VORUCICLIB Polymorphs and Methods for Their Preparation and Use

Abstract

The present disclosure relates to crystalline solid forms of voruciclib (including voruciclib free base and various voruciclib salts), pharmaceutical compositions containing the crystalline solid forms of voruciclib, and methods of treating a condition or disorder by administering a pharmaceutical composition comprising a crystalline solid form of voruciclib.

Description

[0001] Field

[0002] The present disclosure provides novel polymorphs of the CDK inhibitor voruciclib and methods for their preparation and use.

[0003] Background

[0004] Certain chemical compounds, including various pharmaceuticals, may exist in polymorphic forms. Polymorphic forms generally denote different crystal forms with different physical properties, but may also include solvated or hydrated products, as well as amorphous forms (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, Q6A, version dated October 6, 1999). Differences in polymorphic forms can affect the quality and performance of a drug, including drug performance, bioavailability, stability, etc. A variety of physicochemical measurements and techniques can be used to explore and identify polymorphs, including melting point determination, infrared spectroscopy (IR), X-ray diffraction, thermal analysis (DSC, TGA, etc.), Raman spectroscopy, optical microscopy, and NMR.

[0005] Overview

[0006] The present disclosure provides polymorphs of voruciclib, such as crystal forms. In certain embodiments, the polymorphs include the free base voruciclib. In certain embodiments, the polymorphs include voruciclib salts, which include counterions corresponding to acids selected from 1,5-naphthalenedisulfonic acid, 1-hydroxy-2-naphthoic acid, benzenesulfonic acid, benzoic acid, dibenzoyl-L-tartaric acid, ethanesulfonic acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malonic acid, oxalic acid, orthophosphoric acid, sulfuric acid, p-toluenesulfonic acid, etc.

[0007] In one embodiment, the present disclosure provides a crystalline form of voruciclib, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the following: 7.30° ± 0.2°, 13.58° ± 0.2°, 14.06° ± 0.2°, 15.18° ± 0.2°, 15.66° ± 0.2°, 17.50° ± 0.2°, 18.94° ± 0.2°, 19.54° ± 0.2°, 22.22° ± 0.2°, 23.38° ± 0.2°, 24.10° ± 0.2°, 24.98° ± 0.2°, 25.94° ± 0.2°, 27.26° ± 0.2°, 28.50° ± 0.2° and 32.82° ± 0.2° 2θ. In certain embodiments, the crystalline form comprises voruciclib malonate.

[0008] In one embodiment, the present disclosure provides a crystalline form of voruciclib, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the following: 5.06° ± 0.2°, 6.42° ± 0.2°, 9.34° ± 0.2°, 10.14° ± 0.2°, 12.30° ± 0.2°, 13.66° ± 0.2°, 14.14° ± 0.2°, 15.82° ± 0.2°, 17.02° ± 0.2°, 19.74° ± 0.2°, 20.38° ± 0.2°, 21.82° ± 0.2°, 22.66° ± 0.2°, 24.62° ± 0.2°, 25.78° ± 0.2°, 26.58° ± 0.2°, 28.66° ± 0.2° and 29.98° ± 0.2° 2θ. In certain embodiments, the crystalline form comprises voruciclib dibenzoyl-tartrate.

[0009] In one embodiment, the present disclosure provides a crystalline form of voruciclib, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the following: 4.94° ± 0.2°, 6.78° ± 0.2°, 9.34° ± 0.2°, 10.94° ± 0.2°, 12.70° ± 0.2°, 13.38° ± 0.2°, 14.90° ± 0.2°, 15.66° ± 0.2°, 17.54° ± 0.2°, 18.82° ± 0.2°, 22.02° ± 0.2°, 23.98° ± 0.2°, 24.78° ± 0.2°, 25.30° ± 0.2°, 26.66° ± 0.2° and 29.98° ± 0.2° 2θ. In certain embodiments, the crystalline form comprises voruciclib phosphate.

[0010] In one embodiment, the present disclosure provides a crystalline form of voruciclib, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from: 6.86° ± 0.2°, 12.66° ± 0.2°, 13.58° ± 0.2°, 14.74° ± 0.2°, 15.98° ± 0.2°, 19.38° ± 0.2°, 23.94° ± 0.2°, 24.78° ± 0.2°, and 25.94° ± 0.2° 2θ. In certain embodiments, the crystalline form comprises voruciclib oxalate.

[0011] In one embodiment, the present disclosure provides a crystalline form of voruciclib, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from: 9.02° ± 0.2°, 10.50° ± 0.2°, 11.06° ± 0.2°, 12.30° ± 0.2°, 12.82° ± 0.2°, 13.90° ± 0.2°, 14.82° ± 0.2°, 15.30° ± 0.2°, 15.94° ± 0.2°, 17.26° ± 0.2°, 19.34° ± 0.2°, 20.62° ± 0.2°, 22.18° ± 0.2°, 22.86° ± 0.2°, 24.58° ± 0.2°, 25.42° ± 0.2°, 25.86° ± 0.2°, 27.38° ± 0.2°, and 28.66° ± 0.2° 2θ. In certain embodiments, the crystalline form comprises voruciclib naphthalenedisulfonate.

[0012] In one embodiment, the present disclosure provides a crystalline anhydrous form of voruciclib. In one embodiment, the present disclosure provides a crystalline hydrate form of voruciclib.

[0013] In one embodiment, the present disclosure provides a composition comprising a voruciclib crystalline form described herein and a pharmaceutically acceptable excipient.

[0014] In one embodiment, the present disclosure provides a method of treating a disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a composition comprising a voruciclib crystal form described herein, wherein the disease is selected from: chronic lymphocytic leukemia, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoproliferative disorder, B-cell acute lymphoblastic leukemia, Waldenström macroglobulinemia, Burkitt leukemia, Hodgkin disease, multiple myeloma, acute myeloid leukemia, juvenile myelomonocytic leukemia, hairy cell leukemia, mast cell leukemia, mastocytosis, myeloproliferative disorder (MPD), myeloproliferative neoplasm, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), myelodysplastic syndrome, chronic myeloid leukemia (BCR-ABL1-positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, primary central nervous system (CNS) lymphoma, primary multifocal lymphoma of the peripheral nervous system (PNS), thymic carcinoma, brain cancer, glioblastoma, lung cancer, squamous cell carcinoma, skin cancer (e.g., melanoma), eye cancer, retinoblastoma, uveal melanoma, oral cancer and oropharyngeal cancer, bladder cancer, gastric cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer, head and neck cancer, kidney cancer, renal cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer (e.g., metastatic bone cancer), esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, epidermoid carcinoma, AIDS-related cancer (e.g., lymphoma), virus-induced cervical cancer (human papillomavirus), nasopharyngeal carcinoma (Epstein-Barr virus), Kaposi sarcoma, primary effusion lymphoma (Kaposi sarcoma herpesvirus), hepatocellular carcinoma (hepatitis B and hepatitis C viruses), T-cell leukemia (human T-cell leukemia virus-1), benign skin hyperplasia, restenosis, benign prostatic hyperplasia, tumor angiogenesis, chronic inflammatory diseases, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, ulcerative colitis, atopic dermatitis, hidradenitis suppurativa, spondylarthritis, uveitis, Behçet's disease, polymyalgia rheumatica, giant cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidradenitis suppurativa, Sjögren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, lupus and lupus nephritis.

[0015] In one embodiment, the present disclosure provides a method of treating a hyperproliferative disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a composition comprising a voruciclib polymorph described herein, wherein the hyperproliferative disease is selected from: acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, B-cell lymphoproliferative disease, B-cell acute lymphoblastic leukemia, and Waldenström's macroglobulinemia.

[0016] In one embodiment, the present disclosure provides a method of treating a blood cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a composition comprising a voruciclib polymorph described herein. In certain embodiments, the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), and chronic lymphocytic leukemia (CLL).

[0017] In one embodiment, the present disclosure provides a composition for treating a blood cancer in a patient, the composition comprising a voruciclib polymorph described herein and a pharmaceutically acceptable excipient. In certain embodiments, the blood cancer is selected from: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), and chronic lymphocytic leukemia (CLL).

[0018] In one embodiment, the present disclosure provides a polymorph of voruciclib HCl or a polymorph of voruciclib free base, each characterized by an X-ray diffraction pattern that is substantially consistent with Figure 1 an X-ray diffraction pattern.

[0019] In one embodiment, the present disclosure provides a polymorph of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with one or more Figure 2 X-ray diffraction patterns.

[0020] In one embodiment, the present disclosure provides a polymorph of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with Figure 4 an X-ray diffraction pattern.

[0021] In one embodiment, the present disclosure provides a polymorph of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with Figure 8An X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns.

[0022] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with Figure 11 An X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns.

[0023] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with Figure 12A and 12B An X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns.

[0024] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with Figure 14 An X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns.

[0025] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with Figure 18 An X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns.

[0026] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with Figure 22 An X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns.

[0027] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with Figure 26 An X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns.

[0028] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with Figure 29 An X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns.

[0029] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with Figure 32 An X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns.

[0030] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent withFigure 36 an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of

[0031] In one embodiment, the present disclosure provides a crystal form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 40 an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of

[0032] In one embodiment, the present disclosure provides a crystal form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 45 an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of

[0033] In one embodiment, the present disclosure provides a crystal form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 49 an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of

[0034] In one embodiment, the present disclosure provides a crystal form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 53 an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of

[0035] In one embodiment, the present disclosure provides a crystal form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 57 an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of

[0036] In one embodiment, the present disclosure provides a crystal form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 61 an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of

[0037] In one embodiment, the present disclosure provides a crystal form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 65 an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of

[0038] In one embodiment, the present disclosure provides a crystal form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 69 an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of

[0039] In one embodiment, the present disclosure provides a crystal form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns ofFigure 73 An X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns.

[0040] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns of Figure 77 An X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns.

[0041] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns of Figure 81 An X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns.

[0042] In one embodiment, the present disclosure provides a crystalline form of voruciclib HCl, characterized by an X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns of Figure 82 An X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns.

[0043] In one embodiment, the present disclosure provides a crystalline form of voruciclib free base, characterized by an X-ray diffraction pattern that is substantially identical to the X-ray diffraction patterns of Figure 85 and 142 An X-ray diffraction pattern that is substantially identical.

[0044] In one embodiment, the present disclosure provides a crystalline form of voruciclib free base, characterized by an Figure 89 H-NMR spectrum that is substantially identical to the 1 1H-NMR spectrum. 1 1H-NMR spectrum.

[0045] In one embodiment, the present disclosure provides a crystalline form of voruciclib malonate, characterized by an X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns of Figure 90 and 91 An X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns.

[0046] In one embodiment, the present disclosure provides a crystalline form of voruciclib malonate, characterized by an Figure 94 (Mao1) 1 1H-NMR spectrum that is substantially identical to the 1 1H-NMR spectrum.

[0047] In one embodiment, the present disclosure provides a crystalline form of voruciclib dibenzoyl-L-tartrate, characterized by an X-ray diffraction pattern that is substantially identical to the X-ray diffraction patterns of Figure 96 and 97X-ray diffraction patterns that are substantially identical to one or more X-ray diffraction patterns.

[0048] In one embodiment, the present disclosure provides a crystalline form of voruciclib dibenzoyl-L-tartrate, characterized by an Figure 100 (DiTr1) 1 1H-NMR spectrum that is substantially identical to the 1 1H-NMR spectrum.

[0049] In one embodiment, the present disclosure provides a crystalline form of voruciclib phosphate, characterized by an X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns of Figure 102 and 103 .

[0050] In one embodiment, the present disclosure provides a crystalline form of voruciclib phosphate, characterized by an Figure 106 (Pho1) 1 1H-NMR spectrum that is substantially identical to the 1 1H-NMR spectrum.

[0051] In one embodiment, the present disclosure provides a crystalline form of voruciclib oxalate, characterized by an X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns of Figure 108 .

[0052] In one embodiment, the present disclosure provides a crystalline form of voruciclib oxalate, characterized by an Figure 111 (Oxa) 1 1H-NMR spectrum that is substantially identical to the 1 1H-NMR spectrum.

[0053] In one embodiment, the present disclosure provides a crystalline form of voruciclib naphthalenedisulfonate, characterized by an X-ray diffraction pattern that is substantially identical to one or more X-ray diffraction patterns of Figure 113 and 114 .

[0054] In one embodiment, the present disclosure provides a crystalline form of voruciclib naphthalenedisulfonate, characterized by an Figure 117 (Nds1a) 1 1H-NMR spectrum that is substantially identical to the 1 1H-NMR spectrum.

[0055] In one embodiment, the present disclosure provides a crystal form of voruciclib ethanesulfonate, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 118 ..

[0056] In one embodiment, the present disclosure provides a crystal form of voruciclib ethanesulfonate, characterized by an Figure 120 (Esy1) 1 1H-NMR spectrum that is substantially consistent with the 1 1H-NMR spectrum..

[0057] In one embodiment, the present disclosure provides a crystal form of voruciclib 1-hydroxy-2-naphthoate, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 121 ..

[0058] In one embodiment, the present disclosure provides a crystal form of voruciclib benzoate, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 123 and 124 ..

[0059] In one embodiment, the present disclosure provides a crystal form of voruciclib benzenesulfonate, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 126 ..

[0060] In one embodiment, the present disclosure provides a crystal form of voruciclib gentisate, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 128 and 129 ..

[0061] In one embodiment, the present disclosure provides a crystal form of voruciclib hydrobromide, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 131 ..

[0062] In one embodiment, the present disclosure provides a crystal form of voruciclib maleate, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 133 and 134 ..

[0063] In one embodiment, the present disclosure provides a crystalline form of voruciclib sulfate, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 136 and 137 .

[0064] In one embodiment, the present disclosure provides a crystalline form of voruciclib tosylate, characterized by an X-ray diffraction pattern that is substantially consistent with one or more X-ray diffraction patterns of Figure 139 and 140 . BRIEF DESCRIPTION OF THE DRAWINGS

[0066] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the accompanying drawings.

[0067] Figure 1 Illustrates the comparison of the HR powder diffraction patterns of five different batches of voruciclib HCl with the powder pattern of Form 1 recorded in a previous study. From bottom to top: Form 1 - reference, #1694M - 1401, #1694M - 1301, #1694M - 1201, #P1446A - 05_EN027, and #P1446A - 05_EN017. The orange regions highlight the diffraction peaks that can be attributed to the crystalline impurities in batches 1694M - 1201 and P1446A - 05_EN027, while the gray region highlights the crystalline phase detected only in batch 1694M - 1301.

[0068] Figure 2 Illustrates the DSC traces (heating rate 10 °C / min) of five batches of voruciclib HCl. An endothermic event related to melting / decomposition was observed at approximately 263 °C. Batch 1694M - 1401 (red), P1446A - 05_EN027 (black), 1694M - 1201 (green), P1446A - 05_EN017 (purple), and 1694M - 1301 (blue).

[0069] Figure 3 Illustrates the TGA analysis (heating rate 10 °C / min) of five batches of voruciclib HCl. The mass loss before decomposition varies between 0.3 - 0.6%. Decomposition starts at approximately 250 °C. Batch P1446A - 05_EN017 (brown), P1446A - 05_EN027 (purple), 1694M - 1201 (green), 1694M - 1301 (blue), and 1694M - 1401 (red).

[0070] Figure 4Illustrated is the high-throughput XRPD of voruciclib HCl, batch 1694M-1301, starting material for screening, Form 1.

[0071] Figure 5 Illustrated is the DSC trace (heating rate 10 °C / min) of voruciclib HCl, batch 1694M-1301, starting material. The endothermic event at Tpeak 263.4 °C can be attributed to the melting / decomposition of the compound.

[0072] Figure 6 Illustrated is the TGMS analysis (heating rate 10 °C / min) of voruciclib HCl, batch 1694M-1301, starting material. A 0.3% mass loss was observed prior to decomposition. Decomposition started at approximately 250 °C, accompanied by an endothermic event in the heat flow signal.

[0073] Figure 7 illustrates the LCMS analysis of voruciclib HCL, batch 1694M-1301, starting material. The peak corresponding to the API had a retention time of 6.3 min ( Figure 7A ), and the positive mass spectrum showed an ion with an m / z of 470.1 (M+H) + ). Figure 7B )

[0074] Figure 8 Illustrated is the comparison of the HR XRPD of voruciclib HCl Form 1 used in high-pressure studies. From bottom to top: Form 1 - reference, Exp.ID Gen13 (10 tons, 1 min, RT), Exp.ID Gen14 (10 tons, 10 min, RT), Exp.ID Gen15 (10 tons, 1 min, 80 °C) and Exp.ID Gen16 (10 tons, 10 min, 80 °C).

[0075] Figure 9 Illustrated is the Rietveld analysis of a sample hand-ground with a mortar and pestle for approximately 5 min, including the calculation of the amorphous portion based on the background line. The black line represents the obtained powder pattern, the red is the calculation result and the grey line is the difference between them. The blue bars at the bottom show the peak positions of the matching unit cell. The purple line represents the calculated amorphous portion (10 ± 2%) of the sample.

[0076] Figure 10The Rietveld analysis of a sample milled for 5 min at 30 Hz using a Retch mill is shown, including the calculation of the amorphous fraction based on the background line. The black line represents the obtained powder pattern, the red is the calculated result and the grey line is the difference between them. The blue bars at the bottom show the peak positions of the matching unit cells (cell). The purple line represents the calculated amorphous fraction (7 ± 2%) of the sample.

[0077] Figure 11 The overlay of XRPDs of the solids obtained by freeze-drying compared to the starting material is shown. From bottom to top: Form 1, starting material; Form 2 obtained from MeOH / water (90 / 10 v / v), amorphous (Am) obtained from 1,4-dioxane / water (90 / 10 v / v), and amorphous (Am) obtained from THF / water (90 / 10 v / v).

[0078] Figure 12A and 12B The HT-XRPD of the unique forms identified during the screening is shown (from bottom to top); Figure 12A : Form 1 starting material, Form 2 obtained from thermal cycling in 1,4-dioxane (Exp.ID TCP15), Form 3 obtained from thermal cycling in IPA (Exp.ID TCP13), Form 4 obtained from solvent equilibration in THF at room temperature (Exp.ID SLP30), Form 5 obtained from thermal cycling in 1,4-dioxane (Exp.ID TCP8), Form 6 (poorly crystalline) obtained from solvent equilibration in water at 50 °C (Exp.ID SLP65), Form 7 obtained from thermal cycling in 1,2-dimethoxyethane (Exp.ID TCP5), Form 8 obtained from evaporation crystallization in acetone (Exp.ID ECP34), Form 9 obtained from ambient-dried solids formed by cooling crystallization in DMF (Exp.ID PSM60), Form 10 obtained from vacuum-dried solids formed by cooling crystallization in DMF (Exp.ID PSM60); Figure 12B:Form 11 obtained from ambient-dried solids formed by cooling crystallization in DMA (Exp. ID PSM59), Form 12 obtained from the mother liquor formed by thermal cycling in acetonitrile / water 90 / 10 (v / v) after evaporation (Exp. ID TCP20 ML), Form 13 obtained from cooling crystallization in ethanol (Exp. ID PSM52), Form 14 obtained from thermal cycling in acetonitrile / water 90 / 10 (v / v) (Exp. ID TCP20), Form 15 obtained from vapor diffusion from DMF / 1,4-dioxane into solution (Exp. ID VDL8), Form 16 obtained from evaporation crystallization in DMSO (Exp. ID ECP18), Form 17 obtained from anti-solvent addition of TFE / heptane, Form 18 obtained from ambient-dried solids formed by anti-solvent addition of DMF / isopropyl acetate, Form 19 obtained from evaporation crystallization in methanol / diisopropyl ether 20 / 80, and Form 20 obtained after conversion of Form 10 after AAC.

[0079] Figure 13 The temperature profile of the thermal cycling experiment is illustrated.

[0080] Figure 14 The overlay of HT-XRPD patterns of the material (Exp. ID SLP19) obtained from solvent equilibration experiments in ethanol before and after exposure to AAC is illustrated.

[0081] Figure 15 The TGMS analysis of Form 1 (Exp. ID SLP19) is illustrated (heating rate 10 °C / min). A mass loss of 0.2% is most likely related to residual solvent or moisture.

[0082] Figure 16 The DSC analysis of Form 1 (Exp. ID SLP19) is illustrated (heating rate 10 °C / min). An endothermic event is observed, most likely related to melting and decomposition.

[0083] Figure 17 The HPLC chromatogram of Form 1 (Exp. ID SLP19) is illustrated. The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0084] Figure 18 The overlay of HT-XRPD patterns of the material (Exp. ID TCP2) obtained from thermal cycling experiments in 1,4-dioxane / water 95 / 5 before and after exposure to AAC is illustrated.

[0085] Figure 19Illustrated is the TGMS analysis of Form 2 (Exp.ID TCP15) (heating rate 10 °C / min). 5.4% of the total mass loss is related to solvent loss (equivalent to 0.3 dioxane molecules).

[0086] Figure 20 Illustrated is the DSC analysis of Form 2 (Exp.ID TCP15) (heating rate 10 °C / min). Two broad endothermic events were observed, related to solvent loss. The small endothermic event at 165 °C may be the transition to Form 1, as the small endothermic event observed at 259 °C coincides with the melting of Form 1.

[0087] Figure 21 Illustrated is the HPLC chromatogram of Form 2 (Exp.ID TCP5). The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0088] Figure 22 Illustrated is the overlay of HT-XRPD patterns of the material (Exp.ID TCP13) obtained from the thermal cycling experiment in IPA / water 95 / 5, dried under ambient conditions and under vacuum before and after exposure to AAC.

[0089] Figure 23 Illustrated is the TGMS analysis of Form 3 (Exp.ID TCP13) (heating rate 10 °C / min). 13.2% of the mass loss is related to solvent loss.

[0090] Figure 24 Illustrated is the DSC analysis of Form 3 (Exp.ID TCP13) (heating rate 10 °C / min). One broad endothermic event was observed, most likely related to solvent loss. A very small endotherm was observed at 259 °C, although most likely the entire batch of material had become amorphous after solvent loss.

[0091] Figure 25 Illustrated is the HPLC chromatogram of Form 3 (Exp.ID TCP13). The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0092] Figure 26 Illustrated is the overlay of HT-XRPD patterns of the material (Exp.ID SLP30) obtained from the solvent equilibration experiment in THF, dried under ambient (purple) and under vacuum (blue) and after exposure to AAC (green).

[0093] Figure 27Illustrated is the TGMS analysis (heating rate 10 °C / min) of Form 4 (Exp.ID SLP30). A 4.3% mass loss is associated with solvent loss. The following exothermic and endothermic events are attributed to recrystallization and melting / decomposition, respectively.

[0094] Figure 28 Illustrated is the DSC analysis (heating rate 10 °C / min) of Form 4 (Exp.ID SLP30). Three broad endothermic events are observed, associated with solvent loss. Subsequently, an exothermic recrystallization event at 217 °C, an endothermic melting (at 260 °C), and a decomposition event are observed.

[0095] Figure 29 Illustrated is the overlay of XRPDs of the solid phases obtained from Exp.ID SLP30 (bottom to top): Form 4a (ambient-dried solid), Form 4 (vacuum-dried solid), and Form 4b obtained after a cyclic DSC experiment to 140 °C.

[0096] Figure 30 Illustrated is the TGMS analysis of the solid obtained after a cyclic DSC experiment on Form 4 to 155 °C.

[0097] Figure 31 Illustrated is the HPLC chromatogram of Form 4 (Exp.ID SLP30). The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0098] Figure 32 Illustrated is the overlay of HT-XRPD patterns of the material obtained from a thermal cycling experiment in 1,4-dioxane (Exp.ID TCP8), dried under ambient and vacuum conditions, before and after exposure to AAC.

[0099] Figure 33 Illustrated is the TGMS analysis (heating rate 10 °C / min) of Form 5 (Exp.ID TCP8). A 9.4% total mass loss is associated with solvent loss.

[0100] Figure 34 Illustrated is the DSC analysis (heating rate 10 °C / min) of Form 5 (Exp.ID TCP8). One broad endothermic event is observed, most likely associated with solvent loss, followed by a small endotherm at 259 °C and multiple decomposition events.

[0101] Figure 35 Illustrated is the HPLC chromatogram of Form 5 (Exp.ID TCP8). The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0102] Figure 36Illustrated is the overlay of HT-XRPD patterns of the substance (Exp.ID SLP65) obtained from solvent equilibrium experiments in water, dried under ambient conditions and in vacuo, before and after exposure to AAC.

[0103] Figure 37 Illustrated is the TGMS analysis (heating rate 10 °C / min) of Form 6 (Exp.ID SLP65). A 2.1% mass loss is associated with the loss of water.

[0104] Figure 38 Illustrated is the DSC analysis (heating rate 10 °C / min) of Form 6 (Exp.ID SLP65). A broad endothermic event is observed at 151 °C, associated with the loss of water. The thermal event above 220 °C is associated with the decomposition process.

[0105] Figure 39 Illustrated is the HPLC chromatogram of Form 6 (Exp.ID SLP65). The API peak appears at 6.3 minutes with 100% chemical purity (area %).

[0106] Figure 40 Illustrated is the overlay of HT-XRPD patterns of the substance (Exp.ID TCP5) obtained from thermal cycling experiments in 1,2-dimethoxyethane, before and after exposure to AAC.

[0107] Figure 41 Illustrated is the TGMS analysis (heating rate 10 °C / min) of Form 7 (Exp.ID TCP5). A 2.0% mass loss is most likely associated with solvent loss and / or water.

[0108] Figure 42 Illustrated is the DSC analysis (heating rate 10 °C / min) of Form 7 (Exp.ID TCP5). An endothermic event is observed, most likely associated with solvent loss, followed by an exothermic recrystallization event of Form 1 and melting and decomposition.

[0109] Figure 43 Illustrated is the TGMS analysis (heating rate 10 °C / min) of Form 7 after cyclic DSC to 155 °C. A 2.3% mass loss is most likely associated with the loss of water.

[0110] Figure 44 Illustrated is the HPLC chromatogram of Form 7 (Exp.ID TCP5). The API peak appears at 6.3 minutes with 100% chemical purity (area %).

[0111] Figure 45The overlay of the HT-XRPD patterns of the substance (Exp.ID ECP34) obtained from the evaporation experiment in methanol / acetone 75 / 25 before and after exposure to AAC is shown.

[0112] Figure 46 The TGMS analysis (heating rate 10 °C / min) of Form 8 (Exp.ID ECP34) is shown. A mass loss of 5.3% is most likely related to solvent and / or water loss.

[0113] Figure 47 The DSC analysis (heating rate 10 °C / min) of Form 8 (Exp.ID ECP34) is shown. A broad endothermic event is observed, most likely related to solvent loss, followed by a small endothermic event possibly related to melting.

[0114] Figure 48 The HPLC chromatogram of Form 8 (Exp.ID ECP34) is shown. The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0115] Figure 49 The overlay of the HT-XRPD patterns of the solid (Exp.ID PSM60) obtained from the cooling crystallization experiment in N,N-dimethylformamide before and after exposure to AAC, dried under ambient and under vacuum, is shown.

[0116] Figure 50 The TGMS analysis (heating rate 10 °C / min) of Form 10 (Exp.ID PSM60) is shown. A mass loss of 20.8% is related to solvent loss.

[0117] Figure 51 The DSC analysis (heating rate 10 °C / min) of Form 10 (Exp.ID PSM60) is shown. An endothermic event is observed, most likely related to solvent loss, followed by a second endothermic event related to the melting of Form 1.

[0118] Figure 52 The HPLC chromatogram of Form 10 (Exp.ID PSM60) is shown. The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0119] Figure 53 The overlay of the HT-XRPD patterns of the substance (Exp.ID PSM59) obtained from the cooling crystallization experiment in N,N-dimethylacetamide before and after exposure to AAC is shown.

[0120] Figure 54Illustrated is the TGMS analysis of Form 11 (Exp.ID PSM59) (heating rate 10 °C / min). A 9.1% mass loss is most likely related to solvent loss.

[0121] Figure 55 Illustrated is the DSC analysis of Form 11 (Exp.ID PSM59) (heating rate 10 °C / min). Two endothermic events were observed, most likely related to solvent loss and melting of Form 1, respectively.

[0122] Figure 56 Illustrated is the HPLC chromatogram of Form 11 (Exp.ID PSM59). The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0123] Figure 57 Illustrated is the overlay of HT-XRPD patterns of the material (Exp.ID TCP20_ML) obtained from the mother liquor of the thermal cycling experiment in ACN / water 90 / 10 before and after exposure to AAC.

[0124] Figure 58 Illustrated is the TGMS analysis of Form 12 (Exp.ID TCP20_ML) (heating rate 10 °C / min). A 5.9% mass loss is related to solvent loss.

[0125] Figure 59 Illustrated is the DSC analysis of Form 12 (Exp.ID TCP20_ML) (heating rate 10 °C / min). The endothermic event observed between 25 - 180 °C is most likely related to solvent loss, while the small endothermic event observed at 255 °C may be related to melting of Form 1.

[0126] Figure 60 Illustrated is the HPLC chromatogram of Form 12 (Exp.ID TCP20_ML). The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0127] Figure 61 Illustrated is the overlay of HT-XRPD patterns of the material (Exp.ID PSM52) obtained from the cooling-evaporation crystallization experiment in ethanol before and after exposure to AAC.

[0128] Figure 62 Illustrated is the TGMS analysis of Form 13 (Exp.ID PSM52) (heating rate 10 °C / min). A 6.3% mass loss is most likely related to solvent or water.

[0129] Figure 63The DSC analysis (heating rate 10 °C / min) of Form 13 (Exp. ID AS5 after AAC) is shown. Several broad endothermic events were observed, most likely related to solvent loss, followed by a small endothermic event related to the melting of Form 1.

[0130] Figure 64 The HPLC chromatogram of Form 13 (Exp. ID PSM52) is shown. The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0131] Figure 65 The overlay of HT-XRPD patterns of the solid (Exp. ID TCP20) obtained from the thermal cycling experiment in ACN / water 90 / 10, dried under ambient and under vacuum before and after exposure to AAC is shown.

[0132] Figure 66 The TGMS analysis (heating rate 10 °C / min) of Form 14 (Exp. ID TCP20) is shown. A 2.5% mass loss is most likely related to solvent loss.

[0133] Figure 67 The DSC analysis (heating rate 10 °C / min) of Form 14 (Exp. ID TCP20) is shown. Two endothermic events were observed.

[0134] Figure 68 The HPLC chromatogram of Form 14 (Exp. ID TCP20) is shown. The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0135] Figure 69 The overlay of HT-XRPD patterns of the substance (Exp. ID VDL8) obtained from the vapor to liquid diffusion experiment in N,N-dimethylformamide / 1,4-dioxane before and after exposure to AAC is shown.

[0136] Figure 70 The TGMS analysis (heating rate 10 °C / min) of Form 15 (Exp. ID VDL8) is shown. A 13.2% mass loss is related to solvent loss.

[0137] Figure 71 The DSC analysis (heating rate 10 °C / min) of Form 15 (Exp. ID VDL8) is shown. Two endothermic events were observed, most likely related to solvent loss and the melting of Form 1 respectively.

[0138] Figure 72The HPLC chromatogram of Form 15 (Exp.ID VDL8) is shown. The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0139] Figure 73 The overlay of HT-XRPD patterns of the material (Exp.ID ECP18) obtained from evaporation experiments in DMSO before and after exposure to AAC is shown.

[0140] Figure 74 The TGMS analysis (heating rate 10 °C / min) of Form 16 (Exp.ID ECP18) is shown. A 16.6% mass loss is associated with solvent loss.

[0141] Figure 75 The DSC analysis (heating rate 10 °C / min) of Form 16 (Exp.ID ECP18) is shown. Two endothermic events are observed, most likely associated with solvent loss and melting of Form 1, respectively.

[0142] Figure 76 The HPLC chromatogram of Form 16 (Exp.ID ECP18) is shown. The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0143] Figure 77 The overlay of HT-XRPD patterns of the material (Exp.ID AS3) obtained from anti-solvent experiments in TFE / heptane dried under ambient and under vacuum before and after exposure to AAC is shown.

[0144] Figure 78 The TGMS analysis (heating rate 10 °C / min) of Form 17 (Exp.ID AS3) is shown. A 16.9% mass loss is associated with solvent loss.

[0145] Figure 79 The DSC analysis (heating rate 10 °C / min) of Form 17 (Exp.ID AS3) is shown. Three endothermic events are observed, most likely associated with solvent loss. The final endotherm at 257 °C is associated with melting of Form 1.

[0146] Figure 80 The HPLC chromatogram of Form 17 (Exp.ID AS3) is shown. The API peak appears at 6.3 minutes with 100% chemical purity (area percentage).

[0147] Figure 81Illustrated is the overlay of HT-XRPD patterns of the solid (Exp.ID AS7) obtained in the anti-solvent experiment in DMF / isopropyl acetate dried in an environment and in vacuo before and after exposure to AAC.

[0148] Figure 82 Illustrated is the overlay of HT-XRPD patterns of the substance (Exp.ID ECP45 / PSM13) obtained from the evaporation experiment in methanol / diisopropyl ether 20 / 80 before and after exposure to AAC.

[0149] Figure 83 Illustrated is the TGMS analysis (heating rate 10 °C / min) of Form 19 (Exp.ID ECP45 / PSM13). A mass loss of 4.5% is most likely related to solvent loss, followed by an exothermic recrystallization event and an endothermic melting event of Form 1.

[0150] Figure 84 Illustrated is the molecular structure of voruciclib (free base); the free base has a basic moiety with a pK of 6.46 a .

[0151] Figure 85 Illustrated are the high-throughput XRPD of voruciclib free base, starting material, and Form A.

[0152] Figure 86 Illustrated are the DSC traces (heating rate 10 °C / min) of voruciclib free base, starting material; a small endothermic event was observed at 99 °C, followed by a small endothermic event at 214 °C and a final melting at 225 °C.

[0153] Figure 87 Illustrated are the TGMS data (heating rate 10 °C / min) of voruciclib free base, starting material; a 0.3% mass loss was observed before decomposition; decomposition started at approximately 240 °C; the mass loss is most likely related to residual solvent / moisture, and the onset of decomposition was confirmed by MS data; the heat flow signal shows an endothermic event due to melting at approximately 220 °C.

[0154] Figure 88 Illustrated is the HPLC analysis of voruciclib free base, starting material; the peak corresponding to the free base has a retention time of 6.1 min and shows a chemical purity of 99.3% (area %).

[0155] Figure 89 Illustrated is the 1 1H-NMR spectrum of voruciclib free base, starting material.

[0156] Figure 90 The XRPD patterns (from bottom to top) of the following substances are shown: Form A starting material, malonic acid reference, Mao1 obtained from ethanol (Exp.ID SSm53), and Mao2 obtained from THF (Exp.ID SSm20).

[0157] Figure 91 The XRPD patterns of Mao1 (Exp.ID SSm53) before and after AAC are shown; the starting material and malonic acid are shown as references.

[0158] Figure 92 The TGMS analysis (heating rate 10 °C / min) of Mao1 (Exp.ID SSm53) obtained from malonic acid and ethanol is shown; a 0.2% mass loss was observed before melting / decomposition started at approximately 140 °C.

[0159] Figure 93 The DSC analysis (heating rate 10 °C / min) of Mao1 (Exp.ID SSm53) obtained from malonic acid and ethanol is shown; an endothermic event with a peak temperature at 180 °C was observed, which was attributed to melting / decomposition.

[0160] Figure 94 The 1 1H-NMR spectra of Mao1 (Exp.ID SSm53, bottom) obtained from malonic acid and ethanol are shown compared to the starting material (top).

[0161] Figure 95 The HPLC chromatogram of Mao1 (Exp.ID SSm53) obtained from malonic acid and ethanol is shown.

[0162] Figure 96 The XRPD patterns (from bottom to top) of the following substances are shown: Form A starting material, dibenzoyl-L-tartaric acid reference, DiTr1 obtained from ethanol (Exp.ID SSm46), and the mixture DiTr1+DiTr2 obtained from THF (Exp.ID SSm13).

[0163] Figure 97 The XRPD patterns of DiTr1 (Exp.ID SSm46) before and after AAC are shown; the starting material and dibenzoyl-L-tartaric acid are shown as references.

[0164] Figure 98 The TGMS analysis (heating rate 10 °C / min) of DiTr1 (Exp.ID SSm46) obtained from dibenzoyl-L-tartaric acid in ethanol is shown; a 0.9% mass loss was observed before melting / decomposition started at approximately 180 °C.

[0165] Figure 99 The DSC analysis (heating rate 10 °C / min) of DiTr1 (Exp.ID SSm46) obtained from dibenzoyl-L-tartaric acid in ethanol is shown; a small endothermic event was observed at 172 °C before the decomposition process with a peak temperature of 207 °C.

[0166] Figure 100 Shown is the 1 1H-NMR spectrum of DiTr1 (Exp.ID SSm46, bottom) obtained from dibenzoyl-L-tartaric acid and ethanol compared to the starting material (top).

[0167] Figure 101 The HPLC chromatogram of DiTr1 (Exp.ID SSm46) obtained from dibenzoyl-L-tartaric acid and ethanol is shown.

[0168] Figure 102 The XRPD patterns (from bottom to top) of the following are shown: Form A starting material, Pho1 (Exp.ID SSm81) obtained from acetone, and poorly crystalline Pho2 (Exp.ID SSm15) obtained from THF.

[0169] Figure 103 The XRPD patterns of Pho1 (Exp.ID SSm81) before and after AAC are shown; the starting material and phosphoric acid are shown as references.

[0170] Figure 104 The TGMS analysis (heating rate 10 °C / min) of Pho1 (Exp.ID SSm81) obtained with phosphoric acid in acetone is shown; a 1.9% mass loss was observed between 25 - 160 °C before melting; thermal decomposition started at approximately 200 °C.

[0171] Figure 105 The DSC analysis (heating rate 10 °C / min) of Pho1 (Exp.ID SSm81) obtained with phosphoric acid in acetone is shown.

[0172] Figure 106 Shown is the 1 1H-NMR spectrum of Pho1 (Exp.ID SSm81, bottom) obtained from phosphoric acid and acetone compared to the starting material (top).

[0173] Figure 107 The HPLC chromatogram of Pho1 (Exp.ID SSm81) obtained from phosphoric acid and acetone is shown.

[0174] Figure 108Illustrated are the XRPD patterns of Oxa1 (Exp.ID SSm12) before and after AAC; the starting material and oxalic acid are shown as references.

[0175] Figure 109 Illustrated is the TGMS analysis of Oxa1 (Exp.ID SSm12) obtained with oxalic acid in THF (heating rate 10 °C / min); a 1.4% mass loss was observed between 25 - 100 °C, and a second 1.9% mass loss between 100 - 150 °C; the mass loss above 160 °C is related to the decomposition of the salt.

[0176] Figure 110 Illustrated is the DSC analysis of Oxa1 (Exp.ID SSm12) obtained with oxalic acid in THF (heating rate 10 °C / min); the first two endothermic events are due to solvent / water loss, while the broad endothermic event at about 213 °C is related to the decomposition of the salt.

[0177] Figure 111 Illustrated is the 1 1H-NMR spectrum of Oxa1 (Exp.ID SSm12, bottom) obtained from oxalic acid and THF compared to the starting material (top).

[0178] Figure 112 Illustrated is the HPLC chromatogram of Oxa1 (Exp.ID SSm12) obtained from oxalic acid and THF.

[0179] Figure 113 Illustrated are the XRPD patterns (from bottom to top) of the following: form A starting material, 1,5-naphthalenedisulfonic acid reference, Nds1a obtained from ethanol, solid phase (Exp.ID SSm35), Nds1b obtained from acetone, solid phase (Exp.ID SSm68), Nds2 obtained from ethanol, liquid phase (Exp.ID SSm35), Nds3 obtained from THF (Exp.ID SSm2), Nds4 obtained from THF, solid phase (Exp.ID SSm3), and Nds5 obtained by the conversion of Nds2 after AAC (liquid phase of SSm68 after AAC).

[0180] Figure 114 Illustrated are the XRPD patterns of Nds1a (Exp.ID SSm35) before and after AAC; the starting material and 1,5-naphthalenedisulfonic acid are shown as references.

[0181] Figure 115Illustrated is the TGMS analysis (heating rate 10 °C / min) of Nds1a (Exp.ID SSm35) obtained from 1,5-naphthalenedisulfonic acid in ethanol; due to residual solvent / water, a 1.1% mass loss was observed between 25 - 100 °C; decomposition started at approximately 250 °C.

[0182] Figure 116 Illustrated is the DSC analysis (heating rate 10 °C / min) of Nds1a (Exp.ID SSm35) obtained from 1,5-naphthalenedisulfonic acid in ethanol; a series of small broad endothermic events were observed between 25 - 100 °C, related to the loss of residual solvent.

[0183] Figure 117 Illustrated is the 1 1H-NMR spectrum of Nds1a (Exp.ID SSm35, bottom) obtained from 1,5-naphthalenedisulfonic acid and ethanol compared to the starting material (top).

[0184] Figure 118 Illustrated are the XRPD patterns (from bottom to top) of the following: starting material of Form A, Esy1 or Form D (Exp.ID SSm16) obtained from ethanesulfonic acid in THF, Form D (Exp.ID SSm44 liquid phase) obtained from oxalic acid after evaporation of ethanol, and Form D (Exp.ID SSm48) obtained from phosphoric acid in ethanol.

[0185] Figure 119 Illustrated is the TGMS analysis (heating rate 10 °C / min) of Esy1 / Form D (Exp.ID SSm16) obtained from ethanesulfonic acid in THF; a 4.6% mass loss was observed between 25 - 200 °C due to solvent or water; decomposition started at approximately 250 °C.

[0186] Figure 120 Illustrated is the 1 1H-NMR spectrum of Esy1 / Form D (Exp.ID SSm16, bottom) obtained from ethanesulfonic acid and THF compared to the starting material (top).

[0187] Figure 121 Illustrated are the XRPD patterns of Xin1 (Exp.ID SSm19) obtained from THF before and after AAC; the starting material and 1-hydroxy-2-naphthoic acid are shown as references.

[0188] Figure 122 Illustrated is the TGMS analysis (heating rate 10 °C / min) of Xin1 (Exp.ID SSm19) obtained from 1-hydroxy-2-naphthoic acid and THF; a 12% mass loss was observed between 25 - 200 °C, related to the loss of solvent and the start of decomposition.

[0189] Figure 123 The XRPD patterns (from bottom to top) of the following substances are shown: Form A starting material, benzoic acid reference, Ben2 (Exp. ID SSm63) obtained from acetone, and Mao2 (Exp. ID SSm20) obtained from THF.

[0190] Figure 124 The XRPD patterns of Ben2 (Exp. ID SSm63) before and after AAC are shown; the starting material and benzoic acid are shown as references.

[0191] Figure 125 The TGMS analysis (heating rate 10 °C / min) of Ben2 (Exp. ID SSm63) obtained with benzoic acid and ethanol is shown.

[0192] Figure 126 The XRPD patterns of the solid (Exp. ID SSm10) obtained from THF before and after AAC are shown; the starting material and benzenesulfonic acid are shown as references.

[0193] Figure 127 The TGMS analysis (heating rate 10 °C / min) of Bes1 (Exp. ID SSm10) obtained with benzenesulfonic acid and THF is shown; an 8.1% mass loss between 25 - 180 °C was observed due to the loss of THF, followed by decomposition at approximately 230 °C.

[0194] Figure 128 The XRPD patterns (from bottom to top) of the following substances are shown: Form A starting material, gentisic acid reference, Gen1 (Exp. ID SSm21) obtained from THF, and Gen2_lc (solid phase) (Exp. ID SSm54) obtained from ethanol.

[0195] Figure 129 The XRPD patterns of Gen1 (Exp. ID SSm21) before and after AAC are shown; the starting material and gentisic acid are shown as references.

[0196] Figure 130 The TGMS analysis (heating rate 10 °C / min) of Gen1 (Exp. ID SSm21) obtained with gentisic acid and THF is shown; a 9.2% mass loss was observed between 25 - 200 °C, followed by thermal decomposition.

[0197] Figure 131 The XRPD patterns of HBr1 (Exp. ID SSm34) before and after AAC are shown; the starting material and hydrobromic acid are shown as references.

[0198] Figure 132 The TGMS analysis (heating rate 10 °C / min) of HBr1 (Exp.ID SSm34) obtained with hydrobromic acid and ethanol is shown; a 5.9% mass loss was observed, accompanied by several endothermic events in the heat flow signal; thermal decomposition was observed at approximately 240 °C.

[0199] Figure 133 The XRPD patterns (from bottom to top) of the following are shown: Form A starting material, maleic acid reference, Mae1 (Exp.ID SSm14) obtained from THF, and Mae2 (Exp.ID SSm47) obtained from THF.

[0200] Figure 134 The XRPD patterns of Mae1 (Exp.ID SSm14) before and after AAC are shown; the starting material and maleic acid are shown as references.

[0201] Figure 135 The TGMS analysis (heating rate 10 °C / min) of Mae1 (Exp.ID SSm14) obtained with maleic acid and THF is shown; a 3.4% mass loss was observed between 25 - 110 °C due to solvent / water loss, followed by decomposition.

[0202] Figure 136 The XRPD patterns (from bottom to top) of the following are shown: Form A starting material, Sul1 (Exp.ID SSm37) obtained from ethanol and 1 molar equivalent of sulfuric acid, Sul2 (Exp.ID SSm38, solid phase) obtained from ethanol and 0.5 molar equivalent of sulfuric acid, Sul3 (Exp.ID SSm5, liquid phase) obtained from the mother liquor of an experiment in THF and 0.5 molar equivalent of sulfuric acid, and Sul4 (SSm4) obtained from THF and 1 molar equivalent of sulfuric acid.

[0203] Figure 137 The XRPD patterns of Sul1 (Exp.ID SSm37) before and after AAC are shown; the starting material is shown as a reference.

[0204] Figure 138 The TGMS analysis (heating rate 10 °C / min) of Sul1 (Exp.ID SSm37) obtained with 1 molar equivalent of sulfuric acid in ethanol is shown; a 2.4% mass loss was observed between 25 - 120 °C, and a 5.8% mass loss between 120 - 200 °C, followed by decomposition at temperatures above 240 °C.

[0205] Figure 139The XRPD patterns (from bottom to top) of the following substances are shown: Form A starting material, p-toluenesulfonic acid reference, Tos1 obtained from THF (Exp. ID SSm8), Tos2 obtained from ethanol (Exp. ID SSm41), and Tos1 + Tos3 obtained by the conversion of Tos1 during exposure to AAC (Exp. ID SSm8 after AAC).

[0206] Figure 140 The XRPD patterns of Tos2 (Exp. ID SSm41) before and after AAC are shown; the starting material and p-toluenesulfonic acid are shown as references.

[0207] Figure 141 The TGMS analysis (heating rate 10 °C / min) of Tos2 (Exp. ID SSm41) obtained with p-toluenesulfonic acid and ethanol is shown; due to ethanol, a 4.6% mass loss is observed between 25 - 110 °C, followed by decomposition.

[0208] Figure 142 The XRPD patterns (from bottom to top) of the following substances are shown: Form A starting material, Form B obtained from ethanol (Exp. ID SSm66), and Form C obtained from THF (Exp. ID SSm33).

[0209] Figure 143 The TGMS analysis (heating rate 10 °C / min) of Form B (Exp. ID SSm66) obtained from a control sample in ethanol is shown; due to residual solvent, a small 0.3% mass loss is observed before melting.

[0210] Figure 144 The TGMS analysis (heating rate 10 °C / min) of Form C (Exp. ID SSm17 liquid phase) obtained from the mother liquor of an experiment with glutamic acid in THF is shown; due to THF, a 2.6% mass loss is observed between 25 - 200 °C, followed by decomposition.

[0211] Figure 145 The molecular structure of the sesquioxalate of ME-522 is shown. The molecular weight of the free base is 469.8 g / mol.

[0212] Figure 146 The overlap of HT-XRPD patterns is shown, from bottom to top: oxalic acid, oxalic acid dihydrate, Oxa1 (from project S18128), and Oxa2 (starting material).

[0213] Figure 147Illustrated is a graphical representation of the Rietveld analysis of Oxa2 (starting material). The black line represents the collected data, the red line is the calculated powder pattern and the grey line is the difference between them. The blue bars at the bottom show the peak positions of the matching unit cell. The vertical lines indicate the diffraction peaks related to unspecified crystalline impurities.

[0214] Figure 148 Illustrated is the TGMS thermal analysis of Oxa2 (starting material) (heating rate 10 °C / min). A 1.1% mass loss was recorded between 40 - 100 °C.

[0215] Figure 149 Illustrated is the DSC trace of Oxa2 (starting material) (heating rate 10 °C / min). A single broad endothermic event was observed at T 峰 218.5 °C.

[0216] Figure 150 Illustrated is the UPLC-MS analysis of Oxa2 (starting material). The peak corresponding to the API had a retention time of 1.2 min, and the cationic spectrum showed an ion with m / z of 470.2 [M+H] + which is consistent with the API molecular mass of 469.8 g / mol. The table shows the retention times, peak areas and heights of the API and unidentified impurities.

[0217] Figure 151 Illustrated is the 6 1H-NMR spectra of Oxa2 (SM, bottom), Oxa1 (from S18128, Exp.ID: SSm12, middle) and free base (from S18128, top) measured in DMSO-d 1 (bottom). The letters at the bottom of the spectrum correspond to the hydrogens in the molecular structure of the API.

[0218] Figure 152 Illustrated is the DVS isotherm of Oxa2 (starting material), where the change in mass is plotted as a function of RH. An adsorption curve (red diamonds) from 40% RH to 95% was initially applied, followed by a desorption curve (blue squares) from 95% RH to 0% RH. Finally, the RH was set to the starting value of 40% (green triangles).

[0219] Figure 153 Illustrated is a picture of the suspension obtained after adding a small aliquot of water to Oxa2 (starting material).

[0220] Figure 154 Illustrated is the HT-XRPD pattern of ME-522 oxalate (Exp.ID: QSA8) prepared by lyophilizing the starting material in acetone / water (50 / 50, v / v).

[0221] Figure 155 The TGMS thermal analysis chart (heating rate 10 °C / min) of the amorphous oxalate (Exp.ID: QSA8) obtained after lyophilization is shown. A 3.2% mass loss was recorded between 40 - 140 °C.

[0222] Figure 156 The DSC trace (heating rate 10 °C / min) of the amorphous oxalate (Exp.ID: QSA8) obtained after lyophilization is shown. Three endothermic events were detected between 25 - 140 °C, in addition to a broad endothermic event between 185 - 230 °C.

[0223] Figure 157 The 6 1H-NMR spectra of the free base of ME-522 (SM from project S128128, bottom), amorphous ME-522 oxalate (Exp.ID: QSA8, middle), and ME-522 Oxa2 (SM from the current project S18128A, top) measured in DMSO-d 1 are shown.

[0224] Figure 158 The HT-XRPD diffraction patterns of the forms observed during the polymorph screening process on ME-522 oxalate (from bottom to top) are shown: Oxa1, Oxa1e, Oxa2, Oxa3, Oxa1 + Oxa4, Oxa5, Oxa6, and Oxa7.

[0225] Figure 159 The temperature curve of the thermal cycling experiment is shown.

[0226] Figure 160 The schematic diagram of the Oxa1 form and how these forms are related to each other is shown. All Oxa1 forms are semi-oxalate / semi-hydrate. Oxa1d and Oxa1e have non-stoichiometric solvents and water present in the structure. From left to right, after removing the solvent and water, the unit cell dimensions become smaller. The driest form obtained (i.e., Oxa1a) still contains approximately 0.24 equivalents of non-stoichiometric water per API molecule.

[0227] Figure 161 The crystal packing and H-bond diagrams viewed along the

[100] direction determined by single crystal X-ray diffraction for Oxa1d (left), Oxa1c (middle), and Oxa1a (right) are shown. Molecules a and b (in Figure 175The (middle classification) are shown in green and blue respectively. The oxalate divalent anion is shown in red, and the stoichiometric water molecules (0.5 per 1 API cation) are highlighted in orange. In the left image, the cavity that can accommodate solvent / water molecules is highlighted for Oxa1d. In Oxa1d, ethanol is present in the cavity. In Oxa1c and Oxa1a, water is present in the cavity (as indicated by the purple spheres). From left to right, the unit cell dimensions decrease.

[0228] Figure 162 The overlapping of the HT-XRPD patterns of the Oxa1 form is illustrated, from bottom to top: Oxa1, Oxa1a, Oxa1b, Oxa1c, Oxa1d, and Oxa1e.

[0229] Figure 163 The graphical representation of the Rietveld analysis for Oxa1 (Exp.ID: SSm12, Project S18128) is illustrated. The black line represents the collected data, the red is the calculated powder pattern, and the grey line is the difference between them. The blue bars at the bottom show the peak positions of the matching unit cell.

[0230] Figure 164 The overlapping of the HT-XRPD patterns of the substance obtained in Exp.ID: TCP29 is illustrated, from bottom to top: Oxa1e (ambient dried), Oxa1 (vacuum dried), and Oxa1 (after 2 days at 40 °C / 75% RH).

[0231] Figure 165 The TGMS thermal analysis diagram of Oxa1 (Exp.ID: TCP29) is illustrated (heating rate 10 °C / min). A 5.6% mass loss was recorded between 40 - 140 °C.

[0232] Figure 166 The DSC trace of Oxa1 (Exp.ID: TCP29) is illustrated (heating rate 10 °C / min). The three endothermic events between 25 - 160 °C are most likely related to water / solvent loss. The broad endothermic event between 209 - 230 °C is related to the thermal decomposition of the salt.

[0233] Figure 167 The UPLC-MS analysis of Oxa1 (Exp.ID: TCP29) is illustrated. The peak corresponding to the API has a retention time of 1.2 min, and the cation spectrum shows an ion with m / z of 470.2 + which is consistent with the API molecular mass of 469.8 g / mol. The table shows the retention times, peak areas, and heights of the API and unidentified impurities.

[0234] Figure 168 The illustration in DMSO-d6 (Bottom) The 1 1H-NMR spectra of Oxa1 (Exp.ID: TCP29, bottom), Oxa1 (Exp.ID: SSm12 from S18128, middle), and ME-522 free base (from S18128, top).

[0235] Figure 169 Illustrated are the crystal packing and H-bonding diagram along the

[100] direction in Oxa1a. Molecules a and b (classified in Figure 175 ) are shown in green and blue, respectively. The oxalate dianion is shown in red, the stoichiometric water molecules (0.5 per 1 API cation) are highlighted in orange, while the symmetrically independent (non-stoichiometric) water molecules are depicted as purple circles.

[0236] Figure 170 Illustrated is the X-ray powder pattern of Oxa1a simulated from single crystal data.

[0237] Figure 171 Illustrated is the graphical representation of the Rietveld analysis of Oxa1b. The black line represents the collected data, the red line is the calculated XRPD pattern and the grey line is the difference between them. The blue bars at the bottom show the peak positions of the matching unit cell (cell).

[0238] Figure 172 Illustrated are the crystal packing and H-bonding diagram along the

[100] direction in Oxa1c. Molecules a and b (classified in Figure 175 ) are shown in green and blue, respectively. The oxalate dianion is shown in red, the stoichiometric water molecules (0.5 per 1 API cation) are highlighted in orange, and the purple circles represent the symmetrically independent (non-stoichiometric) water molecules.

[0239] Figure 173 Illustrated is the asymmetric unit of Oxa1c: Two ME-522 cations are found together with one oxalate anion and one water molecule. Interstitial water molecules were also identified but omitted for clarity. For clarity, the atomic numbering scheme is shown only for the oxalate anion and water molecule. The blue dashed lines show the intermolecular hydrogen bonding between the dianion, cation and water.

[0240] Figure 174 Illustrated is the X-ray powder pattern of Oxa1c simulated from single crystal data.

[0241] Figure 175 Illustrated are the molecular structures and atomic numbering schemes of the two symmetrically independent cations found in Oxa1d. The left image shows the cation named a in the cif file, while the right image shows cation b.

[0242] Figure 176 Illustrated are the crystal packing and hydrogen bonding diagram along the

[100] direction in Oxa1d. Molecules a and b (classified in Figure 175 ) are shown in green and blue, respectively. The oxalate divalent anion is shown in red, the stoichiometric water molecules (0.5 per 1 API cation) are highlighted in orange, the pink represents symmetrically independent (non-stoichiometric) water molecules, and the purple represents ethanol molecules.

[0243] Figure 177 Illustrated is the X-ray powder pattern of Oxa1d simulated from single crystal data.

[0244] Figure 178 Illustrated is the overlay of the HT-XRPD patterns of the substance obtained in Exp.ID: TCP29, from bottom to top: Oxa1 (vacuum dried), Oxa1e (ambient dried), Oxa1 (after 2 days at 40 °C / 75% RH), and Oxa1d (generated from single crystal data).

[0245] Figure 179 Illustrated is the overlay of the following HT-XRPD patterns of Oxa2: Oxa2 obtained from the starting material (bottom), Oxa2 obtained from 2-propanol (Exp.ID: TCP18, middle), and Oxa2 obtained from 2-propanol after exposure to AAC (Exp.ID: TCP18, top). In the starting material, an additional diffraction peak was identified at approximately 6.6° 2θ, as indicated by the arrow.

[0246] Figure 180 Illustrated is the TGMS thermal analysis chart of Oxa2 (Exp.ID: TCP18) (heating rate 10 °C / min). A 2.1% mass loss was recorded between 40 - 140 °C.

[0247] Figure 181 Illustrated is the DSC trace of Oxa2 (Exp.ID: TCP18) (heating rate 10 °C / min). A small endothermic event at T 峰 99 °C was followed by a broad endotherm at T 峰 214 °C.

[0248] Figure 182 Illustrated is the UPLC-MS analysis of Oxa2 (Exp.ID: TCP18). The peak corresponding to the API has a retention time of 1.2 min and the cation spectrum shows an ion with an m / z of 470.2 + , which is consistent with the API molecular mass of 470.2 g / mol. The table shows the retention times, peak areas, and heights of the API and unidentified impurities.

[0249] Figure 183 Illustrates the free base (SM of S18128, bottom), Oxa2 (Exp.ID: TCP18, middle), and Oxa2 (SM, S18128A) measured in DMSO-d 6 The 1H-NMR spectra. The integral values and peaks apply to Oxa2 (Exp.ID: TCP18, middle). The doublet signal at 1.05 ppm corresponds to the CH 1 group of 2-propanol. 3

[0250] Figure 184 Illustrates the overlap of the HT-XRPD patterns of the solids obtained from 2-propanol / water (90 / 10, Exp.ID: TCP30). From bottom to top: Oxa3a (ambient dried), Oxa1 + Oxa4 (vacuum dried), and Oxa3b (after AAC).

[0251] Figure 185 Illustrates the overlap of the HT-XRPD patterns of Oxa1 (Exp.ID: TCP29, bottom) and Oxa1 + Oxa4 (Exp.ID: TCP30, top).

[0252] Figure 186 Illustrates the overlap of the HT-XRPD patterns of Oxa5 (Exp.ID: SSm2, bottom) and the same substance after exposure to AAC for 1 day (top).

[0253] Figure 187 Illustrates the overlap of the HT-XRPD patterns of the substance obtained from chloroform (Exp.ID: TCP21). The bottom pattern shows Oxa6 (vacuum dried) and the top pattern belongs to Oxa3 (vacuum dried, after AAC).

[0254] Figure 188 Illustrates the overlap of the HT-XRPD patterns of Oxa7 obtained from the thermal cycling experiment in ethanol (Exp.ID: TCP23). The bottom pattern shows the vacuum-dried sample, while the top pattern belongs to the same sample after subjecting it to AAC (40 °C / 75% RH, 2 days).

[0255] Figure 189 Illustrates the TGMS thermal analysis chart of Oxa7 (Exp.ID: TCP23) (heating rate 10 °C / min). A mass loss of 3.4% was recorded between 40 - 140 °C.

[0256] Figure 190 ​The DSC trace (heating rate 10 °C / min) of Oxa7 (Exp.ID: TCP23) is shown. After two small endothermic events at 85 °C and 154 °C, there is a broad endothermic event at T 峰 214 °C.

[0257] Figure 191 The UPLC-MS analysis of Oxa7 (Exp.ID: TCP23) is shown. The peak corresponding to the API has a retention time of 1.2 min and the cationic spectrum shows an ion with m / z of 470.2 [M+H] + , which is consistent with the API molecular mass of 470.2 g / mol. The table shows the retention times, peak areas, and heights of the API and unidentified impurities.

[0258] Figure 192 The 1H-NMR spectra of the free base (SM of S18128, bottom) and Oxa7 (Exp.ID: TCP23, top) measured in DMSO-d 6 (bottom) are shown. The triplet signals at 1.1 and 1.2 ppm and the quartet signals at 3.5 and 4.0 ppm correspond to the CH 1 and CH 3 and CH 2 groups of ethanol, respectively.

[0259] Figure 193 The molecular structure of the monophosphate of ME-522 is shown. The molecular weight of the free base is 469.8 g / mol.

[0260] Figure 194 The overlay of the HT-XRPD patterns of Pho1 (project S18128, bottom), Pho2 (project S18128, middle), and Pho3 (starting material, current project S18128B, top) is shown.

[0261] Figure 195 The graphical representation of the Rietveld analysis of Pho3 (starting material) is shown. The black line represents the collected data, the red line is the calculated powder pattern, and the gray line is the difference between them. The blue bars at the bottom show the peak positions of the matching unit cell. The vertical lines indicate the diffraction peaks related to unidentified crystalline impurities.

[0262] Figure 196 The TGMS thermal analysis plot (heating rate 10 °C / min) of Pho3 (starting material) is shown. A 5.4% mass loss is recorded between 40 - 160 °C.

[0263] Figure 197 The DSC trace (heating rate 10 °C / min) of Pho3 (starting material) is shown. Except at T峰 In addition to the broad endothermic event at 246 °C, several endothermic events were observed before 200 °C.

[0264] Figure 198A and Figure 198B illustrates the cDSC trace (heating rate 10 °C / min) of Pho3 (starting material). In the first experiment ( Figure 198A ), the substance was heated to 170 °C and cooled to room temperature. After analyzing the substance by HT-XRPD, the compound was heated again to 170 °C, cooled to room temperature and finally heated to 300 °C ( Figure 198B ).

[0265] Figure 199 illustrates the overlap of the HT-XRPD patterns of the received Pho3 and the poorly crystalline (pc) material obtained after cDSC.

[0266] Figure 200 illustrates the UPLC-MS analysis of Pho3 (starting material). The peak corresponding to the API has a retention time of 1.2 min and the cationic spectrum shows an ion with m / z of 470.2 [M+H] + , which is consistent with the free base molecular mass of 469.8 g / mol. The table shows the retention times, peak areas and heights of the API and unidentified impurities.

[0267] Figure 201 illustrates the 6 1H-NMR spectra of Pho3 (SM, bottom), ME-522 free base (from S18128, middle) and Pho1 (from S18128, top) measured in DMSO-d 1 . The letters at the bottom of the spectrum correspond to the hydrogen atoms in the molecular structure of the API.

[0268] Figure 202 illustrates the DVS isotherm plot of Pho3 (starting material), where the change in mass is plotted as a function of RH. Initially, the adsorption curve (red diamonds) from 40% to 95% RH was applied, followed by the desorption curve (blue squares) from 95% to 0% RH. Finally, the RH was set to the starting value of 40% (green triangles).

[0269] Figure 203 illustrates the HT-XRPD pattern of ME-522 phosphate (Exp.ID: QSA8) prepared by lyophilizing the starting material in acetone / water (50 / 50, v / v).

[0270] Figure 204The TGMS thermal analysis chart (heating rate: 10 °C / min) of the amorphous phosphate (Exp.ID: QSA8) obtained by freeze-drying is shown. A 3.0% mass loss was recorded between 40 - 160 °C.

[0271] Figure 205 The DSC trace (heating rate: 10 °C / min) of the amorphous phosphate (Exp.ID: QSA8) obtained by freeze-drying is shown. Three endothermic events were detected between 25 - 150 °C, in addition to a broad endothermic event between 200 - 270 °C.

[0272] Figure 206 The 6 1H-NMR spectra of the amorphous ME-522 phosphate (Exp.ID: QSA8, bottom), ME-522 Pho3 (SM, middle), and ME-522 free base (SM from project S128128, top) measured in DMSO-d 1 are shown.

[0273] Figure 207 The HT-XRPD diffraction patterns of the forms of ME-522 phosphate observed in this study are shown. From bottom to top: Pho1, Pho3, Pho4, Pho5, Pho6, Pho7, Pho8, and Pho9.

[0274] Figure 208 The temperature curve of the thermal cycling experiment is shown.

[0275] Figure 209 The overlap of the HT-XRPD patterns of Pho1 (Exp.ID: TCP23, vacuum dried) and Pho1 (Exp.ID: TCP23, vacuum dried after AAC) is shown.

[0276] Figure 210 The TGMS thermal analysis chart (heating rate: 10 °C / min) of Pho1 (Exp.ID: TCP23) is shown. A 1.4% mass loss was recorded between 40 - 120 °C.

[0277] Figure 211 The DSC trace (heating rate: 10 °C / min) of Pho1 (Exp.ID: TCP23) is shown. In addition to a sharp endotherm at 200 °C and a broad endotherm between 217 - 259 °C, a broad endothermic event before 80 °C was observed.

[0278] Figure 212A and Figure 212B The cDSC trace (heating rate: 10 °C / min) of Pho1 (Exp.ID: TCP23) is shown. In the first experiment (Figure 212A ) The substance was heated to 140 °C and cooled to room temperature. After analyzing the substance by HT-XRPD, the compound obtained from the first cDSC cycle was heated again to 140 °C, cooled to room temperature, and finally heated to 300 °C in the second cDSC cycle ( [[ ).

[0279] ​ The figure shows the overlap of the HT-XRPD patterns of Pho1 (Exp.ID: TCP23) before and after cDSC.

[0280] ​ The figure shows the UPLC-MS analysis of Pho1 (Exp.ID: TCP23). The peak corresponding to the API has a retention time of 1.2 min and the cationic spectrum shows an ion with m / z of 470.2 [M+H] + , which is consistent with the molecular mass of the API of 469.8 g / mol. The table shows the retention times, peak areas, and heights of the API and unidentified impurities.

[0281] ​ The figure shows 6 of Pho1 (Exp.ID: TCP23, bottom) and ME-522 free base (from S18128, top) measured in DMSO-d 1 H-NMR spectra.

[0282] ​ The figure shows the DVS isotherm of Pho1 (Exp.ID: TCP23), where the change in mass is plotted as a function of RH. Initially, an adsorption curve from 40% to 95% RH (red diamonds) was applied, followed by a desorption curve from 95% RH to 0% RH (blue squares). Finally, the RH was set to the starting value of 40% (green triangles).

[0283] ​ The figure shows a photograph of the substance obtained after adding a small amount of water to the solid sample of Pho1 (Exp.ID: TCP23).

[0284] ​ The figure shows the HT-XRPD pattern of Pho2 (Exp.ID: SSm15 from project S18128).

[0285] ​ The figure shows the overlap of the HT-XRPD patterns of the solid obtained by crystallization from ethanol cooling (Exp.ID: SSm2). From bottom to top: Pho3 (ambient dried) and Pho1 (vacuum dried).

[0286] ​Illustrated is the overlay of the HT-XRPD patterns of the material (Exp.ID: TCP16) obtained by thermal cycling in 1,2-dimethoxyethane. From bottom to top: Pho4 (ambient dried), Pho1 (vacuum dried), and Pho4 (ambient dried, after AAC).

[0287] ​ Illustrated is the overlay of the HT-XRPD patterns of the material (Exp.ID: TCP19) obtained by thermal cycling in acetone. From bottom to top: Pho5 (ambient dried), Pho1 + peak (vacuum dried), and Pho8 (ambient dried, after AAC).

[0288] ​ Illustrated is the overlay of the HT-XRPD patterns of the poorly crystalline (pc) material (Exp.ID: TCP26) obtained from TBME. From bottom to top: Pho6 (ambient dried), Pho6 (vacuum dried), amorphous material (ambient dried, after AAC), and amorphous material (vacuum dried, after AAC).

[0289] ​ Illustrated is the TGMS thermal analysis of Pho6 (Exp.ID: TCP26) (heating rate 10 °C / min). A total mass loss of 3.6% was recorded between 30 - 180 °C.

[0290] Figure 224 Illustrated is the DSC trace of Pho6 (Exp.ID: TCP26) (heating rate 10 °C / min). After heating, three endothermic events up to 143 °C are followed by an exothermic event at 146 °C. Subsequently, an endotherm at 176 °C is followed by a broad endotherm between 211 - 267 °C.

[0291] Figure 225 Illustrated is the UPLC-MS analysis of Pho6 (Exp.ID: TCP26). The peak corresponding to the API has a retention time of 1.2 min and the cationic spectrum shows an ion with m / z of 470.2 + [M + H], which is consistent with the free base molecular mass of 469.8 g / mol. The table shows the retention times, peak areas, and heights of the API and unidentified impurities.

[0292] Figure 226 Illustrated is the 6 1H-NMR spectra of the free base (SM of S18128, bottom) and Pho6 (Exp.ID: TCP26, top) measured in DMSO-d 1 The singlet signal at 1.12 ppm represents the protons of the three CH 3 groups of TBME.

[0293] Figure 227 The overlapping of the HT-XRPD patterns of Pho7 obtained from the thermal cycling experiment in 2-propanol / water (90 / 10, v / v; Exp.ID: TCP30) is illustrated. From bottom to top, the XRPD patterns represent the ambient-dried sample, the vacuum-dried material, the ambient-dried sample after exposure to AAC (40 °C / 75% RH, 2 days), and the vacuum-dried material after exposure to AAC (40 °C / 75% RH, 2 days). The additional diffraction peaks are indicated by arrows.

[0294] Figure 228 The TGMS thermal analysis of Pho7 (Exp.ID: TCP30) is illustrated (heating rate 10 °C / min). A 4.0% mass loss was recorded between 25 - 180 °C.

[0295] Figure 229 The DSC trace of Pho7 (Exp.ID: TCP30) is illustrated (heating rate 10 °C / min). Several endothermic and exothermic events were detected before 200 °C, followed by a broad endothermic event between 213 - 261 °C.

[0296] Figure 230 The UPLC-MS analysis of Pho7 (Exp.ID: TCP30) is illustrated. The peak corresponding to the API has a retention time of 1.2 min and the cationic spectrum shows an ion with m / z of 470.2 + [M+H], which is consistent with the free base molecular mass of 469.8 g / mol. The table shows the retention times, peak areas, and heights of the API and unidentified impurities.

[0297] Figure 231 The [H]-NMR spectra of the free base (SM of S18128, bottom) and Pho7 (Exp.ID: TCP30, top) measured in DMSO-d 6 are illustrated. The doublet signal at 1.06 ppm represents the protons of the two CH 1 groups of 2-propanol. 3

[0298] Figure 232 The overlapping of the HT-XRPD patterns of the material obtained from the thermal cycling experiment in acetone (Exp.ID: TCP19) is illustrated. From bottom to top: Pho5 (ambient-dried), Pho1 + peak (vacuum-dried), Pho8 (ambient-dried, after AAC), and Pho8 + peak (vacuum-dried after AAC).

[0299] Figure 233Illustrates the overlap of the HT-XRPD patterns of Pho9 (ambient dried) and Pho1+Pho4 (vacuum dried) (Exp.ID: SSm1) obtained from cooling crystallization experiments in THF.

[0300] Figure 234 Illustrates the molecular structure of ME-522 free base (MW 469.8 g / mol).

[0301] Figure 235 Illustrates the overlap of the HT-XRPD patterns of the following: ME-522 hydrochloride (starting material received for this study), ME-522 free base received for salt formation experiments on S18128, and ME-522 free base obtained from the conversion of the HCl salt to the free base (Exp.ID GEN4).

[0302] Figure 236A and Figure 236B Illustrates the TGA ( Figure 236A ) and TGMS ( Figure 236B ) analysis (heating rate of 10 °C / min) of the free base recovered from the HCl conversion (Exp.ID GEN4). A 3.3% mass loss was observed prior to thermal decomposition (observed above 240 °C).

[0303] Figure 237 Illustrates the DSC curve (heating rate 10 °C / min) of the free base obtained after conversion from the HCl salt (Exp.ID GEN4). A broad endothermic event was recorded between 25 - 70 °C due to water loss. The exothermic / endothermic event recorded between 160 - 182 °C may be due to a recrystallization event. Subsequently, a small endothermic event was observed at 217 °C, followed by a sharp endothermic event at 226 °C.

[0304] Figure 238 Illustrates the UPLC-MS chromatogram of the free base obtained after conversion from the HCl salt (Exp.ID GEN4). The API peak appears at 1.2 minutes with 100% chemical purity (area %). The molecular peak at 470.2 m / z in the mass spectrum may correspond to the positively charged species [M+H] + (API MW: 469 g / mol).

[0305] Figure 239 Illustrates the 1 H-NMR spectra (500 MHz, DMSO-d 6 ) overlap of the ME-522 free base received for a previous project (green line) and the ME-522 free base generated in this study (Exp.ID GEN4, red line).

[0306] Figure 240 The HT-XRPD pattern of ME-522 malonate (Exp.ID GEN8) prepared by lyophilizing a free base solution containing 1 equivalent of malonic acid in THF / water / acetone (32.5 / 32.5 / 35, v / v / v) is shown.

[0307] Figure 241A and Figure 241B The TGA ( Figure 241A ) and TGMS ( Figure 241B ) analyses (heating rate of 10 °C / min) of the amorphous malonate obtained after lyophilization (Exp.ID GEN8) are shown. A 3.6% mass loss was observed before thermal decomposition (observed above 120 °C).

[0308] Figure 242 The UPLC-MS chromatogram of the malonate obtained after lyophilization (Exp.ID GEN8) is shown. The API peak appears at 1.2 minutes with a chemical purity of 99.8% (area %). The molecular peak at 470.2 m / z in the mass spectrum can correspond to the positively charged species [M+H] + (API MW: 469 g / mol).

[0309] Figure 243 The 1 H-NMR spectra (500 MHz, DMSO-d 6 ) of the following are shown in an overlay: the ME-522 free base obtained early in this study (Exp.ID GEN4, green line), the ME-522 malonate found in a previous study (Mao1) (S18128, Exp.SSm53), and the ME-522 malonate obtained by lyophilization (Exp.ID GEN8, red line). The chemical shift observed at 2.85 ppm corresponds to malonic acid. Additional resonance shifts corresponding to residual THF (at 3.60 and 1.76 ppm) were observed.

[0310] Figure 244 The HT-XRPD diffraction patterns of the forms observed in the polymorph screening on ME-522 malonate are shown (from bottom to top): Mao1, Mao3, Mao4, and Mao5.

[0311] Figure 245 The experimental conditions of the thermal cycling experiment are shown. Slurries of ME-522 malonate were prepared in pure solvents and solvent mixtures and placed in a Crystal16 TM reactor to undergo Figure 245The thermal curves described in

[0312] Figure 246 Figure shows the XRPD patterns of Mao1 (Exp. ID TCP7) obtained in the thermal cycling experiment in THF before (bottom pattern) and after (top pattern) exposure to AAC.

[0313] Figure 247 Figure shows the graphical representation of the Rietveld analysis (Rietveld, 1969) of ME-522 Mao1 (Exp. ID TCP7) obtained in the thermal cycling experiment in THF. The black line represents the obtained powder pattern, the red line represents the calculated values and the grey line is the difference between them. The blue bars at the bottom show the peak positions of the fitted cell (cell parameters and atomic positions were taken from the single crystal data reported in Study S18128).

[0314] Figure 248A and Figure 248B Figure shows the TGA ( Figure 248A ) and TGMS ( Figure 248B ) analysis (heating rate of 10 °C / min) of Mao1 (Exp. ID TCP7) obtained in the thermal cycling experiment in THF. A mass loss of 0.7% was observed before melting / decomposition starting at about 160 °C. This mass loss can be attributed to residual water based on the MS signal.

[0315] Figure 249 Figure shows the DSC analysis (heating rate 10 °C / min) of Mao1 (Exp. ID TCP7) obtained in the thermal cycling experiment in THF. An endothermic event was observed due to melting / thermal decomposition, which had a peak temperature at 181.1 °C.

[0316] Figure 250 Figure shows the 1 H-NMR spectra of Mao1 (Exp. ID TCP7, bottom) obtained in the thermal cycling experiment in THF compared to amorphous malonate (Exp. ID GEN8, top).

[0317] Figure 251 Figure shows the UPLC chromatogram of Mao1 (Exp. ID TCP7) obtained in the thermal cycling experiment in THF. The API chemical purity was 99.4% (area %).

[0318] Figure 252A and Figure 252B illustrates the mass change ([ Figure 252B Figure 252A ) and the isotherm plot ([ Figure 252B Figure 252B ) resulting from DVS analysis of Mao1 (Exp. ID TCP7) obtained from a thermal cycling experiment conducted in THF. The DVS analysis consists of an adsorption cycle from 40 - 95% RH, a desorption cycle from 95 - 0% RH, and an adsorption cycle from 0 - 40% RH. The weight balance for each step was set at dm / dt < 0.0002 for a minimum of 1 hour or a maximum of 6 hours.

[0319] Figure 253 illustrates a photograph of the suspension obtained after adding a small aliquot of water to the solid of Mao1.

[0320] Figure 254 illustrates the HT - XRPD pattern of Mao1 (Exp. ID: Ssm4) obtained from a scale - up experiment and an image of the material used for XRPD analysis.

[0321] Figure 255 illustrates a graphical representation of the Rietveld analysis (Rietveld, 1969) of ME - 522 Mao1 (Exp. ID Ssm4) obtained from a scale - up cooling crystallization experiment in THF. The black line represents the obtained powder pattern, the red line represents the calculated values, and the gray line is the difference between them. The blue bars at the bottom show the peak positions of the matching unit cell (unit cell parameters and atomic positions were taken from single - crystal data reported in Study S18128).

[0322] Figure 256A and Figure 256B illustrates the TGA ([ Figure 256A Figure 256A ) and TGMS ([ Figure 256B Figure 256B ) analysis (heating rate of 10°C / min) of Mao1 (Exp. ID Ssm4) obtained from a scale - up cooling crystallization experiment in THF. A mass loss of 0.08% was observed before melting / decomposition began at approximately 160°C.

[0323] Figure 257 illustrates the DSC analysis (heating rate 10°C / min) of Mao1 (Exp. ID Ssm4) obtained from a scale - up cooling crystallization experiment conducted in THF. An endothermic event was observed due to melting / thermal decomposition, with a peak temperature at 182.4°C.

[0324] Figure 258 illustrates the 1 H - NMR spectrum (500 MHz, DMSO - d6 ) Overlap: ME-522 free base obtained from the free base scale-up experiment (Exp.ID: GEN10, top), and Mao1 obtained from the cooling crystallization experiment in THF (Exp.ID: Ssm4).

[0325] Figure 259 The UPLC chromatogram of Mao1 (Exp.ID Ssm4) obtained from the scale-up cooling crystallization experiment carried out in THF is shown. The API chemical purity is 100% (area %). The mass related to the main peak is 470.3 m / z, which corresponds to the positively charged species [M+H] + .

[0326] Figure 260 The overlap of the HT-XRPD patterns of the amorphous solid obtained after the thermal cycling experiment carried out in cyclohexane (Exp.ID TCP3) and Mao4 after exposing the amorphous solid obtained in TCP3 (top pattern) to AAC is shown.

[0327] Figure 261A and Figure 261B The TGA ( Figure 261A ) and TGMS ( Figure 261B ) analyses (heating rate of 10 °C / min) of Mao4 obtained after exposing the amorphous solid obtained in TCP3 (from cyclohexane) to AAC are shown. Due to water (API∶malonic acid∶water 1∶1∶1.1), a 3.5% mass loss is observed in the temperature range of 40 - 150 °C.

[0328] Figure 262 The DSC analysis (heating rate 10 °C / min) of Mao4 obtained after exposing the amorphous solid obtained in TCP3 (from cyclohexane) to AAC is shown. A broad endothermic event attributed to water loss is observed between 25 - 100 °C, followed by an endothermic event peak temperature at 177.1 °C due to melting / thermal decomposition.

[0329] Figure 263 The UPLC-MS chromatogram of Mao4 obtained after exposing the amorphous solid obtained in TCP3 (from cyclohexane) to AAC is shown. The API chemical purity is 98.5% (area %).

[0330] Figure 264 The 1 1H-NMR spectrum of Mao4 obtained after exposing the amorphous solid obtained in TCP3 to AAC (from cyclohexane, Exp.ID TCP3, bottom) compared with Mao1 from Exp.ID TCP7 (top) is shown.

[0331] Figure 265A and Figure 265B illustrates the mass change ([[]] Figure 265A ) and the isotherm plot ([[]] Figure 265B ) resulting from DVS analysis of Mao4 obtained by exposing the amorphous solid (from cyclohexane) that will be obtained in TCP3 to AAC. The DVS analysis consists of an adsorption cycle from 40 - 95% RH, a desorption cycle from 95 - 0% RH, and an adsorption cycle from 0 - 40% RH. The sample was incubated for 1 hour at each relative humidity value.

[0332] Figure 266 illustrates the HT-XRPD patterns of Mao4 (Exp.ID TCP3, after AAC) and Mao1 recovered after DVS (top pattern) measurement.

[0333] Figure 267 illustrates the overlap of the HT-XRPD patterns of the following substances: Mao5 (Exp.ID TCP6_ML) obtained after evaporation crystallization of the mother liquor recovered from the thermal cycling experiment in methanol and Mao4 (top pattern) obtained after exposure to AAC.

[0334] Figure 268A and Figure 268B illustrates the TGA ([[]] Figure 268A ) and TGMS ([[]] Figure 268B ) analyses (heating rate of 10 °C / min) of Mao5 (Exp.ID TCP6_ML) obtained after evaporation crystallization of the mother liquor recovered from the thermal cycling experiment in methanol. A 1.5% mass loss was observed in the temperature range 40 - 100 °C due to water (1.5% water corresponds to 0.5 water molecules per malonate).

[0335] Figure 269 illustrates the DSC analysis (heating rate 10 °C / min) of Mao5 (Exp.ID TCP6_ML) obtained after evaporation crystallization of the mother liquor recovered from the thermal cycling experiment in methanol. A broad endothermic event between 90 - 130 °C attributed to water loss was observed, followed by an exothermic event at 135.4 °C, possibly due to recrystallization. An endothermic event was recorded at 176.1 °C.

[0336] Figure 270 illustrates the UPLC-MS chromatogram of Mao5 (Exp.ID TCP6_ML) obtained after evaporation crystallization of the mother liquor recovered from the thermal cycling experiment in methanol. The API chemical purity is 99.2% (area %).

[0337] Figure 271The content of the asymmetric unit in the structure of Voruciclib oxalate is illustrated by a thermal ellipsoid representation at the 50% probability level using atomic labels. Hydrogen bonds are drawn as thin dashed lines. The molecules are shown in their correct relative orientations as they occur in the structure.

[0338] Figure 272 Hydrogen bonding in the structure of Voruciclib oxalate is illustrated. The O3-H3…O13i, O8-H8…O1Wii, and O1W-H1WA…O14iii interactions crosslink the structural units shown in Figure 271 The atoms with the letter A in their atomic labels are generated by the symmetry operation i: -x+2, y-0.5, -z+1, the letter B indicates the symmetry operation ii: -x+1, y+0.5, -z+1, and the letter C corresponds to the symmetry operation iii: x-1, y, z. The view is the same as in Figure 271 For clarity, the hydrogen atoms bonded to carbon and 2-pentanone are omitted. Hydrogen bonds are drawn as thin dashed lines.

[0339] Figure 273 Packing diagrams of the structure of Voruciclib oxalate in projections along the crystallographic a-, b-, and c-axes (Figures A, B, and C respectively) are illustrated. Hydrogen bonds are drawn as thin dashed lines. Figure A shows the solvent channels that extend along the crystallographic a-axis. For clarity, the hydrogen atoms bonded to carbon are omitted.

[0340] Figure 274 A simulated powder diffraction pattern of the structure of Voruciclib oxalate is illustrated.

[0341] Figure 275 The content of two crystallographically independent molecules of Voruciclib phosphate is illustrated by a thermal ellipsoid representation at the 50% probability level using atomic labels. Hydrogen bonds are drawn as thin dashed lines. For clarity, solvent molecules are omitted. The molecules are not shown in their correct relative orientations but are oriented for maximum clarity. Figure 276 The complete content of the asymmetric unit with two target molecules (two phosphate counterions and solvent) is shown, all in their correct relative orientations.

[0342] Figure 276 The content of the asymmetric unit in the Voruciclib phosphate structure is illustrated by atomic labels. Each group is in its correct relative orientation as it occurs in the crystal structure. Hydrogen bonds are drawn as thin dashed lines, and three half-occupied solvent molecules are drawn with open lines.

[0343] Figure 277It shows that the hydrogen bonds O13-H13…O15, O17-H17…O11, O14-H14…O16i and O18-H18…O12ii connect phosphate ions into an infinite chain extending along the crystallographic b-axis. Atoms with the letter A in their atomic labels are generated by the symmetry operation i: x, y+1, z and the letter B indicates the symmetry operation ii: x, y-1, z. The hydrogen bonds are drawn as thin dashed lines.

[0344] Figure 278 It shows that the hydrogen bonds O3-H3…O11, O8-H8…O12, O9-H9…O10, O1-H1A…O15iii, N1-H1…O13iii and N2-H2…O17iv connect Voruciclib molecules into Figure 277 the phosphate chain shown in Figure 277 The projection along the phosphate chain is depicted, which is perpendicular to the view in

[0345] Figure 279 Atoms with the letter A in their atomic labels are generated by the symmetry operation i: x, y+1, z, the letter B indicates the symmetry operation ii: x, y-1, z, the letter C indicates the symmetry operation iii: -x+2, y-0.5, -z+1, and D indicates the symmetry operation iv: -x+2, y-0.5, -z+1. The hydrogen bonds are drawn as thin dashed lines, the hydrogen atoms do not participate in classical hydrogen bonds, and for clarity, solvent molecules are omitted.

[0346] Figure 280 It shows the packing diagrams of the structure of Voruciclib phosphate isopropanol solvate in projections along the crystallographic a-, b- and c-axes (Figures A, B and C respectively). To better explain the role of solvent molecules, the solvent carbon atoms are drawn in orange. The hydrogen bonds are drawn as thin dashed lines. Figures A and B show how the solvent channels extend parallel to the phosphate chain. For clarity, hydrogen atoms not participating in hydrogen bonds are omitted.

[0347] Figure 281 It shows the simulated powder diffraction pattern of the structure of Voruciclib phosphate isopropanol solvate.

[0348] Figure 282 The molecular structure of Voruciclib malonate is illustrated.

[0349] Figure 283 The micrograph (magnification 10x) of Voruciclib malonate crystals in polarized light is illustrated.

[0350] Figure 284 The molecular structure and atomic numbering scheme of the cation-anion pair of Voruciclib malonate are illustrated.

[0351] Figure 285 The crystal packing and hydrogen bond scheme of Voruciclib malonate along the [0 1 0] direction are illustrated. The Voruciclib cation is shown in green, while the malonate anion is in red. The light blue lines represent hydrogen bonds.

[0352] Figure 286 The comparison of the simulated powder pattern (black) with FWHM = 0.28° based on single crystal data and the HT-XRPD pattern (red) obtained for malonate Exp.ID SSm53 is illustrated.

[0353] Figure 287 The table shown depicts the stability of the polymorphs in different solvents, which were identified in the solid state characterization of Voruciclib HCl.

[0354] Figure 288 Non-limiting examples of the target product properties of Voruciclib (ME-522) are illustrated.

[0355] Figure 289 The results of the initial salt screening are illustrated, comparing the forms, crystallinity, and stability of various acid counterions.

[0356] Figure 290 The results of the second salt screening are illustrated, comparing the number of polymorphs, residual solvent percentage, gelling, and water solubility (mg / mL).

[0357] Figure 291 The illustration is related to Figure 288 The properties of the HCl, malonate, oxalate, and phosphate of Voruciclib related to the product properties shown.

[0358] Figure 292 The crossover design of the dog PK study comparing the HCl and malonate of Voruciclib is illustrated.

[0359] Figure 293Illustrated is the variability analysis of each pre-treatment group and the combination of salt forms administered in a cross-over dog PK study comparing HCl and voruciclib malonate salts.

[0360] Figure 294 Illustrated is the ratio of malonate / HCl calculated for each dog and PK parameter.

[0361] Figure 295 Illustrated is the relationship of voruciclib plasma concentration relative to time following single-dose cross-over oral administration to male beagle dogs.

[0362] Figure 296A -D Illustrated are the XRPD patterns of voruciclib malonate batches 20-00022-01, 20-00026-01, and 20-00062-01.

[0363] Figure 297 Illustrated is the technical specifications of the Area Detector.

[0364] Figure 298 Illustrated are the technical specifications of the Lynxeye detector.

[0365] Detailed description

[0366] While the preferred embodiments of the present invention have been shown and described herein, such embodiments are provided by way of example only and are not intended to limit the scope of the present invention in any other way. Various alternatives of the described embodiments of the present invention may be employed in practicing the present invention.

[0367] Definitions

[0368] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated by reference in their entirety.

[0369] The term "solid form" may refer to a crystalline solid form or phase, including crystalline free base and crystalline salts.

[0370] As used herein, the terms "co-administer", "co-administering", "administering in combination with", and "administering together with" encompass the administration of two or more agents to a subject such that the two agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more agents are present.

[0371] The term "effective amount" or "therapeutically effective amount" means an amount of a compound or combination of compounds as described herein sufficient to achieve the intended application, including, but not limited to, the treatment of a disease. The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age, and sex of the subject), the severity of the disease condition, the mode of administration, etc. (which can be readily determined by one of ordinary skill in the art). The term also applies to the dose that induces a specific response (e.g., CDK inhibition) in target cells. The specific dose will vary depending on the particular compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system that carries the compound.

[0372] The terms "QD", "qd", or "q.d." mean once daily, one time per day, or once a day. The terms "BID", "bid", or "b.i.d." mean twice daily, two times per day, or twice a day. The terms "TID", "tid", or "t.i.d." mean three times daily, three times per day, or three times a day. The terms "QID", "qid", or "q.i.d." mean four times daily, four times per day, or four times a day.

[0373] As used herein, the term "therapeutic effect" encompasses the therapeutic and / or prophylactic benefits described above. Prophylactic effects include delaying or eliminating the onset of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, halting, or reversing the progression of a disease or disorder, or any combination thereof.

[0374] The term "pharmaceutically acceptable salt" means salts derived from a variety of organic and inorganic counterions, including fumarate, maleate, phosphate, L-tartrate, ethanesulfonate, benzenesulfonate, hydrobromide, hydrochloride, citrate, gentisate, oxalate, sulfate counterions, etc. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.

[0375] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. Except for any conventional media or agents that are incompatible with the active ingredient, they are contemplated for use in the therapeutic compositions of the present invention. Supplementary active ingredients can also be incorporated into the described compositions.

[0376] The term "in vivo" means an event that occurs within the body of a subject.

[0377] The term "in vitro" means an event that occurs outside the body of a subject. In vitro assays encompass cell-based assays in which live or dead cells are used, and can also encompass cell-free assays in which intact cells are not used.

[0378] The term "extraparticulate" refers to substances outside the particles, for example, substances added to the particles (multiparticle compacts formed by a granulation process) and physically mixed with the particles but not contained within the particles.

[0379] The term "intraparticulate" refers to substances within the particles (multiparticle compacts formed by a granulation process). The particles can be formed by processes such as wet granulation (i.e., prepared using moisture or steam, heat, melting, freezing, foaming, and other processes) or dry granulation.

[0380] The term "acidifying agent" refers to a substance that increases acidity.

[0381] When used in combination with powder X-ray diffraction, the term "transmission" or "transmission mode" refers to the transmission (also known as the Debye-Scherrer) sampling mode. When used in combination with powder X-ray diffraction, the term "reflection" or "reflection mode" refers to the reflection (also known as the Bragg-Brentano) sampling mode.

[0382] Unless otherwise indicated, the chemical structures described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds in which one or more hydrogen atoms are replaced by deuterium or tritium, or in which one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon are within the scope of the present invention.

[0383] When ranges are used herein to describe physical or chemical properties such as molecular weight or chemical formula, all combinations and subcombinations of the ranges and specific embodiments therein are intended to be included. The terms "about" or "approximately" when referring to a number or numerical range mean that the recited number or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary, for example, between 1% and 15% of the recited number or numerical range. The term "comprising" (and related terms such as "containing" or "having" or "including") includes embodiments such as any composition, method, or process of a substance "consisting of the described features" or "consisting essentially of the described features".

[0384] As used herein, "enantiomeric purity" refers to the relative amount of a particular enantiomer present relative to the presence of other enantiomers, expressed as a percentage. For example, if a compound (which may have an (R)- or (S)-isomeric configuration) is present as a racemic mixture, the enantiomeric purity relative to either the (R)- or (S)-isomer is about 50%. If the compound has one isomeric form that predominates over the other, e.g., 80% (S)-isomer and 20% (R)-isomer, the enantiomeric purity of the compound relative to the (S)-isomeric form is 80%. The enantiomeric purity of a compound can be determined in a variety of ways, including, but not limited to, chromatography using a chiral support, polarimetry of the rotation of polarized light, nuclear magnetic resonance spectroscopy using a chiral shift reagent (including, but not limited to, a chiral complex containing a lanthanide element or a Pirkle reagent), or derivatizing the compound with a chiral compound (such as Mosher's acid) and then performing chromatography or nuclear magnetic resonance spectroscopy.

[0385] In a preferred embodiment, the enantiomerically enriched composition has a higher potency per unit mass of therapeutic utility than the racemic mixture of the composition. Enantiomers can be separated from a mixture by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred enantiomer can be prepared by asymmetric synthesis. See, e.g., Jacques, et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York, 1981; Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, NY, 1962; and Eliel and Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York, 1994.

[0386] As used herein, the terms "enantiomerically enriched" and "non-racemic" refer to a composition in which the weight percentage of one enantiomer is greater than the amount of one enantiomer in the control mixture of the racemic composition (e.g., greater than a 1:1 weight ratio). For example, an enantiomerically enriched preparation of the (S)-enantiomer refers to a preparation of a compound having greater than 50% by weight (such as at least 75% by weight or such as at least 80% by weight) of the (S)-enantiomer relative to the (R)-enantiomer. In certain embodiments, the enrichment can be significantly greater than 80% by weight, thereby providing a "substantially enantiomerically enriched" or "substantially non-racemic" preparation, which refers to a preparation of a composition having at least 85% by weight (such as at least 90% by weight or such as at least 95% by weight) of one enantiomer relative to the other enantiomer. The terms "enantiomerically pure" or "substantially enantiomerically pure" refer to a composition comprising at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.

[0387] "Group" refers to a specific segment or functional group of a molecule. Chemical groups are often recognized chemical entities that are incorporated into or attached to a molecule.

[0388] "Tautomers" are structurally different isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes proton transfer or prototropic tautomerization, which is considered a subset of acid-base chemistry. "Proton transfer tautomerization" or "prototropic tautomerization" involves proton migration accompanied by a change in bond order (often an interchange of a single bond with an adjacent double bond). When tautomerization can occur (e.g., in solution), a chemical equilibrium of tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. The formation of solid forms in different tautomeric states is called "tautomorphism", and such forms are called "tautomorphs".

[0389] The compositions of the present invention also include crystalline forms of formula (1), including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates) and conformational polymorphs, and mixtures thereof. The terms "crystalline form", "form" and "polymorph" are intended to include all crystalline forms of a compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates) and conformational polymorphs, and mixtures thereof, unless a specific crystalline form is mentioned.

[0390] "Solvate" refers to a crystalline phase of a compound that is physically associated with one or more solvent molecules. A crystalline phase of a compound that is physically associated with one or more water molecules is called a "hydrate".

[0391] "Amorphous form" refers to a form of a compound or a salt or molecular complex of a compound that lacks long-range crystalline order.

[0392] Voruciclib

[0393] Voruciclib is a CDK inhibitor described, for example, in U.S. Patent Nos. 7,271,193, 7,915,301, 8,304,449, 7,884,127, and 8,563,596 (incorporated herein by reference in their entirety).

[0394]

[0395] Voruciclib

[0396] In certain embodiments, voruciclib refers to (+)-trans-2-(2-chloro-4-trifluoromethylphenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidin-3-yl)-chromen-4-one. In certain embodiments, voruciclib refers to 2-(2-chloro-4-trifluoromethylphenyl)-5,7-dihydroxy-8-((2R,3S)-2-hydroxymethyl-1-methylpyrrolidin-3-yl)-4H-chromen-4-one.

[0397] Crystalline form

[0398] In one embodiment, the present disclosure provides a crystalline solid form of voruciclib. In one embodiment, the present disclosure provides a crystalline solid form of voruciclib free base. In one embodiment, the present disclosure provides a crystalline solid form of a voruciclib salt. The present disclosure provides polymorphs of voruciclib, such as crystal forms. In certain embodiments, the polymorphs include free base voruciclib. In certain embodiments, the polymorphs include voruciclib salts, including counterions corresponding to acids selected from 1,5-naphthalenedisulfonic acid, 1-hydroxy-2-naphthoic acid, benzenesulfonic acid, benzoic acid, dibenzoyl-L-tartaric acid, ethanesulfonic acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malonic acid, oxalic acid, orthophosphoric acid, sulfuric acid, p-toluenesulfonic acid, and the like.

[0399] Any crystalline form described herein can be characterized by X-ray diffraction. In certain embodiments, X-ray diffraction refers to X-ray powder diffraction. In certain embodiments, X-ray diffraction can be measured using a transmission mode or a reflection mode. In one embodiment, the X-ray diffraction pattern of any embodiment herein is measured in transmission mode. In one embodiment, the X-ray diffraction pattern of any embodiment herein is measured in reflection mode. It is known in the art that, depending on the measurement conditions (such as the equipment, sample preparation, or instrument used), X-ray powder diffraction patterns with one or more measurement errors can be obtained. Specifically, it is well known that the intensities in an X-ray powder diffraction pattern can vary depending on the measurement conditions and sample preparation. For example, those skilled in the art of X-ray powder diffraction will recognize that the relative intensities of the peaks can vary depending on the orientation of the sample being measured and based on the type and settings of the instrument used. The skilled person will also realize that the position of the reflections can be affected by the exact height at which the sample is placed in the diffractometer, the surface flatness of the sample, and the zero calibration of the diffractometer. Thus, those skilled in the art will understand that the diffraction pattern data presented herein should not be construed as absolute, and any crystalline form that provides a powder diffraction pattern that is substantially the same as those disclosed herein falls within the scope of the present disclosure. For further information, see Jenkins and Snyder, Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, 1996.

[0400] Compared to the amorphous form, different crystalline forms can provide surprising advantages, including improved thermodynamic stability, faster dissolution rates, improved performance in the gastric and gastrointestinal environment (including avoiding or reducing precipitation from solution upon becoming more basic), improved exposure in mammals, and excellent processability for formulating the drug into a finished product suitable for the patient.

[0401] In one embodiment, the present disclosure provides a crystalline form of voruciclib malonate, and / or a polymorphic crystalline form (Mao1) of voruciclib malonate, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from:

[0402]

[0403]

[0404] In certain embodiments, each peak can independently include a variation of ±0.1°, ±0.2°, or ±0.3°.

[0405] In one embodiment, the present disclosure provides a crystal form of voruciclib oxalate and / or a polymorphic crystal form (Oxa1) of voruciclib oxalate, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the following:

[0406]

[0407] In certain embodiments, each peak may independently include a variation of ±0.1°, ±0.2°, or ±0.3°.

[0408] In one embodiment, the present disclosure provides a crystal form of voruciclib phosphate and / or a polymorphic crystal form (Pho1) of voruciclib phosphate, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the following:

[0409]

[0410] In certain embodiments, each peak may independently include a variation of ±0.1°, ±0.2°, or ±0.3°.

[0411] In one embodiment, the present disclosure provides a crystal form of voruciclib, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the following: 7.30° ± 0.2°, 13.58° ± 0.2°, 14.06° ± 0.2°, 15.18° ± 0.2°, 15.66° ± 0.2°, 17.50° ± 0.2°, 18.94° ± 0.2°, 19.54° ± 0.2°, 22.22° ± 0.2°, 23.38° ± 0.2°, 24.10° ± 0.2°, 24.98° ± 0.2°, 25.94° ± 0.2°, 27.26° ± 0.2°, 28.50° ± 0.2°, and 32.82° ± 0.2° 2θ. In certain embodiments, the X-ray diffraction pattern comprises at least 1 peak, at least 2 peaks, at least 3 peaks, at least 4 peaks, at least 5 peaks, etc., the peaks being selected from the above peak group. In certain embodiments, the crystal form comprises voruciclib malonate. In certain embodiments, the crystal form comprises hydrated voruciclib malonate. In certain embodiments, the crystal form comprises anhydrous voruciclib malonate.

[0412] In one embodiment, the present disclosure provides a crystalline form of voruciclib, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the following: 5.06° ± 0.2°, 6.42° ± 0.2°, 9.34° ± 0.2°, 10.14° ± 0.2°, 12.30° ± 0.2°, 13.66° ± 0.2°, 14.14° ± 0.2°, 15.82° ± 0.2°, 17.02° ± 0.2°, 19.74° ± 0.2°, 20.38° ± 0.2°, 21.82° ± 0.2°, 22.66° ± 0.2°, 24.62° ± 0.2°, 25.78° ± 0.2°, 26.58° ± 0.2°, 28.66° ± 0.2°, and 29.98° ± 0.2° 2θ. In certain embodiments, the X-ray diffraction pattern comprises at least 1 peak, at least 2 peaks, at least 3 peaks, at least 4 peaks, at least 5 peaks, etc., the peaks being selected from the above group of peaks. In certain embodiments, the crystalline form comprises voruciclib dibenzoyl-tartrate. In certain embodiments, the crystalline form comprises hydrated voruciclib dibenzoyl-tartrate. In certain embodiments, the crystalline form comprises anhydrous voruciclib dibenzoyl-tartrate.

[0413] In one embodiment, the present disclosure provides a crystalline form of voruciclib, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the following: 4.94° ± 0.2°, 6.78° ± 0.2°, 9.34° ± 0.2°, 10.94° ± 0.2°, 12.70° ± 0.2°, 13.38° ± 0.2°, 14.90° ± 0.2°, 15.66° ± 0.2°, 17.54° ± 0.2°, 18.82° ± 0.2°, 22.02° ± 0.2°, 23.98° ± 0.2°, 24.78° ± 0.2°, 25.30° ± 0.2°, 26.66° ± 0.2°, and 29.98° ± 0.2° 2θ. In certain embodiments, the X-ray diffraction pattern comprises at least 1 peak, at least 2 peaks, at least 3 peaks, at least 4 peaks, at least 5 peaks, etc., the peaks being selected from the above group of peaks. In certain embodiments, the crystalline form comprises voruciclib phosphate. In certain embodiments, the crystalline form comprises hydrated voruciclib phosphate. In certain embodiments, the crystalline form comprises anhydrous voruciclib phosphate.

[0414] In one embodiment, the present disclosure provides a crystalline form of voruciclib, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the following: 6.86° ± 0.2°, 12.66° ± 0.2°, 13.58° ± 0.2°, 14.74° ± 0.2°, 15.98° ± 0.2°, 19.38° ± 0.2°, 23.94° ± 0.2°, 24.78° ± 0.2°, and 25.94° ± 0.2° 2θ. In certain embodiments, the X-ray diffraction pattern comprises at least 1 peak, at least 2 peaks, at least 3 peaks, at least 4 peaks, at least 5 peaks, etc., the peaks being selected from the above group of peaks. In certain embodiments, the crystalline form comprises voruciclib oxalate. In certain embodiments, the crystalline form comprises hydrated voruciclib oxalate. In certain embodiments, the crystalline form comprises anhydrous voruciclib oxalate.

[0415] In one embodiment, the present disclosure provides a crystalline form of voruciclib, characterized by an X-ray powder diffraction pattern comprising one or more peaks selected from the following: 9.02° ± 0.2°, 10.50° ± 0.2°, 11.06° ± 0.2°, 12.30° ± 0.2°, 12.82° ± 0.2°, 13.90° ± 0.2°, 14.82° ± 0.2°, 15.30° ± 0.2°, 15.94° ± 0.2°, 17.26° ± 0.2°, 19.34° ± 0.2°, 20.62° ± 0.2°, 22.18° ± 0.2°, 22.86° ± 0.2°, 24.58° ± 0.2°, 25.42° ± 0.2°, 25.86° ± 0.2°, 27.38° ± 0.2°, and 28.66° ± 0.2° 2θ. In certain embodiments, the X-ray diffraction pattern comprises at least 1 peak, at least 2 peaks, at least 3 peaks, at least 4 peaks, at least 5 peaks, etc., the peaks being selected from the above group of peaks. In certain embodiments, the crystalline form comprises voruciclib naphthalenedisulfonate. In certain embodiments, the crystalline form comprises hydrated voruciclib naphthalenedisulfonate. In certain embodiments, the crystalline form comprises anhydrous voruciclib naphthalenedisulfonate.

[0416] Pharmaceutical composition

[0417] In one embodiment, the present invention provides a pharmaceutical composition comprising a crystalline form of voruciclib free base. In one embodiment, the present invention provides a pharmaceutical composition comprising a crystalline form of a voruciclib salt. The pharmaceutical composition is generally formulated to provide a therapeutically effective amount of voruciclib in solid form as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. When needed, the pharmaceutical composition contains its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents, permeation enhancers, solubilizers or adjuvants. The pharmaceutical composition may also contain an acidifying agent as described herein.

[0418] In certain embodiments, relative to the total mass or volume of the pharmaceutical composition, the concentration of the solid form of voruciclib provided in the pharmaceutical composition of the present invention (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is independently less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002% or 0.001% w / w, w / v or v / v. In one embodiment, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate and voruciclib naphthalenedisulfonate, each as described herein.

[0419] In certain embodiments, relative to the total mass or volume of the pharmaceutical composition, the concentration of the solid form of voruciclib provided in the pharmaceutical compositions of the present invention (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) is independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002% or 0.001% w / w, w / v or v / v.

[0420] In one embodiment, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0421] In certain embodiments, relative to the total mass or volume of the pharmaceutical composition, the concentration of the solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is independently in the range of from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, or from about 1% to about 10% w / w, w / v, or v / v. In one embodiment, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0422] In certain embodiments, relative to the total mass or volume of the pharmaceutical composition, the concentration of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is independently in the range of from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% to about 4.5%, from about 0.03% to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, from about 0.1% to about 0.9% w / w, w / v, or v / v. In one embodiment, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0423] In certain embodiments, the amount of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is independently equal to or less than 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g. In one embodiment, the solid form of...

[0424] In certain embodiments, the amount of the solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) independently exceeds 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5 g or 3 g. In one embodiment, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate and voruciclib naphthalenedisulfonate, each as described herein.

[0425] Each solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is effective over a wide dosage range. For example, in the treatment of adult humans, doses independently in the ranges of 0.01 - 1000 mg per day, 0.5 - 100 mg per day, 1 - 50 mg per day, 2 - 40 mg per day, and 5 - 25 mg per day are examples of doses that can be used. The exact dose depends on the route of administration, the form of the compound administered, the sex and age of the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician. In one embodiment, the solid form of voruciclib is selected from voruciclib malate, voruciclib dibenzoyl - tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0426] In a selected embodiment, the present invention provides a pharmaceutical composition for oral administration comprising voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and a pharmaceutically acceptable excipient suitable for oral administration. In one embodiment, the solid form of voruciclib is selected from voruciclib malate, voruciclib dibenzoyl - tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0427] In a selected embodiment, the present invention provides a solid pharmaceutical composition for oral administration comprising: (i) an effective amount of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and (ii) a pharmaceutically acceptable excipient suitable for oral administration. In a selected embodiment, the composition further comprises (iii) an effective amount of another active pharmaceutical ingredient. In one embodiment, the solid form of voruciclib is selected from voruciclib malate, voruciclib dibenzoyl - tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0428] In selected embodiments, the pharmaceutical composition can be a liquid pharmaceutical composition suitable for oral consumption. The pharmaceutical compositions of the present invention suitable for oral administration can be presented as discrete dosage forms (such as capsules, sachets or tablets), or as liquid or aerosol sprays (each containing a predetermined amount of the active ingredient as a powder or in granules), solutions, or suspensions in aqueous or non-aqueous liquids, oil-in-water emulsions or water-in-oil emulsions. The pharmaceutical compositions of the present invention also include powders for reconstitution, powders for oral consumption, bottles (such as powders or liquids in bottles), orally dissolving films, lozenges, pastes, tubes, gums and packets. Such dosage forms can be prepared by any pharmaceutical method, but all methods include the step of combining the active ingredient with a carrier which constitutes one or more essential ingredients. Generally, the compositions are prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired presentation. For example, tablets can be prepared by compression or molding, optionally with one or more auxiliaries. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form (such as a powder or granules), optionally mixed with excipients, such as, but not limited to, binders, lubricants, inert diluents and / or surfactants or dispersants. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0429] The present invention also encompasses anhydrous pharmaceutical compositions and dosage forms, since water can facilitate the degradation of certain compounds. For example, in the pharmaceutical field, water (e.g., 5%) can be added as a means of simulating long-term storage to determine properties such as shelf life or the stability of the formulation over time. Using anhydrous or low-moisture ingredients and low-moisture or low-humidity conditions, the anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared. If substantial contact with moisture and / or humidity is foreseen during production, packaging and / or storage, the pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable prescription kits. Examples of suitable packaging include, but are not limited to, airtight sealed foils, plastics, etc., unit-dose containers, blister packs and strip packs.

[0430] Each solid form of Voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) can be combined in a tight mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a variety of forms, depending on the dosage form required for administration. When preparing a composition for an oral dosage form, any common pharmaceutical medium can be used as the carrier, for example, in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc.; or in the case of oral solid preparations, carriers such as starch, sugar, microcrystalline cellulose, sodium carboxymethylcellulose cross-linked, magnesium stearate, diluents, granulating agents, lubricants, glidants, binders, and disintegrants can be used, and in certain embodiments, lactose is not used. For example, for solid oral preparations, suitable carriers include powders, capsules, and tablets. If desired, tablets can be coated by standard aqueous or non-aqueous techniques.

[0431] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to: corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropylmethylcellulose, microcrystalline cellulose, and mixtures thereof.

[0432] Examples of suitable fillers for the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrin binder, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0433] Disintegrants can be used in the compositions of the present invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant may result in tablets that disintegrate in the bottle. Too little may not be sufficient for disintegration to occur, thus altering the rate and extent of release of the active ingredient from the dosage form. Accordingly, an amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient can be used to form dosage forms of the compounds disclosed herein. The amount of disintegrant used can vary based on the type of formulation and mode of administration and can be readily discernible to one of ordinary skill in the art. About 0.5 to about 15% by weight of disintegrant, or about 1 to about 5% by weight of disintegrant, can be used in pharmaceutical compositions. Disintegrants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, sodium carboxymethylcellulose cross-linked, crospovidone, potassium polacrilate, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other alginates, other celluloses, gums, or mixtures thereof.

[0434] Lubricants that can be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other diols, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl palmitate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, a coagulated aerosol of synthetic silica, silicified microcrystalline cellulose, or mixtures thereof. The lubricant can optionally be added in an amount less than about 1% by weight of the pharmaceutical composition.

[0435] When an aqueous suspension and / or elixir is desired for oral administration, the essential active ingredient therein can be combined with various sweetening or flavoring agents, coloring agents or dyes, and, if desired, with emulsifying and / or suspending agents and diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

[0436] Tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, time delay substances such as glyceryl monostearate or glyceryl distearate can be employed. Oral formulations can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with a water or oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0437] Surfactants useful for forming the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, mixtures of hydrophilic surfactants can be used, mixtures of lipophilic surfactants can be used, or mixtures of at least one hydrophilic surfactant and at least one lipophilic surfactant can be used.

[0438] An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Suitable hydrophilic surfactants generally can have an HLB value of at least 10, while suitable lipophilic surfactants generally can have an HLB value of about 10 or less than about 10. Surfactants with lower HLB values are more lipophilic or hydrophobic and have greater solubility in oil, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds with an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with an HLB value equal to or less than about 10. However, the HLB value of a surfactant is only a rough guide generally used to achieve the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0439] Hydrophilic surfactants can be ionic or nonionic. Suitable ionic surfactants include, but are not limited to: alkylammonium salts; fusidates; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glycerol ester derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysophosphatidylcholine and hydrogenated lysophosphatidylcholine; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactyl lactates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0440] Within the foregoing groups, ionic surfactants include, for example: lecithin, lysophosphatidylcholine, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acyl lactyl lactates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0441] The ionic surfactant may be the ionized form of the following substances: lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactoyl lactate esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartrate esters of monoglycerides / diglycerides, citrate esters of monoglycerides / diglycerides, cholylsarcosine, hexanoates, octanoates, decanoates, laurates, myristates, palmitates, oleates, ricinoleates, linoleates, linolenates, stearates, lauryl sulfates, tetradecyl sulfates, dioctyl sulfosuccinates, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

[0442] The hydrophilic nonionic surfactant may include, but is not limited to, alkyl glucosides; alkyl maltosides; alkylthioglucosides; lauryl polyglycol glycerol esters; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkyl phenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols with at least one of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, their derivatives, and analogs; polyoxyethylated vitamins and their derivatives; polyethylene oxide-polypropylene oxide block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters, and hydrophilic transesterification products of polyols with at least one of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or sugar.

[0443] Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprylic / capric glyceride, PEG-8 caprylic / capric glyceride, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 stigmasterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10-oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

[0444] Suitable lipophilic surfactants include, by way of example only: fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, lactic acid derivatives of glycerol monoesters and glycerol diesters, and hydrophobic transesterification products of polyols with at least one of glycerol esters, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, oil-soluble vitamins / vitamin derivatives, and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or hydrophobic transesterification products of polyols with at least one of vegetable oils, hydrogenated vegetable oils and triglycerides.

[0445] In one embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the compounds of the present invention and to minimize precipitation of the compounds of the present invention. This may be particularly important for compositions for non-oral use (e.g., injectable compositions). A solubilizer may also be added to increase the solubility of hydrophilic drugs and / or other components (such as surfactants), or to maintain the composition as a stable or homogeneous solution or dispersion.

[0446] Examples of suitable solubilizers include, but are not limited to: alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, xylitol, carbitol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000 such as tetrahydrofurfuryl alcohol PEG ether (glycogenol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidones, N-hydroxyalkylpyrrolidones, N-alkylpiperidones, N-alkylcaprolactams, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, triethyl acetylcitrate, tributyl acetylcitrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers known in the art such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidones, monocaprylin, diethylene glycol monoethyl ether and water.

[0447] Mixtures of solubilizers can also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200 - 100, glycogen, carbitol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycogen, and propylene glycol.

[0448] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer can be limited to a biocompatible amount, which can be readily determined by those skilled in the art. In some cases, it may be advantageous to include an amount of solubilizer far in excess of the biocompatible amount, for example, to maximize the concentration of the drug, and to remove the excess solubilizer using conventional techniques (such as distillation or evaporation) before the composition is administered to a patient. Thus, if present, the weight ratio of the solubilizer can be 10 wt%, 25 wt%, 50 wt%, 100 wt%, or up to about 200 wt% based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer can also be used, such as 5%, 2%, 1%, or even less. Generally, the solubilizer can be present in an amount of about 1 wt% to about 100 wt%, more typically about 5 wt% to about 25 wt% by weight.

[0449] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, anti-adhesives, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, coloring agents, fragrances, opacifying agents, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0450] Alternatively, an acid or base can be incorporated into the pharmaceutical composition to facilitate processing, enhance stability or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS), etc. Also suitable are bases that are salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkane sulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic acid, toluenesulfonic acid, uric acid, etc. Salts of polybasic acids such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation such as ammonium, alkali metals and alkaline earth metals. Examples can include, but are not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

[0451] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, etc. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkane sulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, mercaptoacetic acid, toluenesulfonic acid and uric acid.

[0452] Dosage and dosing regimens

[0453] The amount of the solid form of voruciclib administered (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) will depend on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. However, an effective dose is in the range of about 0.001 to about 100 mg / kg body weight / day such as about 1 to about 35 mg / kg / day, in a single dose or in divided doses. For a 70 kg human, this would amount to about 0.05 - 7 g / day, such as about 0.05 to about 2.5 g / day. In some cases, dose levels below the lower limit of the above range may be sufficient, while in other cases, even larger doses may be employed without causing any harmful side effects, for example, by dividing these larger doses into several smaller doses for administration throughout the day.

[0454] In selected embodiments, the solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is administered in a single dose. Generally, such administration will be by injection, for example, by intravenous injection, in order to rapidly introduce the active pharmaceutical ingredient. However, other routes may be appropriately used. The solid form of voruciclib in a single dose (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) can also be used to treat acute conditions.

[0455] In selected embodiments, a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is administered in multiple doses. The dosing can be about once, twice, three times, four times, five times, six times or more than six times per day. The dosing can be about once per month, once every two weeks, once per week or once every other day. In other embodiments, a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is administered from about once per day to about six times per day. In another embodiment, the administration of a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) lasts less than about 7 days. In another embodiment, the administration lasts more than about 6, 10, 14, 28 days, two months, six months or one year. In certain cases, continuous administration can be achieved and maintained as long as needed. In one embodiment, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate and voruciclib naphthalenedisulfonate, each as described herein.

[0456] The administration of the active pharmaceutical ingredient of the present invention can continue as needed. In selected embodiments, a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14 or 28 days. In certain embodiments, a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is administered for less than 28, 14, 7, 6, 5, 4, 3, 2 or 1 day. In selected embodiments, a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is administered long-term on an ongoing basis - for example, for chronic effects. In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate and voruciclib naphthalenedisulfonate, each as described herein.

[0457] In certain embodiments, an effective dose of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is in the range of about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 to about 202 mg. In certain embodiments, an effective dose of a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg or about 500 mg. In certain embodiments, an effective dose of a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg or 500 mg. In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate and voruciclib naphthalenedisulfonate, each as described herein.

[0458] In certain embodiments, an effective dose of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is in the range of from about 0.01 mg / kg to about 4.3 mg / kg, from about 0.15 mg / kg to about 3.6 mg / kg, from about 0.3 mg / kg to about 3.2 mg / kg, from about 0.35 mg / kg to about 2.85 mg / kg, from about 0.15 mg / kg to about 2.85 mg / kg, from about 0.3 mg to about 2.15 mg / kg, from about 0.45 mg / kg to about 1.7 mg / kg, from about 0.15 mg / kg to about 1.3 mg / kg, from about 0.3 mg / kg to about 1.15 mg / kg, from about 0.45 mg / kg to about 1 mg / kg, from about 0.55 mg / kg to about 0.85 mg / kg, from about 0.65 mg / kg to about 0.8 mg / kg, from about 0.7 mg / kg to about 0.75 mg / kg, from about 0.7 mg / kg to about 2.15 mg / kg, from about 0.85 mg / kg to about 2 mg / kg, from about 1 mg / kg to about 1.85 mg / kg, from about 1.15 mg / kg to about 1.7 mg / kg, from about 1.3 mg / kg mg to about 1.6 mg / kg, from about 1.35 mg / kg to about 1.5 mg / kg, from about 2.15 mg / kg to about 3.6 mg / kg, from about 2.3 mg / kg to about 3.4 mg / kg, from about 2.4 mg / kg to about 3.3 mg / kg, from about 2.6 mg / kg to about 3.15 mg / kg, from about 2.7 mg / kg to about 3 mg / kg, from about 2.8 mg / kg to about 3 mg / kg, or from about 2.85 mg / kg to about 2.95 mg / kg. In certain embodiments, an effective dose of a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is about 0.35 mg / kg, about 0.7 mg / kg, about 1 mg / kg, about 1.4 mg / kg, about 1.8 mg / kg, about 2.1 mg / kg, about 2.5 mg / kg, about 2.85 mg / kg, about 3.2 mg / kg or about 3.6 mg / kg. In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate and voruciclib naphthalenedisulfonate, each as described herein.

[0459] In certain embodiments, a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is administered at a dose of 10 - 400 mg once daily (QD), including doses of 5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg once daily (QD). In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0460] In certain embodiments, a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is administered at a dose of 10 - 400 mg twice daily (BID), including doses of 5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg twice daily (BID). In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0461] In certain embodiments, a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is administered at a dose of 10 - 400 mg three times a day (TID), including doses of 5 mg, 10 mg, 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg three times a day (TID). In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl - tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0462] An effective amount of a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) can be administered in a single dose or multiple doses by any accepted mode of administration of an active pharmaceutical ingredient having a similar utility, including rectal, buccal, intranasal, and transdermal routes, by intra - arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0463] Drug compositions for overcoming the effects of acid - reducing agents

[0464] The compositions and methods described herein can be used to overcome the effects of acid - reducing agents. Acid - reducing agents can greatly limit the exposure of weakly acidic drugs in mammals. Smelick, et al., Mol. Pharmaceutics 2013, 10, 4055 - 4062. Acid - reducing agents include proton pump inhibitors such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole; H 2Receptor antagonists, such as cimetidine, ranitidine, and famotidine; and antacids such as bicarbonates, carbonates, and hydroxides of aluminum, calcium, magnesium, potassium, and sodium, as well as mixtures of antacids with agents that target the gastric acid secretion mechanism. Overcoming the effects of acid-reducing agents is an important issue in the treatment of patients with cancer, inflammatory diseases, immune diseases, and autoimmune diseases, as acid-reducing agents are commonly co-administered to these patients to treat the gastric irritation that often accompanies their conditions, as acid-reducing agents are some of the most commonly prescribed drugs in North America and Western Europe. Recently approved oral cancer therapeutics have pH-dependent solubility and thus have potential drug-drug interactions with acid-reducing agents. In cancer patients, it is estimated that 20 - 33% of all patients are using some form of acid-reducing agent. In certain cancers such as pancreatic or gastrointestinal cancer, up to 60 - 80% of patients are using acid-reducing agents. Smelick, et al., Mol. Pharmaceutics 2013, 10, 4055 - 4062.

[0465] In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent selected from fumaric acid, tartaric acid, ascorbic acid, alginic acid, sodium alginate, potassium alginate, and Carbopol 971P (carboxyvinyl polymer). In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent selected from fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-arabinose form of ascorbic acid), alginic acid, Protacid F 120 NM, Protacid AR 1112 (also known as Kelacid NF), Carbomer 941 (polyacrylic acid), and Carbopol 971P (carboxyvinyl polymer). In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein. In one embodiment, the acidifying agent is outside the particle. In one embodiment, the acidifying agent is inside the particle.

[0466] Alginic acid is a polysaccharide copolymer, namely β-D-mannuronic acid (M) and α-L-guluronic acid (G) linked by 1-4 glycosidic bonds. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent, wherein the acidifying agent is alginic acid or a salt thereof, and the alginic acid or a salt thereof exhibits an M / G ratio selected from 0.1 to 0.5, 0.2 to 0.6, 0.3 to 0.7, 0.4 to 0.8, 0.5 to 0.9, 0.6 to 1.0, 0.7 to 1.1, 0.8 to 1.2, 0.9 to 1.3, 1.0 to 1.4, 1.1 to 1.5, 1.2 to 1.6, 1.3 to 1.7, 1.4 to 1.8, 1.5 to 1.9, 1.6 to 2.0, 1.7 to 2.1, 1.8 to 2.2, 1.9 to 2.3, 2.0 to 2.4, and 2.1 to 2.5. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent, wherein the acidifying agent is alginic acid or a salt thereof, and the alginic acid or a salt thereof exhibits an M / G ratio selected from less than 0.5, less than 1.0, less than 1.5, less than 2.0, and less than 2.5. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent, wherein the acidifying agent is alginic acid or a salt thereof, and the alginic acid or a salt thereof exhibits an M / G ratio selected from greater than 0.5, greater than 1.0, greater than 1.5, greater than 2.0, and greater than 2.5. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent, wherein the acidifying agent is alginic acid or a salt thereof, and the alginic acid or a salt thereof exhibits an M / G ratio selected from 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, and 2.5. In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0467] The M / G ratio, and the fractions of M and G groups, the fractions of MM and GG “dyads”, the fractions of “triads” (e.g., MGG), and the fractions of larger sequences of M and G groups can be determined by methods known to those of ordinary skill in the art, including nuclear magnetic resonance (NMR) spectroscopy (with or without digestion) and mass spectrometry. Larsen, et al., Carbohydr.Res., 2003, 338, 2325-2336.

[0468] In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent, the concentration (% by mass) of which is selected from 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, and 30% to 35%. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent, the concentration (% by mass) of which is selected from 1% to 5%, 5% to 10%, 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, and 30% to 35%, wherein the acidifying agent is selected from fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-arabinose-type ascorbic acid), alginic acid, sodium alginate, potassium alginate, Protacid F 120 NM, Protacid AR 1112 (also known as Kelacid NF), and Carbopol 971P (carboxypolymethylene). In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0469] In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent, and the concentration (mass %) of the acidifying agent is selected from less than 1%, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, and less than 35%. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent, and the concentration (mass %) of the acidifying agent is selected from less than 1%, less than 5%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, and less than 35%, wherein the acidifying agent is selected from fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-arabinose-type ascorbic acid), alginic acid, sodium alginate, potassium alginate, Protacid F 120NM, Protacid AR 1112 (also known as Kelacid NF), and Carbopol 971P (carboxyvinyl polymer). In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0470] In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent, the concentration (mass %) of the acidifying agent being selected from greater than 1%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30% and greater than 35%. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and an acidifying agent, the concentration (mass %) of the acidifying agent being selected from greater than 1%, greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30% and greater than 35%, wherein the acidifying agent is selected from fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-arabinose form ascorbic acid), alginic acid, sodium alginate, potassium alginate, Protacid F 120 NM, Protacid AR 1112 (also known as Kelacid NF) and Carbopol 971P (carboxypolymethylene). In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate and voruciclib naphthalenedisulfonate, each as described herein.

[0471] In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) and an acidifying agent, the concentration (% by mass) of the acidifying agent being selected from about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% and about 40%. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) and an acidifying agent, the concentration (% by mass) of the acidifying agent being selected from about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% and about 40%, wherein the acidifying agent is selected from fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-arabinose type ascorbic acid), alginic acid, sodium alginate, potassium alginate, Protacid F 120 NM, Protacid AR 1112 (also known as Kelacid NF) and Carbopol 971P (carboxypolyethylene). In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate and voruciclib naphthalenedisulfonate, each as described herein.

[0472] In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) and an extragranular acidifying agent, wherein the extragranular acidifying agent is selected from fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, erythorbic acid (also known as isoascorbic acid and D-arabinose type ascorbic acid), alginic acid, sodium alginate, potassium alginate, Protacid F 120 NM, Protacid AR 1112 (also known as Kelacid NF), and Carbopol 971P (carboxypolymethylene) and combinations thereof. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) and an extragranular acidifying agent, wherein the extragranular acidifying agent is fumaric acid at a concentration between about 15 wt% and about 33 wt%. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) and an extragranular acidifying agent, wherein the extragranular acidifying agent is alginic acid or a salt thereof (such as sodium alginate or potassium alginate) at a concentration between about 5 wt% and about 33 wt%. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) and an extragranular acidifying agent, wherein the extragranular acidifying agent is L-tartaric acid at a concentration between about 25 wt% and about 33 wt%. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) and an extragranular acidifying agent, wherein the extragranular acidifying agent is ascorbic acid at a concentration between about 20 wt% and about 50 wt% and Carbopol 971P (carboxypolymethylene) at a concentration between about 2.5 wt% and about 10 wt%. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) and an extragranular acidifying agent, wherein the extragranular acidifying agent is fumaric acid at a concentration between about 5 wt% and about 15 wt% and alginic acid or a salt thereof at a concentration between about 15 wt% and about 33 wt%.In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) and an extragalactic acidifying agent, wherein the extragalactic acidifying agent is L-tartaric acid at a concentration between about 5% and 15% by weight and alginic acid at a concentration between about 15% and about 33% by weight.

[0473] In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) and an acidifying agent, wherein the acidifying agent is selected from fumaric acid, maleic acid, phosphoric acid, L-tartaric acid, citric acid, gentisic acid, oxalic acid, and sulfuric acid. In one embodiment, the pharmaceutical composition comprises voruciclib (including any voruciclib free base polymorphs described herein, or any voruciclib salt polymorphs described herein) and an acidifying agent, wherein the acidifying agent is selected from fumaric acid, maleic acid, phosphoric acid, L-tartaric acid, citric acid, gentisic acid, oxalic acid, and sulfuric acid, and wherein the acidifying agent is a salt counterion included in any of the crystal forms described herein.

[0474] In one embodiment, in addition to the acidifying agent, the pharmaceutical composition includes an excipient to prolong the exposure of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) to the acidic microenvironment. In one embodiment, the excipient is a polymer of natural, synthetic, or semi-synthetic origin. The polymer may contain acidic, anionic, or nonionic monomers, oligomers, or polymers, or a mixture of acidic, anionic, and nonionic monomers or copolymers. In one form, the excipient is selected from hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, tocopheryl polyethylene glycol succinate (D-α-tocopheryl polyethylene glycol succinate, TPGS, or vitamin E TPGS), methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methyl acrylate, ethyl acrylate, copolymer of methyl acrylate and ethyl acrylate, hydroxypropyl methylcellulose acetate succinate, gelatin, corn starch, pea starch, modified corn starch, potato starch, modified potato starch, sodium starch glycolate, cross-linked carboxymethylcellulose, crospovidone, copovidone, polyethylene glycol, polypropylene glycol, copolymer of polyethylene and polypropylene glycol, polyvinyl alcohol, copolymer of polyvinyl alcohol and polyethylene oxide. Where applicable, copolymers of the above polymers may also be used. The copolymer may be a block, branched, or end copolymer. In one embodiment, the polymer exhibits swelling, adhesion, or gelling properties that inhibit the disintegration, dissolution, and erosion of the pharmaceutical composition to prolong dissolution or increase total dissolution. In one embodiment, the inclusion of the polymer increases the dissolution rate and dissolution extent compared to using the acidifying agent alone. In one embodiment, the swelling, adhesion, or gelling properties are pH-dependent, where the polymer swells, adheres, or gels in a different manner at one pH or pH range than at other pHs. In one embodiment, this may result in decreased dissolution at a lower pH compared to a higher pH, or vice versa. In another embodiment, this results in similar dissolution of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) at acidic, neutral, or basic pHs. This results in similar plasma exposure, independent of gastric pH.

[0475] The dissolution profiles of formulations containing one or more swelling, gelling, or binding excipients may exhibit zero, one, or two differential rate levels at one or more pH values or a mixture of different rate levels at different pH values. In one embodiment, the pharmaceutical composition will provide a constant level of drug to the gastrointestinal tract of a mammal by dissolution. When voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is absorbed, this results in a sustained plasma level of the drug over a period of time, delaying t max , and reducing the c max of an immediate release formulation of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) at an equivalent dose. In another embodiment, this results in similar exposure in a mammal regardless of gastric pH.

[0476] Treatment Methods of treating solid tumor cancers, hematological malignancies, inflammatory diseases, autoimmune disorders, immune disorders, and other diseases

[0477] The pharmaceutical compositions described herein can be used in methods of treating diseases. In a preferred embodiment, they are used to treat hyperproliferative disorders. They can also be used to treat other disorders described herein and in the following paragraphs.

[0478] In certain embodiments, the present invention provides a method for treating a proliferative disorder in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a crystalline solid form of voruciclib as described herein (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) or a pharmaceutical composition comprising a crystalline solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein). In a preferred embodiment, the mammal is a human. In certain embodiments, the proliferative disorder is cancer. In a preferred embodiment, the cancer is selected from chronic lymphocytic leukemia, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Waldenström's macroglobulinemia. In a preferred embodiment, the cancer is selected from non-Hodgkin lymphoma (such as diffuse large B-cell lymphoma), acute myeloid leukemia, thymic carcinoma, brain cancer, lung cancer, squamous cell carcinoma, skin cancer, eye cancer, retinoblastoma, uveal melanoma, oral cancer and oropharyngeal cancer, bladder cancer, gastric cancer, stomach cancer, pancreatic cancer, bladder cancer, breast cancer, cervical cancer, head cancer, neck cancer, kidney cancer, renal cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, bone cancer (e.g., metastatic bone cancer), esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, CNS cancer, PNS cancer, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), virus-induced cancers such as cervical cancer (human papillomavirus), B-cell lymphoproliferative disorders and nasopharyngeal cancer (Epstein-Barr virus), Kaposi's sarcoma and primary effusion lymphoma (Kaposi's sarcoma herpesvirus), hepatocellular carcinoma (hepatitis B and hepatitis C viruses), and T-cell leukemia (human T-cell leukemia virus-1), B-cell acute lymphoblastic leukemia, Burkitt's leukemia, juvenile myelomonocytic leukemia, hairy cell leukemia, Hodgkin's disease, multiple myeloma, mast cell leukemia, and mastocytosis. In selected embodiments, the method involves the treatment of non-cancerous proliferative disorders such as benign skin hyperplasia (e.g., psoriasis), restenosis, or prostate disorders (e.g., benign prostatic hyperplasia (BPH)). In certain embodiments, the proliferative disorder is an inflammatory disorder, an immune disorder, or an autoimmune disorder.In certain embodiments, the hyperproliferative disorder is selected from tumor angiogenesis, chronic inflammatory diseases, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, and melanoma, ulcerative colitis, atopic dermatitis, cryptitis, spondylarthritis, uveitis, Behçet's disease, polymyalgia rheumatica, giant cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidradenitis suppurativa, Sjögren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, lupus, and lupus nephritis. In one embodiment, the solid form of voruciclib in any of the foregoing embodiments (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0479] In one embodiment, the method of any of the foregoing embodiments further comprises the step of administering an acid reducer to a mammal. In one embodiment, the acid reducer is selected from proton pump inhibitors such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and ilaprazole; H 2 2 receptor antagonists such as cimetidine, ranitidine, and famotidine; and antacids such as bicarbonates, carbonates, and hydroxides of aluminum, calcium, magnesium, potassium, and sodium.

[0480] In certain embodiments, the present invention provides pharmaceutical compositions of a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) for the treatment of cancers such as thymic carcinoma, brain cancer (e.g., glioma), lung cancer, squamous cell carcinoma, skin cancer (e.g., melanoma), eye cancer, retinoblastoma cancer, uveal melanoma cancer, oral cancer, oropharyngeal cancer, bladder cancer, gastric cancer, stomach cancer, pancreatic cancer, bladder cancer, breast cancer, cervical cancer, head and neck cancer, kidney cancer, renal cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, colon cancer, esophageal cancer, testicular cancer, gynecological cancer, ovarian cancer, thyroid cancer, CNS cancer, PNS cancer, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), virus-induced cancers, and epidermoid carcinoma. In certain embodiments, the present invention provides pharmaceutical compositions of a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) for the treatment of non-cancerous hyperproliferative disorders such as benign skin hyperplasia (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)). In certain embodiments, the present invention provides pharmaceutical compositions of a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) for the treatment of disorders such as myeloproliferative disorders (MPD), myeloproliferative neoplasms, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), myelodysplastic syndromes, chronic myeloid leukemia (BCR-ABL1-positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, or mastocytosis. The present invention also provides compositions for the treatment of diseases in mammals related to angiogenesis or vasculogenesis, which mammals may exhibit tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and hemangioma. In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0481] In certain embodiments, the present invention provides a method of treating solid tumor cancers with a composition comprising a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein). In certain embodiments, the present invention provides a method of treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, squamous cell carcinoma (including head and neck cancer), or blood cancer. In one embodiment, the present invention provides a method of treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, colorectal cancer, or blood cancer using a combination of a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein) and a second agent selected from bendamustine, venetoclax, vemurafenib, paclitaxel for injection, enasidenib, pomalidomide, lenalidomide, azacitidine, decitabine, hypomethylating agents, gemcitabine, albumin-bound paclitaxel, rituximab, atezolizumab, ofatumumab, pembrolizumab, nivolumab, durvalumab, avelumab, atezoizumab, bortezomib, marizomib, ixazomib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, carfilzomib, ONX 0912, CEP-18770, MLN9708, epoxomicin, or MG13. In one embodiment, the present invention provides a method for treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, colorectal cancer, or blood cancer using a combination of a CDK inhibitor and bendamustine, venetoclax, vemurafenib, paclitaxel for injection, enasidenib, pomalidomide, lenalidomide, azacitidine, decitabine, hypomethylating agents, gemcitabine, albumin-bound paclitaxel, rituximab, atezolizumab, ofatumumab, pembrolizumab, nivolumab, durvalumab, avelumab, atezoizumab. For certain methods described herein, the proteasome inhibitor is selected from bortezomib, marizomib, ixazomib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, carfilzomib, ONX 0912, CEP-18770, MLN9708, epoxomicin, or MG13, wherein the CDK inhibitor is a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein).In one embodiment, in any of the foregoing embodiments, the solid forms of voruciclib are selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0482] In certain embodiments, the present invention provides a method of treating solid tumor cancers with a composition comprising a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein). In certain embodiments, the present invention provides a method of treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, squamous cell carcinoma (including head and neck cancer). In one embodiment, the present invention provides a method for treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, and colorectal cancer, which uses a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein). In one embodiment, in any of the foregoing embodiments, the solid forms of voruciclib are selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0483] In certain embodiments, the present invention relates to a method of treating an inflammatory, immunological, or autoimmune disorder in a mammal with a composition comprising a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein). In selected embodiments, the present invention also relates to a method of treating a disease with a composition comprising a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein), wherein the disease is selected from tumor angiogenesis, chronic inflammatory diseases, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, and melanoma, ulcerative colitis, atopic dermatitis, cryptitis, spondylarthritis, uveitis, Behçet's disease, polymyalgia rheumatica, giant cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidradenitis suppurativa, Sjögren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, lupus, and lupus nephritis. In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0484] In certain embodiments, the present invention relates to a method of treating a hyperproliferative disorder in a mammal with a composition comprising a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein), wherein the hyperproliferative disorder is a B-cell hematological malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin lymphoma, B-cell acute lymphoblastic leukemia (B-ALL), Burkitt lymphoma, Waldenström macroglobulinemia (WM), Burkitt lymphoma, multiple myeloma, myelodysplastic syndrome, or myelofibrosis. In certain embodiments, the present invention relates to a method of treating a hyperproliferative disorder in a mammal with a composition comprising a solid form of voruciclib (including any voruciclib free base polymorph described herein, or any voruciclib salt polymorph described herein), wherein the hyperproliferative disorder is selected from the group consisting of chronic myelogenous leukemia, acute myeloid leukemia, DLBCL (including activated B-cell (ABC) and germinal center B-cell (GCB) subtypes), follicular center lymphoma, Hodgkin disease, multiple myeloma, indolent non-Hodgkin lymphoma, and mature B-cell ALL. In one embodiment, in any of the foregoing embodiments, the solid form of voruciclib is selected from voruciclib malonate, voruciclib dibenzoyl-tartrate, voruciclib phosphate, voruciclib oxalate, and voruciclib naphthalenedisulfonate, each as described herein.

[0485] In certain embodiments, the hyperproliferative disorder is a subtype of CLL. A number of subtypes of CLL have been characterized. CLL is often classified with respect to the immunoglobulin heavy chain variable region (IgV H ) mutation status in leukemic cells. R.N. Damle, et al., Blood 1999, 94, 1840-47; T.J. Hamblin, et al., Blood 1999, 94, 1848-54. Patients with IgV H mutations generally have a better prognosis than those without IgV HPatients with mutations survive longer. ZAP70 expression (positive or negative) is also used to characterize CLL. L.Z. Rassenti, et al., N. Engl. J. Med. 2004, 351, 893 - 901. Methylation of ZAP-70 at CpG3 is also used to characterize CLL, for example by pyrosequencing. R. Claus, et al., J. Clin. Oncol. 2012, 30, 2483 - 91; J.A. Woyach, et al., Blood 2014, 123, 1810 - 17. CLL is also classified by the stage of the disease under the Binet or Rai criteria. J.L. Binet, et al., Cancer 1977, 40, 855 - 64; K.R. Rai, T. Han, Hematol. Oncol. Clin. North Am. 1990, 4, 447 - 56. Other common mutations, such as deletions of 11q, 13q, and 17p, can be evaluated using well-known techniques such as fluorescence in situ hybridization (FISH). In one embodiment, the present invention relates to a method of treating CLL in a human, wherein the CLL is selected from IgV H mutation-negative CLL, ZAP-70-positive CLL, CLL with methylation of ZAP-70 at CpG3, CD38-positive CLL, chronic lymphocytic leukemia characterized by deletion of 17p13.1 (17p), and CLL characterized by deletion of 11q22.3 (11q).

[0486] In certain embodiments, the hyperproliferative disorder is CLL in which the CLL has undergone Richter's transformation. Methods for assessing Richter's transformation (which is also known as Richter's syndrome) are described in Jain and O'Brien, Oncology, 2012, 26, 1146 - 52. Richter's transformation is a CLL subtype observed in 5 - 10% of patients. It involves the development of an aggressive lymphoma from CLL and has a generally poor prognosis.

[0487] In certain embodiments, the hyperproliferative disorder is CLL or SLL in a patient, wherein the patient is sensitive to lymphocytosis. In one embodiment, the present invention relates to a method of treating CLL or SLL in a patient, wherein the patient exhibits lymphocytosis caused by a disorder selected from: viral infection, bacterial infection, protozoal infection, or post-splenectomy status. In one embodiment, the viral infection in any of the foregoing embodiments is selected from infectious mononucleosis, hepatitis, and cytomegalovirus. In one embodiment, the bacterial infection in any of the foregoing embodiments is selected from whooping cough, tuberculosis, and brucellosis.

[0488] In certain embodiments, the hyperproliferative disorder is a blood cancer. In certain embodiments, the blood cancer is leukemia, such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic lymphoma (ALL), and chronic lymphocytic leukemia (CLL). In certain embodiments, the blood cancer is non-Hodgkin lymphoma, such as B-cell or T-cell lymphoma. B-cell lymphomas include diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, and primary central nervous system lymphoma. T-cell lymphomas include precursor T-lymphoblastic lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, adult T-cell lymphoma with chronic, acute, and lymphoma subtypes of smoldering, angioimmunoblastic T-cell lymphoma, extranodal natural killer / T-cell lymphoma, nasal type, enteropathy-associated intestinal T-cell lymphoma (EATL) with subtypes I and II, and anaplastic large cell lymphoma (ALCL). Example

[0489] Example 1: Polymorph Screening- Voruciclib HCl

[0490] The aim of this study was to explore the polymorph landscape of voruciclib HCl and to identify the form most suitable for further development. For this purpose, extensive polymorph screening was carried out using a variety of crystallization methods and a variety of solvents and solvent mixtures. The amorphous phase of voruciclib was used as the starting material for the screening experiments to allow unbiased crystallization to occur.

[0491] Different crystallization methods were carried out using a variety of solvents and solvent mixtures. The API was highly soluble in solvents with high dielectric constants and hydrogen acceptor tendencies (DMF, DMSO, DMA, and alcohols), and the API was poorly soluble in all other solvents tested. Some polymorph screening experiments were started with the amorphous phase as the starting material to allow unbiased crystallization to occur.

[0492] Without wishing to be bound by any particular theory, it is believed that although only one anhydrous and non-solvated crystalline phase (Form 1) was directly obtained from several crystallization experiments, the API exhibits very complex pseudopolymorphic behavior and twenty new solid forms have been identified. The crystallization of the different forms depends not only on the solvent used but also on the crystallization method. For this reason, and without wishing to be bound by any particular theory, it is believed that even more solvated forms may exist when different crystallization conditions are used. Some of the solvated forms are non-stoichiometric and can be obtained from different solvents (isostructural pseudopolymorphs).

[0493] Without wishing to be bound by any particular theory, it is believed that Form 1 is the unique stable non-solvated and anhydrous form identified herein, suggesting that Form 1 is the thermodynamically stable form. Experiments exploring mixtures of the current process solvents (methanol, 2-propanol, and diisopropyl ether) have shown that the solid phase precipitated from these solvent mixtures is Form 1, except for the solvated forms obtained after evaporation of the solution.

[0494] Twenty (20) unique solid forms of voruciclib HCl have been identified, where Form 1 is the non-solvated and anhydrous form (identical to the starting material, with a melting point of approximately 260 °C). All other forms appear to be solvated forms. After desolvation, these forms appear to convert to Form 1 (based on the melting event observed in the DSC trace at 260 °C) or become amorphous.

[0495] Experiments using the current process solvents (methanol, 2-propanol, diisopropyl ether) resulted in the crystallization of Form 1 by slurry conversion or cooling crystallization, but when the solution was evaporated, the solvated forms were recovered.

[0496] From the analytical characterization of several batches of voruciclib HCl, a small crystalline phase impurity was identified by XRPD, possibly attributable to a solvate form.

[0497] Although only one anhydrous and non-solvated crystalline phase (Form 1) was crystallized in this study, voruciclib exhibits very complex pseudopolymorphic behavior. The crystallization of the different forms depends not only on the solvent used but also on the crystallization method. Many of the solvated forms are non-stoichiometric and can be obtained from different solvents (isostructural pseudopolymorphs).

[0498] Experiments exploring mixtures of the current process solvents (methanol, 2-propanol, and diisopropyl ether) have shown that the solid phase crystallized from these solvent mixtures is Form 1, but by evaporating the solution, a solvated form is obtained. Thus, during the preparation of voruciclib HCl, there is always a risk of forming (trace amounts of) the solvated form. The source of the phase impurities found in some of the batches analyzed can be attributed to the evaporation of the crystallization solvent during the crystallization process, filtration, or final drying stage.

[0499] Abbreviations: AAC: Accelerated aging conditions (40 °C and 75% RH); Am: Amorphous; API: Active pharmaceutical ingredient; AS: Experiment ID for anti-solvent addition experiments; DSC: Differential scanning calorimetry; ECP: Experiment ID for evaporation experiments; HPLC: High-performance liquid chromatography; HR-XRPD: High-resolution X-ray powder diffraction; HT-XRPD: High-throughput X-ray powder diffraction; LCMS: Liquid chromatography-mass spectrometry; MS: Mass spectrometry; PSM: Experiment ID for cooling crystallization experiments; QSA: Experiment ID for solubility determination experiments; RH: Relative humidity; RT: Room temperature; SLP: Experiment ID for solvent equilibrium experiments; SM: Starting material; TCP: Experiment ID for thermal cycling experiments; TGA: Thermogravimetric analysis; TGMS: Thermogravimetric analysis coupled with mass spectrometry; VDL: Experiment ID for vapor diffusion experiments; ACN: Acetonitrile; DMA: N,N-Dimethylacetamide; DMF: N,N-Dimethylformamide; DMSO: Dimethyl sulfoxide; IPA: 2-Propanol; MeOH: Methanol; TBME: tert-Butyl methyl ether; TFE: 2,2,2-Trifluoroethanol; THF: Tetrahydrofuran.

[0500] Five batches of voruciclib HCl were used for analytical characterization, which included HR-XRPD (indexed), DSC, TGMS, and LCMS. Using the single crystal data of voruciclib HCl Form 1 obtained in previous studies, the crystalline phases were quantified from the recorded powder patterns by Rietveld analysis. The overlap of the XRPD patterns is as Figure 1 shown, and the final Rietveld parameters are shown in Table 1. All batches consisted of Form 1. Batches 1694M-1401 and P1446A-05_EN017 were pure Form 1 (no other crystalline phases were detected). Batches 1694M-1301, 1694M-1201, and P1446A-05_EN027 contained approximately 1-2% crystalline impurities.

[0501] Table 1: Final Rietveld parameters for five batches of voruciclib HCl; determination of sample purity (BDL: Below detection limit)

[0502]

[0503] The DSC traces showed that all five batches exhibited endothermic events with onset temperatures of 257 - 258 °C and peak temperatures of approximately 263 - 264 °C ( Figure 2 ). TGA analysis of the batches revealed that the residual solvent / water content varied between 0.3 - 0.5% ( Figure 3 ). Decomposition started at approximately 250 °C.

[0504] The chemical purity of the API was evaluated by HPLC analysis. The results are summarized in Table 2. Based on the HPLC determination, the chemical purity of all batches was comparable. The HPLC chromatogram of batch P1446A - 05_EN017 showed a small shoulder peak in the main peak, giving an area % of 98.9%. The other batches showed a single peak, giving an area % of 100%.

[0505] Table 2: HPLC results for five batches. Purity was determined by area % and by assay (recovery).

[0506]

[0507] Characterization of the five batches showed no significant differences in thermal behavior and chemical purity, although three batches showed less than 2% crystalline impurities by XRPD.

[0508] Voruciclib HCl (approx. 39 g) of batch 1694M - 1301 was used as the starting material for polymorph screening. High - throughput XRPD (HT - XRPD) was shown in the figure for reference purposes.

[0509] DSC analysis showed an endothermic event with an onset temperature of 257 °C and a T peak at 263 °C ( Figure 5 ). TGMS analysis indicated a 0.3% mass loss prior to decomposition due to residual solvent or moisture ( Figure 6 ). Decomposition started at approximately 250 °C and was accompanied by an endothermic event in the heat - flow signal.

[0510] The results of the thermal analysis indicated that the starting material (form 1) was the anhydrous crystalline phase of voruciclib HCl.

[0511] The chemical purity of the API was evaluated by LCMS analysis. The results showed that the purity of the solid was 100% (area %). The cationic spectrum showed an ion with m / z of 470.1, corresponding to the ion (M + H) + , which was consistent with the molecular mass of the free base of 469.8 g / mol.

[0512] The physical stability of Form 1 under pressure was evaluated. Four experiments were conducted. Approximately 100 mg of the API was compressed in a tableting machine (10 tons, 13 mm diameter die) at room temperature for 1 minute, at room temperature for 10 minutes, at 80 °C for 1 minute, and at 80 °C for 10 minutes. The samples were then analyzed by HR-XRPD. The overlap of the XRPD patterns is as Figure 8 shown. All samples retained Form 1, and there were no significant differences between the crystallinity and physical appearance of the solids, indicating that Form 1 is stable under pressure at room temperature and at high temperature.

[0513] The physical stability of Form 1 was evaluated during grinding. One sample was ground using a Retch mill at 30 Hz with 1 mm diameter stainless steel balls for 5 minutes, and a second sample was ground manually using a mortar and pestle for approximately 5 minutes. The samples were then analyzed by HR-XRPD and the amount of amorphous content was calculated (assuming the starting material was 100% crystalline). The results for the manually ground sample are as Figure 9 shown and contained approximately 10% amorphous content. The results for the mechanically ground sample are as Figure 10 shown and contained approximately 7% amorphous phase. No other crystalline phases were observed.

[0514] Preferably, the polymorph screening experiments are started with the amorphous phase to facilitate unbiased crystallization. Therefore, an attempt was made to produce amorphous voruciclib HCl. Solutions of the API were prepared in methanol / water 90 / 10, THF / water 90 / 10, and 1,4-dioxane / water 90 / 10. The solutions were lyophilized and the resulting solids were analyzed by HT-XRPD. The experimental details are reported in §6.2.1 on page 20.

[0515] The XRPD diffraction patterns of the solids obtained by lyophilization are as Figure 11 shown. Amorphous solids were recovered from 1,4-dioxane / water (90 / 10 v / v) and THF / water (90 / 10 v / v). A crystalline solid different from the starting material, designated Form 2, was recovered from methanol / water (90 / 10 v / v).

[0516] The amorphous materials were analyzed by TGMS. Both amorphous solids contained approximately 4% solvent. Since 1,4-dioxane / water is a better solvent mixture for lyophilization, this solvent system was chosen to produce the amorphous material for screening.

[0517] Solubility study

[0518] The thermodynamic solubility was determined by the shake flask method. Suspensions of the amorphous API were prepared in 33 solvents. Subsequently, the solids were equilibrated for 24 h at room temperature under continuous stirring. After equilibration, small aliquots of the mother liquor were filtered and analyzed by HPLC. The concentration of the solute was determined according to the calibration curve of the API.

[0519] According to the classification of the United States Pharmacopeia (USP29), the solubility values were ranked in Table 3. The API was highly soluble in DMA, DMF, and DMSO, with solubility higher than 400 mg / mL. The API was soluble in alcohols. The solubility in short-chain alcohols was higher than that in long-chain alcohols, i.e., the solubility in methanol was 230 mg / mL, while the solubility in 2-butanol was 10 mg / mL. In all other solvents, the solubility was less than 10 mg / mL. These results indicated that the API was more soluble in solvents with high dielectric constants and hydrogen acceptor tendencies. A gel was formed in water.

[0520] Table 3: Solubility results of voruciclib HCl at room temperature. Suspensions were prepared with amorphous API, and aliquots of the mother liquor were filtered after 24 h. The concentration of the solute was determined by HPLC analysis. Suspensions were not obtained in DMA, DMSO, and DMF, and the concentrations mentioned were those of the solutions obtained after the addition of the first aliquot. The solubility was ranked according to the United States Pharmacopeia (USP29).

[0521]

[0522] Polymorph screening

[0523] Polymorph screening was carried out by combining different crystallization techniques with various solvents and solvent mixtures.

[0524] Solvent equilibration experiments were carried out at two temperatures; 2 weeks at room temperature and 1 week at 50 °C. Suspensions were prepared with amorphous API, and after the equilibration time was completed, the solids were separated from the mother liquor. One portion of the solids was dried overnight under ambient conditions and analyzed by HT-XRPD, and the second portion of the solids was dried overnight at 50 °C under vacuum (10 mbar).

[0525] Using the filtered mother liquor recovered from the solvent equilibration experiments at room temperature and from the saturated solutions of the solvent mixtures, evaporation crystallization experiments from pure solvents were established. The mother liquor was slowly evaporated under ambient conditions and then further dried at 50 °C under vacuum.

[0526] Cooling crystallization experiments from pure solvents were established using the solvent equilibration experiments conducted at 50 °C and the filtered mother liquor recovered from the saturated solutions of the solvent mixtures. The mother liquor was slowly cooled to 5 °C and aged for 72 hours. The precipitated solid was separated from the liquid phase and dried overnight at 50 °C under vacuum (10 mbar).

[0527] Crystallization was carried out by thermal cycling experiments in solvent mixtures and solvent / water mixtures. Suspensions were prepared with amorphous API and temperature profiles were performed, which included three heating and cooling cycles between 5 - 50 °C.

[0528] Antisolvent addition experiments were carried out according to the reverse antisolvent addition method, which means that a small volume of (saturated) API solution was rapidly added to 20 mL of antisolvent.

[0529] Vapor diffusion experiments in solution were carried out using (near) saturated solutions of API in solvents (where solubility was high in vials). The open vials were placed in larger vials containing 2 mL of antisolvent. The vials were stored at room temperature for 2 weeks and then the precipitated solid was separated from the liquid.

[0530] Vapor diffusion onto solids was carried out using amorphous API. The amorphous solid was exposed to the vapors of five different solvents at room temperature for two weeks. The open 1.5 mL HPLC vials containing amorphous API were placed in larger containers containing 2 mL of solvent.

[0531] All the obtained solids were analyzed by HT-XRPD. Subsequently, all the solids were exposed to accelerated aging conditions (40 °C / 75% RH, AAC) for two days and then re-analyzed by HT-XRPD.

[0532] Several new XRPD diffraction patterns were obtained from different crystallization conditions. Table 4 shows the list of forms and the crystallization conditions where new forms were found, while the summary of different forms is presented below:

[0533] Form 1, which is the same as the starting material, was found from various solvents and crystallization methods. After exposure to AAC, Form 1 is stable.

[0534] Form 2 is a stable form obtained from different types of solvents and almost all crystallization methods (except the vapor diffusion method).

[0535] Form 3 was mainly observed from experiments conducted in long-chain alcohols and alcohol mixtures. In most cases, Form 3 is unstable after exposure to AAC and a transformation to Form 13 was observed. Form 13 was obtained only once by direct crystallization by evaporation in ethanol.

[0536] Forms 4 and 5 were mainly observed from solvent equilibration and thermal cycling experiments in neat solvents and converted to Form 6 after AAC, which is a poorly crystalline form. Form 6 was also obtained by drying the gel formed in water.

[0537] Form 7 was obtained from solvent equilibration experiments at room temperature and thermal cycling in 1,2-dimethoxyethane. This form is stable upon exposure to AAC.

[0538] Form 8 was mainly recovered from crystallization experiments with short-chain alcohols and alcohol mixtures. Form 8 remained stable during AAC.

[0539] Form 9 crystallized only from DMF and was physically unstable. Several solid form conversions were observed. The vacuum-dried solid from the cooling crystallization experiment in DMF was identified as Form 10. After exposure to AAC, Form 10 was converted to Form 20. Form 20 was not directly found from the crystallization experiments.

[0540] Form 11 is an unstable form found from experiments in DMA.

[0541] Forms 12 and 14 were found from thermal cycling experiments using acetone / water and acetonitrile / water. Although both forms were stable upon exposure to AAC, Form 12 was identified in the solid dried under ambient conditions and converted to Form 14 when dried under vacuum at 50 °C.

[0542] Form 15 was obtained from the vapor diffusion of DMF / 1,4-dioxane into the solution and cooling crystallization from methanol. This form was converted to Form 2 after AAC.

[0543] Form 16 was always obtained when the crystallization experiment contained DMSO and was converted to different forms after AAC.

[0544] Form 17 is an unstable form that was converted to Form 13 after AAC and was obtained from the anti-solvent addition experiment of TFE / heptane.

[0545] Form 18 was obtained from the anti-solvent experiment using DMF / isopropyl acetate and remained stable upon exposure to AAC.

[0546] Form 19 was obtained from the evaporation crystallization experiment in methanol / diisopropyl ether (20 / 80) and was stable during AAC.

[0547] Table 4: List of the forms of voruciclib HCl identified in the screening and the crystallization conditions where they were found. The physical stability of the forms was evaluated after exposure to accelerated aging conditions (AAC, 40 °C / 75% RH) for 2 days.

[0548]

[0549]

[0550] *Method: SLP = Solvent equilibration, PSM = Cooling, ECP = Evaporation, TCP = Thermal cycling, AS = Anti-solvent, VDL = Vapor diffusion.

[0551] The unique XRPD diffraction patterns observed during the study are shown in Figure 12A and 12B .

[0552] The new solid forms were further analyzed by DSC, TGMS and HPLC to confirm the integrity of the compound and the nature of the forms. For each form, a sample was selected for further analysis. The analytical results are reported in detail herein and summarized in Table 5.

[0553] Form 1, which is the same as the crystallization starting material, appears to be the only non-solvated and anhydrous form obtained directly from the crystallization experiments. All other forms contain solvents and / or water.

[0554] Forms 7, 10, 16 and 19 were obtained from specific solvents, but the mass losses observed from TGMS analysis indicate that these forms are non-stoichiometric solvates. The thermal events observed by DSC analysis indicate that each of these forms can be converted to form 1 upon heating (based on the melting event observed at approximately 260 °C).

[0555] Cyclic DSC experiments were performed on form 7 to investigate whether a solvent-free form could be obtained. Just after the solvent loss and before the first endothermic event, the solid was heated to 155 °C. The XRPD of the solid obtained after heating to 155 °C was the same as that of the solid before the experiment. TGMS analysis of the dried solid showed a 2.3% mass loss of water. Once the sample was removed from the DSC crucible, the solid was likely to absorb water. These results suggest that form 7 could be a 1,2-dimethoxyethane solvate and / or a hydrated form.

[0556] Forms 2, 3, 4, 5, 8, 11, 12, 13, 14, 15 and 17 appear to be solvated forms obtained from different crystallization solvents; therefore, they are likely to be isostructural solvates (similar crystal structures obtained with different solvents and solvent contents). Thermal analysis results indicate that forms 3 and 8 become amorphous after desolvation, while the other solvated forms can be converted to form 1 (based on the melting event observed at approximately 260 °C).

[0557] Forms 3 and 8 were mainly obtained from alcohols. In many cases, form 3 is converted to form 13, suggesting that form 13 may be a hydrated form or a mixed solvate / hydrate.

[0558] Form 4 was obtained from several solvents. Cyclic DSC experiments on Form 4 showed behavior similar to that observed for Form 7. The XRPD pattern of the heated solid was slightly different from Form 4 (designated as Form 4b). TGMS analysis of the solid recovered after cyclic DSC showed a mass loss of approximately 2%, suggesting that the solid adsorbs water immediately once under ambient conditions.

[0559] Forms 12 and 14 were obtained from acetone / water and acetonitrile / water mixtures. After vacuum drying, Form 12 was converted to Form 14. Additional cyclic DSC experiments were performed on Forms 12 and 14 by heating the solid samples to 155 °C (just after solvent loss). The powder patterns of the recovered solids were similar to Form 14. TGMS analysis of the solids obtained after the cyclic DSC experiments contained approximately 1.9% water, suggesting that Form 14 may be a solvated and / or hydrated form.

[0560] Form 6 is a poor crystalline form and contains approximately 0.5 molar equivalents of water. After dehydration, the solid becomes amorphous.

[0561] Forms 9 and 18 were only identified in ambient-dried solids and were converted to multiple other forms after vacuum drying. Without wishing to be bound by any particular theory, it is believed that these forms are most likely metastable solvated forms.

[0562] Table 5: Summary of the analytical characterization of the new forms of voruciclib HCl. Form 1 is the non-solvated and anhydrous form. All other forms are (isostructural) solvated (or hydrated) forms that either (eventually) convert to Form 1 or become amorphous after solvent removal.

[0563]

[0564] (m: melting; broad endotherm: broad endothermic event; exotherm: exothermic event).

[0565] Materials and methods

[0566] Six batches of voruciclib HCl were provided. Batches P1446A-05_EN017, P1446A-05_EN027, 1694M-1201, 1694M-1301, 1694M-1401, each of 250 mg, were used only for analysis, and the 39 g batch 1694M-1301 was used for polymorph screening. Other chemicals were obtained from Fisher Scientific, Sigma Aldrich or VWR. The chemicals used were at least research grade, and the HPLC mobile phase was HPLC grade.

[0567] Attempts were made to produce amorphous solids. The API was weighed into a standard HPLC vial and an aliquot of solvent was added until the API dissolved. The solution was frozen in liquid nitrogen and placed under deep vacuum using a freeze dryer (Alpha 2-4 LD, Christ). The solid was additionally dried under vacuum (10 mbar) at 50 °C for 24 h. The solid obtained was analyzed by HT-XRPD. The experimental conditions and results are shown in Table 6. The amorphous material was further analyzed by TGMS to determine the solvent content.

[0568] An amorphous batch with experimental ID Gen12 was used as the starting material for the screening experiment. The solution was aliquoted into 1.8 mL glass vials and then freeze-dried, with each vial yielding approximately 40 mg of amorphous API.

[0569] Table 6: Experimental conditions and results of attempts to produce amorphous solids. Solutions were prepared with voruciclib HCl. The solutions were freeze-dried overnight and the resulting solids were analyzed by HT-XRPD.

[0570]

[0571] Solubility determination

[0572] The solubility was determined in 33 solvents. A defined volume of solvent was added in small steps to the amorphous solid in a 1.8 mL glass vial until a thin suspension was obtained (Table 7). The suspension was equilibrated with continuous stirring at room temperature. After 24 h, a small aliquot of the mother liquor was taken and filtered using a 0.2 μM PTFE syringe filter. The concentration of the solute was determined by HPLC analysis. Calibration lines were prepared from two independent stock solutions of acetonitrile / water 25 / 75 (v / v).

[0573] The remaining suspension was used for solvent equilibration experiments at room temperature for two weeks.

[0574] Table 7: Experimental conditions for the determination of thermodynamic solubility by the shake-flask method. Suspensions were prepared and equilibrated at room temperature. After 24 h, a small aliquot of the mother liquor was filtered and the concentration of the solute was determined by HPLC analysis.

[0575]

[0576] Equilibrium experiments at room temperature and at 50 °C

[0577] Solvent equilibration experiments were carried out in 33 solvents. Solvent was added in small steps to vials containing approximately 40 mg of amorphous API until a thin suspension was obtained. The suspension was equilibrated with continuous stirring for 2 weeks at room temperature (Table 8) and for 1 week at 50 °C (Table 9).

[0578] After the equilibration time, the solid was separated by centrifugation. A portion of the solid was collected and harvested on a 96-well plate and dried overnight under ambient conditions. The remaining solid was dried overnight under vacuum (50 °C and 10 mbar) and then harvested on a 96-well plate. All solids were analyzed by HT-XRPD. Subsequently, all solids were exposed to accelerated aging conditions for 2 days (AAC, 40 °C / 75% RH) and reanalyzed by HT-XRPD.

[0579] Table 8: Experimental conditions and XRPD results of the solvent equilibration experiments on voruciclib HCl at room temperature. Suspensions of amorphous voruciclib HCl were prepared in the solvents listed and stirred at room temperature for 2 weeks. After the equilibration time, the solids were analyzed by HT-XRPD after drying under ambient conditions (ambient) and after drying under vacuum (vacuum). All solids were exposed to AAC for 2 days and reanalyzed by XRPD.

[0580]

[0581] Table 9: Experimental conditions and XRPD results of the solvent equilibration experiments on voruciclib HCl at 50 °C. Suspensions of voruciclib HCl were prepared in the solvents listed and stirred at 50 °C for 1 week. After the equilibration time, the solids were analyzed by HT-XRPD after drying under ambient conditions (ambient) and after drying under vacuum (vacuum). All solids were exposed to AAC for 2 days and reanalyzed by XRPD.

[0582]

[0583] Evaporative crystallization experiment

[0584] For the evaporation crystallization experiments from pure solvents, the mother liquor recovered from the room temperature solvent equilibration experiments was used. For the evaporation crystallization experiments from solvent mixtures, new suspensions were prepared.

[0585] The mother liquor was filtered using a 0.2 μm PTFE syringe filter. The solution was transferred to a vial (without cap) and left under ambient conditions to allow the solvent to slowly evaporate for 3 days under ambient conditions, followed by vacuum at 50 °C until all the solvent had evaporated. The solid obtained was analyzed by HT-XRPD. Subsequently, the solid was exposed to accelerated aging conditions (40 °C / 75% RH) for 2 days and reanalyzed by HT-XRPD.

[0586] Table 10: Experimental conditions and XRPD results of the evaporation crystallization experiments. The solution was placed under ambient conditions to allow the solvent to slowly evaporate. The solid recovered was analyzed by HT-XRPD. If no solid was obtained, it was indicated by "-".

[0587]

[0588]

[0589] Cooling crystallization experiment

[0590] Cooling crystallization experiments from pure solvents were carried out at 50 °C using the mother liquor recovered from the solvent equilibrium experiments. For the cooling crystallization experiments from solvent mixtures, new suspensions were prepared.

[0591] The mother liquor was filtered at 50 °C using a 0.2 μm PTFE syringe filter. The solution was transferred to a standard HPLC vial and the solution was slowly cooled in a Crystal16 TM reactor. The solution was cooled to 5 °C at 1 °C / h and aged at 5 °C for 72 h. The precipitated solid was separated by centrifugation and dried under vacuum (50 °C / 10 mbar) overnight and analyzed by HT-XRPD.

[0592] The mother liquor and solution in which precipitation did not occur were placed under ambient conditions to allow the solvent to evaporate and then evacuated. The recovered solid was analyzed by HT-XRPD.

[0593] Subsequently, all solids were exposed to AAC for 2 days and re-analyzed by HT-XRPD.

[0594] Table 11: Experimental conditions and XRPD results of the cooling crystallization experiments. The saturated solution obtained at 50 °C was cooled to 5 °C at 1 °C / h and aged for 72 h. The precipitated solid was analyzed by HT-XRPD after vacuum drying (solid). The mother liquor and solution in which precipitation did not occur were evaporated and the obtained solid was analyzed by HT-XRPD (ML). All solids were exposed to AAC for 2 days and re-analyzed by XRPD. If no solid was obtained, it was indicated by "-".

[0595]

[0596]

[0597] Thermal cycling

[0598] The polymorphic behavior of the selected salt was evaluated by thermal cycling in 6 solvents. Aliquots of the solvent were added to a vial containing the (amorphous) salt until a suspension was obtained. The experimental details are shown in Table 12.

[0599] The vials were subjected to a temperature profile including 3 thermal cycles between 5 - 50 °C and aged at room temperature for 2 days, see Figure 13. After the temperature profile, the samples were dried under vacuum (10 mbar) at room temperature for 24 h. The samples were collected and analyzed by HT-XRPD. Subsequently, the solids were exposed to accelerated aging conditions (AAC, 40 °C / 75% RH) for two days and re-analyzed by HT-XRPD.

[0600] Table 12: Experimental conditions and XRPD results for the thermal cycling experiments of voruciclib salts. Suspensions of amorphous API were subjected to a temperature profile consisting of three heating and cooling cycles ( Figure 13 ). After the aging time, the solids were analyzed by HT-XRPD after drying under ambient conditions (ambient) and after drying under vacuum (vacuum). The solvent was evaporated from the liquid phase and the recovered solids were analyzed. All solids were exposed to AAC for 2 days and re-analyzed by XRPD. If no solid was obtained, it was indicated by "-". "tr" refers to "trace".

[0601]

[0602]

[0603] Antisolvent

[0604] The anti-solvent addition experiment was carried out according to the reverse anti-solvent addition method. A high-concentration solution of voruciclib HCl was prepared in a solvent in which the API had good solubility. The solution was immediately added to 20 mL of anti-solvent (in which the API was insoluble) while stirring vigorously. The precipitated solid was separated by centrifugation, and one portion of the solid was harvested and dried under ambient conditions. Another portion of the solid was dried under vacuum (10 mbar) at 50 °C for 24 h. Subsequently, the solids were exposed to accelerated aging conditions (AAC, 40 °C / 75% RH) for two days and re-analyzed by HT-XRPD.

[0605] Table 13: Experimental conditions and XRPD results for the anti-solvent experiments. The solution in the solvent / water mixture was added to 20 mL of THF. No precipitation occurred, nor did it occur after aging at 5 °C for 72 h. "tr" refers to "trace".

[0606]

[0607] Vapor diffusion into solution

[0608] A (near)-saturated solution of voruciclib HCl was prepared by dissolving approximately 50 mg of the API in a solvent in a 1.5 mL or 8 mL glass vial. The API did not dissolve completely in ethanol and THF, so these suspensions were filtered to obtain a saturated solution. The solution in the vial was placed in a larger vial containing 2 mL of antisolvent (see Table 14). The vial was stored at room temperature for 2 weeks, then the precipitated solid was carefully collected from the liquid and analyzed by HT-XRPD. In the case where no solid precipitated, the solvent was evaporated under ambient conditions and then under vacuum (10 mbar / 50 °C) and the recovered solid was analyzed by XRPD. Subsequently, all solids were exposed to AAC (40 °C / 75% RH) and re-analyzed by XRPD.

[0609] Table 14: Experimental conditions and XRPD results for the vapor diffusion into solution experiment. A near-saturated solution was prepared in a solvent and the solution was exposed to the vapor of the antisolvent. After equilibration at room temperature for 2 weeks, the solid was analyzed by XRPD (solid). In the case where no precipitation occurred, the solvent was evaporated and the recovered solid was analyzed by XRPD (liquid). All solids were exposed to AAC and re-analyzed by XRPD.

[0610]

[0611] Vapor diffusion on solid

[0612] Vapor diffusion on solid experiments were carried out using amorphous voruciclib HCl as the starting material. A vial containing approximately 20 mg of amorphous API was placed in a larger vial containing 2 mL of solvent (see Table 15). The vial was stored at room temperature for 2 weeks, then the solid was analyzed by HT-XRPD. In the solvent trapped in the vial, the solvent was evaporated under vacuum (10 mbar / 50 °C) and the recovered solid was analyzed by XRPD. Subsequently, all solids were exposed to AAC (40 °C / 75% RH) and re-analyzed by XRPD.

[0613] Table 15: Experimental conditions and XRPD results for the vapor diffusion on solid experiment. The amorphous API was exposed to the solvent vapor. After equilibration at room temperature for 2 weeks, the solid was analyzed by XRPD (solid). In one sample, the solvent was trapped in the vial and the solvent was evaporated (liquid). All solids were exposed to AAC and re-analyzed by XRPD.

[0614]

[0615] X-ray powder diffraction

[0616] The XRPD pattern was obtained using a Crystallics T2 high-throughput XRPD instrument. The plate was mounted on a Bruker D8 Discover General Area Detector Diffraction System (GADDS) equipped with a gas area detector (Product Sheet XRD 37, DOC-S88-EXS037V3, Figure 297 ). Calibration of the measurement accuracy (peak position) was performed using a NIST SRM1976 standard (corundum).

[0617] Data collection was carried out in the 2θ region between 1.5° and 41.5° using monochromatic CuKα radiation at room temperature, which is the most distinctive part of the XRPD pattern. The diffraction pattern of each well was collected in two 2θ ranges (the first frame was 1.5° ≤ 2θ ≤ 21.5°, and the second frame was 19.5° ≤ 2θ ≤ 41.5°), with an exposure time of 45 s for each frame. No background subtraction or curve smoothing was applied to the XRPD pattern.

[0618] The carrier material used during XRPD analysis was X-ray transmissive and contributed only slightly to the background.

[0619] TGA / SDTA and TGMS analysis

[0620] Mass loss due to solvent or water loss from the crystal was determined by TGMS analysis. The sample weight was monitored during heating in a TGA / DSC 3+ STARe system (Mettler-Toledo GmbH, Switzerland) to obtain a curve of weight versus temperature. The temperature of the TGA / DSC 3+ was calibrated using indium and aluminum. The sample (ca. 2 mg) was weighed into a 100 μL aluminum crucible and sealed. The seal was perforated with a needle, and the crucible was heated in the TGA from 25 °C to 300 °C at a heating rate of 10 °C / min. Dry nitrogen was used for purging.

[0621] The gas evolved from the TGA sample was analyzed by an Omnistar GSD 301 T2 mass spectrometer (Pfeiffer Vacuum GmbH, Germany). The MS is a quadrupole mass spectrometer that analyzes masses in the range of 0 - 200 amu.

[0622] DSC analysis

[0623] The melting properties were obtained from DSC thermograms recorded using a heat flux DSC3+ STARe system (Mettler-Toledo GmbH, Switzerland). The DSC3+ was calibrated with a small piece of indium (melting point = 156.6 °C; δH f= 28.45 J / g) and zinc (melting point = 419.6 °C; δH f = 107.5 J / g) were used to calibrate temperature and enthalpy. The sample (ca. 2 mg) was sealed in a standard 40 μL aluminum pan, perforated with a needle, and heated from 25 °C to 300 °C at a heating rate of 10 °C / min in a DSC. During the measurement, the DSC equipment was purged with dry nitrogen at a flow rate of 50 mL / min.

[0624] LCMS analysis method

[0625] Method name: S18099_01; HPLC system: Agilent 1200; Detector 1: DAD set at 264 nm; Detector 2: HP1100 LC / MSD in positive scan mode.

[0626] HPLC conditions: Autosampler temperature: 15 °C; Column: Waters Sunfire C18 (100 x 4.6 mm; 3.5 μm); Column temperature: 35 °C; Flow cell: 10 mm path; Gradient: Table 16; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Flow rate: 1.0 ml / min.

[0627] Table 16: HPLC mobile phase gradient

[0628] Time [min] Mobile phase A Mobile phase B 0 90％ 10％ 9 10％ 90％ 10 5％ 95％ 11 5％ 95％ 。

[0629] Sample: Concentration: ca. 1 mg / ml; Solvent: water∶acetonitrile∶TFA (50∶50∶0.1 v / v / v); Injection volume: 5 μL.

[0630] The compound integrity was expressed as % peak area and calculated from the area of each peak (except the "injection peak") and the total peak area in the chromatogram as follows:

[0631]

[0632] The % peak area of the target compound was used as an indication of the component purity in the sample.

[0633] Form 1

[0634] Form 1 was obtained from the solvent equilibration experiment conducted in ethanol and used for characterization (Exp.ID SLP19) for comparison with the starting material. After 2 days of exposure to AAC (40 °C / 75% RH), Form 1 was physically stable. The HT-XRPD patterns of the materials of Exp.ID SLP19 before and after exposure to AAC are as Figure 14 shown. The TGMS analysis of Form 1 ( Figure 15) indicates a 0.2% mass loss in the temperature range of 25 - 220 °C. Without wishing to be bound by any particular theory, it is believed that the mass loss is most likely related to residual solvents or moisture. From the heat flow curve, a single endothermic event was observed at approximately 260 °C. Without wishing to be bound by any particular theory, it is believed that this is related to melting and decomposition. In the DSC curve of Form 1 ( Figure 16 ), a single endothermic event was recorded at 259 °C. Without wishing to be bound by any particular theory, it is considered most likely related to the melting and decomposition of Form 1. In the Figure 17 The HPLC chromatogram of Form 1 shown reveals the presence of the API with 100% chemical purity (area %).

[0635] Form 2

[0636] Form 2 was obtained from the thermal cycling experiment carried out in 1,4 - dioxane / water 95 / 5 (v / v) and used for characterization (Exp.ID TCP2). Form 2 is physically stable after 2 days of exposure to AAC (40 °C / 75% RH). The HT - XRPD patterns of the material of Exp.ID TCP2 before and after exposure to AAC are as shown in Figure 18 . The TGMS analysis of Form 2 ( Figure 19 ) indicates a total mass loss of 5.4% in the temperature range of 25 - 150 °C. This mass loss is equivalent to 0.3 molar equivalents of 1,4 - dioxane. Form 2 was found from different types of solvents. Without wishing to be bound by any particular theory, it is believed to be a non - stoichiometric isostructural solvate. In the DSC curve of Form 2 ( Figure 20 ), two broad endothermic events were recorded between 25 - 150 °C, which are related to the mass loss. Without wishing to be bound by any particular theory, it is believed that the small endothermic event at 165 °C may be a transition to Form 1 because a small endothermic event was observed at 259 °C (consistent with the melt of Form 1). The HPLC chromatogram of Form 2 shown in Figure 21 reveals the presence of the API with 100% chemical purity (area %).

[0637] Form 3

[0638] Form 3 was obtained from the thermal cycling experiment carried out in 2 - propanol / water 95 / 5 (v / v) and used for characterization (Exp.ID TCP2). Form 3 was obtained from both air - dried and vacuum - dried solids, but it is physically unstable after 2 days of exposure to AAC (40 °C / 75% RH) and becomes a mixture of Form 3 + 13. The HT - XRPD patterns of the air - dried and vacuum - dried solids of Exp.IDTCP13 before and after exposure to AAC are as shown in Figure 22as shown. TGMS analysis of Form 3 ( Figure 23 ) shows a 13.2% mass loss in the temperature range of 80 - 160 °C. Without wishing to be bound by any particular theory, it is thought to be due to the loss of IPA (1.3 equivalents of IPA), accompanied by a large endothermic event (T peak at 103 °C) in the heat flow signal. No melting event was observed after the mass loss, indicating, without wishing to be bound by any particular theory, that the substance becomes amorphous after the loss of the solvent. Without wishing to be bound by any particular theory, it is believed that Form 3 was found from different alcohols and is thus a non-stoichiometric isostructural solvate. In the DSC curve of Form 3 ( Figure 24 ), a broad endothermic event was recorded at 103 °C, which, without wishing to be bound by any particular theory, is thought to be related to the loss of IPA. A very small endothermic event was observed at 259 °C, which is consistent with the melt of Form 1, although the bulk material is likely to be amorphous after the loss of the solvent. The HPLC chromatogram of Form 3 shown in Figure 25 reveals the presence of the API with 100% chemical purity (area %).

[0639] Form 4

[0640] Form 4 was obtained from a solvent equilibration experiment carried out in tetrahydrofuran and used for characterization (Exp.ID SLP30). The pattern of the solid dried under ambient conditions (Form 4a) is slightly different from that of the solid dried under vacuum (Form 4). Form 4(a) is physically unstable and transforms into Form 6 after 2 days of exposure to AAC (40 °C / 75% RH). The HT-XRPD patterns of the solids of Exp.ID SLP30 before and after exposure to AAC are as shown in Figure 26 . TGMS analysis of Form 4 ( Figure 27 ) shows a 4.3% mass loss in the temperature range of 25 - 160 °C. Without wishing to be bound by any particular theory, it is believed that the mass loss is most likely related to the loss of THF (0.3 equivalents of THF). After the mass loss, an exothermic recrystallization event was observed at approximately 220 °C, followed by melting and decomposition at approximately 260 °C (the melt of Form 1). Without wishing to be bound by any particular theory, it is believed that Form 4 was obtained from different solvents and is thus a non-stoichiometric isostructural solvate. In the DSC curve of Form 4 ( Figure 28) Three endothermic events were recorded, the first two of which occurred during solvent loss. A small endothermic event at 157 °C was observed at the direct temperature after solvent loss. An exothermic recrystallization event was observed at 217 °C, followed by melting (melt of Form 1) and decomposition at 260 °C. A cyclic DSC experiment was conducted in which the solid of Form 4 was heated to 140 °C (after solvent removal). The recovered solid was analyzed by XRPD and TGMS, showing a similar pattern (Form 4b) and a water content of 2%. Figure 31 The HPLC chromatogram of Form 4 shown reveals the presence of the API with 100% chemical purity (area %).

[0641] Form 5

[0642] Form 5 was obtained from a thermal cycling experiment conducted in 1,4-dioxane and used for characterization (Exp. ID TCP8). The ambient-dried solid of Exp. ID TCP8 was a physical mixture of Form 4a and 5. The vacuum-dried solid was Form 5. Form 5 was physically unstable and turned into Form 6 after 2 days of exposure to AAC (40 °C / 75% RH). The HT-XRPD patterns of the solids of Exp. ID TCP8 before and after exposure to AAC are as Figure 32 shown. Without wishing to be bound by any particular theory, it is believed that the TGMS analysis of Form 5 ( Figure 33 ) indicates a total mass loss of 9.4% in the temperature range of 25 - 160 °C due to the loss of 1,4-dioxane (0.6 molar equivalent of 1,4-dioxane). The mass loss occurs in two steps, accompanied by two endothermic events. Without wishing to be bound by any particular theory, it is believed that the substance most likely becomes amorphous after solvent loss. Without wishing to be bound by any particular theory, it is believed that Form 5 is obtained from samples containing dioxane and 2-methyl THF and is therefore most likely an isostructural solvate. In the DSC curve of Form 5 ( Figure 34 ), a broad endothermic event was recorded at 110 °C, most likely related to solvent loss. A very small endothermic event was observed at 259 °C, consistent with the melt of Form 1, but most of the solid most likely becomes amorphous after solvent removal. As Figure 35 shown, the HPLC chromatogram of Form 5 reveals the presence of the API with 100% chemical purity (area %).

[0643] Form 6

[0644] Form 6 was obtained from a solvent equilibration experiment conducted in water at 50 °C and used for characterization (Exp. ID SLP65). Form 6 is a poorly crystalline material and is physically stable after 2 days of exposure to AAC (40 °C / 75% RH). The HT-XRPD patterns of the material of Exp. ID SLP65 before and after exposure to AAC are as Figure 36 shown. TGMS analysis of Form 6 ( Figure 37 ) indicates a mass loss of 2.1% in the temperature range of 25 - 160 °C. Without wishing to be bound by any particular theory, it is believed that the mass loss is most likely related to water loss (0.6 molar equivalent of water), and the material becomes amorphous after losing water upon heating. Form 6 was obtained from samples in water and was obtained after exposure to AAC. Without wishing to be bound by any particular theory, it is believed that Form 6 may be a hemihydrate. In the DSC curve of Form 6 ( Figure 38 ), a broad endothermic event was recorded at 151 °C, which is related to the loss of water. The thermal event observed above 220 °C is related to the decomposition process. Figure 39 The HPLC chromatogram of Form 6 shown as

[0645] Form 7

[0646] reveals the presence of the API with 100% chemical purity (area %). Figure 40 shown. TGMS analysis of Form 7 ( Figure 41 ) indicates a mass loss of 2.0% in the temperature range of 25 - 170 °C. Without wishing to be bound by any particular theory, it is believed that the mass loss is most likely related to the loss of 1,2-dimethoxyethane and possibly water (the mass loss would be equal to 0.1 molar equivalent of 1,2-dimethoxyethane). Without wishing to be bound by any particular theory, it is believed that the material recrystallizes to Form 1 after solvent loss. Without wishing to be bound by any particular theory, it is believed that Form 7 is only observed in samples with 1,2-dimethoxyethane and is therefore most likely a non-stoichiometric dimethoxyethane solvate or a mixed dimethoxyethane solvate / hydrate. In the DSC curve of Form 7 ( Figure 42) In [the relevant situation], due to solvent loss, a weak and broad endotherm was observed between 25 - 160 °C. An endothermic event was recorded at 172 °C, and an exothermic recrystallization event was recorded at 216 °C, followed by an endothermic event (melt of Form 1) recorded at 262 °C. Without wishing to be bound by any particular theory, it is believed that Form 7 is most likely to convert to Form 1 upon heating. A cyclic DSC experiment was performed on the solid of Form 7 to observe whether a (stable) non-solvated form was obtained after solvent loss. The solid recovered after the cyclic DSC experiment up to 155 °C was analyzed by XRPD and TGMS. The XRPD patterns were the same, and a 2.3% mass loss was observed from the TGMS analysis (without wishing to be bound by any particular theory, it is believed that it is most likely adsorbed water)( Figure 43 ). In Figure 44 The HPLC chromatogram of Form 7 shown reveals the presence of the API with 100% chemical purity (area %).

[0647] Form 8

[0648] Form 8 was obtained from an evaporation experiment carried out in methanol / acetone 75 / 25 (v / v) and used for characterization (Exp. IDECP34). Form 8 was physically stable after 2 days of exposure to AAC (40 °C / 75% RH). The HT-XRPD patterns of the substance of Exp. ID ECP34 before and after exposure to AAC are as Figure 45 shown. The TGMS analysis of Form 8 ( Figure 46 ) indicates a 5.3% mass loss in the temperature range of 25 - 130 °C. The mass loss is related to the loss of water and / or acetone (0.5 equivalent of acetone or 1.5 equivalents of water). From the heat flow curve, a broad endothermic event concurrent with the mass loss was observed. Without wishing to be bound by any particular theory, it is believed that Form 8 is observed in samples from different solvents and is therefore most likely a non-stoichiometric isostructural solvate / hydrate. In the DSC curve of Form 8 ( Figure 47 ), a broad endothermic event was recorded, most likely related to solvent loss, followed by a small endothermic event observed at 147 °C, possibly attributable to melting. Figure 48 The HPLC chromatogram of Form 8 shown reveals the presence of the API with 100% chemical purity (area %).

[0649] Form 10 (and Form 9)

[0650] Form 10 was obtained from a cooling crystallization experiment in N,N-dimethylformamide (after vacuum drying) and used for characterization (Exp.ID PSM60). The ambient-dried solid was Form 9, and the vacuum-dried solid was Form 10. Forms 9 and 10 were physically unstable and converted to Form 20 after 2 days of exposure to AAC (40 °C / 75% RH). The HT-XRPD patterns of the solids of Exp.ID PSM60 before and after exposure to AAC are as shown in Figure 49 . The TGMS analysis of Form 10 ( Figure 50 ) indicated a mass loss of 20.8% in the temperature range of 25 - 200 °C. The mass loss was most likely related to the loss of DMF (1.8 molar equivalents of DMF). From the heat flow curve, an endothermic event was observed at approximately 80 °C (due to mass loss) and a second endothermic event at approximately 250 °C (most likely the melting of Form 1). Form 10 was observed in samples from DMF and was thus a non-stoichiometric DMF solvate. In the DSC curve of Form 10 ( Figure 51 ), an endothermic event was recorded at 84 °C, most likely related to solvent loss. A second endothermic event was observed at 256 °C, most likely related to the melting of Form 1. Figure 52 The HPLC chromatogram of Form 10 shown in

[0651] Form 11

[0652] revealed the presence of the API with 100% chemical purity (area %). Figure 53 . The TGMS analysis of Form 11 ( Figure 54 ) indicated a mass loss of 9.1% in the temperature range of 25 - 230 °C. The mass loss was most likely related to the loss of DMA (0.6 molar equivalents of DMA). From the heat flow curve, a broad endothermic event consistent with mass loss was observed. A second endothermic event was observed at approximately 250 °C (most likely the melting of Form 1). Form 11 was observed in samples from DMA but was sometimes also observed in mixtures with other forms from other solvents and was thus most likely a non-stoichiometric isostructural solvate. In the DSC curve of Form 11 ( Figure 55) An endothermic event was recorded at 85 °C, most likely due to solvent loss. A second endothermic event was observed at 257 °C, attributed to the melting of Form 1. Figure 56 The HPLC chromatogram of Form 11 shown reveals the presence of the API with 100% chemical purity (area %).

[0653] Form 12

[0654] After evaporation of the mother liquor from the thermal cycling experiment carried out with acetonitrile / water 90 / 10 (v / v), Form 12 was obtained and used for characterization (Exp.ID TCP20_ML). Form 12 was physically stable after 2 days of exposure to AAC (40 °C / 75% RH). The HT-XRPD patterns of the substance of Exp.ID TCP20_ML before and after exposure to AAC are as Figure 57 shown. The TGMS analysis of Form 12 ( Figure 58 ) indicates a mass loss of 5.9% in the temperature range of 25 - 200 °C. The mass loss is most likely related to the loss of acetonitrile (0.8 molar equivalent of acetonitrile). From the heat flow curve, a broad endothermic event attributed to the mass loss was observed. Decomposition started at about 220 °C. Without wishing to be bound by any particular theory, it is believed that Form 12 was observed in samples from acetonitrile / water and acetone / water (moderately dried) and is thus most likely a non-stoichiometric isostructural solvate. In the DSC curve of Form 12 ( Figure 59 ), endothermic events were recorded between 25 - 180 °C, which are related to solvent loss, and a small endothermic event was observed at 255 °C, which may be attributed to the melting of Form 1. Figure 60 The HPLC chromatogram of Form 12 shown reveals the presence of the API with 100% chemical purity (area %).

[0655] Form 13

[0656] Form 13 was obtained from a cooling-evaporation crystallization experiment carried out in ethanol and used for characterization (Exp.ID PSM52). Form 13 was physically stable after 2 days of exposure to AAC (40 °C / 75% RH). The HT-XRPD patterns of the substance of Exp.ID PSM52 before and after exposure to AAC are as Figure 61 shown. The TGMS analysis of Form 13 ( Figure 62 ) indicates a mass loss of 6.3% in the temperature range of 25 - 220 °C. Due to the low sample amount available, it is not clear which solvent is lost during the mass loss (6.3% is equal to 1.9 equivalents of water). In the DSC curve of Form 13 ( Figure 63) Several broad endothermic events related to mass loss (in the temperature range of 25 - 170 °C) were recorded and finally a small endothermic event (due to the melting of Form 1) was observed at 258 °C. Figure 64 The HPLC chromatogram of Form 13 shown reveals the presence of the API with 100% chemical purity (area %).

[0657] Form 14

[0658] Form 14 was obtained from the thermocycling experiment in acetonitrile / water 90 / 10 (v / v) on vacuum-dried solid and used for characterization (Exp.ID TCP20). The ambient-dried solid is Form 12 and the vacuum-dried solid is Form 14. Form 14 is physically stable after 2 days of exposure to AAC (40 °C / 75% RH). The HT-XRPD patterns of the solid of Exp.ID TCP20 before and after exposure to AAC are as Figure 65 shown. The TGMS analysis of Form 14 ( Figure 66 ) indicates a gradual mass loss of 2.5% in the temperature range of 25 - 170 °C. This mass loss is equal to 0.3 molar equivalent of acetonitrile. From the heat flow curve, an endothermic event was observed at 165 °C, just after the mass loss. The endothermic event observed at about 250 °C is most likely related to the melting of Form 1. Form 14 was observed in samples dried vigorously from acetonitrile / water and acetone / water and is thus most likely a non-stoichiometric isostructural solvate. In the DSC curve of Form 14 ( Figure 67 ), an endothermic event was recorded at 172 °C and a small endothermic event (due to the melting of Form 1) was observed at 258 °C. Without wishing to be bound by any particular theory, it is believed that Form 14 most likely converts to Form 1 after solvent loss. Figure 68 The HPLC chromatogram of Form 14 shown reveals the presence of the API with 100% chemical purity (area %).

[0659] Form 15

[0660] Form 15 was obtained from the vapor diffusion into liquid experiment in N,N-dimethylformamide / 1,4-dioxane and used for characterization (Exp.ID VDL8). Form 15 is physically unstable after 2 days of exposure to AAC (40 °C / 75% RH) and turns into a mixture of Form 2 and 1. The HT-XRPD patterns of the solid of Exp.ID VDL8 before and after exposure to AAC are as Figure 69 shown. The TGMS analysis of Form 15 ( Figure 70) shows a 13.2% mass loss in the temperature range of 25 - 220 °C. The mass loss is most likely related to the loss of DMF (1 molar equivalent of DMF). From the heat flow curve, an endothermic event consistent with the mass loss (70 °C) was observed, followed by another endothermic event at approximately 250 °C (melting of Form 1). Form 15 was mainly obtained from experiments using DMF, but sometimes Form 15 was observed mixed with other forms from other solvents and is thus most likely an isostructural solvate. In the DSC curve of Form 15 ( Figure 71 ), an endothermic event was recorded at 77 °C, most likely related to the loss of solvent. The final endotherm at 256 °C corresponds to the melting of Form 1. Figure 72 The HPLC chromatogram of Form 15 shown reveals the presence of the API with 100% chemical purity (area %).

[0661] Form 16

[0662] Form 16 was obtained from evaporation experiments carried out in dimethyl sulfoxide and used for characterization (Exp.ID ECP18). Form 16 was physically stable after 2 days of exposure to AAC (40 °C / 75% RH). The HT-XRPD patterns of the material of Exp.ID ECP18 before and after exposure to AAC are as Figure 73 shown. The TGMS analysis of Form 16 ( Figure 74 ) shows a 16.6% mass loss in the temperature range of 25 - 240 °C. The mass loss is most likely related to the loss of DMSO (1.3 equivalents of DMSO). From the heat flow curve, a broad endothermic event consistent with the mass loss was observed. The final endothermic event was observed at approximately 250 °C, most likely related to the melting of Form 1. Without wishing to be bound by any particular theory, it is believed that Form 16 was found in samples containing DMSO and is thus a non-stoichiometric DMSO solvate. In the DSC curve of Form 16 ( Figure 75 ), an endothermic event was recorded at 102 °C, most likely related to the loss of solvent. The final endotherm at 256 °C corresponds to the melting of Form 1. Figure 76 The HPLC chromatogram of Form 16 shown reveals the presence of the API with 100% chemical purity (area %).

[0663] Form 17

[0664] Form 17 was obtained from an anti-solvent experiment in 2,2,2-trifluoroethanol / heptane and used for characterization (Exp. ID AS3). Both the ambient-dried and vacuum-dried solids were Form 17. Form 17 was physically unstable and converted to Form 13 after 2 days of exposure to AAC (40 °C / 75% RH). The HT-XRPD patterns of the solids of Exp. ID AS3 before and after exposure to AAC are as Figure 77 shown. TGMS analysis of Form 17 ( Figure 78 ) indicated a 16.9% mass loss in the temperature range of 25 - 200 °C. Without wishing to be bound by any particular theory, it is believed that the mass loss is most likely related to the loss of solvent released in a stepwise manner (16.9% is equal to 1 molar equivalent of heptane or TFE). From the heat flow curve, three endothermic events consistent with the mass loss were observed. Without wishing to be bound by any particular theory, it is believed that Form 17 is most likely a stoichiometric TFE or heptane solvate. In the DSC curve of Form 17 ( Figure 79 ), three endothermic events were recorded at 97, 135, and 153 °C, most likely related to the loss of solvent. A small endothermic event was observed at 257 °C due to the melting of Form 1. Figure 80 The HPLC chromatogram of Form 17 shown as

[0665] Form 18

[0666] revealed the presence of the API with 100% chemical purity (area %). Figure 81 shown.

[0667] Form 19

[0668] Form 19 was obtained from an evaporation experiment in methanol / diisopropyl ether 20 / 80 (v / v) and used for characterization (Exp. ID ECP45 / PSM13). Form 19 was physically stable after 2 days of exposure to AAC (40 °C / 75% RH). The HT-XRPD patterns of the material of Exp. ID ECP45 / PSM13 before and after exposure to AAC are as Figure 82 shown. TGMS analysis of Form 19 ( Figure 83) shows a 4.5% mass loss in the temperature range of 25 - 120 °C. The mass loss is most likely associated with diisopropyl ether (0.23 molar equivalent of diisopropyl ether). From the heat flow curve, a broad endothermic event consistent with the mass loss was observed. After solvent loss, an exothermic recrystallization event of Form 1 was observed, followed by melting of Form 1 (endotherm at approximately 250 °C). Without wishing to be bound by any particular theory, it is believed that Form 19 is most likely a non-stoichiometric solvate.

[0669] Example 2: Polymorph screening - Voruciclib salt

[0670] The aim of this study was to identify alternative salts of voruciclib with better and / or different physicochemical properties than voruciclib HCl. Without wishing to be bound by any particular theory, it is believed that the HCl salt has complex pseudopolymorphic behavior and is prone to gelling in aqueous media. The salt screening presented in this study included 25 acidic counterions and was performed according to the saturated solution method in THF, ethanol, and acetone.

[0671] General abbreviations: AAC: Accelerated aging conditions (40 °C and 75% RH); Am: Amorphous; API: Active pharmaceutical ingredient; CI: Counterion; DSC: Differential scanning calorimetry; HPLC: High-performance liquid chromatography; HR-XRPD: High-resolution X-ray powder diffraction; HT-XRPD: High-throughput X-ray powder diffraction; LCMS: Liquid chromatography-mass spectrometry; MS: Mass spectrometry; RH: Relative humidity; RT: Room temperature; SM: Starting material; SSm: Experiment ID of the salt screening experiment; TGA: Thermogravimetric analysis; TGMS: Thermogravimetric analysis coupled with mass spectrometry; EtOH: Ethanol; THF: Tetrahydrofuran.

[0672] Starting material characterization

[0673] Approximately 5 g of voruciclib free base ( Figure 84 ) was obtained as a light yellow powder. For reference purposes, the starting material was analyzed by XRPD, DSC, TGMS, LCMS, and 1 1H-NMR. High-throughput XRPD (HT-XRPD) analysis confirmed the crystalline nature of the starting material ( Figure 85 ). The crystalline starting material was designated as Form A. DSC analysis ( Figure 86 ) showed a small endothermic event at 99 °C, followed by a second small endothermic event at 214 °C, and finally melting at 225 °C. Without wishing to be bound by any particular theory, it is believed that the small endothermic event suggests the possible existence of more than one polymorph of the free base. TGMS analysis ( Figure 87) showed a 0.3% mass loss before decomposition at approximately 240 °C. This mass loss was associated with water and possibly residual solvents (released during a small heat event at 100 °C). The heat flow signal was similar to the DSC trace and showed a sharp endothermic event at 215 °C before thermal decomposition, which could be attributed to the melting of voruciclib free base. The chemical purity of the free base was evaluated by HPLC analysis ( Figure 88 ). The results showed that the purity of the solid was 99.3% (area %). The 1 H-NMR spectrum was recorded for reference purposes and is shown in Figure 89 . In the case of salt formation, the peak at 2.47 ppm (proton of the CH 3 -group attached to the basic N atom) showed the strongest resonance shift. The results of the characterization indicated that the starting material was in the form of a non-solvated and anhydrous solid.

[0674] Solvent selection

[0675] The approximate solubility of the free base in several organic solvents was evaluated by the solvent addition method (Table 17). Aliquots of the solvent were added to approximately 5 mg of the free base until complete dissolution was observed or until a concentration below 1 mg / mL was reached. Aliquots of 100 μL were used up to 2 mL, and then aliquots of 1 mL were used up to 8 mL. The free base was soluble in THF and slightly soluble in methanol, ethanol, and acetone. In other solvents, the solubility of the free base was below 10 mg / mL, and voruciclib was almost insoluble in water. Based on the solubility results, in certain embodiments, the crystallization solvents selected for salt formation were THF, ethanol, and acetone.

[0676] Table 17: Evaluation of the approximate solubility of ME-522 in 10 solvents at room temperature

[0677] Solvent Solubility (mg / mL) Methanol 17＜S＜26 Chloroform ～5 Ethanol 14＜S＜18 Acetonitrile ～5 Tetrahydrofuran 30＜S＜60 Acetone 10＜S＜13 1,4-Dioxane ～1 2-Propanol ～8 Ethyl acetate ～1 Water ＜1 .

[0678] Counterion

[0679] The acidic counterions used for salt screening are listed in Table 18. The abbreviations of the counterions were used for the naming of the potential salt forms. The counterions were used at 1 molar equivalent, and acids with two ionization sites were also used at 0.5 molar equivalent.

[0680] Table 18: List of acidic counterions used for salt screening of voruciclib.

[0681] # Acid counterion ICH category <![CDATA[pka 1 > <![CDATA[pka 2 > Abbreviation 1 Hydrobromic acid 3 ＜-6 HBr 2 Naphthalene-1,5-disulfonic acid 2 -3.4 -2.6 Nds 3 Sulfuric acid 1 -3 1.9 Sul 4 Ethane-1,2-disulfonic acid 2 -2.1 -1.5 Edy 5 p-Toluenesulfonic acid 2 -1.3 - Tos 6 Naphthalene-2-sulfonic acid 2 0.2 - Nsa 7 Benzenesulfonic acid 2 0.7 - Bes 8 Oxalic acid 2 1.3 4.3 Oxa 9 Dibenzoyl-L-tartaric acid 2 1.9 - DiTr 10 Maleic acid 1 1.9 6.2 Mae 11 Phosphoric acid 1 2.0 7.1 Pho 12 Ethanesulfonic acid 2 2.1 - Esy 13 Glutamic acid 1 2.2 4.3 Glm 14 1-Hydroxy-2-naphthoic acid 2 2.7 13.5 Xin 15 Malonic acid 2 2.8 5.7 Mao 16 Gentisic acid 2 2.9 - Gen 17 (+)-L-Tartaric acid 1 3.0 4.4 Tar 18 Fumaric acid 1 3.0 4.4 Fum 19 D-Glucuronic acid 1 3.2 - Glr 20 Citric acid 1 3.1 4.8 Cit 21 (-)-L-Malic acid 1 3.5 5.1 Mal 22 D-Gluconic acid 1 3.8 - Glc 23 Benzoic acid 2 4.2 - Ben 24 Succinic acid 1 4.2 5.6 Suc 25 Glutaric acid 1 4.3 5.3 Glt .

[0682] Temperature curve

[0683] To select the temperature profile for the salt screening experiments, the thermal stability of the free base in solution was tested. Solutions of the free base were prepared in THF, ethanol, and acetone and dispensed into three vials. The vials were placed at room temperature for 24 h and at 50 °C and 80 °C for 1 h. The solutions were analyzed by HPLC. No significant differences in chemical purity were observed compared to the starting material. Thus, the free base was considered to be thermally stable in solution.

[0684] Salt screening

[0685] The salt screening was carried out using the saturated solution method. Saturated solutions of the free base were prepared in THF, ethanol, and acetone at 50 °C. Aliquots of the counterion aqueous solution were added, resulting in a free base:counterion stoichiometry of 1:1.1 or 1:0.55.

[0686] The vials were incubated at 50 °C for 1 h and then slowly cooled to 5 °C and then aged at 5 °C for 72 h. If a solid had precipitated, the solid was separated and dried in vacuo at 50 °C. All liquid phases were evaporated under ambient conditions and the resulting solids were then dried under vacuum until dry. All obtained solids were analyzed by XRPD. Subsequently, the solids were exposed to accelerated aging conditions (40 °C / 75% RH, AAC) for 2 days to evaluate their physical stability. The nomenclature uses the abbreviation of the counterion followed by “0” (in the case where the pure counterion was recovered) or a number (in the case where a new XRPD pattern was obtained). For example, the recovery of pure glutamic acid was named Glm0, and the unique XRPD patterns obtained from the 1,2-ethanedisulfonic acid experiments were named Edy1 and Edy2. XRPD patterns with very small differences were grouped under one number and distinguished by a letter, e.g., Nds1a and Nds1b. In the case of the recovery of the free base, the solids were classified as Form B or C (since they were different from the starting material Form A).

[0687] The results of the salt screening are summarized in Table 19. Signs of salt formation were observed for almost all 25 counterions used (counterions are listed alphabetically). Only a mixture of the free base and the counterion was recovered from the experiments with glutamic acid. For citric acid and gluconic acid, only amorphous or poorly crystalline solids were recovered.

[0688] For hydrobromic acid, benzenesulfonic acid, oxalic acid, and 1-hydroxy-2-naphthoic acid, only one crystalline salt form was obtained. For all other counterions, more than one solid form was identified even though only 3 crystallization solvents were tested. Most solids were physically stable during exposure to stress conditions.

[0689] Table 19: Summary of results of salt screening of voruciclib. Potential salt forms are listed by counterion and the free base:counterion ratio from which the particular form was derived.

[0690]

[0691]

[0692] Malonic acid

[0693] The malonate salt Mao1 was obtained by evaporation from ethanol and was physically stable after exposure to AAC. From THF and acetone, a poorly crystalline solid (Mao2) was obtained, which was partially converted to Mao1 during AAC, indicating that, without wishing to be bound by any particular theory, Mao1 is a more stable salt form than Mao2. The results of DSC, TGMS, HPLC and 1 Mao1 was further analyzed by H-NMR and the results are described herein. HPLC and 1 H-NMR confirmed the integrity of the compound, and from the NMR spectrum, the formation of a salt with a stoichiometric ratio of free base: malonic acid of 1:1 was confirmed. Thermal analysis showed that the salt contained about 0.2% residual solvent. Decomposition began at about 140°C, while an endothermic melting / decomposition event was observed in the DSC trace at 180°C. In addition, the solubility of the salt was determined in water and 0.2 M phosphate buffer pH 6 at 37°C after incubation for 4 hours. In water, Mao1 formed a very fine suspension and the solubility was determined to be 4.4 mg / mL, and the recovered solid was still the same as Mao1. In phosphate buffer solution, the salt dissociated and the solubility was 0.07 mg / mL. Although the salt seemed to precipitate as oil at first, a yellow suspension was obtained after about 20 min, and no gelation or viscosity increase was observed.

[0694] Dibenzoyl-L-tartaric acid

[0695] Salt formation with dibenzoyl tartaric acid in ethanol results in precipitation of DiTr1, while a mixture of DiTr1 and DiTr2 is formed in THF and acetone. The solid is physically stable under AAC. Without wishing to be bound by any particular theory, it is believed that DiTr2 is only observed in mixtures with DiTr1. DiTr1 was further characterized and the analytical results are reported herein. The solid contains 0.9% residual solvent and decomposes above 180 °C. HPLC and NMR spectroscopy confirmed the integrity of the compound, salt formation, and a 2:1 free base:DiTr stoichiometry; thus, DiTr1 is the semi-dibenzoyl tartrate salt. The solubility of the salt was determined in water and phosphate buffer pH 6. In both media, the solubility was approximately 0.03 - 0.04 mg / mL. The salt has poor wettability, mixes poorly with the aqueous phase, and DiTr1 was recovered after incubation for 4 h. In both media, the color of the solid did not change and the suspension remained pale yellow.

[0696] Orthophosphoric acid

[0697] The crystalline salt form was obtained from acetone with phosphoric acid. Experiments carried out in THF resulted in the formation of poorly crystalline solid (Pho2), and the free base form (Form D) was collected from ethanol. All solid phases were physically stable for 2 days under AAC. The crystalline salt Pho1 was further analyzed and the characterization is described herein. From TGMS analysis, a 1.9% mass loss was observed between 25 - 160 °C, most likely due to residual solvent or moisture, and thermal decomposition began at approximately 200 °C. From the DSC trace, a melting event was observed at 202 °C, followed immediately by decomposition. The integrity of the compound was confirmed by HPLC and NMR analysis. 1 The 1H-NMR spectrum confirmed salt formation, and the stoichiometric ratio was calculated from HPLC data to be 1:1. After 4 h, the solubility of the phosphate salt was determined in water and 0.2 M phosphate buffer pH 6 at 37 °C. Suspensions were prepared using approximately 5 mg of solid, and an oil was formed after addition of the first aliquot of 200 μL of water. More water was added to a volume of 800 μL, and a clear solution (pH 3.7) was obtained only after mixing the oil with a spatula. Thus, an accurate solubility was not determined and the actual solubility was higher than 5 mg / mL. Although an oil was formed, no gelling was observed due to the high solubility. In the phosphate buffer, the solubility was approximately 0.03 mg / mL, and XRPD of the solid recovered subsequently indicated that the salt had dissociated in the buffer solution.

[0698] Oxalic acid

[0699] Only one crystalline form, Oxa1, was found using oxalic acid. This form was obtained from experiments using 0.5 or 1 molar equivalent. Oxa1 is physically stable under short-term stress conditions. The solid obtained from the experiment with half molar equivalent of oxalic acid in THF was used for characterization and is described herein. HPLC analysis confirmed the integrity of the compound and determined a free base∶oxalic acid stoichiometry of 1∶0.5, indicating, without wishing to be bound by any particular theory, that Oxa1 is a hemioxalate. From thermal analysis and 1 the 1H-NMR spectrum, it was observed that the solid contains water. TGMS analysis showed a 3.2% mass loss in two steps. Therefore, without wishing to be bound by any particular theory, it is believed that the hemioxalate is a monohydrate or hemihydrate (containing residual solvent / moisture). After 4 hours, the solubility of Oxa1 was determined in 0.2 M phosphate buffer pH 6 at 37 °C and was 0.03 mg / mL. The salt had dissociated in the buffer. Attempts to determine the solubility in water failed because very fine particles could still be observed after filtering the sample. The residual solid of the suspension was the same as Oxa1. The suspension was bright yellow in both media.

[0700] 1,5-Naphthalenedisulfonic acid

[0701] Several forms were observed with 1,5-naphthalenedisulfonic acid, suggesting that the salt exhibits polymorphic / pseudopolymorphic behavior. However, Nds1a was obtained mainly by precipitation, while Nds2 was obtained by evaporation. Nds1a was stable during exposure to AAC for 2 days. Nds1b had the same pattern as Nds1a, but with a slight shift in peak position and was therefore designated as Nds1b. Nds1b was converted to Nds2 during exposure to accelerated aging conditions. Nds1a obtained from the salt formation experiment (with 1 molar equivalent of 1,5-naphthalenedisulfonic acid in ethanol) was selected for further characterization. Thermal analysis showed that the solid contains 1.1% residual solvent / moisture, and the melting and decomposition of the salt started at about 250 °C. From 1 the 1H-NMR spectrum, a free base∶Nds stoichiometric ratio of 1∶0.5 was determined. Therefore, without wishing to be bound by any particular theory, Nds1a appears to be an unsolvated and anhydrous hemimaphthalenedisulfonate. After 4 hours, the solubility of Nds1a in water and 0.2 M phosphate buffer at 37 °C was 0.02 mg / mL in both media. The suspension in water was white (pH 3.4), while the suspension at pH 6 was yellow. The salt was stable in both media as the residual solid was the same as Nds1a.

[0702] Solvated salt

[0703] Other crystalline salts (physically stable and / or with limited polymorphic behavior) were characterized by thermal analysis. Those salts were identified with the following acids (in alphabetical order): 1-hydroxy-2-naphthoate, Xin1; benzoate, Ben2; benzenesulfonate, Bes1; ethanesulfonate, Esy1 / Form D; gentisate, Gen1; hydrobromide, HBr1; maleate, Mae1; sulfate, Sul1; tosylate, Tos2. All of these salt forms contained substantial amounts of solvent, and melting or thermal decomposition was observed immediately after solvent loss (Table 20). Without wishing to be bound by any particular theory, it is believed that this behavior may indicate that in some embodiments these solids are only stable as solvates and do not convert to crystalline non-solvated salt forms upon desolvation.

[0704] Table 20: Characterization of solvated salts of voruciclib

[0705]

[0706] Polymorphic forms of free base

[0707] The control sample (without counterion) resulted in a recovery in a different form than the starting material. The same form, designated Form B, was obtained from ethanol and acetone, and the solid obtained from THF was designated Form C. Form B appears to be the non-solvated form, with a melting of approximately 220 °C. The small endothermic events (at 100 °C and at 214 °C) in the heat flow observed with Form A were absent, suggesting that Form B is a more stable form than Form A. Form C appears to be a solvated form with a melting at 220 °C, which is consistent with the melting of Form B.

[0708] Solubility assessment

[0709] Solubility assessments were performed according to the aliquot addition method and visually evaluated. Approximately 5 mg of the free base was weighed into an 8 mL glass vial. Aliquots of 100 μL were added to 2 mL, followed by aliquots of 1 mL added to 8 mL. The experimental conditions are described in Table 21. Additionally, a suspension in water was heated at 60 °C for 30 minutes but did not dissolve.

[0710] Table 21: Approximate solubility assessment of voruciclib in 10 solvents.

[0711]

[0712] Thermal stability

[0713] Prepare voruciclib solution (0.2 mg / mL) in tetrahydrofuran, ethanol, and acetone. Divide the solution into 3 vials. Place the vials at room temperature for 24 hours and at 50 °C and 80 °C for 1 hour. Then measure the solution by HPLC analysis. The experimental conditions and results are shown in Table 22.

[0714] Table 22: Experimental details and results of the thermal stability test.

[0715]

[0716] Salt screening

[0717] Perform salt screening using the saturated solution method. Prepare saturated solutions of the free base in tetrahydrofuran, ethanol, and acetone at 50 °C (Table 23). Aliquot the stock solution into 33 glass vials (1.8 mL). L(+)-glutamic acid is added as a solid, while fumaric acid and 1-hydroxy-2-naphthoic acid are added from 0.3 M and 0.4 M ethanol solutions, respectively. All other counterions are added as 1 M aqueous solutions, resulting in a free base:counterion stoichiometry of 1:1.1 or 1:0.55. The experimental conditions and results are listed in Table 24.

[0718] Heat the experiment at 50 °C, then cool from 50 °C to 5 °C and age at 5 °C for 72 hours. After the aging time, if a solid has precipitated, separate the solid and dry it under vacuum at 50 °C. Evaporate the liquid phase for 2 days under ambient conditions and for 24 hours under vacuum at 50 °C. Analyze all the obtained solids by HT-XRPD. Subsequently, expose the solids to accelerated aging conditions (40 °C / 75% RH, AAC) for 2 days and re-analyze by HT-XRPD.

[0719] The XRPD nomenclature uses the abbreviation of the counterion followed by "0" (in the case where the pure counterion is observed) or a number (in the case where a new XRPD pattern is obtained). For example, the recovery of pure glutamic acid is named Glm0, and the unique XRPD patterns obtained from the 1,2-ethanedisulfonic acid experiment are named Edy1, Edy2. XRPD patterns with very small differences are grouped under one number and distinguished by letters, such as Nds1a and Nds1b. In the case of recovering the free base, the solids are classified as Form B, C, D, or E (since they are different from the starting material Form A).

[0720] Table 23: Experimental details of the stock solution of the free base.

[0721] Quality API Volume Solvent (mg) (mL) Dissolve Tetrahydrofuran 1100.1 18.3 Dissolve at 50 °C Ethanol 1100.8 36.6 Dissolve at 50 °C Acetone 1100.6 36.6 Dissolve at 50 °C 。

[0722]

[0723]

[0724]

[0725]

[0726]

[0727] Solubility of salt

[0728] The solubility of five candidate salts was determined in 0.2 M phosphate buffer pH 6 and water. Two sets of solubility experiments were conducted. In one set of solubility experiments, approximately 1 mg of salt was weighed into a 1.8 mL glass vial and 1 mL of the medium was added immediately. In the second set of solubility experiments, approximately 5 mg of salt was weighed into a standard 1.8 mL HPLC vial. Subsequently, aliquots of up to 200 μL of the aqueous medium were added while observing the dissolution behavior of the salt. The vials were continuously stirred at 37 °C to reach equilibrium (see Table 25 for details). After 4 hours, the solid was separated from the liquid by centrifugation and the liquid phase was further filtered through a 0.2 μM PTFE filter to remove any particulate matter. The concentration of the solute was determined by HPLC-DAD analysis. The calibration curve was made from two independent voruciclib stock solutions prepared in acetonitrile / water. The pH was recorded at the end of the equilibrium time.

[0729] Table 25: Experimental conditions and results for the solubility determination of salts in 0.2 M phosphate buffer pH 6 and water. Solubility was determined by HPLC analysis at 37 °C after 4 hours.

[0730]

[0731] X-ray powder diffraction

[0732] XRPD patterns were obtained using a Crystallics T2 high-throughput XRPD instrument. The plate was mounted on a Bruker D8 Discover General Area Detector Diffraction System (GADDS) which was equipped with a gas area detector (product sheet XRD 37, DOC-S88-EXS037V3, Figure 297 ). Calibration of the measurement accuracy (peak position) was performed using a NIST SRM1976 standard (corundum). Monochromatic CuK αData collection for the 2θ region between 1.5° and 41.5° was carried out, which is the most distinctive part of the XRPD pattern. The diffraction patterns of each hole were collected in two 2θ ranges (the first frame was 1.5° ≤ 2θ ≤ 21.5°, and the second frame was 19.5° ≤ 2θ ≤ 41.5°), with an exposure time of 45 s for each frame. No background subtraction or curve smoothing was applied to the XRPD pattern.

[0733] TGA / SDTA and TGMS analysis

[0734] The mass loss due to the loss of solvent or water in the crystal was determined by TGA / SDTA. The sample weight was monitored during heating in a TGA / DSC 3+ STARe system (Mettler-Toledo GmbH, Switzerland) to obtain a curve of weight versus temperature. The temperature of the TGA / DSC 3+ was calibrated with indium and aluminum. The sample (about 2 mg) was weighed into a 100 μL aluminum crucible and sealed. The seal was perforated with a needle, and the crucible was heated from 25 °C to 300 °C in the TGA at a heating rate of 10 °C / min. Dry nitrogen was used for purging.

[0735] The gas evolved from the TGA sample was analyzed by an Omnistar GSD 301 T2 mass spectrometer (Pfeiffer Vacuum GmbH, Germany). This MS is a quadrupole mass spectrometer that analyzes masses in the range of 0 - 200 amu.

[0736] DSC analysis

[0737] The melting properties were obtained from the DSC thermogram and recorded using a heat flux DSC3+ STARe system (Mettler-Toledo GmbH, Switzerland). The DSC3+ was calibrated for temperature and enthalpy with a small piece of indium (melting point = 156.6 °C; δH f = 28.45 J / g) and zinc (melting point = 419.6 °C; δH f = 107.5 J / g). The sample (about 2 mg) was sealed in a standard 40 μL aluminum pan, perforated with a needle, and heated from 25 °C to 300 °C in the DSC at a heating rate of 10 °C / min. During the measurement, dry nitrogen with a flow rate of 50 mL / min was used to purge the DSC equipment.

[0738] Proton-NMR

[0739] The 6 in 1H-NMR spectroscopy was used to characterize the compound integrity and determine the stoichiometry of the salt. Spectra were recorded at room temperature (32 scans) on a 500 MHz instrument (Bruker BioSpin GmbH) using a standard pulse sequence. Data were processed using ACD Labs software Spectrus Processor 2016.2.2 (Advanced Chemistry Development Inc., Canada).

[0740] LCMS analysis method

[0741] Method name: S18099_01; HPLC system: Agilent 1200; Detector 1: DAD set at 264 nm; Detector 2: HP1100 LC / MSD in positive scan mode. HPLC conditions: Autosampler temperature: 15 °C; Column: Waters Sunfire C18 (100 x 4.6 mm; 3.5 μm); Column temperature: 35 °C; Flow cell: 10 mm path; Gradient: Table 26; Mobile phase A: 0.1% TFA in water; Mobile phase B: 0.1% TFA in acetonitrile; Flow rate: 1.0 ml / min.

[0742] Table 26: HPLC mobile phase gradient

[0743]

[0744]

[0745] Sample: Concentration: approximately 0.5 mg / ml; Solvent: water∶acetonitrile∶TFA (50∶50∶0.1 v / v / v); Injection volume: 5 μL.

[0746] The compound integrity was expressed as % peak area, calculated from the area of each peak (except the "injection peak") and the total peak area in the chromatogram as follows:

[0747]

[0748] The % peak area of the target compound was used as an indication of the component purity in the sample. The calculation of the free base∶CI stoichiometry in the salt was based on the ratio of the area (free base recovery) to the sample weight. The sample weight was corrected for the mass loss observed by TGMS analysis.

[0749] Malonate, Mao1

[0750] Two different XRPD patterns were obtained using malonic acid. Crystalline salt Mao1 was obtained from experiments in ethanol. Poorly crystalline solid, Mao2, was recovered from acetone and THF. The XRPD patterns of the two forms are as Figure 90As shown. Based on crystallinity and physical stability, Mao1 was selected for further characterization. In Figure 91 , the powder patterns of Mao1 before and after 2 days of exposure to AAC are presented. The peak listings of Mao1 are shown in Table 27. The stable crystalline malonate Mao1 (Exp.ID SSm53) was further characterized by DSC, TGMS, HPLC, and 1H-NMR analysis.

[0751] Table 27: Peak listings of XRPD of Mao1.

[0752] Peak ID Angle (2θ) d-spacing Intensity 1 7.30 12.10 10.97 2 13.58 6.51 23.49 3 14.06 6.29 18.99 4 15.18 5.83 49.23 5 15.66 5.65 39.60 6 17.50 5.06 15.62 7 18.94 4.68 44.63 8 19.54 4.54 33.07 9 22.22 4.00 11.64 10 23.38 3.80 18.97 11 24.10 3.69 75.50 12 24.98 3.56 85.99 13 25.94 3.43 49.70 14 27.26 3.27 28.18 15 28.50 3.13 19.10 16 32.82 2.73 14.09

[0753] Without wishing to be bound by any particular theory, it is believed that the TGMS analysis of Mao1 ( Figure 92 ) indicates that the form is a non-solvated anhydrous form, as the mass loss is only 0.2% before the onset of decomposition. The decomposition starts at approximately 140 °C. The DSC trace of Mao1 ( Figure 93 ) shows an endothermic event with a peak temperature at 180 °C due to melting / decomposition. The proton NMR spectrum obtained for Mao1 ( Figure 94 ) confirms salt formation as the proton resonances of the salt are shifted compared to those of the starting material. The determined free base:malonic acid stoichiometry is 1:1. The HPLC chromatogram obtained for Mao1 ( Figure 95 ) confirms the integrity of the compound with a chemical purity of 99.3% (area %).

[0754] Dibenzoyl-tartrate, DiTr1

[0755] Using dibenzoyl-L-tartaric acid, two different XRPD patterns were observed. Crystallization of the solid from ethanol led to the identification of DiTr1. A mixture of DiTr1 and DiTr2 was recovered from acetone and THF. The XRPD patterns of the two forms are as Figure 96 shown. DiTr1 was selected for further characterization and it was physically stable after 2 days of exposure to AAC ( Figure 97 ). The peak listings of DiTr1 are shown in Table 28. The pure form DiTr1 (Exp.ID SSm46) was further characterized by DSC, TGMS, HPLC, and 1 1H-NMR analysis.

[0756] Table 28: Peak listings of XRPD of DiTr1.

[0757] Peak ID Angle (2θ) d-spacing Intensity 1 5.06 17.44 24.43 2 6.42 13.75 9.60 3 9.34 9.46 55.48 4 10.14 8.71 69.81 5 12.30 7.19 17.51 6 13.66 6.47 24.46 7 14.14 6.26 40.05 8 15.82 5.60 18.80 9 17.02 5.20 8.06 10 19.74 4.49 55.96 11 20.38 4.35 28.74 12 21.82 4.07 19.17 13 22.66 3.92 11.14 14 24.62 3.61 29.48 15 25.78 3.45 16.36 16 26.58 3.35 11.44 17 28.66 3.11 18.50 18 29.98 2.98 14.56

[0758] Without wishing to be bound by any particular theory, it is believed that the TGMS analysis ( Figure 98) indicates that DiTr1 is in a non-solvated anhydrous form with a residual solvent / water content of 0.9%. This mass loss was observed before the onset of thermal decomposition (at approximately 180 °C). The DSC trace of DiTr1 ( Figure 99 ) shows a small endothermic event at 172 °C before the decomposition process with a peak temperature of 207 °C. The proton NMR spectrum of DiTr1 ( Figure 100 ) confirmed salt formation as the proton resonances of the salt were shifted compared to those of the starting material. The stoichiometry determined for the free base∶dibenzoyl-L-tartaric acid was 1∶0.5. The HPLC chromatogram obtained for DiTr1 ( Figure 101 ) confirmed the integrity of the compound with a chemical purity of 95.7% (area %).

[0759] Phosphate, Pho1

[0760] Using phosphoric acid, two different XRPD patterns were observed. The crystalline salt Pho1 was obtained from experiments conducted in acetone. Poorly crystalline solid Pho2 was recovered from THF. The XRPD patterns of the two forms are as Figure 102 shown. Pho1 with high crystallinity was obtained and it was physically stable after 2 days of exposure to AAC ( Figure 103 ). The peak listings are shown in Table 29. The stable crystalline phosphate Pho1 (Exp.ID SSm81) was further characterized by DSC, TGMS, HPLC, and 1H-NMR analysis.

[0761] Table 29: Peak listings of XRPD of Pho1.

[0762] Peak ID Angle (2θ) d-spacing Intensity 1 4.94 17.87 30.40 2 6.78 13.02 45.04 3 9.34 9.46 10.19 4 10.94 8.08 31.93 5 12.70 6.96 28.03 6 13.38 6.61 22.23 7 14.90 5.94 55.90 8 15.66 5.65 27.65 9 17.54 5.05 8.82 10 18.82 4.71 17.04 11 22.02 4.03 23.49 12 23.98 3.71 39.67 13 24.78 3.59 31.46 14 25.30 3.52 23.89 15 26.66 3.34 15.25 16 29.98 2.98 14.07

[0763] The TGMS analysis of Pho1 ( Figure 104 ) indicates that a 1.9% mass loss is most likely related to water. Mass loss was observed between 25 - 160 °C before melting. Thermal decomposition was observed above 200 °C. The DSC trace of Pho1 ( Figure 105 ) shows a series of small thermal events (related to water / solvent loss) at 202 °C before melting, followed by decomposition. The proton NMR spectrum obtained for Pho1 ( Figure 106 ) confirmed salt formation as the proton resonances of the salt were shifted compared to those of the starting material. The HPLC chromatogram obtained for Pho1 ( Figure 107 ) confirmed the integrity of the compound with a chemical purity of 99.8% (area %). The stoichiometry of the salt was determined based on the area of the main chromatographic peak (attributed to the free base), and it was free base∶phosphoric acid 1∶1.

[0764] Oxalate, Oxa1

[0765] For oxalic acid, only one potential salt, Oxa1, was identified. This form was identified independently of the molar equivalents of oxalic acid used in the experiment. Oxa1 was physically stable after 2 days of exposure to AAC. The XRPD of Oxa1 showed peaks at Figure 108 and the peak listing is shown in Table 30. The solid obtained from THF with half molar equivalent of oxalic acid (Exp.ID SSm12) was further characterized by DSC, TGMS, HPLC, and 1H-NMR analysis.

[0766] Table 30: Peak listing of XRPD of Oxa1.

[0767] Peak ID Angle (2θ) d-spacing Intensity 1 6.86 12.87 100 2 12.66 6.98 24.49 3 13.58 6.51 44.55 4 14.74 6.00 40.82 5 15.98 5.54 26.86 6 19.38 4.57 37.91 7 23.94 3.71 36.71 8 24.78 3.59 26.63 9 25.94 3.43 31.37

[0768] TGMS analysis of Oxa1 ( Figure 109 ) showed a 1.4% mass loss between 25 - 100 °C and a second 1.9% mass loss between 100 - 150 °C. The mass loss above 160 °C was associated with the decomposition of the salt. The total mass loss of 3.3% corresponded to approximately 1 molar equivalent of water. Thus, the salt was a monohydrate or hemihydrate containing residual solvent / water. The DSC trace of Oxa1 ( Figure 110 ) showed two endothermic events between 25 - 130 °C related to the loss of solvent or water and a broad endothermic event attributed to the thermal decomposition of the salt with a peak temperature at 213 °C. The proton NMR spectrum obtained for Oxa1 ( Figure 111 ) confirmed the salt formation as the proton resonances of the salt were shifted compared to those of the starting material. The HPLC chromatogram obtained for Oxa1 ( Figure 112 ) confirmed the integrity of the compound with a chemical purity of 99.6% (area %). The calculation of the salt stoichiometry was based on the area of the main chromatographic peak (attributed to the free base). The free base∶oxalic acid stoichiometry was 1∶0.5.

[0769] Naphthalenedisulfonate, Nds1a

[0770] Several different XRPD patterns were obtained using 1,5-naphthalenedisulfonic acid. From the experiment in ethanol, the crystalline salt Nds1a had precipitated, while Nds2 was obtained after evaporation of the mother liquor. Other forms were obtained from acetone and THF. The different XRPD patterns obtained from the experiment using 1,5-naphthalenedisulfonic acid are shown as Figure 113 shown. Nds1a was highly crystalline and physically stable after 2 days of exposure to AAC ( Figure 114 ). For this reason, Nds1a (Exp.ID SSm35) was further characterized by DSC, TGMS, HPLC, and 1H-NMR analysis. XRPD showed peaks at Figure 114and the peaks are listed in Table 31.

[0771] Table 31: List of peaks of XRPD of Nds1a.

[0772] Peak ID Angle (2θ) d-spacing Intensity 1 9.02 9.79 45.30 2 10.50 8.42 51.58 3 11.06 7.99 45.06 4 12.30 7.19 83.54 5 12.82 6.90 46.39 6 13.90 6.36 42.01 7 14.82 5.97 63.93 8 15.30 5.78 84.42 9 15.94 5.55 60.95 10 17.26 5.13 74.96 11 19.34 4.58 45.30 12 20.62 4.30 71.25 13 22.18 4.00 75.41 14 22.86 3.89 86.24 15 24.58 3.62 100 16 25.42 3.50 44.96 17 25.86 3.44 41.64 18 27.38 3.25 43.27 19 28.66 3.11 35.08

[0773] Without wishing to be bound by any particular theory, it is believed that the TGMS analysis ( Figure 115 ) indicates that Nds1 is in the unsolvated anhydrous form with a residual solvent content of 1.1% between 25 - 100 °C. Decomposition starts at about 250 °C. Due to the loss of residual solvent, the DSC trace of Nds1a ( Figure 116 ) shows a series of small endothermic events between 25 - 100 °C. The endothermic event with a peak temperature of 280 °C is due to melting / decomposition. The proton NMR spectrum obtained for Nds1a ( Figure 117 ) confirms salt formation as the proton resonances of the salt are shifted compared to those of the starting material. The free base∶1,5-naphthalenedisulfonic acid stoichiometry determined for Nds1a is 1∶0.5.

[0774] Form D / ethanesulfonate, Esy1

[0775] Esy1 or Form D was obtained with ethanesulfonic acid. Without wishing to be bound by any particular theory, it is believed that the same XRPD pattern was observed in experiments with phosphoric acid and oxalic acid, and thus this can be attributed to the solid form of the free base rather than the salt. The XRPD patterns obtained from experiments with ethanesulfonic acid, phosphoric acid, and oxalic acid are as Figure 118 shown. In all cases, very similar powder patterns were obtained, with some diffraction peaks having small shifts. Without wishing to be bound by any particular theory, it is believed that the TGMS analysis of Esy1 or Form D obtained with ethanesulfonic acid in THF ( Figure 119 ) indicates that this form is most likely the solvated or hydrated form. A 4.6% mass loss was observed between 25 - 200 °C, followed by decomposition starting at about 250 °C. The proton NMR spectrum obtained for Esy1 / Form D ( Figure 120 ) indicates salt formation as the proton resonances are shifted compared to the starting material. The free base∶ethanesulfonic acid stoichiometry could not be determined.

[0776] 1-Hydroxy-2-naphthoate, Xin1

[0777] Using 1-hydroxy-2-naphthoic acid, the same XRPD pattern Xin1 was obtained from all three solvents. Xin1 is physically stable during exposure to AAC and Figure 121Powder patterns of Xin1 before and after 2 days of exposure to AAC are presented. The stable crystalline malonate Xin1 (Exp.ID SSm19) was further analyzed by TGMS. The TGMS analysis of Xin1 ( Figure 122 ) showed a gradual mass loss of 12% between 25 - 200 °C. The mass loss was related to the loss of THF and subsequent decomposition. The endothermic event in the heat flow signal between 160 - 180 °C most likely indicated the dissociation / decomposition of the salt.

[0778] Benzoate, Ben2

[0779] Three different XRPD patterns were obtained with benzoic acid. Ben1 was obtained from THF, and Ben2 was obtained from ethanol and acetone. Ben1 was physically unstable during 2 days of exposure to AAC and transformed into Ben3. The XRPD patterns of the different forms had some similarities, as shown in Figure 123 . In Figure 124 , powder patterns of Ben2 (Exp.ID SSm63) obtained from ethanol before and after 2 days of exposure to AAC are presented. The benzoate Ben2 (Exp.ID SSm63) obtained from ethanol was further analyzed by TGMS. The TGMS analysis ( Figure 125 ) showed a mass loss of 4.5% between 25 - 100 °C, followed by decomposition. The mass loss was most likely due to ethanol and water. The heat flow showed an endothermic event at approximately 170 °C, which may be due to a melting / decomposition event.

[0780] Benzenesulfonate, Bes1

[0781] With benzenesulfonic acid, one salt Bes1 was obtained from each solvent. Bes1 was physically unstable during exposure to AAC and became less crystalline and most likely underwent salt dissociation. In Figure 126 , powder patterns of Bes1 (Exp.ID SSm10) obtained from THF before and after 2 days of exposure to AAC are presented. The benzenesulfonate Bes1 obtained from THF was further analyzed by TGMS. The TGMS analysis of Bes1 ( Figure 127 ) showed an immediate mass loss of 8.1% (25 - 180 °C), followed by decomposition at approximately 230 °C. The benzenesulfonate was most likely in a solvated form and was unstable as a non-solvated form.

[0782] Gentisate, Gen1

[0783] Two different XRPD patterns were obtained using gentisic acid. From the experiment in THF, the crystalline salt Gen1 was obtained after evaporation of the solvent. The poorly crystalline solid, Gen2_lc, was precipitated from acetone and ethanol. The XRPD patterns of the two forms are as Figure 128 shown. Based on crystallinity and physical stability, Gen1 was selected for further characterization. In Figure 129 , the powder patterns of Gen1 before and after 2 days of exposure to AAC are presented. The solid obtained from THF (Exp.ID SSm21) was further characterized by TGMS analysis. The TGMS analysis of Gen1 ( Figure 130 ) showed a 9.2% mass loss between 25 - 200 °C. The mass loss is related to solvent loss and thermal decomposition. The endothermic event observed in the heat flow signal at approximately 130 °C may be related to solvent loss.

[0784] Hydrobromide, HBr1

[0785] The crystalline salt HBr1 was obtained using hydrobromic acid in ethanol. The poorly crystalline / amorphous solid was recovered from acetone and THF. The crystalline solid HBr1 was physically unstable during exposure to accelerated aging conditions and transformed into HBr2. In Figure 131 , the powder patterns of the solid before and after 2 days of exposure to AAC are presented. The hydrobromide salt HBr1 (Exp.ID SSm34) was further characterized by TGMS analysis. The TGMS analysis of HBr1 ( Figure 132 ) showed a 5.9% mass loss due to the loss of ethanol. The heat flow signal recorded several endothermic events related to the mass loss, and the endothermic event at 170 °C is most likely related to melting. Decomposition started at approximately 240 °C. The results suggest that HBr1 is a solvated salt and is unstable as the non-solvated form.

[0786] Maleate, Mae1

[0787] Two different XRPD patterns were obtained using maleic acid. The pure salt phase Mae1 was obtained from the experiment in THF and acetone. A mixture of Mae1 and Mae2 was obtained from ethanol. The XRPD patterns of the two forms are as Figure 133 shown. Mae1 was physically stable during AAC, while the mixture of Mae1 and Mae2 transformed into Mae1. In Figure 134 , the powder patterns of Mae1 before and after 2 days of exposure to AAC are presented. The stable crystalline salt Mae1 (Exp.ID SSm14) was further analyzed by TGMS. The TGMS analysis of Mae1 ( Figure 135 ) showed a 3.4% mass loss between 25 - 110 °C, which is most likely due to the loss of THF and / or water and subsequent decomposition.

[0788] Sulfate, Sul1

[0789] Sulfuric acid experiments were carried out with half - molar and one - molar equivalents. A total of four different XRPD patterns were observed. In the experiment using 1 - molar equivalent, Sul1 and Sul4 were mainly observed, while Sul2 was only observed in the experiment using half - molar equivalent sulfuric acid. However, after evaporation of the mother liquor of the experiment in which Sul2 was ...

Claims

1. The crystalline form of voruciclib malonate, characterized in that it comprises an X-ray powder diffraction pattern with peaks at 15.21° ± 0.2°, 18.98° ± 0.2°, 24.15° ± 0.2°, 25.00° ± 0.2° and 25.57° ± 0.2° 2θ.

2. The crystalline form according to claim 1, characterized in that it comprises an X-ray powder diffraction pattern with one or more peaks selected from 6.36° ± 0.2° 2θ, 7.31° ± 0.2° 2θ, 9.34° ± 0.2° 2θ, 10.05° ± 0.2° 2θ, 13.59° ± 0.2° 2θ, 14.08° ± 0.2° 2θ, 15.67° ± 0.2° 2θ, 17.53° ± 0.2° 2θ, 18.70° ± 0.2° 2θ, 19.38° ± 0.2° 2θ, 19.67° ± 0.2° 2θ, 20.16° ± 0.2° 2θ, 20.39° ± 0.2° 2θ, 21.01° ± 0.2° 2θ, 22.27° ± 0.2° 2θ, 23.35° ± 0.2° 2θ, 24.67° ± 0.2° 2θ, 25.18° ± 0.2° 2θ, 25.93° ± 0.2° 2θ, 26.21° ± 0.2° 2θ, 27.19° ± 0.2° 2θ and 27.38° ± 0.2° 2θ.

3. The crystalline form according to claim 1 or 2, wherein the crystalline form is a crystalline anhydrate.

4. A composition comprising the crystalline form according to any one of claims 1 to 3 and a pharmaceutically acceptable excipient.

5. A dosage form comprising the composition according to claim 4, wherein the dosage form is selected from one or more of the following: capsules, sachets, tablets, liquids, aerosol sprays, powders, orally dissolving films, lozenges and pastes.

6. Use of a therapeutically effective amount of the crystalline form according to any one of claims 1 - 3, the composition according to claim 4 or the dosage form according to claim 5 in the manufacture of a medicament for treating a hyperproliferative disease in a patient, wherein the hyperproliferative disease is selected from acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, non-Hodgkin lymphoma and B-cell lymphoproliferative disorders.

7. Use of a therapeutically effective amount of the crystalline form according to any one of claims 1 - 3, the composition according to claim 4 or the dosage form according to claim 5 in the manufacture of a medicament for treating a hyperproliferative disease in a patient, wherein the hyperproliferative disease is selected from mantle cell lymphoma, Waldenström's macroglobulinemia, diffuse large B-cell lymphoma, follicular lymphoma and B-cell acute lymphoblastic leukemia.

8. Use of a therapeutically effective amount of the crystalline form according to any one of claims 1 - 3, the composition according to claim 4 or the dosage form according to claim 5 in the manufacture of a medicament for treating blood cancer in a patient.

9. Use according to claim 8, wherein the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic lymphoma (ALL), and chronic lymphocytic leukemia (CLL).

10. Use of the composition according to claim 4 in the preparation of a medicament for the treatment of blood cancer in a patient.

11. Use according to claim 10, wherein the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic lymphoma (ALL), and chronic lymphocytic leukemia (CLL).

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