crystalline lincitinib for cancer treatment

Abstract

This invention provides novel salts and crystalline forms of lincitinib (OSI-906; cis-3-[8-amino-1-(2-phenyl-7-quinolinyl)imidazo[1,5-a]pyrazine-3-yl]-1-methylcyclobutanol). These novel forms of lincitinib increase the solubility of orally administered pharmaceutical formulations and improve the pharmacokinetic profile. Thus, this invention enables improved methods for treating human insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR)-mediated conditions.

Description

[Technical Field]

[0001] The chemical structure of cis-3-[8-amino-1-(2-phenyl-7-quinolinyl)imidazo[1,5-a]pyrazine-3-yl]-1-methylcyclobutanol (also known as OSI-906, hereafter abbreviated as lincitinib) is as follows: [ka] [Background technology]

[0002] Lincitinib is a small molecule inhibitor of the human insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR), and has been studied as an antiproliferative agent. For example, lincitinib has been designated as an orphan drug for adrenocortical cell carcinoma, and clinical trials have been conducted for various cancers, including myeloma and ovarian cancer. However, these studies were discontinued because the efficacy against the target cancers was insufficient.

[0003] Preparation of lincitinib in the form of a solid free base is disclosed in U.S. Patent Nos. 7,534,797 and 8,101,613 of OSI Pharmaceuticals, LLC (see Example 31). Numerous acid and base addition salts are listed (see columns 154 and 164, respectively), but formic acid and hydrochloric acid addition salts are identified as particularly preferred acid addition salts of the comprehensively disclosed compounds.

[0004] More recently, lincitinib has been developed for the treatment of thyroid eye disease (TED) by oral administration in the form of anhydrous / non-solvated free base. While this form of lincitinib has shown promise, it suffers from the problem of low pH-dependent solubility. Therefore, an improved form of lincitinib is needed to increase pH-dependent solubility. For example, if the dissolution and pharmacokinetic profile is improved by a new form, it may lead to improved efficacy, better tolerability, and a more advantageous dosage form. This invention addresses these and other objectives, as will be disclosed in more detail below. [Overview of the project]

[0005] In one embodiment, the present invention provides a solid salt form of lincitinib.

[0006] In one embodiment, a crystalline esylate salt of lincitinib having the structure of formula II is provided: [ka]

[0007] In one embodiment, a crystalline L-malate salt of lincitinib having the structure of formula III is provided: [ka]

[0008] In one embodiment, a pharmaceutical composition is provided comprising a crystalline esylate salt or a crystalline L-malate salt of lincitinib and a pharmaceutically acceptable excipient.

[0009] In one embodiment, a combination therapy is provided comprising a crystalline esylate salt or a crystalline L-malate salt of lincitinib and a TSHR inhibitor.

[0010] In one embodiment, there is provided a method for treating a condition mediated by human insulin-like growth factor 1 receptor (IGF-1R) or insulin receptor (IR), the method comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline esylate salt of linsitinib, a crystalline L-malate salt of linsitinib, or a pharmaceutical composition thereof.

[0011] In one embodiment, the present invention provides a method for treating thyroid eye disease (TED) in a subject in need thereof, the method comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline esylate salt of linsitinib, a crystalline L-malate salt of linsitinib, or a pharmaceutical composition thereof. In one embodiment, the thyroid eye disease is chronic thyroid eye disease. This patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Patent Office upon request and payment of the necessary fee.

Brief Description of the Drawings

[0012] [Figure 1] FIG. 1 is a diagram showing the PXRD of linsitinib sample 1 (starting material).

[0013] [Figure 2] FIG. 2 is a diagram showing the 1H-NMR of sample 1.1 (starting material).

[0014] [Figure 3] FIG. 3 is a diagram showing the PXRD comparison of the crystalline salt forms identified in the salt screen.

[0015] [Figure 4] FIG. 4 is a diagram showing the PXRD of esylates 1 to 5.

[0016] [Figure 5] FIG. 5 is a diagram showing the PXRD of esylate 1 (sample 2-5).

[0017] [Figure 6] Figure 6 shows the 1H-NMR spectrum of esylate 1 (samples 2-5) in DMSO-d6.

[0018] [Figure 7] Figure 7 shows the DSC thermogram and TGA thermogram of Esilate 1 (sample 2-5).

[0019] [Figure 8] Figure 8 shows the PXRD of Esilate 2 (sample 3-3).

[0020] [Figure 9] Figure 9 shows the 1H-NMR spectrum of esylate 2 (sample 3-3) in DMSO-d6.

[0021] [Figure 10] Figure 10 shows the DSC thermogram and TGA thermogram of Esilate 2 (sample 3-3).

[0022] [Figure 11] Figure 11 shows the asymmetric unit cell of the esylate 2 single crystal structure. Carbon atoms are gray, nitrogen atoms are blue, oxygen atoms are red, and sulfur atoms are yellow. Hydrogen atoms have been omitted for clarity.

[0023] [Figure 12] Figure 12 shows a packing diagram of an esylate 2 single crystal viewed from the a-axis.

[0024] [Figure 13] Figure 13 shows a packing diagram of an esylate 2 single crystal viewed from the b-axis.

[0025] [Figure 14] Figure 14 shows a packing diagram of an esylate 2 single crystal viewed from above along the c-axis.

[0026] [Figure 15] Figure 15 shows the XRPD pattern calculated from esylate 2 single crystal data superimposed on the reference XRPD pattern of lincitinib esylate 2. The patterns overlap well, indicating that they represent the same crystalline phase. The observed peak shifts are due to the temperature difference between the single crystal and X-ray powder diffraction data collection.

[0027] [Figure 16] Figure 16 shows the PXRD of the Ethylate 2 scale-up (samples 3-43).

[0028] [Figure 17] Figure 17 shows the DVS thermogram of the Esilate 2 scale-up (samples 3-43).

[0029] [Figure 18] Figure 18 shows the TGA thermogram of the Esilate 2 scale-up (samples 3-43).

[0030] [Figure 19] Figure 19 shows the PXRD of the esylate 2 scale-up after exposing samples 3-43 to 75% RH stress at room temperature for 24 days (sample 3-44).

[0031] [Figure 20] Figure 20 shows the TGA thermogram of Esilate 2 scale-up after samples 3-43 were exposed to 75% RH stress at room temperature for 24 days (sample 3-44).

[0032] [Figure 21] Figure 21 shows the PXRD of the Ethylate 2 scale-up after milling samples 3-43 at maximum power for 30 minutes (sample 3-45).

[0033] [Figure 22] Figure 22 shows the PXRD of Ethylate 3 (sample 3-13).

[0034] [Figure 23] Figure 23 shows the 1H-NMR spectrum of esylate 3 (sample 3-13) in DMSO-d6.

[0035] [Figure 24] Figure 24 shows the DSC thermogram and TGA thermogram of Esilate 3 (sample 3-13).

[0036] [Figure 25] Figure 25 shows the PXRD of esylate 4 (sample 3-24).

[0037] [Figure 26] Figure 26 shows the 1H-NMR spectrum of esylate 4 (sample 3-24) in DMSO-d6.

[0038] [Figure 27] Figure 27 shows the DSC thermogram and TGA thermogram of Esilate 4 (sample 3-24).

[0039] [Figure 28] Figure 28 shows the PXRD of sample 3-26 after removing the cap, placing it in a vacuum oven, and drying it at 60°C for 18 hours (sample 3-46).

[0040] [Figure 29] Figure 29 shows the DSC thermogram and TGA thermogram of Esilate 5 (samples 3-47).

[0041] [Figure 30] Figure 30 shows the PXRD of diesylate 1 (sample 3-24).

[0042] [Figure 31] Figure 31 shows the 1H-NMR spectrum of esylate 5 (sample 3-24) in DMSO-d6.

[0043] [Figure 32] Figure 32 shows the DSC thermogram and TGA thermogram of Esilate 5 (sample 3-24).

[0044] [Figure 33] Figure 33 shows the PXRD of L-malate 1 (sample 2-16).

[0045] [Figure 34] Figure 34 shows the 1H-NMR spectrum of L-malate 1 (sample 2-16) in DMSO-d6.

[0046] [Figure 35] Figure 35 shows the DSC thermogram and TGA thermogram of L-malate 1 (sample 2-16).

[0047] [Figure 36] Figure 36 shows the PXRDs for L-malate 2 (sample 4-45), L-malate 3 (sample 4-22), L-malate 4 (sample 4-10), L-malate 5 (sample 4-58), L-malate 6 (sample 4-56), L-malate 7 (sample 4-78), L-malate 8 (sample 4-76), and L-malate 9 (sample 4-66).

[0048] [Figure 37] Figure 37 shows the 1H-NMR spectrum of L-malate 2 (samples 4-45) in DMSO-d6.

[0049] [Figure 38] Figure 38 shows the 1H-NMR spectrum of L-malate 3 (sample 4-22) in DMSO-d6.

[0050] [Figure 39] Figure 39 shows the DSC thermogram and TGA thermogram of L-malate 3 (sample 4-22).

[0051] [Figure 40] Figure 40 shows the 1H-NMR spectrum of L-malate 4 (sample 4-10) in DMSO-d6.

[0052] [Figure 41] Figure 41 shows the DSC thermogram and TGA thermogram of L-malate 4 (sample 4-10).

[0053] [Figure 42] Figure 42 shows the 1H-NMR spectrum of L-malate 5 (samples 4-58) in DMSO-d6.

[0054] [Figure 43] Figure 43 shows the DSC thermogram and TGA thermogram of L-malate 5 (sample 4-58).

[0055] [Figure 44] Figure 44 shows the 1H-NMR spectrum of L-malate 6 (sample 4-56) in DMSO-d6.

[0056] [Figure 45] Figure 45 shows the DSC thermogram and TGA thermogram of L-malate 6 (sample 4-56).

[0057] [Figure 46] Figure 46 shows the 1H-NMR spectrum of L-malate 7 (sample 4-78) in DMSO-d6.

[0058] [Figure 47] Figure 47 shows the 1H-NMR spectrum of L-malate 8 (sample 4-76) in DMSO-d6.

[0059] [Figure 48] Figure 48 shows the 1H-NMR spectrum of L-malate 9 (sample 4-66) in DMSO-d6.

[0060] [Figure 49] Figure 49 shows the PXRD of edicilate 1 (sample 2-4).

[0061] [Figure 50] Figure 50 shows the PXRD of edicilate 1 (samples 2-4 after 20 days of storage in RT).

[0062] [Figure 51] Figure 51 shows the 1H-NMR spectrum of edisylate 1 (samples 2-4) in DMSO-d6.

[0063] [Figure 52] Figure 52 shows the DSC thermogram and TGA thermogram of edicilate 1 (sample 2-4).

[0064] [Figure 53] Figure 53 shows the PXRD of maleate 1 (sample 2-15).

[0065] [Figure 54] Figure 54 shows the 1H-NMR spectrum of maleate 1 (sample 2-15) in DMSO-d6.

[0066] [Figure 55] Figure 55 shows the DSC thermogram and TGA thermogram of Maleate 1 (Sample 2-15).

[0067] [Figure 56] Figure 56 shows the PXRD of napsylate 1 (sample 2-20).

[0068] [Figure 57] Figure 57 shows the 1H-NMR spectrum of napsylate 1 (sample 2-20) in DMSO-d6.

[0069] [Figure 58] Figure 58 shows the DSC thermogram and TGA thermogram of napsilate 1 (sample 2-20).

[0070] [Figure 59] Figure 59 shows the PXRD of Phosphate 1 (Sample 2-22).

[0071] [Figure 60] Figure 60 shows the 1H-NMR spectrum of phosphate 1 (sample 2-22) at DMSO-d6.

[0072] [Figure 61] Figure 61 shows the DSC thermogram and the TGA thermogram of Phosphate 1 (Sample 2-22).

[0073] [Figure 62] Figure 62 shows the PXRD of HCl (hydrochloric acid) 1 (sample 2-11).

[0074] [Figure 63] Figure 63 shows the PXRD of HCl1 (sample 2-11 after storage at room temperature for 17 days).

[0075] [Figure 64] Figure 64 shows the 1H-NMR spectrum of HCl1 (sample 2-11) at DMSO-d6.

[0076] [Figure 65] Figure 65 shows the DSC thermogram and TGA thermogram of HCl1 (sample 2-11).

[0077] [Figure 66] Figure 66 shows the PXRD of fumarate 1 (samples 2-6).

[0078] [Figure 67] Figure 67 shows the 1H-NMR spectrum of fumarate 1 (sample 2-6) in DMSO-d6.

[0079] [Figure 68] Figure 68 shows the PXRD of Gluconate 1 (Sample 2-40).

[0080] [Figure 69] Figure 69 shows the PXRD of Orotate 1 and Coformer (Sample 2-57).

[0081] [Figure 70] Figure 70 shows the PXRD of salicylate 1 and coformer (samples 2-60).

[0082] [Figure 71] Figure 71 shows the PXRD of morphological B free bases (samples 2-33) from the benzamide coformer.

[0083] [Figure 72] Figure 72 shows the PXRD of morphological B free bases from benzamide coformers (samples 2-33 after 3 days of storage in RT).

[0084] [Figure 73] Figure 73 shows the 1H-NMR spectrum of morphology B free base from a benzamide coformer (sample 2-33 after 23 days of storage in RT) in DMSO-d6.

[0085] [Figure 74] Figure 74 shows the DSC thermogram and TGA thermogram of free morpho B base from benzamide coformer (sample 2-33).

[0086] [Figure 75] Figure 75 shows the PXRD of morphological H free bases (samples 2-30) from 4-aminosalicylic acid coformers.

[0087] [Figure 76] Figure 76 shows the 1H-NMR spectrum of morphological H free bases (samples 2-30) from 4-aminosalicylic acid coformers in DMSO-d6.

[0088] [Figure 77] Figure 77 shows the DSC thermogram and TGA thermogram of the free morphological H base (samples 2-30) from the 4-aminosalicylic acid coformer.

[0089] [Figure 78] Figure 78 shows the PXRD of morphology I (sample 2-13) from 2-hydroxyethanesulfonic acid.

[0090] [Figure 79] Figure 79 shows the PXRD of morphology I (sample 2-13 after 20 days of storage in RT) from 2-hydroxyethanesulfonic acid.

[0091] [Figure 80] Figure 80 shows the 1H-NMR spectrum of morphology I free base (sample 2-13) from the 2-hydroxyethanesulfonic acid coformer at DMSO-d6.

[0092] [Figure 81]Figure 81 shows the DSC thermogram and TGA thermogram of the free base of morphology I from the 2-hydroxyethanesulfonic acid coformer (sample 2-13).

[0093] [Figure 82] Figure 82 shows the PXRD of morphology I (sample 2-74 after 17 days of storage in RT) from vanillin.

[0094] [Figure 83] Figure 83 shows the 1H-NMR spectrum of morphology I free base from vanillin (sample 2-74 after 17 days of storage in RT) in DMSO-d6.

[0095] [Figure 84] Figure 84 shows the DSC thermogram and TGA thermogram of free morpho I base from vanillin (sample 2-74 after 17 days of storage in RT).

[0096] [Figure 85] Figure 85 shows the PXRD of morphology J (sample 2-74) from vanillin.

[0097] [Figure 86] Figure 86 shows the PXRD of morphology K (sample 2-63) from sorbic acid.

[0098] [Figure 87] Figure 87 shows the 1H-NMR spectrum of the morphological K free base (sample 2-63) from sorbic acid at DMSO-d6.

[0099] [Figure 88] Figure 88 shows the DSC thermogram and TGA thermogram of the morphological K free base (sample 2-63) from sorbic acid.

[0100] [Figure 89] Figure 89 shows the pH-solubility profiles of lincitinib free base and its salt. Data points circled in black represent experiments where no solid was present after 24 hours, and therefore do not represent equilibrium solubility values.

[0101] [Figure 90] Figure 90 shows the solubility of lincitinib free base and its salts in biomedical media. [Modes for carrying out the invention]

[0102] This invention provides novel salts and crystalline forms of lincitinib (OSI-906; cis-3-[8-amino-1-(2-phenyl-7-quinolinyl)imidazo[1,5-a]pyrazine-3-yl]-1-methylcyclobutanol). These new forms of lincitinib offer numerous advantages, including improved solubility and absorption of orally administered pharmaceutical formulations. Therefore, this invention enables improved methods for treating human insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR)-mediated conditions.

[0103] definition "Lincitinib" refers to the compound cis-3-[8-amino-1-(2-phenyl-7-quinolinyl)imidazo[1,5-a]pyrazine-3-yl]-1-methylcyclobutanol, shown in formula I.

[0104] "Salt" refers to an acid addition salt prepared by combining lincitinib free base with a pharmaceutically acceptable acid.

[0105] "Pharmacologically acceptable" is a term recognized in the art and, where used herein to refer to compositions, excipients, adjuvants, or other materials and / or dosage forms, means a substance that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues in proportion to a reasonable benefit / risk ratio, without excessive toxicity, irritation, allergic reactions, or other problems or complications. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, phosphates, acetates, L-lactates, maleates, fumarates, succinates, L-malates, adipates, L-tallates, equine urate, citrates, mucates, glycolates, D-glucuronates, benzoates, cholates, nicotinic acid, ethanesulfonates, ethanedisulfonates, oxalates, mesylates, benzenesulfonates, 2-hydroxyethanesulfonates, and hydrobromes.

[0106] "Esylate" refers to a pharmaceutically acceptable acid addition salt of an ethanesulfonate. Other terms for esylate include ethanesulfonate, ethanesulfonic acid, and ethyl acid. Esylate has the following structure: [ka]

[0107] "L-malate" refers to pharmaceutically acceptable acid addition salts of L-malates. Other terms for L-malate include L-malic acid, (-)-malic acid, L-hydroxybutanediic acid, and (S)-hydroxybutanediic acid. L-malates have the following structure: [ka]

[0108] "Edisylate" refers to a pharmaceutically acceptable acid addition salt of ethane disulfonate. Other terms for edisylate include ethane disulfonate, ethane disulfonic acid, and edisyl acid. Edisylate has the following structure: [ka]

[0109] "Maleate" refers to a pharmaceutically acceptable acid addition salt of a maleate. Other terms for maleate include (2Z)-butenidioic acid, cis-butenidioic acid, and maleic acid. Maleates have the following structure: [ka]

[0110] "Napsilate" refers to the pharmaceutically acceptable acid addition salt of naphthalene-2-sulfonate. Other terms for napsilate include naphthalene-2-sulfonic acid and napsylic acid. Napsilate has the following structure: [ka]

[0111] "Phosphate" refers to a pharmaceutically acceptable acid addition salt of a phosphate. Other terms related to phosphate include phosphoric acid. Phosphates have the following structure: [ka]

[0112] "Fumarate" refers to the pharmaceutically acceptable acid addition salt of (E)-3-carboxyacrylate. Other terms for fumarate include (2E)-butenioic acid, trans-1,2-ethylenedicarboxylic acid, aromaleic acid, boretinic acid, donitic acid, lichenic acid, and fumaric acid. Fumarate has the following structure: [ka]

[0113] "Crystalline form" refers to the solid form of a compound in which constituent molecules are arranged in a regular, repeating pattern. Crystalline forms can be triclinic, monoclinic, orthorhombic, tetragonal, triangular, hexagonal, or cubic. A crystalline form may contain one or more regions (i.e., particles) with distinct crystal boundaries. A crystalline solid may contain two or more crystal structures.

[0114] As used herein, the term “treatment” means, unless otherwise specified, restoring, alleviating, slowing the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. As used herein, the term “treatment” refers to the act of treating, as defined above.

[0115] The "therapeutic effective dose" is the amount of lincitinib or its crystalline form necessary to deliver a desired level of the drug to the patient's tissues, bloodstream, or other body parts, the desired level being the amount that produces the expected physiological response or biological effect when the lincitinib salt or crystalline form is administered via a selected route of administration. The exact amount will vary depending on various factors, such as the specific lincitinib salt or crystalline form, the specific pharmaceutical formulation or delivery device used, the severity of the condition, and the patient's adherence to the treatment plan. The therapeutic effective dose of lincitinib salt and crystalline form can be readily determined by those skilled in the art based on the information provided herein.

[0116] The terms “about” and “approximately” used herein to modify numerical values ​​indicate a defined range around that value. If the value is “X”, then “about X” or “approximately X” generally refers to values ​​between 0.95X and 1.05X, such as 0.98X to 1.02X or 0.99X to 1.01X. The references “about X” or “approximately X” specifically indicate values ​​of at least X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, “about X” and “approximately X” are intended to teach and provide explanatory support for a claim limitation such as “0.98X”. When the quantity "X" contains only integer values ​​(for example, "X carbon atoms"), "about X" or "approximately X" indicates a range from (X-1) to (X+1). In such cases, "about X" or "approximately X" specifically indicates at least the values ​​of X, X-1, and X+1.

[0117] Lincitinib salt Those skilled in the art will understand that a number of pharmaceutically acceptable acids can be used to prepare lincitinib salts. Examples of pharmaceutically acceptable acids include, but are not limited to, hydrochloric acid, acetic acid, benzenesulfonic acid, benzoic acid, camphor sulfonic acid, citric acid, ethanesulfonic acid (esylic acid), ethanedisulfonic acid (edicylic acid), formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, napsylic acid, and similar acids. In certain embodiments, the lincitinib salt contains anion derived from a pharmaceutically acceptable acid selected from edsylic acid, esylic acid, hydrochloric acid, maleic acid, L-malic acid, napsylic acid, and phosphoric acid.

[0118] Ethylate salt In another embodiment, the present invention provides esylate salts of compounds of formula I: [ka]

[0119] As described above, formula I corresponds to lincitinib. Ethanesulfonic acid is a monobasic acid whose conjugate base is ethanesulfonate. In this specification, "esylate" refers to ethanesulfonate. In this specification, "esylate salt" refers to a salt containing at least one ethanesulfonate anion. In certain embodiments, the esylate salt of lincitinib is the salt according to formula II: [ka]

[0120] In one embodiment, the present invention provides a crystalline form of the esylate salt of the compound of formula I: [ka]

[0121] Eshilate 1 In one embodiment, a crystalline phosphate esylate salt containing crystalline esylate 1 is provided. Esylate 1 is also referred to herein as "crystalline morphology 1 of phosphate esylate salt". In one embodiment, crystalline morphology esylate 1 of phosphate esylate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 5 when measured with a Cu-Kα diffractometer.

[0122] In one embodiment, the crystalline form of phosphate citinib esylate salt, esylate 1, is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 7.

[0123] In one embodiment, the crystalline form of phosphate cesylate 1 of the phosphate cesylate salt is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 7.

[0124] In one embodiment, a crystalline form esylate 1 of phosphate citinib esylate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form esylate 1 based on the total amount of phosphate citinib esylate salt. In one embodiment, the crystalline form esylate 1 contains at least about 98% by weight of crystalline form esylate 1 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form esylate 1 contains at least about 99% by weight of crystalline form esylate 1 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form esylate 1 contains at least about 99.5% by weight of crystalline form esylate 1 based on the total amount of phosphate citinib esylate salt in the substance.

[0125] Eshilate 2 In one embodiment, a crystalline phosphate esylate salt containing crystalline esylate 2 is provided. Esylate 2 is also referred to herein as "crystalline morphology 2 of phosphate esylate salt". In one embodiment, crystalline morphology esylate 2 of phosphate esylate salt is characterized by a powder X-ray diffraction (PXRD) pattern, when measured with a Cu-Kα diffractometer, containing at least three peaks selected from the group consisting of 6.74, 8.92, 10.26, 11.04, 14.76, 16.80, 17.60, 17.90, 18.56, 20.24, 20.56, 20.74, 24.58, 25.80, 26.12, and 27.34 ± 0.20°²θ. In another embodiment, the crystalline form of phosphate citinib esylate salt, esylate 2, is characterized by a powder X-ray diffraction (PXRD) pattern, when measured with a Cu-Kα diffractometer, that includes at least six peaks selected from the group consisting of 6.74, 8.92, 10.26, 11.04, 14.76, 16.80, 17.60, 17.90, 18.56, 20.24, 20.56, 20.74, 24.58, 25.80, 26.12, and 27.34 ± 0.2°²θ. In another embodiment, crystalline form esylate 2 of the lincitinib esylate salt is characterized by a powder X-ray diffraction (PXRD) pattern, when measured with a Cu-Kα diffractometer, containing at least 10 peaks selected from the group consisting of 6.74, 8.92, 10.26, 11.04, 14.76, 16.80, 17.60, 17.90, 18.56, 20.24, 20.56, 20.74, 24.58, 25.80, 26.12, and 27.34 ± 0.2°²θ. In yet another embodiment, crystalline form esylate 2 of the lincitinib esylate salt is characterized by a powder X-ray diffraction (PXRD) pattern having substantially the same peaks as those in Table 8. In one embodiment, the crystalline form of phosphate citinib esylate salt, esylate 2, is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern shown in Figure 8 when measured with a Cu-Kα diffractometer.

[0126] In one embodiment, the crystalline form of lincitinib esylate salt, esylate 2, is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 10. In one embodiment, the crystalline form of lincitinib esylate salt, esylate 2, is characterized by a TGA signal substantially similar to the TGA signal in Figure 10.

[0127] In one embodiment, the crystalline form of phosphate citinib esylate salt esylate 2 is provided, and the single crystal structure of esylate 2 includes an orthorhombic crystal structure. In one embodiment, the single crystal structure of esylate 2 includes the P212121 space group.

[0128] In one embodiment, a crystalline form of phosphate citinib esylate salt, esylate 2, is provided, and the single-crystal structure of esylate 2 includes a unit cell having the parameters shown in Table 1. [Table 1] The asymmetric unit cell is shown in Figure 11. Packing diagrams along the a, b, and c axes are shown in Figures 12, 13, and 14. The PXRD pattern calculated from single crystal data is shown superimposed on the reference PXRD pattern of esylate 2 in Figure 15.

[0129] In one embodiment, a crystalline form esylate 2 of phosphate citinib esylate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form esylate 2 based on the total amount of phosphate citinib esylate salt. In one embodiment, the crystalline form esylate 2 contains at least about 98% by weight of crystalline form esylate 2 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form esylate 2 contains at least about 99% by weight of crystalline form esylate 2 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form esylate 2 contains at least about 99.5% by weight of crystalline form esylate 2 based on the total amount of phosphate citinib esylate salt in the substance.

[0130] Eshilate 3 In one embodiment, a crystalline phosphate esylate salt containing crystalline esylate 3 is provided. Esylate 3 is also referred to herein as "crystalline morph 3 of phosphate esylate salt". In one embodiment, crystalline morph esylate 3 of phosphate esylate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 22 when measured with a Cu-Kα diffractometer.

[0131] In one embodiment, the crystalline form of phosphate citinib esylate salt, esylate 3, is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 24.

[0132] In one embodiment, the crystalline form of phosphate citinib esylate salt, esylate 3, is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 24.

[0133] In one embodiment, a crystalline form esylate 3 of phosphate citinib esylate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form esylate 3 based on the total amount of phosphate citinib esylate salt. In one embodiment, the crystalline form esylate 3 contains at least about 98% by weight of crystalline form esylate 3 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form esylate 3 contains at least about 99% by weight of crystalline form esylate 3 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form esylate 3 contains at least about 99.5% by weight of crystalline form esylate 3 based on the total amount of phosphate citinib esylate salt in the substance.

[0134] Eshilate 4 In one embodiment, a crystalline phosphate esylate salt containing crystalline esylate 4 is provided. Esylate 4 is also referred to herein as "crystalline morph 4 of phosphate esylate salt". In one embodiment, crystalline morph esylate 4 of phosphate esylate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 25 when measured with a Cu-Kα diffractometer.

[0135] In one embodiment, the crystalline form of phosphate citinib esylate salt, esylate 4, is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 27.

[0136] In one embodiment, the crystalline form of phosphate citinib esylate salt, esylate 4, is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 27.

[0137] In one embodiment, a crystalline form esylate 4 of phosphate citinib esylate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form esylate 4 based on the total amount of phosphate citinib esylate salt. In one embodiment, the crystalline form esylate 4 contains at least about 98% by weight of crystalline form esylate 4 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form esylate 4 contains at least about 99% by weight of crystalline form esylate 4 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form esylate 4 contains at least about 99.5% by weight of crystalline form esylate 4 based on the total amount of phosphate citinib esylate salt in the substance.

[0138] Eshilate 5 In one embodiment, a crystalline phosphate esylate salt containing crystalline esylate 5 is provided. Esylate 5 is also referred to herein as "crystalline morph 5 of phosphate esylate salt". In one embodiment, crystalline morph esylate 5 of phosphate esylate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 4 when measured with a Cu-Kα diffractometer.

[0139] In one embodiment, the crystalline form of phosphate citinib esylate salt, esylate 5, is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 29.

[0140] In one embodiment, the crystalline form of phosphate citinib esylate salt, esylate 5, is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 29.

[0141] In one embodiment, a crystalline form esylate 5 of phosphate citinib esylate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form esylate 5 based on the total amount of phosphate citinib esylate salt. In one embodiment, the crystalline form esylate 5 contains at least about 98% by weight of crystalline form esylate 5 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form esylate 5 contains at least about 99% by weight of crystalline form esylate 5 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form esylate 5 contains at least about 99.5% by weight of crystalline form esylate 5 based on the total amount of phosphate citinib esylate salt in the substance.

[0142] Diesylate 1 In one embodiment, a crystalline phosphate citinib esylate salt containing crystalline phosphate 1 is provided. phosphate 1 is also referred to herein as "crystalline phosphate 1 of phosphate citinib esylate salt". In one embodiment, crystalline phosphate 1 of phosphate citinib esylate salt is characterized by a DSC thermogram substantially similar to the DSC thermogram of Figure 32. In one embodiment, crystalline phosphate 1 of phosphate citinib esylate salt is characterized by a TGA signal substantially similar to the TGA signal of Figure 32.

[0143] In one embodiment, a crystalline form diesylate 1 of a phosphate citinib esylate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form diesylate 1 based on the total amount of phosphate citinib esylate salt. In one embodiment, the crystalline form diesylate 1 contains at least about 98% by weight of crystalline form diesylate 1 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form diesylate 1 contains at least about 99% by weight of crystalline form diesylate 1 based on the total amount of phosphate citinib esylate salt in the substance. In one embodiment, the crystalline form diesylate 1 contains at least about 99.5% by weight of crystalline form diesylate 1 based on the total amount of phosphate citinib esylate salt in the substance.

[0144] L-malate salt In one embodiment, the present invention provides the L-malate of a compound of formula I: [ka]

[0145] As described above, formula I corresponds to lincitinib. (S)-hydroxybutanediic acid is also referred to by synonyms such as (S)-2-hydroxysuccinic acid and L-malic acid. L-malic acid is a dibasic acid having conjugate bases including (S)-3-carboxy-2-hydroxypropanoate, (S)-3-carboxy-3-hydroxypropanoate, and (S)-hydroxysuccinate. In this specification, "L-malate" or "L-malate salt" refers to a salt containing at least one (S)-3-carboxy-2-hydroxypropanoate anion, (S)-3-carboxy-3-hydroxypropanoate anion, or at least one (S)-hydroxysuccinate anion. In certain embodiments, the (L)-malate salt of lincitinib is the salt according to formula III: [ka]

[0146] In one embodiment, the present invention provides a crystalline form of the (L)-malate salt of the compound of formula I: [ka]

[0147] L-Malate 1 In one embodiment, a crystalline lincitinib L-malate salt containing crystalline form L-malate 1 is provided. L-malate 1 is also referred to herein as "crystalline form 1 of lincitinib L-malate salt". In some embodiments, crystalline form L-malate 1 is characterized by an X-ray powder diffraction (XRPD) pattern, when measured with a Cu-Kα diffractometer, containing at least three peaks selected from the group consisting of 5.42, 8.68, 11.88, 12.40, 16.24, 17.36, 17.96, 18.22, 19.20, 20.88, 22.08, 22.58, 22.90, 23.86, 24.44, 24.92, 25.66, 26.1, 28.58, or 29.44 ± 0.2°²θ. In one embodiment, the crystalline form L-malate 1 is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 33 when measured with a Cu-Kα diffractometer.

[0148] In one embodiment, the crystalline form of lincitinib L-malate salt L-malate 1 is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 32.

[0149] In one embodiment, the crystalline form L-malate 1 of lincitinib L-malate salt is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 32.

[0150] In one embodiment, a crystalline form L-malate 1 of lincitinib L-malate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form L-malate 1 based on the total amount of lincitinib L-malate salt. In one embodiment, the crystalline form L-malate 1 contains at least about 98% by weight of crystalline form L-malate 1 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 1 contains at least about 99% by weight of crystalline form L-malate 1 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 1 contains at least about 99.5% by weight of crystalline form L-malate 1 based on the total amount of lincitinib L-malate salt in the substance.

[0151] L-Malate 2 In one embodiment, a crystalline lincitinib L-malate salt containing crystalline form L-malate 2 is provided. L-malate 2 is also referred to herein as "crystalline form 2 of lincitinib L-malate salt". In one embodiment, crystalline form L-malate 2 of lincitinib L-malate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 36 when measured with a Cu-Kα diffractometer.

[0152] In one embodiment, a crystalline form L-malate 2 of lincitinib L-malate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form L-malate 2 based on the total amount of lincitinib L-malate salt. In one embodiment, the crystalline form L-malate 2 contains at least about 98% by weight of crystalline form L-malate 2 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 2 contains at least about 99% by weight of crystalline form L-malate 2 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 2 contains at least about 99.5% by weight of crystalline form L-malate 2 based on the total amount of lincitinib L-malate salt in the substance.

[0153] L-Malate 3 In one embodiment, a crystalline lincitinib L-malate salt containing crystalline form L-malate 3 is provided. L-malate 3 is also referred to herein as "crystalline form 3 of lincitinib L-malate salt". In one embodiment, crystalline form L-malate 3 of lincitinib L-malate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 36 when measured with a Cu-Kα diffractometer.

[0154] In one embodiment, the crystalline form of lincitinib L-malate salt L-malate 3 is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 39.

[0155] In one embodiment, the crystalline form L-malate 3 of lincitinib L-malate salt is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 39.

[0156] In one embodiment, a crystalline form L-malate 3 of lincitinib L-malate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight or more of crystalline form L-malate 3 based on the total amount of lincitinib L-malate salt. In one embodiment, the crystalline form L-malate 3 contains at least about 98% by weight or more of crystalline form L-malate 3 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 3 contains at least about 99% by weight or more of crystalline form L-malate 3 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 3 contains at least about 99.5% by weight or more of crystalline form L-malate 3 based on the total amount of lincitinib L-malate salt in the substance.

[0157] L-Malate 4 In one embodiment, a crystalline lincitinib L-malate salt containing crystalline form L-malate 4 is provided. L-malate 4 is also referred to herein as "crystalline form 4 of lincitinib L-malate salt". In one embodiment, crystalline form L-malate 4 of lincitinib L-malate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 36 when measured with a Cu-Kα diffractometer.

[0158] In one embodiment, the crystalline form of lincitinib L-malate salt L-malate 4 is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 41.

[0159] In one embodiment, the crystalline form L-malate 4 of the lincitinib L-malate salt is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 41.

[0160] In one embodiment, a crystalline form L-malate 4 of lincitinib L-malate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form L-malate 4 based on the total amount of lincitinib L-malate salt. In one embodiment, the crystalline form L-malate 4 contains at least about 98% by weight of crystalline form L-malate 4 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 4 contains at least about 99% by weight of crystalline form L-malate 4 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 4 contains at least about 99.5% by weight of crystalline form L-malate 4 based on the total amount of lincitinib L-malate salt in the substance.

[0161] L-Malate 5 In one embodiment, a crystalline lincitinib L-malate salt containing crystalline form L-malate 5 is provided. L-malate 5 is also referred to herein as "crystalline form 5 of lincitinib L-malate salt". In one embodiment, crystalline form L-malate 5 of lincitinib L-malate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 36 when measured with a Cu-Kα diffractometer.

[0162] In one embodiment, the crystalline form of lincitinib L-malate salt L-malate 5 is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 43.

[0163] In one embodiment, the crystalline form L-malate 5 of lincitinib L-malate salt is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 43.

[0164] In one embodiment, a crystalline form L-malate 5 of lincitinib L-malate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form L-malate 5 based on the total amount of lincitinib L-malate salt. In one embodiment, the crystalline form L-malate 5 contains at least about 98% by weight of crystalline form L-malate 5 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 5 contains at least about 99% by weight of crystalline form L-malate 5 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 5 contains at least about 99.5% by weight of crystalline form L-malate 5 based on the total amount of lincitinib L-malate salt in the substance.

[0165] L-Malate 6 In one embodiment, a crystalline lincitinib L-malate salt containing crystalline form L-malate 6 is provided. L-malate 6 is also referred to herein as "crystalline form 6 of lincitinib L-malate salt". In one embodiment, crystalline form L-malate 6 of lincitinib L-malate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 36 when measured with a Cu-Kα diffractometer.

[0166] In one embodiment, the crystalline form of lincitinib L-malate salt L-malate 6 is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 45.

[0167] In one embodiment, the crystalline form L-malate 6 of lincitinib L-malate salt is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 45.

[0168] In one embodiment, a crystalline form L-malate 6 of lincitinib L-malate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form L-malate 6 based on the total amount of lincitinib L-malate salt. In one embodiment, the crystalline form L-malate 6 contains at least about 98% by weight of crystalline form L-malate 6 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 6 contains at least about 99% by weight of crystalline form L-malate 6 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 6 contains at least about 99.5% by weight of crystalline form L-malate 6 based on the total amount of lincitinib L-malate salt in the substance.

[0169] L-Malate 7 In one embodiment, a crystalline lincitinib L-malate salt containing crystalline form L-malate 7 is provided. L-malate 7 is also referred to herein as "crystalline form 7 of lincitinib L-malate salt". In one embodiment, crystalline form L-malate 7 of lincitinib L-malate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 36 when measured with a Cu-Kα diffractometer.

[0170] In one embodiment, a crystalline form L-malate 7 of lincitinib L-malate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form L-malate 7 based on the total amount of lincitinib L-malate salt. In one embodiment, the crystalline form L-malate 7 contains at least about 98% by weight of crystalline form L-malate 7 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 7 contains at least about 99% by weight of crystalline form L-malate 7 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 7 contains at least about 99.5% by weight of crystalline form L-malate 7 based on the total amount of lincitinib L-malate salt in the substance.

[0171] L-Malate 8 In one embodiment, a crystalline lincitinib L-malate salt containing crystalline form L-malate 8 is provided. L-malate 8 is also referred to herein as "crystalline form 8 of lincitinib L-malate salt". In one embodiment, crystalline form L-malate 8 of lincitinib L-malate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 36 when measured with a Cu-Kα diffractometer.

[0172] In one embodiment, a crystalline form L-malate 8 of lincitinib L-malate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form L-malate 8 based on the total amount of lincitinib L-malate salt. In one embodiment, the crystalline form L-malate 8 contains at least about 98% by weight of crystalline form L-malate 8 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 8 contains at least about 99% by weight of crystalline form L-malate 8 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 8 contains at least about 99.5% by weight of crystalline form L-malate 8 based on the total amount of lincitinib L-malate salt in the substance.

[0173] L-Malate 9 In one embodiment, a crystalline lincitinib L-malate salt containing crystalline form L-malate 9 is provided. L-malate 9 is also referred to herein as "crystalline form 9 of lincitinib L-malate salt". In one embodiment, crystalline form L-malate 9 of lincitinib L-malate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 36 when measured with a Cu-Kα diffractometer.

[0174] In one embodiment, a crystalline form L-malate 9 of lincitinib L-malate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form L-malate 9 based on the total amount of lincitinib L-malate salt. In one embodiment, the crystalline form L-malate 9 contains at least about 98% by weight of crystalline form L-malate 9 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 9 contains at least about 99% by weight of crystalline form L-malate 9 based on the total amount of lincitinib L-malate salt in the substance. In one embodiment, the crystalline form L-malate 9 contains at least about 99.5% by weight of crystalline form L-malate 9 based on the total amount of lincitinib L-malate salt in the substance.

[0175] Edisylate salt In one embodiment, the present invention provides an edisylate salt of a compound of formula I: [ka]

[0176] As described above, formula I corresponds to lincitinib. Ethane-1,2-disulfonic acid is a dibasic acid having conjugate bases 2-sulfoethane-1-sulfonate and ethane-1,2-disulfonate, corresponding to the dissociation of each dibasic acid. In this specification, "edisylate" refers to either 2-sulfoethane-1-sulfonate or ethane-1,2-disulfonate. In this specification, "edisylate salt" refers to a salt containing at least one 2-sulfoethane-1-sulfonate or ethane-1,2-disulfonate anion. In certain embodiments, the edisylate salt of lincitinib is the salt according to formula IV: [ka]

[0177] In one embodiment, the present invention provides a crystalline form of the edisylate salt of a compound of formula I: [ka]

[0178] Edisile 1 In one embodiment, a crystalline lincitinib edisylate salt containing crystalline edisylate 1 is provided. Edisylate 1 is also referred to herein as "crystalline morph 1 of lincitinib edisylate salt". In one embodiment, crystalline morph edisylate 1 of lincitinib edisylate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 49 when measured with a Cu-Kα diffractometer.

[0179] In one embodiment, the crystalline form of lincitinib edisylate salt, edisylate 1, is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 52.

[0180] In one embodiment, the crystalline form of lincitinib edisylate salt, edisylate 1, is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 52.

[0181] In one embodiment, a crystalline form of edicilate 1 of lincitinib edicilate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form of edicilate 1 based on the total amount of lincitinib edicilate salt. In one embodiment, the crystalline form of edicilate 1 contains at least about 98% by weight of crystalline form of edicilate 1 based on the total amount of lincitinib edicilate salt in the substance. In one embodiment, the crystalline form of edicilate 1 contains at least about 99% by weight of crystalline form of edicilate 1 based on the total amount of lincitinib edicilate salt in the substance. In one embodiment, the crystalline form of edicilate 1 contains at least about 99.5% by weight of crystalline form of edicilate 1 based on the total amount of lincitinib edicilate salt in the substance.

[0182] Maleate salt In one embodiment, the present invention provides a maleate salt of a compound of formula I:

Chemical formula

[0183] As described above, formula I corresponds to ruxolitinib. Cis-butenedioic acid is a dibasic acid having the conjugate base (Z)-3-carboxyacrylate and maleate, corresponding to each dissociation of the dibasic acid. As used herein, "maleate" or "maleate salt" refers to a salt containing at least one (Z)-3-carboxyacrylate anion or at least one maleate anion. In certain embodiments, the maleate salt of ruxolitinib is a salt according to formula V:

Chemical formula

[0184] In one aspect, the present invention provides a crystal of a maleate salt of a compound of formula I:

Chemical formula

[0185] Maleate 1 In one embodiment, a crystalline ruxolitinib maleate salt comprising crystalline form maleate 1 is provided. Maleate 1 is also referred to herein as "crystalline form 1 of ruxolitinib maleate salt". In one embodiment, the crystalline form maleate 1 of ruxolitinib maleate salt is characterized by a powder X-ray diffraction (PXRD) pattern that is substantially similar to the pattern of FIG. 53 when measured with a diffractometer using Cu-Kα radiation.

[0186] In one embodiment, the crystalline form maleate 1 of ruxolitinib maleate salt is characterized by a DSC thermogram that is substantially similar to the DSC thermogram of FIG. 55.

[0187] In one embodiment, the crystalline form maleate 1 of the lincitinib maleate salt is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 55.

[0188] In one embodiment, a crystalline maleate 1 of lincitinib maleate salt, characterized by any aspect of the present invention, is provided, which exists as a substance containing at least about 95% by weight of crystalline maleate 1 based on the total amount of lincitinib maleate salt. In one embodiment, the crystalline maleate 1 contains at least about 98% by weight of crystalline maleate 1 based on the total amount of lincitinib maleate salt in the substance. In one embodiment, the crystalline maleate 1 contains at least about 99% by weight of crystalline maleate 1 based on the total amount of lincitinib maleate salt in the substance. In one embodiment, the crystalline maleate 1 contains at least about 99.5% by weight of crystalline maleate 1 based on the total amount of lincitinib maleate salt in the substance.

[0189] napsylate salt In one embodiment, the present invention provides a naphthalene-2-sulfonate of a compound of formula I: [ka]

[0190] As described above, formula I corresponds to lincitinib. Naphthalene-2-sulfonic acid is a monobasic acid whose conjugate base is naphthalene-2-sulfonate. In this specification, “napsylate” refers to the naphthalene-2-sulfonate anion. In this specification, “napsylate salt” refers to a salt containing at least one naphthalene-2-sulfonate anion. In certain embodiments, the napsylate salt of lincitinib is the salt according to formula VI: [ka]

[0191] In one embodiment, the present invention provides a crystalline form of the napsylate salt of the compound of formula I: [ka]

[0192] Napsilate 1 In one embodiment, a crystalline phosphate citinib napsylate salt containing crystalline napsylate 1 is provided. Napsylate 1 is also referred to herein as "crystalline form 1 of phosphate citinib napsylate salt". In one embodiment, crystalline form napsylate 1 of phosphate citinib napsylate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 56 when measured with a Cu-Kα diffractometer.

[0193] In one embodiment, the crystalline form of phosphate citinib napsylate salt napsylate 1 is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 58.

[0194] In one embodiment, the crystalline form napsylate 1 of the lincitinib napsylate salt is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 58.

[0195] In one embodiment, a crystalline napsylate 1 of phosphate napsylate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline napsylate 1 based on the total amount of phosphate napsylate salt. In one embodiment, the crystalline napsylate 1 contains at least about 98% by weight of crystalline napsylate 1 based on the total amount of phosphate napsylate salt in the substance. In one embodiment, the crystalline napsylate 1 contains at least about 99% by weight of crystalline napsylate 1 based on the total amount of phosphate napsylate salt in the substance. In one embodiment, the crystalline napsylate 1 contains at least about 99.5% by weight of crystalline napsylate 1 based on the total amount of phosphate napsylate salt in the substance.

[0196] Phosphate salt In one embodiment, the present invention provides a phosphate of a compound of formula I: [Chemical formula]

[0197] As described above, formula I corresponds to nilotinib. Phosphoric acid is a tribasic acid having conjugate bases such as dihydrogen phosphate, hydrogen phosphate, and phosphate. As used herein, "phosphate" or "phosphate salt" refers to a salt containing at least one dihydrogen phosphate anion, at least one hydrogen phosphate anion, or at least one phosphate anion. In certain embodiments, the phosphate salt of nilotinib is a salt according to formula VII: [Chemical formula]

[0198] In one aspect, the present invention provides a crystalline form of a phosphate salt of a compound of formula I: [Chemical formula]

[0199] Phosphate 1 In one embodiment, a crystalline nilotinib phosphate salt comprising crystalline form phosphate 1 is provided. Phosphate 1 is also referred to herein as "crystalline form 1 of the nilotinib phosphate salt". In one embodiment, crystalline form phosphate 1 of the nilotinib phosphate salt is characterized by a powder X-ray diffraction (PXRD) pattern that is substantially similar to the pattern of FIG. 59 when measured with a diffractometer using Cu-Kα radiation.

[0200] In one embodiment, crystalline form phosphate 1 of the nilotinib phosphate salt is characterized by a DSC thermogram that is substantially similar to the DSC thermogram of FIG. 61.

[0201] In one embodiment, phosphate 1, a crystalline form of lincitinib phosphate salt, is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 61.

[0202] In one embodiment, a crystalline form phosphate 1 of a lincitinib phosphate salt characterized by any aspect of the present invention is provided, which exists as a substance containing at least about 95% by weight of crystalline form phosphate 1 based on the total amount of lincitinib phosphate salt. In one embodiment, the crystalline form phosphate 1 contains at least about 98% by weight of crystalline form phosphate 1 based on the total amount of lincitinib phosphate salt in the substance. In one embodiment, the crystalline form phosphate 1 contains at least about 99% by weight of crystalline form phosphate 1 based on the total amount of lincitinib phosphate salt in the substance. In one embodiment, the crystalline form phosphate 1 contains at least about 99.5% by weight of crystalline form phosphate 1 based on the total amount of lincitinib phosphate salt in the substance.

[0203] HCl salt In one embodiment, the present invention provides a hydrochloride salt of a compound of formula I: [ka]

[0204] As described above, formula I corresponds to lincitinib. In this specification, “hydrochloride” or “HCl salt” refers to a salt containing at least one chloride. In certain embodiments, the HCl salt of lincitinib is the salt according to formula VIII: [ka]

[0205] In one embodiment, the present invention provides a crystalline form of the HCl salt of a compound of formula I: [ka]

[0206] HCl1 In one embodiment, a crystalline lincitinib HCl salt containing crystalline form HCl1 is provided. HCl1 is also referred to herein as "crystalline form 1 of lincitinib HCl salt". In one embodiment, crystalline form HCl1 of lincitinib HCl salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 62 when measured with a Cu-Kα diffractometer.

[0207] In one embodiment, the crystalline form of lincitinib HCl salt HCl1 is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 65.

[0208] In one embodiment, the crystalline form HCl1 of the lincitinib HCl salt is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 65.

[0209] In one embodiment, a crystalline form HCl1 of lincitinib HCl salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form HCl1 based on the total amount of lincitinib HCl salt. In one embodiment, the crystalline form HCl1 contains at least about 98% by weight of crystalline form HCl1 based on the total amount of lincitinib HCl salt in the substance. In one embodiment, the crystalline form HCl1 contains at least about 99% by weight of crystalline form HCl1 based on the total amount of lincitinib HCl salt in the substance. In one embodiment, the crystalline form HCl1 contains at least about 99.5% by weight of crystalline form HCl1 based on the total amount of lincitinib HCl salt in the substance.

[0210] fumarate salt In one embodiment, the present invention provides a fumarate of a compound of formula I: [ka]

[0211] As described above, formula I corresponds to lincitinib. Trans-butenioic acid is a dibasic acid having a conjugate base (E)-3-carboxyacrylate and fumarate, corresponding to the dissociation of the dibasic acid. In this specification, “fumarate” or “fumarate salt” means a salt containing at least one (E)-3-carboxyacrylate anion or at least one fumarate anion. In certain embodiments, the fumarate salt of lincitinib is the salt according to formula IX: [ka]

[0212] In one embodiment, the present invention provides a crystalline form of a fumarate salt of a compound of formula I: [ka]

[0213] Fumarate 1 In one embodiment, a crystalline phosphate citinib fumarate salt containing crystalline form fumarate 1 is provided. Fumarate 1 is also referred to herein as "crystalline form 1 of phosphate citinib fumarate salt". In one embodiment, crystalline form fumarate 1 of phosphate citinib fumarate salt is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 66 when measured with a Cu-Kα diffractometer.

[0214] In one embodiment, a crystalline form of fumarate 1 of lincitinib fumarate salt is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form of fumarate 1 based on the total amount of lincitinib fumarate salt. In one embodiment, the crystalline form of fumarate 1 contains at least about 98% by weight of crystalline form of fumarate 1 based on the total amount of lincitinib fumarate salt in the substance. In one embodiment, the crystalline form of fumarate 1 contains at least about 99% by weight of crystalline form of fumarate 1 based on the total amount of lincitinib fumarate salt in the substance. In one embodiment, the crystalline form of fumarate 1 contains at least about 99.5% by weight of crystalline form of fumarate 1 based on the total amount of lincitinib fumarate salt in the substance.

[0215] Lincitinib cocrystal Those skilled in the art will understand that numerous pharmaceutically acceptable coformers can be used to prepare lincitinib cocrystals. Coformers represent various different hydrogen bond donor and acceptor groups that can pair with the donor and acceptor in the structure of lincitinib. The list of coformers included several weak acids that could potentially participate in hydrogen bonding, although they were not expected to be potent enough to completely protonate lincitinib. Examples of pharmaceutically acceptable coformers include acesulfame K, adenine, adipic acid, 4-aminosalicylic acid, L-arginine, L-ascorbic acid, benzamide, benzoic acid, betaine HCl, caffeine, cinnamic acid, creatinine, D-fructose, D-gluconic acid, glucosamine HCl, D-glucose, L-glutamine, glutaric acid, glycine, hippuric acid, isonicotinamide, L-lactic acid, lactose, L-leucine, malonic acid, and maltol. Examples of such substances include, but are not limited to, D-mannitol, methylparaben, sodium glutamate, nicotinamide, orotic acid, propyl gallic acid, saccharin, salicylic acid, sebacic acid, sodium lauryl sulfate, sorbic acid, stearic acid, succinic acid, sucrose, taurine, thiamine chloride HCl, L-threonine, tromethamine HCl, L-tryptophan, urea, L-valine, vanillin, xanthine, xylitol, and similar substances. In certain embodiments, the lincitinib cocrystal comprises a cocrystal derived from gluconic acid, orotic acid, or salicylic acid.

[0216] Salicylic acid cocrystal In another embodiment, the present invention provides a salicylic acid cocrystal of a compound of formula I: [ka]

[0217] As described above, formula I corresponds to lincitinib. Salicylic acid is a weak acid. In this specification, “salicylic acid cocrystal” or “salicylate” refers to a cocrystal containing at least one salicylic acid. In certain embodiments, the salicylic acid cocrystal of lincitinib is a cocrystal relating to formula X: [ka]

[0218] In one embodiment, the present invention provides a crystalline form of the compound salicylic acid of formula I cocrystal: [ka]

[0219] Salicylic acid 1 In one embodiment, a crystalline phosphate-citinib-salicylic acid cocrystal containing crystalline form salicylic acid 1 is provided. Salicylic acid 1 is also referred to herein as "crystalline form 1 of the phosphate-citinib-salicylic acid cocrystal." In one embodiment, crystalline form salicylic acid 1 of the phosphate-citinib-salicylic acid cocrystal is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 70 when measured with a Cu-Kα diffractometer.

[0220] In one embodiment, a crystalline form salicylic acid 1 of phosphate citinib salicylic acid cocrystals is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form salicylic acid 1 based on the total amount of phosphate citinib salicylic acid cocrystals. In one embodiment, the crystalline form salicylic acid 1 contains at least about 98% by weight of crystalline form salicylic acid 1 based on the total amount of phosphate citinib salicylic acid cocrystals in the substance. In one embodiment, the crystalline form salicylic acid 1 contains at least about 99% by weight of crystalline form salicylic acid 1 based on the total amount of phosphate citinib salicylic acid cocrystals in the substance. In one embodiment, the crystalline form salicylic acid 1 contains at least about 99.5% by weight of crystalline form salicylic acid 1 based on the total amount of phosphate citinib salicylic acid cocrystals in the substance.

[0221] gluconic acid cocrystal In another embodiment, the present invention provides a compound gluconic acid cocrystal of formula I: [ka]

[0222] As described above, formula I corresponds to lincitinib. Gluconic acid is a weak acid. In this specification, “gluconic acid cocrystal” or “gluconate” refers to a cocrystal containing at least one gluconic acid. In certain embodiments, the gluconic acid cocrystal of lincitinib is the cocrystal according to formula XI: [ka]

[0223] In one embodiment, the present invention provides a crystalline form of the compound gluconic acid cocrystal of formula I: [ka]

[0224] Gluconic acid 1 In one embodiment, a crystalline phosphate citinib gluconate cocrystal containing crystalline gluconate 1 is provided. Gluconate 1 is also referred to herein as "crystalline gluconate 1 of the phosphate citinib gluconate cocrystal." In one embodiment, crystalline gluconate 1 of the phosphate citinib gluconate cocrystal is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 68 when measured with a Cu-Kα diffractometer.

[0225] In one embodiment, a crystalline form of gluconic acid 1 of phosphate citinib gluconate cocrystals, characterized by any aspect of the present invention, is provided, which exists as a substance containing at least about 95% by weight of crystalline form of gluconic acid 1 based on the total amount of phosphate citinib gluconate cocrystals. In one embodiment, the crystalline form of gluconic acid 1 contains at least about 98% by weight of crystalline form of gluconic acid 1 based on the total amount of phosphate citinib gluconate cocrystals in the substance. In one embodiment, the crystalline form of gluconic acid 1 contains at least about 99% by weight of crystalline form of gluconic acid 1 based on the total amount of phosphate citinib gluconate cocrystals in the substance. In one embodiment, the crystalline form of gluconic acid 1 contains at least about 99.5% by weight of crystalline form of gluconic acid 1 based on the total amount of phosphate citinib gluconate cocrystals in the substance.

[0226] Orotic acid cocrystal In another embodiment, the present invention provides orotic acid cocrystals of compounds of formula I: [ka]

[0227] As described above, formula I corresponds to lincitinib. Orotic acid is a weak acid. In this specification, “orotic acid cocrystal” or “orotic salt” refers to a cocrystal containing at least one orotic acid. In certain embodiments, the orotic acid cocrystal of lincitinib is the cocrystal according to formula XII: [ka]

[0228] In one embodiment, the present invention provides a crystalline form of an orotic acid cocrystal of the compound of formula I: [ka]

[0229] Orotic Acid 1 In one embodiment, a crystalline lincitinib orotic cocrystal containing crystalline orotic acid 1 is provided. Orotic acid 1 is also referred to herein as "crystalline form 1 of the lincitinib orotic cocrystal." In one embodiment, crystalline form orotic acid 1 of the lincitinib orotic cocrystal is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 69 when measured with a Cu-Kα diffractometer.

[0230] In one embodiment, a crystalline form of orotic acid 1 of lincitinib orotic acid cocrystals is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form of orotic acid 1 based on the total amount of lincitinib orotic acid cocrystals. In one embodiment, the crystalline form of orotic acid 1 contains at least about 98% by weight of crystalline form of orotic acid 1 based on the total amount of lincitinib orotic acid cocrystals in the substance. In one embodiment, the crystalline form of orotic acid 1 contains at least about 99% by weight of crystalline form of orotic acid 1 based on the total amount of lincitinib orotic acid cocrystals in the substance. In one embodiment, the crystalline form of orotic acid 1 contains at least about 99.5% by weight of crystalline form of orotic acid 1 based on the total amount of lincitinib orotic acid cocrystals in the substance.

[0231] Lincitinib polymorphism In one embodiment, polymorphs of the free base of lincitinib are provided. In one embodiment, the polymorphs of the free base of lincitinib are produced by crystallization with a pharmaceutically acceptable salt. In another embodiment, the polymorphs of the free base of lincitinib are produced by crystallization with a pharmaceutically acceptable coformer.

[0232] Form H In one embodiment, the present invention provides a crystalline form H of a compound of formula I: [ka]

[0233] As described above, Formula I corresponds to lincitinib. As used herein, “lincitinib form H” or “form H” refers to the crystalline form of the free base of lincitinib having the characteristics of form H as shown herein.

[0234] In one embodiment, a crystalline lincitinib free base containing crystalline form H is provided. In one embodiment, crystalline form H of the lincitinib free base is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 75 when measured with a Cu-Kα diffractometer.

[0235] In one embodiment, the crystalline morphology H of lincitinib free base is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 77.

[0236] In one embodiment, the crystalline form H of the lincitinib free base is characterized by a TGA signal substantially similar to the TGA signal in Figure 77.

[0237] In one embodiment, a crystalline form H of lincitinib free base is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form H based on the total amount of lincitinib free base. In one embodiment, the crystalline form H contains at least about 98% by weight of crystalline form H based on the total amount of lincitinib free base in the substance. In one embodiment, the crystalline form H contains at least about 99% by weight of crystalline form H based on the total amount of lincitinib free base in the substance. In one embodiment, the crystalline form H contains at least about 99.5% by weight of crystalline form H based on the total amount of lincitinib free base in the substance.

[0238] Form I In one embodiment, the present invention provides a crystalline form I of a compound of formula I: [ka]

[0239] As described above, Formula I corresponds to lincitinib. As used herein, “lincitinib form I” or “form I” refers to the crystalline form of the free base of lincitinib having the characteristics of form I as shown herein.

[0240] In one embodiment, crystalline lincitinib free base containing crystalline morphology I is provided. In one embodiment, crystalline morphology I of lincitinib free base is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 78 when measured with a Cu-Kα diffractometer.

[0241] In one embodiment, crystalline morphology I of lincitinib free base is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 81.

[0242] In one embodiment, crystalline morphology I of lincitinib free base is characterized by a TGA signal substantially similar to the TGA signal shown in Figure 81.

[0243] In one embodiment, a crystalline form I of lincitinib free base is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form I based on the total amount of lincitinib free base. In one embodiment, the crystalline form I contains at least about 98% by weight of crystalline form I based on the total amount of lincitinib free base in the substance. In one embodiment, the crystalline form I contains at least about 99% by weight of crystalline form I based on the total amount of lincitinib free base in the substance. In one embodiment, the crystalline form I contains at least about 99.5% by weight of crystalline form I based on the total amount of lincitinib free base in the substance.

[0244] Form J In one embodiment, the present invention provides a crystalline form J of a compound of formula I: [ka]

[0245] As described above, Formula I corresponds to lincitinib. As used herein, “lincitinib form J” or “form J” refers to the crystalline form of the free base of lincitinib having the characteristics of form J as shown herein.

[0246] In one embodiment, crystalline lincitinib free base containing crystalline form J is provided. In one embodiment, crystalline form J of lincitinib free base is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 85 when measured with a Cu-Kα diffractometer.

[0247] In one embodiment, a crystalline form J of lincitinib free base is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form J based on the total amount of lincitinib free base. In one embodiment, the crystalline form J contains at least about 98% by weight of crystalline form J based on the total amount of lincitinib free base in the substance. In one embodiment, the crystalline form J contains at least about 99% by weight of crystalline form J based on the total amount of lincitinib free base in the substance. In one embodiment, the crystalline form J contains at least about 99.5% by weight of crystalline form J based on the total amount of lincitinib free base in the substance.

[0248] Form K In one embodiment, the present invention provides a crystalline form K of a compound of formula I: [ka]

[0249] As described above, Formula I corresponds to lincitinib. As used herein, “lincitinib morph K” or “morph K” refers to the crystalline form of the free base of lincitinib having the characteristics of morph K as shown herein.

[0250] In one embodiment, a crystalline lincitinib free base containing crystalline morphology K is provided. In one embodiment, crystalline morphology K of the lincitinib free base is characterized by a powder X-ray diffraction (PXRD) pattern substantially similar to the pattern in Figure 86 when measured with a Cu-Kα diffractometer.

[0251] In one embodiment, the crystalline form K of lincitinib free base is characterized by a DSC thermogram substantially similar to the DSC thermogram in Figure 88.

[0252] In one embodiment, the crystalline form K of the lincitinib free base is characterized by a TGA signal substantially similar to the TGA signal in Figure 88.

[0253] In one embodiment, a crystalline form K of lincitinib free base is provided, characterized by any aspect of the present invention, which exists as a substance containing at least about 95% by weight of crystalline form K based on the total amount of lincitinib free base. In one embodiment, the crystalline form K contains at least about 98% by weight of crystalline form K based on the total amount of lincitinib free base in the substance. In one embodiment, the crystalline form K contains at least about 99% by weight of crystalline form K based on the total amount of lincitinib free base in the substance. In one embodiment, the crystalline form K contains at least about 99.5% by weight of crystalline form K based on the total amount of lincitinib free base in the substance.

[0254] Pharmaceutical composition In a related embodiment, the present invention provides pharmaceutical compositions for administering the salts and crystalline forms described herein. These pharmaceutical compositions can be prepared by any method known in the fields of pharmacy and drug delivery. Generally, methods for preparing the compositions include the step of combining an active ingredient with a carrier containing one or more auxiliary ingredients. The pharmaceutical compositions are typically prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into a desired formulation. The compositions can be conveniently prepared and / or packaged in unit dosage forms.

[0255] Pharmaceutical compositions can take the form of sterile aqueous or oily solutions and suspensions for injection. Sterile injectable preparations can be formulated using non-toxic, parenterally acceptable media, including water, Ringer's solution, and isotonic sodium chloride solution, and acceptable solvents such as 1,3-butanediol. Furthermore, sterile fixatives have conventionally been used as solvents or suspension media. For this purpose, any sterile fixative, including synthetic monoglycerides or synthetic diglycerides, can be used. In addition, fatty acids such as oleic acid are also used in the manufacture of injectable preparations.

[0256] The aqueous suspension contains an active substance mixed with excipients, including but not limited to suspending agents such as sodium carboxymethylcellulose, methylcellulose, oleaginopropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersing or wetting agents such as lecithin, polyoxyethylene stearate, and polyethylene sorbitan monooleate; and preservatives such as ethyl, n-propyl, and p-hydroxybenzoic acid.

[0257] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or mineral oil (e.g., liquid paraffin). Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0258] Dispersible powders and granules (suitable for preparing aqueous suspensions by adding water) may contain active ingredients mixed with dispersants, wetting agents, suspending agents, or combinations thereof. Additional excipients may be present.

[0259] The pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. The oil phase may be, for example, a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include natural gums such as acacia gum or tragacanth gum, natural phospholipids such as soy lecithin, fatty acids such as sorbitan monooleate and esters or partial esters derived from hexitol anhydride, and condensation products of ethylene oxide such as polyoxyethylene sorbitan monooleate and the aforementioned partial esters.

[0260] Pharmaceutical compositions containing salts and crystalline forms described herein may be in forms suitable for oral administration. Suitable oral compositions include, but are not limited to, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. Compositions for oral administration can be formulated according to any method known to those skilled in the art. Such compositions may contain one or more agents selected from sweeteners, flavorings, colorants, antioxidants, and preservatives to provide a pharmaceutically smooth and palatable formulation.

[0261] Tablets generally contain an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents such as corn starch and alginic acid; binders such as polyvinylpyrrolidone (PVP), cellulose, polyethylene glycol (PEG), starch, gelatin, and acacia; and lubricants such as magnesium stearate, stearic acid, and talc. Even without coating, tablets can be coated using known techniques to slow disintegration and absorption in the gastrointestinal tract, thereby prolonging their effect over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used. Tablets can also be coated with a semipermeable membrane and any polymer permeability enhancer according to known techniques to form an osmotic pump composition for controlled release.

[0262] Compositions for oral administration can be formulated as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium (such as peanut oil, liquid paraffin, or olive oil).

[0263] The salts and crystalline forms described herein can also be administered topically as solutions, ointments, creams, gels, suspensions, mouthwashes, eye drops, and the like. Furthermore, transdermal delivery of salts and crystalline forms can be achieved by iontophoresis patches and the like. The compounds can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore dissolves in the rectum to release the drug. Examples of such substances include cocoa butter and polyethylene glycol.

[0264] In some embodiments, the salt or crystalline form described herein is administered by intraperitoneal injection. In some embodiments, the salt or crystalline form is administered orally. In some embodiments, the salt or crystalline form is administered intravenously.

[0265] The pharmaceutical compositions of the present invention may also include micronized lincitinib, micronized lincitinib salts, or crystalline forms of micronized lincitinib salts. Generally, compositions containing micronized lincitinib contain particles essentially consisting of lincitinib with an average diameter of less than 50 μm. The average diameter of lincitinib particles may be, for example, less than 45 μm, less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, or less than 20 μm. The average diameter of lincitinib particles may be about 10 μm to about 49 μm, or about 10 μm to about 45 μm, or about 15 μm to about 40 μm, or about 20 μm to about 35 μm, or about 25 μm to about 30 μm. The average diameter of lincitinib particles is approximately 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 μm. In some embodiments, the particles consist essentially of finely ground lincitinib in free base form. In some embodiments, the particles consist essentially of finely ground lincitinib salts in amorphous or crystalline form, as described herein.

[0266] Treatment method IGF1R signaling has been found to be dysregulated in many diseases. Inhibition of IGF1R signaling has been studied as a potential approach to modulate immune responses in many diseases.

[0267] Thyroid eye disease (TED), also known as Graves' ophthalmopathy, is an autoimmune disease characterized by inflammation and swelling of the tissues around the eye. It is often associated with hyperthyroidism, a condition in which the thyroid gland is overactive. TED primarily affects patients with Graves' disease, an autoimmune disease in which antibodies that stimulate the thyroid gland are produced, leading to the overproduction of thyroid hormones.

[0268] In TED, IGF1R signaling has been found to be dysregulated. Although the exact mechanism is not fully understood, it is thought that antibodies associated with Graves' disease bind to and activate IGF1R, leading to the release of pro-inflammatory cytokines and the recruitment of immune cells to orbital tissue. This inflammatory response results in characteristic symptoms of TED, such as eyelid retraction, proptosis, diplopia, and eye pain. Inhibition of IGF1R signaling has been studied as a potential approach to modulate the immune response and reduce inflammation in TED.

[0269] In one embodiment, a method is provided for inhibiting IGF1R signaling, comprising administering a pharmaceutically acceptable salt of the compound of formula (I) to a subject. In some embodiments, the salt is an edisylate salt. In some embodiments, the salt is an esylate salt. In some embodiments, the salt is a maleate salt. In some embodiments, the salt is an L-malate salt. In some embodiments, the salt is a napsylate salt. In some embodiments, the salt is a phosphate salt. In some embodiments, the salt is an HCl salt. In some embodiments, the salt is a fumarate salt. In some such embodiments, the present invention comprises administering a salt of lincitinib described herein or a crystalline form of a salt of lincitinib.

[0270] In one embodiment, a method is provided for inhibiting IGF1R signaling, comprising administering a pharmaceutically acceptable salt of a compound of formula (X) to a target: [ka] (In the formula, A -(This includes an anion containing an edisylate anion, an esylate anion, a maleate anion, an L-maleate anion, a napsylate anion, a phosphate anion, an HCl anion, or a fumarate ion). In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 1, esylate 2, esylate 3, esylate 4, esylate 5, diesylate 1, L-maleate 1, L-maleate 2, L-maleate 3, L-maleate 4, L-maleate 5, L-maleate 6, L-maleate 7, L-maleate 8, L-maleate 9, edisylate 1, maleate 1, napsylate 1, phosphate 1, HCl 1, or fumarate 1. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 1. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 2. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 3. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 4. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 5. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is diesylate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 2. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 3. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 4. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 5. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 6. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 7. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 8. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 9. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is edicilate 1.In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is maleate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is napsylate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is phosphate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is HCl 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is fumarate 1.

[0271] In one embodiment, a method for inhibiting IGF1R signaling is provided, comprising administering a cocrystal of a compound according to formula (I). In some embodiments, the cocrystal is a salicylic acid-lincitinib cocrystal. In some embodiments, the cocrystal is a gluconic acid-lincitinib cocrystal. In some embodiments, the cocrystal is an orotic acid-lincitinib cocrystal. In one embodiment, the cocrystal is salicylic acid 1. In another embodiment, the cocrystal is gluconic acid 1. In another embodiment, the cocrystal is orotic acid 1. In some embodiments, the present invention includes administering a cocrystal of lincitinib as described herein.

[0272] In one embodiment, a method for inhibiting IGF1R signaling is provided, comprising administering a crystalline form of the free base of a compound according to formula (I) to the target. In some embodiments, the crystalline form of the free base is form H. In some embodiments, the crystalline form of the free base is form I. In some embodiments, the crystalline form of the free base is form J. In some embodiments, the crystalline form of the free base is form K. In some embodiments, the present invention comprises administering the crystalline form of the lincitinib free base described herein.

[0273] In one embodiment, a method for treating thyroid eye disease is provided, comprising administering a pharmaceutically acceptable salt of a compound according to formula I to a subject. In some embodiments, the salt is an edisylate salt. In some embodiments, the salt is an esylate salt. In some embodiments, the salt is a maleate salt. In some embodiments, the salt is an L-malate salt. In some embodiments, the salt is a napsylate salt. In some embodiments, the salt is a phosphate salt. In some embodiments, the salt is an HCl salt. In some embodiments, the salt is a fumarate salt. In some such embodiments, the present invention includes administering a salt or crystalline form of lincitinib as described herein.

[0274] In one embodiment, a method for treating thyroid eye disease is provided, comprising administering a therapeutically effective amount of a pharmaceutically acceptable crystalline salt form relating to formula (X) to a subject in need: [ka] (In the formula, A -(This includes an anion containing an edisylate anion, an esylate anion, a maleate anion, an L-maleate anion, a napsylate anion, a phosphate anion, an HCl anion, or a fumarate ion). In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 1, esylate 2, esylate 3, esylate 4, esylate 5, diesylate 1, L-maleate 1, L-maleate 2, L-maleate 3, L-maleate 4, L-maleate 5, L-maleate 6, L-maleate 7, L-maleate 8, L-maleate 9, edisylate 1, maleate 1, napsylate 1, phosphate 1, HCl 1, or fumarate 1. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 1. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 2. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 3. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 4. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is esylate 5. In one embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is diesylate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 2. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 3. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 4. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 5. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 6. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 7. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 8. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is L-malate 9. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is edicilate 1.In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is maleate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is napsylate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is phosphate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is HCl 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of formula (X) is fumarate 1.

[0275] In one embodiment, a method for treating thyroid eye disease is provided, comprising administering a therapeutically effective amount of a cocrystal of a compound relating to formula (I) to a subject in need: [ka] In some embodiments, the cocrystal is a salicylic acid-lincitinib cocrystal. In some embodiments, the cocrystal is a gluconic acid-lincitinib cocrystal. In some embodiments, the cocrystal is an orotic acid-lincitinib cocrystal. In one embodiment, the cocrystal is salicylic acid 1. In another embodiment, the cocrystal is gluconic acid 1. In yet another embodiment, the cocrystal is orotic acid 1.

[0276] In one embodiment, a method for treating thyroid eye disease is provided, comprising administering a therapeutically effective amount of a crystalline form of a compound relating to formula (I) to a subject in need: [ka] The crystal form is form H, form I, form J, or form K. In one embodiment, the crystal form is form H. In one embodiment, the crystal form is form I. In one embodiment, the crystal form is form J. In one embodiment, the crystal form is form K.

[0277] The salts and crystalline forms described herein can be administered in any suitable dose in the method of the present invention. Generally, the salts or crystalline forms are administered in doses ranging from about 0.01 milligrams to about 1000 milligrams per kilogram of body weight of the subject (i.e., about 0.01 to 1000 mg / kg). The dose of the salts or crystalline forms may be, for example, about 0.01 to 1000 mg / kg, or about 0.1 to 500 mg / kg, or about 0.5 to 250 mg / kg, or about 1 to 200 mg / kg, or about 2 to 150 mg / kg. The dosage of the salt or crystalline form may be approximately 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg / kg. Dosages of salt or crystalline form are approximately less than 0.1 mg / kg, less than 0.5 mg / kg, less than 1 mg / kg, less than 1.5 mg / kg, less than 2 mg / kg, less than 2.5 mg / kg, less than 3 mg / kg, less than 3.5 mg / kg, less than 4 mg / kg, less than 4.5 mg / kg, less than 5 mg / kg, less than 10 mg / kg, less than 15 mg / kg, less than 20 mg / kg, less than 25 mg / kg, less than 30 mg / kg, less than 35 mg / kg, less than 40 mg / kg, less than 45 mg / kg, less than 50 mg / kg, less than 55 mg / kg, less than 60 mg / kg, less than 65 mg / kg, less than 70 mg / kg, less than 75 mg / kg It can be administered in doses of less than 1 kg, less than approximately 85 mg / kg, less than approximately 90 mg / kg, less than approximately 95 mg / kg, less than approximately 100 mg / kg, less than approximately 150 mg / kg, less than approximately 200 mg / kg, less than approximately 250 mg / kg, less than approximately 300 mg / kg, less than approximately 350 mg / kg, less than approximately 400 mg / kg, less than approximately 450 mg / kg, less than approximately 500 mg / kg, less than approximately 550 mg / kg, less than approximately 600 mg / kg, less than approximately 650 mg / kg, less than approximately 700 mg / kg, less than approximately 750 mg / kg, less than approximately 800 mg / kg, less than approximately 850 mg / kg, less than approximately 900 mg / kg, less than approximately 950 mg / kg, or less than approximately 1000 mg / kg.In some embodiments, the salt or crystalline form is administered at a dose of less than 200 mg (200 mg / kg) of the compound per kg of body weight of the subject. In some embodiments, the salt or crystalline form is administered at a dose of less than 150 mg / kg. In some embodiments, the salt or crystalline form is administered at a dose of less than 100 mg / kg. In some embodiments, the salt or crystalline form is administered at a dose of less than 50 mg / kg. In some embodiments, the salt or crystalline form is administered at a dose of less than 20 mg / kg. In some embodiments, the salt or crystalline form is administered at a dose of less than 15 mg / kg. In some embodiments, the salt or crystalline form is administered at a dose of less than 10 mg / kg. In some embodiments, the salt or crystalline form is administered at a dose of less than 5 mg / kg. In some embodiments, the salt or crystalline form is administered at a dose of less than 4 mg / kg. In some embodiments, the salt or crystalline form is administered at a dose of less than 3 mg / kg. In some embodiments, the salt or crystalline form is administered at a dose of less than 2 mg / kg. In some embodiments, the salt or crystalline form is administered in a dose of less than 1 mg / kg. In some embodiments, the salt or crystalline form is administered in a dose of less than 0.5 mg / kg. In some embodiments, the salt or crystalline form is administered in a dose of less than 0.1 mg / kg.

[0278] Combination therapy Lincitinib can be used in combination with at least one other drug. In one embodiment, a pharmaceutically acceptable salt of lincitinib can be used in combination with at least one other drug. In a further embodiment, a pharmaceutically acceptable salt of lincitinib is an esylate salt, L-malate salt, edisylate salt, maleate salt, napsylate salt, phosphate salt, HCl salt, or fumalate salt. In another embodiment, a pharmaceutically acceptable crystalline salt form of lincitinib can be used in combination with at least one other drug. In further embodiments, the pharmaceutically acceptable crystalline salt forms of lincitinib are esylate 1, esylate 2, esylate 3, esylate 4, esylate 5, diesylate 1, L-malate 1, L-malate 2, L-malate 3, L-malate 4, L-malate 5, L-malate 6, L-malate 7, L-malate 8, L-malate 9, edisylate 1, maleate 1, napsylate 1, phosphate 1, HCl 1, or fumarate 1. In one embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is esylate 1. In one embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is esylate 2. In one embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is esylate 3. In one embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is esylate 4. In one embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is esylate 5. In another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is diesylate 1. In yet another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is L-malate 1. In yet another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is L-malate 2. In yet another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is L-malate 3. In yet another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is L-malate 4. In yet another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is L-malate 5. In yet another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is L-malate 6. In yet another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is L-malate 7.In another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is L-malate 8. In another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is L-malate 9. In another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is edisylate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is maleate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is napsylate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is phosphate 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is HCl 1. In another embodiment, the pharmaceutically acceptable crystalline salt form of lincitinib is fumarate 1.

[0279] In one embodiment, the lincitinib cocrystal can be used in combination with at least one other drug. In some embodiments, the cocrystal is a salicylic acid-lincitinib cocrystal. In some embodiments, the cocrystal is a gluconic acid-lincitinib cocrystal. In some embodiments, the cocrystal is an orotic acid-lincitinib cocrystal. In one embodiment, the cocrystal is salicylic acid 1. In another embodiment, the cocrystal is gluconic acid 1. In yet another embodiment, the cocrystal is orotic acid 1.

[0280] In one embodiment, the crystalline form of lincitinib free base can be used in combination with at least one other drug. In some embodiments, the crystalline form of the free base is form H. In some embodiments, the crystalline form of the free base is form I. In some embodiments, the crystalline form of the free base is form J. In some embodiments, the crystalline form of the free base is form K.

[0281] In one embodiment, at least one other drug used in combination therapy includes, but is not limited to, a thyroid-stimulating hormone receptor (TSHR) inhibitor. [Examples]

[0282] Measurement technology The following measurement techniques were used to characterize the salt or crystalline salt forms of lincitinib shown in the following examples.

[0283] Differential Scanning Calorimetry (DSC) DSC analysis was performed using a TA Instruments Q2500 Discovery series instrument. The instrument's temperature calibration was performed using indium. During the analysis, the DSC cell was kept under a nitrogen purge of approximately 50 mL per minute. The sample was placed in a standard crimped aluminum pan and heated from approximately 25°C to 300°C at a rate of 10°C per minute.

[0284] 1 H nuclear magnetic resonance (NMR) 1 ¹H-NMR spectra were acquired using a Bruker Avance NEO 400 spectrometer. Samples were prepared by dissolving the substance in DMSO-d6. The solutions were placed in separate 5mm NMR tubes for subsequent spectrum acquisition. Temperature-controlled (298K) spectra were acquired using the Avance NEO 400. 1 For 1H-NMR, a 5mm cryoprobe operating at an observation frequency of 400.18MHz was used. Each spectrum was processed using TopSpin version 4.1.4 and referenced to the chemical shift of the residual DMSO-d6 (2.5 ppm) peak.

[0285] Powder X-ray diffraction (PXRD) The Rigaku SmartLab X-ray diffractometer features a Bragg-Brentano reflection geometry with a beam stop and knife edge to reduce incident beam and air scattering. The data acquisition parameters are shown in Table 2. [Table 2]

[0286] Thermogravimetric analysis (TGA) TG analysis was performed using TA Instruments Q5500 Discovery series instruments. The measuring balance was calibrated using Class M weights, and temperature calibration was performed using Alumel. Nitrogen purging was performed at approximately 10 mL per minute for the balance and approximately 25 mL per minute for the furnace. The sample was placed in a platinum pan with a pre-weighed tare and heated from approximately 25°C to 300°C at a rate of 10°C per minute.

[0287] Example 1: Preliminary Characterization Lincitinib is in clinical development as a TED (Thoroughly Transmitted Therapeutic Epileptic Agent) and is currently being developed as a non-hygroscopic, high-melting-point (endothermic onset at 246°C, maximum 249°C by differential scanning calorimetry (DSC)) anhydrous / non-solvated free base. Polymorphic screening to date has suggested a complex set of solid forms, including one anhydrous form (form A), four hydrated forms (forms B, C, D, and E), and two solvated forms (form F - IPA solvate and form G - nitromethane solvate). Form A, the anhydrous form, was selected as the target form for development. This compound exhibits good solubility and permeability under acidic conditions, suggesting that maintaining supersaturation and avoiding precipitation in the upper intestinal tract are crucial factors for achieving the desired exposure level and, consequently, the required dose.

[0288] Lincitinib samples were used for polymorphism and salt screening. Powder X-ray diffraction (PXRD) and 1 Initial characterization of the lincitinib starting material (Table 3) was performed using 1H nuclear magnetic resonance (NMR) spectroscopy. The initial lot of lincitinib was found to be crystalline and visually consistent with morphology A (Figure 1). Proton NMR spectroscopy results for this lot were generally consistent with the chemical structure of lincitinib, but there were a few unidentified peaks (Figure 2). [Table 3]

[0289] Example 2: Screening of salts and cocrystals To find novel solid-state forms of lincitinib with physical properties suitable for development, we screened lincitinib salts and cocrystals.

[0290] salt screen The counterions for the salt screen were selected based on structural diversity and their relative pKa values ​​to the pKa of lincitinib. The selected acids are either listed on the GRAS list or designated as Class I or II by Stahl and Wermuth. The pKa of lincitinib is estimated to be between 5.0 and 5.51. Based on the molecular structure, the pKa values ​​were predicted to be 6.5 (pyrazine nitrogen) and 2.8 (quinoline nitrogen).

[0291] In the experiments, equimolar ratios of lincitinib to acid were used. Various solvent systems were investigated to utilize diverse conditions. Similarly, various crystallization techniques such as slurry, cooling, and evaporation were incorporated into the screen. One trial was performed for each acid. The samples produced and analyzed are shown in Table 4. Each unique crystal pattern of a possible lincitinib salt was given a unique name including the name of the acid (i.e., fumarate 1, maleate 1, etc.). [Table 4-1] [Table 4-2]

[0292] Experiments using several acids, including 1,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, hydrochloric acid, maleic acid, L-malic acid, 2-naphthalenesulfonic acid, and phosphoric acid, yielded materials with unique crystalline PXRD patterns (Figure 3).

[0293] Cocrystal screen A variety of different coformers were selected for inclusion in the lincitinib cocrystal screen. The coformers represent various different hydrogen bond donor and acceptor groups that can pair with the donor and acceptor groups in the lincitinib structure. The list of coformers included several weak acids that were not expected to be potent enough to fully protonate lincitinib but could potentially participate in hydrogen bonding. Some coformers, such as sorbic acid, were included because their surfactant-like structure was expected to potentially influence the solubility / elution profile compared to the free base of lincitinib. Generally, the screened coformers were either listed as GRAS (Generally Recognized as Safe) or considered Class I or II by Stahl and Wermuth.

[0294] Most cocrystal screening experiments were performed using equimolar ratios of lincitinib to coformer. Selected experiments were performed using 5-fold or 10-fold excess coformer to create conditions that would reduce the solubility of the cocrystal and promote its crystallization. One trial was performed for each coformer. Initial conditions focused on various solvent systems and crystallization methods, including the use of solvent-mediated grinding experiments. Table 5 shows the samples generated and analyzed during cocrystal screening. Each possible lincitinib cocrystal had a unique crystal pattern, which was given a distinctive name including the name of the acid (i.e., orotate 1, salicylate 1, etc.).

[0295] Experiments using gluconic acid, orotic acid, and salicylic acid revealed materials with unique crystalline PXRD patterns (Figure 18). Each of these phases was found to be either poorly crystalline or isolated as a mixture with the starting material. [Table 5-1] [Table 5-2] [Table 5-3]

[0296] Characterization of the morphology of selected solids Each substance other than fumarate 1 (Table 6), which had inferior crystallinity compared to other substances, 1 Further characterization was performed by 1H-NMR spectroscopy, DSC, and thermogravimetric analysis (TGA). These analyses were conducted to confirm the chemical structure, determine the stoichiometry if possible, and evaluate the properties of the resulting substance (anhydrous, solvated, hydrated, etc.). Some of the characterization results are discussed in more detail in the following examples. [Table 6-1] [Table 6-2] [Table 6-3]

[0297] Example 3: Crystalline salt of lincitinib esylate Esilate 1 was prepared from a 70°C isopropanol (IPA) slurry of lincitinib and ethanesulfonic acid. Specifically, 25.5 mg of lincitinib was added to 0.5 mL of isopropanol and heated to 70°C. 5.2 μL of ethanesulfonic acid was added to produce a finely turbid suspension. After equilibration for 4 days, a yellow to orange suspension was produced. The sample was filtered to produce an orange filtrate and a yellow solid. The solid was dried overnight under ambient conditions before analysis.

[0298] The preparation of esylate 1 was subsequently scaled up. 4.0193 g of lincitinib was suspended in 70 mL of isopropanol and reacted with 0.82 mL (1 equivalent) of ethanesulfonic acid at room temperature. Seed crystals of esylate 1 were added to this slurry and stirred overnight at 75°C. The resulting yellow solid was isolated, dried, and characterized, revealing that crystallization of esylate 1 had been successful (Figure 5). This was used as a starting material in other parts of this study.

[0299] Esilate Polymorphic Screen To identify further polymorphs of lincitinib esylate salts, various crystallization experiments were conducted using a diverse set of conditions. Each lincitinib esylate crystalline salt was given a unique name, including the name of the acid, due to its distinctive crystal pattern. Different crystalline forms of lincitinib esylate salts were prepared and identified by PXRD: esylate 1, esylate 2, esylate 3, esylate 4, esylate 5, diesylate 1, etc. Different crystallization techniques, including slurry, cooling, and evaporation, were incorporated into the screen.

[0300] The polymorph screen for lincitinib esylate was initiated with an emphasis on slurries at room temperature (RT), sub-ambient temperature (ST), and high temperature (ET) to quickly determine stable forms under different conditions. Water was incorporated into specific slurries to investigate the presence of possible hydrates. From the slurry experiments, two anhydrous / non-solvated forms of lincitinib esylate were observed, designated esylate 2 (green, Figure 3) and esylate 3 (blue, Figure 3). Esylate 3 was recovered primarily from solvent systems containing alcohol, while esylate 2 was recovered from a wider range of conditions, including most of the slurries performed at room temperature. These forms are discussed in detail in sections 3.1.1 and 3.1.2, respectively. Esylate 1, used as the starting material for the screen, was recovered from only a single slurry, suggesting that esylate 1 may be in a metastable state.

[0301] The additional samples generated and analyzed, along with the corresponding crystallization conditions, are shown in Table 7. [Table 7]

[0302] A typical PXRD pattern for esylate 2 is shown in Figure XX of sample 3-3. The typical peak positions and intensities of esylate 2 from sample 3-3 are shown in Table 8 below. [Table 8-1] [Table 8-2]

[0303] Dynamic screening experiments identified further forms of lincitinib esylate. Attempts to form a salt from IPA and 1 equivalent (Eq) ESA using RT yielded a solvate called esylate 4 (black, Figure 4). Drying of this same esylate 4 sample yielded a desolvated solvate called esylate 5 (red, Figure 4). The same patterns for esylates 4 and 5 were observed in other solvent systems, including ST slurries of 95:5 IPA:H2O and chloroform at 4°C (blue and green, respectively, Figure 4). This indicates that esylate 4 is an isostructural solvate capable of forming different crystallization solvents and solvates. [Table 9-1] [Table 9-2] [Table 10]

[0304] To find the thermodynamically stable form of the monosalt, interconversion slurries were set up at three different temperatures in two different solvent systems between esylates 1, 2, and 3, and esylate 4 + esylate 5 (Table 11). Although esylate 4 is a solvate, esylate 5 could not be separated as a separate pure phase until drying experiments of esylate 4 were performed towards the end of this study; therefore, samples of esylate 4 + esylate 5 were included as part of the interconversion slurry. Slurries were set up in MEK and 2:1 EtOH:HEP at 4°C, RT, and 60°C, and a total of six experiments were conducted over a total of seven days. All slurries unanimously resulted in esylate 2, which was shown to be the most stable form among all the forms under the conditions examined. [Table 11] a. Approximately 5 mg of esylate 4 + esylate 5 (1341-21-8) and approximately 10 mg of esylate 3 (1341-21-14,16), esylate 2 (1341-21-2,3), and esylate 1 (1341-3-1-1) were used in all slurries. b. SL = slurry, ET = high temperature, IPA = isopropanol, MIBK = methyl isobutyl ketone, RT = room temperature, AE = acetone, EA = ethyl acetate, HEP = heptane, EOH = ethanol, IPE = isopropyl ether, THF = tetrahydrofuran, ST = near ambient temperature, CLF = chloroform, H2O = water, WA = water activity, SE = slow evaporation, MOH = methanol, ACN = acetonitrile, CL = cooling, DOX = dioxane, MEK = methyl ethyl ketone, VD = vapor diffusion, MCH = methylcyclohexane, MTBE = methyl tert-butyl ether, NME = nitromethane, TOL = toluene, IPAE = isopropyl acetate, HFIPA = hexafluoroisopropanol, DMF = dimethylformamide, DCM = dichloromethane

[0305] Characterization of crystalline polymorphism of phosphate citinib esylate For each of the five phosphate citinib esylate crystalline salt polymorphs, selected samples were identified for further characterization. A summary of the results is as follows:

[0306] Water activity test of Esilate 2 Water-active slurries were prepared using seed crystals of esylate 2 and esylate 1, and the presence of possible hydrates and any relevant critical water activity was investigated (Table 12). Four slurries were set up with various THF and H2O ratios corresponding to 0.45, 0.63, 0.78, and 0.91 Aw, respectively. After stirring at RT for 17 days, the residues all uniformly consisted of esylate 2 (Figure 7), and it was revealed that no hydrates were present under ambient conditions, and the critical water activity (if present) was greater than Aw=0.91. The results confirm that esylate 1 is metastable under these conditions, suggesting that esylate 1 may not be hydrated and that the previously observed weight loss may be residual water rather than water incorporated into the lattice. [Table 12] a) All slurries were started with Esilate 2, Esilate 1 seed crystals were added, and the mixture was stirred at RT for a total of 10 days.

[0307] Esilate 2 scale-up, relative humidity stress testing, and mechanical stress testing. We attempted to scale up Esilate 2 against relative humidity stress and mechanical stress tests (Table 13). Even after 24 days of long-term 75% RH stress under RT, no weight increase due to TGA was observed, and no shape changes were observed in the stressed samples by PXRD analysis (Figure 10). When Esilate 2 was ground as is for 30 minutes and subjected to mechanical stress, low-crystallinity Esilate 2 and amorphous residue were produced, suggesting that it is best to avoid excessive mechanical stress. [Table 13]

[0308] Characterization of Esilate 2 Esilate salt 2 appears to be a stable polymorph of phosphate esylate. Esilate 2 was isolated from various techniques, solvents, and temperatures, and several samples were further characterized (Table 14). NMR analysis confirmed it to be 1:1 phosphate esylate. DSC analysis revealed a major endothermic reaction at 225°C, likely due to melting, and TGA analysis suggested an anhydrous / non-solvated form (Figure 8). This was further supported by successful indexing of the PXRD pattern, and the calculated unit cell volume indicated a 1:1 salt (Section 0). Single crystals grown by vapor diffusion of DCM into DMF were successfully characterized as esylate 2 by SCXRD, confirming its anhydrous / non-solvated nature. 2DVS analysis showed that esylate 2 was slightly hygroscopic, with a 1% weight increase and decrease during adsorption and desorption cycles, respectively, but no net weight change was observed after analysis (Figure 9). Since the majority of water absorption (approximately 0.8%) was observed to occur above 85% RH, it is suggested that exposure to very high RH levels should be avoided. [Table 14]

[0309] Solubility of Ethylate 2 To study solubility, a second attempt was made to scale up esylate 2. Lincitinib was slurryed with 1 equivalent of ethanesulfonic acid in ethanol at room temperature for 3 days, and seed crystals were added. PXRD analysis of the dried product revealed that esylate 2 was successfully synthesized on a 4-gram scale with a 94% yield. The results of the solubility test are shown in Example 16.

[0310] Ethylate 2 single crystal structure The crystal structure of phosphate citinib esylate form 2 (esylate 2) was elucidated according to the following procedure (Figure 1). The structure was confirmed to be anhydrous / non-solvated. This compound crystallized in a chiral space group, but no chiral centers were observed because the cations contain molecular mirrors.

[0311] The ruxolitinib free base was used in the preparation of ruxolitinib esylate Form 1. 50.1 mg of ruxolitinib esylate Form 1 was dissolved in 0.25 mL of DMF. The resulting solution was filtered into a new clean vial using a 0.2 μm PTFE syringe filter. The vial was placed without capping into a larger vial containing dichloromethane. The larger vial was capped and stored at room temperature to promote the diffusion of vapor. Through this experiment, transparent plates of sufficient size and quality for single crystal analysis were produced.

[0312] The approximate dimensions were 0.05 × 0.20 × 0.41 mm, and colorless plate-like crystals with the chemical formula C 26 H 24 N5O·C2H5O3S were mounted in a random orientation on a Mitegen micromesh mount. The data were collected from a single crystal shock-cooled to 150(2) K on a Bruker AXS D8 Quest four-axis diffractometer equipped with an I-mu-S micro-source X-ray tube, using a horizontally inclined multilayer (Goebel) mirror as a monochromator and a PhotonIII_C14 charge integration and photon counting pixel array detector. The diffractometer used CuKα radiation (λ = 1.54178 Å). All data were integrated with SAINT V8.40B, and multi-scan absorption correction using SADABS 2016 / 2 was applied. The structure was analyzed by the dual method with SHELXT and refined by full-matrix least-squares against F 2 . All non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms bonded to carbon were refined isotropically at calculated positions using a riding model. For methyl CH3, rotation was made possible but tilt was not, to best fit the experimental electron density. The positions of H atoms of amines and alcohols and H atoms of water were refined isotropically. The U iso values were restricted to 1.5 times U eq of the pivot atom for methyl groups and hydroxyl groups, and 1.2 times for all other hydrogen atoms.

[0313] The Flack-X parameters were determined using the Parson method with the quotient [(I+)-(I-)] / [(I+)+(I-)] and refined to 0.003(7). Anions and cations do not have chiral centers (cations have molecular mirrors).

[0314] Crystal data and structural refinement data are summarized in Table 15. [Table 15]

[0315] The XRPD pattern calculated from single-crystal data is superimposed on the reference XRPD pattern of phosphate citinib esylate 2. The patterns overlap well, indicating that they represent the same crystalline phase. The observed peak shift is due to the temperature difference between the single-crystal and X-ray powder diffraction data collection.

[0316] Characterization of Esilate 3 Esilate 3 was isolated primarily from experiments involving alcohol, but it was also isolated from attempts to cool dioxane. Esilate 3 was characterized using multiple techniques (Table 16). NMR analysis of this form revealed a 1:1 phosphate citinib esylate salt. DSC analysis revealed a major, broad-range endothermic melting at 194°C (Figure 16). This was linked to a minor endothermic reaction at 231°C, similar to that observed in esylate 2, suggesting that it may have been originally present or originated from trace amounts of esylate 2 that crystallized after esylate 3 melted. TGA analysis showed no weight loss before the major endothermic reaction, suggesting an anhydrous / non-solvated form. This was further confirmed by the successful indexing of a PXRD pattern (section 0) to calculate the unit cell volume capable of accommodating the 1:1 salt. This unit cell volume is also slightly larger than that of esylate 2, indicating a lower density and suggesting that it may be metastable relative to esylate 2. [Table 16]

[0317] Characterization of Esilate 4 Esilate 4 was obtained from salt formation experiments using 1 equivalent of ESA in IPA in RT and ST, and further characterized using multiple techniques (Table 17). NMR analysis revealed that it was a 1:1 phosphate citinib esylate with 0.6 moles of IPA present. TGA analysis revealed a 2.7% weight loss at ~73°C, which is highly likely to be due to surface solvent or moisture. Further heating to 125°C resulted in a 5.7% weight loss, corresponding to approximately 0.6 moles of IPA, suggesting that esylate 4 is an IPA solvate. When the esylate 4 sample was heated under vacuum at 60°C for 18 hours and dried, a morphological change to esylate 5 was revealed (Table 18).

[0318] Ethylates 4 and 5 were obtained from several other slurries with different solvent systems (Figure 4). This suggests that ethylate 4 can form solvates with various crystallization solvents, indicating an isostructural solvate system and the possibility of desolvation to ethylate 5. Since ethylate 4 was not obtained from any of the interconversion slurries, it was shown to be metastable under the conditions investigated (Table 19). [Table 17] [Table 18]

[0319] Characterization of Eshilate 5 Ethylate 5 was originally obtained simultaneously with ethylate 4 from slurries of several different solvent systems (Figure 4). When a sample of ethylate 4 was vacuum-dried at 60°C for 18 hours, it transformed into ethylate 5. Thermal analysis revealed a rapid weight loss of 3.3% at ~75°C by TGA, accompanied by a major, broad endothermic peak at 84°C by DSC. Since the sample was produced by drying at high temperatures, the weight loss observed upon heating is likely due to moisture absorbed from the surface or channels during exposure to ambient conditions. The absence of the high-temperature (>80°C) weight loss previously observed in the solvate of ethylate 4 suggests that ethylate 5 is a desolvated solvate of ethylate 4. Since ethylate 5 was not obtained from any of the interconversion slurries, it was shown to be metastable under the conditions investigated (Table 19). [Table 19]

[0320] Characterization of diesylate 1 Diesylate 1 was obtained by attempting salt formation with lincitinib in IPA and 2 equivalents of ESA at RT. NMR analysis revealed the presence of 1:2 lincitinib diesylate and trace amounts of IPA. DSC analysis revealed a broad, minor endothermic peak at 74°C, and the TGA spectrum showed a 1.2% weight loss at ~75°C, likely due to evaporation of the surface solvent. Further heating revealed a continuous slight weight loss. DSC showed a shoulder peak at 197°C and a major endothermic peak at 219°C, suggesting the possibility of melting. Similar salt formation attempts (using 3 equivalents of ESA) also yielded diesylate 1 with several additional peaks (Table 20, Figure 30). [Table 20]

[0321] Example 5: Crystalline salt of lincintinib L-malate L-Malate 1 An equimolar slurry of L-malic acid and lincitinib in acetonitrile at room temperature produced a unique phase, which was referred to as L-malate 1. Specifically, 24.8 mg of lincitinib was combined with 7.9 mg of L-malic acid and 0.5 mL of acetonitrile. When the sample was stirred overnight at room temperature, a thick white paste was produced. An additional 0.5 mL of isopropanol was added to this sample to produce a mobile suspension. This suspension was stirred for a further 6 days to produce a white slurry. After filtration and drying overnight under ambient conditions, a white solid was produced.

[0322] Sample 1 Analysis by 1H-NMR spectroscopy revealed that the spectrum matched that of a 1:1 malic acid:phosphorus citinib salt in the presence of residual acetonitrile. Thermal analysis of the sample showed that the apparent melting point was consistent with the anhydrous / non-solvated form at 179°C (Figure 35).

[0323] For the L-malate scale-up, L-malic acid (1 equivalent) was added to 2.0 g of lincitinib free base suspended in ACN (37 mL) at RT to obtain a concentrated suspension. Additional solvent was added, and a slurry was prepared at RT for 5 days. The solid was isolated by VF and vacuum-dried at RT for 2 days. Analysis of the sample by PXRD yielded the diffraction pattern shown in Figure 33. The representative peak positions and intensities of L-malate 1 from the scale-up sample are shown in Table 21 below. [Table 21-1] [Table 21-2]

[0324] Polymorphic screening of L-malate salts Polymorphic screening of lincitinib malate was performed (Table 22). The experiments were designed to target thermodynamically stable forms, and therefore techniques such as long-term slurrying, cooling, antisolvent addition, and evaporation were used. Reaction crystallization experiments using free lincitinib base and L-malic acid were also performed (Table 23). Amorphous materials were used as alternative starting materials because they provide access to polymorphs that are not accessible from crystalline starting materials (Table 24). Heating experiments were performed (Table 25). [Table 22-1] [Table 22-2] [Table 22-3] [Table 22-4] [Table 23] [Table 24] [Table 25]

[0325] Eight substances were also identified that, when added to malate 1 (the starting form for most current screening experiments), exhibit a unique peak by PXRD (i.e., not containing peaks for free base, malate, or known forms of malic acid). 1 Those confirmed to be malates by 1H-NMR spectroscopy were designated as malate 2 to malate 9.

[0326] Malate 2, Malate 4, and Malate 5 were all obtained under high water activity conditions and are considered to be in hydrated forms. Based on the weight loss of the TG thermograms of Malate 4 and Malate 5, they were likely dihydrates. The water activity boundary between Malate 4 and Malate 1 was determined to be approximately a water activity of 0.9 or a relative humidity of 90%. Malate 1 was obtained at a water activity of 0.8, but an additional peak was present in the PXRD.

[0327] Upon dehydration, both malate 4 and malate 5 are converted to malate 7. Malate 7 could be either an anhydrous or a lower hydrate.

[0328] Note that in PXRD, malate 2 and malate 5 appear very similar. This suggests that their crystal structures are closely related and may differ only slightly due to small amounts of water.

[0329] Both malate 3 and malate 6 were obtained from experiments using ethanol. 1 While no organic solvents were detected by 1H-NMR spectroscopy, a weight loss was observed in the TG thermogram. This weight loss corresponds to approximately 1 mole of water, suggesting that malate 3 and malate 6 may be monohydrates.

[0330] Malate 8 and Malate 9 were observed in experiments starting from amorphous malate salts. 1 Based on the 1H-NMR data, the substances were likely methanol solvate and ethanol solvate, respectively.

[0331] Characteristics of lincitinib L-malate salt polymorphisms For each of the nine lincitinib L-malate crystalline salt polymorphs, samples were selected for further characterization. The results are shown in Table 26 below. [Table 26-1] [Table 26-2]

[0332] It should be noted that the PXRD patterns of several new materials appear very similar to each other, suggesting they are likely related. A peak shift was observed in some samples, particularly between maleate 2 and maleate 5, suggesting that volatile content may vary despite having the same crystal lattice (Figure 2).

[0333] Malate 3, Malate 4, Malate 5, and Malate 6 were further characterized by TG and DSC. Malate 3 and Malate 6 were possibly monohydrates. Malate 3 contained only trace amounts of organic solvent in its NMR spectrum, but showed a 3.6% weight loss in its TG thermogram. Residual solvent accounted for approximately 1% of the loss, with the remaining approximately 2.6% corresponding to about 1 mole of water per mole of salt. Similarly, Malate 6 1 Although no organic solvent was observed in the 1H-NMR spectrum, a 4.2% weight loss was detected in the TG thermogram.

[0334] Malate 4 and Malate 5 were possibly dihydrates. While no organic solvents were present in the NMR spectrum, the TG thermogram showed a 7.3-7.4% decrease in the weight of each substance. This is thought to correspond to approximately 2.4 moles of water per mole of salt.

[0335] The water activity boundary between malate 4 and malate 1 was determined to be approximately a water activity of 0.9 or a relative humidity of 90%. While malate 1 was obtained at a water activity of 0.8, an additional peak was observed in the PXRD analysis.

[0336] Based on thermal data, malate 4 and malate 5 were heated at approximately 90°C for 15 minutes. After heating, the solids were re-analyzed by PXRD to examine the change in shape due to dehydration. Based on the data, malate 4 and malate 5 appear to be dehydrated and become a new form called malate 7. The amount of sample was insufficient to further characterize malate 7, but based on the conditions under which it was generated, it may have been in the form of a lower hydrate or anhydrous form.

[0337] Example 6: Phosphate citinib crystalline salt form edicilate 1 Edisylate 1 was prepared from an equimolar slurry of dioxane. 25.0 mg of lincitinib was combined with 13.4 mg of 1,2-ethanedisulfonic acid dihydrate and 1.0 mL of dioxane. When this sample was heated to 90°C, a cloudy white solution was produced with a small amount of yellow sticky residue at the bottom of the vial. When the sample was kept at 90°C overnight, a thick yellow slurry was produced. The sample was removed from the heat and rapidly cooled to room temperature. When the sample was stirred at ambient temperature for 5 days, a dark yellow slurry was produced. This solid was isolated by filtration and dried overnight at ambient temperature. Shrinkage of the sample was observed macroscopically. The sample was crushed with a spatula to produce a yellow powder.

[0338] PXRD analysis of the sample after storing it capped at room temperature for 20 days showed no significant changes, indicating that the sample is physically stable under these conditions. 1¹H-NMR analysis confirmed a 1:1 molar ratio of lincitinib to acid (Figure 51). Thermal analysis of the material (Figure 52) showed a 1.7% weight loss upon heating to 150°C, and DSC data showed a broad endothermic reaction with a peak maximum at 51°C. No significant dioxane or other organic solvents were observed in the NMR spectrum, suggesting the weight loss is likely related to water. The theoretical hemihydrate of the lincitinib monoedicilate salt is thought to contain 1.4% water. Further endothermic reactions were observed at 252°C and 278°C, likely due to melting / decomposition, given that the corresponding weight loss in TGA begins at approximately 244°C. Characterization results indicated that edicilate 1 is a possible hemihydrate monosalt of lincitinib.

[0339] Example 7: Lincitinib crystalline salt form maleate 1 Maleate 1 was prepared from an equimolar slurry of lincitinib and maleic acid in 95 / 5 IPA / water at room temperature. Specifically, 24.8 mg of lincitinib and 6.8 mg of maleic acid were mixed with 0.5 mL of 95-5(vv) isopropanol-water. After stirring overnight at room temperature, a thick white paste was observed. An additional 0.5 mL of isopropanol was added to this sample to produce a fluid suspension. After stirring for a further 6 days, the sample was observed to have become a white slurry. This solid was filtered and dried under ambient conditions to produce a pale yellow solid.

[0340] The obtained solid 1 The 1H-NMR spectrum showed a 1:1 molar ratio of lincitinib to maleic acid, and the spectrum showed no evidence of organic solvents (Figure 54). Thermal analysis was consistent with the possible hydration form (Figure 55). The sample showed a broad endothermic reaction corresponding to 71°C on DSC and a process loss of 2.8% at ~100°C. 1Based on the absence of organic solvents observed in the 1H-NMR spectrum, the weight loss is expected to be due to water. The monohydrate monomaleate salt of lincitinib is expected to contain approximately 3.2% water. Multiple endothermic and exothermic events were observed, and the corresponding significant weight loss at approximately 174°C suggests a possible melting / decomposition event, but further testing is needed to confirm. Characterization results indicate that maleate 1 is a possible hydrate monosalte of lincitinib.

[0341] Example 8: Phosphate citinib crystalline salt form napsylate 1 Napsilate 1 was produced from a 70°C acetonitrile slurry of lincitinib and 2-naphthalenesulfonic acid hydrate. Specifically, 25.5 mg of lincitinib and 13.7 mg of 2-naphthalenesulfonic acid hydrate were mixed with 0.5 mL of acetonitrile. When this sample was heated to 70°C, a turbid yellow suspension was produced after 1 hour. After 4 days of equilibrium, a white slurry was observed. The solid was isolated by filtration and then dried overnight at room temperature.

[0342] 1 The 1H-NMR spectrum was consistent with that of the monosalt, and no organic solvent was observed in this spectrum. 1 The H-NMR spectrum (Figure 57) showed no organic solvent, indicating that heating the sample resulted in a 3.9% weight loss due to water (Figure 58). For the 1.5-hydrate mononapsylate of lincitinib, 4.1% water content is expected in the sample. Multiple thermal events were observed in DSC, showing a complex thermal profile. Further investigation using hot-stage microscopy is needed to confirm the nature of these events. Characterization results indicated that napsylate 1 is a potential hydrated monosalte of lincitinib.

[0343] Example 9: Phosphate 1 in the form of phosphate 1 When equimolar amounts of lincitinib and phosphoric acid were slurryed in acetonitrile at 70°C, a unique phase called phosphoric acid 1 was formed. Specifically, 25.0 mg of lincitinib was added to 0.5 mL of acetonitrile. After heating this sample to 70°C, 4.1 μL of phosphoric acid (85% (w / w) aqueous solution) was added to produce a lumpy, yellow suspension. After 4 days of equilibrium, a yellow slurry with a pale pink residue on the liquid surface of the wall was formed. This suspension was filtered, and the solid was dried overnight under ambient conditions to produce a pale yellow solid.

[0344] Sample 1 The 1H-NMR spectrum was consistent with lincitinib, but showed a peak shift compared to the free base, suggesting salt formation, although the stoichiometry of the possible salt could not be determined. Residual acetonitrile was also observed in the spectrum (Figure 60). A slight weight loss of 0.3% was observed upon heating, but it is likely that 1 The H-NMR spectrum showed trace amounts of acetonitrile, indicating that the sample is anhydrous / non-solvable (Figure 60). DSC showed broad, overlapping endothermic and exothermic reactions at approximately 160°C and 181°C, respectively, which could be attributed to possible melting / recrystallization events. The final major endothermic reaction was observed at 229°C, which, based on the weight change observed by TGA at that temperature, is likely due to a melting / decomposition event (Figure 61). Characterization results showed that phosphate 1 is anhydrous / non-solvable.

[0345] Example 10: Phosphate citinib crystalline salt form HCl1 HCl1 was produced by evaporating a 1:1 lincitinib:acid-containing tetrahydrofuran (THF) / water solution at 70°C. PXRD analysis of the sample after 17 days of storage at room temperature with the cap on showed no significant changes, indicating that the sample is physically stable under these conditions. 1No evidence of organic solvents was observed in the 1H-NMR spectrum (Figure 64). The spectrum showed a peak shift compared to the as-received free lincitinib base, suggesting salt formation, but the stoichiometry of the possible salt could not be determined. Thermal analysis revealed a consistent weight loss upon heating, with DSC showing a 12.5% ​​weight loss at ~76°C and a corresponding broad endothermic reaction at 104°C (Figure 65). The weight loss was likely due to the release of water and possibly hydrochloric acid.

[0346] Example 11: Scale-up of selected crystalline salts of lincitinib Three salts were selected for solubility evaluation: phosphate 1, L-malate 1, and esylate 1. The phosphate and malate were selected based on their non-solvable / anhydrous properties. Esylate 1 appeared hydrated, but often produces hydrates if the appropriate physical properties are present. Thermal analysis also suggested the possibility of further forms of the salt. Ethanesulfonic acid is a stronger acid than phosphoric acid and L-malic acid and can affect the corresponding water solubility (see Section 3.5).

[0347] To generate sufficient material for solubility data, salts were prepared on a scale of approximately 1.5 g and 2.0 g. The salts were prepared using conditions similar to those used when initially preparing the salts on a small scale. In each scale-up experiment, the desired salts were successfully produced based on PXRD.

[0348] Scaling up Esirate 1 For the 1.5 g scale-up of Esilate 1, 1.5002 g of lincitinib was mixed with 20 mL of isopropanol and 305.6 μL of ethanesulfonic acid (95% (w / v)), and heated to 75°C to produce a yellow slurry. A small amount of Esilate 1 was added to this sample and stirred overnight to produce another yellow slurry. This suspension was cooled and filtered to produce a pale yellow solid. The sample was dried overnight under ambient conditions to produce a slightly viscous off-white powder. 1.8738 g of the material was recovered.

[0349] For the 2.0 g scale-up of Esilate 1, 2.0014 g of lincitinib (using a combination of TCL18673 and TCL17230 as starting materials) and 25 mL of isopropanol were added to a flask and stirred at 75°C. 407.6 μL of ethanesulfonic acid (95% (w / v)) was added dropwise, and a thick, pale yellow slurry was formed within a few minutes. Esilate 1 was added to this sample using the tip of a spatula as a seed crystal. The sample was stirred overnight at 75°C to produce a yellow slurry. The sample was vacuum filtered, and the solid was air-dried overnight in a hood to produce an off-white / yellow solid. 2.4960 g of the material was recovered.

[0350] Scaling up L-Marate 1 To scale up L-malate 1 to 1.5 g, 1.5006 g of lincitinib was combined with 0.4774 g of L-malic acid and 25 mL of acetonitrile to produce a yellow slurry. A small amount of L-malate 1 was added to the sample. After stirring overnight at room temperature, a yellow slurry was produced. This solid was isolated by vacuum filtration to produce a wet solid, which was dried overnight under ambient conditions. A solid mass was formed, which was lightly crushed with a spatula to produce an off-white powder. 1.7289 g of the material was recovered.

[0351] To scale up L-malate 1 to 2.0 g, 2.0095 g of lincitinib (using TCL17230 as the starting material) was added to a flask equipped with a stirring bar, and 0.6393 g of malic acid and 35 mL of acetonitrile were added. When this sample was stirred, a yellow slurry was formed, to which L-malate 1 was added using the tip of a small spatula. When the sample was stirred overnight at room temperature, an off-white slurry was formed. The solid was isolated by vacuum filtration. The isolated solid was dried overnight in a hood to obtain an off-white / pale yellow solid. 2.6167 g of the material was recovered.

[0352] Scaling up Phosphate 1 To scale up phosphate 1 to 1.5 g, 1.5004 g of lincitinib was added to 25 mL of acetonitrile. This sample was heated to 70°C, and then 241.4 μL of phosphoric acid (85% (w / w) aqueous solution) was added. Phosphate 1 (sample 2-22) was added to the sample and stirred overnight at room temperature to produce a yellow slurry. This solid was vacuum filtered to produce a yellow solid, which was dried overnight under ambient conditions. A brittle solid mass was formed, which was pulverized into a yellow powder using a spatula. 1.6696 g of the substance was produced. [Table 27]

[0353] Example 12: Lincitinib free base crystal polymorph B An attempt to produce a cocrystal via an isomolecular slurry of lincitinib and benzamide resulted in the generation of a unique crystalline phase. 25.2 mg of lincitinib and 8.0 mg of benzamide were contacted with 0.5 mL of ethanol to produce an off-white slurry. The sample was allowed to slurry at room temperature for 3 days to produce a pale yellow suspension. After filtering and drying overnight at ambient temperature, a yellow solid was formed.

[0354] The product was analyzed by powder X-ray diffraction spectroscopy. The PXRD pattern was visually similar to the previously identified morphology B, as shown in Figures 71 and 72. 1 Further characterization was performed by 1H-NMR spectroscopy (Figure 73), and the presence of lincitinib and the absence of benzamide were confirmed. No residual solvent was observed in the spectrum. Thermal analysis of the sample (Figure 74) showed a weight loss of 3.7% at ~75°C, and a corresponding broad endothermic reaction was observed at 89°C in the DSC trace. A further weight loss of 1.1% was observed at ~150°C, and a large endothermic reaction, possibly due to melting, was also observed at approximately 247°C. Form B has been reported as a monohydrate, and the observed weight loss is similar to that of a theoretical monohydrate (4.1%).

[0355] Example 13: Lincitinib free base crystal polymorph H Attempts to produce cocrystals via an isomolecular slurry of lincitinib and 4-aminosalicylic acid resulted in the generation of unique crystalline phases. In one example, 24.9 mg of lincitinib, 10.0 mg of 4-aminosalicylic acid, and 0.5 mL of methanol were mixed to produce an off-white suspension. After stirring for 3 days, an off-white / light brown suspension was observed. Filtration of this sample yielded a light purple solid and a clear brown filtrate. After drying overnight under ambient conditions, shrinkage of the solid was observed, and grinding with a spatula produced a light brown powder.

[0356] Morphology H was also observed in several other cocrystal screening experiments using methanol as the organic solvent. Morphology H was also obtained as a physical mixture with the starting coformer in experiments using adenine, L-arginine, and L-threonine.

[0357] Thermal analysis of morphology H showed a 4.0% weight loss at ~100°C in the DSC, with a corresponding broad and shallow endothermic reaction at 93°C (Figure 77). The DSC thermogram showed further endothermic and exothermic reactions, including overlapping major endothermic reactions at 243°C and 247°C, which, based on the weight change of TGA, may be partly due to decomposition.

[0358] The weight loss was expected to be due to methanol, but the sample 1 1H-NMR analysis indicated that the sample did not contain any organic solvents. NMR analysis performed after thermal analysis suggested that solvent loss may have occurred during storage at ambient temperature. Re-analysis of the substance was consistent with initial data suggesting that the weight loss was likely due to water. The weight loss is consistent with the theoretical monohydrate of lincitinib free base.

[0359] Example 14: Lincitinib free base crystal polymorph I Lincitinib form I was initially produced from attempts to form a salt with 2-hydroxyethanesulfonic acid in acetonitrile. In one example, 25.0 mg of lincitinib was slurryed with 8.8 mg of 2-hydroxyethanesulfonic acid sodium salt in 0.5 mL of acetonitrile at room temperature. This slurry was initially white but turned pale yellow after stirring for 1 hour. After stirring at room temperature for 6 days, the solid was isolated. The solid was dried overnight at ambient temperature to produce a white solid.

[0360] Morphology I was also observed when a sample of morphology J (see section 3.3.4 below for details), generated from an attempt at co-crystallization with vanillin, was stored in a capped vial at room temperature for 20 days. 1 1H-NMR spectroscopy revealed that the sample contained a trace amount (<0.1 mol / mol) of residual vanillin. 1 The presence of free lincitinib base was also confirmed by 1H-NMR spectroscopy (Figure 75). No organic solvents were observed in the spectrum. Thermal analysis of morphology I showed a 1.8% weight loss upon heating to 163°C (Figure 81). DSC indicates the presence of several thermal events, including a complex thermal profile with exothermic reaction at 173°C, which may be due to recrystallization of the sample. Further investigation, such as hot-stage microscopy, is needed to confirm the nature of these events. The observed weight loss suggests that morphology I can be hydrated, and the observed weight loss is considered to be consistent with a possible hemihydrate (theoretical value 2.1%).

[0361] Example 15: Lincitinib free base crystal polymorphism J Morphology J was produced from an attempt at co-crystallization with vanillin in acetone. 25.8 mg of lincitinib and 10.2 mg of vanillin were mixed with 0.5 mL of acetone to produce an off-white slurry, which was stirred at room temperature for 3 days. During equilibration, the slurry turned yellow, and the solid was isolated from the suspension by filtration. The solid was dried overnight under ambient conditions to produce a pale yellow solid.

[0362] The sample was first analyzed by PXRD and stored in a capped vial at room temperature (Figure 85). After 20 days of storage at room temperature, the sample was re-analyzed by PXRD and found to have been converted to morphology I, indicating that morphology J is metastable when stored at ambient temperature.

[0363] Example 16: Lincitinib free base crystal polymorph K Morphology K was initially formed during an attempt at co-crystallization with sorbic acid in acetone. 25.2 mg of lincitinib, 7.4 mg of sorbic acid, and 0.5 mL of acetone were mixed at room temperature to produce a yellow slurry. After stirring for 6 days, a dark yellow slurry was produced. It was isolated by filtration and dried overnight under ambient conditions to obtain a yellow solid.

[0364] 1 The 1H-NMR spectrum was consistent with lincitinib, and there was no evidence of the presence of sorbic acid (Figure 87). The spectrum also showed the presence of 0.4 equivalents of acetone.

[0365] Thermal analysis of the aforementioned sample (Figure 88) showed a stepwise weight decrease of 4.6% (corresponding to 0.4 moles of acetone) during heating. DSC revealed further thermal events, including overlapping endothermic and exothermic events, at 156°C and 174°C, suggesting the possibility of recrystallization of the sample. However, further investigation is needed to confirm the nature of these events. Similar to morphology H, double endothermic events were observed at 241°C and 247°C.

[0366] Example 17: Solubility of crystalline lincitinib salt The pH solubility of selected salts (phosphate 1, L-malate 1, esylate 1, and esylate 2) was evaluated and compared with that of lincitinib free base. Solubility analysis was performed using a method consistent with previous studies using lincitinib free base. Aqueous solutions were prepared by titration with NaOH and HCl, increasing the pH between 1.5 and 6.5 in 0.5 pH increments. For each salt or free base, an attempt was made to reach saturation of each solution by adding sufficient substance to the solution so that an excess solid remained. Once saturation was achieved, the pH of the solution was measured and adjusted to the target pH, with additional substance added as needed. The samples were then equilibrated overnight. The final pH of the solution was measured, the solid was filtered, and selected samples were analyzed by PXRD. The concentration of lincitinib in the filtrate was quantified by HPLC (diluted as needed). In some cases, a significant drift of ±1 pH or more from the target pH was observed in the final pH after overnight equilibration.

[0367] Table 28 shows a summary of solubility data, along with previously collected data for free bases. The pH-solubility data is graphically shown in Figure 89. The profiles for each sample were consistent with the fact that basic compounds exhibited low solubility under high pH conditions and significantly improved solubility under acidic conditions. The high solubility at low pH likely suggests that lincitinib (in all forms) dissolves rapidly in the acidic environment of the stomach. Indeed, it should be noted that in most low pH systems, high initial solubility / solubility was observed, followed by precipitation of the substance from the solution after prolonged equilibrium. In some cases, precipitation did not occur, and saturation of the system was not achieved. [Table 28]

[0368] L-malate 1, esylate 1, and esylate 2 showed significantly higher solubility than free base or phosphate 1 at lower pH levels (<3). Esylates 1 and 2 showed the highest solubility between pH 3 and pH 4 compared to free base and other salts. The data suggest that these salts may increase solubility compared to free base at higher pH levels, which may be important when high-pH gastric conditions are anticipated (for example, when they occur in certain patient populations).

[0369] In addition to pH solubility data, a comparison of the equilibrium solubility of lincitinib free base and salt in two biorelevant media (Table 29), namely fasting simulated gastric juice (FaSSGF pH 1.6) and intestinal juice (FaSSIF pH 6.5), was completed. Similar to the pH-solubility data, the solubility of each substance tested was significantly higher in FaSSGF (pH 1.6) than in FaSSIF (pH 6.5) (Figure 90). The solubility of L-malate 1 and phosphate 1 was approximately the same as that of the free base, while esylate 1 and esylate 2 showed significantly higher solubility. Since a saturated solution of esylate 1 was not achieved in this study, the equilibrium solubility may be higher than the measured value. It should be noted that there was almost complete variation in pH units between samples, making direct comparisons more difficult. No clear trend was observed in the FaSSIF data; some salts (L-malate 1) showed higher solubility than free bases, while others (esylate 1) showed lower solubility.

[0370] The solubility results suggest that L-malate 1 and esylate 2 have superior solubility compared to free base. [Table 29]

[0371] Further embodiments can be provided by combining the various embodiments described above. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety. The embodiments may be modified to provide further embodiments by adopting concepts from various patents, applications, and publications as needed.

[0372] In consideration of the detailed description above, these and other modifications can be made to the embodiments. In general, the terms used in the following claims should not be construed as limiting the claims to this specification and any specific embodiments disclosed herein, but rather as encompassing all possible embodiments, along with the entire scope of equivalents to which such claims are entitled. Thus, the claims are not limited by this disclosure.

[0373] This application claims priority to U.S. Patent Application No. 63 / 509,248, filed on June 20, 2023, and U.S. Patent Application No. 18 / 341,620, filed on June 26, 2023, which are incorporated herein by reference in their entirety.

Claims

1. Crystalline esylate salt of lincitinib having the structure of formula II: 【Chemistry 1】

2. The crystalline lincitinib esylate salt according to claim 1, comprising crystalline form 2 of the lincitinib esylate salt.

3. When measured with a Cu-Kα diffractometer, the values ​​were 6.74±0.20°2θ, 8.92±0.20°2θ, 10.26±0.20°2θ, 11.04±0.20°2θ, 14.76±0.20°2θ, 16.80±0.20°2θ, 17.60±0.20°2θ, 17.90±0.20°2θ, 18.56±0.20°2θ, 20.24±0.20°2θ, 2 Crystal morphology 2 of the lincitinib esylate salt according to claim 2, characterized by a powder X-ray diffraction (PXRD) pattern including at least three peaks selected from the group consisting of 0.56±0.20°2θ, 20.74±0.20°2θ, 24.58±0.20°2θ, 25.80±0.20°2θ, 26.12±0.20°2θ, and 27.34±0.20°2θ.

4. When measured with a Cu-Kα diffractometer, the values ​​were 6.74±0.20°2θ, 8.92±0.20°2θ, 10.26±0.20°2θ, 11.04±0.20°2θ, 14.76±0.20°2θ, 16.80±0.20°2θ, 17.60±0.20°2θ, 17.90±0.20°2θ, 18.56±0.20°2θ, 20.24±0.20°2θ, 20 Crystal morphology 2 of the phosphate citinib esylate salt according to claim 2 or 3, characterized by a powder X-ray diffraction (PXRD) pattern containing at least six peaks selected from the group consisting of 56±0.20°2θ, 20.74±0.20°2θ, 24.58±0.20°2θ, 25.80±0.20°2θ, 26.12±0.20°2θ, and 27.34±0.20°2θ.

5. When measured with a Cu-Kα diffractometer, the values ​​were 6.74±0.20°2θ, 8.92±0.20°2θ, 10.26±0.20°2θ, 11.04±0.20°2θ, 14.76±0.20°2θ, 16.80±0.20°2θ, 17.60±0.20°2θ, 17.90±0.20°2θ, 18.56±0.20°2θ, 20.24±0.20°2θ, and 20.56± Crystalline form 2 of the phosphate citinib esylate salt according to any one of claims 2 to 4, characterized by a powder X-ray diffraction (PXRD) pattern containing at least 10 peaks selected from the group consisting of 0.20°2θ, 20.74±0.20°2θ, 24.58±0.20°2θ, 25.80±0.20°2θ, 26.12±0.20°2θ, and 27.34±0.20°2θ.

6. When measured with a Cu-Kα diffractometer, the values ​​were 6.74±0.20°2θ, 8.92±0.20°2θ, 10.26±0.20°2θ, 11.04±0.20°2θ, 14.76±0.20°2θ, 16.80±0.20°2θ, 17.60±0.20°2θ, 17.90±0.20°2θ, 18.56±0.20°2θ, and 20.24±0.20°2θ. Crystalline form 2 of the phosphate citinib esylate salt according to any one of claims 2 to 5, characterized by a powder X-ray diffraction (PXRD) pattern including peaks at °2θ, 20.56±0.20°2θ, 20.74±0.20°2θ, 24.58±0.20°2θ, 25.80±0.20°2θ, 26.12±0.20°2θ, and 27.34±0.20°2θ.

7. Crystal morphology 2 of the phosphate citinib esylate salt according to any one of claims 2 to 6, characterized in that when measured with a Cu-Kα diffractometer, the powder X-ray diffraction (PXRD) pattern is substantially similar to the PXRD pattern in Figure 8.

8. Crystalline form 2 of the phosphate citinib esylate salt according to any one of claims 2 to 7, characterized by a DSC thermogram substantially similar to the DSC thermogram of Figure 10.

9. Crystalline form 2 of the phosphate citinib esylate salt according to any one of claims 2 to 8, characterized by a TGA signal substantially similar to the TGA signal of Figure 10.

10. Crystal form 2 of the phosphate citinib esylate salt according to any one of claims 2 to 9, wherein the single crystal structure of esylate 2 includes an orthorhombic crystal structure.

11. The single crystal structure of esylate 2 is P2 １ 2 １ 2 １ Crystal morphology 2 of the phosphate citinib esylate salt according to any one of claims 2 to 10, including a space group.

12. Crystal morphology 2 of the phosphate citinib esylate salt according to any one of claims 2 to 11, wherein the single crystal structure of esylate 2 includes a unit cell having the following parameters: 。

13. A composition comprising a crystalline form 2 of a lincitinib esylate salt according to any one of claims 1 to 12, wherein the crystalline form 2 of the lincitinib esylate salt is present at a level of at least about 95% by weight of the total amount of the lincitinib esylate salt in the composition.

14. Crystalline L-malate salt of lincitinib having the structure of formula III: 【Chemistry 2】

15. The crystalline L-malate salt of lincitinib according to claim 14, comprising crystalline form 1 of the lincitinib L-malate salt.

16. When measured with a Cu-Kα diffractometer, the values ​​were 5.42±0.2°2θ, 8.68±0.2°2θ, 11.88±0.2°2θ, 12.40±0.2°2θ, 16.24±0.2°2θ, 17.36±0.2°2θ, 17.96±0.2°2θ, 18.22±0.2°2θ, 19.20±0.2°2θ, 20.88±0.2°2θ, 22.08±0.2°2θ, 22.58±0.2°2θ, 22. Crystalline form 1 of lincitinib L-malate salt according to claim 15, characterized by a powder X-ray diffraction (PXRD) pattern including at least three peaks selected from the group consisting of 90±0.2°2θ, 23.86±0.2°2θ, 24.44±0.2°2θ, 24.92±0.2°2θ, 25.66±0.2°2θ, 26.1±0.2°2θ, 28.58±0.2°2θ, and 29.44±0.2°2θ.

17. When measured with a Cu-Kα diffractometer, the values ​​were 5.42±0.2°2θ, 8.68±0.2°2θ, 11.88±0.2°2θ, 12.40±0.2°2θ, 16.24±0.2°2θ, 17.36±0.2°2θ, 17.96±0.2°2θ, 18.22±0.2°2θ, 19.20±0.2°2θ, 20.88±0.2°2θ, 22.08±0.2°2θ, 22.58±0.2°2θ, and 22.

90. Crystalline form 1 of lincitinib L-malate salt according to claim 15 or 16, characterized by a powder X-ray diffraction (PXRD) pattern including at least six peaks selected from the group consisting of ±0.2°2θ, 23.86±0.2°2θ, 24.44±0.2°2θ, 24.92±0.2°2θ, 25.66±0.2°2θ, 26.1±0.2°2θ, 28.58±0.2°2θ, and 29.44±0.2°2θ.

18. When measured with a Cu-Kα diffractometer, the values ​​were 5.42±0.2°2θ, 8.68±0.2°2θ, 11.88±0.2°2θ, 12.40±0.2°2θ, 16.24±0.2°2θ, 17.36±0.2°2θ, 17.96±0.2°2θ, 18.22±0.2°2θ, 19.20±0.2°2θ, 20.88±0.2°2θ, 22.08±0.2°2θ, 22.58±0.2°2θ, and 22.90±0.2°2θ. Crystalline form 1 of lincitinib L-malate salt according to any one of claims 15 to 17, characterized by a powder X-ray diffraction (PXRD) pattern including at least 10 peaks selected from the group consisting of °2θ, 23.86±0.2°2θ, 24.44±0.2°2θ, 24.92±0.2°2θ, 25.66±0.2°2θ, 26.1±0.2°2θ, 28.58±0.2°2θ, and 29.44±0.2°2θ.

19. When measured with a Cu-Kα diffractometer, the values ​​were 5.42±0.2°2θ, 8.68±0.2°2θ, 11.88±0.2°2θ, 12.40±0.2°2θ, 16.24±0.2°2θ, 17.36±0.2°2θ, 17.96±0.2°2θ, 18.22±0.2°2θ, 19.20±0.2°2θ, 20.88±0.2°2θ, 22.08±0.2°2θ, and 22.58±0.2°2θ. Crystal morphology 1 of lincitinib L-malate salt according to any one of claims 15 to 18, characterized by a powder X-ray diffraction (PXRD) pattern including peaks at 22.90±0.2°2θ, 23.86±0.2°2θ, 24.44±0.2°2θ, 24.92±0.2°2θ, 25.66±0.2°2θ, 26.1±0.2°2θ, 28.58±0.2°2θ, or 29.44±0.2°2θ.

20. Crystal morphology 1 of lincitinib L-malate salt according to any one of claims 15 to 19, characterized in that when measured with a diffractometer using Cu-Kα rays, the powder X-ray diffraction (PXRD) pattern is substantially similar to the PXRD pattern in Figure 33.

21. Crystalline form 1 of lincitinib L-malate salt according to any one of claims 15 to 20, characterized by a DSC thermogram substantially similar to the DSC thermogram of Figure 35.

22. Crystalline form 1 of lincitinib L-malate salt according to any one of claims 15 to 21, characterized by a TGA signal substantially similar to the TGA signal of Figure 35.

23. A composition comprising crystalline form 1 of lincitinib L-malate salt according to any one of claims 15 to 22, wherein the crystalline form 1 of lincitinib L-malate salt is present at a level of at least about 95% by weight of the total amount of lincitinib L-malate salt in the composition.

24. A compound according to any one of claims 1 to 22 or a composition according to claim 23, A pharmaceutical composition comprising pharmaceutically acceptable excipients.

25. A compound according to any one of claims 1 to 22 or a composition according to claim 23 or 24, Combination therapy, including TSHR inhibitors.

26. A method for treating a condition mediated by a human insulin-like growth factor 1 receptor (IGF-1R) or insulin receptor (IR), comprising administering to a subject requiring the treatment a therapeutically effective amount of a compound according to any one of claims 1 to 22 or a therapeutically effective amount of a composition according to claim 23 or 24.

27. A method for treating thyroid eye disease in a subject requiring treatment for thyroid eye disease, comprising administering to the subject requiring treatment a therapeutically effective amount of a compound according to any one of claims 1 to 22 or a therapeutically effective amount of a composition according to claim 23 or 24.

28. Use of a compound according to any one of claims 1 to 22 or a composition according to claim 23 or 24 in the treatment of a condition mediated by a human insulin-like growth factor 1 receptor (IGF-1R) or insulin receptor (IR), wherein a therapeutically effective amount of the compound according to any one of claims 1 to 22 or a therapeutically effective amount of the composition according to claim 23 or 24 is administered to a subject requiring the said therapeutically effective amount.

29. Use of a compound according to any one of claims 1 to 22 or a composition according to claim 23 or 24 in the treatment of thyroid eye disease, wherein a therapeutically effective amount of the compound according to any one of claims 1 to 22 or a therapeutically effective amount of the composition according to claim 23 or 24 is administered to a subject requiring the said therapeutically effective amount.

30. A compound according to any one of claims 1 to 22 or a composition according to claim 23 or 24, for use as a pharmaceutical.

31. A compound according to any one of claims 1 to 22 or a composition according to claim 23 or 24, for use in a subject requiring treatment for a condition mediated by a human insulin-like growth factor 1 receptor (IGF-1R) or insulin receptor (IR).

32. A compound according to any one of claims 1 to 22 or a composition according to claim 23 or 24, for use in a subject requiring the aforementioned treatment in the treatment of thyroid eye disease.

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