 1369.331000 0.100368 6.37359 45.31 14.224000 719.882100 0.083640 6.22681 23.82 14.462850 330.416300 0.083640 6.12451 10.93 14.833930 456.447600 0.083640 5.97213 15.10 15.161300 555.737900 0.100368 5.84390 18.39 15.748080 2080.974000 0.083640 5.62745 68.85 16.276370 385.186400 0.083640 5.44597 12.74 16.443410 242.224700 0.050184 5.39102 8.01 16.861240 550.223000 0.083640 5.25836 18.20 17.072820 744.158800 0.100368 5.19367 24.62 17.302290 530.229200 0.100368 5.12530 17.54 18.340920 713.336700 0.100368 4.83734 23.60 18.819760 2881.377000 0.150552 4.71532 95.33 19.096160 839.291700 0.133824 4.64769 27.77 19.388570 976.708500 0.167280 4.57825 32.32 20.275920 455.813400 0.066912 4.37985 15.08 20.438010 427.424600 0.083640 4.34548 14.14 20.723140 220.927800 0.100368 4.28633 7.31 21.117380 1154.695000 0.117096 4.20719 38.20 21.530200 495.792000 0.066912 4.12745 16.40 21.755420 1232.721000 0.100368 4.08523 40.79 21.999510 850.546000 0.050184 4.04045 28.14 22.141850 3022.416000 0.100368 4.01480 100.00 22.385390 1191.534000 0.083640 3.97167 39.42 22.687480 2621.654000 0.083640 3.91946 86.74 22.979790 961.488300 0.083640 3.87026 31.81 23.465970 1607.096000 0.083640 3.79116 53.17 23.645910 712.008700 0.050184 3.76272 23.56 24.155120 540.993800 0.066912 3.68454 17.90 24.301470 579.326200 0.100368 3.66268 19.17 24.911450 243.123700 0.066912 3.57436 8.04 25.135970 195.778000 0.133824 3.54294 6.48 25.598240 107.599300 0.066912 3.48000 3.56 26.067820 716.321200 0.100368 3.41837 23.70 26.485630 450.658200 0.133824 3.36539 14.91 26.957080 545.243200 0.133824 3.30759 18.04 27.307470 482.697900 0.133824 3.26594 15.97 27.873180 372.340000 0.100368 3.20093 12.32 28.533940 405.375900 0.066912 3.12829 13.41 29.195540 128.013500 0.066912 3.05889 4.24 29.628390 283.333300 0.066912 3.01518 9.37 30.294290 107.314900 0.117096 2.95040 3.55 Stability of Form A

To evaluate the stability of the solid form, Form A was stored at 40°C/75% RH (relative humidity, accelerated) and 25°C/60% RH (long term). Form A showed physical and chemical stability for up to 6 months at 40°C/75% RH and up to 48 months at 25°C/60% RH. The samples were analyzed for appearance, HPLC purity, and polymorphic form. No form changes were detected by XRPD, and no purity changes were observed by HPLC. Table 11. Form A Stability Evaluation Time point condition Appearance XRPD HPLC purity total impurities (%) initial NA Off-white powder Form A 0.4 6 months 40 ºC/75%RH 25 ºC/60%RH Off-white powder Off-white powder Form A Form A 0.3 0.3 48 months 25 ºC/60%RH Off-white powder Form A 0.3 Form A + Form B (mixture)

The Form A + Form B mixture was prepared by adding cyclohexane (anti-solvent) to the methyl isobutyl ketone solution. The Form A + Form B mixture was characterized by XRPD (Figure 3) Table 12. List of diffraction peaks of the Form A + Form B mixture Position [°2θ] Height [cts] FWHM left [°2θ] Lattice spacing [Å] Relative strength [%] 8.040031 647.488100 0.076752 10.99690 100.00 9.178742 103.390800 0.102336 9.63503 15.97 9.931249 76.670200 0.076752 8.90659 11.84 10.509380 124.220600 0.076752 8.41789 19.19 12.362780 358.379600 0.076752 7.15976 55.35 13.814890 125.699200 0.102336 6.41027 19.41 14.191680 91.339680 0.076752 6.24092 14.11 14.403340 79.310290 0.076752 6.14968 12.25 14.830910 156.307800 0.102336 5.97334 24.14 15.159580 132.673000 0.076752 5.84456 20.49 15.709770 114.289400 0.076752 5.64109 17.65 16.127980 170.184600 0.076752 5.49574 26.28 17.051560 133.386000 0.076752 5.20010 20.60 17.285010 110.226500 0.076752 5.13039 17.02 18.788090 188.651000 0.076752 4.72320 29.14 19.053450 150.729300 0.102336 4.65801 23.28 19.429520 60.674270 0.102336 4.56870 9.37 19.914820 83.314620 0.127920 4.45845 12.87 20.746630 45.453600 0.127920 4.28153 7.02 21.130140 111.443400 0.076752 4.20468 17.21 22.169870 117.592900 0.102336 4.00979 18.16 22.666270 225.011500 0.102336 3.92308 34.75 23.234480 126.403500 0.076752 3.82841 19.52 24.256870 61.243640 0.204672 3.66931 9.46 26.293350 18.725340 0.614016 3.38956 2.89 Form C ( amorphous )

Form C (amorphous free base) was prepared by heating Form A at 110 °C until the solid was completely melted and then transferred to -20 °C.

Form C was characterized by XRPD and DSC. The XRPD trace showed a characteristic amorphous halo and no significant diffraction peaks (Figure 6). Single crystal determination of Form A Form A XRPD characterization

Select appropriate single crystals from the bulk crystals and analyze them by single crystal X-ray diffraction (SCXRD). The structure of the single crystal was successfully determined. SCXRD characterization and analysis showed that the crystal system is triclinic and the space group is P , the unit cell parameters and calculated unit cell volume are: a = 10.3230(4) Å, b = 12.7742(6) Å, c = 16.3999(5) Å, α = 83.133(3)º, β = 89.725(3)º, γ = 67.773(4)º, V = 1985.63(14). The formula weight is 421.44 g mol-1, and Z = 4, giving a calculated density of 1.410 g cm-3. Crystal growth procedure

Bulk single crystals of Form A for single crystal X-ray diffraction (SCXRD) characterization were obtained by liquid vapor diffusion from a DMSO and H ₂ O solvent system at room temperature. The PLM image of Form A single crystal is shown in FIG7 . Data Collection

Colorless bulk single crystals selected from the Form A single crystal sample were mounted in a random orientation and immersed in a nitrogen stream at 150 K. Preliminary inspection and data collection were performed on an Agilent SuperNova (dual, Cu below zero, Eos) diffractometer equipped with a SuperNova microfocus X-ray source (Cu/Kα = 1.54184 Å) and an Eos CCD detector, and analyzed using the CrysAlisPro (version: 1.171.38.41) software package. The unit cell constants and orientation matrix for the data collection were obtained from least squares refinement using a set angle of 9816 reflections in the range of 4.3580 ° < θ < 70.5170 °. Data were collected at 150 K to a maximum diffraction angle (2θ) of 141.114 °. The data set is 97.97% complete, with an average I/σ of 27.8 and a D min (Cu) of 0.82 Å. Data reduction

The frames were integrated using CrysAlisPro (version: 1.171.38.41). A total of 14156 reflections were collected, of which 7446 were unique. Lorentz and polarization corrections were applied to the data. The linear absorption coefficient for Cu/Kα radiation was 0.944 mm−1. A semi-empirical absorption correction was performed using spherical harmonic functions (multiple scan method), implemented in the SCALE3 ABSPACK scaling algorithm. The transmission coefficient ranged from 0.95582 to 1.00000. The intensities of the equivalent reflections were averaged. The agreement factor for the average was 1.65% based on the intensity. Single crystal structure solution and refinement

The structure was solved using the Superflip structure solver with Charge Flipping and refined using the ShelXL (version 2014/7) refinement package included in OLEX2 using F2 full matrix least squares. Hydrogen atoms were refined as riding models on the atoms they bond to. Calculated X-ray powder diffraction (XRPD) pattern

For Cu irradiation, the calculated XRPD pattern was generated using the Mercury (Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P., Taylor, R., Towler, M., and van de Streek, J. J. Appl. Cryst. 2006, 39, 453–457) program and the atomic coordinates, space group, and unit cell parameters of the single crystal structure. The calculated XRPD pattern generated from the Form A single crystal structure is consistent with the experimental XRPD pattern. Single crystal structure diagram

Crystal structure representations were generated by Diamond (Brandenburg, K. DIAMOND, 1999, Crystal Impact GbR, Bonn, Germany). Thermoellipse diagrams were generated by ORTEP-III (J. Appl. Cryst. (2012). 45, 849–854). Instruments and parameters

Single crystal X-ray diffraction data were collected at 150 K using an Agilent SuperNova (dual, Cu at subzero, Eos) diffraction instrument (Cu/Kα radiation, λ = 1.54178 Å). Micrographs were captured using a Shanghai Cewei PXS9-T stereo microscope. Table 13. SCXRD instrument parameters Device Agilent SuperNova X-ray source generator SuperNova microfocus X-ray source (Cu/kα: 1.54178 Å) 50KV, 0.8mA Detector Eos CCD detector (detector resolution: 16.0450 pixels mm ^-1 ) Goniometer Four-circle Kappa goniometer Low temperature device Oxford Cryosystems Software CrysAlisPro (Version: 1.171.38.41) Table 14. Crystallographic data and refinement parameters Empirical C ₁₈ H ₂₂ F ₃ N ₉ Formula 421.44 temperature 150K Wavelength Cu/Kα (λ = 1.54184 Å) Crystal system, space group Triclinic system, P Unit cell size a = 10.3230(4) Å b = 12.7742(6) Å c = 16.3999(5) Å α = 83.133(3)º β = 89.725(3)º γ = 67.773(4)º Volume 1985.63(14) Å ³ Z , calculate density 4, 1.410 g/cm ³ Absorption coefficient 0.944 mm ^-1 F (000) 880.0 Crystal size 0.65 × 0.5 × 0.45 mm ³ 2θ range of data collection 7.538° to 141.114° Restriction Index -12 ≤ h ≤ 12 -15 ≤ k ≤ 15 -20 ≤ l ≤ 11 Collected Reflection/Independent Reflection 14156/7446 [R _int = 0.0165, R _σ = 0.0210] Completeness 97.97% Refinement method ^F2 Full Matrix Least Squares Data/Constraints/Parameters 7446/0/548 F2 goodness ^of fit 1.029 Final R index [I ≥ 2σ(I)] _R1 = 0.0336, _wR2 = 0.0868 Final R Index [All Data] _R1 = 0.0365, _wR2 = 0.0892 Maximum difference peaks and holes 0.23/-0.24 e.Å ^-3

The thermoellipsometry of the asymmetric unit molecule of Form A is shown in Figure 5. Table 15. Fractional atomic coordinates (×10 ⁴ ) and equivalent isotropic displacement parameters (Å ² × 10 ³ ) of single crystal of free base Form A (810014-28-A6) . atom x y z U(eq) F4 10340.4(8) 1544.9(6) 3307.2(5) 29.70(18) F6 8267.3(8) 1765.7(8) 2921.6(5) 37.8(2) F5 9317.8(10) 544.3(7) 3964.4(6) 44.7(2) F1 10150.6(10) 2474.9(9) 10045.5(6) 47.0(2) F2 9197.0(13) 2437.9(9) 11204.5(5) 59.4(3) F3 8037.4(11) 3568.5(7) 10161.5(7) 54.2(3) N14 6597.6(10) 4927.9(9) 7207.1(6) 20.6(2) N16 11013.4(10) 3923.9(8) 7874.8(6) 20.5(2) N13 6560.7(10) 4614.6(9) 5796.0(6) 22.6(2) N2 7667.3(11) 742.7(9) 9189.8(6) 23.0(2) N15 7435.1(10) 5053.1(9) 7793.7(6) 21.3(2) N11 8621.4(10) 3374.2(9) 5329.2(6) 22.3(2) N6 5553.7(11) -1820.1(9) 8194.4(6) 23.9(2) N18 10877.1(11) 2973.7(9) 8211.4(7) 27.3(2) N1 8543.4(12) 2089.9(9) 8704.1(6) 26.3(2) N7 5907.6(11) -13.5(9) 6353.7(6) 22.9(2) N5 5950.2(11) -1724.6(9) 8966.6(6) 23.6(2) N10 10672.7(11) 2114.6(9) 4908.2(7) 27.2(2) N12 6414.1(11) 3893.7(9) 4600.4(6) 23.7(2) N4 6818.7(13) -636.9(10) 9702.1(7) 29.0(2) N9 6968.0(12) -231.7(10) 5859.5(7) 30.9(3) N17 12232.7(11) 3779.2(10) 7540.7(7) 27.9(2) N3 7651.4(13) 146.6(10) 10638.1(7) 30.4(3) N8 5235.6(14) 1083(1) 6424.4(8) 37.9(3) C3 8244.0(12) 1486.2(10) 9349.5(8) 22.1(2) C21 9281.3(13) 2647.1(10) 4792.7(7) 21.6(2) C10 5846.1(12) -1032.2(10) 7710.2(7) 22.2(2) C26 7234.4(12) 4774.9(10) 6477.9(7) 19.4(2) C22 8488.9(13) 2481.7(10) 4144.7(7) 22.8(3) C27 8539.1(12) 4798(1) 6596.3(7) 21.8(2) C28 8606.8(12) 4972.3(10) 7417.5(7) 19.1(2) C7 7413.1(13) 123(1) 9836.4(8) 24.4(3) C9 6408.6(13) -414.2(11) 8151.5(8) 25.3(3) C25 7244.1(12) 3931.9(10) 5221.3(7) 20.4(2) C17 6938.1(14) -3228.2(11) 10187.0(8) 27.8(3) C4 8487.4(13) 1617.9(11) 10178.6(8) 24.9(3) C24 7078.7(13) 3144.4(11) 4084.3(7) 23.6(3) C29 9836.7(12) 5050.6(10) 7863.9(7) 21.4(2) C34 5265.5(13) 4880.1(12) 7423.8(8) 28.0(3) C11 5474.4(13) -901.4(10) 6801.1(8) 23.7(3) C8 6443.7(13) -878.5(11) 8956.8(8) 23.9(3) C16 5693.8(13) -2382.0(11) 9675.5(8) 24.3(3) C33 12102.6(14) 2151.8(11) 8086.9(8) 29.8(3) C18 6091.4(14) -3629.4(11) 9653.1(8) 26.3(3) C23 9097.8(14) 1600.9(11) 3587.6(8) 25.7(3) C31 10264.7(14) 5962.1(11) 7396.4(9) 31.6(3) C13 3889.7(15) -508.9(13) 6676.4(9) 33.8(3) C30 9538.3(14) 5288.2(12) 8748.6(8) 28.7(3) C2 8230.0(15) 2008.9(11) 7852.4(8) 28.2(3) C6 8169.9(15) 920.7(11) 10782.7(8) 28.8(3) C14 6985.3(15) 791.2(13) 5600.5(9) 35.1(3) C1 9265.0(16) 972.9(13) 7518.1(9) 36.2(3) C32 12934.5(14) 2649.0(12) 7674.7(8) 32.4(3) C15 5914.4(16) 1602.0(12) 5946.2(9) 36.3(3) C36 5089.6(16) 4487.6(16) 8295.6(9) 41.1(4) C20 11466.5(13) 2321.4(12) 5563.7(8) 29.2(3) C12 6212.6(17) -2021.0(12) 6449.2(9) 34.6(3) C19 11768.7(14) 3393.6(12) 5357.9(9) 32.1(3) C35 4352.0(14) 5717.3(15) 7958.2(9) 40.5(4) C5 8965.6(15) 2506.9(12) 10397.9(8) 31.4(3)

_Ueq is defined as 1/3 of the trace of the orthogonalized _Uij tensor. Table 16. Anisotropic displacement parameters (Å ² × 10 ³ ) of the alkali form A single crystal (810014-28-A6) atom U11 U22 U33 U23 U13 U12 F4 27.1(4) 32.0(4) 32.3(4) -11.5(3) 11.2(3) -11.7(3) F6 34.3(4) 51.3(5) 34.5(4) -24.3(4) 6.9(3) -18.3(4) F5 67.6(6) 23.4(4) 46.2(5) -10.8(4) 27.4(4) -19.4(4) F1 46.6(5) 61.8(6) 52.1(6) -20.3(5) 8.7(4) -38.8(5) F2 110.5(9) 71.4(7) 28.9(5) -13.1(4) 1.2(5) -69.3(7) F3 61.5(6) 25.4(4) 79.5(7) -15.2(4) -0.2(5) -18.1(4) N14 18.3(5) 26.7(5) 18.3(5) -5.1(4) 1.2(4) -9.8(4) N16 18.9(5) 21.9(5) 21.7(5) -2.6(4) 0.0(4) -8.8(4) N13 15.8(5) 28.9(5) 19.4(5) -7.4(4) -0.4(4) -3.0(4) N2 26.1(5) 20.6(5) 23.8(5) -2.7(4) -0.6(4) -10.6(4) N15 20.7(5) 26.4(5) 19.2(5) -4.8(4) -0.4(4) -11.0(4) N11 19.5(5) 23.8(5) 20.6(5) -3.9(4) 0.8(4) -4.6(4) N6 27.6(5) 24.8(5) 21.5(5) -2.8(4) -0.3(4) -12.7(4) N18 28.6(6) 22.5(5) 31.4(6) 0.9(4) -1.8(4) -11.7(4) N1 35.0(6) 24.3(5) 25.3(5) -4.9(4) 2.2(4) -17.3(5) N7 23.8(5) 21.0(5) 20.8(5) -2.7(4) 3.0(4) -5.1(4) N5 29.9(5) 24.2(5) 20.6(5) -1.8(4) 0.0(4) -15.0(4) N10 21.5(5) 26.0(5) 28.7(6) -8.5(4) 2.1(4) -1.6(4) N12 21.1(5) 27.9(5) 20.7(5) -6.5(4) 0.5(4) -6.7(4) N4 44.4(7) 30.5(6) 21.0(5) -0.4(4) -0.8(5) -24.9(5) N9 26.6(6) 32.8(6) 29.6(6) -4.8(5) 8.4(4) -6.9(5) N17 23.0(5) 33.7(6) 26.0(6) -5.8(4) 6.5(4) -9.0(5) N3 44.8(7) 28.3(6) 23.0(6) -1.0(4) -3.4(5) -20.1(5) N8 44.9(7) 20.2(6) 43.9(7) -4.4(5) 18.2(6) -7.1(5) C3 21.3(6) 18.6(6) 25.5(6) -3.7(5) -0.3(5) -6.3(5) C21 22.1(6) 19.8(6) 21.2(6) -1.5(5) 3.3(5) -6.3(5) C10 21.7(6) 20.5(6) 23.5(6) -2.0(5) 1.1(5) -7.3(5) C26 19.2(5) 19.4(6) 17.4(6) -3.3(4) 0.3(4) -4.4(4) C22 25.5(6) 22.4(6) 21.6(6) -4.4(5) 5.6(5) -10.1(5) C27 19.0(6) 25.0(6) 20.1(6) -3.6(5) 3.1(4) -6.8(5) C28 18.1(5) 17.3(5) 21.0(6) -1.8(4) 0.6(4) -5.9(4) C7 28.0(6) 20.6(6) 25.1(6) -2.4(5) -2.3(5) -10.0(5) C9 30.7(7) 24.4(6) 24.4(6) -0.6(5) -0.4(5) -15.2(5) C25 20.3(6) 21.3(6) 18.5(6) -2.3(4) 1.1(4) -6.8(5) C17 35.6(7) 31.5(7) 20.5(6) -1.4(5) 0.8(5) -18.0(6) C4 27.0(6) 22.4(6) 26.6(6) -5.4(5) -0.7(5) -10.2(5) C24 25.4(6) 27.5(6) 20.5(6) -5.6(5) 2.3(5) -12.3(5) C29 19.1(6) 20.0(6) 25.2(6) -3.6(5) -0.1(5) -7.3(5) C34 22.3(6) 45.6(8) 22.3(6) -7.8(6) 3.0(5) -18.9(6) C11 26.7(6) 21.4(6) 22.8(6) -1.7(5) -0.2(5) -9.2(5) C8 27.5(6) 23.4(6) 23.9(6) -3.1(5) -0.6(5) -13.3(5) C16 28.4(6) 25.7(6) 22.4(6) -3.9(5) 5.6(5) -14.2(5) C33 34.0(7) 22.4(6) 28.5(7) -4.8(5) -6.6(5) -5.1(5) C18 34.5(7) 26.4(6) 23.3(6) -1.6(5) 1.8(5) -17.8(6) C23 29.1(6) 25.6(6) 26.4(6) -7.0(5) 7.1(5) -13.9(5) C31 29.1(7) 26.0(7) 42.8(8) 1.4(6) -3.6(6) -15.5(6) C13 29.7(7) 40.9(8) 32.1(7) 3.8(6) -5.9(6) -17.1(6) C30 26.2(6) 32.0(7) 29.4(7) -11.7(5) -0.4(5) -10.5(5) C2 36.8(7) 25.3(6) 24.1(6) -0.9(5) 0.1(5) -14.4(6) C6 37.6(7) 26.9(6) 24.0(6) -3.6(5) -3.7(5) -14.6(6) C14 35.5(7) 40.4(8) 30.3(7) 1.2(6) 8.4(6) -17.1(6) C1 41.5(8) 36.2(8) 32.5(7) -11.6(6) 4.2(6) -14.6(6) C32 28.0(7) 33.2(7) 28.1(7) -8.4(6) 3.5(5) -1.5(6) C15 47.0(8) 25.9(7) 34.5(8) 2.0(6) 7.0(6) -14.0(6) C36 38.0(8) 72.7(11) 26.3(7) -4.1(7) 6.7(6) -37.2(8) C20 21.4(6) 31.8(7) 26.4(7) -1.1(5) -2.6(5) -1.8(5) C12 49.4(9) 24.1(7) 28.9(7) -6.1(5) 0.5(6) -11.7(6) C19 28.3(7) 37.5(8) 28.3(7) -7.6(6) 2.7(5) -9.2(6) C35 20.1(6) 69.7(11) 31.9(7) -18.1(7) 6.9(5) -13.9(7) C5 40.8(8) 32.5(7) 28.0(7) -8.3(5) 2.9(6) -20.7(6)

The anisotropic displacement factor index is in the form of: -2π ² [h ² a* ² U ₁₁ + 2hka*b*U ₁₂ + ∙∙∙]. Table 17. Bond lengths of free alkali form A single crystals atom atom Length/Å atom atom Length/Å F4 C23 1.3397(14) N4 C7 1.3677(16) F6 C23 1.3378(15) N4 C8 1.3871(16) F5 C23 1.3510(15) N9 C14 1.3315(19) F1 C5 1.3391(17) N17 C32 1.3386(18) F2 C5 1.3319(16) N3 C7 1.3447(17) F3 C5 1.3426(17) N3 C6 1.3335(17) N14 N15 1.3594(14) N8 C15 1.3294(19) N14 C26 1.3607(15) C3 C4 1.4249(17) N14 C34 1.4404(15) C21 C22 1.4269(17) N16 N18 1.3290(14) C10 C9 1.4042(17) N16 N17 1.3267(14) C10 C11 1.5150(17) N16 C29 1.4895(15) C26 C27 1.3736(17) N13 C26 1.3950(15) C22 C24 1.3765(18) N13 C25 1.3679(15) C22 C23 1.4835(17) N2 C3 1.3468(16) C27 C28 1.3972(17) N2 C7 1.3318(16) C28 C29 1.5101(16) N15 C28 1.3296(15) C9 C8 1.3763(18) N11 C21 1.3460(16) C17 C16 1.5050(18) N11 C25 1.3290(15) C17 C18 1.4989(18) N6 N5 1.3660(14) C4 C6 1.3744(19) N6 C10 1.3309(16) C4 C5 1.4785(18) N18 C33 1.3373(18) C29 C31 1.5204(17) N1 C3 1.3389(16) C29 C30 1.5239(17) N1 C2 1.4596(16) C34 C36 1.4912(19) N7 N9 1.3220(15) C34 C35 1.5014(19) N7 N8 1.3265(15) C11 C13 1.5255(18) N7 C11 1.4854(16) C11 C12 1.5257(18) N5 C8 1.3565(16) C16 C18 1.4925(17) N5 C16 1.4348(16) C33 C32 1.379(2) N10 C21 1.3396(16) C2 C1 1.5138(19) N10 C20 1.4619(17) C14 C15 1.373(2) N12 C25 1.3510(15) C36 C35 1.498(2) N12 C24 1.3397(16) C20 C19 1.516(2) Table 18. Bond angles of free alkali form A single crystal atom atom atom Angle / ^o atom atom atom Angle / ^o N15 N14 C26 111.73(9) N11 C25 N12 127.01(11) N15 N14 C34 119.53(10) N12 C25 N13 114.95(10) C26 N14 C34 128.54(10) C18 C17 C16 59.58(8) N18 N16 C29 120.69(10) C3 C4 C5 122.73(12) N17 N16 N18 115.26(10) C6 C4 C3 116.82(11) N17 N16 C29 124.03(10) C6 C4 C5 120.32(12) C25 N13 C26 123.59(10) N12 C24 C22 124.60(11) C7 N2 C3 116.65(11) N16 C29 C28 106.66(9) C28 N15 N14 104.56(9) N16 C29 C31 108.76(10) C25 N11 C21 118.06(10) N16 C29 C30 108.45(10) C10 N6 N5 104.28(10) C28 C29 C31 109.91(10) N16 N18 C33 103.75(11) C28 C29 C30 112.68(10) C3 N1 C2 123.41(11) C31 C29 C30 110.24(11) N9 N7 N8 114.49(11) N14 C34 C36 118.11(11) N9 N7 C11 124.05(10) N14 C34 C35 118.75(12) N8 N7 C11 121.46(10) C36 C34 C35 60.08(11) N6 N5 C16 121.00(10) N7 C11 C10 109.65(10) C8 N5 N6 111.44(10) N7 C11 C13 107.89(10) C8 N5 C16 127.20(10) N7 C11 C12 108.78(10) C21 N10 C20 122.79(10) C10 C11 C13 109.17(10) C24 N12 C25 114.13(10) C10 C11 C12 110.88(10) C7 N4 C8 128.24(11) C13 C11 C12 110.42(11) N7 N9 C14 103.94(11) N5 C8 N4 118.20(11) N16 N17 C32 103.33(11) N5 C8 C9 107.72(11) C6 N3 C7 114.07(11) C9 C8 N4 134.05(12) N7 N8 C15 104.11(11) N5 C16 C17 118.02(11) N2 C3 C4 119.93(11) N5 C16 C18 117.85(11) N1 C3 N2 117.23(11) C18 C16 C17 60.00(8) N1 C3 C4 122.83(11) N18 C33 C32 108.49(12) N11 C21 C22 119.55(11) C16 C18 C17 60.41(9) N10 C21 N11 116.65(11) F4 C23 F5 105.55(10) N10 C21 C22 123.80(11) F4 C23 C22 113.94(10) N6 C10 C9 112.57(11) F6 C23 F4 106.01(10) N6 C10 C11 116.93(11) F6 C23 F5 106.38(10) C9 C10 C11 130.43(11) F6 C23 C22 112.56(11) N14 C26 N13 120.96(10) F5 C23 C22 111.81(10) N14 C26 C27 106.77(10) N1 C2 C1 114.00(11) C27 C26 N13 132.26(11) N3 C6 C4 124.19(12) C21 C22 C23 123.19(11) N9 C14 C15 108.89(12) C24 C22 C21 116.43(11) N17 C32 C33 109.18(12) C24 C22 C23 120.27(11) N8 C15 C14 108.58(13) C26 C27 C28 104.95(10) C34 C36 C35 60.30(10) N15 C28 C27 111.99(10) N10 C20 C19 113.28(11) N15 C28 C29 121.66(10) C36 C35 C34 59.62(10) C27 C28 C29 126.35(11) F1 C5 F3 104.57(11) N2 C7 N4 118.56(11) F1 C5 C4 113.45(11) N2 C7 N3 128.23(12) F2 C5 F1 106.50(12) N3 C7 N4 113.20(11) F2 C5 F3 106.07(12) C8 C9 C10 103.97(11) F2 C5 C4 112.68(11) N11 C25 N13 118.03(11) F3 C5 C4 112.90(12) Table 19. Hydrogen atomic coordinates (Å × 10 ⁴ ) and isotropic displacement parameters (Å ² × 10 ³ ) of free alkali form A single crystal atom x y z U _eq H13 5646 4972 5732 27 H1 8950 2560 8798 32 H10 11128 1619 4575 33 H4 6653 -1021 10145 35 H27 9242 4714 6205 26 H9 6698 185 7943 30 H17A 7883 -3296 10012 33 H17B 6847 -3341 10789 33 H24 6539 3065 3646 28 H34 4768 4655 6997 34 H16 4837 -1991 9979 29 H33 12357 1359 8254 36 H18A 6517 -3948 9150 32 H18B 5482 -3992 9927 32 H31A 11097 5977 7671 47 H31B 9496 6708 7384 47 H31C 10477 5790 6833 47 H13A 3433 229 6880 51 H13B 3574 -1072 6979 51 H13C 3645 -432 6090 51 H30A 9243 4705 9040 43 H30B 8791 6042 8752 43 H30C 10389 5270 9023 43 H2A 8213 2703 7504 34 H2B 7283 1990 7812 34 H6 8330 995 11339 35 H14 7633 936 5236 42 H1A 10209 977 7563 54 H1B 9012 991 6940 54 H1C 9243 280 7835 54 H32 13859 2252 7512 39 H15 5695 2400 5858 44 H36A 5894 4288 8691 49 H36B 4516 4019 8399 49 H20A 12365 1660 5677 35 H20B 10933 2382 6071 35 H12A 5943 -1921 5864 52 H12B 5940 -2615 6743 52 H12C 7229 -2246 6514 52 H19A 12355 3317 4880 48 H19B 12261 3506 5829 48 H19C 10885 4051 5233 48 H35A 4703 6275 8144 49 H35B 3325 6005 7852 49 EutecticCrystal Screening

Approximately fifty-five co-constructs were used for cocrystal screening experiments. The experiments were planned based on the solubility of the API and co-constructs and combined a variety of techniques including slurrying, grinding, co-melting and cooling. For the dicarboxylic acid, 1:1 and 2:1 compound of Formula I:co-construct chemistries were used. The experimental details are summarized in Table 20. Table 20. Samples generated and analyzed Co-construct (CF) condition XRPD results 4-Acetamidobenzoic acid Solvent-mediated trituration; EtOH, 1 cycle, 30 min Form A + CF Add API and co-construct to a saturated solution of both components in THF. Slurry, RT, 6 days. Form A + CF + Peak Lyophilize; dioxane/H ₂ O. Slurry, hexane, RT, 5 days. New 1 Acetyl salicylic acid Solvent-mediated trituration; acetone, 1 cycle, 30 min New 1 Eutectic; rapid cooling (FC) to RT. New 1+CF API and co-constructs were added to a saturated solution of both components in 50:50 acetone/H ₂ O. Slurry, RT, 6 days. New 1+CF The aqueous solution of the co-construct was added to the IPA solution of the API. New 1 Adipic acid Solvent-mediated trituration; acetone, 1 cycle, 30 min New 1+CF Eutectic; rapidly cool to RT. New 1+New 2+Form A+CF API and co-constructs were added to a saturated solution of both components in 50:50 EtOH/H ₂ O. Slurry, RT, 6 days. New 1+CF Adipic acid (2:1 API:CF) Solvent-mediated trituration; acetone, 1 cycle, 30 min New 1+ Micro Form A API and co-constructs were added to a saturated solution of both components in 50:50 EtOH/H ₂ O. Slurry, RT, 6 days. New 1+CF L-Alanine Solvent-mediated trituration; EtOH/H ₂ O, 1 cycle, 30 min Form A + CF API and co-construct were added to a saturated solution of both components in 50:50 MeOH/H ₂ O. Slurry, RT, 6 days. Form A + CF L-Ascorbic acid Solvent-mediated trituration; MeOH, 1 cycle, 30 min Form A + CF API and co-constructs were added to a saturated solution of both components in 50:50 acetone/H ₂ O. Slurry, RT, 6 days. Form A + CF Lyophilize; dioxane/H ₂ O. Slurry, hexane, RT, 5 days. NC + Form A + Peak at 18° Trans-Aconitic Acid Solvent-mediated trituration; acetone, 1 cycle, 30 min New 1 API and co-constructs were added to a saturated solution of both components in 50:50 EtOH/H ₂ O. Slurry, RT, 6 days. New 1 + CF Trans-Aconitic Acid (2:1) Solvent-mediated trituration; EtOH/H ₂ O, 1 cycle, 30 min New 2 + Form A L-Aspartic Acid Solvent-mediated trituration; EtOH/H ₂ O, 1 cycle, 30 min Form A + CF API and co-construct were added to a saturated solution of both components in 50:50 MeOH/H ₂ O. Slurry, RT, 6 days. Form A + CF benzoic acid Solvent-mediated trituration; ACN, 1 cycle, 30 min New 1 Eutectic; rapidly cool to RT. New 1+peak+CF API and coconstructs were added to a saturated solution of both components in 50:50 ACN/H ₂ O. Slurry, RT, 6 days. New 1 + CF Butyric acid Solvent-mediated trituration; EtOH, 1 cycle, 30 min New 1 (+)-Camphoric acid Solvent-mediated grinding; acetone, 1 cycle, 30 minutes, vacuum drying for about 2 days NC + CF + Peak Add API and co-construct to a saturated solution of both components in ACN. Slurry, RT, 6 days. NC + CF Solvent-mediated trituration; EtOH, 1 cycle, 30 min NC (+)-Camphoric acid (2:1 API:CF) Solvent-mediated trituration; acetone, 1 cycle, 30 min, vacuum drying Form A Decanoic acid (caproic acid) Solvent-mediated trituration: EtOH, 1 cycle, 30 min, vacuum drying for about 2 days Form A Solvent-mediated trituration; ACN, 1 cycle, 30 min Gel Eutectic; rapidly cool to RT. Clear oil Caprylic acid Grind; 1 cycle, 30 minutes. Form A+ small peak Eutectic; rapidly cool to RT. Form A Freeze-dried; dioxane, thermal stress 40 °C, 24 hours Form A L-Carnitine Solvent-mediated trituration; acetone/H ₂ O, 1 cycle, 30 min Form A + CF + Peak Add API and co-construct to a saturated solution of both components in IPA. Slurry, RT, 6 days. Form A + CF Lyophilize; dioxane/H ₂ O. Slurry, hexane, RT, 5 days. Form A+NC; small peak at 18° Bile acid Solvent-mediated trituration; acetone, 1 cycle, 30 min Form A + CF Add API and co-construct to a saturated solution of both components in IPA. Slurry, RT, 6 days. New 1 Lyophilize; dioxane/H ₂ O. Slurry, hexane, RT, 5 days. Form A+ peak; may contain CF Citric Acid Solvent-mediated grinding; acetone, 1 cycle, 30 minutes, vacuum drying for about 3 days NC + CF Eutectic; Rapid cooling to RT. H ₂ O vapor stress at RT NC+Peak Add API and co-construct to a saturated solution of both components in 50:50 ACN/H ₂ O. Slurry, RT, 6 days. Move to 2-8°C and stir CF L-Cysteine Solvent-mediated trituration; acetone/H ₂ O, 1 cycle, 30 min Form A + CF API and co-constructs were added to a saturated solution of both components in 50:50 IPA/H ₂ O. Slurry, RT, 6 days. Form A + CF Freeze-dried; dioxane/H ₂ O, oil Oily substance Fumaric acid Solvent-mediated trituration; acetone, 1 cycle, 30 min Form A + CF API and co-constructs were added to a saturated solution of both components in 50:50 IPA/H ₂ O. Slurry, RT, 6 days. New 1 + CF Solvent-mediated crystallization from EtOAc/n-heptane New 1 Solvent-mediated crystallization from THF/n-heptane New 2 Fumaric Acid (2:1 API:CF) Solvent-mediated trituration; acetone, 1 cycle, 30 min Form A + CF Add API and co-construct to a saturated solution of both components in 50:50 IPA/H ₂ O. Slurry, RT. New 1 + CF Galactaric acid (mucic acid) Solvent-mediated trituration; ACN, 1 cycle, 30 min Form A + CF API and co-constructs were added to a saturated solution of both components in 50:50 acetone/H ₂ O. Slurry, RT, 6 days. Form A + CF Solvent-mediated trituration; IPA, 1 cycle, 30 min Form A + CF Galactaric acid (Mucic acid) (2:1 API:CF) Solvent-mediated trituration; ACN, 1 cycle, 30 min Form A + CF Glucosyl heptanoate (Na salt) Solvent-mediated trituration; IPA/H ₂ O, 1 cycle, 30 min Form A + CF Add API and co-construct to a saturated solution of both components in MeOH. Slurry, RT, 6 days. New 1 D-Gluconic Acid Grind; 1 cycle, 30 minutes. Form A Eutectic; Rapidly cool to RT. Form A Solvent-mediated trituration; IPA, 1 cycle, 30 min Form A+ NC Gallic acid Solvent-mediated trituration; MeOH, 1 cycle, 30 min New 1 API and co-construct were added to a saturated solution of both components in 50:50 MeOH/H ₂ O. Slurry, RT, 6 days. New 1 + CF Gallic acid (2:1) Solvent-mediated trituration; MeOH, 1 cycle, 30 min New 2 + trace new 1 D-Glucuronic acid Solvent-mediated trituration; MeOH, 1 cycle, 30 min Form A + CF API and co-constructs were added to a saturated solution of both components in 50:50 EtOH/H ₂ O. Slurry, RT, 6 days. Form A Freeze-dried; dioxane/H ₂ O Form A + CF Glycolic acid Solvent-mediated grinding; acetone, 1 cycle, 30 minutes, vacuum drying for about 3 days Form A+ Peak Eutectic; Rapidly cool to RT. Form A Freeze-dried; dioxane, thermal stress 40 °C, 24 hours Oil film Glutaric acid Solvent-mediated grinding; IPA, 1 cycle, 30 minutes, vacuum drying for about 3 days New 1 API and co-constructs were added to a saturated solution of both components in 50:50 IPA/H ₂ O. Slurry, RT, 6 days. New 3 + CF Eutectic; Rapidly cool to RT. New 1 + New 2 + CF Hippuric acid Solvent-mediated trituration; MeOH, 1 cycle, 30 min Form A + CF Solvent-mediated trituration; THF, 1 cycle, 30 min Form A + CF Add API and co-construct to a saturated solution of both components in 50:50 acetone/H ₂ O. Slurry, RT. CF + NC 4-Hydroxybenzoic acid Solvent-mediated trituration; acetone, 1 cycle, 30 min New 1 + Form A; may contain CF API and co-constructs were added to a saturated solution of both components in 50:50 acetone/H ₂ O. Slurry, RT, 6 days. New 1 Solvent-mediated trituration; acetone/H ₂ O, 1 cycle, 30 min Form A+ New 2 Isobutyric acid Grind; 1 cycle, 30 minutes. Form A Solvent-mediated trituration; acetone, 1 cycle, 30 min New 1 Eutectic; Rapidly cool to RT. D-isoascorbic acid Add API and co-construct to a saturated solution of both components in 50:50 acetone/H ₂ O. Slurry, RT, 6 days. Transfer to stirring at 2-8 °C. Form A + CF Solvent-mediated trituration; acetone/H ₂ O, 1 cycle, 30 min Form A + CF Solvent-mediated trituration; EtOH/H ₂ O, 1 cycle, 30 min Form A + CF Freeze-dried; dioxane/H ₂ O NC L-Isoleucine Solvent-mediated trituration; EtOH/H ₂ O, 1 cycle, 30 min Form A + CF API and co-constructs were added to a saturated solution of both components in 50:50 IPA/H ₂ O. Slurry, RT, 6 days. Form A + CF Freeze-dried; dioxane/H ₂ O Form A + CF D,L-Lactic Acid Grind; 1 cycle, 30 minutes. Form A Solvent mediated trituration; EtOAc, 1 cycle, 30 min Gel Eutectic; rapidly cool to RT. Form A+ New 1 Lauric acid Solvent-mediated trituration: EtOH, 1 cycle, 30 min, vacuum drying for about 2 days Form A + CF Eutectic; Rapidly cool to RT. Form A + CF Add API and co-construct to a saturated solution of both components in 50:50 ACN/H ₂ O. Slurry, RT. Gel Lactobionic acid Solvent-mediated trituration; MeOH/H ₂ O, 1 cycle, 30 min Form A Eutectic; Rapidly cool to RT. Form A+ NC Dissolve the API in dioxane and the co-conjugate in _H2O until clear, immediately cloudy, and evaporate quickly. Form A+ NC Linoleic acid Eutectic; Rapidly cooled to RT. Et ₂ O vapor stress at RT Gel Grinding; 1 cycle, 30 minutes. Vacuum drying Gel Solvent-mediated trituration; acetone, 1 cycle, 30 min Gel L-Apple acid Solvent-mediated grinding; acetone, 1 cycle, 30 minutes, vacuum drying for about 2 days NC Add API and co-construct to a saturated solution of both components in 50:50 EtOAc/Et ₂ O. Slurry, RT, 6 days. Move to stirring at 2-8 °C. NC + CF Eutectic; Rapidly cooled to RT. Et ₂ O vapor stress at RT Form A+ NC Malonic acid Solvent-mediated grinding; acetone, 1 cycle, 30 minutes, vacuum drying for about 2 days New 1 Add API and co-construct to a saturated solution of both components in 50:50 acetone/H ₂ O. Slurry, RT, 6 days. Transfer to stirring at 2-8 °C. CF + New 1, LC Eutectic; Rapidly cooled to RT. Et ₂ O vapor stress at RT NC + Peak Mandelic acid Solvent-mediated grinding; IPA, 1 cycle, 30 minutes, vacuum drying for about 2 days New 1 Eutectic; Rapidly cool to RT. New 1 + Form A + Trace CF Add API and co-construct to a saturated solution of both components in IPA. Slurry, RT, 6 days. Stir, 2-8°C. CF+Peak L-Methionine Solvent-mediated trituration; EtOH/H ₂ O, 1 cycle, 30 min Form A + CF Add API and co-construct to a saturated solution of both components in 50:50 acetone/H ₂ O. Slurry, RT. Form A + CF + Peak Freeze-dried; dioxane/H ₂ O Form A New Sweet Eutectic; Rapid cooling to RT. Et ₂ O vapor stress at RT. NC Solvent-mediated trituration; EtOH, 1 cycle, 30 min Form A+ NC Solvent-mediated trituration; acetone, 1 cycle, 30 min Form A + CF Niacinamide Solvent-mediated trituration; acetone, 1 cycle, 30 min Form A + CF + Peak Add API and co-construct to a saturated solution of both components in IPA. Slurry, RT. Form A+ CF + Peak Freeze-dried; dioxane, thermal stress 40 °C, 24 hours Oil film Niacin Solvent-mediated trituration; EtOH, 1 cycle, 30 min Form A + CF Add API and co-conjugate to a saturated solution of components in acetone/H ₂ O. Slurry, RT. Form A + CF Oleic acid Eutectic; Rapidly cooled to RT. Et ₂ O vapor stress at RT Gel Grind; 1 cycle, 30 minutes. Gel Solvent-mediated trituration; IPA, 1 cycle, 30 min Gel Orotic acid Solvent-mediated trituration; EtOH, 1 cycle, 30 min Form A + CF Add API and co-construct to a saturated solution of both components in 50:50 acetone/H ₂ O. Slurry, RT. Form A + CF Freeze-dried; dioxane/H ₂ O NC Palmitic acid Solvent-mediated trituration; acetone, 1 cycle, 30 min Form A + CF Eutectic; Rapidly cool to RT. New 1 + CF + Microform A Solvent-mediated trituration; EtOH, 1 cycle, 30 min Form A + CF Freeze-dried; dioxane/H ₂ O Form A + CF Acid Solvent-mediated trituration; MeOH, 1 cycle, 30 min New 1 + CF Add API and co-conjugate to a saturated solution of both components in MeOH. Slurry, RT. Form A + CF + trace amount of new 1 Solvent-mediated trituration; chloroform, 1 cycle, 30 min New 1+New 2+CF D-Calcium Pantothenate Solvent-mediated trituration; MeOH, 1 cycle, 30 min Form A Add API and co-construct to a saturated solution of both components in 50:50 acetone/H ₂ O. Slurry, RT. New 1 Freeze-dried; dioxane/H ₂ O Form A L-Phenylalanine Solvent-mediated trituration; EtOH, 1 cycle, 30 min Form A + CF Add API and co-construct to a saturated solution of both components in 50:50 IPA/H ₂ O. Slurry, RT. Form A + CF Freeze-dried; dioxane/H ₂ O Form A+ Peak Propionic acid Grind; 1 cycle, 30 minutes. New 1 Solvent-mediated trituration; ACN, 1 cycle, 30 min L-Pyroglutamic acid Solvent-mediated trituration; MeOH, 1 cycle, 30 min Form A + CF Add API and co-construct to a saturated solution of both components in acetone/H ₂ O. Slurry, RT. New 1+Form A+CF Solvent-mediated trituration; IPA, 1 cycle, 30 min Salicylic acid Solvent-mediated crystallization from IPA/water New 1 Sebacic acid Solvent-mediated trituration; EtOH, 1 cycle, 30 min New 1 + CF Eutectic; Rapidly cool to RT. New 1 + CF Sebacic acid (2:1) Solvent-mediated trituration; EtOH, 1 cycle, 30 min New 1+ Micro Form A Succinic acid Solvent-mediated crystallization from EtOH/n-heptane New 1 (hydrate) Solvent-mediated crystallization from IPA/water New 1 (hydrate) Solvent-mediated crystallization from EtOAc/n-heptane New 2 Solvent-mediated crystallization from THF/n-heptane New 2 Stearic acid Solvent-mediated trituration; acetone, 1 cycle, 30 min Form A + CF Eutectic; Rapidly cool to RT. New 1 + Form A Solvent-mediated trituration; EtOH, 1 cycle, 30 min Form A + CF tartaric acid Solvent-mediated grinding; acetone, 1 cycle, 30 minutes, vacuum drying for about 2 days NC + CF Add API and co-construct to a saturated solution of both components in acetone/hexane. Slurry, RT. NC + CF Tartaric acid (2:1) Solvent mediated trituration; EtOAc, 1 cycle, 30 min NC L-Theanine Freeze-dried; dioxane/H ₂ O Form A+ Peak Solvent-mediated trituration; acetone, 1 cycle, 30 min Form A + CF Add API and co-construct to a saturated solution of both components in IPA/H ₂ O. Slurry, RT. Form A + CF Terephthalic acid Solvent mediated trituration; EtOAc, 1 cycle, 30 min New 1 Add API and co-conjugate to a saturated solution of both components in EtOAc. Slurry, RT. New 1 + trace CF Tyrosine Solvent-mediated trituration; IPA/H ₂ O, 1 cycle, 30 min Form A + CF Add API and co-construct to a saturated solution of both components in MeOH/H ₂ O. Slurry, RT. Form A + CF Freeze-dried; dioxane/H ₂ O Form A + CF Vanillic acid Solvent-mediated trituration; EtOH, 1 cycle, 30 min New 1 Freeze-dried; dioxane Vanillic acid (2:1) Solvent-mediated trituration; EtOH, 1 cycle, 30 min Form A+ New 1 CF = conformational isomers; NC = non-crystalline, API = active pharmaceutical ingredient, RT = room temperature

Twenty-six new species were generated using the following co-constructs: 4-acetamidobenzoic acid, acetylsalicylic acid, adipic acid, trans-aconitic acid, benzoic acid, butyric acid, cholic acid, fumaric acid, sodium glucoheptanoate, gallic acid, glutaric acid, 4-hydroxybenzoic acid, isobutyric acid, D,L-lactic acid, malonic acid, mandelic acid, palmitic acid, naphthoic acid, propionic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, terephthalic acid, and vanillic acid. Table 21 below shows the melting points as characterized by DSC analysis of the selected co-crystals formed. Table 21 Co-construct MP (DSC , °C, peak) 4-Acetamidobenzoic acid 151.0 Acetyl salicylic acid 155.6 Trans-Aconitic Acid 183.2 Adipic acid 99.2, 106.2 Bile acid 188 (IPA solvent) benzoic acid 143.2 Butyric acid 98.7 Fumaric acid 150.5 (Form 1) 143.8 (Form 2) Gallic acid 185.1 Glutaric acid 99.5 4-Hydroxybenzoic acid 169.1 Isobutyric acid 97.3, 109.8 Malonic acid 157.2 D,L-Mandelic acid 106.6 Propionic acid 94.4 (hydrate) Salicylic acid 111.1, 146.4 Succinic acid 139.2 (anhydrous) 98.9, 135.5 (hydrate) Terephthalic acid 152.5 (EtOAc solvent) Vanillic acid 142.5 General Methods for Cocrystal Analysis

DSC analyses were performed on a TA Instruments Q2500 Discovery Series instrument. Indium was used for instrument calibration. The DSC cell was maintained under a nitrogen purge of approximately 50 mL per minute during each analysis. The samples were placed in an aluminum crimped pan and heated from approximately 25°C to 350°C at a rate of 10°C per minute. Pharmaceutical Compositions and Formulations

Polymorphic forms of Formula I can be formulated according to standard pharmaceutical practice and according to the procedures of Example 9 for therapeutic treatment (including prophylactic treatment) of mammals (including humans). The present disclosure provides pharmaceutical compositions comprising a compound of Formula I and a combination of one or more pharmaceutically acceptable carriers, glidants, diluents or excipients.

Suitable carriers, diluents, glidants and formulators are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The formulations may be prepared using conventional dissolution and mixing procedures. The compounds of the present disclosure are typically formulated into pharmaceutical dosage forms to provide easily controlled drug dosages and to enable patients to comply with the prescribed regimen.

Pharmaceutical compositions (or formulations) for use may be packaged in a variety of ways, depending on the method used to administer the drug. Generally, an article for distribution includes a container in which the pharmaceutical formulation in an appropriate form is placed. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), blister packs, pouches, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-evident assembly to prevent easy access to the contents of the package. Additionally, a label is placed on the container describing the contents of the container. The label may also include appropriate warnings.

Pharmaceutical formulations of polymorphic forms of the compounds of Formula I can be prepared with pharmaceutically acceptable diluents, carriers, excipients, glidants or stabilizers for various routes and types of administration (Remington's Pharmaceutical Sciences (1995) 18th edition, Mack Publ. Co., Easton, PA), in the form of lyophilized formulations, ground powders or aqueous solutions. Formulation can be carried out by mixing with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the recipient at the dose and concentration employed) at ambient temperature, appropriate pH and desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but can be in the range of about 3 to about 8.

Pharmaceutical formulations can be sterile. Specifically, formulations for intravenous administration must be sterile. The sterilization is easily achieved by filtering through a sterile filter membrane.

Pharmaceutical formulations are typically stored as solid compositions, tablets, pills, capsules, lyophilized formulations or as aqueous solutions.

The pharmaceutical formulations of the present invention will be dosed and administered in a manner consistent with good medical practice (i.e., amount, concentration, schedule, course of treatment, vehicle, and route of administration). Factors that need to be considered in this context include the specific disease being treated, the clinical condition of the individual patient, the cause of the disease, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to medical practitioners.

Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethylammonium chloride; benzalkonium chloride, benzathonine chloride; phenol, butyl, ethanol or benzyl alcohol; alkyl parabens such as methyl or propyl parabens; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues); yl) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, aspartic acid, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrin; chelating agents, such as EDTA; sugars, such as lactose, sucrose, mannitol, trehalose or sorbitol; salt-forming relative ions, such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants, such as TWEEN, including Tween 80, PLURONICS or polyethylene glycol (PEG), including PEG400. The active pharmaceutical ingredient can also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions, respectively. Such techniques are disclosed in Remington's Pharmaceutical Sciences 18th edition, (1995) Mack Publ. Co., Easton, PA. Other examples of drug formulations can be found in Pharmaceutical Dosage Forms, edited by Liberman, H. A. and Lachman, L., Marcel Decker, Vol. 3, 2nd edition, New York, NY.

Tablets may contain one or more pharmaceutically acceptable excipients, such as carriers, glidants, diluents, binders, disintegrants or lubricants. Pharmaceutically acceptable diluents may be selected from microcrystalline cellulose, lactose, sodium starch glycolate, calcium carbonate, corn starch, sugar alcohols such as sorbitol, xylitol, mannitol and combinations thereof.

The pharmaceutically acceptable glidant may be selected from silicon dioxide, powdered cellulose, metal stearate, sodium aluminosilicate, sodium benzoate, calcium silicate, magnesium carbonate, asbestos-free talc, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof.

The pharmaceutically acceptable binder may be selected from corn starch and pregelatinized starch, sodium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, calcium cellulose hydroxyacetate, calcium carmellose, PEG (polyethylene glycol) povidone, compressible sugars and combinations thereof.

The pharmaceutically acceptable disintegrant may be selected from microcrystalline cellulose, powdered cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium starch glycolate, crospovidone and a combination thereof.

The pharmaceutically acceptable lubricant may be selected from magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, polyethylene glycol, colloidal silicon dioxide, talc, beeswax, hydrogenated vegetable oil and combinations thereof.

Pharmaceutical formulations include those suitable for the administration routes described in detail herein. The formulations may be conveniently presented in unit dose form and may be prepared by any method known in the pharmaceutical art. Techniques and formulations may generally be found in Remington's Pharmaceutical Sciences 18th edition (1995) Mack Publishing Co., Easton, PA. Such methods include the step of combining the active ingredient with a carrier that constitutes one or more auxiliary ingredients. The formulation may be prepared by uniformly and intimately combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then molding the product if necessary.

The pharmaceutical composition may be in the form of a sterile injectable preparation, such as a sterile aqueous or oily suspension. This suspension may be prepared using the appropriate dispersants or wetting agents and suspending agents mentioned above according to known techniques. The sterile injectable preparation may be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol) or a freeze-dried powder. Acceptable media and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile nonvolatile oils may be used as solvents or suspending media as usual, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may also be used to prepare injectables.

In another aspect, the present disclosure relates to methods for treating diseases or conditions mediated at least in part by leucine-rich repeat kinase 2 (LRRK2). Specifically, the present disclosure provides methods for preventing or treating LRRK2-related disorders in mammals, comprising the step of administering to the mammal a therapeutically effective amount of a compound provided herein. In some embodiments, the disease or condition mediated at least in part by LRRK2 is a neurodegenerative disease, such as a central nervous system (CNS) disorder, such as Parkinson's disease (PD), Alzheimer's disease (AD), dementia (including Lewy body dementia and vascular dementia), amyotrophic lateral sclerosis (ALS), age-related memory dysfunction, mild cognitive impairment (e.g., including transition from mild cognitive impairment to Alzheimer's disease), argyrophilic granulopathy, lysosomal disorders (e.g., Niemann-Pick Type C disease, Gaucher disease, disease)) corticobasal degeneration, progressive supranuclear palsy, hereditary frontotemporal dementia and Parkinson's disease associated with chromosome 17 (FTDP-17), withdrawal symptoms/relapse associated with drug addiction, L-Dopa induced dyskinesia, Huntington's disease (HD) and HIV-associated dementia (HAD). In other embodiments, the disease is an ischemic disease of an organ (including but not limited to the brain, heart, kidney and liver).

In some other embodiments, the disease or condition mediated at least in part by LRRK2 is cancer. In certain specific embodiments, the cancer is thyroid cancer, kidney cancer (including papillary kidney cancer), breast cancer, lung cancer, blood cancer and prostate cancer (e.g., solid tumors), leukemia (including acute myeloid leukemia (AML)), or lymphoma. In some embodiments, the cancer is kidney cancer, breast cancer, prostate cancer, blood cancer, papillary cancer, lung cancer, acute myeloid leukemia or multiple myeloma.

In other embodiments, the compounds disclosed herein are used in methods for treating inflammatory conditions. In some embodiments, the condition is an inflammatory bowel disease, such as Crohn's disease or ulcerative colitis (the two are often collectively referred to as inflammatory bowel disease). In other embodiments, the inflammatory disease is leprosy, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis. In some embodiments, the inflammatory disease is leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.

In other embodiments, the compounds disclosed herein are used in methods of treating multiple sclerosis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis, bullous skin disorders, type 1 diabetes, Sjogren's syndrome, Devic's disease, and inflammatory myopathy.

Although the foregoing invention has been described in detail by way of illustration and examples for the purpose of clear understanding, such description and examples should not be considered to limit the scope of the invention. Therefore, all appropriate modifications and equivalents may be considered to fall within the scope of the invention as defined by the scope of the attached patent applications. The disclosures of all patents and scientific literature cited herein are expressly incorporated by reference in their entirety.

FIG1 schematically shows the interconversion relationship between the polymorphs Form A and Form B of the compound of Formula I and the amorphous Form C. FIG2 shows the XRPD pattern of the Form A polymorph. FIG3 shows the overlay of the XRPD patterns of the polymorphs Form A and Form B of the compound of Formula I. FIG4 shows the TGA and DSC data of the Form A polymorph. FIG5 shows the thermoellipse diagram of the asymmetric unit molecule of the single crystal X-ray structure of the Form A polymorph. FIG6 shows the XRPD diffraction pattern of the amorphous Form C. FIG7 shows the PLM image of the Form A single crystal. FIG8 shows the XRPD overlay of the Form A after storage for 6 months at 40°C/75%RH and 25°C/60%RH. Figure 9 shows a comparison of the XRPD overlays of Form A after storage at 25°C/60%RH for 48 months.

Claims (20)

A crystalline compound N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine or a co-crystal thereof. The crystalline compound of claim 1, selected from: Form A polymorph, which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 12.3, 13.8, 15.7, 18.7, 22.1 and 22.6; and Form B polymorph, which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 8.0, 9.9, 16.1, 19.9 and 23.2. The crystalline compound of claim 2, wherein the compound is the Form A polymorph, which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 12.3, 13.8, 15.7, 18.7, 22.1 and 22.6. The crystalline compound of claim 3, wherein the Form A polymorph further comprises peaks at approximately 5.4 and 7.4 degrees 2θ. The Form A polymorph of claim 2, wherein differential scanning calorimetry (DSC) shows a melting endotherm with an onset at about 107.1 °C. The crystalline compound of claim 2, wherein the Form A polymorph is an anhydrate. The Form A polymorph of claim 2 characterized by the X-ray powder diffraction pattern shown in FIG. The crystalline compound of claim 2, wherein the compound is the Form B polymorph, which exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ at approximately 8.0, 9.9, 16.1, 19.9 and 23.2. The crystalline compound or co-crystal thereof of any one of claims 1 to 8, wherein the compound is in substantially pure form. A crystalline compound or a co-crystal thereof as claimed in any one of claims 1 to 7, wherein the X-ray powder diffraction pattern is obtained using CuKα1 irradiation. A crystalline compound N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine exhibits an X-ray powder diffraction pattern having characteristic peaks at approximately 12.3, 13.8, 15.7, 18.7, 22.1 and 22.6 expressed as ± 0.3 degrees 2θ. A pharmaceutical composition comprising the crystalline polymorph of any one of claims 1 to 11 and a pharmaceutically acceptable carrier, glidant, diluent, binder, disintegrant or lubricant. The pharmaceutical composition of claim 12, wherein the crystalline polymorph is Form A. An amorphous compound, an amorphous form of CN2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine. A pharmaceutical composition comprising the amorphous compound of claim 14 and a pharmaceutically acceptable carrier, glidant, diluent, binder, disintegrant or lubricant. A process for preparing amorphous Form C of compound N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine comprises heating a crystalline form of the compound until dissolved, followed by cooling to form the amorphous compound. A co-crystal comprising N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and co-structures, and hydrates thereof. The cocrystal of claim 17, wherein the coconstruct is selected from 4-acetamidobenzoic acid, acetylsalicylic acid, trans-aconic acid, adipic acid, benzoic acid, butyric acid, cholic acid, fumaric acid, gallic acid, glutaric acid, 4-hydroxybenzoic acid, isobutyric acid, malonic acid, D,L-mandelic acid, propionic acid, salicylic acid, succinic acid, terephthalic acid and vanillic acid. A pharmaceutical composition comprising the co-crystal of any one of claims 17 to 18 and a pharmaceutically acceptable carrier, glidant, diluent, binder, disintegrant or lubricant. A process for preparing a co-crystal as claimed in any one of claims 17 to 18, comprising contacting N2-(3-(2-(2H-1,2,3-triazol-2-yl)propan-2-yl)-1-cyclopropyl-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine with a co-construct.