(S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrroridine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide solid form and formulation

Abstract

Compositions for treating cancer or other diseases are provided. [Solution] A composition containing crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base. Preferably, the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is characterized by a transmission X-ray powder diffraction pattern containing peaks at 6.4, 8.6, 10.5, 11.6, and 15.7°2θ±0.2°2θ.

Description

[Technical Field]

[0001] Cross-reference of related applications This application is an international application claiming the benefits of U.S. Provisional Application No. 62 / 188,468, filed on 2 July 2015, and U.S. Provisional Application No. 62 / 271,708, filed on 28 December 2015. Each of these documents is incorporated herein by reference in its entirety.

[0002] Field of Invention In some embodiments, the present invention relates to crystalline form I of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide. In other embodiments, the present invention relates to pharmaceutical compositions including form I, including pharmaceutical compositions that negate the effects of gastric acid inhibitors, and methods for treating cancer or other diseases by administering these pharmaceutical compositions to a subject. In some embodiments, the present invention relates to the crystalline salt of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide. In other embodiments, the present invention relates to pharmaceutical compositions that negate the effects of gastric acid inhibitors, including pharmaceutical compositions comprising a crystalline salt of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrroridine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide, and methods for treating cancer or other diseases by administering these pharmaceutical compositions to a subject. [Background technology]

[0003] Background of the Invention Bruton's tyrosine kinase (BTK) is a Tec-family non-receptor protein kinase expressed in B cells and myeloid cells. BTK consists of a presctrinnine homolog (PH) domain, a Tec homolog (TH) domain, a Src homolog 3 (SH3) domain, a Src homolog 2 (SH2) domain, and a tyrosine kinase or Src homolog 1 (TK or SH1) domain. The function of BTK in signaling pathways activated by the binding of the B cell receptor (BCR) in mature B cells and FCER1 on mast cells is well established. Functional mutations in human BTK lead to primary immunodeficiency (X-linked agammaglobulinemia) characterized by B cell developmental deficiency with blockade between the pro-B cell and pre-B cell phases. This results in a near-complete absence of B lymphocytes and a significant decrease in all classes of serum immunoglobulins. These findings support the important role of BTK in regulating autoantibody production in autoimmune diseases.

[0004] BTK is expressed in many B-cell lymphomas and leukemias. Other diseases in which dysfunctional B cells play a significant role include B-cell malignancies, as described in Hendriks, et al., Nat. Rev. Cancer, 2014, 219-231. The reported role of BTK in regulating B-cell proliferation and apoptosis suggests potential for BTK inhibitors in the treatment of B-cell lymphomas. BTK inhibitors are being developed as promising therapeutic agents for many of these malignancies, as described in D'Cruz, et al., Oncotargets and Therapy 2013, 6, 161-176. International Patent Application Publication No.: International Publication 2013 / 010868 discloses a BTK inhibitor comprising (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide for use as a therapeutic agent.

[0005] The present invention involves the unexpected discovery of novel crystalline solid forms of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide (referred to herein as formula (1)), including crystalline free base form I. Formula (1) is a BTK inhibitor particularly useful in pharmaceutical compositions and methods for the treatment of cancer, inflammation, immunology, and autoimmune diseases. The novel solid forms of formula (1) disclosed herein, including form I, possess remarkable and useful properties. [Overview of the project] [Means for solving the problem]

[0006] Summary of the Invention In one embodiment, the present invention provides a composition comprising a crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrroridine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base.

[0007] In one embodiment, the present invention provides a composition comprising a crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base, wherein the crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base is characterized by an X-ray powder diffraction pattern including peaks at 6.4, 8.6, 10.5, 11.6, and 15.7°2θ±0.2°2θ.

[0008] In one embodiment, the present invention provides a composition comprising a crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base, wherein the crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base is characterized by an X-ray powder diffraction pattern that includes peaks at 6.4, 8.6, 10.5, 11.6, and 15.7°2θ±0.2°2θ, and further includes peaks at 10.9, 12.7, 13.4, 14.3, 14.9, and 18.2°2θ±0.2°2θ.

[0009] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base, wherein the crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base includes peaks at 6.4, 8.6, 10.5, 11.6, and 15.7°2θ±0.2°2θ, and further at 10.9, 12.7, 13.4, 14.3, 14.9, and 18.2°2θ±0.2°2θ. The peak is at °2θ, and further at 11.3, 15.1, 15.7, 16.1, 17.3, 19.2, 19.4, 19.8, 20.7, 21.1, 21.4, 21.6, 21.9, 22.6, 23.3, 23.6, 24.9, 25.2, 25.4, 25.7, 26.1, 26.4, 26.8, 26.9, 27.7, and 28.6. The X-ray powder diffraction pattern is characterized by including one or more peaks selected from the group consisting of 29.1, 29.4, 30.1, 30.5, 31.7, 31.9, 32.2, 32.6, 33.1, 33.4, 34.5, 35.9, 36.1, 36.8, 37.4, 38.1, 38.9, and 39.5°2θ±0.2°2θ.

[0010] In one embodiment, the present invention provides a composition comprising a crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base, wherein the crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base is characterized by a transmission X-ray powder diffraction pattern substantially identical to the typical X-ray powder diffraction pattern shown in Figure 1.

[0011] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base, wherein the crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base is 1620, 1609, 1547, 1514 and 1495 cm⁻¹ -1 ±2cm -1 It is characterized by a Raman spectrum that includes a peak.

[0012] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base, wherein the crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base is 1620, 1609, 1547, 1514 and 1495 cm⁻¹ -1 ±2cm -1 The peaks include 1680, 1574, 1454, 1433, 1351, 1312, 1255, 1232, 1187, 1046, 995, 706, 406, and 280 cm. -1 ±2cm -1It is characterized by a Raman spectrum containing one or more peaks selected from the group consisting of.

[0013] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base is characterized by a Raman spectrum substantially the same as the representative Raman spectrum shown in FIG. 2.

[0014] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base has peaks at 1621, 1608, 1403, 1303, and 764 cm -1 ±4 cm -1 and is characterized by an infrared (IR) spectrum containing peaks.

[0015] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base, wherein the crystalline (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide free base has peaks at 1621, 1608, 1403, 1303, and 764 cm -1 ±4 cm -1The peaks include 3367, 3089, 2246, 1682, 1574, 1514, 1504, 1454, 1428, 1345, 1248, 1194, 1177, 1149, 1109, 1049, 1023, 1003, 947, 900, 858, 842, 816, 734, 729, 701, 689, 665, 623, and 612 cm. -1 ±4cm -1 It is characterized by an infrared (IR) spectrum containing one or more peaks selected from the group consisting of the following.

[0016] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base, wherein the crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base is characterized by an IR spectrum substantially identical to that of a typical IR spectrum shown in Figure 3.

[0017] In one embodiment, the present invention provides a composition comprising a crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base, wherein the crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base is characterized by the absence of water in its crystalline structure.

[0018] In one embodiment, the present invention provides a composition comprising a crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base and an extragranular acidulant.

[0019] In one embodiment, the present invention provides a composition comprising a crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base and a granular exogenous acidulant, wherein the granular exogenous acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-aloascorbic acid), alginic acid or its salts, protacid F120NM, protacid AR1112 (also known as keracid NF), and carbopol 971P (carboxypolymethylene), and combinations thereof.

[0020] In one embodiment, the present invention provides a composition comprising a crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base and a granular exogenous acidulant, wherein the granular exogenous acidulant is alginic acid, or its sodium or potassium salt, in a concentration of about 5% to about 33% by weight.

[0021] In one embodiment, the present invention provides a composition comprising a crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base and a granular exogenous acidulant, wherein the granular exogenous acidulant is alginic acid, or its sodium or potassium salt, in a concentration of about 5% to about 33% by weight, and the composition further comprises at least one pharmaceutically acceptable excipient.

[0022] In one embodiment, the present invention provides a method for treating hyperproliferative diseases, comprising the step of administering a therapeutically effective amount of a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I to a mammal, where the hyperproliferative disease is: 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's disease, multiple myeloma, acute myeloid leukemia, juvenile myelomonocytic leukemia, hairy cell leukemia, mastocell leukemia, mastocytosis, myeloproliferative disorder (MPD), myeloproliferative neoplasm, erythrocyte Cyltosis (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 tumor, glioblastoma, lung cancer, squamous cell carcinoma, skin cancer (e.g., melanoma), eye cancer, retinoblastoma, intraocular melanoma, oral and gastrointestinal cancers. Nasopharyngeal cancer, bladder cancer, gastric 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, epidermal carcinoma, AIDS-related cancers (e.g., lymphoma), virus-induced cervical cancer (human papillomavirus), nasopharyngeal cancer (Epstein-Barr virus), Kaposi's sarcoma, primary exudative lymphoma (Kaposi's sarcoma herpesvirus), hepatocellular carcinoma (hepatitis B and hepatitis C viruses), T-cell leukemia (human T-cell leukemia virus-1)The following conditions are selected from the group consisting of virus-1), benign hyperplasia and restenosis of the skin, benign prostatic hyperplasia, tumor angiogenesis, chronic inflammatory diseases, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, eczema and other skin diseases such as scleroderma, diabetes mellitus, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, ulcerative colitis, atopic dermatitis, pouchitis, spondyloarthritis, 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.

[0023] In one embodiment, the present invention provides a method for treating a hyperproliferative disorder, comprising the step of administering to a mammal a therapeutically effective amount of a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I, wherein the hyperproliferative disorder is selected from the group consisting of: chronic lymphocytic leukemia, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Waldenström macroglobulinemia.

[0024] In one embodiment, the present invention provides a method for treating hyperproliferative disorders, comprising the step of administering to a mammal a therapeutically effective amount of a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I and a granular exogenous acidulant, wherein the hyperproliferative disorder is selected from the group consisting of: chronic lymphocytic leukemia, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Waldenström macroglobulinemia.

[0025] In one embodiment, the present invention provides a method for treating a hyperproliferative disease, comprising the steps of administering a therapeutically effective amount of a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I and a granular exogenous acidulant to a mammal, and further comprising the steps of administering a therapeutically effective amount of a gastric acid inhibitor to the mammal.

[0026] In one embodiment, the present invention provides a method for treating a hyperproliferative disease, comprising the steps of administering to a mammal a therapeutically effective amount of a composition comprising a crystalline fumarate, maleate, phosphate, L-tartrate, citrate, gentisinate, oxalate, or sulfate of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrroridine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I, and further comprising the steps of administering to a mammal a therapeutically effective amount of a gastric acid inhibitor.

[0027] The above summary, as well as the following detailed description of the present invention, will be better understood when read in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0028] [Figure 1] The transmission PXRD pattern of free base form I (sample PP502-P1) of formula (1) is shown. [Figure 2] The Raman spectrum of form I of the free base in equation (1) is shown. [Figure 3] The infrared (IR) spectrum of form I of the free base of equation (1) is shown. [Figure 4] The permeabilized PXRD pattern of the free base of formula (1) in form II is shown. [Figure 5] The Raman spectrum of form II of the free base in equation (1) is shown. [Figure 6] The permeabilized PXRD pattern of the free base of formula (1) in form III is shown. [Figure 7]The Raman spectrum of form III of the free base in equation (1) is shown. [Figure 8] The PXRD pattern of metastable form IV of the free base in equation (1) is shown. [Figure 9] The PXRD pattern of the metastable form V of the free base in equation (1) is shown. [Figure 10] The PXRD pattern of metastable form VI of the free base in equation (1) is shown. [Figure 11] The PXRD pattern of metastable form VII of the free base in equation (1) is shown. [Figure 12] The PXRD pattern of metastable form VIII of the free base in equation (1) is shown. [Figure 13] The PXRD pattern of amorphous type (1) is shown. [Figure 14] The Raman spectrum of amorphous formula (1) is shown. [Figure 15] The reflective PXRD pattern of morphology A of fumarate (1) is shown. [Figure 16] The reflective PXRD pattern of form A of the maleate of formula (1) is shown. [Figure 17] The PXRD pattern of form A of the phosphate of formula (1) is shown. [Figure 18] The PXRD pattern of form A of L-tartrate of formula (1) is shown. [Figure 19] This shows the PXRD pattern of morphology A of citrate of formula (1) (sample SP211-CIT-P4) crystallized from acetone-water. [Figure 20] This shows the PXRD pattern of morphology A of citrate of formula (1) (sample SP211-CIT-P6) crystallized from 1-propanol. [Figure 21] The PXRD pattern of a sample of form A of gentisic acid monohydrate (1) is shown. [Figure 22] The PXRD pattern of morphology A of the oxalate of formula (1) is shown. [Figure 23] The PXRD pattern of a sample of form A of the sulfate of formula (1) is shown. [Figure 24]The species distribution of equation (1) based on calculated pH values ​​of 2.2, 6.1, and 11.5 is shown. [Figure 25] The pH-dependent solubility of the free base of formula (1) (sample PP502-P1) using HCl and a buffer solution as a solvent is shown. Circles correspond to results from the first experimental set, and diamonds correspond to results from the second experimental set. [Figure 26] The species distribution and solubility as a function of pH in equation (1) are shown. [Figure 27] The temperature-dependent solubility of formula (1) for acetone (square), ethanol (dot and line), 96% ethanol (triangle), and 1-propanol (diamond) is shown. The vertical line indicates the boiling point of ethanol. [Figure 28] The results for the intrinsic elution rates of free base forms I and II (formula 1) are shown. [Figure 29] Exposure data in dogs for forms I and II of free bases (formula 1) are shown. [Figure 30] A comparison of the dissolution profiles of the formulation of formula (1) at pH 3.4 is shown. [Figure 31] A comparison of the dissolution profiles of the formulation of formula (1) at pH 5.5 is shown. [Figure 32]Trends in AUC, Cmax, and Tmax are shown for conditioned dogs treated with formulations of formula (1), including the acidulant and the four salt forms of formula (1). Liquid capsules ("liq cap") (100 mg) were administered for comparison with the solid form. Solid capsules of 100 mg strength from the clinical formulation of form I of formula (1) were administered to dogs before or after daily treatment with omeprazole to reduce gastric acidity. After 4 days of omeprazole (10 mg / day) administration, the subsequent study period was carried out; omeprazole treatment was continued throughout the study. The acidulant formulation of form I of formula (1) ("FA-3") was compared with F-1 maleate, F-1 phosphate, F-1 fumarate, F-1 tartrate, and control formulations (F-1 free base and F-2), administered as 100 mg equivalent of free base in a capsule. Exposure to salts and capsules of formula (1) form I, formulated with acidulants or using the salt form of formula (1), was increased compared to exposure to formula (1) in the presence of omeprazole. [Figure 33] The dose-normalized AUC and Cmax of formula (1) in dogs are shown and compared with liquid capsules ("Liq Caps") (mean of n=2), formulation F-2 (mean of n=5), formulation F-2 containing omeprazole ("F-2 / Omep", showing a reduction in exposure of formula (1)), and five formulations of the present invention that restore exposure in the presence of omeprazole: FA-3 (containing an acidulant, "FA-3 / Omep"), F-1 maleate ("maleate / Omep"), F-1 phosphate ("phosphate / Omep"), F-1 fumarate ("fumarate / Omep"), and F-1 tartrate ("tartrate / Omep"). [Modes for carrying out the invention]

[0029] Detailed description of the invention Preferred embodiments of the present invention are shown and described herein, but such embodiments are provided only as examples and are not intended to limit the scope of the invention. Various substitutes for the embodiments of the invention described may be used in carrying out the invention.

[0030] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which the present invention pertains. All patents and publications referenced herein are incorporated herein by reference in their entirety.

[0031] The term "solid form" may refer to crystalline solid forms or phases, including crystalline free bases and crystalline salts.

[0032] The terms “simultaneous administration,” “administering simultaneously,” “administered in combination with,” and “administered in combination with,” as used herein, encompass the administration of two or more drugs to a subject so that both drugs and / or their metabolites are present in the subject at the same time. Simultaneous administration includes simultaneous administration using separate compositions, administration using separate compositions at different time points, or administration using a single composition containing two or more drugs.

[0033] The term “effective dose” or “therapeutic dose” refers to a sufficient amount of the composition or combination of compositions described herein to carry out the intended use, such as the treatment of a disease, but is not limited to this definition. The therapeutic dose may vary depending on the intended use (in vitro or in vivo), the subject being treated and their condition (e.g., the subject’s weight, age, and sex), the severity of the condition, the mode of administration, etc., which can be readily determined by those skilled in the art. The term also applies to the dose that induces a specific response in target cells (e.g., reduced platelet adhesion and / or cell migration). The specific dose may vary depending on the specific compound selected, the administration regimen 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 through which the compound is transported.

[0034] The terms "QD," "qd," or "qd" mean once a day (quaque die), once per day, or once every day. The terms "BID," "bid," or "bid" mean twice a day (bis in die), twice per day, or twice every day. The terms "TID," "tid," or "tid" mean three times a day (ter in die), three per day, or three times every day. The terms "QID," "qid," or "qid" mean four times a day (quater in die), four per day, or four times every day.

[0035] When this term is used herein, “therapeutic effect” encompasses the therapeutic and / or preventive benefits described herein. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0036] The term "pharmaceutically acceptable salt" refers to salts obtained from a variety of organic and inorganic counterions, including fumarates, maleates, phosphates, L-tartrates, citrates, gentisates, oxalates, and sulfate counterions. Pharmacochemically acceptable acid addition salts can be formed with inorganic and organic acids.

[0037] "Pharmacologically acceptable carriers" or "pharmaceutically acceptable excipients" are intended to include any solvent, dispersion medium, coating agent, antimicrobial and antifungal agent, isotonic agent, and absorption retarder. Their use in the therapeutic compositions of the present invention is considered unless any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients may also be incorporated into the compositions described.

[0038] The term "in vivo" refers to events that occur within the subject's body.

[0039] The term "in vitro" refers to events that occur outside the body of a subject. In vitro assays include cell assays that use live or dead cells, and may also include cell-free assays that do not use intact cells.

[0040] The term "external to granules" refers to substances that are located outside the granules but not contained within them, such as substances added to granules (multi-particle molded bodies formed by granulation) and substances physically mixed with granules.

[0041] The term "granular-intrinsic" refers to the substance located inside a granule (a multi-particle molded body formed by granulation). Granules can be formed by methods such as wet granulation (i.e., prepared using water or steam, heat, melting, freezing, foaming, and other methods) or dry granulation.

[0042] The term "acidulant" refers to a substance that increases acidity.

[0043] The term "transmission" or "transmission method," when used with powder X-ray diffraction, refers to the transmission (also known as Debye-Scherrer) sampling mode. The term "reflection" or "reflection mode," when used with powder X-ray diffraction, refers to the reflection (also known as Bragg-Brentano) sampling mode.

[0044] Unless otherwise stated, 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, one or more hydrogen atoms are substituted with deuterium or tritium, or one or more carbon atoms are 13 C or 14 Compounds substituted with carbon-enriched carbon are included within the scope of the present invention.

[0045] In this specification, when a range is used to describe a physical or chemical property, such as molecular weight or chemical formula, all combinations and partial combinations of ranges, and specific embodiments within them, are intended to be included. The use of the terms “about” or “approximately” means, when relating to a numerical value or numerical range, that the numerical value or numerical range shown is an approximation within experimental variability (or statistical experimental error), and therefore the numerical value or numerical range may vary, for example, between 1% and 15% of the stated numerical value or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) includes embodiments, such as any composition, method or process embodiment of a substance that “consists” or “consists” of the described features.

[0046] In the context of this specification, "enantiomer purity" refers to the relative amount, expressed as a percentage, of the presence of a particular enantiomer relative to other enantiomers. For example, if a compound that may possibly have (R)- or (S)-isomer structures exists as a racemic mixture, the enantiomer purity is about 50% with respect to either the (R)- or (S)-isomer. If a compound has one dominant isomer form relative to the other, for example, 80% (S)-isomer and 20% (R)-isomer, the enantiomer purity of this compound is 80% with respect to the (S)-isomer form. The enantiomer purity of a compound can be determined by various methods, including, but not limited to, chromatography using a chiral support, optical rotation of polarization, but not limited to, nuclear magnetic resonance spectroscopy using chiral shift reagents such as lanthanides containing chiral complexes or Pirkle reagents, or chromatography or nuclear magnetic resonance spectroscopy following derivatization of the compound using a chiral compound such as Mosher's acid.

[0047] In preferred embodiments, the enantiomer-concentrated composition has higher efficacy per unit mass of the composition than the racemic mixture of the composition. The enantiomers can be isolated from the mixture by methods well known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric synthesis. See, for example, 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 Carbon Compounds, Wiley-Interscience, New York, 1994.

[0048] In the context of this specification, “enantiomerically concentrated” and “non-racemic” refer to a composition in which the weight percentage of one enantiomer is higher than the amount of the same enantiomer in a control mixture of racemic compositions (e.g., greater than 1:1 by weight). For example, an enantiomerically concentrated preparation of an (S)-enantiomer means a preparation of a compound having more than 50% by weight of the (S)-enantiomer, such as at least 75% by weight or at least 80% by weight, relative to the (R)-enantiomer. In some embodiments, concentration may be significantly greater than 80% by weight to provide a “substantially concentrated” or “substantially non-racemic” preparation, which refers to a preparation of a composition having at least about 85% by weight of one enantiomer, such as at least 90% by weight or at least 95% by weight, relative to the other enantiomer. The terms “enantiomerically pure” or “substantially pure” refer to a composition containing at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.

[0049] A "moiety" refers to a specific segment or functional group within a molecule. A chemical moiety is often perceived as a chemical entity that is incorporated within or attached to a molecule.

[0050] Tautomers are structurally distinct isomers that interconvert through tautomerization. Tautomerization is a form of isomerization, including protropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. Protropic or proton-shift tautomerization involves a change in bond order, often involving the exchange of single bonds via adjacent double bonds, and the movement of protons. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. One example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypento-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. The formation of solid forms in various tautomerized states is known as "desmotropy," and such forms are known as "desmotoropes."

[0051] The compositions of the present invention also include crystalline forms of formula (1), such forms include, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrous), and higher-order polymorphs, as well as mixtures thereof. Unless a specific crystalline form is indicated, “crystalline form,” “form,” and “polymorph” are intended to encompass all crystalline forms of the compound, such as, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrous), and higher-order polymorphs, as well as mixtures thereof.

[0052] A "solvate" refers to the crystalline phase of a compound that is physically bonded to one or more molecules of a solvent. The crystalline phase of a compound that is physically bonded to one or more molecules of water is called a "hydrate."

[0053] "Amorphous form" refers to a compound, or the form of a salt or molecular complex of a compound, that lacks long-range crystalline order.

[0054] Crystal morphology In one embodiment, the present invention provides a crystalline solid form of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide (formula (1)). Formula (1) has the following chemical structure: [ka]

[0055] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I, wherein the crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I is (1) measured at peak positions of 6.4, 8.6, 10.5, 10.9, 11.3, 11.6, 12.7, 13.4, 14. 3, 14.9, 15.1, 15.7, 16.1, 17.3, 18.2, 19.2, 19.4, 19.8, 20.7, 21.1, 21.4, 21.6, 21.9, 22.6, 23.3, 23.6, 24.9, 25.2, 25.4, 25.7, 26.1, 26.4, 26.8, 26.9, 27.7, 28.6, 2 (2) An X-ray powder diffraction pattern containing at least five peaks selected from the group consisting of 9.1, 29.4, 30.1, 30.5, 31.7, 31.9, 32.2, 32.6, 33.1, 33.4, 34.5, 35.9, 36.1, 36.8, 37.4, 38.1, 38.9, and 39.5; (2) Peak positions in cm -1 ±2cm -1(3) Measure the Raman spectrum containing at least three peaks selected from the group consisting of 1680, 1620, 1609, 1574, 1547, 1514, 1495, 1454, 1433, 1351, 1312, 1255, 1232, 1187, 1046, 995, 706, 406, and 280; (3) measure the peaks to cm -1 ±4cm -1 (4) an IR spectrum characterized by the absence of water in the crystal structure, measured and containing at least three peaks selected from the group consisting of 3367, 3089, 2246, 1682, 1621, 1608, 1574, 1514, 1504, 1454, 1428, 1403, 1345, 1303, 1248, 1194, 1177, 1149, 1109, 1049, 1023, 1003, 947, 900, 858, 842, 816, 764, 734, 729, 701, 689, 665, 623, and 612; and (4) at least one of the absence of water in the crystal structure.

[0056] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I, wherein the crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I is characterized by an X-ray powder diffraction pattern including peaks at 6.4, 8.6, 10.5, 11.6, and 15.7°2θ±0.2°2θ. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2- Free base form I of (yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide is characterized by an X-ray powder diffraction pattern containing peaks at 6.4, 8.6, 10.5, 11.6, and 15.7°2θ±0.2°2θ, as well as peaks at 10.9, 12.7, 13.4, 14.3, 14.9, and 18.2°2θ±0.2°2θ. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I is characterized by an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern of Figure 1, which can be measured using transmission mode or reflection mode. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in transmission mode. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in reflection mode.

[0057] It is known in the art that X-ray powder diffraction patterns with one or more errors can be obtained depending on the measurement conditions (e.g., the apparatus, sample preparation, or instrument used). In particular, it is generally known that the intensity of the X-ray powder diffraction pattern can vary depending on the measurement conditions and sample preparation. For example, those skilled in the art will understand that the relative intensity of the peaks can vary depending on the orientation of the sample under test, and further based on the type and settings of the instrument used. Furthermore, those skilled in the art will understand that the position of the reflection can be affected by the exact height at which the sample is located in the diffractometer, the surface flatness of the sample, and the zero calibration of the diffractometer. Accordingly, those skilled in the art will understand that the diffraction pattern data presented herein should not be interpreted as absolute, and that any crystalline form that yields substantially the same powder diffraction pattern as disclosed herein is included in the scope of this disclosure. For further information, see Jenkins and Snyder, Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, 1996.

[0058] Furthermore, it is known in the art that IR and Raman spectra can be obtained that vary depending on the measurement conditions. The instrument, sampling mode (e.g., attenuated total internal reflection IR sampling versus transmission IR sampling), and instrument calibration can affect peak position and intensity. Those skilled in the art will understand that the spectra shown herein should not be interpreted as absolute, and that any crystalline form that yields substantially the same spectra as those disclosed herein is included within the scope of this disclosure. For further information, see Colthup, et al., Introduction to Infrared and Raman Spectroscopy, 3rd Ed, Academic Press, 1990.

[0059] Crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base form I offers many remarkable advantages over the conventional amorphous (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base, including improved chemical stability and significantly reduced hygroscopicity. Compared to other novel crystalline forms of the free base of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide disclosed herein, Form I offers remarkable advantages, including improved thermodynamic stability, faster dissolution rates, improved performance in the gastric environment (such as avoidance or reduction of precipitation from solution when pH changes to higher levels), improved exposure in mammals, and superior processability for formulation of the drug into patient-friendly finished formulations.

[0060] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrroridine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide fumarate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide fumarate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide fumarate form A has a peak position of °2θ±0. (2) X-ray powder diffraction pattern measured within 2°2θ, including at least five peaks selected from the group consisting of 4.9, 5.4, 7.0, 9.8, 10.8, 11.5, 12.1, 14.1, 16.1, 16.6, 17.8, 18.5, 19.4, 20.3, 20.5, 21.9, 22.1, 22.5, 23.1, 24.0, 24.8, 26.6, 26.8, 27.3, and 28.2; and (2) characterized by at least one water molecule present in the crystalline structure in a stoichiometric ratio to formula (1) that is approximately equivalent to that of sesquihydrate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide fumarate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide fumarate form A is characterized by an X-ray powder diffraction pattern including peaks at 4.9, 5.4, 7.0, 10.8, and 11.5°2θ±0.2°2θ.In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide fumarate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide fumarate form A is characterized by an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern of Figure 15.

[0061] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrroridine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide maleate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide maleate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide maleate form A has peak positions measured at °2θ±0.2°2θ: 5.3, 9.8, 10.6, 11.6, 13.5, 13.8, 13.9, 14.3, 15.3, 15. X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 6, 15.8, 15.9, 16.6, 17.4, 17.5, 18.7, 19.3, 19.6, 19.8, 20.0, 20.9, 21.3, 22.1, 22.3, 22.7, 23.2, 23.4, 23.7, 23.9, 24.5, 24.8, 25.2, 25.6, 26.1, 26.4, 26.9, 27.1, 27.6, 28.8, 29.5, 30.0, 30.3, 30.9, 31.5, 31.9, 32.5, 34.0, and 35.1; and (2) characterized by at least one water molecule present in the crystal structure in a stoichiometric ratio to formula (1) that is approximately equivalent to that of the monohydrate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide maleate, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide maleate form A is characterized by an X-ray powder diffraction pattern including peaks at 5.3, 9.8, 10.6, 11.6, and 19.3°2θ±0.2°2θ.In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide maleate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide maleate form A is characterized by an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern of Figure 16. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in transmission mode. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in reflection mode.

[0062] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrroridine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamid phosphate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamid phosphate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamid phosphate form A has peak positions measured at °2θ±0.2°2θ: 4.5, 6.0, 7.2, 10.4, 12.0, 12.5, 13. X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 1, 14.3, 15.5, 17.4, 18.0, 18.3, 18.9, 19.3, 20.2, 20.5, 20.9, 21.4, 21.9, 22.0, 22.6, 22.9, 23.1, 23.3, 24.2, 24.6, 25.0, 25.7, 26.2, 26.4, 26.9, 27.3, 27.5, 29.3, 30.0, 30.3, 30.5, 30.9, 31.2, 31.9, and 35.7; and (2) characterized by at least one water molecule present in the crystal structure in a stoichiometric ratio to formula (1) that is approximately equivalent to that of the dihydrate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamid phosphate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamid phosphate form A is characterized by an X-ray powder diffraction pattern including peaks at 4.5, 6.0, 10.4, 12.0, and 14.3°2θ±0.2°2θ.In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamid phosphate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamid phosphate form A is characterized by an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern of Figure 17. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in transmission mode. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in reflection mode.

[0063] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide L-tartrate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide L-tartrate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide L-tartrate form A has peak positions measured at °2θ±0.2°2θ as 4.6, 5.5, 7.2, 9.3, 10.7, 10.9, X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 11.8, 14.3, 14.9, 16.4, 17.0, 17.7, 19.2, 19.4, 19.5, 20.3, 21.6, 22.4, 23.3, 23.8, 24.3, 24.5, 24.7, 25.1, 25.6, 26.8, 27.2, 27.8, 28.4, 28.7, 29.0, 29.5, 30.0, 30.9, 31.6, 32.1, 32.4, 33.0, 33.5, and 33.9; and (2) characterized by at least one water molecule present in the crystal structure in a stoichiometric ratio to formula (1) that is approximately equivalent to that of sesquihydrate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide L-tartrate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide L-tartrate form A is characterized by an X-ray powder diffraction pattern including peaks at 4.6, 5.5, 10.9, 11.8, and 14.9°2θ±0.2°2θ.In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide L-tartrate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide L-tartrate form A is characterized by an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern of Figure 18. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in transmission mode. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in reflection mode.

[0064] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrroridine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A is (a) peak position (b) The X-ray powder diffraction pattern is measured at °2θ±0.2°2θ and includes at least five peaks selected from the group consisting of 6.1, 6.6, 7.2, 7.9, 8.3, 9.7, 10.8, 11.2, 12.2, 13.5, 14.1, 14.9, 15.9, 16.6, 17.5, 17.9, 18.3, 18.9, 19.5, 20.3, 21.5, 21.9, 22.7, 23.8, 24.4, 24.8, 26.1, 26.3, 27.2, 27.4, 27.9, and 29.3; (b) the peak positions are measured in cm -1 ±2cm -1(c) Raman spectra including at least three peaks selected from the group consisting of 3068, 2921, 2237, 1682, 1612, 1551, 1505, 1436, 1332, 1313, 1241, 1188, 993, and 712, measured at cm; (c) peak positions in cm -1 ±4cm -1 (d) an IR spectrum measured at 3396, 2234, 1673, 1606, 1537, 1428, 1304, 1264, 1200, 1092, 1008, 893, 866, 773, 735, and 693, and characterized by (d) at least one of the water molecules present in the crystalline structure at concentrations from about 0% to about 8% by weight. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A is (a) peak position (b) The X-ray powder diffraction pattern is measured at °2θ±0.2°2θ and includes at least five peaks selected from the group consisting of 6.1, 6.4, 7.2, 7.9, 8.2, 9.6, 10.9, 12.0, 13.4, 13.8, 14.0, 14.9, 15.5, 15.9, 16.4, 17.3, 17.5, 18.2, 18.6, 19.3, 20.1, 20.4, 21.4, 22.6, 23.2, 23.7, 24.3, 26.0, 27.0, 27.3, 27.8, and 29.2; (b) Peak positions are measured in cm -1 ±2cm -1 (c) Raman spectra including at least three peaks selected from the group consisting of 3055, 2920, 2237, 1685, 1612, 1549, 1504, 1436, 1333, 1313, 1286, 1240, 1187, 993, and 712, measured at cm; (c) peaks measured at cm -1 ±4cm -1(4) an IR spectrum measured and containing at least three peaks selected from the group consisting of 3403, 2960, 2872, 2233, 1678, 1608, 1582, 1538, 1434, 1403, 1352, 1302, 1253, 1201, 1094, 1055, 1010, 967, 895, 813, 772, 750, 735, 693, and 612; and (4) at least one presence of water in the crystalline structure at a concentration of about 0% to about 8% by weight. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A is characterized by an X-ray powder diffraction pattern including peaks at 6.1, 7.2, 9.7, 11.1, and 12.2°2θ±0.2°2θ. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A is characterized by an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern of Figure 19. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A is characterized by an X-ray powder diffraction pattern including peaks at 6.1, 7.2, 9.6, 10.9, and 12.0°2θ±0.2°2θ.In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide citrate form A is characterized by an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern of Figure 20. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in transmission mode. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in reflection mode.

[0065] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide gentisate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide gentisate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide Dogentisinate form A is an X-ray powder diffraction pattern with peak positions measured at °2θ ± 0.2°2θ and containing at least five peaks selected from the group consisting of 4.6, 8.2, 9.0, 9.7, 11.8, 12.9, 13.8, 14.5, 15.5, 16.6, 16.8, 18.4, 19.6, 20.5, 21.4, 24.1, 24.5, 25.5, 25.8, 26.0, 26.6, 26.9, 27.4, and 29.8; (b) peak positions measured at cm -1 ±2cm -1(c) Raman spectra obtained by measuring at cm, including at least three peaks selected from the group consisting of 3057, 2919, 2223, 1681, 1613, 1576, 1552, 1518, 1437, 1333, 1312, 1228, 1192, 1156, 990, 716, 485, and 257; (c) Peak positions in cm -1 ±4cm -1(d) an IR spectrum measured at 2957, 1682, 1668, 1602, 1574, 1523, 1504, 1481, 1429, 1377, 1346, 1302, 1274, 1228, 1157, 1092, 1010, 939, 896, 865, 826, 810, 778, 748, 734, 686, 660, and 617, characterized by (d) at least one water molecule present in the crystal structure in a stoichiometric ratio to formula (1) that is approximately equivalent to that of the monohydrate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamidogentidicate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamidogentidicate form A is characterized by an X-ray powder diffraction pattern including peaks at 4.6, 9.0, 12.9, 13.8, and 19.6°2θ±0.2°2θ. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamidogentidicate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamidogentidicate form A is characterized by an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern of Figure 21. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in transmission mode. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in reflection mode.

[0066] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide oxalate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide oxalate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide gentisinate form A (a) X-ray powder diffraction pattern with peaks selected from the group consisting of 5.5, 5.8, 7.4, 9.3, 11.0, 11.5, 12.7, 15.2, 16.5, 17.3, 18.5, 18.7, 19.1, 19.7, 20.2, 20.8, 22.0, 22.33, 23.32, 23.6, 24.8, 27.4, 28.6, 29.3, 29.6, 31.2, 33.1, and any combination thereof, with the peak position measured at °2θ ± 0.2°2θ; (b position measured at cm -1 ±4cm -1 (c) Raman spectra including peaks selected from the group consisting of 3073, 2992, 2950, ​​2922, 2247, 1671, 1612, 1584, 1552, 1504, 1469, 1440, 1336, 1311, 1273, 1235, 1191, 1162, 1095, 1012, 897, 718, 633, 409, 370, 263 and any combination thereof, measured at cm; (c) peak positions at cm -1 ±4cm -1(d) an IR spectrum characterized by (d) the presence of at least one water in the crystalline structure at concentrations from 0 wt% to about 9 wt%. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide oxalate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide oxalate form A is characterized by an X-ray powder diffraction pattern including peaks at 5.5, 5.8, 9.3, 11.5, and 12.7°2θ±0.2°2θ. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide oxalate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide oxalate form A is characterized by an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern of Figure 22. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in transmission mode. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in reflection mode.

[0067] In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide sulfate. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide sulfate, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide sulfate is ( a) X-ray powder diffraction pattern including at least five peaks selected from the group consisting of 4.6, 5.0, 8.0, 9.0, 9.8, 12.0, 12.7, 13.2, 14.6, 15.0, 15.6, 16.2, 17.5, 18.0, 19.8, 20.2, 21.9, 23.8, 24.4, 24.9, 25.7, 26.0, 27.2, 29.5, 30.4, 31.6, and 32.5, with the peak position measured at °2θ±0.2°2θ; (b) X-ray powder diffraction pattern including at least five peaks selected from the group consisting of 4.6, 5.0, 8.0, 9.0, 9.8, 12.0, 12.7, 13.2, 14.6, 15.0, 15.6, 16.2, 17.5, 18.0, 19.8, 20.2, 21.9, 23.8, 24.4, 24.9, 25.7, 26.0, 27.2, 29.5, 30.4, 31.6, and 32.5, with the peak position measured at cm -1 ±4cm -1 (c) Raman spectra including at least three peaks selected from the group consisting of 3115, 2977, 2926, 2224, 1675, 1611, 1537, 1498, 1449, 1409, 1361, 1327, 1310, 1288, 1243, 1198, 1155, 1042, 1009, 978, 948, 906, 849, 771, 713, 652, 632, 464, 370, and 254, measured at cm; (c) peak positions in cm -1 ±4cm -1(d) an IR spectrum measured at 3430, 3101, 3029, 2225, 1667, 1633, 1615, 1598, 1563, 1557, 1508, 1428, 1350, 1328, 1308, 1276, 1225, 1088, 1036, 1018, 925, 891, 848, 816, 783, 736, 723, 694, and 612, and characterized by (d) at least one of the water molecules present in the crystalline structure at a concentration of approximately 2.5% by weight to approximately 12.5% ​​by weight. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide oxalate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide oxalate form A is characterized by an X-ray powder diffraction pattern including peaks at 4.6, 9.0, 9.8, 17.5, and 18.0°2θ±0.2°2θ. In one embodiment, the present invention provides a composition comprising crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide oxalate form A, wherein crystalline (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide oxalate form A is characterized by an X-ray powder diffraction pattern substantially consistent with the X-ray powder diffraction pattern of Figure 23. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in transmission mode. In one embodiment, the X-ray powder diffraction pattern of any of the embodiments described above is measured in reflection mode.

[0068] Pharmaceutical composition In one embodiment, the present invention provides a pharmaceutical composition comprising the crystalline form of the free base of a BTK inhibitor of formula (1). In one embodiment, the present invention provides a pharmaceutical composition comprising the crystalline solvate of the free base of formula (1). In one embodiment, the present invention provides a pharmaceutical composition comprising the crystalline hydrate of the free base of a BTK inhibitor of formula (1). In one embodiment, the present invention provides a pharmaceutical composition comprising the crystalline salt of formula (1). In one embodiment, the present invention provides a pharmaceutical composition comprising form I of the free base of formula (1).

[0069] The pharmaceutical composition is typically formulated to provide a therapeutically effective amount of a BTK inhibitor of formula (1) in solid form, as an active ingredient or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. If desired, the pharmaceutical composition contains a pharmaceutically acceptable salt thereof, as well as 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 acidulant, as described herein, to reduce or eliminate the effects of gastric acid inhibitors upon exposure to the BTK inhibitor of formula (1).

[0070] In some embodiments, the concentration of the BTK inhibitor of formula (1) in solid form imparted to the pharmaceutical composition of the present invention is independently, with respect to the total mass or volume of the pharmaceutical composition, 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%, The percentages are 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 less than 0.001% w / w, w / v, or v / v. In one embodiment, the solid form of any of the embodiments of formula (1) described above is form I of the free base.

[0071] In some embodiments, the concentrations of the BTK inhibitor of formula (1) provided in the pharmaceutical composition of the present invention in solid form are independently 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%, and 17% of the total mass or volume of the pharmaceutical composition. 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 0.75%, 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. The percentages are 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 greater than 0.001% w / w, w / v, or v / v. In one embodiment, the solid form of any of the embodiments of formula (1) described above is form I of the free base.

[0072] In some embodiments, the concentration of the BTK inhibitor of formula (1) of the present invention in solid form is independently about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, and about 0.07% relative to the total mass or volume of the pharmaceutical composition. The percentages are in the range of approximately 24% w / w, w / v, or v / v, as described above.

[0073] In some embodiments, the concentration of the solid form of the BTK inhibitor of formula (1) of the present invention is independently in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v, or v / v, relative to the total mass or volume of the pharmaceutical composition. In one embodiment, any of the solid forms of formula (1) described above is form I of the free base.

[0074] In some embodiments, the amounts of the BTK inhibitor of formula (1) of the present invention in solid form are independently 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, and 0.07g. The amounts are g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g or less. In one embodiment, the solid form of any of the embodiments of formula (1) described above is form I of the free base.

[0075] In some embodiments, the amount of the BTK inhibitor of formula (1) of the present invention in solid form is independently 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5g, or more than 3g. In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0076] Each solid form of the BTK inhibitor of formula (1) of the present invention is effective over a wide dose range. For example, for the treatment of adults, doses are independently in the range of 0.01 to 1000 mg and 0.5 to 100 mg, with 1 to 50 mg per day, 2 to 40 mg per day, and 5 to 25 mg per day being examples of doses that can be used. The exact dose will vary depending on the route of administration, the form in which the compound is administered, the sex and age of the subject being treated, the body weight of the subject being treated, and the choice and experience of the attending physician. In one embodiment, any solid form of formula (1) of the embodiments described above is form I of the free base.

[0077] In selected embodiments, the present invention provides a pharmaceutical composition for oral administration comprising a BTK inhibitor of formula (1) and a pharmaceutical additive suitable for oral administration. In one embodiment, any solid form of formula (1) in the embodiments described above is form I of the free base.

[0078] In selected embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising: (i) an effective amount of a BTK inhibitor of formula (1); and (ii) a pharmaceutical excipient suitable for oral administration. In selected embodiments, the composition further comprises (iii) an effective amount of another pharmaceutical component. In one embodiment, any solid form of formula (1) in the embodiments described above is form I of the free base.

[0079] In selected embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions of the present invention suitable for oral administration can be provided in individual dosage forms such as capsules, sachets, tablets, or liquids or aerosol sprays, each containing a predetermined amount of the active ingredient in the form of powder or granules, solution, suspension in aqueous or non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. Pharmaceutical compositions of the present invention also include powders for reconstitution, powders for oral administration, bottles (such as powder or liquid in the bottle), orally disintegrating films, lozenges, pastes, tubes, gums, and packs. These dosage forms may be prepared by any of the compounding methods, all of which involve a step of associating the active ingredient with a carrier constituting one or more required components. Generally, compositions are prepared by homogeneously and thoroughly mixing the active ingredient with a liquid carrier or a finely ground solid carrier, or both, and then, if necessary, shaping the product into the desired form. For example, tablets can optionally be prepared by compression or molding together with one or more auxiliary components. Compressed tablets can be prepared by optionally mixing an active ingredient in a free-flowing form, such as powder or granules, with excipients, including but not limited to binders, lubricants, inert diluents, and / or surfactants or dispersants, and compressing the mixture using a suitable machine. Molded tablets can be produced by molding a mixture of powder compounds moistened with an inert liquid diluent using a suitable machine.

[0080] Since water can accelerate the decomposition of some compounds, the present invention further encompasses anhydrous pharmaceutical compositions and dosage forms. For example, in the field of formulation, water (e.g., 5%) may be added as a means of simulating long-term storage to determine characteristics such as shelf life or stability of the formulation over time. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture-containing components and low-moisture or low-humidity conditions. The pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage. Anhydrous pharmaceutical compositions can be prepared and stored so as to maintain their anhydrous properties. Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water so that they can be contained in suitable pharmaceutical kits. Examples of suitable packaging, but not limited to, include unit dose containers, blister packs, and strip packs, such as sealed foil and plastic.

[0081] Each solid form of the BTK inhibitor of formula (1) can be carefully mixed and bound with a pharmaceutical carrier according to conventional compounding techniques. The carrier can take a wide variety of forms depending on the desired form of preparation for administration. When preparing compositions for oral dosage forms, any of the usual pharmaceutical media may be used as the carrier, for example, in the case of oral liquid preparations (suspensions, solutions, and elixirs, etc.) or aerosols, carriers such as water, glycol, oil, alcohol, flavoring agents, preservatives, and colorants may be used, or in the case of oral solid preparations, carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants may be used, and lactose is not used in some embodiments. For example, suitable carriers for solid oral preparations include powders, capsules, and tablets. If desired, tablets can be coated with standard aqueous or non-aqueous techniques.

[0082] Suitable binders 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 rubber such as acacia, sodium alginate, alginic acid, other alginates, tragacanth powder, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0083] Examples of fillers suitable for use in 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, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0084] A disintegrant may be used in the composition of the present invention to provide a tablet that disintegrates when exposed to an aqueous environment. Too much disintegrant may result in tablets that disintegrate in the bottle. Too little may result in insufficient disintegration, potentially altering the rate and extent of release of the active ingredient from the dosage form. Therefore, a sufficient amount of disintegrant, neither too little nor too much, that would adversely alter the release of the active ingredient, can be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary depending on the type of formulation and the method of administration, but will be readily identifiable to those skilled in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. 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, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clay, other algins, other celluloses, rubber, and mixtures thereof.

[0085] 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, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, 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 laurylate, agar, or mixtures thereof. Other lubricants include, for example, syloid silica gel, synthetic silica coagulation aerosol, silicified microcrystalline cellulose, or mixtures thereof. Lubricants may optionally be added in amounts less than about 1 weight percent of the pharmaceutical composition.

[0086] If an aqueous suspension and / or elixir is desired for oral administration, the essential active ingredients may be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof, along with various sweeteners or flavorings, colorants or dyes, and, if desired, emulsifiers and / or suspending agents.

[0087] Tablets may be left uncoated or coated by known techniques to slow their disintegration and absorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delaying substances such as glyceryl monostearate or glyceryl distearate can be used. Oral formulations may also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, phosphorylated or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, such as peanut oil, liquid paraffin or olive oil.

[0088] The surfactants that can be used to form the pharmaceutical compositions and dosage forms of the present invention are not limited to hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

[0089] The 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 have an HLB value of at least 10, while suitable lipophilic surfactants generally have an HLB value of about 10 or less. Surfactants with lower HLB values ​​are more lipophilic or hydrophobic and therefore have higher solubility in oil, while surfactants with higher HLB values ​​are more hydrophilic and therefore have higher solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be compounds with an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds to which the HLB scale is generally inapplicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds with an HLB value of about 10 or less. However, the HLB value of surfactants is only a rough criterion commonly used to enable the formulation of industrial, pharmaceutical, and cosmetic emulsions.

[0090] Hydrophilic surfactants may be either ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and their derivatives; lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acylactylates; mono and diacetylated tartaric acid esters of mono and diglycerides; succinylated mono and diglycerides; citrate esters of mono and diglycerides; and mixtures thereof.

[0091] In the aforementioned group, ionic surfactants include, for example, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfates; fatty acid salts; sodium docusate; acylactylates; mono and diacetylated tartaric acid esters of mono and diglycerides; succinyl mono and diglycerides; citrate esters of mono and diglycerides; and mixtures thereof.

[0092] Ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactylate esters, stearoyl-2-lactylate, stearoyl lactylate, and s This may include ionized forms of xinyl monoglycerides, mono / diacetylated tartrates of mono / diglycerides, citrates of mono / diglycerides, cholyl sarcosine, caproates, caprylates, caprinates, laurates, myristates, palmitates, oleates, ricinoleates, linoleates, linolenates, stearates, lauryl sulfates, teracecil sulfates, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and their salts and mixtures.

[0093] Examples of hydrophilic nonionic surfactants include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl macrogol glycerides; polyoxyalkylene alkyl ethers, e.g., polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols, e.g., polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters, e.g., polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; and polyoxyalkylene sorbates. Examples include sorbitan fatty acid esters, such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, their derivatives, and analogues; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters, and hydrophilic transesterification products of polyols with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or saccharide.

[0094] 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, 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, Capric Acid / Caprylate PEG-6 Glyceride, Capric Acid / Caprylate PEG-8 Glyceride, Polyglyceryl-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterol, PEG-30 Soybean Sterol, PEG-20 Trioleate, PEG-40 Sorbitan Oleate, PEG-80 Sorbitan Laurate, Polysorbate 20, Polysorbate 80, POE-9 Lauryl Ether Examples include POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl succinate PEG-100, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween40, Tween60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG10-100 nonylphenol series, PEG15-100 octylphenol series, and poloxamer.

[0095] Suitable lipophilic surfactants include, but are not limited to, 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, polyethylene glycol 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 mono and diglycerides, as well as hydrophobic transesterification products of polyols with at least one member of the group consisting of glycerides, 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 member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0096] In one embodiment, the composition may contain 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 parenteral compositions, such as injectable compositions. Solubilizers may 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.

[0097] Examples of suitable solubilizers include, but are not limited to, alcohols and polyols, e.g., ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, xylitol, transktol, dimethylisosorbide, 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 (glycoflor) or methoxyPEG; amides and 2-pyrrolidone, 2-piperidone, ε-capt Other nitrogen-containing compounds such as loractam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyltriethyl citrate, acetyltributyl citrate, 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-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0098] Mixtures of solubilizers can also be used. Examples, but not limited to, include triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycoflor, transktol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycoflor, and propylene glycol.

[0099] The amount of solubilizer that can be included is not particularly limited. A given amount of solubilizer can be limited to a bioacceptable amount, which can be easily determined by those skilled in the art. In some situations, for example, to maximize the concentration of the drug, it may be advantageous to include an amount of solubilizer that exceeds the bioacceptable amount, in which case the excess solubilizer is removed by the prior art, such as distillation or evaporation, before providing the composition to the patient. Therefore, if present, the solubilizer may be in a weight ratio of 10% by weight, 25% by weight, 50% by weight, 100% by weight, or up to about 200% by weight, based on the combined weight of the drug and other excipients. If desired, very small amounts of solubilizer, for example 5%, 2%, 1%, or less, may be used. Typically, the solubilizer can be present in an amount of about 1% by weight to about 100% by weight, more typically, about 5% by weight to about 25% by weight.

[0100] The composition may further contain one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, detackifiers, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, isotonic agents, flavoring agents, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0101] Furthermore, acids or bases may be incorporated into pharmaceutical compositions to facilitate processing, improve 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, aluminum magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, aluminum magnesium hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, and tris(hydroxymethyl)aminomethane (TRIS). Furthermore, bases that are salts of pharmaceutically acceptable acids, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic 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, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid, are also preferred. 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 may be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, and alkaline earth metals. Examples, but not limited to, include sodium, potassium, lithium, magnesium, calcium, and ammonium.

[0102] 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, and phosphoric acid. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic 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, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, and uric acid.

[0103] Dosage and administration regimen The amount of the BTK inhibitor of formula (1) in solid form or form I of the free base of formula (1) administered may vary depending on the mammal being treated, the severity of the disorder or condition, the administration rate, the pharmacokinetics of the compound, and the judgment of the prescribing physician. However, the effective dose is in the range of approximately 0.001 to approximately 100 mg / kg body weight / day, for example, approximately 1 to approximately 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would be approximately 0.05 to 7 g / day, for example, approximately 0.05 to 2.5 g / day. In some cases, doses below the lower limit of the aforementioned range may exceed the appropriate dose, while in other cases, for example, a larger dose may be used without causing adverse side effects by dividing it into several smaller doses for daytime administration.

[0104] In selected embodiments, the solid form of the BTK inhibitor of formula (1) is administered in a single dose. Typically, such administration may be carried out by injection, for example, intravenous injection, in order to rapidly deliver the active pharmaceutical ingredient. However, other routes may be used as needed. Also, a single dose of the solid form of the BTK inhibitor of formula (1) may be used for the treatment of acute medical conditions.

[0105] In selected embodiments, the solid form of the BTK inhibitor of formula (1) is administered in multiple doses. Doses may be approximately once, twice, three times, four times, five times, six times, or seven or more times per day. Doses may be approximately once per month, once every two weeks, once per week, or once every two days. In other embodiments, the solid form of the BTK inhibitor of formula (1) is administered from approximately once per day to approximately six times per day. In yet another embodiment, administration of the solid form of the BTK inhibitor of formula (1) is continued for less than approximately seven days. In yet another embodiment, administration is continued for approximately six, ten, fourteen, or twenty-eight days, two months, six months, or more than one year. In some cases, continuous administration is achieved and maintained as long as necessary. In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0106] The administration of the active pharmaceutical ingredient of the present invention may be continued for as long as necessary. In selected embodiments, the solid form of the BTK inhibitor of formula (1) is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the solid form of the BTK inhibitor of formula (1) is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In selected embodiments, the solid form of the BTK inhibitor of formula (1) is administered continuously for a long period of time, for example, for treatment with a long-lasting effect. In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0107] In some embodiments, the effective dose of the BTK inhibitor of formula (1) in solid form is approximately 1 mg to 500 mg, approximately 10 mg to 300 mg, approximately 20 mg to 250 mg, approximately 25 mg to 200 mg, approximately 10 mg to 200 mg, approximately 20 mg to 150 mg, approximately 30 mg to 120 mg, approximately 10 mg to 90 mg, approximately 20 mg to 80 mg, approximately 30 mg to 70 mg, approximately 40 mg to 60 mg, approximately 45 mg to 55 mg, approximately 48 mg to The ranges are approximately 52 mg, 50 mg to 150 mg, 60 mg to 140 mg, 70 mg to 130 mg, 80 mg to 120 mg, 90 mg to 110 mg, 95 mg to 105 mg, 150 mg to 250 mg, 160 mg to 240 mg, 170 mg to 230 mg, 180 mg to 220 mg, 190 mg to 210 mg, 195 mg to 205 mg, or 198 mg to 202 mg. In some embodiments, the effective dose of the BTK inhibitor of formula (1) in solid form is approximately 25 mg, approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg, or approximately 500 mg. In some embodiments, the effective dose of the BTK inhibitor of formula (1) in solid form 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, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0108] In some embodiments, the effective dose of the BTK inhibitor of formula (1) in solid form is approximately 0.01 mg / kg to approximately 4.3 mg / kg, approximately 0.15 mg / kg to approximately 3.6 mg / kg, approximately 0.3 mg / kg to approximately 3.2 mg / kg, approximately 0.35 mg / kg to approximately 2.85 mg / kg, approximately 0.15 mg / kg to approximately 2.85 mg / kg, approximately 0.3 mg / kg to approximately 2.15 mg / kg, approximately 0.45 mg / kg to approximately 1.7 mg / kg, approximately 0.15 mg / kg to approximately 1.3 mg / kg, approximately 0.3 mg / kg to approximately 1.15 mg / kg, approximately 0.45 mg / kg to approximately 1 mg / kg, approximately 0.55 mg / kg to approximately 0.85 mg / kg, approximately 0.65 mg / kg to approximately 0.8 mg / kg, and approximately 0. The ranges are approximately 0.7 mg / kg to 0.75 mg / kg, approximately 0.7 mg / kg to 2.15 mg / kg, approximately 0.85 mg / kg to 2 mg / kg, approximately 1 mg / kg to 1.85 mg / kg, approximately 1.15 mg / kg to 1.7 mg / kg, approximately 1.3 mg / kg to 1.6 mg / kg, approximately 1.35 mg / kg to 1.5 mg / kg, approximately 2.15 mg / kg to 3.6 mg / kg, approximately 2.3 mg / kg to 3.4 mg / kg, approximately 2.4 mg / kg to 3.3 mg / kg, approximately 2.6 mg / kg to 3.15 mg / kg, approximately 2.7 mg / kg to 3 mg / kg, approximately 2.8 mg / kg to 3 mg / kg, or approximately 2.85 mg / kg to 2.95 mg / kg. In some embodiments, the effective dose of the BTK inhibitor of formula (1) in solid form is approximately 0.35 mg / kg, approximately 0.7 mg / kg, approximately 1 mg / kg, approximately 1.4 mg / kg, approximately 1.8 mg / kg, approximately 2.1 mg / kg, approximately 2.5 mg / kg, approximately 2.85 mg / kg, approximately 3.2 mg / kg, or approximately 3.6 mg / kg. In some embodiments, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0109] In some embodiments, the solid form of the BTK inhibitor of formula (1) is administered in doses ranging from 10 to 400 mg (QD) once daily, such as 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 (QD). In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0110] In some embodiments, the solid form of the BTK inhibitor of formula (1) is administered in doses ranging from 10 to 400 mg BID, such as 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, or 500 mg BID. In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0111] In some embodiments, the solid form of the BTK inhibitor of formula (1) is administered in doses ranging from 10 to 400 mg TID, such as 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 TID. In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0112] The effective dose of the BTK inhibitor of formula (1) in solid form may be administered as a single or multiple dose by any accepted method of administration of an active pharmaceutical ingredient having similar utility, such as rectal, oral, nasal, and transdermal routes, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation.

[0113] Pharmaceutical composition for counteracting the effects of gastric acid suppressants The effects of acid-suppressing agents can be neutralized using the compositions and methods described herein. Acid-suppressing agents can significantly limit exposure to weakly acidic drugs (e.g., free base of formula (1)) in mammals. Smelick, et al., Mol. Pharmaceutics 2013, 10, 4055-4065. Acid-suppressing agents include proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, dexranprazole, pantoprazole, rabeprazole, and iraprazole; H2 receptor 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 juice secretion mechanism. Resolving the effects of acid-suppressants is a significant challenge in the treatment of patients with cancer, inflammatory diseases, immune diseases, and autoimmune diseases, as these patients are often concurrently administered acid-suppressants due to gastric irritation symptoms associated with their conditions. Acid-suppressants are most commonly prescribed in North America and Western Europe. Recently approved oral cancer drugs have pH-dependent solubility and can therefore lead to drug interactions with acid-suppressants. In cancer patients, it is estimated that 20–33% of all patients use some form of acid-suppressant. In certain cancers, such as pancreatic cancer or gastrointestinal cancers, the use of acid-suppressants is higher, at 60–80% of patients. Smelick, et al., Mol. Pharmaceutics 2013, 10, 4055-4062.

[0114] In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an acidulant. In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an acidulant selected from the group consisting of fumaric acid, tartaric acid, ascorbic acid, alginic acid, sodium alginate, potassium alginate, and Carbopol 971P (carboxypolymethylene). In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an acidulant selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-aloascorbic acid), alginic acid, protacid F120NM, protacid AR1112 (keracid (also known as Kelacid NF)), Carbomer 941 (polyacrylic acid), and Carbopol 971P (carboxypolymethylene). In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base. In one embodiment, the acidulant is granularly exogenous. In one embodiment, the acidulant is granularly endogenous.

[0115] Alginic acid is a polysaccharide copolymer in which β-D-mannuronic acid (M) and α-L-guluronic acid (G) are linked by 1-4 glycosidic bonds. In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an acidulant which is alginic acid or a salt thereof, wherein the alginic acid or salt thereof exhibits an M / G ratio selected from the group consisting of 0.1-0.5, 0.2-0.6, 0.3-0.7, 0.4-0.8, 0.5-0.9, 0.6-1.0, 0.7-1.1, 0.8-1.2, 0.9-1.3, 1.0-1.4, 1.1-1.5, 1.2-1.6, 1.3-1.7, 1.4-1.8, 1.5-1.9, 1.6-2.0, 1.7-2.1, 1.8-2.2, 1.9-2.3, 2.0-2.4, and 2.1-2.5. In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an acidulant which is alginic acid or a salt thereof, wherein the alginic acid or salt thereof exhibits an M / G ratio selected from the group consisting of 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 a BTK inhibitor of formula (1) and an acidulant which is alginic acid or a salt thereof, wherein the alginic acid or salt thereof exhibits an M / G ratio selected from the group consisting of 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 a BTK inhibitor of formula (1) and an acidulant which is alginic acid or a salt thereof, wherein the alginic acid or salt thereof represents an M / G ratio selected from the group consisting of 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, the solid form of formula (1) in any of the embodiments described above is form I of the free base. The M / G ratio, as well as the fractions of M and G groups, the fractions of MM and GG "diacids", "triacids" (e.g., MGG), and the fractions of larger sequences of M and G groups, can be determined by methods well known to those skilled in the art, including magnetic resonance (NMR) spectroscopy (with or without digestion) and mass spectrometry. Larsen, et al., Carbohydr. Res., 2003, 338, 2325-2336.

[0116] In one embodiment, the pharmaceutical composition contains a BTK inhibitor of formula (1) and an acidulant in a concentration (% by mass) selected from the group consisting of: 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 a BTK inhibitor of formula (1) and an acidulant in a concentration (% by mass) selected from the group consisting of: 1%~5%, 5%~10%, 10%~15%, 15%~20%, 20%~25%, 25%~30%, and 30%~35%, wherein the acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-aloascorbic acid), alginic acid, sodium alginate, potassium alginate, protacid F120NM, protacid AR1112 (also known as keracid NF), and carbopol 971P (carboxypolymethylene). In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0117] In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an acidulant in a concentration (% by mass) selected from the group consisting of 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 a BTK inhibitor of formula (1) and an acidulant in a concentration (% by mass) selected from the group consisting of 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 acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-aloascorbic acid), alginic acid, sodium alginate, potassium alginate, protacid F120NM, protacid AR1112 (also known as keracid NF), and carbopol 971P (carboxypolymethylene). In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0118] In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an acidulant in a concentration (% by mass) selected from the group consisting of: 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 a BTK inhibitor of formula (1) and an acidulant in a concentration (% by mass) selected from the group consisting of: 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 acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-alboascorbic acid), alginic acid, sodium alginate, potassium alginate, protacid F120NM, protacid AR1112 (also known as keracid NF), and carbopol 971P (carboxypolymethylene). In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0119] In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an acidulant in a concentration (% by mass) selected from the group consisting of approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, and 40%. In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and a concentration (% concentration) selected from the group consisting of approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, and 40%. The mixture contains an amount of an acidulant, where the acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-aloascorbic acid), alginic acid, sodium alginate, potassium alginate, protacid F120NM, protacid AR1112 (also known as keracid NF), and carbopol 971P (carboxypolymethylene). In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0120] In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an exogenous granular acidulant, where the exogenous granular acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-alboascorbic acid), alginic acid, sodium alginate, potassium alginate, protacid F120NM, protacid AR1112 (also known as keracid NF), and carbopol 971P (carboxypolymethylene), and combinations thereof. In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an exogenous granular acidulant, where the exogenous granular acidulant is fumaric acid in a concentration of about 15% to about 33% by weight. In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and a granular exogenous acidulant, wherein the granular exogenous acidulant is alginic acid or a salt thereof (e.g., sodium alginate or potassium alginate) in a concentration of about 15% to about 33% by weight. In another embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and a granular exogenous acidulant, wherein the granular exogenous acidulant is L-tartaric acid in a concentration of about 25% to about 33% by weight. In yet another embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and a granular exogenous acidulant, wherein the granular exogenous acidulant is ascorbic acid in a concentration of about 20% to about 50% by weight and Carbopol 971P (carboxypolymethylene) in a concentration of about 2.5% to about 10% by weight. In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an exogenous granular acidulant, wherein the exogenous granular acidulant is fumaric acid at a concentration of about 5% to about 15% by weight and alginic acid or a salt thereof at a concentration of about 15% to about 33% by weight. In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an exogenous granular acidulant, wherein the exogenous granular acidulant is L-tartaric acid at a concentration of about 5% to about 15% by weight and alginic acid at a concentration of about 15% to about 33% by weight.

[0121] In one embodiment, the pharmaceutical composition comprises a BTK inhibitor of formula (1) and an acidulant, where the acidulant is selected from the group consisting of 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 a BTK inhibitor of formula (1) and an acidulant, where the acidulant is selected from the group consisting of fumaric acid, maleic acid, phosphoric acid, L-tartaric acid, citric acid, gentisic acid, oxalic acid, and sulfuric acid, and the acidulant is a salt counterion contained in the single crystal phase of formula (1).

[0122] In one embodiment, in addition to the acidulant, the pharmaceutical composition includes an excipient for extending the exposure of formula (1) to an acidic microenvironment. In one embodiment, this excipient is a polymer of natural, synthetic, or semi-synthetic origin. The polymer may contain acidic, anionic, or nonionic monomers, oligomers, or polymers, or mixtures of acidic, anionic, and nonionic monomers or copolymers. In one embodiment, the excipient is selected from the group consisting of: hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, tocopherol polyethylene oxide succinate (D-α-tocopherol polyethylene glycol succinate, TPGS, or vitamin E TPGS), methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, methyl acrylate, ethyl acrylate, copolymers of methyl acrylate and ethyl acrylate, hydroxypropyl methylcellulose acetate / succinate, gelatin, corn starch, pea starch, pregelatinized corn starch, potato starch, pregelatinized potato starch, sodium starch glycolate, croscarmellose, crospovidone, copovidone, polyethylene glycol, polypropylene glycol, polyethylene and polypropylene glycol copolymer, polyvinyl alcohol, polyvinyl alcohol and polyethylene oxide copolymer. Copolymers of the aforementioned polymers may also be used if applicable. The copolymers may be block, branched, or terminal copolymers. In one embodiment, the polymer exhibits swelling, binding, or gelling properties that inhibit the breakdown, dissolution, and erosion of the pharmaceutical composition in order to prolong dissolution or increase total dissolution. In one embodiment, the inclusion of the polymer increases the dissolution rate and degree when the acidulant is used alone. In one embodiment, the swelling, binding, or gelling properties are pH-dependent, where the polymer swells, binds, or gels at one pH or pH range differently from another. In one embodiment, this may be that lower pH reduces dissolution more than higher pH, or vice versa. In another embodiment, this results in similar dissolution of formula I at acidic, neutral, or basic pH.This allows for similar plasma exposure to be achieved independently of gastric pH.

[0123] The dissolution profile of a formulation containing one or more swelling, gelling, or binding excipients may show a mixture of zero, primary, secondary differential rates at one or more pH values, or different rates at different pH values. In one embodiment, the pharmaceutical composition delivers a constant level of drug into the digestive tract of a mammal by dissolution. Once formula (1) is absorbed, this achieves sustained plasma levels of the drug over a period of time, and t max Delays the release of the equivalent dose of the immediate-release formulation of formula (1) max This reduces the risk. In another embodiment, this achieves similar exposure in mammals, regardless of gastric pH.

[0124] Methods for treating solid tumors, malignant hematological disorders, inflammatory diseases, autoimmune diseases, immune disorders, and other diseases. The pharmaceutical compositions described herein can be used in methods for treating diseases. In preferred embodiments, they are used for the treatment of hyperproliferative diseases. These compositions may also be used to treat other diseases, such as those described herein and in the following paragraphs.

[0125] In some embodiments, the present invention provides a method for treating a mammalian hyperproliferative disorder, comprising administering to a mammal a therapeutically effective amount of a crystalline salt form of formula (1), including form I of the free base of formula (1), or a pharmaceutical composition comprising a crystalline salt form of formula (1), as described herein. In preferred embodiments, the mammal is a human. In some embodiments, the hyperproliferative disorder is cancer. In preferred embodiments, the cancer is selected from the group consisting of chronic lymphocytic leukemia, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Waldenström macroglobulinemia. In preferred embodiments, cancers include: non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma), acute myeloid leukemia, thymic carcinoma, brain tumors, lung cancer, squamous cell carcinoma, skin cancer, eye cancer, retinoblastoma, intraocular melanoma, oral and oropharyngeal cancers, bladder cancer, gastric 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 cancers, thyroid cancer, CNS, PNS, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), virus-induced cervical cancers such as cervical cancer (human papillomavirus (HPV)), B-cell proliferative disorders and nasopharyngeal cancers (Epstein-Barr virus (Epstein-Barr)). The group consists of Kaposi's sarcoma and primary exudative 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, mastocell leukemia, and mastocytosis. In selected embodiments, the method relates to the treatment of noncancerous hyperproliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostatic conditions (e.g., benign prostatic hyperplasia (BPH)). In some embodiments, the hyperproliferative disorder is an inflammatory, immune, or autoimmune disorder.In some embodiments, the hyperproliferative disease is selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, eczema, and skin diseases such as scleroderma, diabetes mellitus, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondyloarthritis, 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 formula (1) in any of the embodiments described above is form I of the free base. In one embodiment, the method in any of the embodiments described above further comprises the step of administering a gastric acid inhibitor to a mammal. In one embodiment, the gastric acid suppressant is selected from the group consisting of proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, dexranprazole, pantoprazole, rabeprazole, and iraprazole; H2 receptor antagonists, such as cimetidine, ranitidine, and famotidine; and antacids, such as bicarbonates, carbonates, and hydroxides of aluminum, calcium, magnesium, potassium, and sodium.

[0126] In some embodiments, the present invention provides a pharmaceutical composition in solid form of formula (1) described herein, used for the treatment of cancers such as thymic carcinoma, brain tumors (e.g., glioma), lung cancer, squamous cell carcinoma, skin cancer (e.g., melanoma), eye cancer, retinoblastoma, intraocular melanoma, oral cancer, oropharyngeal cancer, bladder cancer, gastric cancer, pancreatic 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, thyroid cancer, CNS cancer, PNS cancer, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), virus-induced cervical cancer, and epidermal carcinoma. In some embodiments, the present invention provides a solid-form pharmaceutical composition of formula (1) described herein for the treatment of noncancerous hyperproliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hyperplasia (BPH)). In some embodiments, the present invention provides a solid-form pharmaceutical composition of formula (1) described herein for use in the treatment of diseases such as myeloproliferative disorders (MPD), myeloproliferative neoplasms, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), myelodysplastic syndrome, chronic myeloid leukemia (BCR-ABL1 positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, or mastocytosis. The present invention also provides compositions for use in the treatment of diseases related to vascular formation or neovascularization in mammals, which may manifest as tumor angiogenesis, chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, and hemangiomas. In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0127] In some embodiments, the present invention provides a method for treating solid tumor cancer with a composition comprising the solid form of formula (1) described herein. In one embodiment, the present invention provides a method for treating squamous cell carcinoma, such as visceral cancer, breast cancer, ovarian cancer, melanoma, lung cancer, and 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 using in combination with the solid form of formula (1) described herein and a second agent selected from the group consisting of: bendamustine, venetoclax, gemcitabine, albumin-conjugated paclitaxel, rituximab, obnutuzumab, ofatumumab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolitumab. 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 using a BTK inhibitor in combination with bendamustine, venetoclax, gemcitabine, albumin-conjugated paclitaxel, rituximab, obnutuzumab, ofatumumab, pembrolizumab, nivolumab, durvalumab, avelumab, and atezolitumab, wherein the BTK inhibitor is the solid form of formula (1) described herein. In one embodiment, the solid form of formula (1) in any of the embodiments described above is the free base form I.

[0128] In some embodiments, the present invention relates to a method for treating inflammatory, immune, or autoimmune diseases in mammals using a composition comprising the solid form of formula (1) described herein. In selected embodiments, the present invention also relates to a method of treating a disease using a composition comprising a solid form of formula (1) described herein, wherein the disease is selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, eczema, and scleroderma, diabetes mellitus, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondyloarthritis, 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 formula (1) in any of the embodiments described above is form I of a free base.

[0129] In some embodiments, the present invention relates to a method for treating hyperproliferative disorders in mammals with a composition comprising a solid form of formula (1) as described herein, wherein hyperproliferative disorders are B-cell hematological malignancies 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 some embodiments, the present invention relates to a method for treating mammalian hyperproliferative disorders with a composition comprising a solid form of formula (1) described herein, wherein the hyperproliferative disorders are selected from the group consisting of: chronic myeloid leukemia, acute myeloid leukemia, DLBCL (such as activated B cell (ABC) and germinal center B cell (GCB) subtypes), follicular central lymphoma, Hodgkin's disease, multiple myeloma, painless Hodgkin lymphoma, and mature B cell ALL. In one embodiment, the solid form of formula (1) in any of the embodiments described above is form I of the free base.

[0130] In some embodiments, hyperproliferative disorders are subtypes of CLL. Several subtypes of CLL have been characterized. CLL is often characterized by the immunoglobulin heavy chain variable region (IgV) in leukemia cells. H Classified according to the mutation state. RN Damle, et al., Blood 1999, 94, 1840-47; TJ Hamblin, et al., Blood 1999, 94, 1848-54. IgV H Patients with mutations generally have IgV HPatients with the mutation survive longer than those without. ZAP70 expression (positive or negative) is also used to characterize CLL. LZ Rassenti, et al., N. Engl. J. Med. 2004, 351, 393-901. For example, methylation of ZAP-70 at CpG3 by pyrosequencing is also used to characterize CLL. R. Claus, et al., J. Clin. Oncol. 2012. 30, 2483-91; JA Woyach, et al., Blood 2014, 123, 1810-17. CLL is also classified by stage based on Binet or Rai criteria. JL Binet, et al., Cancer 1977, 40, 8550-64; KR Rai, T. Han, Hematol. Oncol. Clin. North Am. 1990, 4, 447-56. Other common mutations such as 11q deletion, 13q deletion, and 17p deletion can be evaluated using known techniques such as fluorescence in situ hybridization (FISH). In one embodiment, the present invention relates to a method for treating human CLL, wherein CLL is IgV H The group is selected from mutation-negative CLL, ZAP-70-positive CLL, ZAP-70 methylated with CpG3CLL, CD38-positive CLL, chronic lymphocytic leukemia characterized by 17p13.1 (17p) deletion, and CLL characterized by 11q22.3 (11q) deletion.

[0131] In some embodiments, hyperproliferative disease is CLL that has undergone Richter's transformation. Methods for evaluating Richter's transformation (also known as Richter's syndrome) are described in Jian and O'Brien, Oncoloty, 2012, 26, 1146-52. Richter's transformation is a subtype of CLL found in 5–10% of patients. It includes the development of aggressive lymphoma from CLL and generally has a poor prognosis.

[0132] In some embodiments, the hyperproliferative disorder is CLL or SLL in the patient, in which case the patient is susceptible to lymphoproliferative disorder. In one embodiment, the present invention relates to a method for treating CLL or SLL in a patient, wherein the patient presents with lymphoproliferative disorder resulting from a disorder selected from the group consisting of: viral infection, bacterial infection, protozoal infection, or splenectomy condition. In one embodiment, the viral infection in any of the embodiments described above is selected from the group consisting of: infectious mononucleosis, hepatitis, and cytomegalovirus. In one embodiment, the bacterial infection in any of the embodiments described above is selected from the group consisting of: pertussis, tuberculosis, and brucellosis. [Examples]

[0133] Example 1. (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide (free base) crystalline anhydride form I Example 1.1. Preparation of crystalline anhydrous form I Crystallization tests were performed using amorphous (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide as the input. The amorphous nature of this batch was confirmed by PXRD. In the cold crystallization experiment, 25 mg of amorphous formula (1) was dissolved in 300 μL of solvent, heated to 60°C at a rate of 5°C / hour, held at that temperature for 1 hour, and then cooled to 5°C at the same rate. In the slurry experiment, 25 mg of amorphous formula (1) was suspended in 150 μL of solvent at 20°C over 3 days. All solids were isolated for PXRD analysis. When the solvent was evaporated under vacuum (200 mbar), a clear solution was obtained. The results are summarized in Table 1.

[0134] [Table 1]

[0135] [Table 2]

[0136] [Table 3]

[0137] The results indicate that when a solid is obtained, the amorphous form of formula (1) can be obtained from most solvents, and that form I, although difficult to crystallize, can be prepared from a very limited set of solvents, particularly in specific mixtures containing n-heptane (e.g., acetone). Form I can be crystallized or recrystallized from ethanol on larger scales, including a 60 g scale.

[0138] Poor solvent addition experiments were conducted by gradually adding a poor solvent to a clear solution of formula (1) in the solvents shown in Table 2 until crystallization occurred. These results also highlight the difficulty in preparing the crystalline form of formula (1).

[0139] [Table 4]

[0140] Example 1.2. Determination of the physical properties of morphological I crystalline anhydride The characterization of free base form I of formula (1), produced by crystallization from acetone in the presence of methanol, was carried out using various techniques including transmission PXRD (Figure 1), Raman (Figure 2) and IR spectroscopy (Figure 3), solution NMR spectroscopy after dissolution of form I, TG-FTIR, differential scanning calorimetry (DSC), semi-quantitative solubility testing, and dynamic vapor sorption (DVS: also known as gravity-measured vapor absorption or GVS) (referred to herein as sample PP502-P1).

[0141] Equipped with a Mythen1K Detector and a Cu-Kα1 source, and operating under standard conditions of 40kV tube voltage and 40mA tube current, the Stoe Stadi P high-precision double-circle goniometer; curved Ge monochromator; 0.02°²θ step size; 48-second step time; 1.5–50.5°²θ scanning range; and a detector mode including step scanning at a 1°²θ detector step, transmission PXRD patterns of morphology I were acquired. Samples were prepared by placing 10–20 mg of material between two acetate foils in a Stoe transmission sample holder, which was rotated during measurement. Measurements using the Stoe Stadi diffractometer were acquired in transmission (Debye-Scherrer) mode. This instrument can also be operated in reflection (Bragg-Brentano) mode.

[0142] Figure 1 shows the PXRD pattern of morphology I measured using transmission geometry. The following peaks were identified in the PXRD pattern of Figure 1: 6.4, 8.7, 10.5, 11.0, 11.4, 11.6, 12.8, 13.5, 14.3, 14.9, 15.1, 15.5, 15.7, 16.1, 17.3, 18.2, 19.1, 19.2, 19.5, 19.8, 20.6, 20.8, 21.2, 21.4, 21.6, 22. 0, 22.2, 22.3, 22.6, 22.8, 23.3, 23.7, 24.9, 25.2, 25.4, 25.8, 26.1, 26.5, 26.8, 27.0, 27.1, 27.7, 28.7, 29.2, 29.9, 30.5, 31.7, 32.0, 32.6, 33.1, 33.2, 33.5, 34.5, and 35.1°2θ±0.2°2θ. Morphology I exhibits characteristic peaks (compared to other morphologies) at 6.4, 8.6, 10.5, 11.6, and 15.7°2θ±0.2°2θ, and another characteristic peak (compared to other morphologies) at 10.9, 12.7, 13.4, 14.3, 14.9, and 18.2θ±0.2°2θ. Along with the birefringence observed in the polarized light microscope image of morphology I (sample PP502-P1), the PXRD pattern in Figure 1 indicates that the anhydrous morphology I of formula (1) is crystalline.

[0143] Furthermore, reflection-type PXRD measurements were also performed using a second instrument, namely a Bruker D8 Advance powder X-ray diffractometer equipped with a LynxEye detector and operating in Bragg-Bretano reflection geometry mode. The 2θ values ​​were generally accurate to within ±0.2°. Samples were generally prepared without any special treatment other than applying some pressure to obtain a flat plane. Samples were measured uncovered unless otherwise noted. Operating conditions included a 40kV tube voltage and a 40mA current. A variable divergence slit with a 3° window was used. The step size was 0.02°2θ, and the step time was 37 seconds. During the measurement, the sample was rotated at 0.5 rps. After calibration, the reflection-mode PXRD pattern of morphology I may be compared to the transmission-mode PXRD pattern of morphology I, but those skilled in the art will understand that the diffraction pattern may vary, particularly with respect to peak intensity, as described herein.

[0144] The reflective PXRD pattern of morphology I of equation (1) was measured, and the following peaks were identified in the reflective PXRD pattern: 6.36, 8.60, 10.50, 10.90, 11.32, 11.57, 12.73, 13.4, 14.27, 14.86, 15.08, 15.66, 16.09, 17.28, 18.17, 19.15, 19.39, 19.76, 20.70, 21.10, 21.36, 21.56, 21.94, 22.59, 23.3, 23.63, 24.87, 25.19, 25.37, 25.72, 26.05, 26.42, 26.77, 26.93, 27.68, 28.62, 29.11, 29.42, 30.14, 30.49, 31.69, 31.90, 32.22, 32.57, 33.05, 33.39, 34.45, 35.87, 36.09, 36.80, 37.42, 38.08, 38.86, and 39.54°2θ±0.20°2θ.

[0145] Fourier transform (FT) Raman spectra of morphology I were acquired using a Bruker RFS 100 FT-Raman spectrophotometer equipped with a liquid nitrogen-cooled germanium detector and a near-IR Nd:YAG laser, operating at 1064 nm with a 100 mW power supply setting. The spectra were obtained from 3500 to 50 cm⁻¹.-1 Within the range of 2cm -1 The result was obtained from 64 scans at the resolution shown. The FT-Raman spectrum of morphology I is shown in Figure 2, which has peaks at 1680, 1620, 1609, 1574, 1547, 1514, 1495, 1454, 1433, 1351, 1312, 1255, 1232, 1187, 1046, 995, 706, 406, and 280 (Raman shift, cm). -1 ±2cm -1 ) indicates.

[0146] IR spectroscopy was used to acquire the IR spectrum of morphology I (sample PP502-P1). Attenuation total reflectance (ATR) sampling and a Perkin Elmer BXII IR spectrometer were used to obtain two wavenumbers (cm²). -1 The spectrum was acquired by recording 32 scans at a resolution of ). For the spectrum shown here, the original spectrum in transmission mode was converted to absorption mode using Bruker's OPUS 7.0 software, and a peak table was created. The IR spectrum of morphology I is shown in Figure 3. The characteristic peaks of morphology I are 3367, 3089, 2246, 1682, 1621, 1608, 1574, 1514, 1504, 1454, 1428, 1403, 1435, 1303, 1248, 1194, 1177, 1149, 1109, 1049, 1023, 1003, 947, 900, 858, 842, 816, 764, 734, 729, 701, 689, 665, 623 and 612 (IR frequencies, cm). -1 ±4cm -1 It was observed at ).

[0147] Morphology I recorded in deuterated dimethyl sulfoxide (d6-DMSO) 1 The molecular structure of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide in this crystalline anhydride was confirmed by 1H NMR spectroscopy.

[0148] TGA and TG-FTIR analysis were performed using a Netzsch Thermo-Microbalance TG 209 connected to a Bruker FTIR spectrometer (instrument model Vector 22). After tare weighing a sample pan containing pinholes, the sample was introduced and heated to 350°C at a gradient rate of 10°C / min under a constant flow rate of nitrogen. TG-FTIR analysis of the morphological I sample revealed a mass loss of approximately 0.8% when heated up to 250°C. TG-FTIR spectroscopy indicated that the mass loss up to 250°C was almost entirely due to the acetone solvent, suggesting that the morphological I sample is more robustly retained, as the mass loss occurs above 200°C. The weight loss above 250°C was mostly due to decomposition.

[0149] DSC was performed using a Perkin Elmer DSC-7 or TA Instruments Q2000 instrument. Samples were prepared in a sealed gold sample pan at a gradient rate of 10°C / min or 20°C / min up to approximately 250°C. Melting began at approximately 200°C with a heat flow of approximately 16 mW (81.9 J / g) due to endothermic melting, and a peak was observed at approximately 214.7°C. However, since melting occurred simultaneously with thermal decomposition, the enthalpy of melting is an estimate. Nevertheless, the temperature range of mass loss observed by TGA analysis suggests that morphology I must melt to release residual solvent. From the DSC thermogram, it was found that after the melting event at approximately 214.7°C, exothermic decomposition occurred at 226.4°C.

[0150] Furthermore, Form I was tested for solubility in various water-solvent mixtures and non-aqueous solvents. Solubility tests were performed by serially diluting a suspension of approximately 10 mg of Form I in 0.1 mL of analytical-grade solvent. Approximate solubility results are shown in Table 3. Solubility values ​​are estimated approximations and are subject to variable experimental errors.

[0151] [Table 5]

[0152] After equilibration at 25°C for 3 days, the water solubility of morphology I was determined. High-performance liquid chromatography (HPLC) was used to determine the concentration in the filtered solution, yielding approximately 68 μg / mL of S. PXRD of the solid residue confirmed that morphology I was retained.

[0153] Gravity-measured water vapor absorption tests were performed using standard procedures. Samples were analyzed using a dynamic water vapor absorption (DVS) analyzer. The sample size was approximately 10 mg. Water adsorption-desorption isotherm tests were performed as outlined below. Samples were exposed to humidity decreases from 50% RH, to 0% RH, to 95% RH, and finally to a decrease back to 50% RH. DVS results, including adsorption and desorption isothermal curves, revealed that the total weight increase observed from 0%RH to 80%RH was approximately 0.17%, indicating that morphology I is nonhygroscopic according to the European Pharmacopoeia (EP) classification (nonhygroscopic: <0.2%; slightly hygroscopic: ≥0.2% and <2%; hygroscopic: ≥2% and <15%; extremely hygroscopic: ≥15%; deliquescent: sufficient water is absorbed to form a liquid; all values ​​were measured as weight increase at 80%RH and 25°C). The desorption curve shows water loss at a similar rate to the water acquired during absorption, along with limited hysteresis. Most of the absorbed water was removed at the end of the DVS experiment. No change in shape was observed by PXRD after the DVS experiment.

[0154] Example 2. Form II of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide (free base) trihydrate. Example 2.1. Preparation of Form II Crystalline Trihydrate As mentioned above, morphology II was also obtained using a very limited set of solvents through the crystallization tests described in Table 1.

[0155] Form II of the free base of equation (1) (sample PP502-P21) was also produced by dissolving form I in an acetone-water (8:2) mixture at reflux temperature, then cooling the solution and removing 50% of the solvent volume under partial nitrogen purging. The resulting sample was dried in air under ambient conditions at room temperature (approximately 45% RH). After drying, a mass loss of approximately 9.7% was observed, which corresponds to approximately 2.7 water molecules per molecule of equation (1) (i.e., the trihydrate).

[0156] Example 2.2. Determination of physical properties of morphological II crystalline anhydride The free base morphology I of formula (1) was identified using a variety of techniques, including PXRD (Figure 4), optical microscopy, Raman spectroscopy (Figure 5), IR spectroscopy, TG-FTIR, DSC, DVS, and semi-quantitative solubility testing. The characterization of the method used for formula II was carried out in the same manner as described for the identification of morphology I.

[0157] Figure 4 shows the PXRD pattern of morphology II of equation (1) measured in transmission mode. In the PXRD pattern of Figure 4, the following characteristic peaks were identified: 6.6, 9.9, 11.0, 13.6, 14.0, 14.3, 18.1, 18.4, 18.9, 19.3, 20.2, 21.1, 22.0, 22.2, 22.5, 22.7, 22.9, 23.4, 23.5, 23.9, 24.2, 24.6, 25.0, 26.1, 26.6, 26.9, 27.5, 28.2, 31.0, 32.1, 32.4, 32.7, 33.4, 33.9, and 34.4°2θ±0.2°2θ. The PXRD patterns of morphology I and morphology II show characteristic reflectances for each of these forms of the free base of formula (1). Morphology II shows characteristic peaks (compared to the other morphologies) at 5.7, 6.6, 8.2, and 9.8°2θ±0.2°2θ, and yet another characteristic peak (compared to the other morphologies) at 11.0, 14.1, 14.3, 18.9, 20.1, and 24.6°2θ±0.2°2θ. Optical microscopy images of morphology II revealed that the morphology II sample (PP502-P21) exhibited rod-shaped particles up to approximately 50 μm in size, which can adversely affect the fluidity and processability of this morphology, as described in Example 12.

[0158] The FT-Raman spectrum of morphology II is shown in Figure 5, which has peaks (Raman shift, cm) at 1668, 1611, 1580, 1564, 1537, 1506, 1493, 1454, 1436, 1416, 1401, 1349, 1321, 1287, 1272, 1252, 1244, 1183, 1165, 1097, 1039, 1025, 996, 950, 871, 853, 776, 730, 645, 633, 375, 352, 279, and 247. -1 ±2cm -1 ) indicates.

[0159] The IR spectrum of morphology II (sample PP502-P21) shows characteristic peaks (IR frequencies, cm) at 3212, 2206, 1665, 1618, 1577, 1548, 1535, 1504, 1465, 1452, 1432, 1416, 1397, 1348, 1316, 1243, 1208, 1181, 1164, 1149, 1095, 1038, 1004, 948, 891, 869, 821, 776, 736, 716, 643, and 617. -1 ±4cm -1 ) was shown.

[0160] The TG-FTIR preparations for the morphology II samples consisted of exposing two samples (PP502-P14 and PP502-P21) to 60% RH for approximately 3 days, at which point both contained equal amounts of water. TG-FTIR analysis of the morphology II samples revealed a mass loss of approximately 10.2% upon heating to approximately 130°C. This loss was almost entirely due to water release, which is in good agreement with the theoretical water content of the trihydrate at 10.4%. The subsequent mass loss of approximately 0.3% upon heating to approximately 250°C was mainly due to decomposition.

[0161] Representative DSC analysis was performed on morphology II samples. The samples were stabilized at equilibrium under approximately 62% RH using a temperature gradient rate of 10°C / min or 20°C / min up to approximately 150°C prior to analysis. Melting began at approximately 75°C with a melting enthalpy of approximately 127 J / g, and the peak was observed at approximately 109°C. The DSC thermogram showed a slight shoulder to the left of the peak, suggesting that some hydrate water was released from the sample into the residual volume in the sealed sample pan.

[0162] DVS analysis of morphology II (samples PP502-P14) was performed by exposing the sample to a starting 50% RH, decreasing the humidity to 0% RH, increasing the humidity to 95% RH, and finally decreasing the humidity again to the starting 50% RH. From the DVS results, including the water adsorption and desorption curves, it can be seen that significant water loss occurs below approximately 10% RH, at which point the water content of the trihydrate rapidly decreases from approximately 10% to approximately 0%. This result is consistent with the mass loss in TGA analysis. When the RH was increased to 95%, water was reabsorbed, reaching a maximum water content of approximately 10.4%, which is consistent with the predicted water content of the trihydrate. Hysteresis was observed between the water adsorption and desorption curves. Therefore, morphology II behaves as a variable hydrate. DVS results, including isothermal curves for moisture adsorption and desorption, revealed that the total weight increase observed between 0%RH and 80%RH was approximately 10%, indicating that form II is hygroscopic according to the EP classification (see Example 1.2).

[0163] Finally, form II was tested for solubility in various water-solvent mixtures and non-aqueous solvents. The water solubility of form II was determined after equilibration at 25°C for 3 days. High-performance liquid chromatography (HPLC) was used to determine the concentration of form II in the filtered solution to approximately 14 μg / mL, which corresponds to a critical water activity (a) of approximately 0.59. w It is converted to ). In comparison, the water solubility of form I was 68 μg / mL.

[0164] Critical water activity is a measure of the relative thermodynamic stability of form I compared to form II of the trihydrate.w If the water activity is lower than approximately 0.59, form I is more stable at room temperature, but above this value, form II is more stable. This indicates that form I is the more stable form in solvent mixtures with low water content, which are preferable for crystallization of formula (1). This conclusion was confirmed by suspension equilibrium experiments in ethanol-water mixtures, each with different water activity. The water activity in the experiments was maintained at approximately 0.35 (ethanol-water ratio of 95:5, PP502-P32), approximately 0.53 (ethanol-water ratio of 9:1, PP502-P33), and approximately 0.77 (ethanol-water ratio of 7:3, PP502-P34). w Therefore, pure form I was obtained by suspension experiments with a mixture of form I and form II, with a concentration of approximately 0.77 a w Therefore, we obtained pure form II.

[0165] Example 3. Form III of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide (free base) dihydrate. Example 3.1. Preparation of Form III Crystalline Dihydrate Free base of morph (I) was prepared in morph (III) form from seed-added crystallization experiments using morph (I) nuclei. The saturated solution of formula (1) was prepared at 60°C. After cooling the solution and adding the morph (I) seed, spontaneous crystallization occurred. The results are summarized in Table 4.

[0166] [Table 6]

[0167] Form III can be prepared by crystallization of amorphous formula (1) in pure water. For example, sample PP502-P120 was the result of a slurry of amorphous formula (1) free base (sample PP502-P107A) in water. After one day, form III was present in the suspension, and after a long period of stirring for three days, form III was still maintained. However, since form II can be obtained in other experiments under similar conditions, another method for preparing form III was growth.

[0168] Form III can also be prepared from amorphous formula (1) suspended in water. Approximately 160 mg of amorphous formula (1) is added to 5.0 mL of water, and the resulting suspension is stirred at ambient temperature. Crystallization of Form III was achieved by examining the solid after equilibrium at room temperature for approximately 24 hours.

[0169] Furthermore, form III can also be prepared by direct precipitation by pH adjustment. 940 mg of form I of formula (1) was dissolved in 4.0 mL of 1N hydrochloric acid aqueous solution. The solution was neutralized with the same volume of 1N hydrochloric acid aqueous solution. A concentrated suspension was obtained by further dilution with 8.0 mL of water, and the solid was separated from this suspension by filtration. After rinsing the glass bottle with 16 mL of water, the washing solution was poured onto a glass frit filter and removed from the filtration apparatus by applying a vacuum. The obtained solid material was dried in an air dryer at 40°C for approximately 24 hours. Powder X-ray diffraction confirmed that form III of formula (1) was obtained, and thermogravimetric analysis combined with infrared spectroscopy revealed that the sample contained approximately 6% water, suggesting that the material was slightly over-dried. Nevertheless, the determined water content is consistent with the results from DVS, as this water content was observed at approximately 40% RH.

[0170] Example 3.2. Determination of the physical properties of Form III crystalline dihydrate Initial TGA and DSC characterization of free base morph III of formula (1) was performed using a Mettler Toledo TGA / DSC1 STARe System equipped with a 34-position autosampler. Samples were prepared using 40 μL perforated aluminum crucibles. Typically, 5–10 mg of sample was packed into pre-weighed aluminum crucibles, maintained at 30°C for 5 minutes, and then heated from 30°C to 300°C at 10°C / min. A nitrogen purge of 40 mL / min was maintained over the samples. Indium and zinc were used as references for system compatibility checks. The software used for data acquisition and evaluation was STARe Software v10.00 build 2480. No correction was applied to the thermograms. Further DSC characterization of morph III was performed as described in Examples 1 and 2, using a heating rate of 20°C / min and an open-pan configuration.

[0171] The transmission PXRD pattern of morphology III is shown in Figure 6 (sample PP502-P120). In the PXRD pattern of Figure 6, the following peaks were identified: 10.4, 12.6, 12.8, 17.9, 21.3, 21.7, 23.1, 24.2, 25.2, and 27.0°2θ±0.2°2θ. Morphology III exhibits characteristic peaks (compared to other morphologies) at 7.6, 8.5, 12.6, 12.8, 14.6, 16.8, and 23.2°2θ±0.2°2θ. The weak nature of the PXRD pattern indicates that morphology III is poorly crystalline. Images of morphology III obtained by optical microscopy showed the presence of a somewhat crystalline material with irregular characteristics.

[0172] The Raman spectrum of morphology III was obtained in the same manner as described for morphology I in Example 1.2 and is shown in Figure 7. This spectrum has peaks (Raman shift, cm) at 1668, 1609, 1562, 1535, 1494, 1450, 1350, 1324, 1306, 1264, 1245, 1190, 997, and 272. -1 ±2cm -1 ) indicates.

[0173] The IR spectrum of morphology III was obtained in the same manner as described for morphology I in Example 1.2. The IR spectrum of morphology III (sample PP502-P120) shows characteristic peaks (IR frequencies, cm) at 3446, 2248, 1667, 1592, 1531, 1504, 1428, 1349, 1305, 1243, 1189, 1158, 1089, 1001, 896, 862, 829, 780, 759, 736, and 699. -1 ±4cm -1 ) was shown.

[0174] DSC thermograms of morphology III showed events at 147°C (-23.7 J / g) and 215°C (141 J / g), attributed to solvent loss and melting, respectively. DSC thermograms obtained using an open pan and a heating rate of 20°C / min showed endothermic activity at 128.6°C. TGA observed that morphology III lost 4.8% of its mass over a temperature range of 40–130°C. Another TGA experiment confirmed that morphology III lost approximately 6.9% of its mass over a temperature range of about 25–200°C.

[0175] When a sample of morphology III was dried under vacuum at 40°C for approximately 20 hours, a very slight change was observed in the morphology III PXRD pattern. This change was minor, and the pattern remained characteristic of morphology III. However, a substantial peak shift was observed in the PXRD pattern during drying at 90-100°C in an air dryer.

[0176] Since it was known that Form III is a metastable hydrate, the DVS analysis of Form III (sample PP502-P120) was programmed to begin with an increase in relative humidity, rather than a decrease. The experiment started at 50% RH, increased to 95% RH, then decreased to 0% RH, and finally increased again to the starting 50% RH. The obtained DVS showed a maximum water content of approximately 8.5% at 95% RH, indicating that almost all water was removed at 0% RH. From the DVS results, including the water adsorption and desorption isotherm curves, it was found that the total weight increase observed from 0% RH to 80% RH was approximately 8%, indicating that Form III is hygroscopic according to the EP classification (see Example 1.2). There was little hysteresis observed between the water adsorption and desorption curves. The DVS results, combined with PXRD data acquired before and after the DVS experiment, indicate that morphology III is a non-stoichiometric channel-type hydrate, not a dihydrate, because the water content can fluctuate continuously across the entire relative humidity range. Therefore, morphology III behaves as a variable hydrate, similar to morphology II.

[0177] Example 4. Forms prepared from Form II (Forms IV-VIII of the free base of formula (1)) In addition to form II, a trihydrate with a typical water content of approximately 10%, several other derivatives of form II were also examined. For example, dehydrating form II at less than approximately 20% relative humidity (RH) yields another non-solvated form, which is referred to as form IV. Characterization of form IV was carried out using various techniques, including PXRD and DSC, as described above for the characterization of forms I and II.

[0178] To evaluate the state of dehydrated form II, a sample of the trihydrate (form II) was placed in a 1.0 mm PXRD sample holder and maintained overnight under dry nitrogen. After 24 hours, the sample holder was covered with a poly(methyl methacrylate) (PMMA) dome, and the sample was maintained under nitrogen while the PXRD pattern was recorded. Figure 8 shows the PXRD pattern of form IV. In the PXRD pattern shown in Figure 8, the following peaks were identified: 7.0, 8.5, 9.6, 10.3, 11.5, 11.9, 14.3, 14.9, 16.1, 17.0, 18.2, 19.3, 20.2, 20.6, 21.1, 21.6, 22.1, 22.8, 23.1, 24.0, 25.4, 26.9, 27.6, 28.4, 28.7, 29.3, 30.4, 31.8, 32.5, 33.5, 33.9, and 34.9°2θ±0.2°2θ.

[0179] Since the DVS results for morphology II show reversible water adsorption-desorption behavior (see above), tests were conducted to confirm that the trihydrate morphology (morphology II) could be re-obtained by storing the dehydrated morphology II sample (i.e., morphology IV) at approximately 60% RH. Re-examination by PXRD confirmed that dehydrated morphology IV reverted to morphology II after 3 days of storage at 60% RH.

[0180] After equilibrating the samples under dry nitrogen for approximately 60 hours, DSC analysis of morphology IV was performed. Dehydrated samples were exposed to a temperature gradient rate of 10°C / min or 20°C / min up to approximately 240°C. The DSC thermogram shows a melting peak at approximately 159°C with a melting enthalpy of approximately 57 J / g. Pyrolysis begins immediately after melting.

[0181] When morphology II was dried under vacuum at 100°C for 2 hours, another dehydrated morphology was obtained. This morphology is referred to as morphology V. DVS analysis of morphology II (see above) shows that morphology II loses water when maintained under dry nitrogen. Morphology V was identified while testing the properties of morphology II after exposure to high temperature. Characterization of morphology V was performed using various methods, including PXRD (Figure 9); TG-FTIR; DSC; and Raman spectroscopy. Morphology V exhibited a unique PXRD pattern and a novel Raman spectrum, which were performed as previously described for the characterization of morphology I and II. Chemical integrity of the compound was confirmed by 1H NMR spectroscopy.

[0182] Figure 9 shows the PXRD pattern of morphology V, specifically sample PP502-P44. In the PXRD pattern of Figure 9, the following peaks were identified: 4.5, 5.5, 5.9, 8.1, 10.6, 11.1, 11.9, 13.2, 17.9, 19.2, 19.9, 20.4, 21.3, 21.8, 22.6, 23.9, 24.3, 24.7, 25.0, 26.0, 26.3, 27.6, 28.6, and 30.0°2θ±0.2°2θ. Comparing the PXRD patterns of morphology II and morphology V, for morphology II, the values ​​are 11.0, 19.3, 22.0, 22.5, 22.7, 23.9, 24.2, 24.6, 25.0, 26.1, and 27.5°2θ±0.2°2θ, while for morphology V, the values ​​are 11.1, 19.2, 21.8, 22.6, 23.9, 24.3, 24.7, 25.0, and 2 Overlapping peaks were observed at 6.0 and 27.6°2θ±0.2°2θ, and the following peaks of morphology II either completely disappeared or had reduced intensity: 9.9, 11.0, 14.3, 18.1, 18.4, 18.9, 20.2, 22.0, 22.2, 22.5, 22.7, 22.9, 23.9, 24.6, 26.1, 26.6, 28.2, and 32.7°2θ±0.2°2θ.

[0183] The thermal characteristics of morphology V were determined using TG-FTIR and DSC analysis. The TG-FTIR thermogram showed that the sample immediately lost approximately 5% of its water mass when heated from approximately 100°C to 120°C at a rate of 10°C per minute. This sample maintained stability up to approximately 200°C, at which point a further mass change of approximately 17% was observed due to sample decomposition during continuous heating up to approximately 340°C to 350°C.

[0184] DSC was performed on morphological V samples in a sealed sample pan under ambient conditions. The DSC thermogram showed a very broad endothermic range with a peak at approximately 125°C. The TG-FTIR thermogram revealed that water release began as soon as the ambient temperature was exceeded, so a substantial portion of the endothermic signal coincided with the release of water from the sample into the void volume of the sealed sample pan, which likely indicates that the water is loosely bound to the crystalline structure.

[0185] Related fingerprint area (200cm²) -1 ~1800cm -1 The FT-Raman spectrum of morphology V within ) shows peaks at 1686, 1613, 1574, 1540, 1504, 1488, 1349, 1314, 1288, 1266, 1193, 1153, 1052, 1027, 852, 775, 708, and 378 (Raman shift, cm). -1 ±2cm -1 The difference between the Raman spectra of morphology V and morphology II is shown at 1686, 1574, 1488, 1314, 1266, 1193, 1153, 1052, and 708 cm⁻¹ for the morphology V spectrum. -1 These are revealed by the peaks, all of which do not appear in the morphology II spectrum. Furthermore, the peaks at 1668, 1580, 1564, 1493, 1454, 1436, 1416, 1401, 1321, 1272, 1252, 1244, 1183, 1165, 1097, 1039, 996, 950, 871, 730, 645, 633, 352, 279, and 247 cm in the morphology II spectrum are also present. -1 The peaks that appear in this region are not present in the morphological V spectrum, indicating the presence of a different phase.

[0186] Crystallization of formula (1) present in methanol and methanol-water mixture (95:5) yielded samples with novel PXRD patterns (samples PP502-P26 and PP502-P16, respectively). Form VI was the product obtained from a crystallization experiment conducted in methanol-water mixture (95:5) at 5°C (sample PP502-P16). Form VI presents a unique PXRD pattern (Figure 10) and Raman spectrum. Comparing the PXRD patterns of Form VI with those of Forms I and II, it can be seen that neither Form I nor Form II are present in sample PP502-P16. The following characteristic peaks were identified in the PXRD pattern of morphology VI: 6.5, 6.8, 8.5, 11.8, 12.6, 13.5, 13.8, 14.8, 15.0, 16.2, 16.4, 16.9, 18.5, 19.4, 19.9, 20.6, 21.6, 22.1, 22.7, 23.6, 24.5, 24.8, 25.3, 26.0, 27.2, 27.8, 28.5, 28.9, 30.2, and 34.3°2θ±0.2°2θ. Characteristic Raman peaks of morphology VI are located at 1667, 1609, 1580, 1562, 1535, 1495, 1450, 1350, 1323, 1306, 1264, 1245, 1190, 1161, 1042, 997, 838, 762, 717, 630, and 272 cm. -1 ±2cm -1 It is observed in this way.

[0187] Morphology VII was obtained from a crystallization experiment conducted in pure water-methanol, in which case the resulting solid sample PP502-P26 precipitated upon storage at 4°C. Morphology VII exhibits a unique PXRD pattern (Figure 11) and Raman spectrum. Comparing the PXRD patterns of morphology VII with those of morphology I and II, it can be seen that neither morphology I nor morphology II are present in the sample PP502-P26. In the PXRD pattern of morphology VII, the following characteristic peaks were identified: 5.9, 6.5, 6.9, 7.8, 8.5, 9.6, 9.9, 10.4, 13.4, 13.9, 15.0, 16.5, 16.9, 17.7, 18.5, 19.0, 19.9, 20.8, 21.6, 22.4, 23.7, 23.9, 24.8, 25.2, 27.5, 28.3, and 30.0°2θ±0.2°2θ. Characteristic Raman peaks of morphology VII are located at 1687, 1663, 1604, 1578, 1561, 1534, 1486, 1462, 1443, 1397, 1361, 1348, 1327, 1305, 1251, 1234, 1184, 1163, 1037, 1001, 835, 774, 757, 717, 653, 606, 422, 348, and 268 cm. -1 ±2cm -1 It is observed in this way.

[0188] 1 ¹H NMR spectroscopy shows that both forms VI and VII contain approximately 0.7 equivalents of methanol, and TG-FTIR indicates that both forms contain substantial amounts of water. Forms VI and VII are likely to be measurable methanol solvates or mixed solvate-hydrates (i.e., methanolate-hydrates). Suspension equilibrium experiments conducted in methanol at 5°C with mixtures of forms I, VI, and VII showed that pure form I was recovered after 5 days, suggesting that form I is likely more stable than either form VI or VII, even in pure methanol.

[0189] Form VIII (sample PP502-P23) is the putative acetic acid disolvate. The PXRD pattern of Form VIII is shown in Figure 12. The following peaks were identified in the PXRD pattern of Form VIII: 4.3, 6.2, 6.6, 8.6, 11.8, 12.0, 12.4, 15.6, 17.2, 18.0, 18.6, 19.4, 20.0, 20.9, 22.1, 22.7, 23.7, 25.1, 26.0, 26.4, and 27.5°2θ±0.2°2θ. Characteristic Raman peaks of morphology VIII are located at 1681, 1580, 1529, 1497, 1456, 1437, 1349, 1313, 1302, 1268, 1243, 1193, 1157, 1047, 1025, 1006, 951, 896, 851, 775, and 264 cm. -1 ±2cm -1 It is observed in this way.

[0190] Table 5 shows an overview of these forms.

[0191] [Table 7]

[0192] Example 5. Preparation and characterization of amorphous (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide Amorphous (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide can be prepared by various methods, including the procedure described in Example 6 of U.S. Patent Application Publication No. 2014 / 0155385A1 and International Patent Application Publication No. 2013 / 010868A1 (the disclosure thereof is incorporated herein by reference). The amorphous form can be produced by rapid evaporation of the solvent from a solution in dichloromethane or a cosolvent, such as acetone or a mixture of alcohol and dichloromethane. Furthermore, the amorphous form can also be produced by freeze-drying an aqueous solution containing a small amount of acid, such as formic acid or acetic acid, to solubilize the free base form I.

[0193] Amorphous (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide can be prepared by adding 3.0 mL of water to 200 mg of crystalline form I. Formic acid is then added dropwise until the solid is completely dissolved. Approximately 50 microliters of formic acid is generally sufficient to achieve complete dissolution of form I. The clear solution is filtered into a 100 mL round-bottom flask through a 0.22 μm micropore polytetrafluoroethylene (PTFE) filter (e.g., using a syringe), and the solution in the round-bottom flask is freeze-dried. The resulting product (sample PP502-P107) is amorphous. Characterization of the freeze-dried product by powder X-ray diffraction confirms that the amorphous form was obtained. The obtained PXRD pattern is shown in Figure 13. Bragg reflection was not observed, and the PXRD pattern featured diffuse scattering typical of amorphous materials.

[0194] Figure 14 shows the Raman spectra of similarly prepared samples (samples PP502-P118) of amorphous formula (1). The spectra differ from those of other crystalline forms of formula (1). Characteristic Raman peaks are at 1674, 1608, 1577, 1537, 1492, 1449, 1348, 1307, 1238, 1188, and 992 cm⁻¹. -1 ±2cm -1 It is observed in this way.

[0195] The IR spectra of similarly prepared amorphous formula (1) samples (samples PP502-P184) obtained by ATR sampling differ from those of other crystalline forms of formula (1). Characteristic IR peaks are located at 1668, 1605, 1505, 1428, 1302, 1237, 1200, 1153, 1091, 997, 944, 894, 863, 776, and 753 cm⁻¹. -1 ±4cm -1 It is observed in this way.

[0196] Further characterization of the freeze-dried product by TG-FTIR revealed the presence of a small amount of formic acid. Therefore, the obtained amorphous sample was further dried under vacuum at 80°C for approximately 20 hours and re-tested by TG-FTIR and DSC (samples PP502-P107A). TG-FTIR of the dried sample revealed the presence of only very small amounts of water and residual solvent. DSC of the nearly solvent-free amorphous form showed a ΔC of approximately 0.3 J / (g·K). p It exhibits a glass transition temperature of approximately 130°C. The smaller change in heat capacity at approximately 120°C is thought to be due to another fraction of amorphous material that may contain trace amounts of solvent, hence the lower glass transition temperature. Thermal decomposition begins above approximately 160°C.

[0197] DVS results for similarly prepared amorphous formula (1) samples (samples PP502-P148), including moisture adsorption and desorption curves, were performed by exposing the samples to humidity decreases from 50% RH, to 0% RH, to 95% RH, and finally to a decrease in humidity back to 50% RH. The DVS results, including moisture adsorption and desorption curves, show that a significant increase in moisture occurs during adsorption, starting at approximately 20% RH. The total moisture increase observed from 0% RH to 80% RH was approximately 6%, indicating that morphology II is hygroscopic according to the EP classification (see Example 1.2). Furthermore, the total mass increase at a maximum of 95% RH was approximately 13%, and the mass increases irreversibly after adsorption (only 5% of the 10% moisture increased in the 50-95% RH range was removed by the final decrease to 50% RH). These results demonstrate the hygroscopicity of the amorphous morphology, including the irreversible uptake of large amounts of moisture upon exposure to high RH.

[0198] Example 6. Crystalline salt of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide Salt screening for (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide free base (sample PP502-P1, prepared as described above) included crystallization experiments using 11 different acids, including benzoic acid, benzenesulfonic acid, citric acid, fumaric acid, hydrochloric acid, maleic acid, nicotinic acid, phosphoric acid, saccharin, succinic acid, and L-tartaric acid. Of these, crystalline samples were obtained using citric acid, fumaric acid, maleic acid, phosphoric acid, succinic acid, and L-tartaric acid.

[0199] Table 6 outlines the starting materials for salt preparation. Each prepared product is assigned a sample identifier, which is as follows: SP221-XXX-Pn (XXX = salt identification code, n = experiment / number of samples).

[0200]

Table 8

[0201] The characterization of fumarate, maleate, phosphate and L-tartrate was carried out using 1 1H NMR spectroscopy, TG-FTIR, DSC, dynamic water vapor absorption, optical microscopy, high performance liquid chromatography (HPLC) purity, laser diffraction, apparent bulk density and tapped density, and water solubility analysis.

[0202] When the seed crystals were obtained, it was found that the formation of the crystal salts was reproducible, and various salts showed excellent tendencies towards crystallization. An overview of the salt properties is shown in Table 7.

[0203]

Table 9

[0204] The solubility was measured without pH adjustment after only 3 hours of equilibration time, so the solubility of all salts increased significantly compared to the free base. The free base is a poorly water-soluble drug, while the salts were sufficiently water-soluble.

[0205] All of the salts described above are thought to form hydrates. The preliminary experiments consisted of three suspension equilibration experiments for each salt. From the results, it can be seen that all four salts can exist in multiple solid forms, including polymorphs.

[0206] Example 6.1. Form A of the fumarate of formula (1) Crystalline form A of the fumarate of formula (1) was prepared by dissolving 16.294 g of PP502-P1 free base and 4.065 g of fumaric acid in 500 mL of acetone. The mixture was then heated to 50°C, and 50 mL of water was added. A clear solution was obtained by adding water, and at this point, the solution was cooled to room temperature while stirring at approximately 300 rpm. At room temperature, approximately 20 mg of SP221-FUM-P5 was added as a seed to the clear solution, and after approximately 48 hours, the suspension was filtered to obtain a solid, which was air-dried at 40°C for approximately 24 hours. Initial characterization of the obtained solid, measured by high-performance liquid chromatography (HPLC), showed a purity of approximately 99.9% and a yield of approximately 13.6 grams (approximately 64%).

[0207] Form A of fumarate 1 The samples were characterized by 1H NMR spectroscopy, optical microscopy, Fraunhofer laser diffraction, reflective PXRD (Figure 15), TG-FTIR, DSC, and dynamic water vapor absorption (DVS).

[0208] The chemical identity of fumarate 1 Confirmed by 1H NMR spectroscopy. The fumarate (sample SP221-FUM-P9) was recorded using acetone solvent. 1 The 1H NMR spectrum matches that of a 1:1 fumarate. The peak around 2.1 ppm indicates trace amounts of acetone as a residual solvent present after drying.

[0209] The fumarate was obtained as minute particles. Because the resulting salt was lumpy, the dried material was sieved through a 500 μm sieve before further characterization. After dispersing the compound in heptane, it was examined using polarized light microscopy after short-duration sonic treatment sufficient to disperse the crystals. Optical microscopy revealed minute crystalline particles, but these remained largely aggregated even after sieving and dispersion.

[0210] For a given volume percentage of the samples shown in Table 8 below, particle size distribution tests were performed using fraunhofer laser diffraction at the maximum particle size value. For example, a size dimension of ×50 (42 μm) represents the maximum particle size, and 50% of the sample volume contains particles smaller than this. This parameter is also known as the median particle size distribution per unit volume.

[0211] [Table 10]

[0212] By monitoring these three parameters (×10, ×50, ×90), it is possible to determine whether there are significant changes in the main particle size and changes in the extreme values ​​of the distribution, likely due to the presence of fine or oversized particles or aggregates in the particle size distribution. The results are consistent with optical microscopy and show a particle size distribution function with a significant proportion of aggregates.

[0213] Static light scattering, such as laser diffraction, imparts a volume-weighted distribution, where the contribution of each particle to the distribution is related to its volume (equivalent to its mass if the density is uniform). This is extremely useful because the distribution represents the composition of the sample in relation to its volume / mass.

[0214] The crystallinity of the salt was confirmed by PXRD in addition to optical microscopy. The reflective PXRD pattern of the fumarate sample SP221-FUM-P9 is shown in Figure 15 and exhibits the following representative peaks: 4.9, 5.4, 7.0, 9.8, 10.8, 11.5, 12.1, 14.1, 16.1, 16.6, 17.8, 18.5, 19.4, 20.3, 20.5, 21.8, 22.1, 22.5, 23.1, 24.0, 24.8, 26.6, 26.8, 27.3, and 28.2°2θ±0.2°2θ.

[0215] Thermal analysis characterization of fumarate morphology A was performed using TG-FTIR (sample SP221-FUM-P9) and DSC (sample SP221-FUM-P9a). TG-FTIR analysis of the representative crystalline formula (1) fumarate sample revealed a mass loss of approximately 4.5%, which is likely due to water loss. The amount of water attributable to the mass loss is in close agreement with the theoretical water content of sesquihydrate, 4.6%. Subsequently, approximately 12.75% of the mass loss during heating up to approximately 300°C was mainly due to decomposition. The DSC of the same sample showed an endothermic peak around 162°C, which deviates from the baseline above approximately 120°C and rises slowly. However, due to thermal decomposition that begins around 170°C, the enthalpy of fusion cannot be reliably evaluated.

[0216] The hygroscopic properties of fumarate (sample SP221-FUM-P9a) were measured using dynamic water vapor absorption. DVS adsorption and desorption results showed that this salt loses almost all moisture under low humidity conditions, but reaches a maximum saturation of approximately 6% at approximately 95% RH. The change in moisture content from 20% to 80% RH is approximately 0.8%. Similar to the previously described moisture adsorption-desorption isotherms, the samples were exposed to humidity decreases from 50% RH to 0% RH, humidity increases to 95% RH, and finally, humidity decreases again to 50% RH.

[0217] Example 6.2. Form A of maleate of formula (1) Crystalline form A maleate (Sample SP221-MLE-P9) was prepared by dissolving 16.296 g of PP502-P1 free base in a mixture of 350 mL of acetone and 35 mL of water. Subsequently, the mixture was heated to 50 °C, thereby obtaining a clear solution. Thereafter, 20 mL of an aqueous solution containing 4.043 g of maleic acid was added. Further, the container holding the maleic acid aqueous solution and the pipette were washed with 1.0 mL of water, and the aqueous solution was also introduced into the mixture. The solution was cooled while stirring at about 300 rpm. At about 45 °C, about 20 mg of SP221-MILE-8 was added as a seed to the solution, and then it was further cooled to about 20 °C. After about 24 hours, the suspension was filtered to obtain a solid, which was air-dried at 40 °C for about 20 hours. By initial characterization of the obtained solid, a yield of about 14.1 grams (about 66%) was obtained.

[0218] The maleate 1 was characterized by 1H NMR spectroscopy, optical microscopy, Fraunhofer laser diffraction, reflection PXRD (Figure 16), TG-FTIR, DSC, and DVS.

[0219] The chemical identity of the maleate 1 was confirmed by 1H NMR spectroscopy. The 1H NMR spectrum of the maleate (Sample SP221-MLE-P9) recorded using an acetone solvent 1 is consistent with a 1:1 maleate. Similar to the 1H NMR analysis of the fumarate of formula (1), trace amounts (0.7%) of acetone as a residual solvent are also present in the spectrum. 1

[0220] Examination by polarized light microscopy revealed that the maleate consists of minute crystalline particles in the particle size range of about 10 μm to about 100 μm. The prepared maleate was substantially larger than the particles of fumarate (described above), phosphate, and L-tartrate (the latter two are described below). Since the fine powder showed favorable fluidity, no sieving was necessary after drying.

[0221] For a given volume percentage of the samples shown in Table 9 below, a particle size distribution test was carried out using Fraunhofer laser diffraction at the value of the maximum particle size.

[0222]

Table 11

[0223] Optical microscopy analysis showing a particle size distribution in the range of approximately 10 μm to 100 μm was confirmed by the particle size distribution function of maleate.

[0224] Together with the optical microscopy images, the crystallinity of the salt was confirmed by powder X-ray diffraction. The reflection-type PXRD pattern of the maleate sample SP221-MLE-P9 is depicted in Figure 16 and shows the following representative peaks: 5.3, 9.8, 10.6, 11.6, 13.5, 13.8, 13.9, 14.3, 15.3, 15.6, 1...........5, 24.8, 25.2, 25.6, 26.1, 26.4, 26.7, 26.9, 27.1, 27.6, 28.8, 29.5, 30.0, 30.3, 30.9, 31.5, 31.9, 32.5, 34.0, and 35.1° 2θ ± 0.2° 2θ.

[0225] Thermal analysis characteristics determination of maleate was carried out using TG-FTIR and DSC. From the TG-FTIR analysis of the representative crystalline form (1) maleate sample, a mass loss of approximately 5.3% was revealed; this could be attributed mainly to water loss. The amount of water resulting in the mass loss almost coincides with the theoretical moisture content of 4.6% for the sesquihydrate...........However, acetone was not detected. Subsequently, a mass loss of approximately 10.1% during heating up to about 300 °C was mainly due to decomposition. The DSC of the same sample showed an endothermic peak around 174 °C, followed by decomposition.

[0226] The hygroscopic properties of maleate (sample SP221-MLE-P9) were measured using dynamic water vapor absorption. DVS adsorption and desorption results indicate that this salt exhibits almost no water loss at 0% RH. The sample reaches a maximum saturation of approximately 5.8% at approximately 95% RH. The change in moisture content from 20% to 80% RH is approximately 0.5%. The sample was exposed to humidity decreases from a starting humidity of 50% RH to 0% RH, then to humidity increases up to 95% RH, and finally back to a starting humidity of 50% RH.

[0227] Example 6.3. Form A of the phosphate of formula (1) The preparation of crystalline form A of the phosphate of formula (1) was achieved as follows: First, 350 mL of acetone and 35 mL of water were added to 16.2998 g (35 mmol) of the free base PP502-P1 of formula (1). When heated to 50°C, a clear solution was obtained. To this solution, 2.5 mL of 85-90% phosphoric acid (35 mmol) was slowly added. The solution was cooled to room temperature while stirring at approximately 300 rpm. At approximately 38°C, crystals were observed without seed addition. After approximately 80 hours, the suspension was filtered, and the obtained solid was air-dried at 40°C for approximately 24 hours. The yield was approximately 20.48 g (approximately 97%). The phosphate was obtained as fine particles. After drying, the material was lumpy, and extremely strongly aggregated particles were observed. For tap density testing and particle size analysis, dried material was sieved using a 500 μm sieve to obtain a freely flowing powder. The dried sample was designated SP221-PO4-P5, and the sieved sample was designated SP221-PO4-P5a.

[0228] Initial characterization of the obtained solid, measured by HPLC, revealed a purity of approximately 99.9%. DVS and TG-FTIR indicated that the resulting phosphate form was likely a dihydrate with a theoretical phosphorus content of approximately 5.2%. Inductively coupled plasma emission spectrometry (ICP-OES) revealed a phosphorus content of approximately 4.7%, which is slightly below the content required for a 1:1 salt.

[0229] Phosphate 1The samples were characterized by 1H NMR spectroscopy, optical microscopy, Fraunhofer laser diffraction, reflective PXRD (Figure 17), TG-FTIR, DSC, and DVS.

[0230] Chemical identity of phosphate (sample SP221-PO4-P5) 1 ¹H NMR spectroscopy confirmed that the structure was consistent with that of crystalline phosphate. Polarizing microscope examination revealed that the phosphate is a crystalline material composed of fine particles, the majority of which have a particle size of less than approximately 10 μm. In the case of sample SP221-PO4-P5, the particles were distinctly needle-shaped.

[0231] Particle size distribution tests were conducted using fraunhofer laser diffraction, based on the maximum particle size values ​​for a given volume percentage of the samples shown in Table 10 below.

[0232] [Table 12]

[0233] The crystallinity of the salt was confirmed by PXRD in addition to optical microscopy analysis. The reflective PXRD pattern of the sample obtained from a 20-gram batch (sample SP221-PO4-P5) is shown in Figure 17 and exhibits the following representative peaks: 4.5, 6.0, 7.2, 10.4, 12.0, 12.5, 13.1, 14.3, 15.5, 17.4, 18.0, 18.3, 18.9, 19.3, 20.2. 20.5, 20.9, 21.4, 21.9, 22.0, 22.6, 22.9, 23.1, 23.3, 24.2, 24.6, 25.0, 25.7, 26.2, 26.4, 26.9, 27.3, 27.5, 29.3, 30.0, 30.3, 30.5, 30.9, 31.2, 31.9, and 35.7°2θ±0.2°2θ. The phosphate exists in at least two distinct crystalline forms: anhydrous crystalline form and hydrated crystalline form, each form exhibiting a unique PXRD pattern. The peaks in Figure 17 correspond to the hydrated form of crystalline phosphate.

[0234] The thermal characteristics of the phosphate were determined using TG-FTIR and DSC. TG-FTIR analysis of the phosphate sample (sample SP221-PO4-P1) revealed a mass loss of approximately 5.9%, which is likely due to water loss. This result, with a water content of approximately 5.9% in the phosphate sample being close to the expected water content of a dihydrate (6.0%), suggests that the crystalline form of the obtained phosphate is a dihydrate. Further mass loss during heating to approximately 250°C was mainly due to decomposition. DSC of the same sample showed a broad endothermic peak around 138°C. The enthalpy of fusion is estimated to be approximately 134 J / g.

[0235] The hygroscopic properties of the phosphate (sample SP221-PO4-P1) were measured using DVS. DVS adsorption and desorption results showed that the salt loses almost all moisture under low RH conditions, but reaches a maximum saturation of approximately 6.6% at approximately 95% RH. DVS analysis suggests that the phosphate forms a dihydrate with a water content of approximately 6.0%. The samples were exposed to humidity decreases from a starting point of 50% RH to 0% RH, then to humidity increases up to 95% RH, and finally back to a starting point of 50% RH.

[0236] Example 6.4. Form A of L-tartrate of formula (1) Crystalline form A of formula (1) L-tartarate was prepared by dissolving 16.298 g of PP502-P1 free base in a mixture of 350 mL of acetone and 35 mL of water. The mixture was then heated to 50°C to obtain a clear solution. Next, 20 mL of aqueous solution containing 5.257 g of L-tartaric acid was added to this clear solution. The solution was cooled to approximately 20°C while stirring at approximately 300 rpm. After approximately 24 hours, the suspension was filtered to obtain a solid, which was air-dried at 40°C for approximately 20 hours. Initial characterization of the obtained solid, measured by HPLC, showed a purity of approximately 99.78% and a yield of 20.1 grams (approximately 89%).

[0237] L-tartrate 1The samples were characterized by 1H NMR spectroscopy, optical microscopy, Fraunhofer laser diffraction, reflective PXRD (Figure 18), TG-FTIR, DSC, and DVS.

[0238] The chemical identity of L-tartrate (sample SP221-LTA-P8) 1 ¹H NMR spectroscopy confirmed that the structure was consistent with that of 1:1 crystalline L-tartrate. The L-tartrate was obtained as a crystalline material; examination using polarized light microscopy revealed that this material consists of partially aggregated minute needle-like structures ranging in length from approximately 2 μm to 40 μm and with a width of several μm.

[0239] Particle size distribution tests were conducted using fraunhofer laser diffraction, based on the maximum particle size values ​​for a given volume percentage of the samples shown in Table 11 below.

[0240] [Table 13]

[0241] The crystallinity of the salt was confirmed by PXRD, along with the light microscope image in Figure 18. The reflective PXRD pattern of the L-tartrate sample SP221-LTA-P8 is shown in Figure 18 and exhibits the following representative peaks: 4.6, 5.5, 7.2, 9.3, 10.7, 10.9, 11.8, 14.3, 14.9, 16.4, 17.0, 17.7, 19.2, 19.4, 19.5, 20.3, 21.6, 22.4, 23.3, 23.8, 24.3, 24.5, 24.7, 25.1, 25.6, 26.8, 27.2, 27.8, 28.4, 28.7, 29.0, 29.5, 30.0, 30.9, 31.6, 32.1, 32.4, 33.0, 33.5, and 33.9°2θ±0.2°2θ.

[0242] The thermal characteristics of L-tartrate were determined using TG-FTIR and DSC. TG-FTIR analysis of crystalline formula (1) L-tartrate (sample SP221-LTA-P8) revealed a mass loss of approximately 4.8%, which is likely due to water loss. This amount of water is roughly consistent with the theoretical water content of sesquihydrate, which is 4.3%. Subsequently, the approximately 20% mass loss upon heating to approximately 300°C was mainly due to decomposition. The DSC of sample SP221-LTA-P8a showed an endothermic peak around 156.5°C, along with a fusion enthalpy of approximately 40.70 J / g.

[0243] The hygroscopic properties of L-tartrate (sample SP221-LTA-P8a) were measured using dynamic water vapor absorption. DVS adsorption and desorption results indicate that this salt loses water under low humidity conditions, reaching a maximum saturation of approximately 5.4% at approximately 95% RH. Furthermore, the initial water content of approximately 4.8% at 50% RH (confirmed by TG-FTIR, which indicated a total water content of approximately 4.8%) suggests that approximately 30% of this water was removed within the measurement timescale by DVS analysis. The change in water content from 20% to 80% RH was approximately 0.7%. Water adsorption-desorption isotherms were prepared in the same manner as previously described.

[0244] Example 6.5. Form A of citrate of formula (1) Citric acid has the molecular formula C6H8O7 and a molecular weight of 192.12 g / mol. The pK of the three carboxylic acid groups in citric acid is... a The values ​​were 2.93, 4.76, and 6.40. Crystallization of citrate from an acetone-water mixture yielded a sample containing a significant amount of acetone and some water, while crystallization from 1-propanol yielded a sample containing a large amount of 1-propanol, indicating that both phases can be solvates.

[0245] Sample SP221-CIT-P4 was prepared as follows: 941 mg of the free base of formula (1) (PP502-P1) and 384.5 mg of citric acid were dissolved in 22 mL of acetone-water (10:1) by heating the mixture to 50°C. After cooling to room temperature, a dilute suspension was formed, which was stirred in an open vial to evaporate some of the solvent. Further acetone was added to produce a more concentrated suspension, which was stirred at room temperature for about 1 hour and then filtered. After air drying at room temperature, approximately 436 mg of a white product was obtained. The product SP221-CIT-P4 obtained from the experiment was further dried at 40°C for 24 hours to obtain sample SP221-CIT-P4A. The batches prepared using the procedure used for SP221-CIT-P4 and SP221-CIT-P4A may be further exposed to controlled humidity to replace the acetone with water.

[0246] Sample SP221-CIT-P6 was prepared as follows: 466 mg of the free base of formula (1) (PP502-P1) and 96.4 mg of citrate were dissolved in 10 mL of 1-propanol in a 10:1 ratio by heating the mixture to 70°C. At 50°C, SP221-CIT-P4 was added to the mixture as a seed and cooled to room temperature. A suspension was formed and stirred at room temperature for about 1 hour, after which the solid product was filtered. After air drying at room temperature, approximately 660 mg of white product was obtained. The batch prepared using the procedure for SP221-CIT-P6 may be further exposed to controlled humidity to replace the 1-propanol with water.

[0247] Products obtained from experiment SP221-CIT-P4 1 ¹H NMR spectroscopy revealed that the ratio of formula (1) to citric acid is approximately 2:1 (1.83), based on the quotient obtained by dividing the sum of the integrals of the 10 aromatic protons in formula (1) by the integral from the 4 protons derived from the methylene group of citric acid at 2.6–2.9 ppm. The 1:2 citrate:formula (1) phase may contain both ionized citrate (as a salt) and non-ionized citrate (as a cocrystal). The molecular formula of the 2:1 salt or cocrystal of formula (1) containing citric acid is 2·[C26 H 23 With [N7O2]+C6H8O7, the molecular weight is 1123.1 g / mol. In the first attempt to convert the acetone solvate to the hydrate sample, SP221-CIT-P4 was subjected to a suspension equilibrium in water at 25 °C for 24 hours, thereby achieving the conversion of the free base of formula (1) to form III (dihydrate).

[0248] The reflection-type PXRD patterns of the citrate salts obtained from acetone-water (SP221-CIT-P4) and 1-propanol (SP221-CIT-P6) are shown in Figures 19 and 20, respectively. By comparing the two PXRD patterns, it can be seen that the PXRD patterns of the two forms show significant similarity, which indicates a similar crystal lattice for both samples. Therefore, the two patterns are considered to represent two different solvation states of the citrate salt and the single host structure containing formula (1). For this reason, both samples are designated as Form A. Form A of the citrate salt of formula (1) may contain various amounts of other low molecular weight organic solvents and water. In the nearly solvated state of sample SP221-CIT-P4a, the following peaks are characteristic of Form A of the citrate salt of formula (1): 6.1, 6.6, 7.2, 7.9, 8.3, 9.7, 10.8, 11.1, 12.2, 13.5, 14.1, 14.9, 15.9, 16.6, 17.5, 17.9, 18.3, 18.9, 19.5, 20.3, 21.5, 21.9, 22.7, 23.8, 24.4, 24.8, 26.1, 2, 27.4, 27.9, and 29.3° 2θ ± 0.2° 2θ. In the nearly solvated state of sample SP221-CIT-P6, the following peaks are characteristic of Form A of the citrate salt of formula (1): 6.1, 6.4, 7.2, 7.9, 8.2, 9.6, 10.9, 12.0, 13.4, 13.8, 14.0, 14.9, 15.5, 15.9, 16.4, 17.3, 17.5, 18.2, 18.6, 19.3, 20.1, 20.4, 21.4, 21.6, 22.6, 23.2, 23.7, 24.3, 26.0, 27.0, 27.3, 27.8, and 29.2° 2θ ± 0.2° 2θ. The characteristic peaks listed above may vary in their positions due to the exchange of solvents into this crystal phase.

[0249] Raman spectroscopy was performed on samples SP221-CIT-P4a and SP221-CIT-P6 for morph A of the citrate of formula (1). The Raman spectrum of a dried sample of SP221-CIT-P4, referred to as SP221-CIT-P4a, was obtained. In the nearly solvated state of sample SP221-CIT-P4a, characteristic Raman peaks for morph A of the citrate of formula (1) were observed as follows: 3068, 2921, 2237, 1682, 1612, 1551, 1505, 1436, 1332, 1313, 1241, 1188, 993, and 712 (Raman shift, cm). -1 ±2 -1 The Raman spectrum of SP221-CIT-P6 was obtained. In the nearly solvated state of the sample SP221-CIT-P6, characteristic Raman peaks for form A of the citrate of formula (1) were observed as follows: 3055, 2920, 2237, 1685, 1612, 1549, 1504, 1436, 1333, 1313, 1286, 1240, 1187, 993, and 712 (Raman shift, cm). -1 ±2 -1 The characteristic peaks mentioned above can vary at each position due to the exchange of solvent into this crystalline phase.

[0250] ATR-IR spectroscopy was performed on samples SP221-CIT-P4a and SP221-CIT-P6 for morphology A of the citrate of formula (1). The IR spectrum of sample SP221-CIT-P4a was obtained. In the nearly solvated state of sample SP221-CIT-P4a, the characteristic IR peaks of morphology A of the citrate of formula (1) were observed as follows: 3396, 2234, 1673, 1606, 1537, 1428, 1304, 1264, 1200, 1092, 1008, 893, 866, 773, 735, and 693 (IR frequencies, cm). -1 ±4 -1The IR spectrum of sample SP221-CIT-P6 was obtained. In the nearly solvated state of sample SP221-CIT-P6, the characteristic IR peaks of morph A of the citrate of formula (1) were observed as follows: 3403, 2960, 2872, 2233, 1678, 1608, 1582, 1538, 1434, 1403, 1352, 1302, 1253, 1201, 1094, 1055, 1010, 967, 895, 813, 772, 750, 735, 693, and 612 (IR frequencies, cm). -1 ±4 -1 The characteristic peaks mentioned above can vary at each position due to the exchange of solvent into this crystalline phase.

[0251] TG-FTIR analysis was performed on three different samples of citrate. The TG-FTIR thermogram of sample SP221-CIT-P4 revealed that the sample contained both water and acetone, and that water was weaker bound than acetone. The SP221-CIT-P4 sample was stored for 3 months after preparation under ambient conditions, and this was designated as sample SP221-CIT-P3. TG-FTIR analysis of this sample revealed that most of the mass loss was due to water. This provides evidence that acetone is slowly replaced by water over time, increasing the water content to approximately 8%. This observation is supported by the finding that mass loss typically occurs in two steps. In the first step, water and some acetone are released, and in the second step, the mass loss is mainly due to acetone. Formula (1): The theoretical acetone content of citrate 2:1 salt acetone monosolvate is 5%, and the theoretical water content of pentahydrate is 8%. Therefore, in addition to acetone solvate (or mixed acetone solvate-hydrate), a pure hydrated form of citrate A of formula (1) can be prepared. The results from TG-FTIR analysis of 1-propanol showed two different steps, which may indicate the existence of a second 1-propanol solvated phase with a different stoichiometry.

[0252] A sample of citrate (form A) SP221-CIT-P3 was selected for DSC testing in a sealed sample pan, and it was observed that melting exhibited broad endothermy with indistinct melting. For a second DSC experiment, the citrate sample SP221-CIT-P3 was stored at 33% relative humidity for several days of equilibrium. The resulting DSC thermograms showed no significant difference. The maximum endothermic signal was at 90°C; however, the deviation from baseline began below 60°C, and a prominent shoulder was observed at approximately 82°C. The endothermy, which began at approximately 140°C, is considered to be a result of thermal decomposition.

[0253] The dynamic water vapor absorption (DVS) of the citrate (sample SP221-CIT-P4) indicates that a given salt form absorbs a substantial amount of water (up to 12% over a range of 0-100% RH) under high humidity conditions, and that the water content at the end of the test is approximately 7.5% by weight. It is thought that some of the acetone detected by TG-FTIR was replaced by water during the DVS test.

[0254] Example 6.6. Form A and other forms of gentisic acid salt of formula (1) Gentisic acid has the molecular formula C7H6O4 and a molecular weight of 154.12 g / mol. The pK of gentisic acid is... a The value is 2.93. First, gentisic acid salt was identified using the previously described screen (sample SP221-GEN-P1), and then regenerated as acetone hesolvate by crystallization from an acetone-water mixture (SP221-GEN-P2). A crystalline sample free of residual organic solvents was obtained by suspension equilibrium of acetone hesolvate in acetonitrile (sample SP221-GEN-P3). TG-FTIR revealed that this sample contained approximately 2.6% water. This result was in perfect agreement with the theoretical water content of gentisic acid monohydrate, which is 2.8%.

[0255] Sample SP221-GEN-P1 was prepared as follows: 235.6 mg of formula (1) free base (PP502-P1, 0.5 mmol) was dissolved in 4.0 mL of acetone-water (9:1) at 57°C, and then 5.0 mL of 0.1 M gentisic acid acetone storage solution was added. With the cap left open, the mixture was cooled to room temperature while the acetone evaporated, and stirred. After obtaining a suspension of approximately 3 mL in volume, this solid product was filtered and air-dried at room temperature.

[0256] Sample SP221-GEN-P2 was prepared as follows: 470 mg of formula (1) free base (PP502-P1, 0.5 mmol) was dissolved in 11.0 mL of 0.1 M gentisic acid acetone storage solution. 2.0 mL of water was added to this solution. A small amount of SP221-GEN-P1 was added to the solution as a seed, and the mixture was stirred in an open container to evaporate the solvent. The solution was cooled to room temperature, and with the cap left open, the mixture was continued to evaporate the acetone while stirring. After obtaining a suspension of approximately 3 mL in volume, the solid product was filtered and air-dried at room temperature.

[0257] Sample SP221-GEN-P3 was prepared as follows: 2.0 mL of acetonitrile was added to sample SP221-GEN-P2, and the resulting suspension was stirred at room temperature for 3 days. The solid product was filtered and air-dried at room temperature.

[0258] Sample SP221-GEN-P4 was prepared as follows: 466 mg of PP502-P1 (0.5 mmol) and 154 mg of gentisic acid were dissolved in 10.0 mL of 2-propanol by heating to 70°C. 0.2 mL of formic acid was added to promote dissolution. The solution was cooled to room temperature, and SP221-GEN-P2 was added as a seed at approximately 45°C, followed by the addition of 5.0 mL of 2-propanol. A suspension was obtained within approximately 4 hours, from which the solid product was filtered and air-dried at room temperature.

[0259] Another batch of gentisic acid monohydrate of formula (1) (sample SP221-GEN-P5) was prepared in the same manner as that used to prepare SP221-GEN-P3. Approximately 400 mg of sample SP221-GEN-P4 was added to acetonitrile containing 5% water. The resulting suspension was stirred at room temperature for 1 day. The solid product was filtered and air-dried at room temperature. Sample SP221-GEN-P5A was prepared by maintaining sample SP221-GEN-P5 at 33% relative humidity for 2 weeks.

[0260] The second hydrate, likely the dihydrate, was obtained as a solid residue after the solubility test (sample SP221-GEN-P6).

[0261] Products obtained from experiment SP221-GEN-P5 1 ¹H NMR spectroscopy revealed that the ratio of the free base of equation (1) to gentisic acid is approximately 1:1, based on the sum of the integral signals of the four aromatic protons of equation (1) at 7.5–8.5 ppm and the two aromatic protons of gentisic acid at 6.6–7.0 ppm. 1 The 1H NMR spectrum also revealed that the obtained material contained virtually no organic solvents.

[0262] Furthermore, sample SP221-GEN-P5 was analyzed for CHNO content by elemental composition analysis. The molecular formula of the 1:1 salt of formula (1) and gentisic acid is C 33 H 29 The molecular weight is predicted to be 619.6 g / mol for N7O6. The monohydrate of the 1:1 salt of formula (1) and gentisic acid has the molecular formula C 33 H 31 It contains N7O6 and has a molecular weight of 637.65 g / mol (and a water content of 2.8%). The results shown in Table 12 are consistent with the predicted formula for the monohydrate.

[0263] [Table 14]

[0264] Optical microscopy of the monohydrate of formula (1) (sample SP221-GEN-P5) revealed a crystalline material mainly consisting of needle-shaped particles with a length of approximately 5-50 μm and a width of approximately 1-10 μm.

[0265] The reflective PXRD pattern of the monohydrate of formula (1) is shown in Figure 21 (sample SP221-GEN-P3). The PXRD pattern of sample SP221-GEN-P5 (not shown) was indistinguishable from that of sample SP221-GEN-P3, indicating that both samples represent the same crystalline phase. This crystalline phase is called form A (monohydrate) of the gentisic acid salt of formula (1). The following peaks are characteristic of form A (monohydrate) of gentisic acid of formula (1): 4.6, 8.2, 9.0, 9.7, 11.8, 12.9, 13.8, 14.5, 15.5, 16.6, 16.8, 18.4, 19.6, 20.5, 21.1, 24.1, 24.5, 25.5, 25.8, 26.0, 26.6, 26.9, 27.4, and 29.8°2θ±0.2°2θ.

[0266] Raman spectroscopy was performed on sample SP221-GEN-P5 of gentisic acid salt form A (monohydrate) of formula (1). The Raman spectrum was obtained in the same manner as described for form I in Example 1.2. The characteristic Raman peaks of gentisic acid salt form A (monohydrate) of formula (1) were observed as follows: 3057, 2919, 2223, 1681, 1613, 1576, 1552, 1518, 1437, 1333, 1312, 1228, 1192, 1156, 990, 716, 485, and 257 (Raman shift, cm). -1 ±2 -1 ).

[0267] IR spectroscopy was performed on a sample (Sample SP221-GEN-P5) of morph A (monohydrate) of gentisic acid salt of formula (1). The IR spectrum was obtained in the same manner as described for morph I in Example 1.2. The characteristic IR peaks of morph A (monohydrate) of gentisic acid salt of formula (1) were observed as follows: 2957, 1682, 1668, 1602, 1574, 1523, 1504, 1481, 1429, 1377, 1346, 1302, 1274, 1228, 1157, 1092, 1010, 939, 896, 865, 826, 810, 778, 748, 734, 686, 660, and 617 (IR frequencies, cm⁻¹). -1 ±4 -1 ).

[0268] The TG-FTIR thermogram of gentisic acid form A (monohydrate) of formula (1) (sample SP221-GEN-P3) showed a 2.64% mass loss by 120°C and decomposition initiated at 220°C. DSC of gentisic acid form A (monohydrate) of formula (1) (sample SP221-GEN-P5A) revealed two small endothermic peaks at 106°C and 121°C. These peaks do not appear to coincide with the melting of the salt but may be due to a phase transition. The deviation from the baseline at 180°C is likely due to the initiation of the melting process; however, above 195°C, thermal decomposition is the dominant phenomenon, and a clear melting point could not be identified by DSC.

[0269] DVS analysis of gentisic acid form A (monohydrate) of formula (1) (sample SP221-GEN-P5) reveals several steps of approximately 2% water content during scanning from high RH to low RH. This suggests the possibility of the presence of two or more hydrates. Although the observed hysteresis was not symmetric, a second test of the same sample revealed that the entire DVS hydration-dehydration cycle was reversible. The PXRD of the sample recovered from the DVS sample shows the same pattern as the solid residue in the solubility experiment. The 5.2% water content is consistent with the water content of the dihydrate. The following peaks are characteristic of the gentisic acid dihydrate of formula (1) obtained after the DVS test: 4.6, 8.7, 11.7, 12.5, 12.8, 13.1, 14.1, 15.1, 15.6, 16.5, 16.8, 19.7, 24.1, 24.5, 25.3, 25.7, 25.9, 26.6, 26.9, and 29.4°2θ±0.2°2θ.

[0270] A total of five different PXRD patterns were obtained for six different samples of gentisic acid salt of formula (1). The PXRD pattern of gentisic acid acetone solvate (sample SP221-GEN-P2) was different. TG-FTIR analysis of this solvate (sample SP221-GEN-P2) showed a mass loss of 5.0% by 150°C, and decomposition began at 220°C. The PXRD pattern of gentisic acid salt of formic acid solvate of formula (1) (sample SP221-GEN-P2) was also different. TG-FTIR analysis of this solvate (sample SP221-GEN-P4) showed a mass loss of 8.6% by 150°C (consistent with formic acid and water), and decomposition began at 220°C. Finally, the PXRD pattern of gentisic acid salt of dihydrate of formula (1) (sample SP221-GEN-P6) was also different from the other phases.

[0271] Example 6.7. Form A of oxalate of formula (1) Oxalic acid has the molecular formula C2H2O4 and a molecular mass of 90.04 g / mol. The pKa values ​​of its two acid groups are 1.27 and 4.27. First, oxalic acid was identified using the screen described above.

[0272] Sample SP221-OXA-P1 was prepared as follows: 236 mg of sample PP502-P1 and 45.45 mg of oxalic acid (Sigma Aldrich #75688) were added to 5.0 mL of acetone:water (95:5), and the mixture was heated to approximately 55°C. The compound did not dissolve; the mixture was allowed to cool to room temperature, stirred overnight, and the solid was filtered and air-dried at room temperature.

[0273] Sample SP221-OXA-P2 was prepared as follows: 468.2 mg of sample PP502-P1 and 90.9 mg of oxalic acid (Sigma Aldrich #75688) were added to 10.0 mL of 1-propanol and heated to 70°C. A nearly unmixable gel was obtained, to which 15.0 mL of 1-propanol and 1.0 mL of water were added. After stirring at room temperature for 3 days, the solid was filtered, air-dried briefly at room temperature, and then examined by PXRD.

[0274] Sample SP221-OXA-P3 was prepared as follows: 468 mg of sample PP502-P1 was dissolved in 10.0 mL of methanol under reflux, and 90 mg of oxalic acid dissolved in 2.0 mL of methanol was added. The material was cooled to room temperature, SP221-OXA-P2 was added as a seed, then about half of the suspension was taken out, stirred at room temperature, and then heated again to 50°C; after which all solids dissolved. The solution was cooled again to room temperature, stirred, and then a portion of the sample was filtered, air-dried at room temperature, and the solid was examined. This sample was designated SP221-OXA-P3A. 3.0 mL of water was added to the remaining half of the suspension. All solids dissolved immediately, and then the mixture was stirred under nitrogen purging at room temperature until all solvent was removed. To the dried residue, 2.0 mL of acetonitrile, 2.0 mL of ethanol, and 0.2 mL of water were added, and the mixture was stirred at room temperature for 2 days. A suspension was obtained, from which the solid was filtered and air-dried at room temperature. This sample was designated SP221-OXA-P3B.

[0275] Sample SP221-OXA-P4 was prepared as follows: 468 mg of sample PP502-P1 was dissolved in 10.0 mL of acetone and 1.0 mL of water under reflux, and 45 mg of oxalic acid (Sigma Aldrich #75688) dissolved in 1.0 mL of water was added. No crystallization was observed. Further, 46 mg of solid oxalic acid and 5.0 mL of acetone were added, and stirring was continued at room temperature with the container open. After stirring overnight, a thick paste was obtained. Complete dissolution was achieved by heating the mixture to 50°C, and a very thick suspension was obtained by cooling again to room temperature. A portion of the suspension was filtered, and the solid was air-dried at room temperature.

[0276] Sample SP221-OXA-P5 was prepared as follows: 470 mg of sample PP502-P1 and 90 mg of oxalic acid (Sigma Aldrich #75688) were combined in 10.0 mL of tetrahydrofuran and 1.0 mL of methanol, and heated under reflux to achieve solid dissolution. SP221-OXA-P2 was added as a seed, and the mixture was cooled to room temperature to obtain a thick paste. This paste was heated to 60°C-65°C and stirred for 2 days, after which the solid was filtered and air-dried at room temperature.

[0277] Sample SP221-OXA-P7 was prepared as follows: The remaining products (approximately 300 mg) obtained from experiments SP221-OXA-P4 and SP221-OXA-P5 were combined and suspended in 5.0 mL of water. The mixture was stirred at room temperature for 4 days. The suspension was filtered, and the solid was air-dried at room temperature for 24 hours.

[0278] Because oxalic acid lacks non-exchangeable hydrogen, oxalates 1 ¹H NMR spectroscopy was not performed. The CHNO water content of SP221-OXA-P1 was determined by elemental composition analysis, and the results are shown in Table 13. The molecular formula of the 1:1 salt of formula (1) and oxalic acid is C 28 H 25 The molecular weight of N7O6 is predicted to be 555.55 g / mol. The hydrate, which has the stoichiometric ratio of 2.5 moles of water to 1 mole of formula (1), has the molecular formula C28 H 30 N7O 8.5 It also has a molecular weight of 602.6 g / mol (water content 7.5%). The results shown for sample SP221-OXA-P7 are roughly consistent with the molecular formula of this "2.5-hydrate". The assumed water content of approximately 7.5% is based on the results from TG-FTIR, which revealed an 8.3% mass loss that is almost entirely due to water. The trihydrate is also possible, as it contains 8.9% water.

[0279] [Table 15]

[0280] The reflective PXRD pattern of the oxalate monohydrate of formula (1) is shown in Figure 22 (sample SP221-OXA-P7). This crystalline phase is referred to as morphology A (2.5-hydrate) of the oxalate of formula (1). The following peaks are characteristic of morphology A (2.5-hydrate) of the oxalate of formula (1): 5.5, 5.8, 7.4, 9.3, 11.0, 11.5, 12.7, 15.2, 16.5, 17.3, 18.5, 18.7, 19.1, 19.7, 20.2, 20.8, 22.0, 22.3, 23.3, 23.6, 24.8, 27.4, 28.6, 29.3, 29.6, 31.2, and 33.1°2θ±0.2°2θ.

[0281] Raman spectroscopy was performed using a sample (Sample SP221-OXA-P7) of morph A (2.5-hydrate) of the oxalate of formula (1). The Raman spectrum was obtained in the same manner as described for morph I in Example 1.2. The characteristic Raman peaks of morph A (2.5-hydrate) of the oxalate of formula (1) are observed as follows: 3073, 2992, 2950, ​​2922, 2247, 1671, 1612, 1584, 1552, 1504, 1469, 1440, 1336, 1311, 1273, 1235, 1191, 1162, 1095, 1012, 897, 718, 633, 409, 370, and 263 (Raman shift, cm). -1 ±2 -1 ).

[0282] IR spectroscopy was performed using a sample (Sample SP221-OXA-P7) of morph A (2.5-hydrate) of the oxalate of formula (1). The IR spectrum was obtained in the same manner as described for morph I in Example 1.2. The characteristic IR peaks of morph A (2.5-hydrate) of the oxalate of formula (1) were observed as follows: 3419, 2249, 1670, 1615, 1544, 1503, 1438, 1391, 1334, 1304, 1262, 1195, 1151, 1126, 1093, 1013, 894, 877, 823, 783, 765, 738, and 652 (IR frequencies, cm⁻¹). -1 ±4 -1 ).

[0283] A TG-FTIR thermogram was obtained for oxalate form A (2.5-hydrate) of formula (1) (sample SP221-OXA-P7). The observed mass loss is likely due to water and is between the predicted water content of the trihydrate (8.9%) and dihydrate (6.1%). Since the mass loss begins at approximately room temperature, the water is thought to be weakly bound. Differential scanning calorimetry of oxalate form A (2.5-hydrate) of formula (1) (sample SP221-OXA-P7) revealed an endothermic melting at 127°C and an enthalpy of melting of approximately 70 J / g. Temperature events observed in the DSC above 150°C are likely due to thermal decomposition.

[0284] DVS analysis of a sample (sample SP221-OXA-P7) of oxalate form A (2.5-hydrate) of formula (1) revealed that water was removed at 0% RH, and a reversible isothermal process for the uptake of approximately 6.5% of water was observed over the range of 0% to 100%. The PXRD of the sample recovered from the DVS sample pan showed the same pattern as before the start of the DVS test. At 50% RH, the water content was approximately 5.5%, and at 95% RH, the water content was approximately 6.5%. These results suggest that form A can form a stable dihydrate.

[0285] Two different PXRD patterns were obtained from other oxalate preparations (samples SP221-OXA-P3B and SP221-OXA-P4). Based on these PXRD patterns, these samples are considered to represent other crystalline forms of the oxalate of formula (1).

[0286] Example 6.8. Form A of the sulfate of formula (1) The sulfate of formula (1) (sample SP221-SO4-P1) was prepared as follows: 5.0 mL of a 0.1 M stock of the free base of formula (1) in acetone-water (sample SL20150415FB, 0.1 M) was mixed with 1 equivalent of sulfuric acid (27.8 μL) in the form of concentrated sulfuric acid. This mixture was heated to 50°C and then cooled to room temperature. Since crystallization did not occur, several mg of crystalline phosphate was added to the mixture as a seed. After stirring overnight at room temperature, a yellow / white suspension was obtained. The solid was filtered from this suspension and air-dried at room temperature.

[0287] Sample SP221-SO4-P3 was prepared by repeating the experiment used to produce SP221-SO4-P1, using sulfuric acid and a free base in a 1:1 ratio.

[0288] Sample SP221-SO4-P4 was prepared by dissolving 941 mg of PP502-P1 in 22 mL of acetone-water 10:1 at approximately 50°C, followed by the addition of 1 equivalent volume of concentrated sulfuric acid (112 μL). A suspension was formed at 50°C; the mixture was cooled to room temperature, stirred overnight, and then the solid was filtered and air-dried at room temperature. Approximately 880 mg of a slightly yellowish solid was obtained.

[0289] Sample SP221-SO4-P5 was prepared by adding 300 mg of SP221-SO4-P4 to 3.0 mL of acetonitrile and 0.3 mL of water. The suspension was stirred at room temperature for 1 day. The suspension was filtered, and the solid was air-dried at room temperature.

[0290] Sample SP221-SO4-P6 was prepared by adding 944 mg of formula (1) free base (sample PP502-P1) to 15.0 mL of acetone-water (9:1), followed by heating to reflux to achieve dissolution. Next, sulfuric acid (0.8 mL / 1 equivalent) was added in the form of a 2.5 M aqueous solution. SP221-SO4-P1 was added to the solution as a seed, and the mixture was cooled to room temperature while stirring overnight. A suspension was obtained, which was reheated to 50°C for about 3 hours, then cooled again to room temperature, stirred for 2 hours, and the solid was filtered and air-dried at room temperature. A yield of approximately 950 mg was obtained.

[0291] Products from experiment SP221-SO4-P4 1 ¹H NMR spectroscopy (spectrum not shown) was consistent with equation (1). CHONS elemental composition analysis was performed on samples SP221-SO4-P4 and SP221-SO4-P5, and the results are shown in Table 14. The expected summation molecular formula for one equivalent of solvent-free sulfate of equation (1) is C 26 H 25 The molecular weight is N7O6S, and it is 563.6 g / mol. The trihydrate equivalent of sulfate in formula (1) has the total molecular formula C 26 H 31 It is expected to have N7O9S and a molecular weight of 617.6 g / mol (water content 8.7%). The tetrahydrate equivalent sulfate of formula (1) has the total molecular formula C 26 H 33 N7O 10 It is expected to contain sulfur and have a molecular weight of 635.7 g / mol (water content 11.3%). The best fit for the experimental values ​​of sample SP221-SO4-P4 is for the tetrahydrate containing an excess amount of sulfuric acid corresponding to a molar ratio of approximately 1.25. The best fit for the experimental values ​​of sample SP221-SO4-P5 is found for the sulfuric acid tetrahydrate salt, in which case good agreement with the theoretically predicted hydrogen, oxygen, and sulfur content was observed, with slight discrepancies for carbon and nitrogen.

[0292] [Table 16]

[0293] Optical microscopy of sample SP221-SO4-P5 revealed a crystalline material primarily containing needle-shaped particles. The particles in sample SP221-SO4-P5 were considerably smaller than those in sample SP221-SO4-P6, exhibiting a maximum particle length of approximately 100 μm and a width of approximately 5–10 μm.

[0294] The reflective PXRD pattern of sample SP221-SO4-P6 is shown in Figure 23. This crystalline phase is referred to as morphology A of the sulfate of formula (1). The following peaks are characteristic of morphology A of the sulfate of formula (1): 4.6, 5.0, 8.0, 9.0, 9.8, 12.0, 12.7, 13.2, 14.6, 15.0, 15.6, 16.2, 17.5, 18.0, 19.8, 20.2, 21.9, 23.8, 24.4, 24.9, 25.7, 26.0, 27.2, 29.5, 30.4, 31.6, and 32.5°2θ±0.2°2θ. The PXRD patterns of three other samples (SP221-SO4-P1, SP221-SO4-P3, and SP221-SO4-P4) indicate that the same crystalline form of the sulfate was obtained in these other experiments as well.

[0295] Raman spectroscopy was performed using a sample of morphology A of the sulfate cocrystal of formula (1) (sample SP221-SO4-P4). The Raman spectrum was obtained in the same manner as described for morphology I in Example 1.2. The characteristic Raman peaks of morphology A of the sulfate of formula (1) are observed as follows: 3115, 2977, 2926, 2224, 1675, 1611, 1537, 1498, 1449, 1409, 1361, 1327, 1310, 1288, 1243, 1198, 1155, 1042, 1009, 978, 948, 906, 849, 771, 713, 652, 632, 464, 370, and 254 (Raman shift, cm). -1 ±2 -1 ).

[0296] IR spectroscopy was performed using a sample of morphology A of the sulfate of formula (1) (sample SP221-SO4-P4). The IR spectrum was obtained in the same manner as described for morphology I in Example 1.2. The characteristic IR peaks of morphology A of the sulfate of formula (1) were observed as follows: 3430, 3101, 3029, 2225, 1667, 1633, 1615, 1598, 1563, 1557, 1508, 1428, 1350, 1328, 1308, 1276, 1225, 1088, 1036, 1018, 925, 891, 848, 816, 783, 736, 723, 694, and 612 (IR frequencies, cm). -1 ±4 -1 ).

[0297] The TG-FTIR thermogram of the sample of form A of the sulfate of formula (1) (sample SP221-SO4-P4) showed an experimentally measured mass loss of 10.1% attributable to water. The mass loss began with heating and was completed by approximately 110°C using a heating rate of 10°C per minute. The DSC results of the sample of form A of the sulfate of formula (1) (sample SP221-SO4-P4) showed endothermic fusion with a peak at 118°C and an enthalpy of fusion of approximately 92 J / g. From the DSC, an endothermic fusion at 127°C with an enthalpy of fusion of approximately 70 J / g was revealed.

[0298] DVS analysis was performed on form A of the sulfate of formula (1) (sample SP221-SO4-P4). The DVS results showed that water was not completely removed at 0% RH after 5 hours. The initial water content of the given sulfate sample was determined by Karl Fischer titration, and the DVS isotherm varied from 2.5% to 12.5% ​​over the range of 0% RH to 100% RH. Water vapor absorption was found to be mostly reversible; at the end of the test, the water content was approximately the same as at the start of the measurement.

[0299] Example 7. Solubility according to pH Example 7.1. Solubility of free base The aqueous solubility of the free base of formula (1) was investigated according to pH. Experiments were conducted in HCl aqueous solutions and buffer solutions at pH 1, 3, 5, 6.8, 7.4, and 9. At low pH values ​​of 1 and 3, the solid was found to dissolve completely over the equilibrium time, and the pH of the system stabilized at approximately 3 in all experiments. The solubility in an HCl solution with a pH of approximately 1 was found to be at least 150 mg / mL. Table 15 shows the solubility of free base form I (PP502-P1) at various pH values ​​above 3.

[0300] [Table 17]

[0301] The data shows that the water solubility of formula (1) free base form I (PP502-P1) stabilizes at approximately pH 6.7 and approximately 50 μg / mL. Figure 24 shows the calculated pK values ​​varying from 2.2 (basic) to 6.1 (basic) to 11.5 (acidic). a The possible species of formula (1) based on the values ​​are shown. Therefore, the dual positively charged molecule is highly soluble, while the single positively charged and neutral forms are sparingly soluble. This highlights the challenge in successfully delivering formula (1) from the stomach to the higher pH environment of the duodenum.

[0302] Figure 25 shows the calculated equilibrium pH-solubility relationship for the free base form of equation (1), compared with experimental measurements at selected intervals. Above pH 6.7, the water solubility reaches a constant level of approximately 50 μg / mL, further highlighting the challenges regarding the delivery of equation (1).

[0303] Equation (1) pK of free base a Determine the value and use it to create the speciation plot shown in Figure 26, displaying the species present when equation (1) passes through the digestive tract. Sample pK aThe values ​​were determined using ultraviolet (UV) spectral analysis. First, the samples were titrated by high-speed UV triple titration under aqueous conditions, at concentrations of 31–19 μM and pH 2–12. Three pK values ​​with average values ​​of approximately 3.6, 5.8, and 12.0 were obtained. a The values ​​were determined. Subsequently, the samples were titrated in six titrations under aqueous conditions, at concentrations of 30–18 μM, over a total pH range of 1.5–12.5. From the collected spectroscopic analysis data, the three pK values ​​of equation (1) were obtained, with mean values ​​of 3.54±0.01, 5.77±0.01, and 12.12±0.03. a The value has been determined.

[0304] The logP of the free base (formula 1) was determined using potentiometric (pH measurement) methods. Samples were titrated in 0.15 M KCl ionic environment with octanol / water in various ratios at concentrations of 1.1–0.5 mM and pH of 1.9–12.1. Using the collected potentiometric data, the logP of neutral (2.03 ± 0.01) and cationic (-0.31 ± 0.06) species was formed.

[0305] Example 7.2. Salt solubility Multiple tests were conducted to determine the water solubility of maleate as a function of pH. Experiments were carried out in HCl aqueous solutions and buffer solutions with pH values ​​of 1, 3, 5, 6.8, 7.4, and 9. At low pH values ​​of 1 and 3, the solid was found to dissolve completely over the equilibrium time, and the pH of the system stabilized at approximately 3 in all experiments. Simultaneously, the water solubility of fumarate, maleate, phosphate, and L-tartrate in pure water is shown. The water solubility of fumarate, maleate, phosphate, and L-tartrate in pure water is listed in Table 16, where phosphate showed the highest total solubility after 24 hours. The solubility data of maleate as a function of pH in various aqueous media is listed in Table 17.

[0306] [Table 18]

[0307] [Table 19]

[0308] Example 8. Optimization of crystallization of free base form I of formula (1). Crystallization experiments were conducted to optimize the production of formula (1) free base I form I. The starting material for the crystallization experiments was recrystallized formula (1) form I. Additional crystallization of the free base from a crude oil sample was added to the tests. Powder X-ray diffraction (PXRD) or Raman spectroscopy was used to examine the crystal morphology, and TG-FTIR or Raman spectroscopy was used to examine the residual solvent content. 1 The obtained products were characterized by 1H NMR or both. Particle size was determined by recording polarized light microscope images.

[0309] Acetone, ethanol, and 1-propanol are the most promising solvents for the recrystallization of morph I. Since crystalline morph I has low solubility in many ICH class 3 solvents, the addition of useful co-solvent candidates was investigated. For example, ethanol, water, and acetic acid are solvents that can be used to increase the solubility of morph I, which is important in designing crystallization processes that maximize volumetric efficiency and yield.

[0310] Solubility data were collected for several solvent systems. The temperature dependence of morph I solubility was estimated for acetone, ethanol, ethanol-water 94:4 (v / v), and 1-propanol. Linear and nonlinear cooling profiles, as well as various temperature cycling designs, were applied to improve the crystallinity quality of morph I.

[0311] One method is based on the crystallization of maleates from crude oil, in which the crystalline maleate is neutralized with a base and the free base is extracted (presumably in amorphous form). The free base is then crystallized from acetone to obtain crystalline form I (anhydrous form). The resulting crystalline form I consistently contains a substantial amount of residual solvent, but the PXRD patterns of all generated samples are identical.

[0312] For example, a sample of recrystallized form I (sample PP502-P1) contains approximately 0.9% acetone, as measured by TG-FTIR. Mass loss was unobservable below approximately 200°C; however, further heating resulted in the release of acetone solvent along with the melting of the solid form (the melting point of the solid form is approximately 215°C). Prolonged drying at normal drying temperatures does not necessarily efficiently reduce the residual solvent. However, recrystallization from other solvents (e.g., ethanol) has been shown to remove the residual solvent from form I.

[0313] The crystallization of amorphous materials after conversion from salt to free base is fundamentally different from the recrystallization process of stable polymorphic forms such as morph I. Morph I is typically much less soluble than the amorphous form, as it is recovered after solvent extraction and evaporation; however, if the free base spontaneously crystallizes after the extraction step, its solubility may change. The specific difference in solubility between the amorphous form and the stable crystalline form is unknown, but it is in the range of 10 to 100.

[0314] In this method, it is preferable to mix 100 mg / mL of stable form I with an ICH class 3 solvent or solvent mixture for the purpose of recrystallization. The possible solvents were narrowed down by collecting detailed solubility data for the most common solvents. Equation (1) has been shown not to crystallize into different polymorphs; that is, no other non-solvated forms were obtained from crystallization experiments from saturated solutions.

[0315] Polymorphic studies revealed that morphology I is stable, and that this morphology is consistently obtained when water activity is below the acceptable limit for hydrate formation. The seeding process is recommended because it allows for superior control of the crystallization process to achieve more reproducible morphology, particle size, and shape distribution. The samples shown in Table 18 were used in this study.

[0316] [Table 20]

[0317] Example 8.1. Solubility by HPLC The solubility of recrystallization formula (1) form I was tested in various water-solvent mixtures and non-aqueous solvents. The complete solubility data obtained for these and other solvent systems is shown in Table 19 below.

[0318] [Table 21]

[0319] Acetone, ethanol, 96% ethanol, and 1-propanol were considered promising solvent systems. Solubility in 96% ethanol was fairly high at room temperature (approximately 22°C), suggesting that cooling to lower temperatures would be necessary to obtain good yields. Since crystallization at sub-zero temperatures leads to hydrate formation, cooling below 0°C was not investigated during polymorphism testing. The presence of water in high-temperature cosolvent mixtures can lead to a deterioration of formula (1) stability (indicated by discoloration to red), but water still serves as a useful cosolvent at low concentrations of approximately 0.5–4%.

[0320] Example 8.2. Multimax Solubility Test To demonstrate control over the crystallization of morphology I, we conducted metastable region width experiments using a Mettler-Toledo Multimax crystallization process optimization system equipped with a turbidimeter.

[0321] Acetone, ethanol, and ethanol-water (96:4) were selected as solvent systems. Three different concentrations were selected for acetone and ethanol; two different concentrations were selected for the ethanol-water (96:4) solvent system. The solubility data obtained from the multimax experiment were consistent with previously obtained data; however, the values ​​from the multimax experiment were slightly lower than the experimental values ​​due to the kinetic nature of the multimax experiment. Figure 27 shows the temperature dependence of the solubility of free base form I of formula (1) in ethanol and acetone.

[0322] Given that the data points for 1-propanol clearly overlap well with the curve fit of the data points for ethanol, ethanol and 1-propanol exhibit similar solubility properties. Furthermore, since the boiling point of 1-propanol is 97°C compared to the boiling point of ethanol (78°C), 1-propanol is considered a viable substitute for ethanol, resulting in a substantial increase in volumetric efficiency and yield.

[0323] Without seed addition, crystallization experiments involving cooling of supersaturated solutions did not occur in any of the tested solvents. As a result, the metastable region in all tested solvents is very broad. Therefore, seed addition is essential to control the crystallization process and should be applied immediately after supersaturation is achieved.

[0324] Example 9. Comparison of elution rates and exposure of free base form I and free base form II in dogs. The intrinsic elution rates (IDRs) were measured for forms I and II of the free base of equation (1). IDRs were measured using an elution apparatus equipped with a paddle-over fixed disk, and concentrations were determined by liquid chromatography against a standard. The results, normalized by the y-intercept, are shown in Figure 28, along with the displayed slope and regression coefficient. Form I was found at 6.8 mg / cm³ in artificial gastric juice (SGF) (pH 1.2). 2 IDR per minute, and 0.44 mg / cm³ in HCl / NaCl buffer at pH 2.5. 2 It has an IDR of / min. Form II is 5.4 mg / cm³ in SGF. 2 IDR per minute, and 0.35 mg / cm³ in HCl / NaCl buffer at pH 2.5. 2 It has an IDR of / min. Therefore, form I shows a 26% increase in IDR compared to form II under both conditions, which results in a significantly higher elution rate and is advantageous.

[0325] In nine fasted beagle dogs, plasma exposure to free base forms I and II of formula (1) was compared after a single oral administration of either form at 6 mg / kg using batches with similar particle size distributions. The experiment was conducted over five weekly periods, with form II being the final phase. The plasma area under the drug concentration-time curve (AUC) shown in Figure 29 represents the exposure to the drug after administration of each preparation of formula (1) and is expressed in ng*h / L. Form II showed a lower AUC than form I in all dogs. Form II also showed a lower C than form I in all dogs. max (Maximum concentration) is shown. It was concluded that form I presented a higher exposure than form II in beagle dogs. When delivered to dogs by oral capsule, excellent in vitro-in vivo correlations were observed between the dissolution rates of forms I and II and the performance of each form in equation (1). The superior performance of form I in this canine study suggests that it may be more convenient to administer than form II in humans.

[0326] Example 10. Overcoming the effects of gastric acid inhibitors with a formulation of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide. Acid suppressants such as omeprazole may limit exposure to the free base of formula (1) in mammals due to the pH solubility profile of formula (1) described above. This is an important issue in the treatment of patients with cancer, inflammatory diseases, immune diseases, and autoimmune diseases, as acid suppressants are commonly administered concurrently due to gastric irritation symptoms that often accompany these conditions. Acid suppressants are most commonly prescribed in North America and Western Europe. Of the recently approved oral cancer drugs, >50% have pH-dependent solubility, so drug interactions with acid suppressants are possible. In cancer patients, it is estimated that 20-33% of all patients use some form of acid suppressant. In certain cancers, such as pancreatic cancer or gastrointestinal cancers, the use of acid suppressants is high, at 60-80% of patients. Smelick, et al., Mol. Pharmaceutics 2013, 10, 4055-4062.

[0327] In the case of weakly basic drugs, concerns about potential drug interactions with gastric acid inhibitors have led to the development of risk assessment plans and drug interaction test designs for novel drugs exhibiting pH-dependent solubility and dissolution. Smelick, et al., Mol. Pharmaceutics 2013, 10, 4055-4062. Examples of gastric acid inhibitors include proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, rabeprazole, and iraprazole; H2 receptor antagonists, such as cimetidine, ranitidine, and famotidine; and antacids, such as bicarbonates, carbonates, and hydroxides of aluminum, calcium, magnesium, potassium, and sodium. Alternatively, mixtures of antacids and drugs that target the gastric juice secretion mechanism may be used as prescribed or unprescribed gastric acid inhibitors. Any other gastric acid inhibitors known in the art may be used. In some cases, the effects of acid-suppressing drugs are temporary and depend on the presence of the drug in the stomach. In other cases, the effects of acid-suppressing drugs are significant throughout the treatment period and can consistently raise the gastric pH to levels above pH 4.

[0328] The terms hypochlorhydria and achlorhydria refer to conditions in which gastric endocrine secretion of hydrochloric acid is below normal or severely reduced to the point of absence. The stomach's natural pH decreases due to acid secretion in response to food stimuli; in certain conditions, the ability of the gastric proton pump to secrete acid is impaired. Infection with H. pylori is associated with impaired gastric acid secretion (hypochlorhydria or achlorhydria). Other conditions, including those involving destruction or deletion of parietal cells or alteration of signaling to parietal cells, can cause hypochlorhydria or achlorhydria. These conditions can also occur with long-term use of proton pump inhibitors or H2 receptor antagonists. As a diagnostic aid, if necessary, an in-situ pH probe may be used to monitor the patient's gastric pH throughout the day (after meals).

[0329] The elution of form 1 of formula (1) into aqueous media such as gastric juice is pH-dependent (see, for example, Figures 30 and 31, and discussed in detail in Example 11). Therefore, the bioavailability of formula (1) can be modified by factors that improve its elution. By testing alternative forms of formula (1) and the acidification of formulations of form 1 of formula (1) in dogs treated with omeprazole 10 mg / day, the extent to which the alternative forms of formula (1) can neutralize the effects of gastric acid inhibitors was evaluated.

[0330] To minimize intra-animal and inter-animal variability, dogs were treated with formula (1) 100 mg capsules in several related studies using the same animals and a strict dosing schedule. To standardize the amount dissolved by each dose, all dogs were given 35 mL of distilled H2O via a feeding needle. On drug-free days, dogs were conditioned to ingest a placebo capsule and drink water; the diet was also adjusted to reduce variability related to gastric acid secretion in response to food presentation and consumption. The conditioning regimen was carried out continuously for at least 6 months, and the same 12 dogs were used in all studies described below.

[0331] Study 2219-057 established an absorption standard without any dissolving components associated with the solid form, using 100 mg of formula (1) in liquid capsules (hydroxy-β-cyclodextrin / citrate, 2 doses). Study 2219-059 used formula (1) with formulation F-1, and Study 2219-061 used formula (1) alone with formulation F-1 or after pretreatment of dogs with omeprazole, followed by testing the salt form of formula (1) in formulation F-1 and the acidic formulation of form I of formula (1) (referred to as FA-3) (see Example 11 below for formulation preparation). Conditioned dogs were administered 100 mg of formula (1) during a continuous administration period with a wash-out period of 4 to 7 days. Liquid capsules or solid capsules containing form I of formula (1) were administered; for comparison, clinical formulations of the Avicel blend or hand-filled capsules were administered. Following these initial trial periods, dogs were treated with 10 mg / day of omeprazole throughout the remainder of the trial. Four days after omeprazole treatment, 100 mg of formula (1) form I was administered as a clinical formulation, a formulation containing an acidulant, or a capsule containing 100 mg of the maleate, phosphate, fumarate, or tartrate of formula (1), and plasma concentrations of formula (1) were measured at multiple time points from 0 to 12 hours.

[0332] Study 2219-061 used Form I of Formula (1) recrystallized from ethanol as described herein, as well as the maleate, phosphate, fumarate, and tartrate forms of Formula (1) as described herein. Following the collection of pharmacokinetic data after a single dose of 100 mg in the F-2 formulation, omeprazole treatment (10 mg / day) was initiated as part of a conditioning regimen. The remaining study stages were carried out in omeprazole-treated dogs. Four days after omeprazole treatment, the dogs were administered the empirical Formula (1) drug form or formulation in addition to the continuing daily omeprazole dose. The salt form was administered to equal 100 mg of the free base of Formula (1). For the administration of the salt form, the F-1 formulation was used after correction of counterions and water content. The prototype acid formulation (FA-3) used both fumarate and alginate as granular extragranular mixtures together with the granular Formula (1) in formulation F-2.

[0333] Figure 32 shows AUC and C for each test period. max and T max The changes are shown, and each test or test period is shown sequentially. An initial test using a liquid formulation in a capsule delivering 100 mg of formula (1) in solution was designed to show exposure after this administration (i.e., unrestricted dissolution) and to characterize variability in dogs when dissolution-related dispersion is removed. After administration of the fully dissolved formulation (1) in a liquid capsule to conditioned dogs, high mean exposure and low intra-animal and inter-animal variability were observed, revealing that dissolution of form I of formula (1) plays a role in limiting oral absorption, and that optimal dissolution enhances absorption.

[0334] The remaining variance in pharmacokinetic parameters observed after administration of liquid capsules is likely due to intrinsic factors that vary among inbred Beer dogs. This effect has also been demonstrated with 25 mg liquid capsules and form I capsules of formula (1) using a dose-graded version of F-1. Inter-animal variability after administration of liquid capsules or the corresponding solid capsules containing form I of formula (1) at a fixed dose may be due to slight variations in the mg / kg dose of the test substance, as well as other intrinsic factors such as those affecting drug metabolism and excretion. Adding AUS-weighted normalization to the solid form experiments using this group of dogs would further limit inter-animal variability at each dosing interval. For statistical analysis of the experimental results, dose-adjusted AUS and C max The values ​​can be compared with extreme accuracy.

[0335] To counteract the effects of omeprazole, after administration of the salt form of formula (1) or form I in an acidic formulation, most dogs showed T max This increased. During these test periods (Figure 32), the average C was lower. maxWhile there was a tendency toward this, this pattern was not observed in all periods or in all dogs. A similar tendency has been observed in dogs and humans when form I of formula (1) is administered with food. In particular, the mean AUC levels of dogs treated with the salt form of formula (1) or the acidic formulation of formula (1) were similar to the AUC observed in dogs after administration of form I without omeprazole. Compared to form I capsules administered to dogs conditioned without omeprazole, there was a tendency for reduced inter-animal variability when these experimental dosage forms were administered. Thus, exposure after oral administration of formula (1) in salt form increases in the presence of omeprazole, and exposure variability decreases in both omeprazole-treated dogs and conditioned dogs without omeprazole. The prototype acidic formulation (FA-3) of form (1) has a similar effect.

[0336] The observed effects of alternative salt forms of formula (1) and acidulants on oral absorption in omeprazole-treated dogs are novel and surprising. The pH dependence of the solubility of formula (1) is related to the stability of acidic and basic species in aqueous solution, as well as the free energy of solubility during the phase transition. In vitro-in vivo interactions revealed that the solubility limit is associated with the low absorption of form (1) in omeprazole-treated dogs (or dogs treated with other acid-suppressants such as famotidine, calcium carbonate, or other therapeutic agents listed above). In a human phase 1, single-center, open-label, fixed-order, 2-period, 3-part study to evaluate the unilateral interaction of calcium carbonate, omeprazole, or rifampine with formula (1) in healthy adult subjects, treatment of subjects with an acid-suppressant before administration of form I of formula (1) resulted in a significant reduction in exposure. The role of pH in the solubility of formula (1) has been demonstrated in vitro, and the solubility limit for absorption has been hypothesized in vivo. Adding acidulants to the formulation, or administering a completely dissolved form of formula (1), are methods that promote dissolution by lowering the pH in the microenvironment, or methods that hinder the dissolution step for a proof-of-concept in vivo model. In contrast, while administration of alternative salt forms of formula (1) was expected to have little effect on gastric pH, the solid form of formula (1) was revealed to have a significant and unexpected effect on oral absorption characteristics in mammals.

[0337] Figure 33 shows dose-normalized AUC and C max This is compared with another average of repeated exposures in dogs for liquid capsules (n=2 per dog) and F-2 (n=2 per dog). The results again show that exposure to formula (1) can be restored in the presence of omeprazole when using the FA-3 acidulant formulation of the present invention and the salt of the present invention.

[0338] These studies demonstrate that good exposure can be achieved in omeprazole-treated dogs by either formulating form I of formula (1) or creating a novel salt form of formula (1). The exposure obtained using formulation FA-3 containing an acidulant and salts containing omeprazole is remarkably similar to the exposure observed without omeprazole, suggesting that other salts and acidulants, as well as other gastric acid inhibitors, will function well. The solubility-mediated absorption observed in human subjects can be modeled in dogs. Furthermore, in vitro solubility assays are also excellent predictors of characteristic in vivo absorption for various encapsulated formulations of form I of formula (1).

[0339] A separate PK compareability study (2219-060) was performed to characterize exposure from acetone-recrystallized and ethanol-recrystallized drugs in capsules manufactured together with the F-2 formulation. These data further characterize inter- and intra-canine variability related to the absorption of formula (1) in conditioned dogs not treated with omeprazole, indicating that the ethanol-recrystallized drug is suitable for late-phase clinical development.

[0340] Example 11. Formulation of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide Formulations of formula (1) in solid form (salt and free base form I) were prepared as shown in Table 20.

[0341] [Table 22]

[0342] Another formulation was prepared using the following procedure, as shown in Table 21: Formula (1) dried granules were blended with an exogenous granular acidulant. The blend was then filled into hard gelatin capsules (for FA-1, FA-2, FA-4, and FA-5) or compressed into tablets (for FA-4).

[0343] [Table 23]

[0344] Figures 30 and 31 show the results of dissolution experiments using representative formulations listed in Table 21 at two different pH values. The dissolution system was a US Pharmacopeia (US Pharmacopeia) Type II apparatus equipped with a paddle (50 rpm) and a 900 mL container equilibrated at 37°C. Samples were acquired at intervals using a cannula of a set depth through an in-line filter and analyzed by reverse-phase HPLC with UV spectroscopy detection. Capsules were tested in a sinker, and tablets were tested directly.

[0345] Another formulation was prepared according to Table 22. Granular endogenous formulations can be prepared by the following procedure: The material is pre-blended in a 250 mL V-blender for 300 rpm. After blending, a lubricant is added and blending is performed for a further 100 rpm. The blend is roller-compressed in a TF-mini-roller compactor and then fed into a vibrating granulator equipped with a 20-mesh screen. Granular exogenous formulations can be prepared by the following procedure: When adding granular exogenous acids or polymers, these are added to the pre-blended or unblended granular exogenous material, and then the granular form is added to a 250 mL V-blender and blended for 300 rpm. After blending, a lubricant is added and blending is performed for a further 100 rpm. Next, the lubricated granules are filled into size 1 rigid gelatin capsules using an injection disc or a semi-automatic or automatic capsule filling machine equipped with a dosator. Alternatively, the material may be compressed using a tablet press or mold.

[0346] [Table 24]

[0347] In addition to the formulations described in Tables 21 and 22, other acidulants may be used as described herein, including fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, racemic tartaric acid, ascorbic acid, isoascorbic acid (also known as erythorbic acid and D-aloascorbic acid), alginic acid, Protacid F120NM, Protacid AR1112 (also known as Kelacid NF), Carbopol 971P (carboxypolymethylene), and Carbomer 941 (polyacrylic acid).

[0348] Further non-limiting formulations are listed in Table 23, which may be prepared as described above or by methods known in the art. These formulations, and all of the formulations described above, may be prepared as capsules or tablets with or without a coating.

[0349] [Table 25]

[0350] Example 12. Comparison of processability of free base form I and free base form II Both forms I and II of the free base of formula (1) were processed using the same method and composition as formulation F-2 (as described above), under similar parameters. Formula (1) was blended with the above components, a lubricant was added, and then the mixture was roller-compressed in a top-feed roller compactor in separate granulation steps. The granules were then lubricated. The granules obtained from forms I and II were characterized for tap density and loose density. Form II granules showed a general tendency toward poor flow and poor homogeneity.

[0351] Flowability typically affects the handling ease of pharmaceuticals during processing. Very poor flowability can lead to handling and processing problems during blending, granulation, and filling / compression processes. Flowability based on interparticle interactions can be measured using the Hausner ratio or compressibility index by measuring the looseness density and tap density of the powder. These values ​​are specified in the United States Pharmacopeia Monograph (USP). <1174> Calculation and ranking are performed as outlined in monographs Hausner, Int. J. Powder Metall. 1967, 3, 7-13; Carr, Chem. Eng. 1965, 72, 163-168. United States Pharmacopeia Monograph (USP) <1174> The following categories are defined for liquidity: good (compressibility index ≤ 10%, Hausner ratio 1.00-1.11); good (compressibility index 11-15%, Hausner ratio 1.12-1.18); average (compressibility index 16-20%, Hausner ratio 1.19-1.25); acceptable (compressibility index 21-25%, Hausner ratio 1.26-1.24); poor (compressibility index 26-31%, Hausner ratio 1.35-1.45); very poor (compressibility index 32-37%, Hausner ratio 1.46-1.59); and extremely poor (compressibility index > 38%, Hausner ratio > 1.60).

[0352] The Hausner ratio and compressibility index of morphology I granules were 1.33 and 25%, respectively, while morphology II granules exhibited a Hausner ratio of 1.47 and a compressibility index of 32%. Therefore, these results indicate that morphology I granules have acceptable flow, while morphology II granules have poor to very poor flow.

[0353] Next, the blend was filled into capsules using an automated capsule filling machine operating on the injection disc principle. After filling to the target weight, the capsules were checked for weight uniformity, and any capsules with excess or insufficient weight were discarded. Form I capsules had an acceptable capsule yield of 90-100%, while Form II-containing capsules had a yield of only 40-60%.

[0354] Regarding hard gelatin capsules: United States Pharmacopeia Monograph (USP) <905> When content uniformity is measured as defined by [the relevant standard], capsules containing form II have an acceptance value greater than 1.5, while capsules containing form I have an acceptance value less than 1.5.

[0355] The results are summarized in Table 24.

[0356] [Table 26]

Claims

1. Crystals of form III of (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide, characterized by an X-ray powder diffraction pattern containing peaks at 7.6°±0.2°2θ, 8.5°±0.2°2θ, 12.6°±0.2°2θ, 12.8°±0.2°2θ, 14.6°±0.2°2θ, 16.8°±0.2°2θ, and 23.2°±0.2°2θ.

2. The crystal according to claim 1, wherein the X-ray powder diffraction pattern further includes one or more peaks at 10.4°±0.2°2θ, 17.9°±0.2°2θ, 21.3°±0.2°2θ, 21.7°±0.2°2θ, 23.1°±0.2°2θ, 24.2°±0.2°2θ, 25.2°±0.2°2θ, and 27.0°±0.2°2θ.

3. The crystal according to claim 1, wherein the X-ray powder diffraction pattern corresponds to a typical X-ray powder diffraction pattern shown in Figure 6.

4. The crystal according to claim 1, wherein the peak is present when the X-ray powder diffraction is performed using Cu-Kα rays.

5. The crystal according to claim 1, wherein the crystal contains water in a stoichiometric ratio to (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide that is approximately equivalent to that of the dihydrate.

6. The crystal has peaks at 1668 cm －１ , －１ , －１ , －１ , －１ , －１ , －１ , －１ , －１ , －１ , －１ , －１ , －１ ±2 cm －１ ,1609 cm －１ ±2 cm －１ ,1562 cm －１ ±2 cm －１ ,1535 cm －１ ±2 cm －１ ,1494 cm －１ ±2 cm －１ ,1450 cm －１ ±2 cm －１ ,1350 cm －１ ±2 cm<00000?14]],1324 cm －１ ±2 cm －１ ,1306 cm －１ ±2 cm －１ [[ID=?36]],1264 cm －１ ±2 cm －１ ,1245 cm －１ ±2 cm －１ ,1190 cm －１ ±2 cm －１ ,997 cm －１ ±2 cm[[ID=?51]] －１ ]],and 272 cm －１ ±2 cm －１ The crystal according to claim 1, further characterized by a Raman spectrum including peaks at these positions. It should be noted that there is a possible error in the original text where some tags seem to be repeated with question marks added in the translation for those parts. You may want to double-check the original text for accuracy.

7. The crystal according to claim 6, wherein the aforementioned Raman spectrum corresponds to a typical Raman spectrum shown in Figure 7.

8. The aforementioned crystal is 3446 cm². －１ ±4cm －１ , 2248cm －１ ±4cm －１ , 1667cm －１ ±4cm －１ 1592cm －１ ±4cm －１ , 1531cm －１ ±4cm －１ , 1504cm －１ ±4cm －１ 1428cm －１ ±4cm －１ 1349cm －１ ±4cm －１ , 1305cm －１ ±4cm －１ , 1243cm －１ ±4cm －１ , 1189cm －１ ±4cm －１ 1158cm －１ ±4cm －１ , 1089cm －１ ±4cm －１ , 1001cm －１ ±4cm －１ , 896cm －１ ±4cm －１ 862cm －１ ±4cm －１ , 829cm －１ ±4cm －１ , 780cm －１ ±4cm －１ 759cm －１ ±4cm －１ 736cm －１ ±4cm －１ , and 699 cm －１ ±4cm －１ The crystal according to claim 1, further characterized by an infrared spectrum containing one or more peaks.

9. The crystal according to claim 1, further characterized by the following: a. 1668 cm －１ ±2 cm －１ 、1609 cm －１ ±2 cm －１ 、1562 cm －１ ±2 cm －１ 、1535 cm －１ ±2 cm －１ 、1494 cm －１ ±2 cm －１ 、1450 cm －１ ±2 cm －１ 、1350 cm －１ ±2 cm －１ 、1324 cm －１ ±2 cm －１ 、1306 cm －１ ±2 cm －１ 、1264 cm －１ ±2 cm －１ 、1245 cm －１ ±2 cm －１ 、1190 cm －１ ±2 cm －１ 、997 cm －１ ±2 cm －１ 、and 272 cm －１ ±2 cm －１ with peaks included in a Raman spectrum; and b. 3446 cm －１ ±4cm －１ , 2248cm －１ ±4cm －１ , 1667cm －１ ±4cm －１ 1592cm －１ ±4cm －１ , 1531cm －１ ±4cm －１ , 1504cm －１ ±4cm －１ 1428cm －１ ±4cm －１ 1349cm －１ ±4cm －１ , 1305cm －１ ±4cm －１ , 1243cm －１ ±4cm －１ , 1189cm －１ ±4cm －１ 1158cm －１ ±4cm －１ , 1089cm －１ ±4cm －１ , 1001cm －１ ±4cm －１ , 896cm －１ ±4cm －１ 862cm －１ ±4cm －１ , 829cm －１ ±4cm －１ , 780cm －１ ±4cm －１ 759cm －１ ±4cm －１ 736cm －１ ±4cm －１ , and 699 cm －１ ±4cm －１ Infrared spectrum containing a peak.

10. The crystal according to claim 12, wherein the crystal contains water in a stoichiometric ratio to (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide that is approximately equivalent to that of the dihydrate.

11. The crystal according to claim 2, further characterized by the following: a. 1668 cm －１ ±2cm －１ 1609cm －１ ±2cm －１ 1562cm －１ ±2cm －１ , 1535cm －１ ±2cm －１ 1494cm －１ ±2cm －１ , 1450cm －１ ±2cm －１ , 1350cm －１ ±2cm －１ , 1324cm －１ ±2cm －１ , 1306cm －１ ±2cm －１ , 1264cm －１ ±2cm －１ , 1245cm －１ ±2cm －１ , 1190cm －１ ±2cm －１ , 997cm －１ ±2cm －１ , and 272 cm －１ ±2cm －１ Raman spectrum containing a peak; and b. 3446 cm －１ ±4cm －１ , 2248cm －１ ±4cm －１ , 1667cm －１ ±4cm －１ 1592cm －１ ±4cm －１ , 1531cm －１ ±4cm －１ , 1504cm －１ ±4cm －１ 1428cm －１ ±4cm －１ 1349cm －１ ±4cm －１ , 1305cm －１ ±4cm －１ , 1243cm －１ ±4cm －１ , 1189cm －１ ±4cm －１ 1158cm －１ ±4cm －１ , 1089cm －１ ±4cm －１ , 1001cm －１ ±4cm －１ , 896cm －１ ±4cm －１ 862cm －１ ±4cm －１ , 829cm －１ ±4cm －１ , 780cm －１ ±4cm －１ 759cm －１ ±4cm －１ 736cm －１ ±4cm －１ , and 699 cm －１ ±4cm －１ Infrared spectrum containing a peak.

12. The crystal according to claim 14, wherein the DSC thermogram further includes an exothermic peak at 147°C.

13. The crystal according to claim 15, wherein the crystal contains water in a stoichiometric ratio to (S)-4-(8-amino-3-(1-(buto-2-inoyl)pyrrolidine-2-yl)imidazo[1,5-a]pyrazine-1-yl)-N-(pyridine-2-yl)benzamide that is approximately equivalent to that of the dihydrate.

14. A pharmaceutical composition comprising the crystal described in claim 1 and at least one pharmaceutically acceptable excipient.

15. A pharmaceutical composition according to claim 17 for use in inhibiting Bruton's tyrosine kinase activity in humans, A pharmaceutical composition in which the human being suffers from an overproliferative disorder selected from the group consisting of chronic lymphocytic leukemia, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Waldenström macroglobulinemia.

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