Crystalline form, composition and use of PCSK9 inhibitors

Abstract

The present disclosure provides crystalline forms of compounds of formula (I), as well as pharmaceutically acceptable compositions thereof, methods for their preparation, and their use in methods for treating hypercholesterolemia and other conditions associated with PCSK9 activity (e.g., atherosclerosis, atherosclerotic cardiovascular disease, peripheral artery disease, cerebrovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular and cardiometabolic diseases).

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 371,690, filed on 17 August 2022, and U.S. Provisional Application No. 63 / 384,298, filed on 18 November 2022. The contents of each application are incorporated herein by reference in their entirety.

[0002] Provided in this specification is Formula I: [ka] [In the ceremony, A - [This is a pharmaceutically acceptable anion.] The crystalline forms of the compounds represented by, as well as pharmaceutically acceptable compositions thereof, methods for preparing them, and their use in methods for treating hypercholesterolemia and other conditions associated with PCSK9 activity (e.g., atherosclerosis, atherosclerotic cardiovascular disease, peripheral artery disease, cerebrovascular disease, coronary heart disease, metabolic syndromes, acute coronary syndromes, or related cardiovascular and cardiometabolic conditions). [Background technology]

[0003] When a compound is used for pharmaceutical purposes, its solid state is important. The physical properties of a compound can change from one solid state to another, and this can affect the suitability of the form for pharmaceutical use. For example, certain crystalline solid compounds can overcome the drawbacks of other solid states of the compound (e.g., instability and / or reduced purity). [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] Provided in this specification is Formula I: [ka] [In the ceremony, A - [This is a pharmaceutically acceptable anion.] This is a crystalline form of the compound represented by formula I. These crystalline forms of the compound represented by formula I enable efficient isolation and purification, thereby avoiding the need for costly operations such as chromatography and lyophilization. Furthermore, these crystalline forms of the compound represented by formula I are advantageous in that they possess high purity, high stability, and low hygroscopicity, making them suitable for use in pharmaceutical formulations. [Means for solving the problem]

[0005] This disclosure is based on formula I: [ka] [In the ceremony, A - [This is a pharmaceutically acceptable anion.] The present invention relates to the crystalline form of a compound (which has activity as a PCSK9 inhibitor), a composition containing the crystalline form, a method for producing the crystalline form, and a method for using the crystalline form. [Brief explanation of the drawing]

[0006] [Figure 1] Figure 1 shows the X-ray powder diffraction pattern of amorphous acetate 1, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against the diffraction angle of 2 theta (2θ) (degrees). [Figure 2] Figure 2 shows the X-ray powder diffraction pattern of acetate 2, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 3] Figure 3 shows the X-ray powder diffraction pattern of acetate 3, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 4] Figure 4 shows the X-ray powder diffraction pattern of acetate 4, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 5] Figure 5 shows the X-ray powder diffraction pattern of acetate 5, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 6] Figure 6 shows the X-ray powder diffraction pattern of acetate 6, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 7] Figure 7 shows the X-ray powder diffraction pattern of amorphous cap 1, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against the diffraction angle 2 theta (2θ) (degrees). [Figure 8] Figure 8 shows the X-ray powder diffraction pattern of caprate 2, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 9] Figure 9 shows the X-ray powder diffraction pattern of caprate 3, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 10] Figure 10 shows the X-ray powder diffraction pattern of caprate 4, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 11] Figure 11 shows the X-ray powder diffraction pattern of caprate 5, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 12] Figure 12 shows the X-ray powder diffraction pattern of couplate 6, indicating 2θ in the range of 2 to 40. The graph plots the peak intensity defined by the number of counts per second against the diffraction angle 2 theta (2θ) (degrees). [Figure 13] Figure 13 shows the X-ray powder diffraction pattern of couplate 7, indicating 2θ in the range of 2 to 40. The graph plots the peak intensity defined by the number of counts per second against the diffraction angle 2 theta (2θ) (degrees). [Figure 14] Figure 14 shows the X-ray powder diffraction pattern of couplate 8, indicating 2θ in the range of 2 to 40. The graph plots the peak intensity defined by the number of counts per second against the diffraction angle 2 theta (2θ) (degrees). [Figure 15] Figure 15 shows the X-ray powder diffraction pattern of couplate 9, indicating 2θ in the range of 2 to 40. The graph plots the peak intensity defined by the number of counts per second against the diffraction angle 2 theta (2θ) (degrees). [Figure 16] Figure 16 shows the X-ray powder diffraction pattern of couplate 10, indicating 2θ in the range of 2 to 40. The graph plots the peak intensity defined by the number of counts per second against the diffraction angle 2 theta (2θ) (degrees). [Figure 17] Figure 17 shows the X-ray powder diffraction pattern of couplate 11, indicating 2θ in the range of 2 to 40. The graph plots the peak intensity defined by the number of counts per second against the diffraction angle 2 theta (2θ) (degrees). [Figure 18] Figure 18 shows the X-ray powder diffraction pattern of couplate 12, indicating 2θ in the range of 2 to 40. The graph plots the peak intensity defined by the number of counts per second against the diffraction angle 2 theta (2θ) (degrees). [Figure 19] Figure 19 shows the X-ray powder diffraction pattern of couplate 13, indicating 2θ in the range of 2 to 40. The graph plots the peak intensity defined by the number of counts per second against the diffraction angle 2 theta (2θ) (degrees). [Figure 20] Figure 20 shows the X-ray powder diffraction pattern of caprate 14, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 21] Figure 21 shows the X-ray powder diffraction pattern of D-lactate 1 for 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 22] Figure 22 shows the X-ray powder diffraction pattern of D-lactate 2 for 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 23] Figure 23 shows the X-ray powder diffraction pattern of succinate 1, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 24] Figure 24 shows the X-ray powder diffraction pattern of succinate 2, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 25] Figure 25 shows the X-ray powder diffraction pattern of L-Taltrate 1, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 26] Figure 26 shows the X-ray powder diffraction pattern of L-Taltrate 2, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 27]Figure 27 shows the X-ray powder diffraction pattern of sulfate 1, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 28] Figure 28 shows the X-ray powder diffraction pattern of sulfate 2, with 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined by the number of counts per second, against a diffraction angle of 2 theta (2θ) (degrees). [Figure 29A] Figure 29A shows the percentage of total impurities (%) for compound A (API Chloride Amorphous; amorphous form of chloride salt), acetate 1, caprate 1, caprate 3, and caprate 7, over a period of 3 months. [Figure 29B] Figure 29B shows the percentage of total impurities for Acetate 1 (amorphous acetate), Caprate 1 (amorphous caprine), Caprate 3, and Caprate 7, over a 3-month period. [Figure 30A] Figure 30A shows the adsorption / desorption cycle of acetate 4, in the range of relative humidity (RH) 5-55%. [Figure 30B] Figure 30B shows the X-ray powder diffraction patterns of acetate 4 before and after the adsorption / desorption cycle shown in Figure 30A. [Figure 31A] Figure 31A shows the adsorption / desorption cycle of acetate 4, with RH ranging from 5% to 95%. [Figure 31B] Figure 31B shows the X-ray powder diffraction patterns of acetate 4 before and after the adsorption / desorption cycle shown in Figure 31A. [Figure 32A] Figure 32A shows the adsorption / desorption cycle of caplate 5, with RH ranging from 5% to 65%. [Figure 32B] Figure 32B shows the X-ray powder diffraction patterns of caplate 5 before and after the adsorption / desorption cycle shown in Figure 32A. [Figure 33A] Figure 33A shows the adsorption / desorption cycle of caplate 5, with RH ranging from 5% to 95%. [Figure 33B] Figure 33B shows the X-ray powder diffraction patterns of caplate 5 before and after the adsorption / desorption cycle shown in Figure 33A. [Figure 34A] Figure 34A shows the adsorption / desorption cycle of caplate 3, with RH ranging from 5% to 85%. [Figure 34B] Figure 34B shows the X-ray powder diffraction patterns of caplate 3 before and after the adsorption / desorption cycle shown in Figure 34A. [Figure 35A] Figure 35A shows the adsorption / desorption cycle of water-free cap plate 3, with RH ranging from 5% to 85%. [Figure 35B] Figure 35B shows the X-ray powder diffraction patterns of water-free cap plate 3 before and after the adsorption / desorption cycle shown in Figure 35A. [Figure 36A] Figure 36A shows the solid-state C-13 CPMAS NMR spectrum for capette 3. [Figure 36B] Figure 36B shows the solid-state C-13 CPMAS NMR spectrum for caprate 5. [Figure 36C] Figure 36C shows the solid-state C-13 CPMAS NMR spectrum for capette 8. [Figure 37] Figure 37 shows selected spectral regions from the CPMAS spectra of caprate C-13 exhibiting shape-recognition features. From top to bottom, the spectral regions for caprate 8, caprate 5, and caprate 3 are shown, respectively. The associated isotropic shifts are shown in ppm (parts per million). [Modes for carrying out the invention]

[0007] Proprotein convertase subtilisin-kexin type 9 (hereinafter referred to as "PCSK9"), also known as neuronal apoptosis regulatory convertase 1 ("NARC-1"), is a proteinase K-like subtilase identified as the ninth member of the secreted subtilase family: see "Seidah et al., 2003 PNAS 100:928-933". PCSK9 belongs to the mammalian proprotein convertase family of serine proteases and contains an N-terminal signal sequence, prodomain, catalytic domain, and C-terminal domain; see "Seidah et al., 2012 Nat. Rev. Drug Discov. 11:367-383". Studies on the transcriptional regulation of PCSK9 have shown that, as seen in other genes involved in cholesterol metabolism (Maxwell et al., 2003 J. Lipid Res. 44:2109-2119), and as is typical in other genes involved in lipoprotein metabolism (Dubuc et al., 2004 Arterioscler. Thromb. Vasc. Biol. 24:1454-1459), PCSK9 is regulated by sterol regulatory element-binding protein ("SREBP"). Statins have been shown to upregulate PCSK9 expression due to their cholesterol-lowering effects. Furthermore, the PCSK9 promoter has been shown to possess two conserved sites involved in cholesterol regulation: the sterol regulatory element and the Sp1 site; see above.

[0008] Within the endoplasmic reticulum, PCSK9 undergoes autocleavage between the Gln-152 and Ser-153 residues as its sole catalytic activity; see "Naureckiene et al., 2003 Arch. Biochem. Biophys. 420:55-67" and "Seidah et al., 2003 Proc. Natl. Acad. Sci. USA 100:928-933". The prodomain remains firmly bound to the catalytic domain while being transported through the trans-Golgi network. Maturation by autocleavage has been shown to be important for PCSK9 secretion and subsequent extracellular function (see "Benjannet et al., 2012 J. Biol. Chem. 287:33745-33755"). Therefore, several pieces of evidence demonstrate that PCSK9 specifically reduces the amount of hepatic LDLR protein, and as a result, reduces the liver's ability to remove low-density lipoprotein ("LDL") cholesterol from circulation.

[0009] Adenovirus-mediated overexpression of PCSK9 in mouse liver leads to a dramatic loss of hepatic LDLR protein, resulting in the accumulation of circulating low-density lipoprotein cholesterol ("LDL-C"), but without affecting LDLR mRNA levels; "Benjannet et al., 2004 J. Biol. Chem. 279:48865-48875", "Maxwell & Breslow, 2004 PNAS 101:7100-7105", "Park et al., 2004 J. Biol. Chem. 279:50630-50638", and "Lalanne et al., 2005 J. Lipid Res. 46:1312-1319". The effect of PCSK9 overexpression on increasing circulating LDL-C levels in mice is entirely dependent on LDLR expression, again indicating that PCSK9-mediated regulation of LDL-C occurs via downregulation of LDLR protein. Consistent with these findings, mice lacking PCSK9 or mice with reduced PCSK9 mRNA due to antisense oligonucleotide inhibitors have higher hepatic LDLR protein levels and a greater ability to remove circulating LDL-C; "Rashid et al., 2005 PNAS 102:5374-5379" and "Graham et al., 2007 J. Lipid Res. 48(4):763-767". Furthermore, reducing PCSK9 levels in cultured human hepatocytes using siRNA similarly increases LDLR protein levels and enhances their ability to take up LDL-C; "Benjannet et al., 2004 J. Biol. Chem. 279:48865-48875" and "Lalanne et al., 2005 J. Lipid Res. 46:1312-1319". Taken together, these data suggest that PCSK9's action leads to increased LDL-C levels by reducing LDLR protein levels.

[0010] Many mutations in the PCSK9 gene are also definitively associated with autosomal dominant hypercholesterolemia ("ADH"), a hereditary metabolic disorder characterized by a significant increase in low-density lipoprotein ("LDL") particles in the plasma, which can lead to premature cardiovascular failure; see "Abifadel et al., 2003 Nature Genetics 34:154-156", "Timms et al., 2004 Hum. Genet. 114:349-353", and "Leren, 2004 Clin. Genet. 65:419-422". Subsequent research by Abifadel et al. (cited above) on the S127R mutation reported that patients with such mutations have high plasma total cholesterol and apoB100 levels due to (1) overproduction of apoB100-containing lipoproteins such as low-density lipoprotein ("LDL"), very low-density lipoprotein ("VLDL"), and intermediate-density lipoprotein ("IDL"), and (2) a resulting reduction in the clearance or conversion of the said lipoproteins; "Ouguerram et al., 2004 Arterioscler. Thromb. Vasc. Biol. 24:1448-1453".

[0011] Therefore, it is undeniable that PCSK9 is involved in LDL regulation. PCSK9 expression or upregulation is associated with elevated plasma LDL cholesterol levels, and corresponding inhibition or absence of PCSK9 expression is associated with decreased plasma LDL cholesterol levels. Lowering of LDL cholesterol levels associated with PCSK9 sequence mutations has been found to provide protection against coronary heart disease; Cohen, 2006 N. Engl. J. Med. 354:1264-1272.

[0012] In clinical trials, a decrease in LDL cholesterol levels has been directly associated with a reduced incidence of coronary events; Law et al., 2003 BMJ 326:1423-1427. A moderate lifetime reduction in plasma LDL cholesterol levels has been shown to correlate with a significant reduction in the incidence of coronary events; Cohen et al., 2006 N. Engl. J. Med. 354:1264-1272. This was also true in populations with high prevalence of non-lipid-related cardiovascular risk factors. Therefore, there are significant benefits to the controlled management of LDL cholesterol levels.

[0013] Therefore, identifying compounds and / or drugs effective in treating cardiovascular diseases, including antagonizing the role of PCSK9 in LDL regulation, is highly desirable. However, because PCSK9 generally circulates in the blood and has modest binding affinity to cell surface LDL receptors, previous attempts to utilize this mechanism in treating diseases associated with high serum LDL levels have focused on the use of large biomolecules (e.g., antibodies). The therapeutic potential of small peptides or small molecules as drugs targeting PCSK9 is still in its early stages of exploration; see, for example, "Tombling et al., Atherosclerosis 330 (2021) 52-60". Furthermore, few compounds can be formulated into dosage forms that utilize an oral route of administration (which is a highly desirable route of administration to provide treatments for conditions in which modulating PCSK9 activity may play a role).

[0014] WO2019 / 246349 discloses a cyclic peptide compound useful in the treatment of cardiovascular disease and conditions associated with PCSK9 activity. This disclosure presents state-of-the-art technology by providing a crystalline form of the compound represented by Formula I, which can be used to treat hypercholesterolemia and other conditions associated with PCSK9 activity, preferably including oral administration of a confirmed PCSK9 inhibitor. Certain crystalline forms have advantages such as ease of processing or handling. In particular, these forms may exhibit improved physicochemical properties, such as being particularly suitable for the manufacture of various pharmaceutical dosage forms, including oral administration forms.

[0015] Therefore, provided herein is Formula I: [ka] [In the ceremony, A - [This is a pharmaceutically acceptable anion.] This is the crystalline form of the salt of the compound represented by A. In further embodiments, A -The crystalline form is selected from acetate, caprate, lactate, tarlate, succinate, and sulfate. The term "caprate" is also known in the art as "decanoate" and can be used interchangeably. In yet another embodiment, provided herein are crystalline forms of compounds represented by formula I, which are selected from acetate 2, acetate 3, acetate 4, acetate 5, acetate 6, caprate 2, caprate 3, caprate 4, caprate 5, caprate 6, caprate 7, caprate 8, caprate 9, caprate 10, caprate 11, caprate 12, caprate 13, caprate 14, D-lactate 1, D-lactate 2, succinate 1, succinate 2, L-tarlate 1, L-tarlate 2, sulfate 1, and sulfate 2. Additional embodiments of this embodiment of the present disclosure provide a specific drug substance comprising at least one of the forms described herein. The presence of a specific crystalline form in the drug substance can be detected by physical methods known to those skilled in the art, such as X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, nuclear magnetic resonance (NMR) spectroscopy, or nitrogen-15CPMAS NMR spectroscopy.

[0016] Compound A is the amorphous form of the chloride salt of the compound represented by formula I.

[0017] Compound B is the bicarbonate of the compound represented by formula I.

[0018] This specification describes the acetate of the compound represented by the following formula I, referred to as Compound 1: [ka]

[0019] Acetate 1 is the amorphous form of compound 1.

[0020] In one embodiment, the crystalline form of compound 1 is provided herein.

[0021] In further embodiments, provided herein are crystalline forms of compound 1, where the crystalline form is selected from acetate 2, acetate 3, acetate 4, acetate 5, and acetate 6.

[0022] Similarly, described herein are caprinates of compounds represented by formula I, as seen below, and referred to as compound 2: [ka]

[0023] Caprate 1 is the amorphous form of compound 2.

[0024] In one embodiment, the crystalline form of compound 2 is provided herein.

[0025] In further embodiments, provided herein are crystalline forms of compound 2, where the crystalline form is selected from caprate 2, caprate 3, caprate 4, caprate 5, caprate 6, caprate 7, caprate 8, caprate 9, caprate 10, caprate 11, caprate 12, caprate 13 and caprate 14.

[0026] Similarly, described herein is a lactate of a compound represented by formula I, as shown below, and referred to as compound 3: [ka]

[0027] In one embodiment, the crystalline form of compound 3 is provided herein.

[0028] In further embodiments, provided herein are crystalline forms of compound 3, where the crystalline form is selected from D-lactate 1 and D-lactate 2. The structures of the D-lactates are shown below: [ka]

[0029] Similarly, described herein is a succinate of a compound represented by formula I, as shown below, and referred to as compound 4: [ka]

[0030] In one embodiment, the crystalline form of compound 4 is provided herein.

[0031] In further embodiments, provided herein are crystalline forms of compound 4, where the crystalline form is selected from succinate 1 and succinate 2.

[0032] Similarly, described herein are tartrate salts of compounds represented by formula I, as seen below, and referred to as compound 5: [ka]

[0033] In one embodiment, the crystalline form of compound 5 is provided herein.

[0034] In further embodiments, provided herein are crystalline forms of compound 5, where the crystalline form is selected from L-Tartrate 1 and L-Tartrate 2. The structures of L-Tartrate are shown below: [ka]

[0035] L-tartrate can also be called (2R,3R)-hydrogen tartrate.

[0036] Similarly, described herein is a sulfate of a compound represented by formula I, as seen below, and referred to as compound 6: [ka]

[0037] In one embodiment, the crystalline form of compound 6 is provided herein.

[0038] In further embodiments, provided herein are crystalline forms of compound 6, where the crystalline form is selected from sulfate 1 and sulfate 2.

[0039] In one embodiment of the above structure, the compound represented by formula I and the sulfate anion have a 2:1 stoichiometry, as shown below: [ka]

[0040] The specific crystalline forms of the compounds represented by Formula I provided herein possess advantageous properties beneficial for the preparation of various drug formulations. For example, Caprate 3, a specific crystalline form of the compound represented by Formula I, is a stable crystalline form. Caprate 3 maintains its crystallinity even with changes in relative humidity (i.e., is physically stable) (see, e.g., Figures 34A-35B). A crystalline form with good stability is important in the processes of drug preparation, packaging, transport, and storage. The manufacturing process of Caprate 3 (see, e.g., Examples 12A, 12B, 12C, and 19) further results in improved chemical stability compared to amorphous chloride salts, which is an important feature for the preparation and use of drugs (see, e.g., Figures 29A and 29B).

[0041] Characterization of crystal morphology In certain embodiments, the crystalline morphologies provided herein can be identified based on characteristic peaks in X-ray powder diffraction analysis. X-ray powder diffraction (XRPD) is a scientific technique that uses X-ray diffraction on powders, microcrystals, or other solid materials to evaluate the structural properties of solid materials. A description of the method used to obtain specific XRPD patterns related to the crystalline morphologies of the present invention can be found in Example 34, “Description of X-ray Powder Diffraction.” In one embodiment, the X-ray powder diffraction data provided herein is obtained by a method utilizing Cu Kα radiation.

[0042] Crystalline form of the compound represented by formula I Acetate 2: In one embodiment, provided herein is acetate 2 (which is the crystalline form of the acetate of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at angles (±0.2°): 4.92, 6.59, 9.82, and 17.91. In a particular embodiment, acetate 2 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at angles (±0.2°): 4.92, 6.59, 9.82, 16.14, 17.37, 17.91, 19.01, 19.67, and 20.16. In another embodiment, the crystalline form of the compound represented by formula I is acetate 2, characterized by an X-ray powder diffraction pattern having peaks shown in Table 1 (represented by degrees -2-θ at angles ±0.2°).

[0043] In this embodiment, about 10% to about 100% of the compound represented by formula I in the pharmaceutical composition, for example, about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%, is in the form of acetate 2. In this embodiment, acetate 2 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 2. In this embodiment, acetate 2 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 1.

[0044] Table 1: X-ray powder diffraction patterns of acetate 2 [Table 1]

[0045] Acetate 3: In another embodiment, provided herein is acetate 3 (which is the crystalline form of the acetate salt of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having a peak represented by degrees -2-θ at the following angles (±0.2°): 4.48, 18.17, 18.79, and 19.27. In a particular embodiment, acetate 3 is characterized by an X-ray powder diffraction pattern having a peak represented by degrees -2-θ at the following angles (±0.2°): 4.48, 16.54, 18.17, 18.79, 19.27, 20.64, 20.93, 21.51, 22.18, and 22.65. In a more specific embodiment, acetate 3 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at angles (±0.2°): 4.48, 8.97, 9.08, 13.80, 14.51, 16.12, 16.54, 18.17, 18.79, 19.27, 20.64, 20.93, 21.51, 22.18, 22.65, 23.83, 24.29, and 24.57. In another embodiment, the crystalline form of the compound represented by formula I is acetate 3, where the crystalline form is characterized by an X-ray powder diffraction pattern having peaks shown in Table 2 (represented by degrees -2-θ at angles ±0.2°).

[0046] In this embodiment, about 10% to about 100% of the compound represented by formula I in the pharmaceutical composition, for example, about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%, is in the form of acetate 3. In this embodiment, acetate 3 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 3. In this embodiment, acetate 3 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 2.

[0047] Table 2: X-ray powder diffraction patterns of acetate 3 [Table 2]

[0048] Acetate 4: In one embodiment, provided herein is acetate 4 (which is the crystalline form of the acetate salt of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 8.36, 17.74, 20.29, and 21.35. In a particular embodiment, acetate 4 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 7.10, 7.89, 8.36, 10.83, 11.45, 12.22, 13.60, 14.57, 15.51, 15.97, 17.00, 17.74, 18.23, 19.16, 19.84, 20.29, 20.81, 21.35, 22.05, 22.71, 23.10, 23.71, 24.26, 25.34, 26.16, and 26.84. In a more specific embodiment, acetate 4 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 7.10, 7.89, 8.36, 9.09, 9.61, 10.30, 10.83, 11.45, 12.22, 12.89, 13.60, 14.57, 15.51, 15.97, 17.00, 17.74, 18.23, 19.16, 19.84, 20.29, 20.81, 21.35, 22.05, 22.71, 23.10, 23.71, 24.26, 25.34, 26.16, 26.8, 27.78, 28.39, 29.39, and 30.30. In another embodiment, the crystalline form of the compound represented by formula I is acetate 4, which is characterized by an X-ray powder diffraction pattern having peaks shown in Table 3 (represented by degrees -2-θ at an angle of ±0.2°).

[0049] In this embodiment, about 10% to about 100% of the compound represented by formula I in the pharmaceutical composition, for example, about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%, is in the form of acetate 4. In this embodiment, acetate 4 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 4. In this embodiment, acetate 4 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 3.

[0050] Table 3: X-ray powder diffraction patterns of acetate 4 [Table 3]

[0051] Acetate 5: In another embodiment, provided herein is acetate 5 (which is the crystalline form of the acetate of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 5.02, 6.66, 9.89, and 19.84. In a particular embodiment, acetate 5 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 5.02, 6.66, 9.89, 14.86, 16.32, 16.46, 16.91, 17.29, 17.54, 18.10, 18.59, 18.79, 19.12, 19.31, 19.65, 19.84, 20.38, 20.60, and 20.93. In a more specific embodiment, acetate 5 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 5.02, 6.66, 9.89, 12.64, 13.33, 14.22, 14.47, 14.86, 15.08, 15.49, 15.77, 16.03, 16.32, 16.46, 16.91, 17.29, 17.54, 18.10, 18.59, 18.79, 19.12, 19.31, 19.65, 19.84, 20.38, 20.60, 20.93, 21.23, 21.65, 21.92, 22.33, 22.61, 22.95, and 23.38. In another embodiment, the crystalline form of the compound represented by formula I is acetate 5, which is characterized by an X-ray powder diffraction pattern having peaks shown in Table 4 (represented by degrees -2-θ at an angle of ±0.2°).

[0052] In this embodiment, about 10% to about 100% of the compound represented by formula I in the pharmaceutical composition, for example, about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%, is in the form of acetate 5. In this embodiment, acetate 5 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 5. In this embodiment, acetate 5 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 4.

[0053] Table 4: X-ray powder diffraction patterns of acetate 5 [Table 4]

[0054] Acetate 6: In another embodiment, provided herein is acetate 6 (which is the crystalline form of the acetate salt of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 7.79, 11.00, 16.24, and 18.89. In a particular embodiment, acetate 6 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 7.79, 11.00, 13.40, 14.70, 15.12, 15.44, 16.24, 17.05, 18.89, 20.34, and 20.96. In a more specific embodiment, acetate 6 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at angles (±0.2°): 7.79, 9.47, 10.30, 11.00, 13.40, 14.01, 14.70, 15.12, 15.44, 16.24, 17.05, 18.89, 20.34, 20.96, and 21.95. In another embodiment, the crystalline form of the compound represented by formula I is acetate 6, where the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (represented by degrees -2-θ at angles ±0.2°) shown in Table 5.

[0055] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of acetate 6. In this embodiment, acetate 6 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 6. In this embodiment, acetate 6 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 5.

[0056] Table 5: X-ray powder diffraction patterns of acetate 6 [Table 5]

[0057] Cap Plate 2: In another embodiment, provided herein is caprate 2 (which is the crystalline form of the caprine salt of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at angles (±0.2°): 4.85, 7.65, 17.16, 18.20, and 19.50. In a particular embodiment, caprate 2 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at angles (±0.2°): 4.85, 6.27, 6.96, 7.65, 9.69, 17.16, 18.20, 19.50, 20.01, and 20.42. In another embodiment, the crystalline form of the compound represented by formula I is caprate 2, where the crystalline form is characterized by an X-ray powder diffraction pattern having peaks shown in Table 6 (represented by degrees -2-θ at angles ±0.2°).

[0058] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 2. In this embodiment, caprate 2 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 8. In this embodiment, caprate 2 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 6.

[0059] Table 6: X-ray powder diffraction pattern of caplate 2 [Table 6]

[0060] Caplate 3: In another embodiment, provided herein is caprate 3 (which is the crystalline form of the caprine salt of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having a peak represented by degrees -2-θ at the following angle (±0.2°): 7.92, 17.33, and 19.60. In another embodiment, provided herein is caprate 3 (which is the crystalline form of the caprine salt of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having a peak represented by degrees -2-θ at the following angle (±0.2°): 7.92, 15.40, 17.33, 18.86, 19.60, and 20.79. In a more specific embodiment, caprate 3 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 7.92, 12.99, 15.40, 17.33, 18.59, 18.86, 19.07, 19.60, 20.79, and 21.27. In a more specific embodiment, caprate 3 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 4.59, 7.92, 9.85, 12.99, 15.40, 16.66, 17.33, 18.59, 18.86, 19.07, 19.60, 20.79, 21.27, 21.73, and 22.24. In a more specific embodiment, caplate 3 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 3.57, 4.59, 4.98, 7.92, 9.37, 9.85, 10.16, 10.38, 10.55, 11.35, 12.72, 12.99, 13.54, 13.75, 14.28, 14.66, 15.40, 16.66, 17.33, 17.97, 18.59, 18.86, 19.07, 19.60, 20.79, 21.27, 21.73, 22.24, 22.89, 23.64, 24.11, and 25.01.In another embodiment, the crystalline form of the compound represented by formula I is caprate 3, which is characterized by an X-ray powder diffraction pattern having peaks shown in Table 7 (represented by degrees -2-θ at an angle of ±0.2°).

[0061] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 3. In this embodiment, caprate 3 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 9. In this embodiment, caprate 3 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 7.

[0062] Table 7: X-ray powder diffraction pattern of caplate 3 [Table 7]

[0063] Caplate 4: In another embodiment, provided herein is caprate 4 (which is a crystalline form of the caprine salt of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 4.18, 6.14, 17.51, and 17.68. In a particular embodiment, caprate 4 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 4.18, 4.86, 6.14, 8.41, 15.72, 16.90, 17.12, 17.51, 17.68, 18.17, 18.57, 19.21, 19.35, 19.96, 20.51, 20.87, 21.19, and 21.78. In another embodiment, the crystalline form of the compound represented by formula I is caprate 4, which is characterized by an X-ray powder diffraction pattern having peaks shown in Table 8 (represented by degrees -2-θ at an angle of ±0.2°).

[0064] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 4. In this embodiment, caprate 4 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 10. In this embodiment, caprate 4 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 8.

[0065] Table 8: X-ray powder diffraction pattern of caprate 4 [Table 8]

[0066] Cap Plate 5: In another embodiment, provided herein is caprate 5 (which is the crystalline form of the caprine salt of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having a peak represented by degree -2-θ at the following angle (±0.2°): 7.66, 16.18, 18.26, and 19.11. In a particular embodiment, caprate 5 is characterized by an X-ray powder diffraction pattern having a peak represented by degree -2-θ at the following angle (±0.2°): 6.75, 7.66, 15.28, 16.18, 18.26, 19.11, and 20.63. In another embodiment, the crystalline form of the compound represented by formula I is caprate 5, where the crystalline form is characterized by an X-ray powder diffraction pattern having the peak shown in Table 9 (represented by degree -2-θ at an angle of ±0.2°).

[0067] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 5. In this embodiment, caprate 5 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 11. In this embodiment, caprate 5 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 9.

[0068] Table 9: X-ray powder diffraction pattern of Caplate 5 [Table 9]

[0069] Caplate 6: In another embodiment, provided herein is caprate 6 (which is a crystalline form of the caprine salt of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 5.33, 6.97, 19.04, and 21.58. In a particular embodiment, caprate 6 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 5.17, 5.33, 6.97, 10.47, 12.24, 13.97, 14.85, 16.23, 17.21, 18.40, 19.04, 20.08, 20.86, 21.58, 22.97, and 24.1. In another embodiment, the crystalline form of the compound represented by formula I is caprate 6, which is characterized by an X-ray powder diffraction pattern having peaks shown in Table 10 (represented by degrees -2-θ at an angle of ±0.2°).

[0070] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 6. In this embodiment, caprate 6 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 12. In this embodiment, caprate 6 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 10.

[0071] table 10: X-ray powder diffraction pattern of caprate 6 [Table 10]

[0072] Caplate 7: In another embodiment, provided herein is caprate 7 (which is the crystalline form of the caprine salt of the compound represented by formula I), characterized by the following X-ray powder diffraction patterns: 7.73, 17.14, 18.75, and 19.48. In another embodiment, the crystalline form of the compound represented by formula I is caprate 7, where the crystalline form is characterized by an X-ray powder diffraction pattern having peaks shown in Table 11 (represented by degrees -2-θ at an angle of ±0.2°).

[0073] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 7. In this embodiment, caprate 7 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 13. In this embodiment, caprate 7 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 11.

[0074] Table 11: X-ray powder diffraction pattern of caprate 7 [Table 11]

[0075] Cap Plate 8: In another embodiment, provided herein is caprate 8 (which is the crystalline form of the caprine salt of the compound represented by formula I), characterized by the following X-ray powder diffraction patterns: 7.45, 17.97, 19.32, and 22.08. In a particular embodiment, caprate 8 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 6.35, 7.45, 14.95, 16.13, 17.46, 17.97, 19.32, 20.62, and 22.08. In another embodiment, the crystalline form of the compound represented by formula I is caprate 8, where the crystalline form is characterized by an X-ray powder diffraction pattern having peaks shown in Table 12 (represented by degrees -2-θ at angles ±0.2°).

[0076] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 8. In this embodiment, caprate 8 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 14. In this embodiment, caprate 8 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 12.

[0077] Table 12: X-ray powder diffraction pattern of caplate 8 [Table 12]

[0078] Caplate 9: In another embodiment, provided herein is caprate 9 (which is a crystalline form of caprate represented by formula I), characterized by the following X-ray powder diffraction patterns: 6.73, 11.95, 18.23, and 19.77. In a particular embodiment, caprate 9 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 5.01, 6.73, 11.33, 11.95, 12.67, 13.05, 13.43, 13.85, 14.05, 14.34, 15.19, 15.61, 16.54, 16.81, 17.03, 17.53, 17.64, 18.23, 18. 56, 19.37, 19.57, 19.77, 20.21, 20.39, 20.53, 21.05, 21.83, 22.14, 22.77, 23.12, 23.69, 23.95, 24.62, 25.07, 25.47, and 26.08. In another embodiment, the crystalline form of the compound represented by formula I is caprate 9, which is characterized by an X-ray powder diffraction pattern having peaks shown in Table 13 (represented by degrees -2-θ at angles ±0.2°).

[0079] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 9. In this embodiment, caprate 9 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 15. In this embodiment, caprate 9 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 13.

[0080] Table 13: X-ray powder diffraction pattern of caplate 9 [Table 13]

[0081] Cap Plate 10: In another embodiment, provided herein is caprate 10 (which is the crystalline form of the caprine salt of the compound represented by formula I), characterized by the following X-ray powder diffraction patterns: 3.50, 7.90, 16.21, and 18.23. In another embodiment, the crystalline form of the compound represented by formula I is caprate 10, where the crystalline form is characterized by an X-ray powder diffraction pattern having peaks shown in Table 14 (represented by degrees -2-θ at an angle of ±0.2°).

[0082] In this embodiment, about 10% to about 100% of the compound represented by formula I in the pharmaceutical composition, for example, about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%, is in the form of caprate 10. In this embodiment, caprate 10 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 16. In this embodiment, caprate 10 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 14.

[0083] Table 14: X-ray powder diffraction pattern of caprate 10 [Table 14]

[0084] Caplate 11: In another embodiment, provided herein is caprate 11 (which is the crystalline form of the caprine salt of the compound represented by formula I), characterized by the following X-ray powder diffraction patterns: 3.93, 4.90, and 7.68. In another embodiment, the crystalline form of the compound represented by formula I is caprate 11, where the crystalline form is characterized by an X-ray powder diffraction pattern having peaks shown in Table 15 (represented by degrees -2-θ at an angle of ±0.2°).

[0085] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 11. In this embodiment, caprate 11 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 17. In this embodiment, caprate 11 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 15.

[0086] Table 15: X-ray powder diffraction pattern of caprate 11 [Table 15]

[0087] Cap Plate 12: In another embodiment, provided herein is caprate 12 (which is a crystalline form of the caprine salt of the compound represented by formula I), characterized by the following X-ray powder diffraction patterns: 6.80, 15.37, 18.22, and 20.63. In a particular embodiment, caprate 12 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at angles (±0.2°) as follows: 5.01, 5.58, 6.80, 10.75, 13.44, 13.85, 14.43, 15.37, 16.00, 16.34, 16.68, 17.67, 18.22, 18.50, 19.09, 19.67, 20.27, 20.63, 21.33, 22.30, 23.22, 23.88, 25.39, and 26.02. In another embodiment, the crystalline form of the compound represented by formula I is caprate 12, where the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (represented by degrees -2-θ at angles ±0.2°) as shown in Table 16.

[0088] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 12. In this embodiment, caprate 12 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 18. In this embodiment, caprate 12 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 16.

[0089] Table 16: X-ray powder diffraction pattern of caprate 12 [Table 16]

[0090] Caplate 13: In another embodiment, provided herein is caprate 13 (which is a crystalline form of the caprine salt of the compound represented by formula I), characterized by the following X-ray powder diffraction patterns: 5.02, 6.29, 7.12, and 20.25. In a particular embodiment, caprate 13 is characterized by an X-ray powder diffraction pattern having a peak represented by degrees -2-θ at the following angles (±0.2°): 4.23, 5.02, 6.29, 7.12, 15.16, 16.47, 16.97, 17.33, 18.12, 18.88, 19.09, 20.25, 21.53, 22.08, and 23.06. In another embodiment, the crystalline form of the compound represented by formula I is caprate 13, which is characterized by an X-ray powder diffraction pattern having peaks shown in Table 17 (represented by degrees -2-θ at an angle of ±0.2°).

[0091] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 13. In this embodiment, caprate 13 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 19. In this embodiment, caprate 13 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 17.

[0092] Table 17: X-ray powder diffraction pattern of caprate 13 [Table 17]

[0093] Caplate 14: In another embodiment, provided herein is caprate 14 (which is a crystalline form of the caprine salt of the compound represented by formula I), characterized by the following X-ray powder diffraction patterns: 6.74, 18.16, 19.51, and 20.68. In a particular embodiment, caprate 14 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 5.01, 5.54, 6.74, 7.06, 15.29, 16.08, 16.64, 17.67, 18.16, 18.54, 19.13, 19.51, 20.68, 21.40, 22.26, and 23.22. In another embodiment, the crystalline form of the compound represented by formula I is caprate 14, which is characterized by an X-ray powder diffraction pattern having peaks shown in Table 18 (represented by degrees -2-θ at an angle of ±0.2°).

[0094] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of caprate 14. In this embodiment, caprate 14 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 20. In this embodiment, caprate 14 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 18.

[0095] Table 18: X-ray powder diffraction pattern of caprate 14 [Table 18]

[0096] TIFF0007866141000032.tif26152

[0097] D-Lactate 1: In another embodiment, provided herein is D-lactate 1 (which is the crystalline form of the lactate of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having a peak represented by degrees -2-θ at the following angles (±0.2°): 18.24, 19.56, 20.07, and 20.45. In a particular embodiment, D-lactate 1 is characterized by an X-ray powder diffraction pattern having a peak represented by degrees -2-θ at the following angles (±0.2°): 17.26, 18.24, 19.56, 20.07, 20.45, 20.89, 21.72, and 22.10. In a more specific embodiment, D-lactate 1 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at angles (±0.2°): 13.74, 14.54, 16.09, 17.26, 18.24, 19.56, 20.07, 20.45, 20.89, 21.72, and 22.10. In another embodiment, the crystalline form of the compound represented by formula I is D-lactate 1, which is characterized by an X-ray powder diffraction pattern having peaks (represented by degrees -2-θ at angles ±0.2°) shown in Table 19.

[0098] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of D-lactate 1. In this embodiment, D-lactate 1 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 21. In this embodiment, D-lactate 1 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 19.

[0099] Table 19: X-ray powder diffraction patterns of D-lactate 1 [Table 19]

[0100] D-Lactate 2: In another embodiment, provided herein is D-lactate 2 (which is the crystalline form of the lactate of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having a peak represented by degree -2-θ at the following angle (±0.2°): 7.38. In a particular embodiment, D-lactate 2 is characterized by an X-ray powder diffraction pattern having a peak represented by degree -2-θ at the following angle (±0.2°): 7.38, and 19.63. In another embodiment, the crystalline form of the compound represented by formula I is D-lactate 2, where the crystalline form is characterized by an X-ray powder diffraction pattern having a peak (represented by degree -2-θ at an angle of ±0.2°) as shown in Table 20.

[0101] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of D-lactate 2. In this embodiment, D-lactate 2 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 22. In this embodiment, D-lactate 2 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 20.

[0102] Table 20: X-ray powder diffraction patterns of D-lactate 2 [Table 20]

[0103] Succine 1 : In another embodiment, provided herein is succinate 1 (which is the crystalline form of the succinate salt of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having a peak represented by degree -2-θ at the following angle (±0.2°): 5.98, 7.05, 17.29, and 20.22. In a particular embodiment, succinate 1 is characterized by an X-ray powder diffraction pattern having a peak represented by degree -2-θ at the following angle (±0.2°): 5.98, 7.05, 17.29, 18.82, 20.22, and 21.39. In a more specific embodiment, succinate 1 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at angles (±0.2°): 4.84, 5.49, 5.98, 7.05, 14.38, 16.79, 17.29, 18.82, 20.22, and 21.39. In another embodiment, the crystalline form of the compound represented by formula I is succinate 1, which is characterized by an X-ray powder diffraction pattern having peaks (represented by degrees -2-θ at angles ±0.2°) shown in Table 21.

[0104] In this embodiment, about 10% to about 100% of the compound represented by formula I in the pharmaceutical composition, for example, about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%, is in the form of succinate 1. In this embodiment, succinate 1 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 23. In this embodiment, succinate 1 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 21.

[0105] Table 21: X-ray powder diffraction pattern of succinate 1 [Table 21]

[0106] Squeeze 2: In another embodiment, provided herein is succinate 2 (which is the succinate form of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having a peak represented by degree -2-θ at the following angles (±0.2°): 5.15, 6.12, 7.22, and 7.90. In another embodiment, the crystalline form of the compound represented by formula I is succinate 2, where the crystalline form is characterized by an X-ray powder diffraction pattern having a peak (represented by degree -2-θ at an angle of ±0.2°) shown in Table 22.

[0107] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of succinate 2. In this embodiment, succinate 2 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 24. In this embodiment, succinate 2 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 22.

[0108] Table 22: X-ray powder diffraction patterns of succinate 2 [Table 22]

[0109] L-Tartrate 1: In another embodiment, provided herein is L-Tartrate 1 (which is the tartrate salt form of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having a peak represented by degree -2-θ at the following angles (±0.2°): 4.71, 6.52, 7.48, and 17.37. In another embodiment, the crystalline form of the compound represented by formula I is L-Tartrate 1, where the crystalline form is characterized by an X-ray powder diffraction pattern having the peak shown in Table 23 (represented by degree -2-θ at an angle of ±0.2°).

[0110] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of L-Tartrate 1. In this embodiment, L-Tartrate 1 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 25. In this embodiment, L-Tartrate 1 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 23.

[0111] Table 23: X-ray powder diffraction pattern of L-Tartrate 1 [Table 23]

[0112] L-Tartrate 2: In another embodiment, provided herein is L-Tartrate 2 (which is the crystalline form of the tartrate salt of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 7.35, 14.19, 15.86, and 18.70. In a particular embodiment, L-Tartrate 2 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 7.35, 10.90, 14.19, 15.86, 16.63, 17.58, 18.20, 18.70, 19.79, 20.54, and 20.94. In another embodiment, the crystalline form of the compound represented by formula I is L-tartorate 2, which is characterized by an X-ray powder diffraction pattern having peaks shown in Table 24 (represented by degrees -2-θ at an angle of ±0.2°).

[0113] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of L-Tartrate 2. In this embodiment, L-Tartrate 2 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 26. In this embodiment, L-Tartrate 2 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 24.

[0114] Table 24: X-ray powder diffraction patterns of L-Tartrate 2 [Table 24]

[0115] Sulfate 1: In another embodiment, provided herein is sulfate 1 (which is the crystalline form of the sulfate of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 6.87, 19.48, 20.38, and 20.94. In a particular embodiment, sulfate 1 is characterized by an X-ray powder diffraction pattern having peaks represented by degrees -2-θ at the following angles (±0.2°): 2.40, 6.87, 9.13, 17.83, 18.50, 19.48, 20.38, 20.94, and 21.94. In another embodiment, the crystalline form of the compound represented by formula I is sulfate 1, where the crystalline form is characterized by an X-ray powder diffraction pattern having peaks shown in Table 25 (represented by degrees -2-θ at angles ±0.2°).

[0116] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of sulfate 1. In this embodiment, sulfate 1 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 27. In this embodiment, sulfate 1 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 25.

[0117] Table 25: X-ray powder diffraction pattern of Sulfate 1 [Table 25]

[0118] Sulfate 2: In another embodiment, provided herein is sulfate 2 (which is the crystalline form of the sulfate of the compound represented by formula I), characterized by an X-ray powder diffraction pattern having a peak represented by degree -2-θ at the following angles (±0.2°): 5.21, 5.75, 6.30, and 7.74. In another embodiment, the crystalline form of the compound represented by formula I is sulfate 2, where the crystalline form is characterized by an X-ray powder diffraction pattern having a peak (represented by degree -2-θ at an angle of ±0.2°) shown in Table 26.

[0119] In this embodiment, about 10% to about 100%, e.g., about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92% of the compound represented by formula I in the pharmaceutical composition is in the form of sulfate 2. In this embodiment, sulfate 2 is characterized substantially by the X-ray powder diffraction pattern shown in Figure 28. In this embodiment, sulfate 2 is characterized by the X-ray powder diffraction substantially described by one or more of the properties listed in Table 26.

[0120] Table 26: X-ray powder diffraction patterns of sulfate 2 [Table 26]

[0121] Further embodiments of such embodiments provide specific drug substances comprising the crystalline form of the compound represented by Formula I as described herein. “Drug substance” means a pharmaceutically active ingredient. The presence of a crystalline form in a drug substance can be detected by physical methods known to those skilled in the art, such as X-ray powder diffraction, carbon-13 cross-polarized magic-angle rotation (CPMAS) nuclear magnetic resonance (NMR) spectroscopy, and nitrogen-15 CPMAS NMR spectroscopy.

[0122] In a further embodiment of this model, compound 2 is made of ethers, esters, linear alkanes (C3-C3). 10 ), crystallization is performed from a solvent system containing a solvent selected from alcohols and water. In a further embodiment of this embodiment, compound 2 is crystallized from ethers, esters, linear alkanes (C3-C 10 ), the compound 2 is crystallized from a solvent system containing a solvent selected from the group consisting of alcohols, water, and mixtures thereof. In some embodiments, compound 2 is crystallized from a solvent system containing a solvent selected from the group consisting of 2-Me-THF, MTBE, ethyl acetate, n-butanol, 1-propanol, and water.

[0123] In the first example, caprate 2 is crystallized from a solvent system containing 1-propanol, MTBE, water, and a mixture thereof. In one embodiment, the solvent system containing compound 2 is aged to form caprate 2. In particular, caprate 2 is crystallized from a solvent system containing MTBE, about 30-40% by weight of 1-propanol, and 0.5-5% of water.

[0124] In subsequent examples, Caprate 2 is filtered and, optionally, dried. In one embodiment, Caprate 2 is dried to yield a crystalline form of formula I, such as Caprate 3. The drying can be carried out at room temperature and / or at a relative humidity of about 50%.

[0125] In another example, caprate 9 is crystallized from a solvent system comprising a solvent selected from 1-propanol, MTBE, water, and mixtures thereof. In one embodiment, the solvent system comprising compound 2 is suspended to form caprate 9. The solvent system may contain multiple forms of compound 2. In particular, caprate 9 is crystallized from a solvent system comprising MTBE, about 5 to 40% by weight of 1-propanol, and 0.5 to 5% of water. In one embodiment, caprate 9 is filtered and optionally dried. In one embodiment, the caprate 9 is dried to yield a crystalline form of formula I, such as caprate 3. The drying can be carried out at room temperature and / or at about 50% relative humidity.

[0126] definition Certain technical and scientific terms are defined below. Unless otherwise specifically defined elsewhere in this specification, all other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art in which this disclosure relates. That is, terms used herein have their usual meanings, and these meanings are independent of each other in their occurrence. Nevertheless, and unless otherwise stated, the following definitions apply throughout this specification and the claims. Chemical names, common names and chemical structures may be used interchangeably to describe the same structure. If a compound is referred to by both a chemical structure and a chemical name, and there is ambiguity between the structure and the name, the structure shall prevail.

[0127] The terms used herein have their usual meanings, and the meanings of such terms are independent in each instance of them. Nevertheless, unless otherwise stated, the following definitions apply throughout this specification and the claims.

[0128] 「FIG」(or, 「FIG.」, or, 「Fig.」, or, 「Fig」, or, 「fig.」, or, 「fig」) means 「Figure」 (or 「figure」), and indicates the corresponding drawing.

[0129] The numerical values provided in this specification, and the use of the term 「about」, may include variations (e.g., variations of ±0.1%, ±0.2%, ±0.3%, ±0.4%, ±0.5%, 0.75, ±1%, ±2%, ±3%, ±4%, ±5% and ±10%) and their numerical equivalents. Numerically defined parameters (e.g., 2θ values of X-ray powder diffraction patterns measured using CuKα radiation, or the 13 C or 15 chemical shift of N) when used to modify 「about」 means that the parameter can vary by up to 10% below or above the numerical value described for that parameter; where appropriate, the described parameter may be rounded to the nearest integer. In addition, the term 「or」 used in this specification indicates options that can be combined where appropriate; that is, the term 「or」 includes not only each of the described options separately, but also combinations thereof.

[0130] Exemplary methods and materials are described in this specification, but methods and materials similar or equivalent to those described herein can also be used in the implementation or testing of this disclosure. Those materials, methods and examples are merely exemplary and not intended to be limiting.

[0131] 「Patient」 includes both humans and other animals.

[0132] 「Mammal」 includes humans and other mammalian animals.

[0133] 「XPRD」 indicates X-ray powder diffraction.

[0134] "Excipients" refer to intrinsically inert substances used to give a formulation stability, shape, or consistency.

[0135] A "diluent" is an excipient that primarily acts as a diluent. Diluents can act to reduce the viscosity of a fluid.

[0136] As used herein, the terms “composition” (or “pharmaceutical composition” or “pharmaceutically acceptable composition”) are intended to encompass products containing specified amounts of specified components, and any products resulting directly or indirectly from combinations of specified amounts of specified components. The terms are intended to encompass products containing active components and inactive components (if present) constituting the carrier, and any products resulting directly or indirectly from any combination, complexation, or aggregation of any two or more components, or from the dissociation of one or more components, or from one or more other types of reactions or interactions of components. Accordingly, the pharmaceutical compositions of the present invention encompass any compositions produced by mixing the crystalline form of the compound represented by Formula I as described herein with a pharmaceutically acceptable carrier. “pharmaceutically acceptable” means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and must not be harmful to its receptor.

[0137] The terms “composition” (or “pharmaceutical composition” or “pharmaceutically acceptable composition” as used herein are also intended to encompass either a bulk composition and / or individual dose units. (Such compositions and units may further contain additional active ingredients as described herein). Bulk compositions and each individual dose unit may contain a certain amount of the active agent. A bulk composition is material that has not yet been formed into individual dose units. Non-limiting examples of dose units include oral dose units such as tablets and pills. Similarly, methods described herein for treating a patient by administering the pharmaceutical compositions of the present invention are also intended to encompass administering the aforementioned bulk compositions and individual dose units.

[0138] The term "caprate anion" as used herein is also known as "decanoate anion."

[0139] The compounds of the present invention also include tautomers. Tautomers arise from the exchange of a single bond with an adjacent double bond, resulting in the movement of a proton. Tautomers include prototropic tautomers, which are isomer protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system (e.g., 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, 1H- and 2H-pyrazoles). Tautomers can exist in equilibrium or be sterically fixed into a single form by appropriate substitution.

[0140] Where used herein, the terms “treating” or “treatment” mean to suppress or improve a disease, condition, or disorder in a person who is experiencing or exhibiting the pathology or symptoms of that disease, condition, or disorder. For example, suppressing a disease, condition, or disorder means preventing further progression of the pathology and / or symptoms of the disease, condition, or disorder. Furthermore, improving a disease, condition, or disorder means reversing its pathology and / or symptoms, for example, by reducing the severity of the disease.

[0141] As used herein, the terms “prevent,” “preventing,” and “prevention” include the prevention of at least one symptom associated with or resulting from a disease, condition, or disorder.

[0142] Where used herein, “subject” refers to an animal in need of treatment, preferably a mammal, in particular a human, or a non-human animal such as a livestock or domestic animal (which includes, but is not limited to, cattle, horses, sheep, pigs, goats, rabbits, cats, and dogs). In some embodiments, the subject is a human.

[0143] Where used herein, the terms “administration” and its variation (e.g., “administering”) relating to the compound represented by Formula I mean providing the compound to a person in need of treatment. Where used herein, “orally” and its variation (e.g., “oral”) mean administration by mouth, i.e., administration of the compound represented by Formula I by mouth.

[0144] The administration of the compound represented by Formula I to a subject includes both self-administration and administration by another person to the subject. The subject may be in a state where treatment is necessary or desirable for an existing disease or medical condition, or may be in a state where prophylactic treatment is necessary or desirable to prevent or reduce the risk of developing such disease or medical condition. Where used herein, a subject who “needs” treatment for an existing condition or prophylactic treatment includes both a determination of necessity by a healthcare professional and the patient’s willingness to receive such treatment.

[0145] process Provided in this specification is Formula I: [ka] [In the ceremony, A - [This is a pharmaceutically acceptable anion.] A process or method for producing a crystalline form of a compound represented by , wherein the crystalline form is formed by a process comprising adding an alcohol to a starting material, wherein the starting material is selected from compound 1, compound 2, compound 3, compound 4, compound 5 and compound 6.

[0146] In one embodiment, the crystalline form of the compound represented by formula I prepared by the above process is selected from acetate 2, acetate 3, acetate 4, acetate 5, acetate 6, caprate 2, caprate 3, caprate 4, caprate 5, caprate 6, caprate 7, caprate 8, caprate 9, caprate 10, caprate 11, caprate 12, caprate 13, caprate 14, D-lactate 1, D-lactate 2, succinate 1, succinate 2, L-tarlate 1, L-tarlate 2, sulfate 1, and sulfate 2.

[0147] In one embodiment of the process for preparing the crystalline form of the compound represented by formula I, the alcohol is selected from ethanol, propanol, and butanol. In a further embodiment, the alcohol is ethanol. In one embodiment, the alcohol is propanol. In another embodiment, the alcohol is butanol. In yet another embodiment, the alcohol is 1-propanol. In yet another embodiment, the alcohol is n-butanol.

[0148] In one embodiment, a process for preparing a crystalline form of a compound represented by formula I includes adding an organic solvent to the compound to form a slurry / solution. In a further embodiment, the process includes aging the slurry / solution. In one embodiment, the process includes aging the slurry / solution in the range of 0°C to 40°C. In a further embodiment, the process includes aging the slurry / solution in the range of 20°C to 35°C.

[0149] In one embodiment, a process for preparing a crystalline form of the compound represented by formula I includes adding a mixture containing an organic solvent and water. In a further embodiment, the process includes adding the alcohol to the mixture. In another embodiment, the process includes aging the mixture. In yet another embodiment, the process includes aging the mixture at 0°C to 40°C. In a further embodiment, the process includes filtering the mixture to form a wet cake. In one embodiment, the process includes drying the wet cake. In a further embodiment, the process includes drying the wet cake at 0°C to 40°C.

[0150] In one embodiment, the process for preparing the crystalline form of the compound represented by formula I includes adding a mixture containing an organic solvent. In a further embodiment, the alcohol is added to the mixture. In another embodiment, the process includes aging the mixture. In yet another embodiment, the process includes aging the mixture at 0°C to 40°C. In a further embodiment, the process includes stirring the mixture. In one embodiment, the process includes stirring the mixture at 0°C to 20°C.

[0151] In one embodiment, a process for preparing a crystalline form of the compound represented by formula I includes washing a starting material with an organic solvent or the alcohol to form a wet cake. In another embodiment, the alcohol and the organic solvent are added together to form a mixture. In a further embodiment, the process further includes drying the wet cake. In one embodiment, the process includes drying the wet cake with nitrogen at 20°C to 40°C.

[0152] In one embodiment, the process for preparing a crystalline form of the compound represented by formula I further includes exposing the crystalline form of the compound represented by formula I to a relative humidity of about 5%, thereby yielding a second crystalline form of the compound represented by formula I. In another embodiment, the process for preparing a crystalline form of the compound represented by formula I further includes exposing the crystalline form of the compound represented by formula I to a relative humidity of about 50%, thereby yielding a second crystalline form of the compound represented by formula I.

[0153] In one embodiment of a process for preparing the crystalline form of a compound represented by formula I, the organic solvent is an ether, an ester, and a linear alkane (C3-C3). 10 ) are selected from. In a further embodiment, the ether is 2-Me-THF. In yet another embodiment, the ether is MTBE. In one embodiment, the ester is ethyl acetate. In another embodiment, the alkane is heptane.

[0154] In a particular embodiment of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is selected from acetate 2, acetate 3, acetate 4, acetate 5 and acetate 6, and the starting material is compound 1 (acetate of the compound represented by formula I).

[0155] In a particular embodiment of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is selected from caprate 2, caprate 3, caprate 4, caprate 5, caprate 6, caprate 7, caprate 8, caprate 9, caprate 10, caprate 11, caprate 12, caprate 13 and caprate 14, and the starting material is compound 2 (the caprine salt of the compound represented by formula I).

[0156] In a particular embodiment of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is selected from D-lactate 1, succinate 1, L-tarlate 1, and sulfate 1, and the starting material is compound B (bicarbonate of the compound represented by formula I).

[0157] In a particular embodiment of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is D-lactate 2, and the starting material is compound 3 (the lactate of the compound represented by formula I). ​​In one embodiment, compound 3 is D-lactate 1.

[0158] In a particular embodiment of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is succinate 2, and the starting material is compound 4 (succinate of the compound represented by formula I). ​​In one embodiment, compound 4 is succinate 1.

[0159] In certain embodiments of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is L-tartrate 2, and the starting material is compound 5 (the tartrate of the compound represented by formula I). In one embodiment, compound 5 is L-tartrate 1.

[0160] In certain embodiments of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is sulfate 2, and the starting material is compound 6 (the sulfate of the compound represented by formula I). In one embodiment, compound 6 is sulfate 1.

[0161] In another aspect, provided herein is a process or method for producing a crystalline form of a caprate of a compound represented by formula I:

Chemical formula

[0162] In one embodiment of the process for preparing the crystalline form of the caprate of the compound represented by formula I, the crystalline form prepared by the above process is selected from caprate 2, caprate 3, caprate 4, caprate 5, caprate 6, caprate 7, caprate 8, caprate 9, caprate 10, caprate 11, caprate 12, caprate 13 and caprate 14.

[0163] In one embodiment of a process for preparing the crystalline form of a caprine salt of a compound represented by formula I, the alcohol is selected from ethanol, propanol, and butanol. In a further embodiment, the alcohol is ethanol. In one embodiment, the alcohol is propanol. In another embodiment, the alcohol is butanol. In yet another embodiment, the alcohol is 1-propanol. In yet another embodiment, the alcohol is n-butanol.

[0164] In one embodiment, a process for preparing the crystalline form of the caprine salt of the compound represented by formula I includes adding an organic solvent to the starting material (compound 2 - caprine salt of the compound represented by formula I) to form a slurry / solution. In a further embodiment, the process includes aging the slurry / solution. In one embodiment, the process includes aging the slurry / solution in the range of 0°C to 40°C. In a further embodiment, the process includes aging the slurry / solution in the range of 20°C to 35°C.

[0165] In one embodiment, a process for preparing a crystalline form of the caprine salt of the compound represented by formula I includes adding a mixture containing an organic solvent and water. In a further embodiment, the process includes adding the alcohol to the mixture. In another embodiment, the process includes aging the mixture. In yet another embodiment, the process includes aging the mixture at 0°C to 40°C. In a further embodiment, the process includes filtering the mixture to form a wet cake. In one embodiment, the process includes drying the wet cake. In a further embodiment, the process includes drying the wet cake at 0°C to 40°C.

[0166] In one embodiment, a process for preparing a crystalline form of the caprine salt of the compound represented by formula I includes adding a mixture containing an organic solvent. In a further embodiment, the alcohol is added to the mixture. In another embodiment, the process includes aging the mixture. In yet another embodiment, the process includes aging the mixture at 0°C to 40°C. In a further embodiment, the process includes stirring the mixture. In one embodiment, the process includes stirring the mixture at 0°C to 20°C.

[0167] In one embodiment, a process for preparing the crystalline form of the caprine salt of the compound represented by formula I includes washing a starting material (compound 2 - caprine salt of the compound represented by formula I) with an organic solvent or the alcohol to form a wet cake. In another embodiment, the alcohol and the organic solvent are added together to form a mixture. In a further embodiment, the process further includes drying the wet cake. In one embodiment, the process includes drying the wet cake with nitrogen at 20°C to 40°C.

[0168] In one embodiment, a process for preparing a crystalline form of the caprate of a compound represented by formula I further includes exposing the crystalline form of the caprate of the compound represented by formula I to a relative humidity of about 5%, thereby yielding a second crystalline form of the caprate of the compound represented by formula I. In one embodiment, a process for preparing a crystalline form of the caprate of a compound represented by formula I further includes exposing the crystalline form of the caprate of the compound represented by formula I to a relative humidity of about 50%, thereby yielding a second crystalline form of the caprate of the compound represented by formula I. In one embodiment, the organic solvent for the process is an ether, an ester, and a linear alkane (C3-C3). 10 ) are selected from. In a further embodiment, the ether is 2-Me-THF. In yet another embodiment, the ether is MTBE. In one embodiment, the ester is ethyl acetate.

[0169] In one embodiment of a process for preparing the crystalline form of a caprine salt of a compound represented by formula I, the starting material is selected from caprate 1, caprate 2, caprate 3, caprate 4, caprate 5, caprate 6, caprate 7, caprate 8, caprate 9, caprate 10, caprate 11, caprate 12, caprate 13 and caprate 14.

[0170] In one embodiment, the crystalline form of the caprine salt of the compound represented by formula I is caprate 4, and its starting material is caprate 1.

[0171] In one embodiment, the crystalline form of the caprine salt of the compound represented by formula I is caprate 5, and its starting material is caprate 4.

[0172] In one embodiment, the crystalline form of the caprate of the compound represented by formula I is caprate 2, and the starting material is compound 2. In another embodiment, the crystalline form of the caprate of the compound represented by formula I is caprate 2, and the starting material is caprate 5. In yet another embodiment, the crystalline form of the caprate of the compound represented by formula I is caprate 2, and the starting material is compound A or compound B. In a further embodiment, the process includes adding a mixture containing an organic solvent and water. In yet another embodiment, the process includes adding an alcohol to the mixture. In one embodiment, the organic solvent is ether. In yet another embodiment, the ether is MTBE. In yet another embodiment, the alcohol is propanol. In a further embodiment, the alcohol is 1-propanol. In one embodiment, the mixture consists of MTBE, about 30-40% by weight of 1-propanol and 0.5-5% of water. In a further embodiment, the mixture consists of MTBE, about 39% by weight of 1-propanol and 1% of water. In another embodiment, the process includes aging the mixture. In further embodiments, the process includes aging the mixture at 20°C to 30°C.

[0173] In one embodiment, the crystalline form of the caprine compound of formula I is caprate 3, and its starting material is caprate 2 or caprate 9. In a further embodiment, the process includes filtering and optionally drying caprate 2. In one embodiment, the process includes drying caprate 2 to form caprate 3. In a further embodiment, the process includes drying caprate 2 at 20°C to 30°C to form caprate 3. The drying can be carried out at room temperature and / or at about 50% relative humidity.

[0174] As described above, Caplate 3 can be formed by drying the composition containing Caplate 9. The drying can be carried out at room temperature and / or at a relative humidity of about 50%.

[0175] In one embodiment, the crystalline form of the caprine salt of the compound represented by formula I is caprate 4, and its starting material is caprate 3.

[0176] In one embodiment, the crystalline form of the caprine salt of the compound represented by formula I is caprate 6, and its starting material is caprate 1.

[0177] In one embodiment, the crystalline form of the caprine salt of the compound represented by formula I is caprate 7, and its starting material is caprate 6.

[0178] In one embodiment, the crystalline form of the caprine salt of the compound represented by formula I is caprate 8, and its starting material is caprate 4.

[0179] In one embodiment, the crystalline form of the caprate salt of the compound represented by formula I is selected from caprate 9 and caprate 12, and the starting material is a mixture of caprate 3, caprate 5 and caprate 8.

[0180] In one embodiment, the process for preparing the crystalline form of the caprate of the compound represented by Formula I further comprises exposing a first crystalline form of the compound represented by Formula I selected from Caprate 3 and Caprate 7 to a relative humidity of about 5%, resulting in a second crystalline form of the caprate of the compound represented by Formula I selected from Caprate 10 and Caprate 11. In a further embodiment, the first crystalline form of the caprate of the compound represented by Formula I is Caprate 3, and the second crystalline form of the caprate of the compound represented by Formula I is Caprate 10. In another embodiment, the first crystalline form of the caprate of the compound represented by Formula I is Caprate 7, and the second crystalline form of the caprate of the compound represented by Formula I is Caprate 11.

[0181] In one embodiment, the crystalline form of the caprate of the compound represented by Formula I is selected from Caprate 13 and Caprate 14, and the starting material is Caprate 3.

[0182] In one embodiment, the process for preparing the crystalline form of the caprate of the compound represented by Formula I comprises exposing Caprate 3 to the vapor containing the alcohol, and the crystalline form of the compound represented by Formula I is Caprate 13. In another embodiment, the process comprises exposing Caprate 3 to the vapor containing the organic solvent and the alcohol, where the crystalline form of the compound represented by Formula I is Caprate 13. In a further embodiment, the organic solvent is MTBE.

[0183] Also provided herein is Formula I:

Chemical formula

[0184] In one embodiment, the process for producing a crystalline compound represented by formula I includes ion exchange.

[0185] In one embodiment, the process for producing a crystalline compound represented by formula I includes ion exchange, wherein the starting material is compound A (a chloride salt of the compound represented by formula I), and the ion exchange is performed on A - It contains an ion exchange resin that has been charged.

[0186] In another embodiment, compound B (a bicarbonate of the compound represented by formula I) is formed by a process including ion exchange, where the initial material is compound A (a chloride salt of the compound represented by formula I), and the ion exchange that forms compound B is: (1) Ion exchange resin charged with bicarbonate anions; or, (2) Liquid-liquid extraction with organic solvent and aqueous bicarbonate anion; Includes.

[0187] In further embodiments, the process for producing the crystalline compound represented by formula I comprises ion exchange, wherein the starting material is compound B (a bicarbonate of the compound represented by formula I), and the ion exchange comprises adding an acid containing a pharmaceutically acceptable anion.

[0188] In one embodiment, the crystalline form of the compound represented by formula I prepared by the above process is selected from acetate 2, acetate 3, acetate 4, acetate 5, acetate 6, caprate 2, caprate 3, caprate 4, caprate 5, caprate 6, caprate 7, caprate 8, caprate 9, caprate 10, caprate 11, caprate 12, caprate 13, caprate 14, D-lactate 1, D-lactate 2, succinate 1, succinate 2, L-tarlate 1, L-tarlate 2, sulfate 1, and sulfate 2.

[0189] In one embodiment of the process for preparing the crystalline form of the compound represented by formula I, the alcohol is selected from ethanol, propanol, and butanol. In a further embodiment, the alcohol is ethanol. In one embodiment, the alcohol is propanol. In another embodiment, the alcohol is butanol. In yet another embodiment, the alcohol is 1-propanol. In yet another embodiment, the alcohol is n-butanol.

[0190] In one embodiment, a process for preparing a crystalline form of a compound represented by formula I includes adding an organic solvent to the compound to form a slurry / solution. In a further embodiment, the process includes aging the slurry / solution. In one embodiment, the process includes aging the slurry / solution in the range of about -10°C to about 40°C. In a further embodiment, the process includes aging the slurry / solution in the range of about 20°C to about 35°C. In another embodiment, the process includes aging the slurry / solution in the range of about -10°C to about 0°C.

[0191] In one embodiment, a process for preparing a crystalline form of the compound represented by formula I includes adding a mixture containing an organic solvent and water. In a further embodiment, the process includes adding the alcohol to the mixture. In another embodiment, the process includes aging the mixture. In yet another embodiment, the process includes aging the mixture at a temperature of about -10°C to about 40°C. In a further embodiment, the process includes filtering the mixture to form a wet cake. In one embodiment, the process includes drying the wet cake. In a further embodiment, the process includes drying the wet cake at a temperature of about 0°C to about 40°C.

[0192] In one embodiment, the process for preparing the crystalline form of the compound represented by formula I includes adding a mixture containing an organic solvent. In a further embodiment, the alcohol is added to the mixture. In another embodiment, the process includes aging the mixture. In yet another embodiment, the process includes aging the mixture at a temperature of about -10°C to about 40°C. In a further embodiment, the process includes stirring the mixture. In one embodiment, the process includes stirring the mixture at a temperature of about 0°C to about 20°C.

[0193] In one embodiment, a process for preparing a crystalline form of the compound represented by formula I includes washing a starting material with an organic solvent or the alcohol to form a wet cake. In another embodiment, the alcohol and the organic solvent are added together to form a mixture. In a further embodiment, the process further includes drying the wet cake. In one embodiment, the process includes drying the wet cake with nitrogen at about 20°C to about 40°C.

[0194] In one embodiment, the process for preparing a crystalline form of the compound represented by formula I further includes exposing the crystalline form of the compound represented by formula I to a relative humidity of about 5% to about 50% to bring about a second crystalline form of the compound represented by formula I. In one embodiment, the relative humidity is about 5%. In another embodiment, the relative humidity is about 50%.

[0195] In one embodiment of a process for preparing the crystalline form of a compound represented by formula I, the organic solvent is an ether, an ester, and a linear alkane (C3-C3). 10 ) are selected from. In a further embodiment, the ether is 2-Me-THF. In yet another embodiment, the ether is MTBE. In one embodiment, the ester is ethyl acetate. In another embodiment, the alkane is heptane.

[0196] In a particular embodiment of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is selected from acetate 2, acetate 3, acetate 4, acetate 5, and acetate 6, and the starting material is compound A (a chloride salt of the compound represented by formula I). ​​In another embodiment of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is selected from acetate 2, acetate 3, acetate 4, acetate 5, and acetate 6, and the starting material is compound B (a bicarbonate of the compound represented by formula I).

[0197] In a particular embodiment of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is selected from caprate 2, caprate 3, caprate 4, caprate 5, caprate 6, caprate 7, caprate 8, caprate 9, caprate 10, caprate 11, caprate 12, caprate 13 and caprate 14, and the starting material is compound A (a chloride salt of the compound represented by formula I). ​​In another embodiment of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is selected from caprate 2, caprate 3, caprate 4, caprate 5, caprate 6, caprate 7, caprate 8, caprate 9, caprate 10, caprate 11, caprate 12, caprate 13 and caprate 14, and the starting material is compound B (a bicarbonate of the compound represented by formula I).

[0198] In a particular embodiment of the process for preparing the crystalline form of the compound represented by formula I, the crystalline form of the compound represented by formula I is selected from D-lactate 1, succinate 1, L-tarlate 1, and sulfate 1, and the starting material is compound B (bicarbonate of the compound represented by formula I).

[0199] Treatment method In another embodiment, provided herein is a method for antagonizing PCSK9 function using a PCSK9-specific antagonist compound described herein (e.g., a compound represented by formula I); such method is further described below. Throughout this application, the use of the term “antagonizing” indicates providing to the affected tissue a substance that acts antagonistically to one or more functions of PCSK9 in the affected tissue, inhibiting, interfering with, neutralizing or suppressing such functions. Inhibition or antagonism of one or more functional properties related to PCSK9 can be readily confirmed according to methodologies known in the art (see, for example, "Barak & Webb, 1981 J. Cell Biol. 90:595-604", "Stephan & Yurachek, 1993 J. Lipid Res. 34:325330", and "McNamara et al., 2006 Clinica Chimica Acta 369:158-167"), in addition to those described herein. Inhibition or antagonism results in a decrease in PCSK9 activity compared to the activity observed in the absence of the antagonist, or compared to the activity observed, for example, in the presence of a control antagonist of irrelevant specificity. Preferably, PCSK9-specific antagonists according to the present invention antagonize PCSK9 function to the extent that there is a reduction of at least 10% of the measured parameter (which includes, but is not limited to, the activities disclosed herein), and more preferably, a reduction of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 95% of the measured parameter. Such inhibition / antagonism of PCSK9 function is particularly effective when PCSK9 function contributes at least partially to a particular phenotype, disease, disorder, or condition that is adversely affecting the subject.

[0200] In one embodiment, the present invention provides a method for antagonizing the activity of PCSK9, the method comprising contacting cells, cell populations, or tissue samples that may be affected by PCSK9 (i.e., expressing and / or containing an LDL receptor) with a PCSK9-specific antagonist disclosed herein (e.g., a compound represented by formula I) under conditions that allow the antagonist to bind to PCSK9 in the presence of PCSK9, thereby inhibiting PCSK9 from inhibiting cytoplasmic LDL uptake. Some embodiments of the present invention encompass such a method in which the cells are human cells. Further embodiments of the present invention encompass such a method in which the cells are mouse cells.

[0201] In one embodiment, the present invention provides a method for antagonizing the activity of PCSK9 in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the PCSK9-specific antagonist of the present invention. In some embodiments, the method for antagonizing the function of PCSK9 is a method for treating a disease, disorder or condition associated with PCSK9, as defined herein, or a method for providing a treatment for a disease, disorder or condition in which the effects of a PCSK9 antagonist can be beneficial.

[0202] Accordingly, the present invention intends to utilize the PCSK9-specific antagonists described herein in various therapeutic methods in which it is desirable to antagonize the function of PCSK9. Where used herein, the term “method of treatment” refers to a course of action that results in a change of at least one symptom of a disease condition, which may be substantially prophylactic or therapeutic. In some embodiments, the present invention relates to a method for treating a condition related to and / or caused by PCSK9 activity, or a condition in which the function of PCSK9 is contraindicated for a particular subject, wherein the method comprises administering to the subject a therapeutically effective amount of a PCSK9-antagonist compound represented by formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the condition may be atherosclerosis, hypercholesterolemia, peripheral artery disease, cerebrovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome or related cardiovascular and cardiometabolic diseases, or a medical condition or state in which PCSK9 activity is contraindicated.

[0203] In one embodiment, the use of a crystalline form of the compound represented by Formula I as an active ingredient in a pharmaceutical for the treatment of hypercholesterolemia in a subject is provided herein.

[0204] In one embodiment, provided herein is the use of a pharmaceutical composition comprising a crystalline form of a compound represented by formula I as a pharmaceutical for treating hypercholesterolemia in a subject.

[0205] In another embodiment, provided herein is the use of a crystalline form of the compound represented by formula I as an active ingredient in a pharmaceutical for lowering LDL-C in a subject.

[0206] In yet another embodiment, provided herein is the use of a crystalline form of the compound represented by formula I as an active ingredient in a pharmaceutical for treating atherosclerotic cardiovascular disease in a subject.

[0207] In one embodiment, a method for treating hypercholesterolemia is provided herein, the method comprising administering a therapeutically effective amount of a compound represented by formula I in crystalline form to a patient who is in need of treatment for hypercholesterolemia.

[0208] In one embodiment, the use of a crystalline form of the compound represented by formula I as an active ingredient in a pharmaceutical for the treatment of peripheral artery disease in subjects is provided herein.

[0209] In one embodiment, provided herein is the use of a pharmaceutical composition comprising a crystalline form of a compound represented by formula I as a pharmaceutical for treating peripheral artery disease in a subject.

[0210] In one embodiment, the use of Caprate 3 as an active ingredient in a pharmaceutical product for treating hypercholesterolemia in a subject is provided herein.

[0211] In one embodiment, the herein provides a pharmaceutical composition comprising caprate 3 as a pharmaceutical for treating hypercholesterolemia in a subject.

[0212] In another embodiment, provided herein is the use of caprate 3 as an active ingredient in a pharmaceutical for lowering LDL-C in a subject.

[0213] In yet another embodiment, provided herein is the use of caprate 3 as an active ingredient in a pharmaceutical product for treating atherosclerotic cardiovascular disease in a subject.

[0214] In one embodiment, a method for treating hypercholesterolemia is provided herein, the method comprising administering a therapeutically effective dose of caprate 3 to a patient in need of treatment for hypercholesterolemia.

[0215] In one embodiment, the use of Caprate 3 as an active ingredient in a pharmaceutical for the treatment of peripheral artery disease in subjects is provided herein.

[0216] In one embodiment, the herein provides a pharmaceutical composition comprising caprate 3 as a pharmaceutical for treating peripheral artery disease in a subject.

[0217] Pharmaceutical composition The therapeutic method according to the present invention comprises administering to an individual a therapeutically (or prophylactically) effective amount of the PCSK9-specific antagonist of the present invention. The use of the terms “therapeutically effective” or “prophylactically effective” in relation to the amount indicates the amount required in the dose intended to achieve the desired therapeutic and / or prophylactic effect for the desired period. The desired effect is, for example, the relief, improvement, reduction, or cessation of at least one symptom associated with the treated condition. These amounts will vary depending on various factors (which include, but are not limited to, the individual’s medical condition, age, sex, and weight, as well as the ability of the PCSK9-specific antagonist to produce the desired effect in the individual), as will be understood by those skilled in the art. The response may be demonstrated by in vitro assays, in vivo non-human animal studies, and / or further supported by clinical trials.

[0218] In some embodiments, the PCSK9 antagonist compound of the present invention is preferably administered in the form of a pharmaceutical composition as described herein.

[0219] The administration of antagonist drugs is within the scope of the art (see, for example, "Lederman et al., 1991 Int. J. Cancer 47:659-664" and "Bagshawe et al., 1991 Antibody, Immunoconjugates and Radiopharmaceuticals 4:915-922") and varies based on many factors (for example, but not limited to the factors described above, such as the patient's symptoms, the site of treatment, the route of administration, and the desired treatment, such as prevention or acute treatment). A physician or veterinarian with ordinary skill can easily determine and prescribe the effective therapeutic dose of the antagonist.

[0220] Subjects may require or desire treatment for a pre-existing disease or medical condition. Where used herein, "subjects requiring treatment for a pre-existing condition" encompass both a determination of need by a medical professional and the subject's desire for such treatment. The term "subject" as used herein refers to mammals, plants, lower animals, or cell cultures. In one embodiment, the subject is a human patient or other animal patient requiring treatment. Where a compound or a salt thereof is provided in combination with one or more other activators, "administration" and its variations are understood to encompass providing the compound or salt thereof and the other agents contemporaneously or simultaneously, or in the course of separate administrations over a period of time. When a combination of agents is administered contemporaneously, they may be administered together in a single composition or they may be administered separately. A "combination" of activators may be a single composition containing all of the activators, or it may be a group of compositions, each containing one or more of the activators. For example, in the case of two types of activators, the combination may be a single composition containing both activators, or two separate compositions, each containing one type of activator; in the case of three types of activators, the combination may be a single composition containing all three types of activators, or three separate compositions, each containing one type of activator, or two compositions, one containing two types of activators and the other containing a third activator; and so on.

[0221] The compositions and combinations of the present invention are appropriately administered in an effective dose. The term "effective dose" means an amount of the active compound sufficient to antagonize PCSK9 and thereby elicit the desired response [i.e., to induce a therapeutic response in the treatment or management of conditions associated with or affected by PCSK9 function (e.g., atherosclerosis, hypercholesterolemia, peripheral artery disease, cerebrovascular disease, coronary heart disease, metabolic syndromes, acute coronary syndromes, and related cardiovascular and cardiometabolic diseases in animals or humans)].

[0222] The actual dosage used may vary depending on the patient's needs and the severity of the symptoms being treated. Determining an appropriate dosage regimen for a particular situation is within the scope of those skilled in the art, as described in standard literature, for example, “Physicians' Desk Reference” (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA), “Physician's Desk Reference, 56th Edition, 2002 (published by Medical Economics Company, Inc. Montvale, NJ 07645-1742),” or “Physician's Desk Reference, 57th Edition, 2003 (published by Thompson PDR, Montvale, NJ 07645-1742)”; these disclosures are incorporated herein by reference. For convenience, the total daily dose may be divided and administered in multiple doses on the same day, or it may be administered continuously, as needed.

[0223] PCSK9-specific antagonists can be administered to an individual, either alone or in combination with other agents designed to adjunct the treatment of the individual, by any route of administration evaluated in the art (e.g., but not limited to, oral administration, injection (specific embodiments of which include intravenous, subcutaneous, intraperitoneal, or intramuscular injection), or inhalation, intranasal administration, or topical administration). The PCSK9-specific antagonist can also be administered by injection devices, syringe pens, needleless devices; and subcutaneous patch delivery systems. The route of administration should be determined based on many considerations evaluated by those skilled in the art (e.g., but not limited to, the desired physicochemical properties of the treatment).

[0224] Dosage and Formulation Furthermore, provided herein is a method for treating hypercholesterolemia in a person requiring treatment for hypercholesterolemia, wherein the method involves administering a specific amount of Formula I to the person. [ka] [In the ceremony, A - [Selected from pharmaceutically acceptable anions] This involves orally administering the crystalline form of the compound represented by formula I, where the specific amount administered is approximately 5 mg to approximately 300 mg of the compound represented by formula I.

[0225] The administration regimen is selected according to various factors (e.g., patient type, breed, age, weight, sex, and condition; severity of the symptoms being treated; route of administration; and patient's renal and hepatic function). A typical, experienced physician, veterinarian, or clinician can easily determine and prescribe the effective dose of medication necessary to prevent, manage, or halt the progression of the symptoms.

[0226] The forms of the present disclosure can be formulated and administered in solid dosage forms intended for oral administration (e.g., tablets, pills, capsules, powders, or granules). Formulation of the compositions according to the present disclosure can be easily carried out by methods known in the art, for example, as described in "Remington's Pharmaceutical Sciences, 18th ed., 1990, and Remington: The Science and Practice of Pharmacy, 22nd ed., 2012." Furthermore, the forms of the present disclosure can be formulated and administered in sterile solutions for enteral (oral), parenteral, intravenous, or intramuscular administration.

[0227] In the methods of this disclosure, the forms described herein can be formulated as active pharmaceutical ingredients and administered in mixture with appropriate pharmaceutically acceptable diluents, excipients, or carriers (collectively referred to herein as "carrier" materials) that are appropriately selected with respect to the intended dosage form and consistent with conventional pharmaceutical practices (i.e., oral tablets, oral capsules, oral suspensions, oral formulations, or sterile solutions for parenteral, intravenous, or intramuscular administration).

[0228] For example, when administered orally in the form of tablets or capsules, the forms described herein can be combined with a non-toxic, pharmaceutically acceptable inert carrier for oral use (e.g., lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.). When administered parenterally, intravenously, or intramuscularly in the form of a sterile solution, the forms described herein can be combined with appropriate excipients and a non-toxic, pharmaceutically acceptable inert carrier to form a preparation that can be provided as a prepared dosage form in a pre-filled injection device, as a lyophilized preparation reconstituted for injection, or as a sterile liquid diluted for injection.

[0229] In one embodiment, the dose administered to the subject is a crystalline form of the compound represented by formula I, ranging from approximately 5 mg to approximately 300 mg. Integers and half-integers between 5 mg and 300 mg are included in the present invention. In one embodiment, the dose is a crystalline form of the compound represented by formula I, ranging from approximately 10 mg to approximately 300 mg. In one embodiment, the dose is a crystalline form of the compound represented by formula I, ranging from approximately 10 mg, approximately 20 mg, or approximately 22 mg. In one embodiment, the dose is a crystalline form of the compound represented by formula I, ranging from approximately 5 mg, approximately 6 mg, approximately 10 mg, approximately 12 mg, approximately 15 mg, approximately 18 mg, approximately 20 mg, approximately 22 mg, approximately 24 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, or approximately 100 mg. In one embodiment, the dosage is approximately 10 mg, approximately 12 mg, approximately 15 mg, approximately 18 mg, approximately 20 mg, approximately 22 mg, approximately 24 mg, approximately 25 mg, approximately 30 mg, or approximately 40 mg of the crystalline form of the compound represented by formula I. In one embodiment, the dose is the crystalline form of the compound represented by formula I in amounts of about 10, about 10.5, about 11, about 11.5, about 12, about 12.5, about 13, about 13.5, about 14, about 14.5, about 15, about 15.5, about 16, about 16.5, about 17, about 17.5, about 18, about 18.5, about 19, about 19.5, about 20, about 20.5, about 21, about 21.5, about 22, about 22.5, about 23, about 23.5, about 24, about 24.5, about 25, about 25.5, about 26, about 26.5, about 27, about 27.5, about 28, about 28.5, about 29, about 29.5, or about 30 mg. In one embodiment, the dose is a daily dose of about 5 mg to about 300 mg. In one embodiment, the dose is a daily dose of the crystalline form of the compound represented by Formula I, approximately 10, approximately 10.5, approximately 11, approximately 11.5, approximately 12, approximately 12.5, approximately 13, approximately 13.5, approximately 14, approximately 14.5, approximately 15, approximately 15.5, approximately 16, approximately 16.5, approximately 17, approximately 17.5, approximately 18, approximately 18.5, approximately 19, approximately 19.5, approximately 20, approximately 20.5, approximately 21, approximately 21.5, approximately 22, approximately 22.5, approximately 23, approximately 23.5, approximately 24, approximately 24.5, approximately 25, approximately 25.5, approximately 26, approximately 26.5, approximately 27, approximately 27.5, approximately 28, approximately 28.5, approximately 29, approximately 29.5, approximately 30 mg, approximately 35 mg, or approximately 40 mg.In one embodiment, the dose is a daily dose of the crystalline form of the compound represented by formula I in the form of approximately 5, approximately 6, approximately 10, approximately 12, approximately 15, approximately 18, approximately 20, approximately 22, approximately 22.5, approximately 24, approximately 25, or approximately 30 mg.

[0230] In one embodiment, the amount of formula I administered to the subject is approximately 10 mg to approximately 40 mg of the crystalline form of the compound represented by formula I. In another embodiment, the amount of formula I administered to the subject is approximately 10 mg to approximately 30 mg of the crystalline form of the compound represented by formula I. In yet another embodiment, the amount administered to the subject is approximately 12 mg to approximately 27 mg of the crystalline form of the compound represented by formula I. In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 25 mg of the crystalline form of the compound represented by formula I. In one embodiment, the amount administered to the subject is approximately 10 mg to approximately 22.5 mg of the crystalline form of the compound represented by formula I. In another embodiment, the amount administered to the subject is approximately 10 mg to approximately 20 mg of the crystalline form of the compound represented by formula I. In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 20 mg of the crystalline form of the compound represented by formula I.

[0231] In one embodiment, the amount administered to the subject is approximately 10 mg to approximately 30 mg of caprate 3. In another embodiment, the amount administered to the subject is approximately 12 mg to approximately 27 mg of caprate 3. In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 25 mg of caprate 3. In one embodiment, the amount administered to the subject is approximately 10 mg to approximately 22 mg of caprate 3. In one embodiment, the amount administered to the subject is approximately 10 mg to approximately 20 mg of caprate 3. In yet another embodiment, the amount administered to the subject is approximately 15 mg to approximately 22 mg of caprate 3. In one embodiment, the amount is a daily dose of caprate 3 of approximately 10, approximately 10.5, approximately 11, approximately 11.5, approximately 12, approximately 12.5, approximately 13, approximately 13.5, approximately 14, approximately 14.5, approximately 15, approximately 15.5, approximately 16, approximately 16.5, approximately 17, approximately 17.5, approximately 18, approximately 18.5, approximately 19, approximately 19.5, approximately 20, approximately 20.5, approximately 21, approximately 21.5, approximately 22, approximately 22.5, approximately 23, approximately 23.5, approximately 24, approximately 24.5, approximately 25, approximately 25.5, approximately 26, approximately 26.5, approximately 27, approximately 27.5, approximately 28, approximately 28.5, approximately 29, approximately 29.5, or approximately 30 mg. In one embodiment, the amount is a daily dose of caprate 3 of about 15, about 15.5, about 16, about 16.5, about 17, about 17.5, about 18, about 18.5, about 19, about 19.5, about 20, about 20.5, about 21, about 21.5, or about 22 mg. In yet another embodiment, the amount administered to a subject in need is about 15 mg, about 17.5 mg, 18 mg, about 20 mg, or about 22 mg of caprate 3. In yet another embodiment, the amount administered to a subject in need is about 20 mg, or about 22 mg of caprate 3. In yet another embodiment, the amount administered to a subject in need is about 20 mg of caprate 3. In yet another embodiment, the amount administered to a subject in need is about 22 mg of caprate 3.

[0232] It should be understood that a specific dose of the crystalline form of the compound represented by formula I corresponds to a dose of the corresponding free form of the compound represented by formula I. For example, a dose of approximately 22 mg of caprate 3 corresponds to a dose of approximately 20 mg of the corresponding free form of the compound represented by formula I.

[0233] In one embodiment, oral administration includes administering a single oral dosage form containing the crystalline form of the compound represented by formula I in such amount. In one embodiment, oral administration includes administering two or more oral dosage forms, each containing the crystalline form or a portion thereof of the compound represented by formula I in such amount. In one embodiment, oral administration includes administering a single oral dosage form containing the crystalline form of the compound represented by formula I once daily. In one embodiment, oral administration includes administering two or more oral dosage forms, each containing the crystalline form or a portion thereof of the compound represented by formula I, once daily. In one embodiment, oral administration includes administering a single oral dosage form containing the crystalline form of the compound represented by formula I two or more times a day (e.g., two, three, or four times a day). In one embodiment, oral administration includes administering two or more oral dosage forms, each containing the crystalline form or a portion thereof of the compound represented by formula I, two or more times a day (e.g., two, three, or four times a day). The oral dosage forms can be administered with or without fasting, i.e., with or without food. In one embodiment, the subject requiring treatment fasts for approximately 30 minutes before administration of the crystalline form of the compound represented by formula I.

[0234] In one embodiment, a single oral dosage form is administered once daily for at least 14 days. In one embodiment, a single oral dosage form is administered once daily for 14 days. In one embodiment, a single oral dosage form is administered once daily for as long as the subject requires treatment.

[0235] Where used herein, “oral dosage form” refers to a pharmaceutical formulation comprising the crystalline form of the compound represented by Formula I and at least one pharmaceutically acceptable excipient, and suitable for administration by mouth to an subject. Where used herein, the terms “oral dosage form” and “pharmaceutical composition” are intended to encompass both a specified amount of a specified combination of specified components and any products arising directly or indirectly from a specified amount of a specified combination of specified components. An oral dosage form may contain the entire amount of the crystalline form of the compound represented by Formula I (e.g., about 5 mg to about 300 mg), which may or may not be a daily dose. An oral dosage form may contain a portion of a daily dose of the crystalline form of the compound represented by Formula I.

[0236] The oral dosage forms provided in this disclosure may be solid, semi-solid, or liquid. Such oral dosage forms include, but are not limited to, powders, dispersible granules, minitablets and beads (which may be used, for example, for tableting, encapsulation, or direct administration), pills, tablets, lacquered tablets, sugar-coated tablets, hard and soft capsules (e.g., gelatin capsules), lozenges, rapidly dissolving tablets, aqueous, alcoholic, or oily solutions, gels, syrups, emulsions, or suspensions. The oral dosage forms provided in this disclosure may further include formulations having one or more coatings that modify the release properties (e.g., coatings that impart delayed release) or sustained-release properties. Furthermore, this disclosure also includes formulations intended to be converted into a suspension or solution immediately before use; examples of such formulations include, but are not limited to, lyophilized formulations and liquid formulations adsorbed onto a solid absorbent medium. In one embodiment, the oral dosage form is a liquid-filled capsule, for example, a hard gelatin capsule filled with the crystalline form of the compound represented by formula I in a combination of Labrasol® and propylene glycol in a ratio of, for example, 2:1. In one embodiment, the oral dosage form is a liquid-filled capsule, for example, a hard gelatin capsule filled with the crystalline form of the compound represented by formula I in a combination of Labrasol® and propylene glycol in a ratio of, for example, 2:1, and is over-encapsulated with an enteric-coated capsule, for example, HPMC Vcaps® Enteric capsule (Capsugel®, Lonza). In one embodiment, the oral dosage form is a suspension, for example, the crystalline form of the compound represented by formula I suspended in a combination of OraBlend SF and propylene glycol in a ratio of, for example, 2:1. In one embodiment, the oral dosage form is a dry-filled enteric-coated capsule, for example, a dry-filled HPMC Vcaps® Enteric capsule (Capsugel®, Lonza). In one embodiment, the oral dosage form is a tablet. In a further embodiment, the oral administration form is a film-coated tablet.

[0237] In one embodiment, the pharmaceutical composition provided herein comprises a diluent selected from polyethylene glycol (polyethylene glycol of various molecular weights greater than 300), microcrystalline cellulose, mannitol, starch, dicalcium phosphate, calcium carbonate, sodium carbonate, lactose, or a combination thereof. In another embodiment, the pharmaceutical composition provided herein comprises a diluent selected from PEG300, macrogol (PEG4000), microcrystalline cellulose, mannitol, lactose, or a combination thereof. In a further embodiment, the diluent is selected from PEG300, macrogol (PEG4000), microcrystalline cellulose, or lactose.

[0238] In one embodiment, the pharmaceutical composition provided herein comprises a binder selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, or polyvinylpyrrolidone. In a further embodiment, the binder is hydroxypropylcellulose. In one embodiment, the binder is used in wet granulation (high shear granulation, twin screw granulation, or fluid bed granulation).

[0239] In one embodiment, the pharmaceutical composition provided herein comprises a disintegrant selected from croscarmellose sodium, crospovidone, or sodium starch glycolate. In a further embodiment, the disintegrant is croscarmellose sodium. In one embodiment, the pharmaceutical composition of the present invention comprises a flow enhancer selected from silicon dioxide, starch, talc, magnesium stearate, or tricalcium phosphate. In a further embodiment, the flow enhancer is selected from silicon dioxide or tricalcium phosphate. In one embodiment, the pharmaceutical composition of the present invention comprises a lubricant selected from magnesium stearate or sodium stearyl fumarate or both. In one embodiment, the pharmaceutical composition of the present invention comprises a solubilizer selected from propylene glycol, polysorbate 80, sorbitol, cremohol EL, castor oil, corn oil, cottonseed oil, safflower oil, sesame oil, soybean oil, peppermint oil, olive oil, migliol, glycerin, or a combination thereof. In a further embodiment, the solubilizer is propylene glycol.

[0240] In one embodiment, the oral dosage form further comprises an osmotic enhancer. As used herein, “osmotic enhancer” refers to a pharmaceutically acceptable excipient that enhances the absorption of an activator (e.g., the crystalline form of the compound represented by formula I) from the gastrointestinal tract. Osmotic enhancers result in the absorption of cell-impermeable compounds by promoting size-restricted movement through tight junctions between intestinal epithelial cells. (DJ Drucker, Advances in oral peptide therapeutics, Nat Rev Drug Discov, 19, pp 277-289 (2020)). Suitable osmotic enhancers include, but are not limited to, sodium caprate, Labrasol®, sodium salcaprozate (SNAC), and combinations thereof. Labrasol®, also known as caprylocaproyl macrogol-8 glyceride, is manufactured by Gattefosse, Saint Priest, Lyon, France. In one embodiment, the oral dosage form comprises Labrasol®. In one embodiment, the oral dosage form comprises sodium caprate. When present in the oral administration form, an amount of osmotic enhancer may be used in amounts up to 1800 mg, up to approximately 720 mg, up to approximately 540 mg, up to approximately 360 mg, in the range of approximately 90 mg to approximately 360 mg, in the range of approximately 180 mg to approximately 360 mg, or in amounts of 90 mg, 180 mg, or 360 mg. In the embodiments provided herein, the oral administration form includes an amount of osmotic enhancer up to approximately 360 mg, in the range of approximately 90 mg to approximately 360 mg, in the range of approximately 180 mg to approximately 360 mg, or in amounts of 90 mg, 180 mg, or 360 mg. In one embodiment, the oral administration form provided herein includes an amount of osmotic enhancer in the range of 90 mg, 180 mg, or 360 mg. In one embodiment, the oral administration form of the present invention includes an amount of osmotic enhancer in the range of 180 mg or 360 mg.

[0241] When present in an oral dosage form, amounts of sodium caprate are used in amounts up to approximately 360 mg, in the range of approximately 90 mg to approximately 360 mg, in the range of approximately 180 mg to approximately 360 mg, or in amounts of 90 mg, 180 mg, or 360 mg. In one embodiment, the oral dosage form provided herein contains 90 mg, 180 mg, or 360 mg of the osmotic enhancer sodium caprate. In one embodiment, 180 mg of sodium caprate is used in the oral dosage form. In one embodiment, 360 mg of sodium caprate is used in the oral dosage form.

[0242] In one embodiment, a crystalline form of the compound represented by formula I can be administered to subjects who require such administration using dry-filled capsules or tablets. The pharmaceutical compositions provided herein may include an osmotic enhancer. In one embodiment, the amount of an osmotic enhancer, such as sodium caprate, may range from about 1% by weight to about 75% by weight. Where used herein, "by weight" refers to the weight percentage of the component relative to the total weight of the pharmaceutical composition. In another embodiment, the amount of an osmotic enhancer in the pharmaceutical composition is about 18% by weight to about 65% by weight. In a further embodiment, the amount of an osmotic enhancer in the pharmaceutical composition is about 22% by weight to about 36% by weight. In the case of tablets, the amount of an osmotic enhancer, such as sodium caprate, may range from about 22% by weight to about 65% by weight. Oral dosage forms can be manufactured by standard methods such as wet granulation and dry granulation.

[0243] Table 27: Examples of formulations using Caprate 3 [Table 27]

[0244] In one embodiment, the formula provided herein is: [ka] [In the ceremony, A - [This is a pharmaceutically acceptable anion.] The pharmaceutical composition comprises a crystalline form of a compound represented by and a penetration enhancer. In a further embodiment, the penetration enhancer is sodium caprate. In another embodiment, the pharmaceutical composition further comprises a diluent. In a further embodiment, the composition comprises two or more diluents, wherein the two or more diluents include a combination of microcrystalline cellulose, macrogol (PEG4000), and lactose. In a further embodiment, the composition comprises two or more diluents, wherein the two or more diluents include a combination of microcrystalline cellulose (Avicel PH 102), macrogol (PEG 4000), and lactose.

[0245] In one embodiment, the pharmaceutical composition contains a crystalline form of the compound represented by formula I in an amount of about 1% to about 8% by weight relative to the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition contains a crystalline form of the compound represented by formula I in an amount of about 1% to about 6% by weight relative to the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition contains a crystalline form of the compound represented by formula I in an amount of about 4% by weight relative to the total weight of the pharmaceutical composition.

[0246] In another embodiment of the present invention, the pharmaceutical composition comprises about 22.5% to about 50% by weight of a penetration enhancer based on the total weight of the pharmaceutical composition. In yet another embodiment, the pharmaceutical composition comprises about 33% by weight of a penetration enhancer based on the total weight of the pharmaceutical composition.

[0247] In one embodiment, the pharmaceutical composition comprises at least one diluent. In another embodiment, the pharmaceutical composition comprises two diluents. In one embodiment, the diluent or combination of diluents comprises about 10% to about 70% by weight, about 20% to about 60% by weight, about 30% to about 50% by weight, or about 40% to about 50% by weight of the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises about 15% to about 72% by weight of the diluent based on the total weight of the pharmaceutical composition. In one embodiment, the diluent constitutes about 40% to about 72% by weight of the total weight of the pharmaceutical composition and is present in the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 58% by weight of the diluent based on the total weight of the pharmaceutical composition.

[0248] In one embodiment, the pharmaceutical composition includes a disintegrant. In one embodiment, the pharmaceutical composition contains a disintegrant in an amount of about 0% to about 3% by weight relative to the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition contains a disintegrant in an amount of about 3% by weight relative to the total weight of the pharmaceutical composition.

[0249] In one embodiment, the pharmaceutical composition comprises a flow promoter. In one embodiment, the pharmaceutical composition comprises about 0% to about 1% by weight of the flow promoter relative to the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises about 1% by weight of the flow promoter relative to the total weight of the pharmaceutical composition.

[0250] In one embodiment, the pharmaceutical composition contains a lubricant. In one embodiment, the pharmaceutical composition contains a lubricant in an amount of about 1% to about 1.5% by weight relative to the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition contains a lubricant in an amount of about 1% by weight relative to the total weight of the pharmaceutical composition.

[0251] In embodiments of the present invention, the pharmaceutical composition comprises (a) about 1% to about 8% by weight of a compound represented by formula I based on the total weight of the pharmaceutical composition; (b) about 1% to about 80% by weight of a penetration enhancer based on the total weight of the pharmaceutical composition; (c) at least one diluent; (d) optionally a flow enhancer and / or lubricant. In one embodiment, the pharmaceutical composition contains about 18% to about 74% by weight of a penetration enhancer based on the total weight of the pharmaceutical composition. In another embodiment of the present invention, the pharmaceutical composition comprises (a) about 1% to about 7% by weight of a compound represented by formula I based on the total weight of the pharmaceutical composition; (b) about 22% to about 67% by weight of a penetration enhancer selected from sodium caprate or Labrasol® based on the total weight of the pharmaceutical composition; (c) at least one diluent or solubilizer selected from PEG4000, microcrystalline cellulose, propylene glycol and lactose; (d) optionally a flow enhancer; and (e) optionally a lubricant. In further embodiments, the pharmaceutical composition further comprises a penetration enhancer selected from sodium caprate or Labrasol® in an amount of about 22% to about 36% by weight, relative to the total weight of the pharmaceutical composition.

[0252] In one embodiment of the present invention, provided herein is a pharmaceutical composition comprising: (a) a crystalline form of a compound represented by formula I in an amount of about 1% to about 8% by weight relative to the total weight of the pharmaceutical composition; (b) a penetration enhancer in an amount of about 22.5% to about 80% by weight relative to the total weight of the pharmaceutical composition (wherein the penetration enhancer is sodium caprate); (c) two diluents selected from microcrystalline cellulose and lactose (wherein the combination of diluents is about 15% by weight relative to the total weight of the pharmaceutical composition) (d) comprising a diluent in an amount of approximately 72% by weight; (e) optionally a disintegrant (wherein the pharmaceutical composition contains a disintegrant in an amount of approximately 0% to approximately 3% by weight relative to the total weight of the pharmaceutical composition); (f) optionally a flow promoter (wherein the pharmaceutical composition contains a flow promoter in an amount of approximately 0% to approximately 1% by weight relative to the total weight of the pharmaceutical composition, wherein the flow promoter is silicon dioxide); and (g) a lubricant in an amount of approximately 1% to approximately 1.5% by weight relative to the total weight of the pharmaceutical composition (wherein the lubricant is magnesium stearate).

[0253] In one embodiment of the present invention, provided herein is a pharmaceutical composition comprising: (a) a crystalline form of a compound represented by formula I in an amount of about 1% to about 6% by weight relative to the total weight of the pharmaceutical composition; (b) a penetration enhancer in an amount of about 22.5% to about 50% by weight relative to the total weight of the pharmaceutical composition (wherein the penetration enhancer is sodium caprate); (c) two diluents selected from microcrystalline cellulose and lactose (wherein the combination of the diluents constitutes a diluent in an amount of about 40% to about 72% by weight relative to the total weight of the pharmaceutical composition); (d) a disintegrant in an amount of about 3% by weight relative to the total weight of the pharmaceutical composition; (e) a flow enhancer in an amount of about 1% by weight relative to the total weight of the pharmaceutical composition (wherein the flow enhancer is silicon dioxide); and (f) a lubricant in an amount of about 1% by weight relative to the total weight of the pharmaceutical composition (wherein the lubricant is magnesium stearate).

[0254] In one embodiment of the present invention, provided herein is a pharmaceutical composition comprising: (a) a crystalline form of a compound represented by formula I in about 4% by weight relative to the total weight of the pharmaceutical composition; (b) a penetration enhancer in about 33% by weight relative to the total weight of the pharmaceutical composition (wherein the penetration enhancer is sodium caprate); (c) two diluents selected from microcrystalline cellulose and lactose (wherein the combination of the diluents constitutes about 58% by weight of the diluent relative to the total weight of the pharmaceutical composition); (d) a disintegrant in about 3% by weight relative to the total weight of the pharmaceutical composition; (e) a flow enhancer in about 1% by weight relative to the total weight of the pharmaceutical composition (wherein the flow enhancer is silicon dioxide); and (f) a lubricant in about 1% by weight relative to the total weight of the pharmaceutical composition (wherein the lubricant is magnesium stearate).

[0255] In one embodiment of the present invention, the pharmaceutical composition comprises: (a) a crystalline form of a compound represented by formula I in an amount of about 2% to about 6% by weight relative to the total weight of the pharmaceutical composition; (b) a penetration enhancer in an amount of about 18% to about 74% by weight relative to the total weight of the pharmaceutical composition (where the penetration enhancer is sodium caprate); (c) at least one diluent selected from PEG4000, microcrystalline cellulose, or lactose; (d) a flow enhancer in an amount of about 0% to about 3% by weight relative to the total weight of the pharmaceutical composition (where the flow enhancer is silicon dioxide); (e) a lubricant in an amount of about 0% to about 2% by weight relative to the total weight of the pharmaceutical composition (where the lubricant is magnesium stearate); and (f) optionally at least one disintegrant.

[0256] In the above embodiment, the diluent constitutes approximately 10% to 70% by weight, approximately 20% to 60% by weight, approximately 30% to 50% by weight, or approximately 40% to 50% by weight, based on the total weight of the pharmaceutical composition.

[0257] In another embodiment of the present invention, provided herein is a pharmaceutical composition comprising: (a) a crystalline form of a compound represented by formula I in about 4% by weight relative to the total weight of the pharmaceutical composition; (b) a penetration enhancer in about 33% by weight relative to the total weight of the pharmaceutical composition (wherein the penetration enhancer is sodium caprate); (c) one or more diluents selected from microcrystalline cellulose or lactose in about 58% by weight relative to the total weight of the pharmaceutical composition; (d) a flow enhancer in about 1% by weight relative to the total weight of the pharmaceutical composition (wherein the flow enhancer is silicon dioxide); (e) a lubricant in about 1% by weight relative to the total weight of the pharmaceutical composition (wherein the lubricant is magnesium stearate); and (f) at least one disintegrant in about 3% by weight relative to the total weight of the pharmaceutical composition.

[0258] In one embodiment, the pharmaceutical composition provided herein comprises caprate 3, a pharmaceutically acceptable anion, and a penetration enhancer. In a further embodiment, the penetration enhancer is sodium caprate. In another embodiment, the pharmaceutical composition further comprises a diluent. In a further embodiment, the composition comprises two or more diluents, wherein the two or more diluents constitute a combination of microcrystalline cellulose, macrogol (PEG4000), and lactose.

[0259] In one embodiment of the present invention, the pharmaceutical composition comprises (a) about 1% to about 8% by weight of caprate 3 relative to the total weight of the pharmaceutical composition; (b) about 1% to about 75% by weight of a penetration enhancer relative to the total weight of the pharmaceutical composition; (c) at least one diluent; (d) optionally a flow enhancer and / or lubricant. In one embodiment, the pharmaceutical composition contains about 18% to about 74% by weight of a penetration enhancer relative to the total weight of the pharmaceutical composition. In another embodiment of the present invention, the pharmaceutical composition comprises (a) about 1% to about 8% by weight of caprate 3 relative to the total weight of the pharmaceutical composition; (b) about 22% to about 67% by weight of a penetration enhancer selected from sodium caprate or Labrasol® relative to the total weight of the pharmaceutical composition; (c) at least one diluent or solubilizer selected from PEG4000, microcrystalline cellulose, propylene glycol and lactose; (d) optionally a flow enhancer; and (e) optionally a lubricant.

[0260] In the above embodiment, the diluent or solubilizer constitutes approximately 10% to approximately 70% by weight, approximately 20% to approximately 60% by weight, approximately 30% to approximately 60% by weight, or approximately 40% to approximately 60% by weight, based on the total weight of the pharmaceutical composition.

[0261] In one embodiment of the present invention, the pharmaceutical composition comprises (a) about 2% to about 6% by weight of caprate 3 relative to the total weight of the pharmaceutical composition; (b) about 18% to about 74% by weight of a penetration enhancer relative to the total weight of the pharmaceutical composition (wherein the penetration enhancer is sodium caprate); (c) at least one diluent selected from PEG4000, microcrystalline cellulose, or lactose; (d) 0% to about 3% by weight of a flow enhancer relative to the total weight of the pharmaceutical composition (wherein the flow enhancer is silicon dioxide); (e) 0% to about 2% by weight of a lubricant relative to the total weight of the pharmaceutical composition (wherein the lubricant is magnesium stearate); and (f) optionally at least one disintegrant.

[0262] In the above embodiment, the diluent or solubilizer constitutes approximately 10% to approximately 70% by weight, approximately 20% to approximately 60% by weight, approximately 30% to approximately 50% by weight, or approximately 40% to approximately 50% by weight, based on the total weight of the pharmaceutical composition.

[0263] In another embodiment of the present invention, provided herein is a pharmaceutical composition comprising: (a) about 4% by weight of caprate 3 relative to the total weight of the pharmaceutical composition; (b) about 33% by weight of a penetration enhancer relative to the total weight of the pharmaceutical composition (wherein the penetration enhancer is sodium caprate); (c) about 58% by weight of one or more diluents selected from PEG4000, microcrystalline cellulose or lactose relative to the total weight of the pharmaceutical composition; (d) about 1% by weight of a flow enhancer relative to the total weight of the pharmaceutical composition (wherein the flow enhancer is silicon dioxide); (e) about 1% by weight of a lubricant relative to the total weight of the pharmaceutical composition (wherein the lubricant is magnesium stearate); and (f) about 3% by weight of at least one disintegrant relative to the total weight of the pharmaceutical composition.

[0264] The present disclosure will be further illustrated by the following examples and synthesis, but these are not intended to limit the scope or spirit of the present disclosure. Those skilled in the art will readily recognize a variety of non-essential parameters that can be changed or modified to obtain essentially identical or similar results. [Examples]

[0265] Examples Preparation examples of the crystalline form of the compound represented by formula I Synthesis of the compound represented by formula I Compounds represented by formula I and methods for producing the same are illustrated in PCT International Patent Application Publication No. WO2019 / 246349, the entire publication of which is incorporated herein by reference. As demonstrated in Example 25 of International Patent Application Publication No. WO2019 / 246349, compound A has Ki Plus at 0.01127 nm and Ki Ultra at 0.00463 nm, as shown in the PCSK9 Alexa FRET Ultra assay.

[0266] Example 1A: Preparation of freeze-dried acetate 1 (amorphous acetate) Macroporous anion exchange resin AG MP-1M (6g, 100-200 mesh, chloride form) was packed into a 60mL funnel. The packed resin was washed five times with 9mL of acetonitrile (MeCN) / water (1:1 ratio) mixture. The resin was then washed with 200mL of 1M sodium hydroxide (NaOH), followed by 50mL of 1M acetic acid (AcOH) in water. The resin was transferred to a 100mL round-bottom flask containing a solution of compound A (0.3g) dissolved in 6mL of acetonitrile / water mixture (1:1). An additional 18mL of MeCN / water (1:1) was added. The mixture was aged at room temperature for 30 minutes, and the resulting mixture was transferred to a 60mL funnel. The filtrate was collected in a 20mL vial, the resin was washed three times with 10mL of MeCN / water (1 / 1), and the filtrate was collected in a 20mL vial. The fractions containing acetate 1 were combined, concentrated, and MeCN was removed. The solution was then freeze-dried to isolate the target amorphous acetate 1 (0.304 g).

[0267] Example 1B: Alternative preparation of acetate 1 Macroporous anion exchange resin AG 1-X2 (8.1 g, 100-200 mesh, acetate form) was packed into a 100 mL filtered funnel. The resin was washed with water (UPLC LC-MS grade, 5 × 12.5 mL; the first three washing fractions were not clear, so the resin was continued to be washed by slurring and applying reduced pressure until the eluate was clear). The resin was eluted by gravity using 10 mL of water and transferred to an empty solid-load cartridge of Redi Sep Rf (Teledyne ISCO). Compound A (0.3 g, 0.189 mmol) was dissolved in 3 mL of water. The solution of compound A was loaded into the cartridge. The resulting compound, acetate 1, was eluted with water (25 mL). The solution was freeze-dried to isolate acetate 1 (0.29 g).

[0268] Example 2: Preparation of lyophilized caprate 1 (amorphous caprine salt) Macroporous anion exchange resin AG MP-1M (6g, 100-200 mesh, chloride form) was packed into a 60mL funnel. The packed resin was washed five times with 9mL of acetonitrile / water (1:1) mixture. The resin was then washed with 200mL of 1M NaOH, followed by two washes with 10mL of water. The resin was transferred to a glass column and washed three times with 10mL of water. The resin was then washed twice with 10mL of ethanol (EtOH), followed by two washes with 9mL of 1M capric acid solution in EtOH, and then three washes with 9mL of EtOH. Compound A (0.3g) was dissolved in 6mL of MeCN / water (1:1) and loaded onto the resin-packed column. The filtrate was collected in a 20mL vial. The column was washed three times with 15 mL of MeCN / aqueous solution (1:1), and the filtrate was collected in a 20 mL vial. The fractions containing caprate 1 were combined, concentrated to remove MeCN, and then freeze-dried to isolate the target amorphous caprate 1 (0.29 g).

[0269] Example 3: Preparation of Acetate 2 Acetate 1 (25.5 mg) was added to a vial, and 2-Me-THF (250 μL) was added. The slurry was aged at room temperature. n-BuOH (150 μL) was added, and the mixture was aged until homogeneous. The homogeneous solution was aged at room temperature for 4 days to obtain a white slurry. Microscopic images of the slurry showed that it contained needle-shaped crystals (acetate 2).

[0270] Example 4: Preparation of Acetate 3 In a round-bottom flask, acetate 1 (37 g) was dissolved in 3 volumes of 1-propanol (111 mL). The solution was aged at 25°C for 20 minutes. 2-Me-THF (46.7 mL) was added. Seed crystals of acetate 2 were added as a slurry, and the mixture was aged for 40 minutes. The remaining seed crystal slurry was added. 2-Me-THF (174 mL) was added over 10 hours at 25°C. The mixture was aged for 4 hours after the addition of 2-Me-THF to obtain acetate 3.

[0271] Example 5: Preparation of Acetate 4 The mixture from Example 4 (Acetate 3) was filtered under reduced pressure, and the wet cake was washed with an n-propanol-2-Me-THF mixture (1:4.3, w / w), followed by a second wash with 2-Me-THF. The solid was dried at ambient temperature for 4 days using nitrogen (N2) to obtain Acetate 4.

[0272] Example 6: Alternative preparation of acetate 1 Acetate 4 (1.755 g) was added to the vial. Wet MeTHF (2% by weight of water in 2-methyltetrahydrofuran (2-MeTHF, 19.99 g)) was added, and the resulting slurry was aged at room temperature. The slurry was filtered, and the wet cake was dried under reduced pressure for 1 hour while sweeping the air. A white solid of acetate 1 (1.75 g) was obtained.

[0273] Example 7: Preparation of Acetate 5 Acetate 1 (4.787 g) was dissolved in 14.4 mL of nPrOH. 2-MeTHF (6.2 mL) was added over 5 minutes while stirring. The Karl Fischer (KF) of the resulting solution was 7628 ppm. An additional 2 mL of 2-MeTHF was added. Seed crystals of acetate 2 were added as a slurry. The resulting slurry was aged at room temperature for 15 minutes. 20.7 mL of 2-MeTHF was slowly added at room temperature over 5 hours. After the addition was complete, the slurry was aged for a further 22 hours. The slurry was filtered, and the wet cake was washed twice with 5 mL of 2-MeTHF to obtain acetate 5.

[0274] Example 8: Preparation of Acetate 6 The wet cake from Example 7 (acetate 5) was dried under reduced pressure while sweeping with N2. A white solid was obtained as acetate 6.

[0275] Example 9: Preparation of Caplate 4 In a glass container, Caprete 1 (40g) was dissolved in 3 volumes of 1-propanol (120mL). The solution was aged at 20°C for 20 minutes. MTBE was added to the solution (14.4mL). The mixture was heated to 28-28.5°C and dissolved. The solution was cooled to 25°C, and the resulting seed crystal of Caprete 4 was added as a slurry. The mixture was aged for 20 minutes, and then MTBE solvent (225.6mL) was added over 10 hours. The suspension was aged at 25°C for 8.5 hours to obtain Caprete 4.

[0276] Example 10: Preparation of Caplate 5 The suspension of Example 10 (Caprate 4) was filtered and washed with MTBE-20% 1-propanol. The solid was dried under an N2 blanket for an extended period (approximately 118 hours) to remove the 1-propanol and MTBE, yielding Caprate 5.

[0277] Example 11: Preparation of Caplate 2 Caprete 5 (1.838 g) was added to a vial, followed by a three-component solvent mixture containing methyl tert-butyl ether (MTBE), 38.3% by weight of n-propanol, and 0.99% by weight of water. The mixture was aged for 3 hours to obtain Caprete 2.

[0278] Example 12A: Preparation of Caprate 3 The mixture from Example 11 (Caprete 2) was filtered by centrifugation using a centrifugal filter. This cake was air-dried under ambient conditions for 2 hours to obtain Caprete 3.

[0279] Example 12B: Alternative preparation of caprate 3 Compound A (chloride salt, 700g) was dissolved in a 1 / 4 mixture of acetonitrile and water (8.4L) at 20°C, and the solution was heated to 35°C. This solution was then mixed with 3.0M aqueous KHCO3 (7.0L; the KHCO3 solution was prepared at 35°C and maintained at 35°C to prevent precipitation), stirred for 10 minutes, and the layers were separated while maintaining the temperature at 35°C. The organic phase was then combined with a 1 / 4 mixture of acetonitrile and water (0.7L) and 3.0M aqueous KHCO3 (7.0L), stirred for 10 minutes, and the layers were separated while maintaining the temperature at 35°C. The organic phase was again combined with a 1 / 4 mixture of acetonitrile and water (0.7L) and 3.0M aqueous KHCO3 (7.0L), stirred for 10 minutes, and the layers were separated while maintaining the temperature at 35°C. The obtained organic phase containing compound B (bicarbonate) was cooled to 20°C, and 1-propanol (7.0 L) was added. The heterogeneous solution was cooled to 4°C and aged overnight. The mixture was filtered, and the filter was washed with 1-propanol (1.4 L). The filtrates were combined, decanoic acid (93 g) was added, and the mixture was stirred at room temperature for 15 minutes to dissolve. The acetonitrile solvent was replaced with 1-propanol by continuous distillation under reduced pressure. 1-propanol was added to the concentrated residue until the total volume of 1-propanol reached 2.0 L. Water (36 mL) was added to make the ratio of water to 1-propanol 2.3% by weight. The mixture was stirred at room temperature, and MTBE (0.984 L) was added (Solution #1). MTBE (2.95 L) was charged into another flask (Solution #2).

[0280] In a separate container, 25 g of Caprete 3 crystal species was added, followed by the addition of 0.6 L of MTBE / 1-PrOH(2 / 1) solution containing 0.5 wt% water to prepare a seed bed. The resulting slurry was aged at 22°C for 1 hour to obtain Caprete 2 crystal species slurry.

[0281] While maintaining a temperature of 22°C, solutions #1 and #2 were simultaneously added to the Kapeto 2 crystal species slurry under stirring over a period of 6 hours. The resulting slurry was aged overnight at 22°C to obtain Kapeto 2 slurry.

[0282] The Caprete 2 slurry was filtered under a nitrogen atmosphere. The wet cake was washed with 1.4 L of MTBE / 1-PrOH(8 / 2)(m:m) solution containing 0.5 wt% water. The cake was dried under a nitrogen stream to remove some of the MTBE and 1-PrOH solvent.

[0283] The caprate 3 (684g) was obtained by humidifying and drying with humidified nitrogen (50% RH) to remove residual 1-PrOH.

[0284] Example 12C: Alternative preparation of caprate 3 A mixture of MTBE (6.75 mL) and n-propanol (3.37 mL) was mixed with water (54 μL) to achieve a water content of at least 0.7% by weight. Caprete 3 crystal species (120 mg) was added, and the slurry was stirred at 22°C for 1 hour to obtain a Caprete 2 crystal species slurry.

[0285] In a separate mixture, Caprate 3 (5 g, containing 6.7% by weight of water) was dissolved in n-propanol (13.8 mL). This solution was diluted by adding MTBE (6.9 mL). Capric acid (120 mg) was then added to this solution.

[0286] Both solutions were simultaneously added to the crystalline species slurry under stirring over 20 hours at 22°C. The addition line to the slurry was rinsed with a solution of MTBE (6.13 mL), n-propanol (3.07 mL), and water (49 μL). The resulting Caprete 2 slurry was filtered. The filter cake was washed with a solution of MTBE (8.30 g), n-propanol (2.07 g), and water (52 μL). The filter cake was dried by passing nitrogen through a filter funnel to surface dry the batch. The batch was then dried under humidified nitrogen at 250 mmHg and 50% relative humidity to obtain Caprete 3 (4.01 g).

[0287] Example 13: Alternative preparation of caprate 4 Caprate 3 (101.9 mg) was added to the vial, followed by 1 mL of a 1-propanol-MTBE (1:1.1) solvent mixture. The mixture was stirred at 5°C and allowed to mature overnight to obtain Caprate 4.

[0288] Example 14: Preparation of Caprate 6 Caprete 1 (0.5 g) was added to the vial. Then, n-propanol (1.35 mL) was added and dissolved. Ethyl acetate (7.2 mL) was added, and the solution was then cooled to below room temperature. An additional 2.7 mL of ethyl acetate was added to the solution. The mixture was allowed to mature overnight to obtain Caprete 6.

[0289] Example 15: Preparation of Caprate 7 The suspension of Example 14 (Caprete 6) was filtered under reduced pressure, and the wet cake was washed with a 1-propanol-ethyl acetate mixture (1:10). The cake was dried overnight in a vacuum oven at 30°C with dry nitrogen sweeping to obtain Caprete 7.

[0290] Example 16: Preparation of Caplate 8 The cake of Example 9 (Caprete 4) was filtered under reduced pressure, and the wet cake was washed with an n-propanol-MTBE mixture (1:4, w / w), followed by a second wash with MTBE (120 mL). The resulting solid was dried in N2 at ambient temperature to obtain Caprete 8.

[0291] Example 17: Alternative preparation of caprate 1 Caprete 8 was subjected to stress at 97% RH for at least 3 days, and then dried under reduced pressure at 40°C for 1 hour while sweeping nitrogen to obtain Caprete 1.

[0292] Example 18: Preparation of Caprate 9 A mixture of caprate 3, caprate 5, and caprate 7 (0.01:1:1) was suspended in a 1-propanol-MTBE mixed solvent (1:12, v / v) at room temperature for at least one week to obtain caprate 9.

[0293] Example 19: Alternative preparation of caprate 3 The wet cake of Example 18 (Caprete 9) was filtered under reduced pressure and dried overnight in a vacuum oven while sweeping with dry nitrogen to obtain Caprete 3.

[0294] Example 20: Preparation of Caprate 10 Caprate 3 was exposed to 5% RH for at least 3 hours to obtain caprate 10.

[0295] Example 21: Preparation of caprate 11 Caprate 7 was exposed to 5% RH for at least 3 hours to obtain caprate 11.

[0296] Example 22: Preparation of Caprate 12 A mixture of caprate 3, caprate 5, and caprate 7 (0.01:1:1) was suspended in a 1-propanol-MTBE mixture (1:1, v / v) at 5°C for one week to obtain caprate 12.

[0297] Example 23: Preparation of Caprate 13 Caprate 3 was exposed to 1-propanol solvent vapor for at least 3 days to obtain Caprate 13.

[0298] Example 24: Preparation of caprate 14 Caprate 3 was exposed to 1-propanol-MTBE solvent vapor for at least 3 days to obtain Caprate 14.

[0299] Example 25: Preparation of Compound B (Bicarbonate) Macroporous anion exchange resin AG MP-1M (chloride form, 100-200 mesh, 160 g) was packed into a 500 mL filter funnel. The resin was washed with water (UPLC LC-MS grade, 5 × 264 mL; the first three washing fractions were not clear, so the resin was continuously washed by slurring and applying reduced pressure until the eluate was clear). The resin in the filter funnel was converted to the HCO3- anion form by eluting with 2.5 bed volumes of 5 wt% NaHCO3 (slightly slurryed) in water (2.5 × 265 mL). The resin was then eluted by gravity using 100 mL of 5 wt% NaHCO3 aqueous solution and transferred to an empty solid-load cartridge of Redi Sep Rf (Teledyne ISCO, diameter: 2.42 inches). The cartridge was then eluted by gravity with 7.5 bed volumes of 5 wt% NaHCO3 aqueous solution (7.5 × 265 mL). Excess NaHCO3 was washed away by gravity elution using 2 × 265 mL of water. Compound A (10 g, 6.14 mmol) was dissolved in 100 mL of water. The solution of compound A was loaded into the cartridge and rinsed with 10 mL of water. The resulting compound and compound B (bicarbonate) were eluted with water (260 mL).

[0300] Example 26: Preparation of D-lactate 1 An aqueous solution of D-lactic acid (280 mg, 3.07 mmol) was added to an aqueous solution of compound B (3.07 mmol). The solution was aged at 0°C for 30 minutes. The solution was then frozen in a dry ice-acetone bath and freeze-dried overnight to obtain 5.0 g of lyophilized D-lactate of the compound represented by formula I. The lyophilized D-lactate (5.0 g) of the compound represented by formula I was dissolved in an ethanol / 2-Me-THF mixture (1:1, 20 mL). The solution was transferred to a 250 mL three-necked round-bottom flask equipped with an overhead stirrer and an N2 inlet. The flask was rinsed with ethanol:2-Me-THF (1:1, 10 mL), and the rinse was added to the 250 mL three-necked round-bottom flask to complete the transfer. 2-Me-THF (10 mL) was added dropwise using a syringe. The addition was stopped, and the crystal species were seeded using a slurry. After 1 hour, a suitable slurry was formed. An ethanol / 2-Me-THF mixture (1:3) was added, followed by the addition of 20 mL of 2-Me-THF using a syringe pump over 2.5 hours. The slurry was allowed to mature overnight to obtain D-lactate 1.

[0301] Example 27: Preparation of D-lactate 2 A slurry of D-lactate 1 (approximately 5 g) was filtered using a portion of the filtrate to complete the transfer. The resulting cake was washed with 2-Me-THF:EtOH (3:1, 7 mL), followed by 2-Me-THF (10 mL), and then heptane (20 mL). The solid was dried under reduced pressure under a nitrogen blanket to obtain D-lactate 2 (3.9 g).

[0302] Example 28: Preparation of succinate 1 An aqueous solution of succinic acid (362.9 mg, 3.07 mmol) was added to an aqueous solution of compound B (167 g; 3.07 mmol) and aged at room temperature for 1 hour. The solution was then frozen in a dry ice-acetone bath and freeze-dried overnight to obtain lyophilized succinate (5.05 g) of the compound represented by formula I. A mixture of succinate (3.50 g, 2.097 mmol) of the compound represented by formula I and EtOH (17.5 mL) was evaporated under a nitrogen stream at 15-25°C to form a gum. EtOH (17.5 mL) was added under a nitrogen stream, and the mixture was evaporated under a nitrogen stream at 45-55°C to form a gum. The residue was dissolved in EtOH (17.5 mL) at 75°C to obtain a homogeneous solution. The mixture was cooled to 25°C, a crystal species (1 mg) was added, and the solid slowly crystallized thereafter. The mixture was stirred for 16 hours, and then cooled to 1-3°C for 2 hours to obtain succinate 1.

[0303] Example 29: Preparation of succinate 2 A suspension of succinate 1 (approximately 3.5 g) was filtered using 10 mL of EtOH through a 30 cc polypropylene filter funnel at 0-5°C, and the slurry was completely transferred to the filter funnel. The filter cake was dried under a nitrogen stream for 24 hours to obtain succinate 2 (2.8 g, 1.678 mmol, 80% yield) as a white crystalline solid.

[0304] Example 30: Preparation of L-Tartrate 1 An aqueous solution of compound B (167 g; 3.07 mmol) was mixed with an aqueous solution of L-(+)-tartaric acid (460.9 mg, 3.07 mmol) and aged at room temperature for 1 hour. The solution was then frozen in a dry ice-acetone bath and freeze-dried overnight to obtain lyophilized L-tartrate (5.15 g) of the compound represented by formula I. The lyophilized L-tartrate (5.0 g) of the compound represented by formula I and n-propanol (50 mL) were placed in a 100 mL EasyMax container equipped with a nitrogen blanket to control humidity. The mixture was stirred and heated to 55°C to dissolve all solids. The solution was cooled to 50°C and the crystal species was added. The slurry was slowly cooled to 45°C, and then several heating and cooling cycles were performed to crystallize the product. In the final cycle, the slurry was heated to 40°C and cooled to 20°C over 4 hours to obtain L-tartorate 1.

[0305] Example 31: Preparation of L-Tartrate 2 L-Tartrate 1 (approximately 5g) was filtered, and the resulting cake was washed with n-propanol. The cake was dried overnight in a 40°C oven under nitrogen sweeping to obtain L-Tartrate 2 (2.57g).

[0306] Example 32: Preparation of Sulfate 1 An aqueous solution of sulfuric acid (1 M, 1.5 mL, 1.5 mmol) was added to an aqueous solution of compound B (167 g; 3.07 mmol) and aged at room temperature for 1 hour. The solution was then frozen in a dry ice-acetone bath and freeze-dried overnight to obtain the freeze-dried sulfate of the compound represented by formula I (4.88 g). The freeze-dried sulfate ester of the compound represented by formula I (2.5 g) was placed in a 250 mL three-necked round-bottom flask equipped with an overhead stirrer. 1-propanol (40 mL) was added to the round-bottom flask and stirred vigorously to dissolve some solids adhering to the flask walls. Crystals formed before all the solids dissolved. The mixture was continued to stir vigorously, and 10 mL of heptane was added over 1 hour using a syringe pump. The mixture was aged for 6 hours to obtain sulfate 1.

[0307] Example 33: Preparation of Sulfate 2 A suspension of sulfate 1 (approximately 4.9 g) was filtered, and the cake was washed with 10 mL of a mixture of 1-propanol and 20% heptane. The cake was then washed with 20 mL of heptane, followed by an additional 10 mL of heptane. The cake was dried under reduced pressure overnight under a nitrogen blanket to obtain sulfate 2 (2.21 g).

[0308] Example 34: Description of X-ray powder diffraction study X-ray powder diffraction studies are widely used to characterize molecular structure, crystallinity, and polymorphism. The X-ray powder diffraction patterns disclosed herein were generated using a Philips Analytical X'Pert PRO X-ray Diffraction System equipped with a PW3040 / 60 console. A PW3373 / 00 ceramic Cu LEFX Kα beam was used as the radiation source. Samples from Examples 1 to 33 were characterized by XRPD. XRPD analysis shows that acetate 1 (Figure 1) and caprate 1 (Figure 7) are amorphous, while acetate 2-6 (Figures 2-6), caprate 2-14 (Figures 8-20), D-lactate 1-2 (Figures 21-22), succinate 1-2 (Figures 23-24), L-tartorate 1-2 (Figures 25-26), and sulfate 1-2 (Figures 27-28) are crystalline.

[0309] Example 35: Chemical stability of crystalline salt superior to compound A (amorphous chloride salt) The crystalline forms disclosed herein offer the advantages of improved chemical purification. In particular, these crystalline forms avoid the use of SFC chromatography and lyophilization required for the purification of compound A (chloride salt). This improved strategy results in reduced product costs and process simplification by decreasing the number of units of operation involved, which is critical to commercial viability.

[0310] The acetate and caprate salts represented by Formula I (which include caprate 3 and caprate 7 in crystalline form) exhibited a satisfactory purity of >99% at 40°C and 75% RH for 3 months (Figure 29A), in contrast to the purity of compound A, which is an amorphous chloride. The graph in Figure 29A shows that the acetate and caprate salts have improved chemical stability compared to the chloride salts. Furthermore, while the chloride salts require storage at -20°C to minimize chemical degradation, the acetate and caprate salts are less prone to degradation even at relatively high temperatures. The graph in Figure 29B shows that the crystalline acetate and caprate salts have improved chemical stability compared to the amorphous forms of caprate and acetate under accelerated stability conditions, which is particularly evident at the 3-month mark. The stability of the crystalline form of the compound represented by Formula I was characterized by XRPD under relative humidity conditions simulating potential storage conditions.

[0311] The adsorption / desorption cycles indicate that acetate 4 is hygroscopic, with its weight increasing by approximately 9% at 55% RH (see Figure 30A). XRPD analysis shows that acetate 4 maintains minimal crystallinity during two adsorption / desorption cycles between 5-55% RH (see Figure 30B). The adsorption / desorption cycles indicate that acetate 4 is extremely hygroscopic, with its weight increasing by approximately 40% at 95% RH (see Figure 31A). Hysteresis is observed during the desorption phase. XRPD analysis shows that acetate 4 loses its crystallinity after adsorption / desorption cycles between 5-95-5% RH (see Figure 31B).

[0312] The adsorption / desorption cycles indicate that Caplate 5 is hygroscopic, with its weight increasing by approximately 7.5% at 65% RH (see Figure 32A). Slight hysteresis is observed during the desorption phases of cycles 1 and 2. XRPD analysis indicates that Caplate 5 retains some crystallinity after two adsorption / desorption cycles at 5-65% RH (see Figure 32B). The adsorption / desorption cycles indicate that Caplate 5 is highly hygroscopic, with its weight increasing by approximately 26% at 95% RH (see Figure 33A). XRPD analysis indicates that Caplate 5 loses its crystallinity after adsorption / desorption cycles at 5-95-5% RH (see Figure 33B).

[0313] The adsorption / desorption cycles indicate that Caplate 3 is hygroscopic, with a weight increase of approximately 4.9% at 85% RH (see Figure 34A). This contrasts with the larger weight increases observed for Acetate 4 (9%; see Figure 30A) and Caplate 5 (7.5%; see Figure 32A) at 55% RH and 65% RH, respectively. XRPD analysis shows that Caplate 3 maintains its crystallinity during the 5–85% RH adsorption / desorption cycle (see Figure 34B). This contrasts with the decrease in crystallinity observed for Acetate 4 (see Figure 30B) and Caplate 5 (see Figure 32B) during two adsorption / desorption cycles at 5–55% RH and 5–65% RH, respectively.

[0314] Caplate 3 was dried under N2 at 40°C for 3 hours to remove residue. The adsorption / desorption cycle showed that water-free Caplate 3 is hygroscopic and its weight increased by approximately 9.4% at 85% RH (see Figure 35A). This adsorption / desorption cycle also showed that Caplate 3 readily absorbed H2O at approximately 25-35% RH and did not lose H2O down to 15% RH. XRPD analysis showed that water-free Caplate 3 maintained its crystallinity even during the adsorption / desorption cycle from 5-85% RH (see Figure 35B).

[0315] The behavior of Caplate 3 demonstrates the high stability of this crystalline form with respect to relative humidity, which is important for further development and, in particular, for withstanding fluctuating storage conditions. This is in contrast to the decrease in crystallinity observed in acetate 4 and caplate 5 with increasing relative humidity.

[0316] Example 36: Solid-state NMR research Batches of caprates 3, 5, and 8 were characterized based on their respective solid carbon-13 nuclear magnetic resonance (NMR) spectra. All carbon-13 spectra were recorded using a Bruker AV400 NMR spectrometer operating at a carrier frequency of 400.14 MHz with a Bruker 4 mm H / F / X BB triple resonance CPMAS probe. The spectra were acquired using proton / carbon-13 variable amplitude cross-polarization (VACP) at 80 kHz with a contact time of 3 minutes. Other experimental parameters used for data acquisition were a 100 kHz proton 90-degree pulse, SPINAL64 decoupling at 100 kHz, a 1.5-second pulse delay, and signal averaging over 50,000 scans. The magic angle spinning (MAS) rate was set to 13 kHz. Lorentzian line broadening at 30 Hz was applied to the spectra before Fourier transform. Chemical shifts are reported on a TMS scale, with the carbonyl carbon of glycine (176.70 ppm) as the secondary reference.

[0317] Figures 36A–36C show the individual carbon-13 CPMAS spectra for caprate 3, caprate 5, and caprate 8, respectively. These three caprate morphologies exhibit similar carbon-13 CPMAS spectra, and furthermore, the deviations shown in the respective spectra for each morphology are small. Nevertheless, each morphology can be clearly distinguished by the carbon-13 CPMAS spectra based on a comparison of specific spectral regions. Figure 37 shows the spectral regions exhibiting characteristic isotropic chemical shifts, along with the relative peak heights and shapes, for each morphology.

Claims

1. The following is the crystalline form of compound 2: 【Chemistry 1】 Here, the crystalline form of compound 2 is caprate 3, characterized by an X-ray powder diffraction pattern having peaks represented by 2θ degrees at angles 7.92, 15.40, 16.66, 17.33, 18.86, 19.60, 20.79 and 21.27 (±0.2°). Crystalline form of the salt of compound 2.

2. A pharmaceutical composition comprising the crystalline form described in claim 1 and a pharmaceutically acceptable carrier.

3. Use of the crystalline form according to claim 1 in the preparation of a pharmaceutical product for treating hypercholesterolemia in a subject.

4. The use of the crystalline form according to claim 1 in the preparation of a pharmaceutical product for lowering LDL-C in a subject.

5. Use of the crystalline form according to claim 1 in the preparation of a pharmaceutical product for treating atherosclerotic cardiovascular disease in a subject.

6. The use of the crystalline form according to claim 1 for the preparation of a pharmacopoeia for inhibiting PCSK9 activity in subjects requiring inhibition of PCSK9 activity, wherein the inhibition comprises orally administering a therapeutically effective amount of caprate 3 to the subject, wherein the therapeutically effective amount of caprate 3 is 5 mg to 300 mg.

7. A pharmaceutical composition comprising the crystalline form and penetration enhancer described in claim 1, The pharmaceutical composition comprises a therapeutically effective amount of caprate 3, wherein the therapeutically effective amount of caprate 3 is 5 mg to 300 mg.

8. The pharmaceutical composition according to claim 7, wherein the penetration enhancer is sodium caprate.

9. The use according to claim 3, 4, or 5, wherein the pharmaceutical product comprises a therapeutically effective amount of caprate 3 in 20 mg in free form.

10. The use according to claim 6, wherein the therapeutically effective dose of 20 mg of caprate 3 is 20 mg in free form.

11. The pharmaceutical composition according to claim 7 or 8, wherein the pharmaceutical composition contains 20 mg of caprate 3 in a free form.

12. The pharmaceutical composition according to claim 7 or 8, wherein the pharmaceutical composition comprises 22 mg, 22.5 mg, 23 mg, 23.5 mg, 24 mg, or 24.5 mg of caprate 3.

13. The pharmaceutical composition according to claim 7 or 8, wherein the pharmaceutical composition is in the form of a tablet.

14. The pharmaceutical composition according to claim 7 or 8, wherein the pharmaceutical composition is in the form of a capsule.

15. The crystal morphology according to claim 1, wherein the caprate 3 is substantially characterized by the X-ray powder diffraction pattern shown in Figure 9. [Figure 9]

16. The crystal morphology according to claim 1, wherein the caprate 3 is characterized by an X-ray powder diffraction pattern such that it is substantially described by the peaks listed in Table 7. Table 7

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