Crystals of 7h-pyrrolo[2,3-d]pyrimidin-4-amine derivatives

Abstract

Crystalline forms of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (TAS3351), a compound having an inhibitory effect against EGFR and an acid. The crystalline forms have advantageous physical properties including stability, hygroscopicity, and oral absorption. The crystalline forms have peaks in a powder X-ray diffraction spectrum at specific diffraction angles (2θ ± 0.2°).

Description

CRYSTALS OF 7H-PYRROLO[2,3-d]PYRIMIDIN-4-AMINE DERIVATIVES BACKGROUND

[0001] EGFR is a receptor-type tyrosine kinase that exerts physiological functions in normal tissues by binding to its ligand, epidermal growth factor (EGF), and contributes to proliferation and inhibition of apoptosis in epithelial tissues. 1 EGF is a major component of the epithelial growth factor family (EGF). (Lacouture et. al., Nature Reviews cancer, vol.6, pp803-812).

[0002] EGFR is also an oncogene, and amplification of the EGFR gene and high expression or mutation of the protein are known in various types of cancer, such as head and neck cancer, breast cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, renal cancer, bladder cancer, skin cancer and brain tumors. Tumors. (Kim, et. al., Current Opinion in Oncology 2001, 13:506–513).

[0003] Among these, the number of deaths from lung cancer reaches approximately 1.4 million per year worldwide, and since non-small cell lung cancer accounts for more than 80% of all lung cancers, the development of effective treatment methods is desired [Doebele, R.C., et. al., Lung Cancer, 2010, 69, 1, 1-12].

[0004] Currently, several EGFR inhibitors have been reported as anti-tumor agents. JPWO2020166680A1 provides, as a compound with excellent EGFR inhibitory activity, N-(4-(4- amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)- 5-methylpyrazine-2-carboxamide (hereinafter referred to as "compound (1)" or “TAS3351”).

[0005] JPWO2020166680A1 also provides a method for producing compound (1). However, the reference does not specifically indicate what kind of crystal form the compound (1) or its salt can adopt.

[0006] When a compound is used as an ingredient in a pharmaceutical composition, it is desirable to have a stable crystal form of the compound in order to maintain stable quality and / or to facilitate storage management. Furthermore, it is desirable that the crystalline form of the compound has low hygroscopicity or good oral absorption, etc. However, it is difficult to predict whether a particular compound or its salt will form crystals and what crystal form will have excellent stability and other physical properties. In the above situation, crystals of compounds or salts having EGFR inhibitory ability and having good stability, hygroscopicity, and oral absorbability are required.BRIEF SUMMARY

[0007] the present disclosure provides salt forms of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (compound 1, TAS3351) that possess advantageous physical and pharmaceutical characteristics, and that permit e.g., efficient, more convenient, and controllable pharmaceutical formulations to be prepared for the treatment of diseases / conditions such as various types of cancer, such as head and neck cancer, breast cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, renal cancer, bladder cancer, skin cancer and brain tumors.

[0008] These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors’ discovery of novel salt forms of compound (I) which possess desirable physical and pharmaceutical characteristics such as one or more of: ease and propensity for salt formation and crystallization (e.g., high yield); stable and well-defined physical properties (e.g., crystallinity, lack of polymorphism, high melting point, and high enthalpy of fusion); stability against moisture including at elevated humidity (hygroscopicity); desirable appearance (e.g., free flowing, lack of cohesion / adhesion, regular morphology); acceptable aqueous solubility; and physiological acceptability, particularly for pulmonary administration (e.g., non-irritant).

[0009] Provided here are crystal forms of a salt or co-crystal of compound (1) (TAS3351) and benzenesulfonic acid, hydrochloric acid, or tartaric acid which may be useful as EGFR inhibitors. These crystal forms of a salt or co-crystal of compound (1) may be useful in the treatment of various types of cancer, such as head and neck cancer, breast cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, renal cancer, bladder cancer, skin cancer and brain tumors.

[0010] Thus, the present disclosure provides: (1) A crystal comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and benzene sulfonic acid, wherein the crystal has peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ ± 0.2°) of: (i) one or more selected from the group consisting of 16.56°, 19.2°, 20.9°, and 24.8°; and (ii) two or more selected from the group consisting of 5.6°, 6.0°, 12.6°, 14.0°, 16.1°, 20.2°, 20.5°, 23.9°, 25.2°, 26.1°, 27.1°, and 28.3°.(2) The crystal according to (1), wherein the crystal has peaks in a powder X-ray diffraction spectrum at a total of five or more diffraction angles (2θ ± 0.2°) selected from groups (i) and (ii) above. (3) The crystal according to (1) or (2), wherein the crystal has peaks in a powder X-ray diffraction spectrum at a total of seven or more diffraction angles (2θ ± 0.2°) selected from groups (i) and (ii) above. (4) The crystal according to any one of (1) to (3), wherein the crystal has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 4. (5) The crystal according to any one of (1) to (4), having an exothermic peak determined by simultaneous thermogravimetric-differential thermal analysis is around 238°C. (6) The crystal according to any one of (1) to (5), wherein the crystal has a crystal purity of 50% by weight or more. (7) The crystal according to any one of (1) to (6) above, wherein the crystal has a chemical purity of 90% or more. (8) A method for producing a crystal comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3- yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2- carboxamide and benzene sulfonic acid according to any one of (1) to (7) above, the method comprising stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and benzene sulfonic acid in a single solvent of a lower alcohol with 2 or more carbon atoms, acetone, or ethyl acetate, or in a mixed solvent comprising two or more of these solvents. (9) A crystal comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and hydrochloric acid, wherein the crystal has peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ ± 0.2°) of: (i) 10.5°; and (ii) at least two selected from the group consisting of 13.0°, 17.7°, 18.4°, 20.8°, 21.1°, 23.6°, and 24.1°.(10) The crystal according to (9), wherein the crystal has peaks in a powder X-ray diffraction spectrum at three or more diffraction angles (2θ ± 0.2°) selected from group (ii). (11) The crystal according to any one of (9) to (10), wherein the crystal has peaks in a powder X-ray diffraction spectrum at five or more diffraction angles (2θ ± 0.2°) selected from group (ii). (12) The crystal according to any one of (9) to (11), wherein the crystal has a powder X- ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 12. (13) The crystal according to any one of (9) to (12), having an exothermic peak determined by simultaneous thermogravimetric-differential thermal analysis is around 263°C. (14) The crystal according to any one of (9) to (13), wherein the crystal has a crystal purity of 50% by weight or more. (15) The crystal according to any one of (9) to (14) above, wherein the crystal has a chemical purity of 90% or more. (16) A method for producing the crystal comprising N-(4-(4-amino-6-ethynyl-5-(quinolin- 3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2- carboxamide and hydrochloric acid according to any one of (9) to (15) above, the method comprising stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and hydrochloric acid in a single solvent of a lower alcohol with 2 or more carbon atoms, acetone, or ethyl acetate, or in a mixed solvent comprising two or more of these solvents. (17) A crystal comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and tartaric acid, wherein the crystal has peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ ± 0.2°) of: (i) 12.2°; and (ii) at least two selected from the group consisting of 4.6°, 6.3°, 8.6°, 9.1°, 9.8°, 12.1°, 13.7°, 18.3°, and 20.6°. (18) The crystal according to (17), wherein the crystal has peaks in a powder X-ray diffraction spectrum at four or more diffraction angles (2θ ± 0.2°) selected from group (ii).(19) The crystal according to (17) or (18), wherein the crystal has peaks in a powder X- ray diffraction spectrum at six or more diffraction angles (2θ ± 0.2°) selected from group (ii). (20) The crystal according to any one of (17) to (19), wherein the crystal has a powder X- ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 17. (21) The crystal according to any one of (17) to (20), wherein an exothermic peak determined by simultaneous thermogravimetric-differential thermal analysis is around 209°C. (22) The crystal according to any one of (17) to (21), wherein the crystal has a crystal purity of 50% by weight or more. (23) The crystal according to any one of (17) to (22) above, wherein the crystal has a chemical purity of 90% or more. (24) A method for producing the crystal comprising N-(4-(4-amino-6-ethynyl-5- (quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2- carboxamide and tartaric acid according to any one of (17) to (23), the method comprising stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and tartaric acid in a solvent comprising ethanol. (25) A crystal comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and tartaric acid, wherein the crystal has peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ ± 0.2°) of: (i) 5.6°; and (ii) two or more selected from the group consisting of 8.6°, 13.4° 16.8°, 21.9°, 26.9°, and 29.8°. (26) The crystal according to (25), wherein the crystal has peaks in a powder X-ray diffraction spectrum at three or more diffraction angles (2θ ± 0.2°) selected from group (ii). (27) The crystal according to (25) or (26), wherein the crystal has peaks in a powder X- ray diffraction spectrum at five or more diffraction angles (2θ ± 0.2°) selected from group (ii).(28) The crystal according to any one of (25) to (27), wherein the crystal has a powder X- ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 22. (29) The crystal according to any one of (25) to (28), wherein an endothermic peak determined by simultaneous thermogravimetric-differential thermal analysis is around 159°C. (30) The crystal according to any one of (25) to (29), wherein the crystal has a crystal purity of 50% by weight or more. (31) The crystal according to any one of (25) to (30), wherein the crystal has a chemical purity of 90% or more. (32) A method for producing the crystal comprising N-(4-(4-amino-6-ethynyl-5- (quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2- carboxamide and tartaric acid according to any one of (25) to (31) above, the method comprising stirring N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and tartaric acid in a mixed solvent comprising at least two selected from the group consisting of a lower alcohol with 3 or more carbon atoms, acetone, ethyl acetate, and water. (33) A pharmaceutical composition comprising the crystal according to any one of (1) to (7), (9) to (15), (17) to (23), and (25) to (31). (34) A pharmaceutical composition comprising the crystal according to any one of (1) to (7), (9) to (15), (17) to (23), and (25) to (31) and a pharmacologically acceptable carrier. (35) An antitumor agent comprising the crystal according to any one of (1) to (7), (9) to (15), (17) to (23), and (25) to (31). (36) A method for treating a tumor, comprising orally administering an effective amount of the crystal according to any one of (1) to (7), (9) to (15), (17) to (23), and (25) to (31) to a subject in need thereof. (37) A method for producing an antitumor agent for oral administration comprising the crystal according to any one of (1) to (7), (9) to (15), (17) to (23), and (25) to (31), the methodcomprising mixing a crystal according to any one of (1) to (7), (9) to (15), (17) to (23), and (25) to (31) and a pharmacologically acceptable carrier. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The forgoing paragraphs have been provided by way of general introduction and are not intended to limit the scope of the following claims. The described embodiments, together with further advantages, will be best understood by reference to the following detailed description when considered in conjunction with the accompanying drawings, wherein:.

[0012] Various aspects of the present disclosure will now be described, by way of example only, with reference to the attached Figures, wherein:

[0013] Figs. 1 and 2 show images taken during the salt screening with first-round solvents, demonstrating the range of colors;

[0014] Fig.3 shows images taken from the scale-up of TAS3351 besylate, Pattern 1-A;

[0015] Fig.4 shows a XRPD diffractogram of TAS3351 besylate, Pattern 1-A in both wet and dry conditions;

[0016] Fig.5 shows a simultaneous TGA / DSC thermogram of TAS3351 besylate, Pattern 1-A;

[0017] Fig.6 shows a DSC thermogram of TAS3351 besylate, Pattern 1-A;

[0018] Fig.7 shows an optical microscopy image of TAS3351 besylate crystals, Pattern 1-A;

[0019] Fig.8 shows a1H NMR in DMSO-d6 of TAS3351 besylate, Pattern 1-A;

[0020] Fig.9 shows a DVS isotherm of TAS3351 besylate, Pattern 1-A;

[0021] Fig. 10 shows XRPD diffractograms of TAS3351 besylate, Pattern 1-A before and after DVS exposure;

[0022] Fig.11 shows images taken during the scale-up of TAS3351 HCl, Pattern 5-H;

[0023] Fig.12 shows a XRPD diffractogram of TAS3351 HCl, Pattern 5-H dried;

[0024] Fig.13 shows a simultaneous TGA / DSC thermogram of TAS3351 HCl, Pattern 5-H;

[0025] Fig.14 shows a DSC thermogram of TAS3351 HCl, Pattern 5-H;

[0026] Fig.15 shows an optical microscopy image of TAS3351 HCl, Pattern 5-H crystals;

[0027] Fig.16 shows a1H NMR in DMSO-d6 of TAS3351 HCl, Pattern 5-H;

[0028] Fig.17 shows a XRPD diffractogram of TAS3351 tartrate, Pattern 14-A;

[0029] Fig.18 shows a simultaneous TGA / DSC thermogram of TAS3351 tartrate, Pattern 14-A;

[0030] Fig.19 shows a DSC thermogram of TAS3351 tartrate, Pattern 14-A;

[0031] Fig.20 shows an optical microscopy image of TAS3351 tartrate, Pattern 14-A crystals;

[0032] Fig.21 shows a1H NMR in DMSO-d6 of TAS3351 tartrate, Pattern 14-A;

[0033] Fig.22 shows a XRPD diffractogram of TAS3351 tartrate, Pattern 14-C;

[0034] Fig.23 shows a simultaneous TGA / DSC thermogram of TAS3351 tartrate, Pattern 14-C;

[0035] Fig.24 shows a DSC thermogram of TAS3351 tartrate, Pattern 14-C;

[0036] Fig.25 shows an optical microscopy image of TAS3351 tartrate, Pattern 14-C crystals;

[0037] Fig.26 shows a DVS isotherm of TAS3351 tartrate, Pattern 14-C;

[0038] Fig. 27 shows XRPD diffractograms of TAS3351 tartrate, Pattern 14-C before and after DVS;

[0039] Fig. 28 shows a calibration curve of TAS3351, using Pattern FB-A (L1NJ111001-1-1, batch ELS- 474-191-39);

[0040] Fig.29 shows unique crystalline patterns from screening with 1.1 eq. of BSA;

[0041] Fig.30 shows unique crystalline patterns from screening with 2.2 eq. of BSA;

[0042] Fig.31 shows unique crystalline patterns from screening with 1.1 eq. of ESA;

[0043] Fig.32 shows unique crystalline patterns from screening with 1.1 eq. of fumaric acid;

[0044] Fig.33 shows unique crystalline patterns from screening with 1.1 eq. of HCl;

[0045] Fig.34 shows unique crystalline patterns from screening with 2.2 eq. of HCl;

[0046] Fig.35 shows unique crystalline patterns from screening with 1.1 eq. of malic acid;

[0047] Fig.36 shows unique crystalline patterns from screening with 1.1 eq. of maleic acid;

[0048] Fig.37 shows unique crystalline patterns from screening with 1.1 eq. of MSA;

[0049] Fig.38 shows unique crystalline patterns from screening with 1.1 eq. of oxalic acid;

[0050] Fig.39 shows unique crystalline patterns from screening with 1.1 eq. of phosphoric acid in EtOH;

[0051] Fig.40 shows unique crystalline patterns from screening with 1.1 eq. of pyruvic acid;

[0052] Fig.41 shows unique crystalline patterns from screening with 0.6 eq. of sulfuric acid;

[0053] Fig.42 shows unique crystalline patterns from screening with 1.1 eq. of sulfuric acid;

[0054] Fig.43 shows unique crystalline patterns from screening with 1.1 eq. of tartaric acid;

[0055] Fig.44 shows unique crystalline patterns from screening with 1.1 eq. of TSA;

[0056] Fig. 45 shows unique crystalline pattern, 15-B, when screening with 2.2 eq. of TSA in EtOH;

[0057] Fig.46 shows a XRPD diffractogram from screening with BSA (1.1 eq.) in EtOH, Pattern 1-A;

[0058] Fig.47 shows a DSC thermogram from screening with BSA (1.1 eq.) in EtOH, Pattern 1- A;

[0059] Fig.48 shows an optical microscopy image of dried solids from screening with BSA (1.1 eq.) in EtOH, Pattern 1-A;

[0060] Fig.49 shows a1H NMR in DMSO-d6 from screening with BSA (1.1 eq.) in EtOH, Pattern 1-A;

[0061] Fig.50 shows a XRPD diffractogram from screening with BSA (1.1 eq.) in EtOAc, Pattern 1-C;

[0062] Fig.51 shows a DSC thermogram from screening with BSA (1.1 eq.) in EtOAc, Pattern 1- C;

[0063] Fig.52 shows a XRPD diffractogram from screening with BSA (2.2 eq.) in EtOH, Pattern 1-D;

[0064] Fig.53 shows a DSC thermogram from screening with BSA (2.2 eq.) in EtOH, Pattern 1- D;

[0065] Fig.54 shows a1H NMR in DMSO-d6 from screening with BSA (2.2 eq.) in EtOH, Pattern 1-D;

[0066] Fig.55 shows a XRPD diffractogram from screening with BSA (2.2 eq.) in IPA:water (9:1 vol.), Pattern 1-B;

[0067] Fig. 56 shows a DSC thermogram from screening with BSA (2.2 eq.) in IPA:water (9:1 vol.), Pattern 1-B;

[0068] Fig.57 shows an optical microscopy image of dried solids from screening with BSA (2.2 eq.) in IPA:water (9:1 vol.), Pattern 1-B;

[0069] Fig.58 shows a XRPD diffractogram from screening with ESA (1.1 eq.) in EtOH, Pattern 2-C;

[0070] Fig.59 shows a DSC thermogram from screening with ESA (1.1 eq.) in EtOH, Pattern 2- C;

[0071] Fig.60 shows a XRPD diffractogram from screening with ESA (1.1 eq.) in EtOAc, Pattern 2-A;

[0072] Fig.61 shows a DSC thermogram from screening with ESA (1.1 eq.) in EtOAc, Pattern 2- A;

[0073] Fig.62 shows an optical microscopy image of dried solids from screening with ESA (1.1 eq.) in EtOAc, Pattern 2-A;

[0074] Fig.63 shows a XRPD diffractogram from screening with ESA (1.1 eq.) in IPA:water (9:1 vol.), Pattern 2-B;

[0075] Fig. 64 shows a DSC thermogram from screening with ESA (1.1 eq.) in IPA:water (9:1 vol.), Pattern 2-B;

[0076] Fig.65 shows a XRPD diffractogram from screening with fumaric acid (1.1 eq.) in EtOH, Pattern 3-C;

[0077] Fig. 66 shows a DSC thermogram from screening with fumaric acid (1.1 eq.) in EtOH, Pattern 3-C;

[0078] Fig. 67 shows an optical microscopy image of dried solids from screening with fumaric acid (1.1 eq.) in EtOH, Pattern 3-C;

[0079] Fig.68 shows a1H NMR in DMSO-d6 from screening with fumaric acid (1.1 eq.) in EtOH, Pattern 3- C;

[0080] Fig.69 shows a XRPD diffractogram from screening with fumaric acid (1.1 eq.) in EtOAc;

[0081] Fig. 70 shows a DSC thermogram from screening with fumaric acid (1.1 eq.) in EtOAc, Pattern 3-B;

[0082] Fig. 71 shows a XRPD diffractogram from screening with fumaric acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 3-A;

[0083] Fig.72 shows a DSC thermogram from screening with fumaric acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 3-A;

[0084] Fig. 73 shows an optical microscopy image of dried solids from screening with fumaric acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 3-A;

[0085] Fig. 74 shows a1H NMR in DMSO-d6 from screening with fumaric acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 3-A;

[0086] Fig.75 shows a XRPD diffractogram from screening with HCl (1.1 eq.) in EtOAc, Pattern 5-H;

[0087] Fig.76 shows a DSC thermogram from screening with HCl (1.1 eq.) in EtOAc, Pattern 5- H;

[0088] Fig.77 shows an optical microscopy image of dried solids from screening with HCl (1.1 eq.) in EtOAc, Pattern 5-H;

[0089] Fig.78 shows a1H NMR in DMSO-d6 from screening with HCl (1.1 eq.) in EtOAc, Pattern 5-H;

[0090] Fig.79 shows a XRPD diffractogram from screening with HCl (1.1 eq.) in IPA:water (9:1 vol.), Pattern 5-A;

[0091] Fig. 80 shows a DSC thermogram from screening with HCl (1.1 eq.) in IPA:water (9:1 vol.), Pattern 5-A;

[0092] Fig.81 shows a XRPD diffractogram from screening with HCl (2.2 eq.) in EtOAc, Pattern 5-G;

[0093] Fig.82 shows a DSC thermogram from screening with HCl (2.2 eq.) in EtOAc, Pattern 5- G;

[0094] Fig.83 shows an optical microscopy image of dried solids from screening with HCl (2.2 eq.) in EtOAc, Pattern 5-G;

[0095] Fig.84 shows a XRPD diffractogram from screening with HCl (2.2 eq.) in IPA:water (9:1 vol.), Pattern 5-F;

[0096] Fig. 85 shows a DSC thermogram from screening with HCl (2.2 eq.) in IPA:water (9:1 vol.), Pattern 5-F;

[0097] Fig. 86 shows a1H NMR in DMSO-d6 from screening with HCl (2.2 eq.) in IPA:water (9:1 vol.), Pattern 5-F;

[0098] Fig. 87 shows a XRPD diffractogram from screening with malic acid (1.1 eq.) in EtOH, Pattern 6-A;

[0099] Fig.88 shows a DSC thermogram from screening with malic acid (1.1 eq.) in EtOH, Pattern 6-A;

[0100] Fig.89 shows an optical microscopy image of the dried solids from screening with malic acid (1.1 eq.) in EtOH, Pattern 6-A;

[0101] Fig.90 shows a1H NMR in DMSO-d6 from screening with malic acid (1.1 eq.) in EtOH, Pattern 6-A;

[0102] Fig.91 shows a XRPD diffractogram from screening with malic acid (1.1 eq.) in EtOAc, Pattern 6-B;

[0103] Fig. 92 shows a DSC thermogram from screening with malic acid (1.1 eq.) in EtOAc, Pattern 6-B;

[0104] Fig.93 shows a1H NMR in DMSO-d6 from screening with malic acid (1.1 eq.) in EtOAc, Pattern 6-B;

[0105] Fig.94 shows a XRPD diffractogram from screening with malic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 6-C;

[0106] Fig.95 shows a DSC thermogram from screening with malic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 6-C;

[0107] Fig. 96 shows a1H NMR in DMSO-d6 from screening with malic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 6-C;

[0108] Fig.97 shows a XRPD diffractogram from screening with maleic acid (1.1 eq.) in EtOH, Pattern 7-A;

[0109] Fig. 98 shows a DSC thermogram from screening with maleic acid (1.1 eq.) in EtOH, Pattern 7-A;

[0110] Fig.99 shows a XRPD diffractogram from screening with maleic acid (1.1 eq.) in EtOAc, Pattern 7-B;

[0111] Fig. 100 shows a DSC thermogram from screening with maleic acid (1.1 eq.) in EtOAc, Pattern 7-B;

[0112] Fig. 101 shows a1H NMR in DMSO-d6 from screening with maleic acid (1.1 eq.) in EtOAc, Pattern 7-B;

[0113] Fig. 102 shows a XRPD diffractogram from screening with maleic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 7-C;

[0114] Fig.103 shows a DSC thermogram from screening with maleic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 7-C;

[0115] Fig. 104 shows a1H NMR in DMSO-d6 from screening with maleic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 7-C;

[0116] Fig.105 shows a XRPD diffractogram from screening with MSA (1.1 eq.) in EtOH, Pattern 8-A;

[0117] Fig.106 shows a DSC thermogram from screening with MSA (1.1 eq.) in EtOH, Pattern 8-A;

[0118] Fig. 107 shows a XRPD diffractogram from screening with MSA (1.1 eq.) in EtOAc, Pattern 8-D;

[0119] Fig.108 shows a DSC thermogram from screening with MSA (1.1 eq.) in EtOAc, Pattern 8-D;

[0120] Fig.109 shows a XRPD diffractogram from screening with MSA (2.2 eq.) in EtOH, Pattern 8-B;

[0121] Fig.110 shows a DSC thermogram from screening with MSA (2.2 eq.) in EtOH, Pattern 8-B;

[0122] Fig. 111 shows a1H NMR in DMSO-d6 from screening with MSA (2.2 eq.) in EtOH, Pattern 8-B;

[0123] Fig.112 shows a XRPD diffractogram from screening with oxalic acid (1.1 eq.) in EtOH, Pattern 9-A;

[0124] Fig. 113 shows a DSC thermogram from screening with oxalic acid (1.1 eq.) in EtOH, Pattern 9-A;

[0125] Fig. 114 shows an optical microscopy image of dried solids from screening with oxalic acid (1.1 eq.) in EtOH, Pattern 9-A;

[0126] Fig.115 shows a1H NMR in DMSO-d6 from screening with oxalic acid (1.1 eq.) in EtOH, Pattern 9-A;

[0127] Fig. 116 shows a XRPD diffractogram from screening with oxalic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 9-B;

[0128] Fig.117 shows a DSC thermogram from screening with oxalic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 9-B;

[0129] Fig. 118 shows an optical microscopy image of dried solids from screening with oxalic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 9-B;

[0130] Fig.119 shows a XRPD diffractogram from screening with pyruvic acid (1.1 eq.) in EtOH, Pattern 11-A;

[0131] Fig. 120 shows a DSC thermogram from screening with pyruvic acid (1.1 eq.) in EtOH, Pattern 11-A;

[0132] Fig.121 shows an optical microscopy image of dried solids from screening with pyruvic acid (1.1 eq.) in EtOH, Pattern 11-A;

[0133] Fig. 122 shows a XRPD diffractogram from screening with pyruvic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 11-C;

[0134] Fig.123 shows a DSC thermogram from screening with pyruvic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 11-C;

[0135] Fig.124 shows an optical microscopy image of dried solids from screening with pyruvic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 11-C;

[0136] Fig. 125 shows a XRPD diffractogram from screening with sulfuric acid (0.55 eq.) in EtOH, Pattern 12-A;

[0137] Fig.126 shows a DSC thermogram from screening with sulfuric acid (0.55 eq.) in EtOH, Pattern 12-A;

[0138] Fig.127 shows an optical microscopy image of dried solids from screening with sulfuric acid (0.55 eq.) in EtOH, Pattern 12-A;

[0139] Fig. 128 shows a XRPD diffractogram from screening with sulfuric acid (0.55 eq.) in IPA:water (9:1 vol.), Pattern 12-C;

[0140] Fig. 129 shows a DSC thermogram from screening with sulfuric acid (0.55 eq.) in IPA:water (9:1 vol.), Pattern 12-C;

[0141] Fig. 130 shows a1H NMR in DMSO-d6 from screening with sulfuric acid (0.55 eq.) in IPA:water (9:1 vol.), Pattern 12-C;

[0142] Fig.131 shows a XRPD diffractogram from screening with tartaric acid (1.1 eq.) in EtOH, Pattern 14-A;

[0143] Fig. 132 shows a DSC thermogram from screening with tartaric acid (1.1 eq.) in EtOH, Pattern 14-A;

[0144] Fig.133 shows a1H NMR in DMSO-d6 from screening with tartaric acid (1.1 eq.) in EtOH, Pattern 14-A;

[0145] Fig. 134 shows a1H NMR in DMSO-d6 from screening with tartaric acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 14-C;

[0146] Fig.135 shows a XRPD diffractogram from screening with TSA (2.2 eq.) in EtOH, Pattern 15-B;.

[0147] Fig. 136 shows a DSC thermogram from screening with TSA (2.2 eq.) in EtOH, Pattern 15-B;

[0148] Fig. 137 shows a1H NMR in DMSO-d6 from screening with TSA (2.2 eq.) in EtOH, Pattern 15-B;

[0149] Fig.138 shows XRPD diffractograms of besylate, Pattern 1-A, before and after one-week stability at 75 % RH and 40 °C;

[0150] Fig. 139 shows XRPD diffractograms of HCl, Pattern 5-H, before and after one-week stability at 75 % RH and 40 °C;

[0151] Fig.140 shows XRPD diffractograms of tartrate, Pattern 14-A, before and after one-week stability at 75 % RH and 40 °C;

[0152] Fig.141 shows XRPD diffractograms of tartrate, Pattern 14-C, before and after one-week stability at 75 % RH and 40 °C;

[0153] Fig. 142 shows XRPD diffractograms from one-week slurries of TAS3351 besylate, Pattern 1-A;

[0154] Fig.143 shows XRPD diffractograms from one-week slurry of besylate in IPA, Pattern 1- A;

[0155] Fig.144 shows XRPD diffractograms from one-week slurry of besylate in acetone, Pattern 1-A;.

[0156] Fig. 145 shows XRPD diffractograms from one-week slurry of besylate in EtOH:water (95:5 vol.), Pattern 1-A;

[0157] Fig.146 shows XRPD diffractograms from one-week slurries of TAS3351 HCl, Pattern 5- H;

[0158] Fig.147 shows XRPD diffractograms from one-week slurry of tartrate Pattern 14-A (L.C.) in IPA;

[0159] Fig.148 shows XRPD diffractograms from one-week slurry of tartrate Pattern 14-A (L.C.) in acetone;

[0160] Fig.149 shows XRPD diffractograms from one-week slurry of tartrate Pattern 14-A (L.C.) in EtOH:water (95:5 vol.);

[0161] Fig.150 shows XRPD diffractograms from one-week slurry of tartrate Pattern 14-C in IPA;

[0162] Fig.151 shows XRPD diffractograms from one-week slurries of tartrate Pattern 14-C;

[0163] Fig.152 shows the XRPD diffractogram of HCl salt, Pattern 5-B, L1NJ111001-5-22;

[0164] Fig.153 shows the XRPD diffractogram of HCl salt, Pattern 5-C, L1NJ111001-5-22-dry;

[0165] Fig. 154 shows the XRPD diffractogram of HCl salt, Pattern 5-D, L1NJ111001-5-22- humidified;

[0166] Fig. 155 shows the XRPD diffractogram of HCl salt, Pattern 5-E, L1NJ111001-5-22- redried;

[0167] Fig.156 shows a XRPD overlay of polymorphs and pseudo-polymorphs;

[0168] Fig.157 shows a schematic diagram of interconversion relationship of polymorphs;

[0169] Fig. 158 shows a XRPD overlay of screening samples with 0.5 equiv. of tartaric acid by slurry evaporation-2;

[0170] Fig. 159 shows a XRPD overlay of screening samples with 1.0 equiv. of tartaric acid by slurry evaporation-3;

[0171] Fig. 160 shows a XRPD overlay of screening samples with 2.0 equiv. of tartaric acid by slurry evaporation-4;

[0172] Fig.161 shows the XRPD overlay of tartaric acid cocrystal polymorphs;

[0173] Fig.162 shows the XRPD pattern of tartaric acid cocrystal Pattern A, sample ID FR02324- 2-RC3-C-2-XRPD-4min;

[0174] Fig. 163 shows the DSC thermogram of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-50C-Dry-DSC;

[0175] Fig. 164 shows the TGA thermogram tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-50C-Dry-TGA;

[0176] Fig. 165 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-2-NMR-50C-Dry;

[0177] Fig.166shows a XRPD overlay of samples obtained by vacuum drying at 50°C;

[0178] Fig.167 shows the 1H-NMR overlay of samples obtained by vacuum drying at 50°C;

[0179] Fig.168 shows the 1H-NMR spectrum of screening sample with 2.0 equiv. of tartaric acid from EtOH by equilibration, sample ID FR02324-2-RC4-A-NMR;

[0180] Fig.169 shows the XRPD pattern of tartaric acid cocrystal Pattern A, sample ID FR02324- 2-RC3-C-scale-up-XRPD-4min-dry-4;

[0181] Fig. 170 shows the DSC thermogram of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up-DSC-dry-4;

[0182] Fig. 171 shows the TGA thermogram of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up-TGA-dry-4;

[0183] Fig. 172 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up-NMR-Dry-4;

[0184] Fig. 173 shows the PLM photograph of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up-NMR-Dry-4;

[0185] Fig.174 shows the XRPD pattern of tartaric acid cocrystal Pattern A, sample ID FR02324- 3-RC3-C-scale-up-XRPD-4min;

[0186] Fig. 175 shows the DSC thermogram of tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up-75RH-DSC;

[0187] Fig. 176 shows the TGA thermogram of tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up-75RH-TGA;

[0188] Fig. 177 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up-75RH-NMR;

[0189] Fig.178 shows the XRPD pattern of tartaric acid cocrystal Pattern B, sample ID FR02324- 2-RC3-D-XRPD-4min;

[0190] Fig. 179 shows the DSC thermogram of tartaric acid cocrystal Pattern B, sample ID FR02324-2-RC3-D-50C-Dry-DSC;

[0191] Fig. 180 shows the TGA thermogram of tartaric acid cocrystal Pattern B, sample ID FR02324-2-RC3-D-50C-Dry-TGA;

[0192] Fig. 181 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern B, sample ID FR02324-2-RC3-D-NMR-2;

[0193] Fig.182 shows the XRPD pattern of tartaric acid cocrystal Pattern C, sample ID FR02324- 2-RC4-C-XRPD-4min;

[0194] Fig. 183 shows the DSC thermogram of tartaric acid cocrystal Pattern C, sample ID FR02324-2-RC4-C-50C-Dry-DSC;

[0195] Fig. 184 shows the TGA thermogram of tartaric acid cocrystal Pattern C, sample ID FR02324-2-RC4-C-50C-Dry-TGA;

[0196] Fig. 185 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern C, sample ID FR02324-2-RC4-C-NMR-2;

[0197] Fig.186 shows the XRPD pattern of tartaric acid cocrystal Pattern D, sample ID FR02324- 3-FE2-XRPD-4min-2;

[0198] Fig. 187 shows the DSC thermogram of tartaric acid cocrystal Pattern D, sample ID FR02324-3-FE2-DSC-2;

[0199] Fig.188 TGA thermogram of tartaric acid cocrystal Pattern D, sample ID FR02324-3-FE2- TGA-3;

[0200] Fig. 189 shows the shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern D, sample ID FR02324-3-FE2-NMR-2;

[0201] Fig.190 shows the XRPD pattern of tartaric acid cocrystal Pattern E, sample ID FR02324- 3-TC5- XRPD-4min;

[0202] Fig. 191 shows the DSC thermogram of tartaric acid cocrystal Pattern E, sample ID FR02324-3-TC5-DSC;

[0203] Fig. 192 shows the TGA thermogram of tartaric acid cocrystal Pattern E, sample ID FR02324-3-TC5-TGA;

[0204] Fig. 193 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern E, sample ID FR02324--3-TC5-NMR;

[0205] Fig.194 shows the XRPD pattern of tartaric acid cocrystal Pattern F, sample ID FR02324- 3-TC8-XRPD-4min;

[0206] Fig. 195 shows the DSC thermogram of tartaric acid cocrystal Pattern F, sample ID FR02324-3-TC8-DSC;

[0207] Fig. 196 shows the TGA thermogram of tartaric acid cocrystal Pattern F, sample ID FR02324-3-TC8-TGA;

[0208] Fig. 197 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern F, sample ID FR02324-3-TC8-NMR;

[0209] Fig.198 shows the XRPD pattern of tartaric acid cocrystal Pattern G, sample ID FR02324- 3-EQ32-scale-up-XRPD-4min-Dry;

[0210] Fig. 199 shows the DSC thermogram of tartaric acid cocrystal Pattern G, sample ID FR02324-3-EQ32-scale-up-DSC-Dry;

[0211] Fig. 200 shows the TGA thermogram of tartaric acid cocrystal Pattern G, sample ID FR02324-3-EQ32-scale-up-TGA-Dry(1);

[0212] Fig. 201 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern G, sample ID FR02324-3-EQ32-scale-up-NMR-1H-Dry;

[0213] Fig.202 shows the XRPD pattern of tartaric acid cocrystal Pattern H, sample ID FR02324- 3-TC11-XRPD-4min;

[0214] Fig. 203 shows the DSC thermogram of tartaric acid cocrystal Pattern H, sample ID FR02324-3-TC11-DSC;

[0215] Fig. 204 shows the TGA thermogram of tartaric acid cocrystal Pattern H, sample ID FR02324-3-TC11-TGA;

[0216] Fig. 205 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern H, sample ID FR02324-3-TC11-NMR;

[0217] Fig.206 shows the XRPD pattern of tartaric acid cocrystal Pattern I, sample ID FR02324- 3-TC12-XRPD-4min;

[0218] Fig. 207 shows the DSC thermogram of tartaric acid cocrystal Pattern I, sample ID FR02324-3-TC12-DSC;

[0219] Fig. 208 shows the TGA thermogram of tartaric acid cocrystal Pattern I, sample ID FR02324-3-TC12-TGA;

[0220] Fig. 209 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern I, sample ID FR02324-3-TC12-NMR;

[0221] Fig.210 shows the XRPD pattern of tartaric acid cocrystal Pattern J, sample ID FR02324- 3-TC13-XRPD-4min;

[0222] Fig. 211 shows the DSC thermogram of tartaric acid cocrystal Pattern J, sample ID FR02324-3-TC13-DSC;

[0223] Fig. 212 shows the TGA thermogram of tartaric acid cocrystal Pattern J, sample ID FR02324-3-TC13-TGA;

[0224] Fig. 213 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern J, sample ID FR02324-3-TC13-NMR;

[0225] Fig.214 shows the XRPD pattern of tartaric acid cocrystal Pattern K, sample ID FR02324- 3-TC14-XRPD-4min;

[0226] Fig. 215 shows the DSC thermogram of tartaric acid cocrystal Pattern K, sample ID FR02324-3-TC14-DSC;

[0227] Fig. 216 shows the TGA thermogram of tartaric acid cocrystal Pattern K, sample ID FR02324-3-TC14-TGA;

[0228] Fig. 217 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern K, sample ID FR02324-3-TC14-NMR;

[0229] Fig.218 shows the XRPD pattern of tartaric acid cocrystal Pattern L, sample ID FR02324- 3-TC17-XRPD-4min;

[0230] Fig. 219 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern L, sample ID FR02324-3-TC17-NMR;

[0231] Fig.220 shows the XRPD pattern of tartaric acid cocrystal Pattern M, sample ID FR02324- 3-TC18-XRPD-4min;

[0232] Fig. 221 shows the DSC thermogram of tartaric acid cocrystal Pattern M, sample ID FR02324-3-TC18-DSC;

[0233] Fig. 222 shows the TGA thermogram of tartaric acid cocrystal Pattern M, sample ID FR02324-3-TC18-TGA;

[0234] Fig. 223 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern M, sample ID FR02324-3-TC18-NMR;

[0235] Fig.224 shows the XRPD pattern of tartaric acid cocrystal Pattern N, sample ID FR02324- 3-EQ24-XRPD-4min;

[0236] Fig. 225 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern N, sample ID FR02324-3-EQ24-NMR;

[0237] Fig.226 shows the XRPD pattern of tartaric acid cocrystal Pattern O, sample ID FR02324- 3-EQ25-XRPD-4min;

[0238] Fig. 227 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern O, sample ID FR02324-3-EQ25-NMR;

[0239] Fig.228 shows the XRPD pattern of tartaric acid cocrystal Pattern P, sample ID FR02324- 3-TC14-140C-XRPD-4min;

[0240] Fig. 229 shows the DSC thermogram of tartaric acid cocrystal Pattern P, sample ID FR02324-3-TC14-140C-DSC;

[0241] Fig. 230 shows the TGA thermogram of tartaric acid cocrystal Pattern P, sample ID FR02324-3-TC14-140C-TGA;

[0242] Fig. 231 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern P, sample ID FR02324-3-TC14-140C-NMR;

[0243] Fig.232 shows the XRPD pattern of tartaric acid cocrystal Pattern Q, sample ID R02324- 3-RC3-C-scale-up-75RH-initial-0RH(4H)-VH-XRPD;

[0244] Fig.233 shows the XRPD pattern of tartaric acid cocrystal Pattern R, sample ID R02324- 3-RC3-C-scale-up-75RH-initial-40-0-40RH(4H)-VH-XRPD;

[0245] Fig. 234 shows the TGA thermogram of tartaric acid cocrystal Pattern R, sample ID FR02324-3- RC3-C-scale-up-VH-TGA;

[0246] Fig. 235 shows the DSC thermogram of tartaric acid cocrystal Pattern R, sample ID FR02324-3-RC3-C-scale-up-VH-DSC;

[0247] Fig. 236 shows a XRPD overlay of samples obtained from VT-XRPD experiments with tartaric acid cocrystal Pattern K as starting material, sample ID FR02324-3-TC14-VT-XRPD;

[0248] Fig. 237 shows a XRPD overlay of samples obtained from VT-XRPD experiments with tartaric acid cocrystal Pattern F as starting material, sample ID FR02324-3-TC8-VT-XRPD;

[0249] Fig. 238 shows a XRPD overlay of samples obtained from VT-XRPD experiments with tartaric acid cocrystal Pattern G as starting material, sample ID FR02324-3-TC10-VT-XRPD;

[0250] Fig. 239 shows a XRPD overlay of samples obtained from VT-XRPD experiments with tartaric acid cocrystal Pattern A as starting material, sample ID FR02324-3-FR02324-3-Pattern A- scale-up-VT-XRPD;

[0251] Fig. 240 shows a XRPD overlay of samples obtained from VH-XRPD experiments with tartaric acid cocrystal Pattern A as starting material, sample ID FR02324-3-RC3-C-scale-up- 75RH-VH-XRPD;

[0252] Fig. 241 shows a XRPD overlay of samples obtained from VH-XRPD experiments with tartaric acid cocrystal Pattern A as starting material, sample ID FR02324-3-Pattern A-scale-up- VH-XRPD;

[0253] Fig.242 shows a XRPD overlay of samples obtained from solid exposure experiments with tartaric acid cocrystal Pattern E as starting material, sample ID FR02324-3-TC5-25C-75%-XRPD- 4min;

[0254] Fig. 243 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern E, sample ID FR02324-3-TC5-25C-75RH-NMR;

[0255] Fig. 244 shows the XRPD of samples obtained from solid exposure experiments with tartaric acid cocrystal Pattern G as starting material, sample ID FR02324-3-TC10-25C-75%- XRPD-4min;

[0256] Fig. 245 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern G, sample ID FR02324-3-TC10-25C-75RH-NMR;

[0257] Fig.246 shows a XRPD overlay of samples obtained from solid exposure experiments with tartaric acid cocrystal Pattern J as starting material, sample ID FR02324-3-TC13-25C-75%- XRPD-4min;

[0258] Fig. 247 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern J, sample ID FR02324-3-TC13-25C-75RH-NMR;

[0259] Fig. 248 shows the XRPD of samples obtained from solid exposure experiments with tartaric acid cocrystal Pattern M as starting material, sample ID FR02324-3-TC18-25C-75%- XRPD-4min;

[0260] Fig. 249 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern M, sample ID FR02324-3-TC18-25C-75RH-NMR;

[0261] Fig. 250 shows a XRPD overlay of samples obtained from VH-XRPD experiments with tartaric acid cocrystal Pattern A as starting material, sample ID FR02324-3-RC3-C-scale-up-VH- XRPD-75RH;

[0262] Fig. 251 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up-75RH-NMR;

[0263] Fig.252 shows a XRPD overlay of samples obtained by bulk stability experiments, sample ID FR02324-3-Pattern A-BS1 to BS5;

[0264] Fig.253 shows a XRPD overlay of samples obtained by bulk stability experiments, sample ID FR02324-3-Pattern G-BS1 to BS5;

[0265] Fig.254 shows a XRPD overlay of samples obtained by bulk stability experiments, sample ID FR02324-3-Pattern P-BS1 to BS5;

[0266] Fig. 255 shows the DVS isotherm plot of tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up-75RH;

[0267] Fig.256 shows a XRPD overlay of tartaric acid cocrystal Pattern A, sample ID FR02324- 3-RC3-C-scale-up-75RH before and after DVS test;

[0268] Fig. 257 shows the DVS isotherm plot of tartaric acid cocrystal Pattern G, sample ID FR02324-3-EQ32-scale-up;

[0269] Fig.258 shows a XRPD overlay of tartaric acid cocrystal Pattern G, sample ID FR02324- 3-EQ32-scale-up before and after DVS test;

[0270] Fig. 259 DVS isotherm plot of tartaric acid cocrystal Pattern P, sample ID FR02324-3- Pattern P-scale-up-DVS;

[0271] Fig.260 XRPD overlay of tartaric acid cocrystal Pattern P, sample ID FR02324-3-Pattern P-scale-up before and after DVS test;

[0272] Fig.261 shows a microphoto of tartaric acid cocrystal Pattern A, sample ID FR02324-2- Pattern A-scale-up-75RH;

[0273] Fig.262 shows a XRPD overlay of samples obtained by compressing tartaric acid cocrystal Pattern A, sample ID FR02324-3-CSE1 to CSE3;

[0274] Fig. 263 shows a XRPD overlay of samples obtained by grinding tartaric acid cocrystal Pattern A, sample ID FR02324-3-GSE1 to GSE3;

[0275] Fig. 264 shows a XRPD overlay of samples obtained by granulating with tartaric acid cocrystal Pattern A, sample ID FR02324-3-GNSE1 to GNSE2;

[0276] Fig.265 shows a XRPD overlay of samples obtained by equilibration at 25°C for 2 weeks- 1;

[0277] Fig.266 shows a XRPD overlay of samples obtained by equilibration at 25°C for 2 weeks- 2;

[0278] Fig.267 shows a XRPD overlay of samples obtained by equilibration at 25°C for 2 weeks- 3;

[0279] Fig.268 shows a XRPD overlay of samples obtained by equilibration at 25°C for 2 weeks- 4;

[0280] Fig.269 shows a XRPD overlay of samples obtained by equilibration at 25°C for 2 weeks- 5;

[0281] Fig.270 shows a XRPD overlay of samples obtained by equilibration at 50°C for 1 week- 1:

[0282] Fig.271 shows a XRPD overlay of samples obtained by equilibration at 50°C for 1 week- 2;

[0283] Fig.272 shows a XRPD overlay of samples obtained by equilibration at 50°C for 1 week- 3;

[0284] Fig.273 shows a XRPD overlay of samples obtained by equilibration at 50°C for 1 week- 4;

[0285] Fig.274 shows a XRPD overlay of samples obtained by equilibration at 50°C for 1 week- 5;

[0286] Fig.275 shows a XRPD overlay of samples obtained by equilibration at 50°C for 1 week- 6;

[0287] Fig. 276 shows the 1H-NMR spectrum of sample obtained from 1,4-dioxane by equilibration at 50°C for 1 week, sample ID FR02324-3-EQ36-NMR;

[0288] Fig.277 shows a XRPD overlay of samples obtained by equilibration under a temperature cycle-1;

[0289] Fig.278 shows a XRPD overlay of samples obtained by equilibration under a temperature cycle-2;

[0290] Fig.279 shows a XRPD overlay of samples obtained by equilibration under a temperature cycle-3;

[0291] Fig.280 shows a XRPD overlay of samples obtained by equilibration under a temperature cycle-4;

[0292] Fig.281 shows a XRPD overlay of samples obtained by equilibration under a temperature cycle-5;

[0293] Fig.282 shows the TGA thermogram of sample obtained from MEK by equilibration under a temperature cycle, sample ID FR02324-3-TC6-TGA;

[0294] Fig.283 shows the DSC thermogram of sample obtained from MEK by equilibration under a temperature cycle, sample ID FR02324-3-TC6-DSC;

[0295] Fig. 284 shows the 1H-NMR spectrum of sample obtained from MEK by equilibration under a temperature cycle, sample ID FR02324-TC6-NMR;

[0296] Fig.285 shows the TGA thermogram of sample obtained from EA by equilibration under a temperature cycle, sample ID FR02324-3-TC7-TGA;

[0297] Fig.286 shows the DSC thermogram of sample obtained from EA by equilibration under a temperature cycle, sample ID FR02324-3-TC7-DSC;

[0298] Fig.287 shows the 1H-NMR spectrum of sample obtained from EA by equilibration under a temperature cycle, sample ID FR02324-TC7-NMR;

[0299] Fig.288 shows the TGA thermogram of sample obtained from ACN by equilibration under a temperature cycle, sample ID FR02324-3-TC9-TGA;

[0300] Fig.289 shows the DSC thermogram of sample obtained from ACN by equilibration under a temperature cycle, sample ID FR02324-3-TC9-DSC;

[0301] Fig. 290 shows the 1H-NMR spectrum of sample obtained from ACN by equilibration under a temperature cycle, sample ID FR02324-TC9-NMR;

[0302] Fig. 291 shows the pattern of tartaric acid cocrystal Pattern G, sample ID FR02324-3- TC10-XRPD-4min;

[0303] Fig. 292 shows the DSC thermogram of tartaric acid cocrystal Pattern G, sample ID FR02324-3-TC10-DSC;

[0304] Fig. 293 shows the TGA thermogram of tartaric acid cocrystal Pattern G, sample ID FR02324-3-TC10-TGA;

[0305] Fig. 294 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern G, sample ID FR02324-3-TC10-NMR;

[0306] Fig.295 shows the TGA thermogram of sample obtained from 1,4-dioxane / water=1 / 1 by equilibration under a temperature cycle, sample ID FR02324-3-TC19-TGA;

[0307] Fig.296 shows the DSC thermogram of sample obtained from 1,4-dioxane / water=1 / 1 by equilibration under a temperature cycle, sample ID FR02324-3-TC19-DSC;

[0308] Fig.297 shows the 1H-NMR spectrum of sample obtained from 1,4-dioxane / water=1 / 1 by equilibration under a temperature cycle, sample ID FR02324-TC19-NMR;

[0309] Fig.298 shows the 1H-NMR spectrum of sample obtained from acetone by equilibration under a temperature cycle, sample ID FR02324-TC5-25C-75RH-NMR;

[0310] Fig.299 shows the 1H-NMR spectrum of sample obtained from heptane by equilibration under a temperature cycle, sample ID FR02324-TC10-25C-75RH-NMR;

[0311] Fig. 300 shows the 1H-NMR spectrum of sample obtained from THF by equilibration under a temperature cycle, sample ID FR02324-TC13-25C-75RH-NMR;

[0312] Fig. 301 shows the 1H-NMR spectrum of sample obtained from THF / water=1 / 1 by equilibration under a temperature cycle, sample ID FR02324-TC18-25C-75RH-NMR;

[0313] Fig.302 shows a XRPD overlay of samples obtained by slow evaporation;

[0314] Fig.303 shows a XRPD overlay of samples obtained by fast evaporation-1;

[0315] Fig.304 shows a XRPD overlay of samples obtained by fast evaporation-2;

[0316] Fig.305 shows a XRPD overlay of samples obtained by slow cooling;

[0317] Fig.306 shows a XRPD overlay of samples obtained by fast cooling;

[0318] Fig.307 shows a XRPD overlay of samples obtained by addition of anti-solvent-1;

[0319] Fig.308 shows a XRPD overlay of samples obtained by addition of anti-solvent-2;

[0320] Fig.309 shows a XRPD overlay of samples obtained by addition of anti-solvent-3;

[0321] Fig.310 shows a XRPD overlay of samples obtained by reverse addition of anti-solvent- 1;

[0322] Fig.311 shows a XRPD overlay of samples obtained by reverse addition of anti-solvent- 2;

[0323] Fig.312 shows a XRPD overlay of samples obtained by reverse addition of anti-solvent- 3’

[0324] Fig.313 shows a XRPD overlay of samples obtained by vapor diffusion;

[0325] Fig.314 shows the XRPD pattern of tartaric acid cocrystal Pattern P, sample ID FR02324- 3-PatternP-140C-XRPD-4min;

[0326] Fig. 315 shows the DSC thermogram of tartaric acid cocrystal Pattern P, sample ID FR02324-3-PatternP-140C-DSC;

[0327] Fig. 316 shows the TGA thermogram of tartaric acid cocrystal Pattern P, sample ID FR02324-3-PatternP-140C-TGA; and

[0328] Fig. 317 shows the 1H-NMR spectrum of tartaric acid cocrystal Pattern P, sample ID FR02324-3-PatternP-140C-NMR. DETAILED DESCRIPTION

[0329] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the methods described herein belong. Any reference to standard methods (e.g., ASTM, TAPPI, AATCC, etc.) refers to the most recent available version of the method at the time of filing of this disclosure unless otherwise indicated.

[0330] For any method disclosed herein that includes discrete steps, the steps may be conducted in any feasible order. And, as appropriate, any combination of two or more steps may be conducted simultaneously.

[0331] All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified.

[0332] The words "preferred" and "preferably" refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful and is not intended to exclude other embodiments from the scope of the invention.

[0333] The term "comprises" and variations thereof do not have a limiting meaning where these terms appear in the description and claims. Such terms will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements.

[0334] By "consisting of" is meant including, and limited to, whatever follows the phrase "consisting of." Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and that no other elements may be present. By "consisting essentially of" is meant including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they materially affect the activity or action of the listed elements.

[0335] The singular form "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. These articles refer to one or to more than one (i.e., to at least one). As used herein, the term "or" is generally employed in its usual sense including "and / or" unless the content clearly dictates otherwise. The term "and / or" means any one or more of the items in the list joined by "and / or". As an example, "x and / or y" means any element of the three-element set {(x), (y), (x, y)}. In other words, "x and / or y" means "one or both of x and y". As another example, "x, y, and / or z" means any element of the seven-element set {(x), (y), (z), (x, y), (x, z), (y, z), (x, y, z)}. In other words, "x, y and / or z" means "one or more of x, y and z".

[0336] Where ranges are given, endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. Herein, "up to" a number (for example, up to 50)includes the number (for example, 50). The term "in the range" or "within a range" (and similar statements) includes the endpoints of the stated range.

[0337] Reference throughout this specification to "one aspect,” "an aspect,” "certain aspects," or "some aspects," etc., means that a particular feature, configuration, composition, or characteristic described in connection with the aspect is included in at least one aspect of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more aspects.

[0338] Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." As used herein in connection with a measured quantity, the term "about" refers to that variation in the measured quantity as would be expected by the skilled artisan making the measurement and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring equipment used. The term "about" as used in connection with a numerical value throughout the specification and the claims denotes an interval of accuracy, familiar and acceptable to a person skilled in the art. In general, such interval of accuracy is + / -10%. Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0339] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. All numerical values, however, inherently contain a range necessarily resulting from the standard deviation found in their respective testing measurements.

[0340] The term "exemplary" means serving as a non-limiting example, instance, or illustration. As utilized herein, the terms "e.g.," and "for example" set off lists of one or more non-limiting aspects, examples, instances, or illustrations.

[0341] As used herein, the term "substantially" refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. Biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term "substantially" is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena. For example, "substantially" may refer to being within at least about 20%, alternatively at least about 10%, alternatively at least about 5% of a characteristic or property of interest.

[0342] The phrases “pharmaceutically acceptable,” “physiologically acceptable,” and the like, are employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0343] As used herein, the language “sustained release” describes the release period for certain formulations of the present disclosure formulated to increase the release period e.g., to a maximum value, which is ultimately limited by the time the gastrointestinal tract naturally excretes all drugs with food. As used herein, the language “release period” describes the time window in which any compound described herein is released from the vehicle (e.g., matrix) to afford plasma concentrations of compounds described herein. The start time of the release period is defined from the point of oral administration to a subject, which when ingested orally is considered nearly equivalent to entry into the stomach, and initial dissolution by gastric enzymes and acid. The end time of the release period is defined as the point when the entire loaded drug is released. In some embodiments, the release period can be greater than about 4 hours, 8 hours, 12 hours, 16 hours, or 20 hours, greater than or equal to about 24 hours, 28 hours, 32 hours, 36 hours, or 48 hours, or less than about 48 hours, 36 hours, 4 hours or less, 3 hours or less, 2 hours or less, or 1 hour or less.

[0344] The language “tamper resistant” is art-recognized to describe aspects of a drug formulation that make it more difficult to use the formulation to abuse the drug moiety of the formulation through e.g., extraction for intravenous use, or crushing for freebase use; and therefore, reduce the risk for abuse of the drug.

[0345] The term “stable,” “stability,” and the like, as used herein includes chemical stability and solid state (physical) stability. The term “chemical stability” means that the compound can be stored in an isolated form, or in the form of a formulation in which it is provided in admixture withfor example, pharmaceutically acceptable carriers, diluents or adjuvants as described herein, under normal storage conditions, with little or no chemical degradation or decomposition. “Solid-state stability” means the compound can be stored in an isolated solid form, or the form of a solid formulation in which it is provided in admixture with, for example, pharmaceutically acceptable carriers, diluents or adjuvants as described herein, under normal storage conditions, with little or no solid-state transformation (e.g., hydration, dehydration, solvatization, desolvatization, crystallization, recrystallization or solid-state phase transition).

[0346] As used herein, the term “composition” is equivalent to the term “formulation.”

[0347] The term “treating” or “treatment” as used herein means the treating or treatment of a disease or medical condition in a patient, such as a mammal (particularly a human) that includes: ameliorating the disease or medical condition, such as, eliminating or causing regression of the disease or medical condition in a patient; suppressing the disease or medical condition, for example by, slowing or arresting the development of the disease or medical condition in a patient; or alleviating a symptom of the disease or medical condition in a patient. A treatment can provide a therapeutic benefit such as the eradication or amelioration of one or more of the physiological or psychological symptoms associated with the underlying condition, disease, or disorder such that an improvement is observed in the patient, notwithstanding the fact that the patient may still be affected by the condition. In some embodiments, treatment may refer to prophylaxis, i.e., preventing the disease or medical condition from occurring or otherwise delaying the onset of the disease or medical condition in a patient.

[0348] A “patient” or “subject,” used interchangeably herein, can be any mammal including, for example, a human. A patient or subject can have a condition to be treated or can be susceptible to a condition to be treated.

[0349] As used herein, and unless otherwise specified, the terms “manage,” “managing” and “management” refer to preventing or slowing the progression, spread or worsening of a disease, disorder, or condition, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease, disorder, or condition. In this regard, the term “managing” encompasses treating a subject who had suffered from the particular disease, disorder, or condition in an attempt to prevent or minimize the recurrence of the disease, disorder, or condition.

[0350] “Therapeutically effective amount” refers to an amount of a compound(s) or its salt form sufficient to treat a specified disorder or disease or one or more of its symptoms and / or to prevent the occurrence of the disease or disorder (prophylactically effective amount).

[0351] The invention is defined in the claims. However, below is a non-exhaustive listing of non- limiting exemplary aspects. Any one or more of the features of these aspects may be combined with any one or more features of another example, embodiment, or aspect described herein. Crystalline Solids Containing Compound (1)

[0352] The present application relates to crystals containing compound (1) and benzenesulfonic acid (type I), crystals containing compound (1) and hydrochloric acid (type II), crystals containing compound (1) and tartaric acid (type III, also referred to as “tartrate polymorph A”, “tartrate type A”, or other similar term), and crystals containing compound (1) and tartaric acid (type IV, also referred to as “tartrate polymorph C”, “tartrate type C”, or other similar term). In this specification, the descriptions of type I, type II, type III, type IV, etc. are names for convenience in distinguishing crystal forms, and the crystals related to the present invention are not limited by these names. For example, the type 1 crystals containing benzene sulfonic acid may be referred t as “compound (1) besylate”, “TAS3351 besylate”, “besylate”, “besylate salt”, “besylate co-crystal”, or other similar term. Similarly, the type II crystals containing hydrochloric acid may be referred to as “compound (1) hydrochloride”, “TAS3351 hydrochloride”, “hydrochloride”, “hydrochloride salt”, “hydrochloride co-crystal” or other similar term. Type III and IV crystals, which both contain tartaric acid, may be referred to individually or collectively as “compound (1) tartrate”, “TAS3351 tartrate”, “tartrate”, “tartrate salt”, “tartrate co-crystal”, or other similar term. Type III and Type IV crystals may be distinguished by a suitable additional label applied to the aforementioned terms, such as “type A”, “type C”, “type III”, “type IV”, “polymorph A”, “polymorph C”, or other similar term.

[0353] In this specification, N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (compound (1)) with an acid indicates salt crystals or co-crystals with the acid . Salt crystals are crystals in which the compound (1) and one or more acid molecules are bound by ionic bonding, while co-crystals are crystals in which the compound (1) and acid molecules are bound by non-ionic interaction.

[0354] In the present invention, crystals of compound (1) with an acid may be salt crystals or co- crystals, and both meanings are encompassed. For example, Type I crystals of N-(4-(4-amino-6- ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5- methylpyrazine-2-carboxamide with benzene sulfonic acid may be crystals containing a salt of compound (1) and benzene sulfonic acid, co-crystals of compound (1) and benzene sulfonic acid, or both.

[0355] Crystals indicate solids in which atoms and molecules are arranged in a regular repeating structure, and are different from amorphous (amorphous) solids that have no repeating structure. Crystalline or amorphous solids can be examined by powder X-ray diffraction measurement (XRD measurement), differential scanning calorimetry (DSC measurement), thermogravimetric- differential thermal analysis (TG-DTA), and single crystal analysis. Crystalline polymorphs represent the same molecule but with different arrangements of atoms or molecules in the crystal, and it is known that the peaks obtained by XRD measurement are different among crystalline polymorphs. It is also known that solubility, oral absorption and / or stability, etc. are different among the respective crystalline polymorphs.

[0356] As used herein, the terms "crystalline" and "amorphous" are used in the usual sense, and the crystalline form can be confirmed by X-ray diffraction spectra. It is worth noting that in powder X-ray diffraction patterns, the diffraction angle and the overall pattern are important in qualifying the identity of crystals due to the nature of the data. The relative intensity of the powder X-ray diffraction pattern should not be strictly interpreted, since it can vary somewhat depending on the direction of crystal growth, particle size, measurement conditions, the state of maintenance of the measurement equipment, and the method of preparing the measurement sample. In this specification, "a powder X-ray diffraction spectrum that is substantially identical to the powder X- ray diffraction spectrum shown in the figure" means a powder X-ray diffraction spectrum that can be recognized by a person skilled in the art as identical to the powder X-ray diffraction spectrum shown in the figure, considering some variation in peak position and intensity. For example, the numerical value of the diffraction angle (2θ) can have a measurement error in the range of ±0.2°.

[0357] In crystals of compound (1) and acid (crystals of its salt or co-crystals), the equivalent amount of acid to compound (1) can be analyzed by NMR or ion chromatography, for example. In this specification, crystals may be either hydrated or anhydrous.

[0358] Salts herein may have any suitable stoichiometry. For example, a salt may have a molar ratio of compound (1) to the acid of from 1:10 to 10:1, preferably 1:9 to 9:1, preferably 1:8 to 8:1, preferably 1:7 to 7:1, preferably 1:6 to 6:1, preferably 1:5 to 5:1, preferably 1:4 to 4:1, preferably 1:3 to 3:1, preferably 1:2 to 2:1, preferably 1:1.5 to 1.5:1, preferably 1.25:1 to 1:1.25, preferably about 1:1.

[0359] Compound (1), or a labeled form of compound (1) or salt thereof, i.e., compound (1) or a salt of compound (1), or a compound in which one or more atoms are replaced by a radioactive or non-radioactive isotope, are also included in the present invention.

[0360] The crystals may contain crystals of compound (1) and an acid, and may be a single crystal or a polymorphic mixture containing crystals containing other compounds (1). Specifically, the crystals may have a purity of 40% by weight or more (i.e., 40% or more of the crystals are single crystals). It is preferred that the crystals have a purity of 50% or more by weight (i.e., 50% or more of the crystals are single crystals), more preferred that the crystals have a purity of 75% or more by weight (i.e., 75% or more of the crystals are single crystals), more preferred that the crystals have a purity of 90% or more by weight (i.e., 90% or more of the crystals are single crystals), more preferred, crystal purity of 95% or more by weight (i.e.95% or more by weight is a single crystal) is even more preferred, crystal purity of 98% or more by weight (i.e.98% or more by weight is a single crystal) is even more preferred, crystal purity of 99% or more by weight (i.e.99% or more by weight is a single crystal) is It is especially preferred that the purity of the crystals be 99% or higher (i.e., 99% or higher is a single crystal). This purity can be measured by differential scanning calorimetry (DSC measurement) or other analysis.

[0361] In this specification, chemical purity refers to the purity of compound (1) as measured by high-performance liquid chromatography (HPLC). In such cases, the wavelength of the detector used for the purity measurement can be set appropriately. Specifically, the chemical purity of the crystal of compound (1) is preferably 90% or higher, 95% or higher is more preferred, 98% or higher is even more preferred, and 99% or higher is especially preferred.

[0362] The crystals containing compound (1) and an acid should be understood to cover the possibility of one more types of acids. For example, a crystal can contain compound (1), hydrochloric acid, and tartaric acid. In this example, such a crystal can contain any or all of compound (1), a hydrochloric acid salt of compound (1), a tartaric acid salt of compound (1), tartaric acid, and hydrochloric acid. That is, such a crystal can be, for example, a co-crystal ofcompound (1), hydrochloric acid, and tartaric acid, a crystal containing a hydrochloric acid salt of compound (1) and a tartaric acid salt of compound (1), a crystal containing a hydrochloric acid salt of compound (1) and tartaric acid, a crystal containing a tartaric acid salt of compound (1) and hydrochloric acid, a crystal containing a hydrochloric acid salt of compound (1) and hydrochloric acid, etc.

[0363] In the context of the above paragraph, a chemical purity of such a crystal can refer to a purity based on a content of compound (1) and the acid(s) included in the crystal.

[0364] The numerical values obtained from various patterns may have some errors depending on the direction of crystal growth, the size of the particles, measurement conditions, and other factors. Therefore, in this specification, the numerical value of the diffraction angle (2θ) in the powder X- ray diffraction pattern can have a measurement error in the range of about ±0.2°. In other words, when "diffraction angle (2θ ± 0.2°)" is described herein, it means that a measurement error of ± 0.2° in the numerical value of diffraction angle (2θ) is allowed. For example, when the diffraction angle (2θ ± 0.2°) is described as "6.6°," it means that a diffraction angle of up to 6.6° ± 0.2° is allowed, which includes a diffraction angle of "6.4° to 6.8°. The value can be obtained by the Bragg formula (2d sinθ = nλ) and varies depending on the wavelength of the measurement. In other words, by substituting the measurement wavelength into the above formula, it can be converted to the diffraction angle at a different measurement wavelength. For example, if the values of diffraction angle (2θ) are 6.6° and 8.8°, respectively, at a wavelength λ of 1.54 Å, which is the characteristic X-ray of CuKα, and the values of d and n are invariant, the diffraction angle (2θ) at 0.75 Å is 3.2° and 4.3°, respectively.

[0365] Compound (1) used in the crystallization method of the present invention is, for example, produced by the methods described herein.

[0366] For crystallization, it is possible to use the synthesized Compound (1) without extracting it as a crystal or after extracting it once as a crystal (crude crystal).

[0367] As used herein, "room temperature" usually indicates from about 18 °C to about 25 °C.

[0368] As used herein, "lower alcohol" indicates an alcohol with a carbon number of 1 to 5, which may be linear or have a branched chain. Examples include methanol, ethanol, propanol, isopropyl alcohol, butanol, and pentanol.

[0369] The endothermic peak in the simultaneous differential thermo-thermogravimetric (TG- DTA) curve usually means ±5.0°C, as the measured temperature may vary depending on the rangeof temperature rise per minute, chemical purity of the sample, etc. Therefore, when crystals of the present invention are measured (TG-DTA), an error of ±5.0°C in the peak (onset value) is considered. The term "near" used in this case means ±5.0°C.

[0370] One aspect of the present invention relates to crystals of compound (1) with benzene sulfonic acid (type I crystal), compound (1) with hydrochloric acid (type II crystal), and compound (1) with tartaric acid acid (type III crystal and type IV crystal). Furthermore, among crystalline forms or co-crystals with a given acid, crystals with one or more of benzene sulfonic acid, hydrochloric acid, and tartaric acid were found to advantageous properties, for example stability, low hygroscopicity, reproducible acquisition, significant solubility in biologically and / or pharmaceutically relevant solvents such as phosphate buffered saline, and lack of polymorphism.

[0371] In this specification, the stability of the crystals can be evaluated, for example, by the solid stability tests shown in the Examples section below. Such stability may be stability to one or more of drying / humidification, polymorphism, solubility in a phosphate buffer, purity, stoichiometry, crystallinity, and residual solvent.

[0372] In this specification, the hygroscopicity of the crystals can be evaluated by the dynamic moisture adsorption / desorption (DVS) test shown in Test Example 2 below. The crystals of compound (1) in one embodiment of the invention preferably have a weight gain of less than 5%, more preferably less than 3%, and more preferably less than 1% when evaluated under the conditions described in the Examples section below.

[0373] One embodiment of the present invention provides an anti-tumor agent containing crystals of the compound (1) described above (i.e., crystals of the compound (1) with acid (salt crystals or co-crystals)). Also, an embodiment of the present invention provides a method of treating a tumor, comprising administering to a subject in need thereof an effective amount of crystals of the compound (1) described above. One embodiment of the invention provides for the use of crystals of compound (1) to produce an anti-tumor agent. Furthermore, one embodiment of the invention provides crystals of compound (1) for use in the treatment of tumors. N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1))

[0374] Compound (1) is a compound having the following structure, which is disclosed in Patent Literature 1 as a compound having an excellent inhibitory effect against EGFR.

[0375] Compound (1) used in the ticularly limited. For example, one produced by the following production method can be used.

[0376] <Method for producing Compound (1)>

[0377] Compound (1) can be produced, for example, by the method described in Patent Literature 1 or the method described herein. Alternatively, the compound can also be produced by combining known reactions using the intermediate described in Patent Literature 1 and herein as a starting material. The product obtained in each step can be isolated and purified by a known isolation / purification method, such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, or the like, or can be subjected to the subsequent step without being isolated or purified. Moreover, in the following production methods, introduction of a protective group or deprotection may be conducted as needed, whether or not it is described, and the order of the steps may be changed as appropriate.

[0378]

[0039] Here, a method for producing Compound (1) using tert-butyl(4-(4-amino-6-bromo- 5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptane-1-yl)carbamate as a starting material will be described.

[0379] (Step 1) - Synthesis of tert-butyl(4-(4-amino-5-(quinoline-3-yl)-6-((triethylsilyl)ethynyl)- 7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptane-1-yl)carbamateacetylene derivative with tert-butyl(4-(4-amino-6-bromo-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptane-1-yl)carbamate obtained by the method described in Patent Literature 1 or by other known method.

[0381] A catalyst can be used for this reaction. For example, a palladium catalyst can be used alone or in combination with an activator if necessary.

[0382] Examples of the palladium catalyst include, but are not particularly limited to, carbon- supported palladium(Pd-C), alumina-supported palladium, silica gel-immobilized palladium, palladium acetate, dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II), tetrakis(triphenylphosphine)palladium(0), dichloro(1,1- bis(diphenylphosphino)ferrocene)palladium(II), and dichlorobis(triphenylphosphine)palladium(II). Examples of a ligand of the catalyst include, but are not particularly limited to, tri(o-tolyl)phosphine, tri(tert-butyl)phosphine, triphenylphosphine, dichlorobis(triphenylphosphine), 2-di-tert-butylphosphino-2’,4’,6’-triisopropylbiphenyl, 2- dicyclohexylphosphino-2’,6’-dimethoxybiphenyl, [4-(N,N-dimethylamino)phenyl]di-tert- butylphosphine, di-tert-butyl(4-dimethylaminophenyl)phosphine, tricyclohexylphosphine, 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and bis(2- (diphenylphosphino)phenyl)ether. The ligand of the catalyst can be either coordinated with the palladium catalyst in advance, or the palladium catalyst and the ligand of the catalyst can be added separately to a solvent to be coordinated in the reaction solvent.

[0383] While examples of the palladium catalyst are listed above, it is preferably dichlorobis[di- tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II). In addition, the ligand of said catalyst is preferably di-tert-butyl(4-dimethylaminophenyl)phosphine or tricyclohexylphosphine.

[0384] As the activator, a copper catalyst, a silver catalyst, a quaternary ammonium, an aqueous amine solution, or the like can be used. Examples of the copper catalyst include salts with monovalent copper ions, specifically copper(I) halides (copper(I) fluoride, copper(I) chloride, copper(I) bromide, copper(I) iodide, copper(I) trifluoromethanesulfonate, etc.). Examples of the silver catalyst include salts with monovalent silver ions, specifically silver(I) oxide. Examples of the quaternary ammonium include quaternary ammonium hydroxides (tetra-n-butylammonium hydroxide: TBAOH, tetraethylammonium hydroxide: TEAOH, n-hexadecyltrimethylammonium hydroxide, choline hydroxide, etc.). As the aqueous amine solution, an aqueous solution of ammonia, a primary amine, a secondary amine, a tertiary amine, or the like can be used. The activator is preferably a copper catalyst, more preferably a salt with a monovalent copper ion, stillmore preferably copper(I) bromide, copper(I) iodide, or copper(I) trifluoromethanesulfonate, and particularly preferably copper(I) iodide.

[0385] The base used for Sonogashira coupling is not particularly limited as long as the base can result the introduction of alkyne groups, and examples thereof include organic bases such as trimethylamine, diethylamine, diisopropylamine (DIPEA), triethylamine (TEA), N- methylmorpholine, diazabicyclononene (DBN), pyridine, 4-dimethylaminopyridine (DMAP), pyridine, morpholine, quinoline, piperidine, and diazabicycloundecene (DBU), and inorganic bases such as alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, calcium acetate, etc.), alkali metal carbonates (sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkaline earth metal carbonates (barium carbonate, calcium carbonate), alkali metal phosphates (sodium phosphate, potassium phosphate, etc.), and acetates (magnesium acetate, potassium acetate, calcium acetate, cesium acetate, etc.). Preferably, the base is an organic base and more preferably diisopropylethylamine.

[0386] The solvent used for Sonogashira coupling is not particularly limited as long as the solvent is capable of carrying out the above reaction, and examples thereof include N,N- diisopropylethylamine, N-methyl-2-pyrrolidone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran 1,4-dioxane, and toluene. Preferably, the solvent is N-methyl-2-pyrrolidone, N,N- dimethylformamide, or N,N-dimethylacetamide.

[0387] The reaction time for Sonogashira coupling is not particularly limited as long as it can result the introduction of alkyne groups. For example, the reaction time is 0.5 to 8 hours, preferably 0.5 to 5 hours, and more preferably 1 to 3 hours.

[0388]

[0047] The reaction temperature for Sonogashira coupling is not particularly limited as long as it can result the introduction of alkyne groups. For example, the reaction temperature is 25°C to 120°C, preferably 50°C to 110°C, and more preferably 80°C to 100°C.

[0389] (Step 2) - Synthesis of 7-(4-aminobicyclo[2.2.1]heptane-1-yl)-5-(quinoline-3-yl)-6- ((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine[039 oc (tert- butoxycarbonyl), in tert-butyl(4-(4-amino-5-(quinoline-3-yl)-6-((triethylsilyl)ethynyl)-7H- pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1]heptane-1-yl)carbamate synthesized as described above.

[0391] Deprotection of the protective group of amine can be performed by a known method according to the protective group. The deprotection can be performed under acidic conditions, under reductive conditions, under basic conditions, using a palladium catalyst, or the like. For example, in the case of Boc, deprotection is generally carried out under acidic conditions, and any acid can be used to provide the acidic conditions as long as the deprotection can proceed. Preferably, the acid is trifluoroacetic acid, hydrochloric acid, or sulfuric acid. Moreover, the amount of the acid used to provide the acidic condition is not particularly limited as long as the reaction can proceed.

[0392] The solvent used for the deprotection reaction of the protective group of amine is not particularly limited as long as the reaction can proceed. The solvent can be selected from the same solvents as those used in step of deprotecting a silicon-linked protective group described below. Preferably, the solvent is methanol, ethanol, 2-propanol, acetonitrile, or tetrahydrofuran, more preferably methanol, ethanol, or 2-propanol, and still more preferably methanol. While the amount of the solvent used is not particularly limited as long as the reaction can proceed, it is preferably 1 to 100 L, more preferably 5 to 50 L, and still more preferably 10 to 30 L per 1 kg of the reactant.

[0393] (Step 3) - Synthesis of N-(4-(4-amino-5-(quinoline-3-yl)-6-((triethylsilyl)ethynyl)-7H- pyrrolo[2,3-d]pyrimidine-7-yl)bicyclo[2.2.1](heptane-1-yl)-5-methylpyrazine-2-carboxamide[039 1-yl)-5- (quinoline-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine obtained in Step 2 with 5-methylpyrazine-2-carboxylic acid.

[0395] The condensing agent used for the condensation reaction is not particularly limited as long as the reaction can proceed. Examples of the condensing agent include: combinations of a carbodiimide condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a hydrochloride thereof (WSC or EDC), dicyclohexylcarbodiimide (DCC), 1-cyclohexyl-3-(2- morpholinoethyl)carbodiimide metho-p-toluenesulfonate (CMC), diisopropylcarbodiimide (DIC), or 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC) and an activated ester- forming alcohol such as 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl(hydroxyimino)cyanoacetate (Oxyma), N-hydroxysuccinimide (HOSu), or pentafluorophenol; uronium condensing agents such as O-(7-azabenzotriazolo-1-yl)-N,N,N’,N’- tetramethylhexauronium hexafluorophosphate (HATU) and (1-cyano-2-ethoxy-2- oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU); 2- halo-N-alkylpyridinium salts (Mukaiyama condensation reagent) such as 2-chloro-6-methyl-1,3- diphenylpyridinium tetrafluoroborate and 1-methyl-2-chloropyridinium iodide; imidazole condensing agents such as N,N’-carbonyldiimidazole (CDI) and 1,1’-carbonyldi(1,2,4-triazole) (CDT); phosphonium condensing agents such as bromotripyrrolidinophosphonium hexafluorophate, chlorotripyrrolidinophosphonium hexafluorophate, 1H-benzotriazole-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), and (7-azabenzotriazole-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP); triazine condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM) and (4,6- dimethoxy-1,3,5-triazine-2-yl)-(octoxy-2-oxoethyl)dimethylammonium trifluoromethanesulfonate; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide(T3P); and diphenylphosphoryl azide (DPPA). Preferably, the condensing agent is a combination of a carbodiimide condensing agent and an activated ester-forming alcohol, and more preferably a combination of EDC and HOBt. These condensing agents include polymer-supported reagents.

[0396]

[0051] The solvent used for the condensation reaction is not particularly limited as long as the reaction can proceed. The solvent can be selected from the same solvents as those used in the step of deprotecting a silicon-linked protective group. Preferably, the solvent is dichloromethane, chloroform, ethyl acetate, dimethyl sulfoxide, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetone, N,N-dimethylformamide, N-methylpyrrolidone, toluene, or acetonitrile tetrahydrofuran, more preferably, dichloromethane, chloroform, ethyl acetate, dimethyl sulfoxide, or N,N- dimethylformamide, and still more preferably dichloromethane or chloroform. While the amount of the solvent used is not particularly limited as long as the reaction can proceed, it is preferably 5 to 100 L, more preferably 15 to 50 L, and still more preferably 25 to 35 L per 1 kg of the reactant.

[0397] (Step 4) - Synthesis of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (Compound (1))of acetylene in N-(4-(4-amino-5-(quinoline-3-yl)-6-((triethylsilyl)ethynyl)-7H-pyrrolo[2,3- d]pyrimidine-7-yl)bicyclo[2.2.1])heptane-1-yl)-5-methylpyrazine-2-carboxamide obtained in Step 3, under basic conditions.

[0399] While the reagent used for providing basic conditions is not particularly limited as long as the reaction can proceed, examples thereof include inorganic bases such as metal hydroxides (sodium hydroxide, calcium hydroxide, etc.), metal hydrides (lithium hydride, sodium hydride, etc.), and metal carbonates (sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, lithium carbonate, magnesium carbonate, sodium bicarbonate, etc.), and organic bases such as metal alkoxides (sodium methoxide, potassium tert-butoxide, etc.), metal amides (sodium amide, lithium diisopropyl amide, etc.), alkyl metal compounds (n-butyllithium,trimethylaluminum, etc.), alkylamines (triethylamine, tetramethylethylenediamine, piperidine, 1,4-diazabicyclo[2.2.2]octane, etc.), heterocyclic amines (diazabicycloundecene, pyridine, imidazole, etc.), and quaternary ammonium fluorides (tetra-n-butylammonium fluoride). Preferably, the reagent used for providing basic conditions is a reagent that does not contain fluoride ions, more preferably a metal carbonate, and still more preferably potassium carbonate. These reagents can be used alone or in combination to adjust the pH to the desired level.

[0400] While the amount of the reagent used is not particularly limited as long as the reaction can proceed, it can be used in an amount of, for example, 0.1 to 50 moles per mole of the starting compound (compound represented by formula (II)). Preferably, it is 0.1 to 10 moles, and more preferably 0.1 to 2 moles.

[0401] The solvent used for the deprotection step is not particularly limited as long as the pH can be set to a basic condition and the compound used in the reaction can be dissolved. Examples of the solvent include a C5-C10 hydrocarbon, a C6-C14 aromatic hydrocarbon, a C1-C6 alcohol, a C3-C10 aliphatic carboxylic ester, a C3-C10 ketone, a C4-C10 ether, a non-protic polar organic solvent, and a mixed solvent thereof. Herein, C followed by a number refers to the number of carbon atoms, which is the total number of carbon atoms contained in the compound.

[0402] C5-C10 hydrocarbons refer to hydrocarbons with 5 to 10 carbon atoms, such as pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane.

[0403] C6-C14 aromatic hydrocarbons refer to aromatic hydrocarbons with 6 to 14 carbon atoms, such as benzene, naphthalene, anthracene, toluene, xylene, cumene, styrene, and phenanthrene.

[0404] C1-C6 alcohols refer to alcohols with 1 to 6 carbon atoms, such as methanol, ethanol, n- propanol, isopropanol, n-butanol, tert-butanol, n-pentanol, and n-hexanol.

[0405] C3-C10 aliphatic carboxylic esters refer to aliphatic carboxylic esters with 3 to 10 carbon atoms, such as propyl formate, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, ethyl propionate, propyl propionate, methyl butanoate, and ethyl butanoate.

[0406] C3-C10 ketones refer to ketones with 3 to 10 carbon atoms, such as acetone, ethyl methyl ketone, diethyl ketone, isopropyl methyl ketone, and cyclohexanone.

[0407] C4-C10 ethers refer to ethers with 4 to 10 carbon atoms, such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, and 1,4-dioxane.

[0408] Non-protic polar organic solvents refer to solvents that do not have a proton to ionize, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, chloroform, and dichloromethane. Pharmaceutical compositions

[0409] Also disclosed herein is a pharmaceutical composition comprising a crystal containing compound (1) and an acid as describe above, and a pharmaceutically acceptable vehicle.

[0410] “Pharmaceutically acceptable vehicles” may be vehicles approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, such as humans. The term “vehicle” herein refers to a diluent, adjuvant, excipient, carrier, or any other auxiliary or supporting ingredient with which a salt form of a compound of the present disclosure is formulated for administration to a mammal. Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical vehicles can be water, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. The pharmaceutical vehicles can include one or more gases, e.g., to act as a carrier for administration via inhalation. In addition, auxiliary, stabilizing, thickening, lubricating, taste masking, coloring agents, and other pharmaceutical additives may be included in the disclosed compositions, for example those set forth hereinafter.

[0411] The crystal described above may be present in the pharmaceutical composition at a purity of at least 50% by weight, at least 60% by weight, at least 70% by weight, at least 80% by weight, at least 90% by weight, at least 95% by weight, at least 99% by weight, based on a total weight of crystals containing compound (1) described above present in the pharmaceutical composition

[0412] Pharmaceutical compositions can take the form of capsules, tablets, pills, pellets, lozenges, powders, granules, syrups, elixirs, solutions, suspensions, emulsions, suppositories, or sustained- release formulations thereof, or any other form suitable for administration to a mammal. In some instances, the pharmaceutical compositions are formulated for administration in accordance with routine procedures as a pharmaceutical composition adapted for oral or intravenous administration to humans. The choice of vehicle will be determined in part by the particular compound, salt form,as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the subject pharmaceutical compositions.

[0413] When administered to a mammal, the compounds and compositions of the present disclosure and pharmaceutically acceptable vehicles may be sterile. In some instances, an aqueous medium is employed as a vehicle e.g., when the subject compound is administered intravenously or via inhalation, such as water, saline solutions, and aqueous dextrose and glycerol solutions.

[0414] The quantity of crystal containing compound (1) as described above in a unit dose preparation may be varied or adjusted to provide (on active basis) e.g., from 0.001 mg to 100 mg, or 0.001 mg to 75 mg, or 0.001 mg to 50 mg, or 0.001 mg to 25 mg, or 0.001 mg to 10 mg, or 0.01 mg to 8 mg, or 0.1 mg to 5 mg, or 1 mg to 3 mg of compound (1), or otherwise as deemed appropriate using sound medical judgment, according to the particular application, administration route, potency of the active component, etc. The composition can, if desired, also contain other compatible therapeutic agents.

[0415] The pharmaceutical compositions disclosed herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens can, and in some cases should, be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.

[0416] In the case wherein the patient's condition does not improve, upon the doctor's discretion the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0417] In the case wherein the patient's status does improve, upon the doctor's discretion the compounds may be given continuously or temporarily suspended for a certain length of time (i.e., a “drug holiday”).

[0418] Once improvement of the patient's conditions has occurred, a maintenance dose may be administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disorder isretained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0419] In some embodiments, the pharmaceutical composition has an onset of therapeutic action of 60, 50, 40, 30, 20, 10, 5 minutes or less. In some embodiments, the pharmaceutical composition has an acute effects duration of 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 5 minutes or less. In some embodiments, the pharmaceutical composition has a drug dissolution time of 120, 90, 60, 50, 40, 30, 20, 10, 5 seconds or less.

[0420] As described below, the pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid, semi-solid, or liquid form, including those adapted for the following: A. Oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, films, or capsules, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, syrups, pastes for application to the tongue; B. Parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained release formulation; C. Topical application / transdermal administration, for example, as a cream, ointment, or a controlled release patch or spray applied to the skin, or orifices and / or mucosal surfaces such as intravaginally or intrarectally, for example, as a pessary, cream or foam; and D. Modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms, such modified release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art.

[0421] Any of the pharmaceutical compositions described herein can comprise (as the active component) at least one of the crystals containing compound (1) and an acid as described herein. Tamper resistant dosage forms / packaging of any of the disclosed pharmaceutical compositions are contemplated. A. Oral Administration

[0422] The pharmaceutical compositions disclosed herein may be provided in solid, semisolid, or liquid dosage forms for oral administration, including both enteric / gastric delivery routes as wellas intraoral routes such as buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable vehicles, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.

[0423] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remains intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC- 581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixtures thereof.

[0424] Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre- gelatinized starch, and mixtures thereof. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions disclosed herein.

[0425] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.

[0426] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions disclosed herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions disclosed herein may contain e.g., from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

[0427] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co. of Boston, Mass.); and mixtures thereof. The pharmaceutical compositions disclosed herein may contain e.g., about 0.1 to about 5% by weight of a lubricant.

[0428] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-free talc. Coloring agents include any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethylalcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.

[0429] It should be understood that many vehicles may serve several functions, even within the same formulation.

[0430] The pharmaceutical compositions disclosed herein may formulated as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

[0431] The tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more vehicles described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

[0432] The pharmaceutical compositions disclosed herein may be formulated as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl-and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms disclosed herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.

[0433] The pharmaceutical compositions disclosed herein may be in the form of orodispersible dosage forms (ODFs). In some embodiments, the pharmaceutical compositions are in the form of fast dissolving tablets, also called orodispersible tablets (ODTs) or fast dispersible tablets (FDTs). Fast dissolving tablets can be prepared by different techniques, such as freeze drying (lyophilization), molding, spray drying, mass extrusion or compressing. Preferably, the fast dissolving tablets are prepared by lyophilization. In some embodiments, fast dissolving tablet refers to forms which disintegrate in less than about 90 seconds, in less than about 60 seconds, in less than about 30 seconds, in less than about 20, in less than about 10 seconds in the oral cavity, in less than about 5 seconds, or in less than about 2 seconds after being received in the oral cavity. In some embodiments, fast dissolving tablet refers to forms which dissolve in less than about 90 seconds, in less than about 60 seconds, or in less than about 30 seconds.

[0434] In some embodiments, the pharmaceutical compositions are in the form of lyophilized FDTs. In some embodiments, the lyophilized FDTs are created by creating a porous matrix by subliming the water from a pre-frozen aqueous formulation of the drug containing matrix-forming agents and other excipients such as lyoprotectants, preservatives, and flavoring agents. In some embodiments, the FDTs comprise two component frameworks of a lyophilized matrix system that work together to ensure the development of a successful formulation. In some embodiments, the first component is water-soluble polymers such as gelatin, dextran, alginate, and maltodextrin. This component maintains the shape and provides mechanical strength to the tablets (binder). In some embodiments, the second constituent is matrix-supporting / disintegration-enhancing agents such as sucrose and mannitol, which acts by cementing the porous framework, provided by the water-soluble polymer and accelerates the disintegration of the FDT. In some embodiments, the lyophilized FDTs include gelatin and mannitol.

[0435] In some embodiments, the pharmaceutical compositions are in the form of lyophilized wafers. In some embodiments, the pharmaceutical compositions are in the form of lyophilized wafers protected for the long-term storage by a specialty packaging excluding moisture, oxygenand light. In some embodiments, the lyophilized wafers are created by creating a porous matrix by subliming the water from a pre-frozen aqueous formulation of the drug containing matrix-forming agents and other excipients such as lyoprotectants, preservatives, and flavoring agents. In some embodiments, the lyophilized wafer includes a thin water-soluble film matrix. In some embodiments, the wafers comprise two component frameworks of a lyophilized matrix system that work together to ensure the development of a successful formulation. In some embodiments, the first component is water-soluble polymers such as gelatin, dextran, alginate, and maltodextrin. This component maintains the shape and provides mechanical strength to the wafer (binder). In some embodiments, the second constituent is matrix-supporting / disintegration-enhancing agents such as sucrose and mannitol, which acts by cementing the porous framework, provided by the water-soluble polymer and accelerates the disintegration of the wafer. In some embodiments, the lyophilized wafers include gelatin and mannitol.

[0436] In some embodiments, the wafer can comprise a monolayer, bilayer, or trilayer. In some embodiments, the monolayer wafer contains an active agent and one or more excipients. In some embodiments, the bilayer wafer contains one or more excipients, such as a solubilizing agent, in a first layer and an active agent in the second layer. This configuration allows the active agent to be stored separately from the excipients and can increase the stability of the active agent and optionally increase the shelf life of the composition compared to the case where the excipients and the active agent were contained in a single layer. For tri-layer wafers, each of the layers may be different or two of the layers, such as the upper and lower layers, may have substantially the same composition. In some embodiments, the lower and upper layers surround a core layer containing the active agent. In some embodiments, the lower and upper layers may contain one or more excipients, such as a solubilizing agent. In some embodiments, the lower and upper layers have the same composition. Alternatively, the lower and upper layers may contain different excipients or different amounts of the same excipient. The core layer typically contains the active agent, optionally with one or more excipients.

[0437] In some embodiments, in addition to the active ingredient(s), the pharmaceutical compositions in orodispersible dosage forms (ODFs) may contain one or more pharmaceutically acceptable carriers or excipients. For example, in some embodiments, pharmaceutical compositions in orodispersible dosage forms (ODFs) include pharmaceutically acceptable antioxidants to further enhance stability of the composition.

[0438] Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0439] Cyclodextrins such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl β- cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, sulfobutyl ether β-cyclodextrin, or other solubilized derivatives can also be advantageously used to enhance delivery of compositions described herein.

[0440] Disclosed herein are pharmaceutical compositions in modified release dosage forms, which comprise a compound as disclosed herein and one or more release controlling excipients or carriers as described herein. Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. The pharmaceutical compositions may also comprise non-release controlling excipients or carriers.

[0441] Further disclosed herein are pharmaceutical compositions in enteric coated dosage forms, which comprise a compound as disclosed herein and one or more release controlling excipients or carriers for use in an enteric coated dosage form. The pharmaceutical compositions may also comprise non-release controlling excipients or carriers.

[0442] Further disclosed herein are pharmaceutical compositions in effervescent dosage forms, which comprise a compound as disclosed herein and one or more release controlling excipients or carriers for use in an effervescent dosage form. The pharmaceutical compositions may also comprise non-release controlling excipients or carriers.

[0443] Additionally, disclosed are pharmaceutical compositions in a dosage form that has an instant releasing component and at least one delayed releasing component, and is capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from about 0.1 up to about 24 hours (e.g., about 0.1, 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 10, 22, or 24 hours). The pharmaceutical compositions comprise a compound as disclosed herein and one or more release controlling and non-release controlling excipients or carriers, such as thoseexcipients or carriers suitable for a disruptable semipermeable membrane and as swellable substances.

[0444] Disclosed herein also are pharmaceutical compositions in a dosage form for oral administration to a subject, which comprise a salt form of a compound as disclosed herein and one or more pharmaceutically acceptable vehicles, enclosed in an intermediate reactive layer comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer.

[0445] In some embodiments, the pharmaceutical compositions are in the form of immediate- release capsules for oral administration, and may further comprise cellulose, iron oxides, lactose, magnesium stearate, and sodium starch glycolate.

[0446] In some embodiments, the pharmaceutical compositions are in the form of delayed-release capsules for oral administration, and may further comprise cellulose, ethylcellulose, gelatin, hypromellose, iron oxide, and titanium dioxide.

[0447] In some embodiments, the pharmaceutical compositions are in the form of enteric coated delayed-release tablets for oral administration, and may further comprise carnauba wax, crospovidone, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow ferric oxide.

[0448] In some embodiments, the pharmaceutical compositions are in the form of enteric coated delayed-release tablets for oral administration, and may further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0449] The pharmaceutical compositions disclosed herein may be formulated as liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and optional preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term “lower” means an alkyl havingbetween 1 and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.

[0450] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) disclosed herein, and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol- 350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates. In some embodiments, examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0451] Cyclodextrins such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl β- cyclodextrin, hydroxypropyl γ-cyclodextrin, sulfated β-cyclodextrin, sulfated α-cyclodextrin, sulfobutyl ether β-cyclodextrin, or other solubilized derivatives can also be advantageously used to enhance delivery of compositions described herein.

[0452] The pharmaceutical compositions disclosed herein for oral administration may be also disclosed in the forms of liposomes, micelles, microspheres, or nanosystems.

[0453] The pharmaceutical compositions disclosed herein may be disclosed as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable vehicles used in the non-effervescent granules or powders mayinclude diluents, sweeteners, and wetting agents. Pharmaceutically acceptable vehicles used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.

[0454] Coloring and flavoring agents can be used in all of the above dosage forms.

[0455] The pharmaceutical compositions disclosed herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action. B. Parenteral Administration

[0456] The pharmaceutical compositions disclosed herein may be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0457] The pharmaceutical compositions disclosed herein may be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science.

[0458] The pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable vehicles, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0459] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil.Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide.

[0460] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzates, thimerosal, benzalkonium chloride, benzethonium chloride, methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including ca-cyclodextrin, β-cyclodextrin, hydroxypropyl-3- cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-O-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

[0461] The pharmaceutical compositions disclosed herein may be formulated for single or multiple dosage administration. The single dosage formulations are packaged in an ampule, a vial, or a syringe. The multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.

[0462] In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile solutions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile suspensions. In some embodiments, the pharmaceutical compositions are disclosed as sterile dry insoluble products to be reconstituted with a vehicle prior to use. In some embodiments, the pharmaceutical compositions are disclosed as ready-to-use sterile emulsions.

[0463] The pharmaceutical compositions may be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In some embodiments, the pharmaceutical compositions disclosed herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.

[0464] Suitable inner matrixes include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0465] Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer. C. Topical Administration

[0466] The pharmaceutical compositions disclosed herein may be administered topically to the skin, orifices, or mucosa. Topical administration, as described herein, includes (intra)dermal, conjuctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, uretheral, respiratory, and rectal administration.

[0467] The pharmaceutical compositions disclosed herein may be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, dermal patches. The topical formulation of the pharmaceuticalcompositions disclosed herein may also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0468] Pharmaceutically acceptable vehicles suitable for use in the topical formulations disclosed herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0469] Transdermal patch dosage forms may be formulated with various amounts of the active agent (compound (1) provided in salt and / or co-crystal form), depending on the disease / condition being treated. The quantity of active agent in a unit dose preparation may be varied or adjusted e.g., from 5 mg to 25 mg, or 10 mg to 20 mg, or 12 mg to 18 mg, or 13 mg to 16 mg, or 14 mg to 15 mg, or otherwise as deemed appropriate using sound medical judgment, according to the particular application and the potency of the active component. Transdermal patches formulated with the disclosed compounds may be suitable for microdosing to achieve durable therapeutic benefits, with decreased toxicity. In some embodiments, compounds of the present disclosure may be administered via a transdermal patch at serotonergic, but sub-psychoactive concentrations, for example, over an extended period such as over a 24 hour period.

[0470] The pharmaceutical compositions may also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp., Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, Oreg.).

[0471] The pharmaceutical compositions disclosed herein may be disclosed in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including such as lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. These vehicles are emollient but generally require addition of antioxidants and preservatives.

[0472] Suitable cream base can be oil-in-water or water-in-oil. Cream vehicles may be water- washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the “internal” phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.

[0473] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, Carbopol®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene- polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and / or stirring.

[0474] The pharmaceutical compositions disclosed herein may be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas.

[0475] Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable vehicles utilized in rectal and vaginal suppositories include bases such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions disclosed herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. Combinations of the various vehicles may be used. Rectal and vaginal suppositories may be prepared by the compressed method or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[0476] The pharmaceutical compositions disclosed herein may be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.

[0477] The pharmaceutical compositions disclosed herein may be administered intranasally. The pharmaceutical compositions may be in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), carbon dioxide, perfluorinated hydrocarbons such as perflubron, and other suitable gases. The pharmaceutical compositions may also be disclosed as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, including chitosan or cyclodextrin.

[0478] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer may be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient disclosed herein, a propellant as solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

[0479] The pharmaceutical compositions disclosed herein may be micronized to a size suitable for delivery, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes may be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0480] Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the pharmaceutical compositions disclosed herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions disclosed herein for inhaled / intranasal administration may further comprise a suitable flavoring agent, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.

[0481] The pharmaceutical compositions disclosed herein for topical administration may be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release. D. Modified Release Dosage Forms

[0482] The pharmaceutical compositions disclosed herein may be formulated as a modified release dosage form. As used herein, the term “modified release” refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix-controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s). 1. Matrix-Controlled Release Devices

[0483] The pharmaceutical compositions disclosed herein in a modified release dosage form may be fabricated using a matrix-controlled release device known to those skilled in the art.

[0484] In some embodiments, the pharmaceutical compositions disclosed herein in a modified release dosage form is formulated using an erodible matrix device, which is water-swellable, erodible, or soluble polymers, including synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.

[0485] Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(−)-3- hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate, (2- dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.

[0486] In further embodiments, the pharmaceutical compositions are formulated with a non- erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device included, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinylacetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, and; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate, and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.

[0487] In a matrix-controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and / or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.

[0488] The pharmaceutical compositions disclosed herein in a modified release dosage form may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt-granulation followed by compression.2. Osmotic Controlled Release Devices

[0489] The pharmaceutical compositions disclosed herein in a modified release dosage form may be fabricated using an osmotic controlled release device, including one-chamber system, two- chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) the core which contains the active ingredient(s); and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).

[0490] In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels,” include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0491] The other class of osmotic agents are osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol, organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p- toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0492] Osmotic agents of different dissolution rates may be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as Mannogeme EZ (SPI Pharma, Lewes, Del.) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.

[0493] The core may also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.

[0494] Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0495] The semipermeable membrane may also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0496] The delivery port(s) on the semipermeable membrane may be formed post-coating by mechanical or laser drilling. Delivery port(s) may also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports may be formed during coating process, as in the case of asymmetric membrane coatings.

[0497] The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.

[0498] The pharmaceutical compositions in an osmotic controlled-release dosage form may further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.

[0499] The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art.

[0500] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.

[0501] In some embodiments, the pharmaceutical compositions disclosed herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers. 3. Multiparticulate Controlled Release Devices

[0502] The pharmaceutical compositions disclosed herein in a modified release dosage form may be fabricated a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 μm to about 3 mm, about 50 m to about 2.5 mm, or from about 100 m to about 1 mm in diameter. Such multiparticulates maybe made by the processes know to those skilled in the art, including wet- and dry-granulation, extrusion / spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores.

[0503] Other vehicles as described herein may be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates. The resulting particles may themselves constitute the multiparticulate device or may be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet. 4. Targeted Delivery

[0504] The pharmaceutical compositions disclosed herein may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Therapeutic applications and methods

[0505] Also disclosed herein is a method of treating a subject with a disease or disorder comprising administering to the subject a therapeutically effective amount of a crystal containing compound (1) and an acid which is at least one selected from the group consisting of benzene sulfonic acid, hydrochloric acid, and tartaric acid.

[0506] The dosage and frequency (single or multiple doses) of the crystals administered can vary depending upon a variety of factors, including, but not limited to, the salt form / compound to be administered; the disease / condition being treated; route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated; presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and crystals disclosed herein.

[0507] Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring response to the treatment and adjusting the dosage upwards or downwards.

[0508] Dosages may be varied depending upon the requirements of the subject and the compound or salt form thereof being employed. The dose administered to a subject, in the context of the pharmaceutical compositions presented herein, should be sufficient to effect a beneficialtherapeutic response in the subject over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.

[0509] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compounds effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual’s disease state.

[0510] The administration schedule may be varied depending on the salt form and compound employed, the condition being treated, the administration route, etc. For example, administration may be performed once a day (QD), or in divided dosages throughout the day, such as 2-times a day (BID), 3-times a day (TID), 4-times a day (QID), or more. In some embodiments administration may be performed nightly (QHS). In some embodiments, the compounds / pharmaceutical compositions may be administered as needed (PRN). Administration may also be performed on a weekly basis, e.g., once a week, twice a week, three times a week, four times a week, every other week, or other administration schedules deemed appropriate using sound medical judgement.

[0511] In some embodiments, the use of formulations of the disclosure may be used as a standalone therapy. In some embodiments, the use of formulations of the disclosure may be used as an adjuvant / combination therapy.

[0512] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity or adverse side effects, and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound and salt form by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.

[0513] A therapeutically effective dose of the crystals disclosed herein may vary depending on the variety of factors described above, but is typically that which provides compound (1) in an amount of about 0.00001 mg to about 10 mg per kilogram body weight of the recipient per day, or any range in between, e.g., about 0.00001 mg / kg, about 0.00005 mg / kg, about 0.0001 mg / kg, about0.0005 mg / kg, about 0.001 mg / kg, about 0.005 mg / kg, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg of compound (1) (active). EXAMPLES Salt Screening

[0514] Throughout the salt screening of TAS3351, 55 unique crystalline salt patterns were observed; 39 remained stable upon both drying and humidification. The freebase was also found to form salts with 13 / 15 of the counter ions selected, with the exception of D-gluconic acid and pyruvic acid.

[0515] The crystalline salts were further assessed by the following physicochemical properties: stability to drying / humidification, polymorphism, solubility in a phosphate buffer, purity, stoichiometry, crystallinity, and residual solvent. The tartrate (patterns 14-A and 14-C), besylate (pattern 1-A), and hydrochloric acid (pattern 5-H) salts were found to be particularly advantageous.

[0516] A summary of the scale-ups is given in Table 1 below: Description Results 3-2 C) C)Description Results Karl Fischer water 06Below Detection 21 67

[0517] All salts had positive physiochemical properties, but some also demonstrated disadvantages. The HCl salt consistently exhibited high residual solvent; as high as 8 wt. % during screening, and 1.6 wt. % from the scale-up. The HCl salt also did not demonstrate any significant advantages with respect to solubility. The besylate demonstrated low residual solvent (below detectable limit to 0.3 wt. %), as well as form stability. However, aside from solubility in gastric fluid, the besylate did not offer any advantages when compared to the other salts and / or freebase. Additionally, benzenesulfonic acid (BSA) is a Class 2 counter ion.

[0518] The tartrate demonstrated form stability, low residual solvent (0.29 wt. %), and was determined to be a hydrate with 6.7 wt. % water present, (2.6 equivalents (eq.)). Additionally, the tartrate was stable after one week at 75 % relative humidity (RH) and 40 °C, as well as during one-week slurries in acetone and ethanol (EtOH):water (95:5 vol); some disproportionation to freebase was observed in 2-propanol (IPA). With respect to solubility, the tartrate also offered an increase in kinetic solubility (30 min) in fed-state simulated intestinal fluid (FeSSIF) when compared to the salts, and in fasted-state simulated gastric fluid (FaSSGF) when compared to the freebase.

[0519] The tartrate (14-A and 14-C) in FeSSIF gave higher solubility at 30 min only, but both showed similar result at 24 h and freebase by XRPD.

[0520] Based on the previous work, and the experimental pKa values of the compound (3.11 and 4.77), 15 counter ions were chosen to screen in three solvents. For the stronger (more acidic) counter ions, 2.2 eq. of counter ion was also explored in addition to 1.1 eq.

[0521] Experiments were set up for the salt screening process in 2 mL vials containing 6.3 mm stir bars. A stock solution of TAS3351 was prepared in trifluoroethanol (TFE) with a concentration of 76.5 mg / mL. Stock solutions of counter ions were prepared in EtOH. The counter ions, their IDs, and corresponding pKa’s are listed in Table 2. The equivalent of 30 mg freeform solution was added to each vial, followed by the appropriate counter ion stock solution. The vials were left to stir at 45 °C for 2 h before being uncapped and left to evaporate while stirring over the weekend at 35 °C in atmosphere. The vials were then placed under active vacuum (~-29 inHg) at 50 °C for 2 h to dry thoroughly.

[0522] Approximately 10 volumes (vol.) (300 μL) of screening solvent (EtOH, ethyl acetate (EtOAc), or isopropyl alcohol (IPA):water (9:1 vol.)) were added to each vial, and the samples were heated to 45 °C while stirring (500 rpm). Vials that demonstrated significant precipitation or gumming were vortexed and sonicated often to ensure thorough mixing. After 2 h, the temperature was reduced to RT and the samples were left to stir for another 2 h prior to sampling.

[0523] X-ray powder diffraction (XRPD) analysis was done in three stages. First, XRPD analysis of the wet cake was completed for all samples where solids were observed. Unique solids were then left on XRPD plates and dried under vacuum at 50 °C (~-29 inHg) for 3 h, after which they were analyzed by XRPD. Finally, solids were exposed to > 95 % RH overnight and XRPD was carried out on the resulting solids. The humid environment was generated by placing a beaker of saturated potassium sulfate in water in a sealed chamber. All XRPD patterns were compared to counter ion XRPD patterns and known freeform patterns. Any crystalline patterns observed will be denoted with the counter ion number followed by a letter in alphabetical order. For example, the first crystalline pattern observed for BSA will be denoted 1-A. A summary of the XRPD data from the salt screening is shown in Table 3 (1.1 eq.) and Table 4 (2.2 eq.).Concentration CI MW pKa Molar of stock CITABLECounter ion ISolvent Wet Dry Humid CommentsCounter ion (CI)Solvent Wet Dry Humid Commentsy. g ry. ry.Counter ion (CI)Solvent Wet Dry Humid CommentsCounter ion (CI)Solvent Wet Dry Humid Commentsl erCnTABLE 4- Summary of the salt screening of TAS3351 using 2.2 eq. CI.

[0524] A variety of colors were observed throughout the screening (beige, peach, orange, yellow, green, brown, etc.). An example of these colors is given in Figures 1 and 2.

[0525] Figure 1 shows an image taken during the salt screening with first-round solvents, demonstrating the range of colors observed: (1) Freebase in EtOH, L1NJ111001-5-1; (2) BSA in EtOH, L1NJ111001-5-4; (3) BSA in IPA:water, L1NJ111001-5-9; (4) Malic acid in EtOH, L1NJ111001-5-24; (5) HCl in EtOAc, L1NJ111001-5-20; and (6) ESA in EtOAc, L1NJ111001- 5-11. Figure 2 shows a second image taken during the salt screening with first-round solvents, demonstrating the range of colors observed: (1) Pyruvic acid in IPA:water, L1NJ111001-5-45; (2) Sulfuric acid in EtOAc, L1NJ111001-4-47. Purity Analysis

[0526] Purity of the select crystalline hits from the salt screening, was assessed by high- performance liquid chromatography (HPLC) analysis. The solids were prepared to a concentration of 0.2 mg / mL in chloroform (CHCl3):MeOH:ACN / water (8:2 vol.) (1.00:1:38 vol.). The results are outlined in Table 5.

[0527] In general, the purity was observed to be greater than 99.4 % a / a for all salts, with the exception of ethanesulfonic acid (ESA) (2-A) and methanesulfonic acid (MSA) (8-D), for which deep brown solids were isolated and decomposition was confirmed. Relative retention time (RRT) L1 4– 9 3, 1, 4Relative retention time (RRT) L1 Input solids040–079 085 090 109 117 164– 9 3 4 4 4 8 4 4 4 3 3 7were observed above the reporting threshold of 0.03 % a / a. Solubility in Phosphate Buffer, pH = 6.31

[0528] Solubility of select crystalline solids was carried out in a phosphate buffer (pH = 6.31) at 37 °C. The results are outlined in Table 6. For these experiments, the solids were weighed directly into 4 mL vials, and a 10 mm stir bar was added. Phosphate buffer (already equilibrated at 37 °C) was added to each vial so that the concentration of the solution would be 1.0 mg / mL if all of the solids were to dissolve. After stirring for 30 min, a portion of each slurry was syringe filtered into an HPLC vial for analysis.

[0529] For each experiment, a thin, flowable slurry was observed, indicating that the solids were not highly soluble in the buffer system. In general, the solubilities observed were similar, orslightly higher, than the freebase (3.6 μg / mL) which was carried out in parallel. The highest observed solubility was from pyruvic acid, Pattern 11-A, which demonstrated a solubility of 101.9 μg / mL. L1 Counter XRPD Mass Buffer Area Solubility NJ111001-Inpution pattern (mg) (mL) counts (µg / mL) TAB otapplicable. Solubility compared to a single injected point of freebase, L1NJ111001-1-1, having a concentration of 0.2 mg / mL and an area count of 3077.88. Summary of Crystalline Salts

[0530] A summary of crystalline salts, along with select characterization, is given in Table 7. Crystalline solids were isolated from all counter ions, except for gluconic acid. In total, 55 unique crystalline patterns were observed, with almost every counter ion demonstrating uniquepatterns from the different solvents assessed. This is indicative of the high polymorphism of the salts.Count ion (C BSA ESA Fumar acid HCl Maliacid Maleacid5-29. . EtOAc 7-B 7-B 7-Bhigh179.2 22.0 99.90Count ion (C MSA OxalacidPhosph acidPyruv acid Sulfu acid Tarta acid TSA2.2,15-B 15-B 15-B High N / A 0.98 1.00:1.40 7.3 99.55TABLE 7- Summary of crystalline solids observed during the salt screening.Further Characterization of Salts

[0532] Salts were assessed based on the following properties: melting point, crystallinity, stability upon drying and humidity exposure, polymorphism, solubility in a buffer, and acceptability of counter ion. Salts were divided into three groups based on these properties: 1. Tier 1: Most advantageous salt. These salts have acceptable physicochemical properties. 2. Tier 2: Somewhat advantageous salt, but not first choice. The physicochemical properties are not all acceptable. 3. Not selected: Not an acceptable salt. These salts have poor physicochemical properties. The salts are ranked in Table 8 below.

[0533] Salts which demonstrated a color change to brown during screening (in any solvent) were not selected for further study, as decomposition was confirmed by HPLC. Maleic acid was predominantly not selected due to high residual solvent, while oxalic acid was not selected due to low crystallinity and the counter ion class.

[0534] Tartaric acid was selected for further study as a consistent stoichiometry was observed, and the solids were physically stable. The tartrate was chosen over the malate, as inconsistent stoichiometries have been observed with the malate in past studies (and in this work), while the tartrate remained stable with water present. The besylate demonstrated physical stability and low residual solvent, and although BSA is a Class 2 counter ion, the solids demonstrated better overall physiochemical properties than other isolated salts.

[0535] The HCl salt demonstrated physical stability (in certain solvents), as well as high purity. Although the residual solvent was high for HCl, it was selected for further study as a more controlled process could aid in decreasing solvent content. Counter ion Tier Pros ConsCounter ion Tier Pros Cons • Class 2 counter ion. e for es =C beCounter ion Tier Pros Cons • Class 1 counter ion. • Could be linked to acute tubular d ic, h es. for wo C . neCounter ion Tier Pros Cons • Pyruvate is an intermediate inBesylate, Pattern 1-A

[0536] The besylate, Pattern 1-A, was scaled up by weighing 316 mg of L1NJ111001-1-1 and 111 mg (1.1 eq.) of BSA into a 20 mL vial. A stir bar was then added, followed by 10 vol. of EtOH. The slurry was heated to 50 °C where it was left to stir for 2 h. The resulting off-white slurry was then cooled to RT and stirred overnight. The following morning, the flowable off- white slurry was filtered, washed with 2 × 1 vol. EtOH, and dried overnight (50 °C, -28 inHg). A loss on drying (LOD) of 28 wt. % was confirmed.

[0537] A yield of 346 mg (84 % molar yield) was isolated. Characterization can be found in Table 9 and Figure 3 through Figure 10. Figure 3 shows images taken from the scale-up of TAS3351 besylate, L1NJ111001-13-1, Pattern 1-A. (1) Immediately on addition of EtOH and heating to 50 °C; (2) 5 min after heating to 50 °C. Figure 4 shows a XRPD diffractogram of TAS3351 besylate, L1NJ111001-13-1, Pattern 1-A. Figure 5 shows a simultaneous TGA / DSC thermogram of TAS3351 besylate, L1NJ111001-13-1, Pattern 1-A. Figure 6 shows a DSC thermogram of TAS3351 besylate, L1NJ111001-13-1, Pattern 1-A. Figure 7 shows an optical microscopy image of TAS3351 besylate, L1NJ111001-13-1, Pattern 1-A, taken prior to filtration at 400X magnification. Figure 8 shows the1H NMR in DMSO-d6 of TAS3351 besylate, L1NJ111001-13-1, Pattern 1-A. Figure 9 shows a DVS isotherm of TAS3351 besylate, L1NJ111001-13-1, Pattern 1-A. Figure 10 shows XRPD diffractograms of TAS3351 besylate, L1NJ111001-13-1, Pattern 1-A, before and after DVS exposure: (1) Input solids; (2) After DVS exposure.

[0538] In the tables reporting peak angles, the angles are ± 0.2◦.. That is the angle 2θ of 5.21 includes 5.01 to 5.41. A peak table for the XRPD diffractogram of TAS3351 besylate is shown in Table 10Description Results SSPI notebook ID L1NJ111001-13-1 TABLE 9- Charact 1-A.Angle (° 2θ) d-spacing (Å) Relative intensity 521 1694 3Angle (° 2θ) d-spacing (Å) Relative intensity 21.31 4.17 6 TABLE 10- XRPDHCl, Pattern 5-H

[0539] The HCl, Pattern 5-H, was scaled up by weighing 308 mg of L1NJ111001-1-1 into a 20 mL vial. EtOH (10 vol.) was added, along with a stir bar, and the resulting slurry was heated to 50 °C. A solution of HCl in EtOH (0.3 g / mL) was then added in four equal portions every 15 min over 1 h, for a total of 1.1 eq. The color of the slurry began to change immediately to a vibrant yellow-orange and was notably thicker after the second addition (0.55 eq.). After stirring at 50 °C for 1.5 h, the slurry was cooled to RT and filtered; the filtration itself was very slow. The vibrant-yellow solids were washed with 2 × 1 vol. EtOH, and dried overnight (50 °C, -28 inHg). An LOD of 35 wt. % was confirmed.

[0540] A yield of 300 mg (91 % molar yield) was isolated. Characterization can be found in Table 11 and Figure 11 to Figure 16. Figure 11 shows images taken during the scale-up of TAS3351 HCl, L1NJ111001-13-2, Pattern 5-H: (1) After the first addition of HCl solution; (2) After adding all of the HCl solution. Figure 12 show a XRPD diffractogram of TAS3351 HCl, L1NJ111001-13-2, Pattern 5-H, dried. Figure 13 shows a simultaneous TGA / DSC thermogram of TAS3351 HCl, L1NJ111001-13-2, Pattern 5-H. Figure 14 shows a DSC thermogram ofTAS3351 HCl, L1NJ111001-13-2, Pattern 5-H. Figure 15 shows an optical microscopy image of TAS3351 HCl, L1NJ111001-13-2, Pattern 5-H, taken prior to filtration at 400X magnification. Figure 16 shows the1H NMR in DMSO-d6 of TAS3351 HCl, L1NJ111001-13-2, Pattern 5-H.

[0541] A peak table for the XRPD diffractogram of TAS3351 hydrochloride, Pattern 5-H is shown in Table 12, the angles are ± 0.2◦. Description Results SSPI notebook ID L1NJ111001-13-2 TABLE 11- Charac H.Angle (° 2θ) d-spacing (Å) Relative intensity 582 1517 18Angle (° 2θ) d-spacing (Å) Relative intensity 21.14 4.20 21 TABLE 12- XRPD -dry_long.Tartrate, Pattern 14- A

[0542] The tartrate, Pattern 14-A, was scaled up by weighing 302 mg of L1NJ111001-1-1 and 100 mg (1.1 eq.) of tartaric acid into a 20 mL vial. A stir bar was then added, followed by 10 vol. of EtOH. The slurry was heated to 50 °C. After stirring for 25 min, the beige slurry became immobile, and an additional 20 vol. EtOH was required to ensure consistent flowability. The slurry was left to stir at 50 °C for 1.5 h prior to adjusting the hot plate to RT and stirring overnight. The following morning, the thick but flowable beige slurry was filtered, washed with 3 × 2 vol. EtOH, and dried (50 °C, -28 inHg) for 6 h. An LOD of 68 wt. % was confirmed.

[0543] A yield of 314 mg (80 % molar yield) was isolated. Characterization can be found in Table 13 and Figure 17 and Figure 21. Figure 17 shows a XRPD diffractogram of TAS3351tartrate, L1NJ111001-53-1, Pattern 14-A: (1) Wet; (2) Dry. Figure 18 shows a simultaneous TGA / DSC thermogram of TAS3351 tartrate, L1NJ111001-53-1, Pattern 14-A. Figure 19 shows a DSC thermogram of TAS3351 tartrate, L1NJ111001-53-1, Pattern 14-A. Figure 20 shows an optical microscopy image of TAS3351 tartrate, L1NJ111001-53-1, Pattern 14-A, taken prior to filtration at 400X magnification. Figure 21 shows the1H NMR in DMSO-d6 of TAS3351 tartrate, L1NJ111001-53-1, Pattern 14-A.

[0544] A peak table for the XRPD diffractogram of TAS3351 tartrate, Pattern 14-A is shown in Table 14, the angles are ± 0.2◦.. Description Results SSPI notebook ID L1NJ111001-53-1 7 , ) TABLE 13- Charac 1-53-1.Angle (° 2θ) d-spacing (Å) Relative intensityAngle (° 2θ) d-spacing (Å) Relative intensity 18.94 4.68 9 TABLE 14- XRPD p 5_dry.Tartrate, Pattern 14-C

[0545] Tartrate, Pattern 14-C, was scaled up by weighing 294 mg of L1NJ111001-1-1 into a 20 mL vial and adding 15 vol. IPA:water (9:1 vol.). The resulting beige slurry was heated to 50 °C while stirring. Tartaric acid, dissolved in 1 mL IPA:water (9:1 vol.) (concentration = 0.099 g / mL), was then added dropwise to the slurry in four equal portions over 1 h. After the fourth and final addition, the slurry became very thick and uniform flowability was not observed. Therefore, an additional 5 vol. IPA:water (9:1 vol.) was added. After stirring at 50 °C for 1.5 h, the hot plate temperature was adjusted to RT, and a flowable light-yellow slurry was observed. After stirring for 4 h at RT, the thick but flowable slurry was filtered, washed with 3 × 2 vol. IPA:water (9:1 vol.), and dried (50 °C, -28 inHg) overnight. An LOD of 56 wt. % was confirmed.

[0546] A yield of 349 mg (92 % molar yield) was isolated. Characterization can be found in Table 15 and Figure 22 through Figure 27. The tartare (14-C) was confirmed to be a hydrate with 2.6 eq. of water present after drying (6.7 wt. %). Figure 22 shows XRPD diffractograms of TAS3351 tartrate, L1NJ111001-53-2, Pattern 14-C: (1) Wet; (2) Dry. Figure 23 shows a simultaneous TGA / DSC thermogram of TAS3351 tartrate, L1NJ111001-53-2, Pattern 14-C. Figure 24 shows a DSC thermogram of TAS3351 tartrate, L1NJ111001-53-2, Pattern 14-C. Figure 25 shows an optical microscopy image of TAS3351 tartrate, L1NJ111001-53-2, Pattern 14-C, taken prior to filtration at 400X magnification. Figure 26 shows a DVS isotherm ofTAS3351 tartrate, L1NJ111001-53-2, Pattern 14-C. Circle at low humidity represents points at which the mass did not stabilize; if left to equilibrate longer, there likely would have been a greater mass loss observed. Figure 27 shows XRPD diffractograms of TAS3351 tartrate, L1NJ111001-53-2, Pattern 14-C before and after DVS: (1) Dried input solids; (2) After DVS exposure.

[0547] A peak table for the XRPD diffractogram of TAS3351 tartrate, Pattern 14-C is shown in Table 16, the angles are±0.2◦.. Description Results SSPI notebook ID L1NJ111001-53-2 , ) TABLE 15- Charac rn 14-C.Angle (° 2θ) d-spacing (Å) Relative intensityAngle (° 2θ) d-spacing (Å) Relative intensity 25.98 3.43 1 TABLE 16- XRPD _wet.One-Week Stability Humidity Exposure – 75 % RH and 40 °C

[0548] Solid-form stability was completed by weighing ~20 mg of solid into a 4 mL vial and covering with a Kimwipe. The solids assessed included: besylate (Pattern 1-A, L1NJ111001-13- 1), hydrochloride (Pattern 5-H, L1NJ111001-13-2, tartrate (Pattern 14-A, L1NJ111001-53-1), and tartrate (Pattern 14-C, L1NJ111001-53-2). The vials were placed inside a humidity chamber set to 75 % RH at 40 °C for one week. The results are summarized in Table 17.

[0549] All solids remained visually the same after one-week humidification, with the same patterns confirmed by XRPD. For the HCl (5-A), a slight increase in crystallinity was also noted. With respect to purity, there were no significant changes observed, and no new impurities created. The results are summarized in Table 18. Purity Purity L1 Mass XRPD XRPD % % / a r) 705 070TABLE 17- Suerns of TAS3351. L.C., low crystalline. a - Increase in crystallinity observed by XRPD. b - Material availability was limited therefore lower amount of solid was used.InputRelative retention time (RRT)L1NJ111001-0.74–1001.13– 2.09– 1 4 3 656TABLE 18- Im bility. Impurities< 0.03 % a / a not included in the analysis. aAPI peak split slightly, not observed in the scaled-up solids. Slurries in Three Solvents

[0550] Solid-form stability was completed by weighing ~10–20 mg of solid into a 2 mL vial and adding a 5.3 mm stir bar as well as 300 μL solvent. For the succinate, 200 μL of solvent wasused. The solids assessed included: besylate (Pattern 1-A, L1NJ111001-13-1), hydrochloride (pattern 5-A, L1NJ111001-13-2), tartrate (Pattern 14-A, L1NJ111001-53-1), and tartrate (Pattern 14-C, L1NJ111001-53-2). Results are outlined in Table 19. L1 MassXRPD XRPD NJ111001 Input( )Solvent i iti l( ft )Observationsy. y. antincrease in crystallinity observed post slurry Solubility in Simulated Fluids

[0551] Solubility in simulated fluids and water was assessed for the besylate (Pattern 1-A, L1NJ111001-13-1), hydrochloride (Pattern 5-A, L1NJ111001-13-2), tartrate (Pattern 14-A, L1NJ111001-53-1), and tartrate (Pattern 14-C, L1NJ111001-53-2). Approximately 6 mg of solid was weighed into a 4 mL vial, and a 10 mm stir bar was added. The simulated fluids were left to equilibrate at 37 °C, prior to the addition of 3 mL of solvent to each vial.

[0552] Calibration samples were prepared using the as-received TAS3351 (L1NJ111001-1-1, batch ELS-474-191-39). The samples were prepared by weighing the solids in a 2 mL HPLC vial, and dissolving in CHCl3:MeOH (1:1 vol.) to achieve a concentration of 4 mg / mL. An aliquot of the solution was then diluted in ACN:water (8:2 vol.) to reach the desired concentration. A fresh 4 mg / mL solution was made for each point. Results for the calibration curve are given in Table 20. The calibration plot and response factor (R2 = 0.9999) are shown in Figure 28. Figure 28 shows a calibration curve of TAS3351, using Pattern FB-A (L1NJ111001- 1-1, batch ELS- 474-191-39).

[0553] After 30 min, a portion of each was sampled, and syringe filtered directly into HPLC vials for analysis. After 24 h, the stirring was stopped, and another aliquot was syringe filtered for HPLC analysis. The pH of the remaining solution / slurry was then taken prior to filtering the solids for XRPD analysis. The HPLC results are outlined in Table 21. L1 Concentration Area NJ111001- (m / mL) (arbitrary TABLE 20- Calibration sL1NJ11 - 54- 54- 54- 54- 54- 54-1 54-1 54-1 54-1 54-1 54-1 54-2 54-2 54-2 54-254-24 Water - 3.10 234.76 10.1 202.10 8.7 - Flowable white slurry. TABLE 21- Solubility of TAS3351 in simulated fluids at 37 °C.Analysis

[0554] After the screening of 15 counter ions (in three solvents) was completed, and the salts were ranked based on their overall physiochemical properties, the tartrate, besylate, and HCl salts were chosen for scale-up and further characterization. The four salts were successfully scaled up, and demonstrated an increase in purity over the freebase to > 99.9 % a / a.

[0555] The HCl salt exhibited high residual solvent (1.7 wt. %, 0.2 eq. EtOH), during the screening and scale-up, and did not offer any advantages with respect to solubility when compared to the other forms. The besylate, Pattern 1-A, demonstrated form stability, low residual solvent (below detectable limits to 0.2 wt. %) during the screening and the scale-up, and was not observed to be hygroscopic (1.8 wt. % from 5–95 % RH) by dynamic vapor sorption (DVS). While the besylate offered positive physicochemical properties, BSA is a Class 2 counter ion. A class 2 counter ion may not be selected unless there were no other options available.

[0556] The tartrate demonstrated form stability when exposed to dry / humid conditions, and consistently resulted in a mono salt. Upon scale-up of 14-C, low (0.29 wt. %) residual solvent was observed, and the water content was determined to be 6.7 wt. % (2.6 eq. water) by Karl Fischer titration (KF). The solids were not highly hygroscopic by DVS until the humidity dropped below 20 % RH, at which point the hydrate began losing its water. Additionally, 14-C demonstrated form stability after one week at 75 % RH and 40 °C, as well as during one-week slurries in acetone and EtOH:water (95:5 vol.); slight disproportionation was observed in IPA. With respect to solubility, the tartrate also offered an increase in kinetic solubility (30 min) in FeSSIF when compared to the salts / freebase. XRPD Diffractograms of Unique Crystalline Forms Observed During Salt Screening

[0557] Figure 29 shows unique crystalline patterns from screening with 1.1 eq. of BSA: (1) EtOH, Pattern 1-A, L1NJ111001-5-4; (2) EtOAc, Pattern 1-C, L1NJ111001-5-5.

[0558] Figure 30 shows unique crystalline patterns from screening with 2.2 eq. of BSA: (1) EtOH, Pattern 1-D, L1NJ111001-5-7; (2) EtOAc, Pattern 1-E, L1NJ111001-5-8; (3) IPA:water, Pattern 1-B, L1NJ111001-5-9.

[0559] Figure 31 shows unique crystalline patterns from screening with 1.1 eq. of ESA: (1) EtOH, Pattern 2-C, L1NJ111001-5-10; (2) EtOAc, Pattern 2-A, L1NJ111001-5-11; (3) IPA:water, Pattern 2-B, L1NJ111001-5-12.

[0560] Figure 32 shows unique crystalline patterns from screening with 1.1 eq. of fumaric acid: (1) EtOH, Pattern 3-C, L1NJ111001-5-10; (2) EtOAc, Pattern 3-B, L1NJ111001-5-11; (3) IPA:water, Pattern 3-A, L1NJ111001-5-12.

[0561] Figure 33 shows unique crystalline patterns from screening with 1.1 eq. of HCl: (1) EtOH, Pattern 5-H, L1NJ111001-5-19; (2) IPA:water, Pattern 5-A, L1NJ111001-5-21.

[0562] Figure 34 shows unique crystalline patterns from screening with 2.2 eq. of HCl: (1) EtOH (wet solids), Pattern 5-B, L1NJ111001-5-22; (2) EtOH (dried solids), Pattern 5-C, L1NJ111001- 5-22; (3) EtOH (humidified solids), Pattern 5-D, L1NJ111001-5-22; (4) EtOH (redried solids), Pattern 5-E, L1NJ111001-5-22; (5) EtOAc, Pattern 5-G, L1NJ111001-5-23; (6) IPA:water, Pattern 5-F, L1NJ111001-5-24.

[0563] Figure 35 shows unique crystalline patterns from screening with 1.1 eq. of malic acid: (1) EtOH, Pattern 6-A, L1NJ111001-5-25; (2) EtOAc, Pattern 6-B, L1NJ111001-5-26; (3) IPA:water, Pattern 6-C, L1NJ111001-5-27.

[0564] Figure 36 shows unique crystalline patterns from screening with 1.1 eq. of maleic acid: (1) EtOH, Pattern 7-A, L1NJ111001-5-28; (2) EtOAc, Pattern 7-B, L1NJ111001-5-29; (3) IPA:water, Pattern 7-C, L1NJ111001-5-30.

[0565] Figure 37 shows unique crystalline patterns from screening with 1.1 eq. of MSA: (1) EtOH, Pattern 8-A, L1NJ111001-5-31; (2) EtOAc, Pattern 8-D, L1NJ111001-5-32; (3) IPA:water (wet solids), Pattern 8-E, L1NJ111001-5-33; (4) IPA:water (dry solids), Pattern 8-F, L1NJ111001-5-33.

[0566] Figure 38 shows unique crystalline patterns from screening with 1.1 eq. of oxalic acid: (1) EtOH, Pattern 9-A, L1NJ111001-5-37; (2) IPA:water, Pattern 9-B, L1NJ111001-5-39.

[0567] Figure 39 shows unique crystalline patterns from screening with 1.1 eq. of phosphoric acid in EtOH, L1NJ111001-5-40: (1) Wet solids, Pattern 10-A; (2) Dried solids, Pattern 10-B; (3) Humidified solids, Pattern 10-C.

[0568] Figure 40 shows unique crystalline patterns from screening with 1.1 eq. of pyruvic acid: (1) EtOH, Pattern 11-A, L1NJ111001-5-43; (2) EtOAc (wet solids), Pattern 11-D, L1NJ1110015-44; (3) EtOAc (dry solids), Pattern 11-E, L1NJ111001-5-44; (4) IPA:water (wetsolids), Pattern 11-B, L1NJ111001-5-45, (5) IPA:water (dry solids), Pattern 11-C, L1NJ111001- 5-45.

[0569] Figure 41 shows unique crystalline patterns from screening with 0.6 eq. of sulfuric acid: (1) EtOH, Pattern 12-A, L1NJ111001-5-46; (2) IPA:water, Pattern 12-C, L1NJ111001-5-48.

[0570] Figure 42 shows unique crystalline patterns from screening with 1.1 eq. of sulfuric acid: (1) EtOH, Pattern 12-D, L1NJ111001-5-49; (2) EtOAc, Pattern 12-B, L1NJ111001-5-50; (3) IPA:water, Pattern 12-E, L1NJ111001-5-51.

[0571] Figure 43 shows unique crystalline patterns from screening with 1.1 eq. of tartaric acid: (1) EtOH, Pattern 14-A, L1NJ111001-5-55; (2) EtOAc, Pattern 14-B, L1NJ111001-5-56; (3) IPA:water, Pattern 14-C, L1NJ111001-5-57.

[0572] Figure 44 shows unique crystalline patterns from screening with 1.1 eq. of TSA: (1) EtOH, Pattern 15-A, L1NJ111001-5-58; (2) EtOAc, Pattern 15-C, L1NJ111001-5-59.

[0573] Figure 45 shows unique crystalline pattern, 15-B, when screening with 2.2 eq. of TSA in EtOH, L1NJ111001-5-61. Select Characterization of Unique Crystalline Forms Observed During Salt Screening Benzenesulfonic Acid

[0574] Figure 46 shows a XRPD diffractogram from screening with BSA (1.1 eq.) in EtOH, Pattern 1-A, L1NJ111001-5-4.

[0575] Figure 47 shows a DSC thermogram from screening with BSA (1.1 eq.) in EtOH, Pattern 1-A, L1NJ111001-5-4.

[0576] Figure 48 shows an optical microscopy image of dried solids from screening with BSA (1.1 eq.) in EtOH, Pattern 1-A, L1NJ111001-5-4 at 400X magnification.

[0577] Figure 49 shows the1H NMR in DMSO-d6 from screening with BSA (1.1 eq.) in EtOH, Pattern 1-A, L1NJ111001-5-4.

[0578] Figure 50 shows a XRPD diffractogram from screening with BSA (1.1 eq.) in EtOAc, Pattern 1-C, L1NJ111001-5-5.

[0579] Figure 51 shows a DSC thermogram from screening with BSA (1.1 eq.) in EtOAc, Pattern 1-C, L1NJ111001-5-5.

[0580] Figure 52 shows a XRPD diffractogram from screening with BSA (2.2 eq.) in EtOH, Pattern 1-D, L1NJ111001-5-7.

[0581] Figure 53 shows a DSC thermogram from screening with BSA (2.2 eq.) in EtOH, Pattern 1-D, L1NJ111001-5-7.

[0582] Figure 54 shows the1H NMR in DMSO-d6 from screening with BSA (2.2 eq.) in EtOH, Pattern 1-D, L1NJ111001-5-7.

[0583] Figure 55 shows a XRPD diffractogram from screening with BSA (2.2 eq.) in IPA:water (9:1 vol.), Pattern 1-B, L1NJ111001-5-9.

[0584] Figure 56 shows a DSC thermogram from screening with BSA (2.2 eq.) in IPA:water (9:1 vol.), Pattern 1-B, L1NJ111001-5-9.

[0585] Figure 57 shows an optical microscopy image of dried solids from screening with BSA (2.2 eq.) in IPA:water (9:1 vol.), Pattern 1-B, L1NJ111001-5-9 at 400X magnification. Ethanesulfonic Acid

[0586] Figure 58 shows a XRPD diffractogram from screening with ESA (1.1 eq.) in EtOH, Pattern 2-C, L1NJ111001-5-10.

[0587] Figure 59 shows a DSC thermogram from screening with ESA (1.1 eq.) in EtOH, Pattern 2-C, L1NJ111001-5-10.

[0588] Figure 60 shows a XRPD diffractogram from screening with ESA (1.1 eq.) in EtOAc, Pattern 2-A, L1NJ111001-5-11.

[0589] Figure 61 shows a DSC thermogram from screening with ESA (1.1 eq.) in EtOAc, Pattern 2-A, L1NJ111001-5-11.

[0590] Figure 62 shows an optical microscopy image of dried solids from screening with ESA (1.1 eq.) in EtOAc, Pattern 2-A, L1NJ111001-5-11 at 400X magnification.

[0591] Figure 63 shows a XRPD diffractogram from screening with ESA (1.1 eq.) in IPA:water (9:1 vol.), Pattern 2-B, L1NJ111001-5-12.

[0592] Figure 64 shows a DSC thermogram from screening with ESA (1.1 eq.) in IPA:water (9:1 vol.), Pattern 2-B, L1NJ111001-5-12. Fumaric Acid

[0593] Figure 65 shows a XRPD diffractogram from screening with fumaric acid (1.1 eq.) in EtOH, Pattern 3-C, L1NJ111001-5-13.

[0594] Figure 66 shows a DSC thermogram from screening with fumaric acid (1.1 eq.) in EtOH, Pattern 3-C, L1NJ111001-5-13.

[0595] Figure 67 shows an optical microscopy image of dried solids from screening with fumaric acid (1.1 eq.) in EtOH, Pattern 3-C, L1NJ111001-5-13 at 400X magnification.

[0596] Figure 68 shows the1H NMR in DMSO-d6 from screening with fumaric acid (1.1 eq.) in EtOH, Pattern 3-C, L1NJ111001-5-13.

[0597] Figure 69 shows a XRPD diffractogram from screening with fumaric acid (1.1 eq.) in EtOAc, Pattern 3-B, L1NJ111001-5-14

[0598] Figure 70 shows a DSC thermogram from screening with fumaric acid (1.1 eq.) in EtOAc, Pattern 3-B, L1NJ111001-5-14

[0599] Figure 71 shows a XRPD diffractogram from screening with fumaric acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 3-A, L1NJ111001-5-15.

[0600] Figure 72 shows a DSC thermogram from screening with fumaric acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 3-A, L1NJ111001-5-15.

[0601] Figure 73 shows an optical microscopy image of dried solids from screening with fumaric acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 3-A, L1NJ111001-5-15 at 400X magnification.

[0602] Figure 74 shows the1H NMR in DMSO-d6 from screening with fumaric acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 3-A, L1NJ111001-5-15. Hydrochloric Acid

[0603] Figure 75 shows a XRPD diffractogram from screening with HCl (1.1 eq.) in EtOAc, Pattern 5-H, L1NJ111001-5-20.

[0604] Figure 76 shows a DSC thermogram from screening with HCl (1.1 eq.) in EtOAc, Pattern 5-H, L1NJ111001-5-20.

[0605] Figure 77 shows an optical microscopy image of dried solids from screening with HCl (1.1 eq.) in EtOAc, Pattern 5-H, L1NJ111001-5-20 at 400X magnification.

[0606] Figure 78 shows the1H NMR in DMSO-d6 from screening with HCl (1.1 eq.) in EtOAc, Pattern 5-H, L1NJ111001-5-20.

[0607] Figure 79 shows a XRPD diffractogram from screening with HCl (1.1 eq.) in IPA:water (9:1 vol.), Pattern 5-A, L1NJ111001-5-21.

[0608] Figure 80 shows a DSC thermogram from screening with HCl (1.1 eq.) in IPA:water (9:1 vol.), Pattern 5-A, L1NJ111001-5-21.

[0609] Figure 81 shows a XRPD diffractogram from screening with HCl (2.2 eq.) in EtOAc, Pattern 5-G, L1NJ111001-5-23.

[0610] Figure 82 shows a DSC thermogram from screening with HCl (2.2 eq.) in EtOAc, Pattern 5-G, L1NJ111001-5-23.

[0611] Figure 83 shows an optical microscopy image of dried solids from screening with HCl (2.2 eq.) in EtOAc, Pattern 5-G, L1NJ111001-5-23 at 400X magnification.

[0612] Figure 84 shows a XRPD diffractogram from screening with HCl (2.2 eq.) in IPA:water (9:1 vol.), Pattern 5-F, L1NJ111001-5-24.

[0613] Figure 85 shows a DSC thermogram from screening with HCl (2.2 eq.) in IPA:water (9:1 vol.), Pattern 5-F, L1NJ111001-5-24.

[0614] Figure 86 shows the1H NMR in DMSO-d6 from screening with HCl (2.2 eq.) in IPA:water (9:1 vol.), Pattern 5-F, L1NJ111001-5-24.

[0615] Peak tables for the XRPD diffractogram of TAS3351 hydrochloride, Patterns 5-A through 5G are shown in Tables 22 through 28. All angles 2θ are ± 0.2◦.. Angle (° 2θ) d-spacing (Å) Relative intensityAngle (° 2θ) d-spacing (Å) Relative intensity 23.58 3.77 20 TABLE 22- XRP dry.Angle (° 2θ) d-spacing (Å) Relative intensity 632 1398 3Angle (° 2θ) d-spacing (Å) Relative intensity 26.69 3.34 32 TABLE 23- XRPAngle (° 2θ) d-spacing (Å) Relative intensity 4.41 20.04 7 TABLE 24- XRPD -dry.Angle (° 2θ) d-spacing (Å) Relative intensityAngle (° 2θ) d-spacing (Å) Relative intensity 12.50 7.08 3 TABLE 25- XRP humidified.Angle (° 2θ) d-spacing (Å) Relative intensity 775 1139 3 TABLE 26- XRPD-redried.Angle (° 2θ) d-spacing (Å) Relative intensity 7.79 11.34 16 TABLE 27- XRPD _dry.Angle (° 2θ) d-spacing (Å) Relative intensityAngle (° 2θ) d-spacing (Å) Relative intensity 23.76 3.74 47 TABLE 28- XRPD _dry.Malic Acid

[0616] Figure 87 shows a XRPD diffractogram from screening with malic acid (1.1 eq.) in EtOH, Pattern 6-A, L1NJ111001-5-25

[0617] Figure 88 shows a DSC thermogram from screening with malic acid (1.1 eq.) in EtOH, Pattern 6-A, L1NJ111001-5-25.

[0618] Figure 89 shows an optical microscopy image of the dried solids from screening with malic acid (1.1 eq.) in EtOH, Pattern 6-A, L1NJ111001-5-25 at 400X magnification.

[0619] Figure 90 shows the1H NMR in DMSO-d6 from screening with malic acid (1.1 eq.) in EtOH, Pattern 6-A, L1NJ111001-5-25.

[0620] Figure 91 shows a XRPD diffractogram from screening with malic acid (1.1 eq.) in EtOAc, Pattern 6-B, L1NJ111001-5-26.

[0621] Figure 92 shows a DSC thermogram from screening with malic acid (1.1 eq.) in EtOAc, Pattern 6-B, L1NJ111001-5-26.

[0622] Figure 93 shows the1H NMR in DMSO-d6 from screening with malic acid (1.1 eq.) in EtOAc, Pattern 6-B, L1NJ111001-5-26.

[0623] Figure 94 shows a XRPD diffractogram from screening with malic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 6-C, L1NJ111001-5-27.

[0624] Figure 95 shows a DSC thermogram from screening with malic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 6-C, L1NJ111001-5-27.

[0625] Figure 96 shows the1H NMR in DMSO-d6 from screening with malic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 6-C, L1NJ111001-5-27.Maleic Acid

[0626] Figure 97 shows a XRPD diffractogram from screening with maleic acid (1.1 eq.) in EtOH, Pattern 7-A, L1NJ111001-5-28.

[0627] Figure 98 shows a DSC thermogram from screening with maleic acid (1.1 eq.) in EtOH, Pattern 7-A,L1NJ111001-5-28.

[0628] Figure 99 shows a XRPD diffractogram from screening with maleic acid (1.1 eq.) in EtOAc, Pattern 7-B, L1NJ111001-5-29.

[0629] Figure 100 shows a DSC thermogram from screening with maleic acid (1.1 eq.) in EtOAc, Pattern 7-B, L1NJ111001-5-29.

[0630] Figure 101 shows the1H NMR in DMSO-d6 from screening with maleic acid (1.1 eq.) in EtOAc, Pattern 7-B,5-29.

[0631] Figure 102 shows a XRPD diffractogram from screening with maleic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 7-C, L1NJ111001-5-30.

[0632] Figure 103 shows a DSC thermogram from screening with maleic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 7-C, L1NJ111001-5-30.

[0633] Figure 104 shows the1H NMR in DMSO-d6 from screening with maleic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 7-C, L1NJ111001-5-30. Methanesulfonic Acid

[0634] Figure 105 shows a XRPD diffractogram from screening with MSA (1.1 eq.) in EtOH, Pattern 8-A, L1NJ111001-5-31.

[0635] Figure 106 shows a DSC thermogram from screening with MSA (1.1 eq.) in EtOH, Pattern 8-A, L1NJ111001-5-31.

[0636] Figure 107 shows a XRPD diffractogram from screening with MSA (1.1 eq.) in EtOAc, Pattern 8-D, L1NJ111001-5-32.

[0637] Figure 108 shows a DSC thermogram from screening with MSA (1.1 eq.) in EtOAc, Pattern 8-D, L1NJ111001-5-32.

[0638] Figure 109 shows a XRPD diffractogram from screening with MSA (2.2 eq.) in EtOH, Pattern 8-B, L1NJ111001-5-34.

[0639] Figure 110 shows a DSC thermogram from screening with MSA (2.2 eq.) in EtOH, Pattern 8-B, L1NJ111001-5-34.

[0640] Figure 111 shows the1H NMR in DMSO-d6 from screening with MSA (2.2 eq.) in EtOH, Pattern 8-B, L1NJ111001-5-34. Oxalic Acid

[0641] Figure 112 shows a XRPD diffractogram from screening with oxalic acid (1.1 eq.) in EtOH, Pattern 9-A, L1NJ111001-5-37

[0642] Figure 113 shows a DSC thermogram from screening with oxalic acid (1.1 eq.) in EtOH, Pattern 9-A, L1NJ111001-5-37.

[0643] Figure 114 shows an optical microscopy image of dried solids from screening with oxalic acid (1.1 eq.) in EtOH, Pattern 9-A, L1NJ111001-5-37 at 400X magnification.

[0644] Figure 115 shows the1H NMR in DMSO-d6 from screening with oxalic acid (1.1 eq.) in EtOH, Pattern 9-A, L1NJ111001-5-37.

[0645] Figure 116 shows a XRPD diffractogram from screening with oxalic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 9-B, L1NJ111001-5-39.

[0646] Figure 117 shows a DSC thermogram from screening with oxalic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 9-B, L1NJ111001-5-39.

[0647] Figure 118 shows an optical microscopy image of dried solids from screening with oxalic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 9-B, L1NJ111001-5-39 at 400X magnification. Pyruvic Acid

[0648] Figure 119 shows a XRPD diffractogram from screening with pyruvic acid (1.1 eq.) in EtOH, Pattern 11-A, L1NJ111001-5-43.

[0649] Figure 120 shows a DSC thermogram from screening with pyruvic acid (1.1 eq.) in EtOH, Pattern 11-A, L1NJ111001-5-43.

[0650] Figure 121 shows an optical microscopy image of dried solids from screening with pyruvic acid (1.1 eq.) in EtOH, Pattern 11-A, L1NJ111001-5-43 at 400X magnification.

[0651] Figure 122 shows a XRPD diffractogram from screening with pyruvic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 11-C, L1NJ111001-5-45.

[0652] Figure 123 shows a DSC thermogram from screening with pyruvic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 11-C, L1NJ111001-5-45.

[0653] Figure 124 shows an optical microscopy image of dried solids from screening with pyruvic acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 11-C, L1NJ111001-5-45 at 400X magnification. Sulfuric Acid

[0654] Figure 125 shows a XRPD diffractogram from screening with sulfuric acid (0.55 eq.) in EtOH, Pattern 12-A, L1NJ111001-5-46.

[0655] Figure 126 shows a DSC thermogram from screening with sulfuric acid (0.55 eq.) in EtOH, Pattern 12-A, L1NJ111001-5-46.

[0656] Figure 127 shows an optical microscopy image of dried solids from screening with sulfuric acid (0.55 eq.) in EtOH, Pattern 12-A, L1NJ111001-5-46 at 400X magnification.

[0657] Figure 128 shows a XRPD diffractogram from screening with sulfuric acid (0.55 eq.) in IPA:water (9:1 vol.), Pattern 12-C, L1NJ111001-5-48.

[0658] Figure 129 shows a DSC thermogram from screening with sulfuric acid (0.55 eq.) in IPA:water (9:1 vol.), Pattern 12-C, L1NJ111001-5-48.

[0659] Figure 130 shows the1H NMR in DMSO-d6 from screening with sulfuric acid (0.55 eq.) in IPA:water (9:1 vol.), Pattern 12-C, L1NJ111001-5-48. Tartaric Acid

[0660] Figure 131 shows a XRPD diffractogram from screening with tartaric acid (1.1 eq.) in EtOH, Pattern 14-A, L1NJ111001-5-55.

[0661] Figure 132 shows a DSC thermogram from screening with tartaric acid (1.1 eq.) in EtOH, Pattern 14-A, L1NJ111001-5-55.

[0662] Figure 133 shows the1H NMR in DMSO-d6 from screening with tartaric acid (1.1 eq.) in EtOH, Pattern 14-A, L1NJ111001-5-55.

[0663] Figure 134 shows the 1H NMR in DMSO-d6 from screening with tartaric acid (1.1 eq.) in IPA:water (9:1 vol.), Pattern 14-C, L1NJ111001-5-57.

[0664] A peak table for the XRPD diffractogram of TAS3351 tartrate, Pattern 14-B is shown in in Table 29, the angles are ± 0.2◦...Angle (° 2θ) d-spacing (Å) Relative intensity 4.20 21.00 100 TABLE 29- XRToluenesulfonic Acid

[0665] Figure 135 shows a XRPD diffractogram from screening with TSA (2.2 eq.) in EtOH, Pattern 15-B, L1NJ111001-5-61.

[0666] Figure 136 shows a DSC thermogram from screening with TSA(2.2 eq.) in EtOH, Pattern 15-B, L1NJ111001-5-61.

[0667] Figure 137 shows the1H NMR in DMSO-d6 from screening with TSA(2.2 eq.) in EtOH, Pattern 15-B, L1NJ111001-5-61. XRPD Diffractograms From One-Week Stability Experiments 75 % RH and 40 °C

[0668] Figure 138 shows XRPD diffractograms of besylate, Pattern 1-A, before and after one- week stability at 75 % RH and 40 °C: (1) Input solids, L1NJ111001-13-1; (2) After humidity exposure, L1NJ111001-58-1.

[0669] Figure 139 shows XRPD diffractograms of HCl, Pattern 5-H, before and after one-week stability at 75 % RH and 40 °C: (1) Input solids, L1NJ111001-13-2; (2) After humidity exposure, L1NJ111001-58-2.

[0670] Figure 140 shows XRPD diffractograms of tartrate, Pattern 14-A, before and after one- week stability at 75 % RH and 40 °C: (1) Input solids, L1NJ111001-53-1; (2) After humidity exposure, L1NJ111001-58-4.

[0671] Figure 141 shows XRPD diffractograms of tartrate, Pattern 14-C, before and after one- week stability at 75 % RH and 40 °C: (1) Input solids, L1NJ111001-53-2; (2) After humidity exposure, L1NJ111001-58-5. One-Week Slurries

[0672] Figure 142 shows XRPD diffractograms from one-week slurries of TAS3351 besylate, L1NJ111001- 13-1, Pattern 1-A: (1) Input solids, Pattern 1-A; (2) IPA, Pattern 1-A, L1NJ111001-57-4; (3) Acetone, Pattern 1-A, L1NJ111001-57-5; (4) EtOH:water (95:5 vol.), Pattern 1-A, L1NJ111001-57-6.

[0673] Figure 143 shows XRPD diffractograms from one-week slurry of besylate in IPA, Pattern 1-A, L1NJ111001-5-4: (1) Wet solids; (2) Solids dried at 50 °C for 4 days.

[0674] Figure 144 shows XRPD diffractograms from one-week slurry of besylate in acetone, Pattern 1-A, L1NJ111001-5-5: (1) Wet solids; (2) Solids dried at 50 °C for 4 days.

[0675] Figure 145 shows XRPD diffractograms from one-week slurry of besylate in EtOH:water (95:5 vol.), Pattern 1-A, L1NJ111001-5-6: (1) Wet solids; (2) Solids dried at 50 °C for 4 days.

[0676] Figure 146 shows XRPD diffractograms from one-week slurries of TAS3351 HCl, L1NJ111001-13-2, Pattern 5-H: (1) Input solids, Pattern A; (2) IPA, Pattern A, L1NJ111001-57- 4; (3) Acetone, Pattern A, L1NJ111001-57-5; (4) EtOH:water (95:5 vol.), Pattern A, L1NJ111001-57-6.

[0677] Figure 147 shows XRPD diffractograms from one-week slurry of tartrate Pattern 14-A (L.C.) in IPA, L1NJ111001-57-13: (1) Input solids, Pattern 14-A (L.C.); (2) Pattern FB-E reference, L1NJ111001-57-3; (3) Solids isolated from IPA, Pattern 14-A + FB-E.

[0678] Figure 148 shows XRPD diffractograms from one-week slurry of tartrate Pattern 14-A (L.C.) in acetone, L1NJ111001-57-14: (1) Pattern 14-C reference, L1NJ111001-53-2 (2) Pattern FB-E reference, L1NJ111001-57-3; (3) Solids isolated from acetone, Pattern 14-C + FB-E.

[0679] Figure 149 shows XRPD diffractograms from one-week slurry of tartrate Pattern 14-A (L.C.) in EtOH:water (95:5 vol.), L1NJ111001-57-15: (1) Input solids, Pattern 14-A (L.C.); (2) Pattern FB-E reference, L1NJ111001-57-3; (3) Solids isolated from EtOH:water (95:5 vol.), Pattern 14-A + FB-E.

[0680] Figure 150 shows XRPD diffractograms from one-week slurry of tartrate Pattern 14-C in IPA, L1NJ111001-57-16: (1) Input solids, Pattern 14-C; (2) Pattern FB-E reference, L1NJ111001-57-3; (3) Solids isolated from IPA, Pattern 14-C + FB-E.

[0681] Figure 151 shows XRPD diffractograms from one-week slurries of tartrate Pattern 14-C: (1) Pattern 14-C reference (wet solids), L1NJ111001-53-2; (2) Acetone, Pattern 14-C, L1NJ111001-57-17; (3) EtOH:water (95:5 vol.), Pattern 14-C, L1NJ111001-57-18. Analytical Techniques Differential Scanning Calorimetry (DSC)

[0682] DSC was performed using a TA Discovery DSC. The sample (1–5 mg) was weighed directly in a 40 μL hermetic aluminum pan with a pinhole and analyzed according to the parameters below: Parameters Method Ramp Sample size 1–5 mg Heating rate 10.0 °C / min Temperature 30 to 300 °C range Method gas N2at 50.00 mL / min TABLE 30 – DSC Parameters Dynamic Vapor Sorption (DVS)

[0683] DVS was performed using a Q5000SA. The sample (5–15 mg) was loaded into a metallic quartz sample pan, suspended from a microbalance, and exposed to a humidified stream of nitrogen gas. Weight changes were relative to a matching empty reference pan opposite the sample, suspended from the microbalance. The sample was held for a minimum of 10 min at each level and only progressed to the next humidity level if there was < 0.002 % change inweight between measurements (interval: 5 s) or 45 min had elapsed (for 5–65 % RH) or 2 h had elapsed (for 80 and 95 % RH). The following program was used: 1- Equilibration at 50 % RH 2- 50 % to 5 %. (50 %, 35 %, 20 %, and 5 %) 3- 5 % to 95 % (5 %, 20 %, 35 %, 50 %, 65 %, 80 %, and 95 %) 4- 95 % to 5 % (95 %, 80 %, 65 %, 50 %, 35 %, 20 %, and 5 %) 5- 5 % to 50 % (5 %, 20 %, 35 %, and 50 %) High-Performance Liquid Chromatography (HPLC)

[0684] HPLC was conducted using an Agilent 1220 Infinity LC. Flow rate range of the instrument is 0.2–5.0 mL / min, operating pressure range is 0–600 bar, temperature range is 5 °C above ambient to 60 °C, and wavelength range is 190–600 nm.

[0685] The HPLC method used in this study is shown below: Parameters Mobile phase A 10 mM PBS (pH ~ 6.9) in water:ACN (95:5 vol.) Mobile phase B ACN Diluent CHCl3:MeOH:(ACN:water (8:2 vol.)) 1:1:38 vol. Injection volume 1 μL Monitoring 220 nm wavelength Column InertSustain Swift C18 (2.1 × 50 mm, 1.9 µm), GL Sciences Column 40 °C temperature Time % A Flow rate (min) (mL / min) 0 80 0.3 Gradient method18 21 0.320 21 0.3 20.5 80 0.3 25 80 0.3TABLE 31 – HPLC Parameters Karl Fischer (KF) Titration

[0686] KF titration for water determination was performed using a Mettler Toledo C20S Coulometric KF Titrator equipped with a current generator cell with a diaphragm, and a double- platinum-pin electrode. The range of detection of the instrument is 1 ppm to 5 % water. Aquastar™ CombiCoulomat fritless reagent was used in both the anode and cathode compartments. Samples of approximately 0.03–0.10 g were dissolved in the anode compartment and titrated until the solution potential dropped below 100 mV. Hydranal 1 wt. % water standard was used for validation prior to sample analysis. Microscopy

[0687] Optical microscopy was performed using a Zeiss AxioScope A1 digital imaging microscope equipped with 2.5X, 10X, 20X, and 40X objectives and polarizer. Images were captured through a built-in Axiocam 105 digital camera and processed using ZEN 2 (blue edition) software provided by Zeiss. Proton Nuclear Magnetic Resonance (1H NMR) Spectroscopy

[0688] 1H NMR was performed on a Bruker Avance 500 MHz spectrometer. Solids were dissolved in 0.75 mL deuterated solvent in a 4 mL vial, transferred to an NMR tube (Wilmad 5 mm thin wall 200 MHz, 506-PP-8) and analyzed according to the following parameters: Parameters – Bruker Avance 500 Instrument Bruker Avance 500 MHz spectrometer Temperature 300 K Probe 5 mm PABBO BB-1H / D Z-GRD Z113652 / 0159 Number of scans 32 Relaxation delay 1.000 s Pulse width 14.0000 μs Acquisition time 3.2506 s Spectrometer 500.13 MHz frequency Nucleus1HTABLE 32 – NMR Parameters pH Measurement

[0689] pH was measured using a Mettler Toledo FP20 bench meter equipped with a Mettler Toledo InLab Micro pH electrode. The electrode has a ceramic junction and membrane resistance of < 600 MΩ. The internal reference electrolyte solution used is KCl and the operating range is 0–14 pH units at 0–80 °C. Simultaneous Thermogravimetric Analysis and Differential Scanning Calorimetry (TGA and DSC)

[0690] TGA and DSC were performed on the same sample simultaneously using a Mettler Toledo TGA / DSC3+. Protective and purge gas was nitrogen at a flowrate of 20–30 mL / min and 50–100 mL / min, respectively. The desired amount of sample (5–10 mg) was weighed directly in a hermetic aluminum pan with pinhole and analyzed according to the parameters below: Parameters Method Ramp Sample size 5–10 mg Heating rate 10.0 °C / min Temperature range 30 to 300 °C TABLE 33 – TGA and DSC Parameters X-Ray Powder Diffraction (XRPD)

[0691] XRPD was performed using a Rigaku MiniFlex 600 in reflection mode (i.e. Bragg- Brentano geometry). Samples were prepared on Si zero-return wafers. The parameters for XRPD methods used are listed below: Parameter Regular scan High resolution scan X-ray wavelength Cu Kα1, 1.540598 Å Cu Kα1, 1.540598 Å X-ray tube setting 40 kV, 15 mA 40 kV, 15 mA Slit condition 1.25 ° div., Ni kβ filter, 0.3 1.25 ° div., Ni kβ filter, 0.3 mm rec. mm rec. Scan mode Continuous Continuous Scan range (°2θ) 4–30 4–40Step size (°2θ) 0.05 0.05 Scan speed (° / min) 5 1.25 Spin No No TABLE 34 – XRPD Parameters Preparation of Simulated Fluids Fasted State Simulated Intestinal Fluid (FaSSIF) – pH = 6.48

[0692] The buffer was made by adding 3.72 g of FaSSIF concentrated buffer and 86.5 mL of distilled water to a beaker. FaSSIF powder, 0.20 g was then added, and the mixture until dissolution was observed. The solution was left to equilibrate overnight prior to use. Fasted State Simulated Gastric Fluid (FaSSGF) – pH = 1.55

[0693] The buffer was made by adding 16.65 g of FaSSGF concentrated buffer and 432 mL of distilled water to a beaker. FaSSGF powder, 0.028 g was then added, and the mixture until dissolution was observed. The solution was left to equilibrate overnight prior to use. Fed State Simulated Intestinal Fluid (FeSSIF) – pH = 4.98

[0694] The buffer was made by adding 7.31 g of FeSSIF concentrated buffer and 83 mL of distilled water to a beaker. FeSSIF powder, 1.00 g was then added, and the mixture until dissolution was observed. The solution was left to equilibrate overnight prior to use. Tartrate Polymorph and Co-Crystal Screening

[0695] 3 tartaric acid cocrystal hits / polymorphs were identified, including mono-tartaric acid cocrystal Pattern A, mono-tartaric acid cocrystal Pattern B and sesqui-tartaric acid cocrystal Pattern C. All the 3 tartaric acid cocrystal hits were characterized by XRPD, DSC, TGA,1H-NMR and KF.

[0696] Tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was used as starting material in the polymorph screening. Polymorphic behaviors of the tartaric acid cocrystal were investigated by equilibration, slow evaporation, fast evaporation, slow cooling, fast cooling, anti-solvent addition, reverse anti-solvent addition and vapor diffusion experiments.

[0697] The tartaric acid cocrystal shows complicated polymorphic behaviors. In total, 18 forms were identified to be polymorphs or pseudo-polymorphs of the tartaric acid cocrystal, including 4hydrates, named as Pattern A, G, P and R, 1 anhydrate, named as Pattern C, and 9 solvates, named as Pattern B, D, E, F, H, I, J, K, and M, and 1 meta-stable form, named as Pattern Q. Besides, 3 forms of disproportionation products, named as Pattern N, O and L were also obtained.

[0698] Tartaric acid cocrystal Pattern A is an isomorphic solvate. With water or ACN / water as solvent, it was obtained from acetonitrile, acetone, MEK, EA, dichloromethane, acetone / water (1:1, v:v) and 1,4-dioxane by equilibration, slow cooling and fast cooling experiments. Pattern A, sample ID FR02324-3-RC3-C-scale-up-75RH is a hydrate with high crystallinity. It contains about 3.2 equivalents (8.1% by weight) of water according to KF result. DSC shows a dehydration peak at Tonset of about 47°C with an enthalpy of about 166 J / g and a melting peak at Tonset of 143.8°C. Decomposition occurs upon melting. TGA shows about 7.5% weight loss at about 80°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and no residual solvent. The Pattern A is the most stable polymorph identified so far. Variable humidity XRPD experiments and bulk stability experiments show that Pattern A is stable across a wide relative humidity ranging from 10% to 92%RH and a wide temperature range raining from 5°C to 80°C. Interrelationship of polymorphs is summarized below.

[0699] Tartaric acid cocrystal Pattern B is an acetone solvate. It was obtained from acetone in cocrystal screening experiment. Pattern B, sample ID FR02324-2-RC3-D-XRPD-4min is of high crystallinity. DSC shows a desolvation peak at Tonset of about 31°C with an enthalpy of about 45J / g and a melting peak at Tonset of 151.5°C. Decomposition occurs upon melting. TGA shows about 4% weight loss at about 100°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and 4.2% acetone residue by weight, equivalent to 0.5 acetone molecule.

[0700] Tartaric acid cocrystal Pattern C is an anhydrate. It was obtained from acetonitrile in cocrystal screening experiment. Pattern C, sample ID FR02324-2-RC4-C-XRPD-4min is of medium to high crystallinity. DSC shows a melting peak at Tonset of 189.3°C. Decomposition occurs upon melting. TGA shows about 0.7% weight loss at about 160°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.5 and no residual solvent.

[0701] Tartaric acid cocrystal Pattern D is a DMF solvate. It was obtained from DMF by fast evaporation. Pattern D, sample ID FR02324-3-FE2-XRPD-4min is of medium crystallinity. DSC shows a melting peak at Tonset of 100.2°C. Decomposition occurs upon melting. TGA showsabout 10% weight loss at about 150°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and 18% DMF residue by weight, equivalent to 2.0 DMF molecules.

[0702] Tartaric acid cocrystal Pattern E is an isomorphic solvate. With acetone / water, ACN, MEK / water or EA as solvent. It was obtained from acetone, ACN, EA and MEK by equilibration experiments. Pattern E, sample ID FR02324-3-TC5-XRPD-4min is an acetone solvate with medium to high crystallinity. DSC shows a melting peak at Tonset of 152.0°C. Decomposition occurs upon melting. TGA shows about 5.9% weight loss at about 80°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and 1.7% acetone residue by weight, equivalent to 0.2 acetone molecule. Pattern E is unstable, it converts to Pattern A when exposure to 75%RH at 25°C for 4 days.

[0703] Tartaric acid cocrystal Pattern F is an IPAc solvate. It was obtained from IPAc by equilibration experiments. Pattern F, sample ID FR02324-3-TC8-XRPD-4min is of medium crystallinity. DSC shows a desolvation peak at Tonset of 23.6°C with an enthalpy of about 14J / g and an endothermic peak at Tonset of 128.8°C with an enthalpy of about 9J / g. Then it melts at Tonset of 146.0°C. Decomposition occurs upon melting. TGA shows about 9.5% weight loss at about 160°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and 8.3% IPAc residue by weight, equivalent to 0.6 IPAc molecule.

[0704] Tartaric acid cocrystal Pattern G is a hydrate. It was obtained from heptane by equilibration. Pattern G, sample ID FR02324-3-EQ32-scale-up is of medium crystallinity. It contains about 2.4 equivalents (6.2% by weight) of water according to KF result. DSC shows a dehydration peak at Tonset of 35.5°C with an enthalpy of 63J / g and a melting peak at Tonset of 153.1°C. Decomposition occurs upon melting. TGA shows about 4.5 % weight loss at about 160°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and 0.4% heptane residue by weight. Pattern G is physically unstable at 80°C / 75%RH.

[0705] Tartaric acid cocrystal Pattern H is a toluene solvate. It was obtained from toluene by equilibration experiments. Pattern H, sample ID FR02324-3-TC11-XRPD-4min is of medium to high crystallinity. DSC shows a desolvation peak at Tonset of 47.7°C with an enthalpy of about 97J / g and a melting peak at Tonset of 147.4°C. Decomposition occurs upon melting. TGA showsabout 8.7% weight loss at about 160°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and 4.0% toluene residue by weight, equivalent to 0.3 toluene molecule.

[0706] Tartaric acid cocrystal Pattern I is a MTBE solvate. It was obtained from MTBE by equilibration experiments. Pattern I, sample ID FR02324-3-TC12-XRPD-4min is of low crystallinity. DSC shows a desolvation peak at Tonset of 31.1°C with an enthalpy of about 42J / g and a melting peak at Tonset of 128.0°C. Decomposition occurs upon melting. TGA shows about 2.1% weight loss at about 80°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and 1.3% MTBE residue by weight, equivalent to 0.1 MTBE molecule.

[0707] Tartaric acid cocrystal Pattern J is a THF solvate. It was obtained from THF by equilibration experiments. Pattern J, sample ID FR02324-3-TC13-XRPD-4min is of medium crystallinity. DSC shows a melting peak at Tonset of 152.8°C. Decomposition occurs upon melting. TGA shows about 6.2% weight loss at about 160°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and 2.6% THF residue by weight, equivalent to 0.25 THF molecule. Pattern J is unstable, it converts to Pattern A when exposure to 75%RH at 25°C for 4 days.

[0708] Tartaric acid cocrystal Pattern K is a 1,4-dioxane solvate. It was obtained from 1,4-dioxane by equilibration experiments. Pattern K, sample ID FR02324-3-TC14-XRPD-4min is of medium to high crystallinity. DSC shows a desolvation peak at Tonset of 47.4°C with an enthalpy of about 107J / g and a melting peak at Tonset of 155.1°C. Decomposition occurs upon melting. TGA shows about 3.6% weight loss at about 160°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and 9.6% 1,4-dioxane residue by weight, equivalent to 0.81,4-dioxane molecule.

[0709] Tartaric acid cocrystal Pattern L is a disproportionation product. It was obtained from ACN / water (1:1, v:v) by equilibration experiments. Pattern L, sample ID FR02324-3-TC17- XRPD-4min is of high crystallinity.1H-NMR shows stoichiometry of free form: tartaric acid is 1:0.5.

[0710] Tartaric acid cocrystal Pattern M is an isomorphic solvate. With THF or 1,4-dioxane / water as solvent. It was obtained from THF / water and1,4-dioxane / water by equilibration. Pattern M, sample ID FR02324-3-TC18-XRPD-4min is a THF solvate with medium to high crystallinity. DSC shows a desolvation peak at Tonset of 44.9°C with an enthalpy of about 100J / g and a melting peak at Tonset of 153.0°C. Decomposition occurs upon melting. TGA shows about 8.5% weightloss at about 160°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and 3.1% THF residue by weight, equivalent to 0.3 THF molecule.

[0711] Tartaric acid cocrystal Pattern N is a disproportionation product. It was obtained from methanol by equilibration. Pattern N, sample ID FR02324-3-EQ24-XRPD-4min is of medium crystallinity.1H-NMR shows stoichiometry of free form: tartaric acid is 1:0.35.

[0712] Tartaric acid cocrystal Pattern O is a disproportionation product. It was obtained from ethanol by equilibration. Pattern O, sample ID FR02324-3-EQ25-XRPD-4min is of medium crystallinity.1H-NMR shows stoichiometry of free form: tartaric acid is 1:0.35.

[0713] Tartaric acid cocrystal Pattern P is a hydrate. It was obtained by heating Pattern G to 140°C. Pattern P, sample ID FR02324-3-TC14-140C-XRPD-4min is of medium crystallinity. It contains about 0.8 equivalent (2.2% by weight) of water according to KF result. DSC shows a desolvation peak at Tonset of 32.8°C with an enthalpy of 53J / g and an endothermic peak at Tonset of 135.1°C with an enthalpy of about 1J / g. Then it melts at Tonset of 147.0°C. Decomposition occurs upon melting. TGA shows about 2.9 % weight loss at about 80°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and no residual solvent. Pattern P is unstable and converts to Pattern A when exposure to ambient condition with humidity about 50%RH.

[0714] Tartaric acid cocrystal Pattern Q is a meta-stable form. It was obtained by dehydration of Pattern A at 0%RH and it converts to Pattern R when humidity is about 40%RH.

[0715] Tartaric acid cocrystal Pattern R is a hydrate. It was obtained from dehydration and rehydration of Pattern A by variable humidity XRPD experiments. Pattern R, sample ID FR02324- 3-RC3-C scale-up-75RH-initial-40-0-40RH(4H)-VH-XRPD is of medium to high crystallinity. It contains about 0.3 equivalent (1.0% by weight) of water according to KF result. DSC shows a desolvation peak at Tonset of 27.1°C with an enthalpy of 53J / g and a melting peak at Tonset of153.5°C. Decomposition occurs upon melting. TGA shows about 2.9 % weight loss at about 80°C.1H-NMR shows stoichiometry of free form: tartaric acid is 1:1.0 and no residual solvent.

[0716] Variable temperature XRPD was conducted for the solvates Pattern K, F and G. The results show that all the solvates converted to hydrate Pattern P after desolvation.

[0717] Variable humidity XRPD was conducted for the hydrate Pattern A. The result show that Pattern A is stable from 10%RH to 90%RH and it dehydrates at 0%RH. Its dehydration and rehydration is not reversible.

[0718] Solid exposure experiments was conducted for the solvates Pattern E and J .The results show that both solvates converted to hydrate Pattern A after exposure at 25°C / 75% RH for 4 days.

[0719] Relative stability of the hydrate Pattern A, G and P was investigated by bulk stability, variable humidity XRPD and DVS experiments. The bulk stability results show that Pattern A is physically and chemically stable. Pattern G is physically unstable at 80°C / 75%RH in an open container. Pattern P is physically unstable at 25°C / 92% RH in an open container, at 40°C / 75% RHin an open container and at 80°C / 75%RH in an open container. (Section 6.2.1) Variable humidity XRPD and DVS results shows that Pattern A is stable from 10%RH to 90%RH.

[0720] Based on above results, tartaric acid cocrystal Pattern A is the most stable polymorph identified so far. Evaluation of tartaric acid cocrystal Pattern A, G and P

[0721] Bulk stability of tartaric acid cocrystal Pattern A, G and P was evaluated at 25°C / 92%RH in an open container, at 40°C / 75%RH in an open container, at 60°C in a tight container, at 5°C in a tight container and at 80°C / 75%RH in an open container over 10 days.

[0722] Tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up-75RH is physically and chemically stable under these conditions.

[0723] Tartaric acid cocrystal Pattern G, sample ID FR02324-3-EQ32-scale-up is physically unstable at 80°C / 75%RH in an open container.

[0724] Tartaric acid cocrystal Pattern P, sample ID FR02324-3-Pattern P-scale-up-140C is physically unstable at 25°C / 92%RH in an open container, at 40°C / 75%RH in an open container and at 80°C / 75%RH in an open container.

[0725] Hygroscopicity of tartaric acid cocrystal Pattern A, G and P was evaluated by dynamic vapor sorption (DVS) test at 25°C.

[0726] Tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up-75RH is slightly hygroscopic. It absorbs about 1.3% water from 40%RH to 95%RH at 25°C. After the DVS test, obtained sample was Pattern R.

[0727] Tartaric acid cocrystal Pattern G, sample ID FR02324-3-EQ32-scale-up is slightly hygroscopic. It absorbs about 3.5% water from 40%RH to 95%RH at 25°C. After the DVS test, obtained sample was Pattern G with unknown extra peaks.

[0728] Tartaric acid cocrystal Pattern P, sample ID FR02324-3-Pattern P-scale-up-140C is slightly hygroscopic. It absorbs about 1.8% water from 40%RH to 95%RH at 25°C. After the DVS test, obtained sample was Pattern A.

[0729] Mechanic properties tartaric acid cocrystal Pattern A was evaluated by compression, grinding, granulation simulation experiments. Tartaric acid cocrystal Pattern A, sample IDFR02324-3-TC14-scale-up-140C-75RH shows good tolerance to compression, grinding, granulation simulation with no form change and no obvious crystallinity decrease.

[0730] The results of the polymorph and cocrystal screening are summarized in Table 35 below.

[0731] Conditions under which the polymorphs and co-crystals were formed is summarized in Table 36 below.

[0732] The interrelationships between the polymorphs and co-crystals is presented in Figure 152.Pattern A, Pattern B, Pattern D, Pattern E, Pattern F, Pattern Pattern H, isomorphic acetone solvate DMF solvate isomorphic IPAc solvate G,hydrate toluene solvate solvate solvate Sample ID FR02324-2- FR02324-2-RC3-D- FR02324-3-FE2- FR02324-3-TC5- FR02324-3-TC8- FR02324-3-EQ32- FR02324-3-TC11- RC3-C-scale-up XRPD-4min XRPD-4min-2 XRPD-4min XRPD-4min scale-up XRPD-4min Crystallinity (by High High Medium Medium to high Medium Medium Medium to high XRPD) Melting onset (by Desolvation Desolvation TonsetDesolvation Tonset152.0°C Desolvation TonsetDehydration n Desolvation TonsetDSC, °C) Tonset 47°C, 31°C, melting Tonset 100.2°C, melting 23.6°C, endo Tonset Tonset 35.5°C, 47.7°C, melting melting Tonset151.5°C Tonset194.8°C 128.8°C, melting melting TonsetTonset147.4°C 143.8°C Tonset 146.0°C 153.1°C Enthalpy (by 166J / g, melting 45J / g, melting 96J / g, melting Melting 14J / g, 9J / g, 63J / g, melting 97J / g, melting DSC, J / g) accompany with accompany with accompany with accompany with melting accompany with accompany with decomposition decomposition decomposition decomposition accompany with decomposition decomposition decomposition Weight loss (by 7.5%@ 80°C 4.0%@ 100°C 10% @150°C 5.9% @80°C 9.5% @160°C 4.5% @160°C 8.7% @160°C TGA) Stoichiometric 1:1 1:1 1:1 1:1 1:1 1:1 1:1 ratio (free form: tartaric acid) (by1H-NMR ) Residual solvent No residual 4.2% acetone by 18% DMF by 1.7% acetone by 8.3% IPAc by 1.5% heptane by 4.0% toluene by (by1H-NMR) solvent weight (0.5 weight (2 weight (0.2 weight (0.6 weight (0.1 weight (0.3 equivalent by molar equivalent by equivalent by equivalent by equivalent by equivalent by ratio) molar ratio) molar ratio) molar ratio) molar ratio) molar ratio) Water content 8.1% water by 2.2% water by / / 2.8% water by 4.1% water by 5.0% water by / / (by KF) weight (3.2 weight weight weight weight equivalent by molar ratio) Pattern I, Pattern J, Pattern K, Pattern M, Pattern P, Pattern Q, meta- Pattern R, MTBE solvate THF solvate 1,4-dioxane isomorphic hydrate stable form hydrate solvate solvate Sample ID FR02324-3- FR02324-3-TC13- FR02324-3-TC14- FR02324-3- FR02324-3-TC14- R02324-3-RC3-C- FR02324-3-RC3- TC12-XRPD- XRPD-4min XRPD-4min TC18-XRPD- 140C-XRPD-4min scale-up-75RH- C-scale-up-75RH- 4min 4min initial-0RH(4H)- initial-40-0- VH-XRPD 40RH(4H)-VH- XRPDCrystallinity (by Low Medium Medium to high Medium to high Medium Medium to high Medium to high XRPD) Melting onset (by Desolvation 152.8°C Desolvation Tonset Desolvation Desolvation Tonset / / desolvation Tonset DSC, °C) Tonset31.1°C, 47.4°C, melting Tonset44.9°C, 27.1°C, melting 47.9°C, melting Tonset Tonset 155.1°C melting Tonset Tonset 153.5°C endo Tonset 79.3°C, 128°C 153.0°C melting Tonset141.7°C Enthalpy (by 42J / g, melting Melting accompany 107J / g, melting 100J / g, melting 53J / g, melting / / 38J / g, 9J / g; melting DSC, J / g) accompany with with decomposition accompany with accompany with accompany with accompany with decomposition decomposition decomposition decomposition decomposition Weight loss (by 2.1% @80°C 6.2% @160°C 13.6% @160°C 8.5% @160°C 2.9% @80°C / / 5.6%@ 80°C TGA) Stoichiometric 1:1 1:1 1:1 1:1 1:1 / / / / ratio (free form: tartaric acid) (by1H-NMR) Residual solvent 1.3% MTBE by 2.6% THF by 9.6% 1,4-Dioxane 3.1%THF by No residual solvent / / / / (by1H-NMR) weight (0.1 weight (0.25 by weight (0.8 weight (0.3 equivalent by equivalent by molar equivalent by equivalent by molar ratio) ratio) molar ratio) molar ratio)Water content / / / / / / 8.0% water by 2.2% water by / / 1.0% water by (by KF) weight weight weight (0.3 equivalent by molar ratio) Pattern C, ACN solvate Pattern L, Pattern N, Pattern O, disproportionation product disproportionation product disproportionation product Sample ID FR02324-2-RC4-C- FR02324-3-TC17-XRPD- FR02324-3-EQ24-XRPD- FR02324-3-EQ25-XRPD-4min XRPD-4min 4min 4min Crystallinity (by XRPD) Medium to high High Medium Medium Melting onset (by DSC, °C) 189.3°C / / / / / / Enthalpy (by DSC, J / g) Melting accompany with / / / / / / decomposition Weight loss (by TGA) 0.7%@ 160°C / / / / / / Stoichiometric ratio (free form: 1:1.5 1:0.5 1:0.35 1:0.35 tartaric acid) (by1H-NMR) Residual solvent No residual solvent 1.8 % ACN by weight / / / / (by1H-NMR) Water content (by KF) 1.0% water by weight / / / / / / TABLE 35 - Summary of characterization of polymorphs and co-crystals. Note “ / / ” indicates not performedPolymorphs or pseudo-polymorphs Screening experiments From acetone, MEK, dichloromethane, y t nSolubility Screening

[0734] Approximate solubility at 25°C and at 50°C

[0735] Initial solubility at 25 °C and 50 °C was performed as follows. About 5mg of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was weighed to a 2mL glass vial. 20μL aliquots of each solvent was added to dissolve the drug substance at 25°C or 50°C. Vortex and sonication was applied to assist dissolution. Max. volume of each solvent added is 1mL. Approximate solubility was determined by visual observation.All features disclosed in the specification, including the claims, abstracts, and drawings, and all the steps in any method orprocess disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. Each feature disclosed in the specification, including the claims, abstract, and drawings, can be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

[0736] The results are summarized in Table 37 below. Exp. ID Solvents Solubility (mg / mL) 25°C 50°CTABLE 37- Approximate solubility at 25°C and at 50°C

[0737] Equilibration with solvents at 25°C for 2 weeks

[0738] Based on approximate solubility results, about 40mg of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was equilibrated in 0.5 mL of solvents at 25°C for 2 weeks with a stirring bar on a magnetic stirring plate at a rate of 300-400 rpm.

[0739] Obtained suspensions were filtered through a 0.45μm nylon membrane filter by centrifugation at 14,000 rpm. Solid parts (wet cakes) were investigated by XRPD.

[0740] Results are shown in Table 38 below. Exp. ID Solvents XRPD Tartaric acid cocrystal Pattern A +Exp. ID Solvents XRPD EQ201,4-Dioxane / water (1:1,*Tartaric acid cocrystal Pattern Med.

[0741] Equilibration with solvents at 50°C for 1 week

[0742] Based on approximate solubility results, about 40mg of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was equilibrated in 0.5 mL of solvents at 50°C for 1 week with a stirring bar on a magnetic stirring plate at a rate of 300-400 rpm.

[0743] Obtained suspensions were filtered through a 0.45μm nylon membrane filter by centrifugation at 14,000 rpm. Solid parts (wet cakes) were investigated by XRPD. For samples with different XRPD patterns, additional analysis including1H-NMR was performed.

[0744] Results are shown in Table 39 below. Exp. ID Solvents XRPD Comments EQ23 Water Free form Pattern C -Exp. ID Solvents XRPD Comments weight (0.8: Water activity is calculated by UNIFAC method.

[0745] Equilibration under a temperature cycle

[0746] Based on approximate solubility results, about 40mg of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was equilibrated in 0.5mL of solvents under a temperature cycle between 5°C to 50°C at a heating / cooling rate of 0.1°C / min for 10 cycles. The equilibration was executed with a stirring bar on a magnetic stirring plate at a rate of 400 rpm.

[0747] Obtained suspensions were filtered through a 0.45μm nylon membrane filter by centrifugation at 14,000 rpm. Solid parts (wet cakes) were investigated by XRPD. For samples with different XRPD patterns, additional analysis including DSC, TGA,1H-NMR and KF was performed.

[0748] Results are shown in Table 40 below. Exp. ID Solvents XRPD CommentsExp. ID Solvents XRPD Comments Free form Pattern ) , t ), ,Exp. ID Solvents XRPD Comments TGA: 6.2% @160°C, DSC: melting ° F e : ), eTABLE 40- Equilibration under a temperature cycle.

[0749] Crystallization at room temperature by slow evaporation

[0750] Based on approximate solubility results, about 50mg of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was dissolved in 2mL of solvents. Obtained solutions were filtered through a 0.45μm syringe nylon membrane filter. The clear solutions were slowly evaporated in ambient condition (about 25°C, 40-80% RH).

[0751] Solid residues were investigated by XRPD. Results are shown in Table 41 below. Exp. ID Solvents XRPD SE1 Tetrahydrofuran Almost amorphous on

[0752] Crystallization at room temperature by fast evaporation

[0753] Based on approximate solubility results, about 50mg of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was dissolved in 2mL of solvents. Obtained solutions were filtered through a 0.45μm syringe membrane filter. The clear solutions were fast evaporated at room temperature (about 25°C) under a dry nitrogen flow.

[0754] Solid residues were investigated by XRPD. For samples with different XRPD patterns, additional analysis including DSC, TGA and1H-NMR was performed. Results are shown in Table 42 below. Exp. ID Solvents XRPD CommentsTABLE 42- Crystallization at room temperature by fast evaporation

[0755] Crystallization from hot saturated solutions by slow cooling

[0756] Based on approximate solubility results, about 30mg of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was dissolved in the minimal amount of selected solvents at 50°C. Obtained solutions were filtered through a 0.45μm syringe membrane filter. The clear solutions were cooled to 5°C at 0.1°C / min. Samples without precipitates at 5°C were further cooled to -20°C.

[0757] Precipitates were collected by centrifugation filtration through a 0.45μm nylon membrane filter at 14,000 rpm. Solid parts (wet cakes) were investigated by XRPD. Results are shown in Table 43 below. Exp. ID Solvents XRPD SC1 Tetrahydrofuran / / Not carried outbecause the drug substance is too soluble.

[0758] Crystallization from hot saturated solutions by fast cooling

[0759] Based on approximate solubility results, about 30mg of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was dissolved in the minimal amount of selected solvents at 50°C. Obtained solutions were filtered through a 0.45μm syringe membrane filter. The clear solutions were put into a 5°C ice bath and agitated.

[0760] Precipitates were collected by centrifugation filtration through a 0.45μm nylon membrane filter at 14,000 rpm. Solid parts (wet cakes) were investigated by XRPD. Results are shown in Table 44 below. Exp. ID Solvents XRPDExp. ID Solvents XRPD FC3 DMSO / water (1:1, v:v) / / t carried out

[0761] Crystallization by addition of anti-solvent

[0762] Based on approximate solubility results, about 50mg of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was dissolved in the minimal amount of selected good solvents at ambient temperature (about 25°C). Obtained solutions were filtered through a 0.45μm syringe membrane filter.0.5-8 folds of anti-solvent was added into the clear solutions slowly until a large amount of solids precipitated out.

[0763] Precipitates were collected by centrifugation filtration through a 0.45μm nylon membrane filter at 14,000 rpm. Solid parts (wet cakes) were investigated by XRPD. Results are shown in Table 45 below. Exp. ID Solvents (mL) Anti-solvents XRPD Comments (mL) drugsubstance is too soluble. “-”: No comments.

[0764] Crystallization by reverse addition of anti-solvent

[0765] Based on approximate solubility results, about 50mg of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was dissolved in the minimal amount of selected goodsolvents at ambient temperature (about 25°C). Obtained solutions were filtered through a 0.45μm syringe membrane filter. The clear solutions were added into 0.5-6 folds of anti-solvent quickly.

[0766] Precipitates were collected by centrifugation filtration through a 0.45μm nylon membrane filter at 14,000 rpm. Solid parts (wet cakes) were investigated by XRPD. Results are shown in Table 46 below. Exp. ID Solvents (mL) Anti-solvents (mL) XRPD RAS1 Water (2.0) Free form Pattern C

[0767] Crystallization by vapor diffusion

[0768] Based on approximate solubility results, about 50mg of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up was dissolved in the minimal amount of selected solvents at ambient temperature (about 20-25°C). Obtained solutions were filtered through a 0.45μm syringe membrane filter. The clear solutions were transferred into 4mL glass vials without lids. Then these 4mL lid less vials were placed to 40mL glass vials. To the 40mL vials were added anti- solvents. Then these 40mL vials were capped tightly and placed at ambient temperature for up to 10 days.

[0769] Precipitates were collected by centrifugation filtration through a 0.45μm nylon membrane filter at 14,000 rpm. Solid parts (wet cakes) were investigated by XRPD. Results are shown in Table 47 below. Exp. ID Solvents (mL) Anti-solvents (mL) XRPD B BTABLE 47- Crystallization by vapor diffusion. “ / / ”: Not carried out because the drug substance is too soluble. Variable temperature XRPD (VT-XRPD) experiments

[0770] Variable temperature XRPD (VT-XRPD) experiments of Pattern K

[0771] Interconversion relationship of Pattern K and Pattern P was investigated by variable temperature XRPD.

[0772] Tartaric acid cocrystal Pattern K, sample ID FR02324-3-TC14 was used as starting material. One temperature cycle was applied. Initial XRPD analysis was carried out in ambient condition. All the other XRPD analysis was carried out in nitrogen atmosphere at each specific temperature. Cycle: 25°C (initial)-100°C (20min)-140°C (20min)-25°C (20min). Results are shown in Table 48 below. Exp. ID Temperature XRPD (equilibration time)

[0773] Variable temperature XRPD (VT-XRPD) experiments of Pattern F

[0774] Interconversion relationship of Pattern F and Pattern P was investigated by variable temperature XRPD.

[0775] Tartaric acid cocrystal Pattern F, sample ID FR02324-3-TC8 was used as starting material. One temperature cycle was applied. Initial XRPD analysis was carried out in ambient condition. All the other XRPD analysis was carried out in nitrogen atmosphere at each specific temperature.Cycle: 25°C (initial)-70°C (20min)-140°C (20min)-25°C (20min). Results are shown in Table 49 below. Exp. ID Temperature XRPD (equilibration time)

[0776] Variable temperature XRPD (VT-XRPD) experiments of Pattern G

[0777] Interconversion relationship of Pattern G and Pattern P was investigated by variable temperature XRPD.

[0778] Tartaric acid cocrystal Pattern G, sample ID FR02324-3-TC10 was used as starting material. One temperature cycle was applied. Initial XRPD analysis was carried out in ambient condition. All the other XRPD analysis was carried out in nitrogen atmosphere at each specific temperature. Cycle: 25°C (initial)-100°C (20min) -25°C (20min). Results are shown in Table 50 below. Exp. ID Temperature XRPD ilib ti tiTABLE 50- Variable temperature XRPD (VT-XRPD) experiments of Pattern G

[0779] Variable temperature XRPD (VT-XRPD) experiments of Pattern A

[0780] Interconversion relationship of Pattern A and Pattern P was investigated by variable temperature XRPD.

[0781] Tartaric acid cocrystal Pattern A, sample ID FR02324-3-Pattern A-scale-up was used as starting material. One temperature cycle was applied. Initial XRPD analysis was carried out in ambient condition. All the other XRPD analysis was carried out in nitrogen atmosphere at each specific temperature. Cycle: 25°C (initial)-130°C (20min) -25°C (20min). Results are shown in Table 51 below. Exp. ID Temperature XRPD (equilibration time)Variable humidity XRPD (VH-XRPD) experiments

[0782] Variable humidity XRPD (VH-XRPD) experiments of Pattern A

[0783] Interconversion relationship of Pattern A and Pattern R was investigated by variable humidity XRPD.

[0784] Tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up-75RH was used as starting material. One RH cycle was applied at 25°C. XRPD analysis was carried out in each specific relative humidity. Cycle 1: 40%RH (initial)-0%RH (6h)-40%RH (6h). Results are shown in Table 52 below. Exp. ID Relative humidity at 25°C XRPD CommentsExp. ID Relative humidity at 25°C XRPD Comments (equilibration time) ,

[0785] Tartaric acid cocrystal Pattern A, sample ID sample ID FR02324-3-Pattern A-scale-up- VH-XRPD was used as starting material. One RH cycle was applied at 25°C. XRPD analysis was carried out in each specific relative humidity. Cycle 1: 40%RH (initial)-90%RH (4h)-10%RH (4h)- 0%RH (4h)-40%RH(4h). Results are shown in Table 53 below. Exp. ID Relative humidity at 25°C XRPD (equilibration time)

[0786] Solid exposure experiments

[0787] Tartaric acid cocrystal Pattern E, sample ID FR02324-3-TC5, Pattern G, sample ID FR02324-3-TC10, Pattern J, sample ID FR02324-3-TC13 and Pattern M, sample ID FR02324-3- TC18 were placed at 25°C / 75% RH humidity chamber in an open container for 4 days. Tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up was placed at 25°C with moistureblowing (75% RH) in an open container for 4 hours. Samples after the exposure test were characterized by XRPD and1H-NMR and inspected for form change and residual solvent. Results are shown in Table 54 below. Exp. ID Conditions XRPD1H-NMR Pattern E 25°C / 75% RH for 4 Tartaric acid cocrystal No residual solvent ht htEvaluation of tartaric acid cocrystal Pattern A, G and P

[0788] A summary of the physicochemical properties of tartaric acid cocrystal Pattern A, G and P is shown in Table 55 below. Polymorph Tartaric acid Tartaric acid Tartaric acid cocr stal Pattern A cocr stal Pattern G cocr stal Pattern P y re y htTABLE 55- Physicochemical characteristics

[0789] Bulk Stability

[0790] Tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up-75RH, Pattern G, sample ID FR02324-3-EQ32-scale-up, and Pattern P, sample ID FR02324-3-Pattern P-scale- up-140C were placed at 25°C / 92% RH in an open container, at 40°C / 75% RH in an open container, at 60°C in a closed container, at 5°C in a closed container and 80°C / 75% RH in an open container for 10 days. Samples after the stress were characterized by XRPD and HPLC and inspected for color change. Results are shown in Table 56 below. Tartaric acid Tartaric acid Tartaric acid cocrystal Pattern cocrystal Pattern G cocrystal Pattern P A Exp. Initial 99.5% 99.6% 99.5% ID purity Purity Color Purity Color Purity Color Solid state, 25°C / 92%RH, open container, 10 days Bulk 99.6% Pale / / Pale 99.3% Pale brown BS1 (HPLC) yellow yellow Bulk Pattern A Pattern G Pattern A (XRPD)BS2 (HPLC) yellow yellow Bulk Pattern A Pattern G Pattern A (XRPD)BS3 (HPLC) yellow yellow Bulk Pattern A Pattern G Pattern P (XRPD)BS4 (HPLC) yellow yellow Bulk Pattern A Pattern G Pattern P (XRPD)Bulk Pattern A Pattern G + extra Pattern A (XRPD) peaks TABLE 56- Bulk Stability. “ / / ”: Not performed.

[0791] Water sorption and desorption experiments of Pattern A

[0792] Water sorption and desorption behavior of tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up-75RH was investigated by DVS at 25°C with a cycle of 40-95-0-95- 40%RH, dm / dt 0.002, min. equilibration time 60 min and max. equilibration time 360 min. XRPD was measured after the DVS test to determine form change. Results are shown in Table 57 below. Method 40-95-0-95-40%RH, dm / dt 0.002, min. equilibration time 60 min, max. equilibration time 360 min, 25°C, licable.

[0793] Water sorption and desorption experiments of Pattern G

[0794] Water sorption and desorption behavior of tartaric acid cocrystal Pattern G, sample ID FR02324-3-EQ32-scale-up was investigated by DVS at 25°C with a cycle of 40-95-0-95-40%RH,dm / dt 0.002, min. equilibration time 60 min and max. equilibration time 360 min. XRPD was measured after the DVS test to determine form change. Results are shown in Table 58 below. Method 40-95-0-95-40%RH, dm / dt 0.002, min. equilibration time 60 min, max. equilibration time 360 min, 25°C, licable.

[0795] Water sorption and desorption experiments of Pattern P

[0796] Water sorption and desorption behavior of tartaric acid cocrystal Pattern P, sample ID FR02324-3-Pattern P-scale-up-140C was investigated by DVS at 25°C with a cycle of 40-95-0- 95-40%RH, dm / dt 0.002, min. equilibration time 60 min and max. equilibration time 360 min. XRPD was measured after the DVS test to determine form change. Results are shown in Table 58 below. Method 40-95-0-95-40%RH, dm / dt 0.002, min. equilibration time 60 min, max. °40% 9.53 9.65 4.83 5.41 50% 9.74 9.89 5.23 6.48 able.

[0797] Morphology

[0798] The morphology and particle size of tartaric acid cocrystal Pattern A, sample ID FR02324- 3-Pattern A-scale-up-75RH was examined by SEM. Particles were shown to be rod-like, about 5μm with agglomeration.

[0799] Compression simulation experiments

[0800] About 10mg of tartaric acid cocrystal Pattern A, sample ID FR02324-3-Pattern A-scale- up-75RH was compressed for 5 minutes under 2MPa, 5MPa and 10MPa with a hydraulic press. Potential form change and degree of crystallinity were evaluated by XRPD. Results are shown in Table 60 below. Exp. ID Pressure XRPD Comment T t i id N b i hTABLE 60- Compression simulation experiments

[0801] Dry grinding simulation experiments

[0802] About 20 mg of tartaric acid cocrystal Pattern A, sample ID FR02324-3-Pattern A-scale- up-75RH was ground manually with a mortar and a pestle for 1, 2 and 5min. Potential form change and degree of crystallinity were evaluated by XRPD. Results are shown in Table 61 below. Exp. ID Grinding time XRPD Comment Tartaric acidNo obvious change e e

[0803] Wet granulation simulation experiments

[0804] Water or ethanol was added drop wise to about 10 mg of tartaric acid cocrystal Pattern A, sample ID FR02324-3-Pattern A-scale-up-75RH until the sample was wetted sufficiently. Wet sample was ground gently with in a mortar and a pestle. Post granulation sample was dried under ambient condition for 10 min. Potential form change and degree of crystallinity were evaluated by XRPD. Results are shown in Table 61 below. GNSE1 Water Tartaric acidNo obvious change tl P tt APreparation of polymorphs

[0805] Preparation of tartaric acid cocrystal Pattern A

[0806] Tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up-75RH was prepared using the procedure as follows. About 1g of tartaric acid cocrystal Pattern A, sample IDFR02324-3-RC3-C-scale-up was placed at 25°C with moisture blowing (75% RH) in an open container for 4 hours. A solvent free tartaric acid cocrystal Pattern A was obtained as a pale yellow solid. Characterization tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up- 75RH is reported in Table 55 above.

[0807] Preparation of tartaric acid cocrystal Pattern G

[0808] Tartaric acid cocrystal Pattern G, sample ID FR02324-3-EQ32-scale-up was prepared using the procedure as follows.300mg of tartaric acid cocrystal Pattern A, sample ID FR02324-3- RC3-C-scale-up was added into a screening solvent in a 8 mL vial. 4 mL of heptane was added into the vial under stirring at 50°C for about 5min to obtain a suspension. Obtained suspension was stirred at 50°C for another 5 days and then at 25°C for at least 2 hours. Solids were collected by suction filtration and then dried at 50°C under vacuum for about 1 hours.280mg of tartaric acid cocrystal Pattern G was obtained as a pale yellow solid in 93.3% yield. Characterization of tartaric acid cocrystal Pattern G, sample ID FR02324-3-EQ32-scale-up is reported in Table 55 above.

[0809] Preparation of tartaric acid cocrystal Pattern P

[0810] Tartaric acid cocrystal Pattern P, sample ID FR02324-3-TC14-scale-up was prepared using the procedure as follows. 300mg of the tartaric acid cocrystal Pattern A, sample ID FR02324-3- RC3-C-scale-up was added into a screening solvent in a 8 mL vial.4 mL 1,4-dioxane of was added into the vial under stirring at 25°C for about 5min to obtain a suspension. Obtained suspension was under a temperature cycle between 5°C to 50°C at a heating / cooling rate of 0.1°C / min for 10 cycles. The equilibration was executed with a stirring bar on a magnetic stirring plate at a rate of 400 rpm. Solids were collected by suction filtration and then dried at 50°C under vacuum for about 1 hours. A 1,4-dioxane solvate Pattern K was obtained. The Pattern K was dried at 140°C under vacuum for about 30min. About 146mg of tartaric acid cocrystal Pattern P was obtained as a pale brown solid in 49% yield. Characterization of tartaric acid cocrystal Pattern P, sample ID FR02324-3-TC14-scale-up-140C-75RH was reported in Table 55 above.

[0811] Preparation of tartaric acid cocrystal Pattern A for polymorph study

[0812] tartaric acid cocrystal Pattern A, sample ID FR02324-3-RC3-C-scale-up was prepared using the procedure as follows.5.1g of the free form Pattern A, batch ELS-519-182-23 and 1.5g(1 equiv.) of tartaric acid were added into a screening solvent in a 1000mL round-bottomed flask. 500mL of acetonitrile was added into the flask under stirring at 50°C for about 5min to obtain a suspension. Obtained suspension was stirred at 50°C for another 10 hours. The suspension was cooled to 25°C and kept stirring at 25°C for about 14 hours. Solids were collected by suction filtration and then dried at 50°C under vacuum for about 2 hours. 6.5g of tartaric acid cocrystal Pattern A was obtained as a pale yellow solid in 98.6% yield. Characterization of tartaric acid cocrystal Pattern A, sample ID FR02324-2-RC3-C-scale-up is reported in Table 63 below. Sample ID FR02324-2-RC3-C-scale-up Parameter Method Result Purity HPLC 99.0% -RC3-C-scale-up.

[0813] During the drying process, solids form and residual solvent were monitored by XRPD and 1H-NMR. A decrease of crystallinity of Pattern A is observed with increase of dry time. Results are shown in Table 64 below. Parameter Method Vacuum dry at 50°C oTABLE 64- XRPD and NMR results of tartaric acid cocrystal Pattern A during drying. Tartaric acid cocrystal screening

[0814] Approximate solubility of tartaric acid cocrystal at 25°C

[0815] About 5mg of free form Pattern A, batch ELS-519-182-23 was weighed to a 2mL glass vial.20μL aliquots of each solvent were added to dissolve the drug substance at 25°C. Vortex and sonication were applied to assist dissolution. Max. volume of each solvent added was 1mL. Approximate solubility was determined by visual observation. Results are shown in Table 65 below. Exp. ID Solvents Solubility (mg / mL) 25°C 50°C

[0816] Tartaric acid cocrystal screening

[0817] About 51mg of free form Pattern A, batch ELS-519-182-23 and 0.5, 1 and 2 equiv. of tartaric acid were added into a screening solvent in a 2mL glass vial. Obtained mixtures were stirred at 50°C for 12 hours and then at 25°C for at least 4 hours.

[0818] Obtained suspension were filtered through a 0.45μm nylon membrane filter by centrifugation at 14,000 rpm. After being dried at 50°C under vacuum for 2 h, solids were analyzed by XRPD.

[0819] Results are shown in Tables 66 and 67 below. Exp. ID A B C D t i l t 1 l t 2 l t l t 4Exp. ID A B C D Counter ions Solvent 1 Solvent 2 Solvent 3 Solvent 4 EtOH IPA / water (9:1, ACN AcetoneTartaric acid cocrystal Tartaric acid cocrystal Tartaric acid cocrystal Pattern A Pattern B Pattern C th

[0820] Instrumental methods for polymorph and co-crystal screening are presented in Table 68 below. X-ray Powder Diffractometer (XRPD) Instrument Bruker D8 Advance X-ray geometry Reflection Detector LYNXEYE_XE_T (1D mode) Open angle 2.9° (max) Radiation Cu / K-Alpha1 (λ=1.5406Å) X-ray generator power 40kV, 40mAPrimary beam path slits Twin_Primary motorized slit: 20.0mm by sample length; Primary Soller slit: 2.5° Secondary beam path slits Secondary Soller slit: 2.5° Scan mode Continuous scan Scan type Locked coupled Step size 0.02° Time per step 0.12 second per step Scan range 3° to 40° Sample rotation speed 15rpm Sample holder Monocrystalline silicon, flat surface Variable Temperature X-ray Powder Diffractometer (VT-XRPD) Instrument Bruker D8 Advance X-ray geometry Reflection Detector LYNXEYE (1D mode) Open angle 2.1° (max) Radiation Cu / K-Alpha1 (λ=1.5406Å) X-ray generator power 40kV, 40mA Primary beam path slits Divergence fixed slit: 0.6 mm; Primary Soller slit: 2.5° Secondary beam path slits Secondary Soller slit: 2.5° Scan mode Continuous scan Scan type Locked coupled Step size 0.02° Time per step 0.6 second per step Scan range 4° to 40° Non-ambient stage CHC Plus+ chamber Variable humidity X-ray Powder Diffractometer (VH-XRPD) Instrument Bruker D8 Advance X-ray geometry Reflection Detector LYNXEYE (1D mode) Open angle 2.1° (max) Radiation Cu / K-Alpha1 (λ=1.5406Å) X-ray generator power 40kV, 40mA Primary beam path slits Divergence fixed slit: 0.6 mm; Primary Soller slit: 2.5° Secondary beam path slits Secondary Soller slit: 2.5° Scan mode Continuous scan Scan type Locked coupled Step size 0.02° Time per step 0.6 second per step Scan range 4° to 40° Non-ambient stage CHC Plus+ chamber Differential Scanning Calorimeter (DSC) Instrument TA Instruments Discovery 2500 Sample pan Tzero pan and Tzero hermetic lid with a manually punched pin hole of about 0.7mm in diameter Temperature range ~30°C to 250°C or before decomposition Heating rate 10°C / minNitrogen flow 50 mL / min Sample mass ~0.5-5 mg Thermal Gravimetric Analysis (TGA) Instrument TA Instruments Discovery 5500 Sample pan Aluminum, open Start temperature Ambient condition (below 35°C) Final temperature 300°C or abort next segment if weight < 80% (w / w) (Weight loss of the compound is more than 20% (w / w).) Heating rate 10°C / min Nitrogen flow Balance 10mL / min; sample chamber 25mL / min Sample mass ~2-10 mg Dynamic Vapor Sorption (DVS) Instrument SMS Intrinsic, Advantage or Adventure Total gas flow 200sccm Oven temperature 25°C Solvent Water Method Cycle: 40-95-0-95-40%RH Stage Step: 10% Equilibrium: 0.002 dm / dt (% / min ) Minimum dm / dt stability duration: 60min Maximum dm / dt stage time: 360min Sample mass ~5-50 mg Karl Fischer (KF) Instrument Mettler Toledo Coulometric KF Titrator C30 Method Coulometric Sample mass ~5-30 mg Scanning Electronic Microscope (SEM) Instrument Phenom Prox SEM-EDS Detector BSD Full Magnification 200x-10000x Polarized Light Microscope (PLM) Instrument Nikon LV100POL Method Crossed polarizer, silicone oil added Nuclear Magnetic Resonance (NMR) Instrument Bruker Avance-AV 400M Frequency 400MHz Probe 5 mm PABBO BB / 19F-1H / D Z-GRD Z108618 / 0406 Number of scan 8 Temperature 297.6K Relaxation delay 1 second Fourier Transform Infrared Spectrum (FT-IR) Instrument Thermo Nicolet iS5 Number of scan 32 Mode ATR Resolution 4Sample compartment Main Detector DTGS KBr Beamsplitter KBr Source IR Accessory ID7 Window Diamond Recommended range 4,000-525 cm-1 Gain:1 1.0 Optical velocity 0.4747 Aperture 100 Ultra Performance Liquid Chromatograph (UPLC) Instrument Agilent 1290 infinityII Binary Pump HPLC method Wave length: 220 nm Column: ACQUITY UPLC®BEH C181.7 μm, 2.1×150mm Detector: DAD Column temperature: 40°C Flow rate: 0.4mL / min Mobile phase A: pH 6.8 phosphate buffer : ACN (950:50, v:v) Mobile phase B: ACN Diluent: ACN: MeOH: Chloroform (45:45:10, v:v:v) Injection volume: 1μL Gradient: Gradient: Time Mobile Phase A Mobile Phase B (min) (%) (%) 0.00 70 30 5.83 40 60 7.29 30 70 High Performance LiquidInstrument SHIMADZU LC-20 HPLC method Wave length: 220 nm Column: XBridge® C183.5 μm, 4.6×150mm Detector: PAD Column temperature: 40°C Flow rate: 1mL / min Mobile phase A: pH 6.8 phosphate buffer : ACN (950:50, v:v) Mobile phase B: water : ACN (20:80, v:v)Diluent: ACN: MeOH: Chloroform (45:45:10, v:v:v) Injection volume: 5μL Gradient: Time (min) Mobile Phase A Mobile Phase B (%) (%) 0.00 70 30 12.00 40 60 15.00 30 70 18.00 5 95 21.00 5 95 27.00 70 30 30.01 70 30 TABLE 68- Instrumental methods

[0821] It will be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

CLAIMS What is Claimed is:

1. A crystal comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and benzene sulfonic acid, wherein the crystal has peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ ± 0.2°) of: (i) one or more selected from the group consisting of 16.56°, 19.2°, 20.9°, and 24.8°; and (ii) two or more selected from the group consisting of 5.6°, 6.0°, 12.6°, 14.0°, 16.1°, 20.2°, 20.5°, 23.9°, 25.2°, 26.1°, 27.1°, and 28.3°.

2. The crystal of claim 1, wherein the crystal has peaks in a powder X-ray diffraction spectrum at a total of five or more diffraction angles (2θ ± 0.2°) selected from groups (i) and (ii).

3. The crystal of claim 1, wherein the crystal has peaks in a powder X-ray diffraction spectrum at a total of seven or more diffraction angles (2θ ± 0.2°) selected from groups (i) and (ii).

4. The crystal of claim 1, wherein the crystal has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 4.

5. The crystal of claim 1, having an exothermic peak determined by simultaneous thermogravimetric-differential thermal analysis is around 238°C.

6. The crystal of claim 1, wherein the crystal has a crystal purity of 50% by weight or more.

7. The crystal of claim 1, wherein the crystal has a chemical purity of 90% or more.

8. A method for producing a crystal comprising N-(4-(4-amino-6-ethynyl-5- (quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2- carboxamide and benzene sulfonic acid of claim 1, the method comprising stirring N-(4-(4-amino- 6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and benzene sulfonic acid in a single solvent of a lower alcohol with 2 or more carbon atoms, acetone, or ethyl acetate, or in a mixed solvent comprising two or more of these solvents.

9. A crystal comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and hydrochloric acid, wherein the crystal has peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ ± 0.2°) of: (i) 10.5°; and (ii) at least two selected from the group consisting of 13.0°, 17.7°, 18.4°, 20.8°, 21.1°, 23.6°, and 24.1°.

10. The crystal of claim 9, wherein the crystal has peaks in a powder X-ray diffraction spectrum at three or more diffraction angles (2θ ± 0.2°) selected from group (ii).

11. The crystal of claim 9, wherein the crystal has peaks in a powder X-ray diffraction spectrum at five or more diffraction angles (2θ ± 0.2°) selected from group (ii).

12. The crystal of claim 9, wherein the crystal has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 12.

13. The crystal of claim 9, having an exothermic peak determined by simultaneous thermogravimetric-differential thermal analysis is around 263°C.

14. The crystal of claim 9, wherein the crystal has a crystal purity of 50% by weight or more.

15. The crystal of claim 9, wherein the crystal has a chemical purity of 90% or more.

16. A method for producing the crystal comprising N-(4-(4-amino-6-ethynyl-5- (quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2- carboxamide and hydrochloric acid of claim 9, the method comprising stirring N-(4-(4-amino-6- ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5- methylpyrazine-2-carboxamide and hydrochloric acid in a single solvent of a lower alcohol with2 or more carbon atoms, acetone, or ethyl acetate, or in a mixed solvent comprising two or more of these solvents.

17. A crystal comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and tartaric acid, wherein the crystal has peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ ± 0.2°) of: (i) 12.2°; and (ii) at least two selected from the group consisting of 4.6°, 6.3°, 8.6°, 9.1°, 9.8°, 12.1°, 13.7°, 18.3°, and 20.6°.

18. The crystal of claim 17, wherein the crystal has peaks in a powder X-ray diffraction spectrum at four or more diffraction angles (2θ ± 0.2°) selected from group (ii).

19. The crystal of claim 17, wherein the crystal has peaks in a powder X-ray diffraction spectrum at six or more diffraction angles (2θ ± 0.2°) selected from group (ii).

20. The crystal of claim 17, wherein the crystal has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 17.

21. The crystal of claim 17, wherein an exothermic peak determined by simultaneous thermogravimetric-differential thermal analysis is around 209°C.

22. The crystal of claim 17, wherein the crystal has a crystal purity of 50% by weight or more.

23. The crystal of claim 17, wherein the crystal has a chemical purity of 90% or more.

24. A method for producing the crystal comprising N-(4-(4-amino-6-ethynyl-5- (quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2- carboxamide and tartaric acid of claim 17, the method comprising stirring N-(4-(4-amino-6- ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5- methylpyrazine-2-carboxamide and tartaric acid in a solvent comprising ethanol.

25. A crystal comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide and tartaric acid,wherein the crystal has peaks in a powder X-ray diffraction spectrum at diffraction angles (2θ ± 0.2°) of: (i) 5.6°; and (ii) two or more selected from the group consisting of 8.6°, 13.4° 16.8°, 21.9°, 26.9°, and 29.8°.

26. The of claim 25, wherein the crystal has peaks in a powder X-ray diffraction spectrum at three or more diffraction angles (2θ ± 0.2°) selected from group (ii).

27. The crystal of claim 25, wherein the crystal has peaks in a powder X-ray diffraction spectrum at five or more diffraction angles (2θ ± 0.2°) selected from group (ii).

28. The crystal of claim 25, wherein the crystal has a powder X-ray diffraction spectrum substantially identical to the powder X-ray diffraction spectrum shown in Figure 22.

29. The crystal of claim 25, wherein an endothermic peak determined by simultaneous thermogravimetric-differential thermal analysis is around 159°C.

30. The crystal of claim 25, wherein the crystal has a crystal purity of 50% by weight or more.

31. The crystal of claim 25, wherein the crystal has a chemical purity of 90% or more.

32. A method for producing the crystal comprising N-(4-(4-amino-6-ethynyl-5- (quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2- carboxamide and tartaric acid of claim 25, the method comprising stirring N-(4-(4-amino-6- ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5- methylpyrazine-2-carboxamide and tartaric acid in a mixed solvent comprising at least two selected from the group consisting of a lower alcohol with 3 or more carbon atoms, acetone, ethyl acetate, and water.

33. A pharmaceutical composition comprising the crystal of claim 1.

34. The pharmaceutical composition of claim 33, further comprising a pharmacologically acceptable carrier.

35. A pharmaceutical composition comprising the crystal of claim 9.

36. The pharmaceutical composition of claim 35, further comprising a pharmacologically acceptable carrier.

37. A pharmaceutical composition comprising the crystal of claim 17.

38. The pharmaceutical composition of claim 37, further comprising a pharmacologically acceptable carrier.

39. A pharmaceutical composition comprising the crystal of claim 25.

40. The pharmaceutical composition of claim 39, further comprising a pharmacologically acceptable carrier.

41. An antitumor agent comprising the crystal of claim 1.

42. An antitumor agent comprising the crystal of claim 9.

43. An antitumor agent comprising the crystal of claim 17.

44. An antitumor agent comprising the crystal of claim 25.

45. A method for treating a tumor, comprising orally administering an effective amount of the crystal of claim 1 to a subject in need thereof.

46. A method for treating a tumor, comprising orally administering an effective amount of the crystal of claim 9 to a subject in need thereof.

47. A method for treating a tumor, comprising orally administering an effective amount of the crystal of claim 17 to a subject in need thereof.

48. A method for treating a tumor, comprising orally administering an effective amount of the crystal of claim 25 to a subject in need thereof.

49. A method for producing an antitumor agent for oral administration comprising the crystal of claim 1, the method comprising mixing the crystal of claim 1 and a pharmacologically acceptable carrier.

50. A method for producing an antitumor agent for oral administration comprising the crystal of claim 9, the method comprising mixing the crystal of claim 9 and a pharmacologically acceptable carrier.

51. A method for producing an antitumor agent for oral administration comprising the crystal of claim 17, the method comprising mixing the crystal of claim 17 and a pharmacologically acceptable carrier.

52. A method for producing an antitumor agent for oral administration comprising the crystal of claim 25, the method comprising mixing the crystal of claim 25 and a pharmacologically acceptable carrier.

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