Crystalline forms, compositions and uses 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 August 17, 2022, and U.S. Provisional Application No. 63 / 384,298, filed November 18, 2022, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Provided herein are compounds of formula I: [ka] [In the ceremony, A - is a pharmaceutically acceptable anion. and 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 syndrome, acute coronary syndrome, or related cardiovascular and cardiometabolic conditions). [Background technology]

[0003] When a compound is used for pharmaceutical purposes, the solid state of the compound is important. The physical properties of the compound may change from one solid form to another, which may affect the suitability of the form for pharmaceutical use. For example, a certain crystalline solid compound may overcome the shortcomings (e.g., instability and / or reduced purity) of other solid forms of the compound. Summary of the Invention [Problem to be solved by the invention]

[0004] Provided herein are compounds of formula I: [ka] [In the ceremony, A - is a pharmaceutically acceptable anion. These crystalline forms of the compound of formula I allow for efficient isolation and purification, thereby avoiding the need for costly procedures such as chromatography and lyophilization. Furthermore, the crystalline forms of the compound of formula I are advantageous in that they have high purity, high stability, and low hygroscopicity, making them suitable for use in pharmaceutical formulations. [Means for solving the problem]

[0005] The present disclosure provides compounds of formula I: [ka] [In the ceremony, A - is a pharmaceutically acceptable anion. The present invention relates to crystalline forms of the compounds represented herein, which have activity as PCSK9 inhibitors, as well as compositions comprising the crystalline forms, methods of making the crystalline forms, and methods of using the crystalline forms. [Brief explanation of the drawings]

[0006] [Figure 1] Figure 1 shows the X-ray powder diffraction pattern of amorphous acetate 1, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2-theta (2θ) (degrees). [Figure 2] Figure 2 shows the X-ray powder diffraction pattern of acetate 2, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) (degrees). [Figure 3] Figure 3 shows the X-ray powder diffraction pattern of acetate 3, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined in counts per second, against diffraction angle 2 theta (2θ) (degrees). [Figure 4] Figure 4 shows the X-ray powder diffraction pattern of acetate 4, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) (degrees). [Figure 5] Figure 5 shows the X-ray powder diffraction pattern of acetate 5, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) (degrees). [Figure 6] Figure 6 shows the X-ray powder diffraction pattern of acetate 6, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined in counts per second, against diffraction angle 2 theta (2θ) (degrees). [Figure 7] Figure 7 shows the X-ray powder diffraction pattern of amorphous Cuprate 1, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2-theta (2θ) in degrees. [Figure 8] Figure 8 shows the X-ray powder diffraction pattern of Kaplate 2, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) in degrees. [Figure 9] Figure 9 shows the X-ray powder diffraction pattern of Cuprate 3, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined in counts per second, against diffraction angle 2 theta (2θ) in degrees. [Figure 10] Figure 10 shows the X-ray powder diffraction pattern of Cuprate 4, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) in degrees. [Figure 11] Figure 11 shows the X-ray powder diffraction pattern of Cuprate 5, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) in degrees. [Figure 12] Figure 12 shows the X-ray powder diffraction pattern of Cuprate 6, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) in degrees. [Figure 13] Figure 13 shows the X-ray powder diffraction pattern of Cuprate 7, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) in degrees. [Figure 14] Figure 14 shows the X-ray powder diffraction pattern of Cuprate 8, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) in degrees. [Figure 15] Figure 15 shows the X-ray powder diffraction pattern of Cuprate 9, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) in degrees. [Figure 16] Figure 16 shows the X-ray powder diffraction pattern of Kaplate 10, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) in degrees. [Figure 17] Figure 17 shows the X-ray powder diffraction pattern of Kaprate 11, showing 2θ in the range of 2 to 40. The graph plots the intensity of the peaks, defined as counts per second, against the diffraction angle 2-theta (2θ) in degrees. [Figure 18] Figure 18 shows the X-ray powder diffraction pattern of Cuprate 12, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2-theta (2θ) in degrees. [Figure 19] Figure 19 shows the X-ray powder diffraction pattern of Kaprate 13, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) in degrees. [Figure 20] Figure 20 shows the X-ray powder diffraction pattern of Kaplate 14, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2-theta (2θ) in degrees. [Figure 21] Figure 21 shows the X-ray powder diffraction pattern of D-lactate 1, showing 2θ ranging from 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) (degrees). [Figure 22] Figure 22 shows the X-ray powder diffraction pattern of D-lactate 2, showing 2θ ranging from 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) (degrees). [Figure 23] Figure 23 shows the X-ray powder diffraction pattern of succinate 1, showing 2θ ranging from 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) (degrees). [Figure 24] Figure 24 shows the X-ray powder diffraction pattern of succinate 2, showing 2θ in the range of 2 to 40. The graph plots peak intensity, defined in counts per second, against diffraction angle 2 theta (2θ) (degrees). [Figure 25] Figure 25 shows the X-ray powder diffraction pattern of L-tartrate 1, showing 2θ ranging from 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2-theta (2θ) (degrees). [Figure 26] Figure 26 shows the X-ray powder diffraction pattern of L-tartrate 2, showing 2θ ranging from 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2-theta (2θ) (degrees). [Figure 27]Figure 27 shows the X-ray powder diffraction pattern of sulfate 1, showing 2θ ranging from 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) (degrees). [Figure 28] Figure 28 shows the X-ray powder diffraction pattern of sulfate 2, showing 2θ ranging from 2 to 40. The graph plots peak intensity, defined as counts per second, against diffraction angle 2 theta (2θ) (degrees). [Figure 29A] FIG. 29A depicts the % of total impurities for Compound A (API Chloride Amorphous; amorphous form of the chloride salt), Acetate 1, Caprate 1, Caprate 3, and Caprate 7 over a 3-month range. [Figure 29B] FIG. 29B depicts the % total impurities for Acetate 1 (amorphous acetate), Caprate 1 (amorphous caprate), Caprate 3, and Caprate 7 over a 3-month range. [Figure 30A] FIG. 30A shows the adsorption / desorption cycle of acetate 4 over the range of 5-55% relative humidity (RH). [Figure 30B] FIG. 30B shows the X-ray powder diffraction patterns of acetate 4 before and after the adsorption / desorption cycle of FIG. 30A. [Figure 31A] Figure 31A shows the adsorption / desorption cycle of acetate 4 over the range of RH 5-95%. [Figure 31B] FIG. 31B shows the X-ray powder diffraction patterns of acetate 4 before and after the adsorption / desorption cycle of FIG. 31A. [Figure 32A] FIG. 32A shows the adsorption / desorption cycle of Caprate 5, ranging from RH 5 to 65%. [Figure 32B] FIG. 32B shows the X-ray powder diffraction patterns of Cuprate 5 before and after the adsorption / desorption cycle of FIG. 32A. [Figure 33A] FIG. 33A shows the adsorption / desorption cycle of Caprate 5, ranging from 5 to 95% RH. [Figure 33B] FIG. 33B shows the X-ray powder diffraction patterns of Cuprate 5 before and after the adsorption / desorption cycle of FIG. 33A. [Figure 34A] FIG. 34A shows the adsorption / desorption cycle of Caprate 3, ranging from 5 to 85% RH. [Figure 34B] FIG. 34B shows the X-ray powder diffraction patterns of Cuprate 3 before and after the adsorption / desorption cycle of FIG. 34A. [Figure 35A] FIG. 35A shows the adsorption / desorption cycle of water-free Caprate 3, ranging from 5 to 85% RH. [Figure 35B] FIG. 35B shows the X-ray powder diffraction patterns of water-free Caprate 3 before and after the adsorption / desorption cycle of FIG. 35A. [Figure 36A] FIG. 36A shows the solid-state C-13 CPMAS NMR spectrum for cuprate 3. [Figure 36B] FIG. 36B shows the solid-state C-13 CPMAS NMR spectrum for cuprate 5. [Figure 36C] FIG. 36C shows the solid-state C-13 CPMAS NMR spectrum for cuprate 8. [Figure 37] Figure 37 shows selected spectral regions from the cuprate C-13 CPMAS spectrum of the cuprate forms showing shape-distinguishing features. From top to bottom, the spectral regions are shown for cuprate 8, cuprate 5, and cuprate 3, respectively. The associated isotropic chemical shifts are given in ppm (parts per million). DETAILED DESCRIPTION OF THE INVENTION

[0007] Proprotein convertase subtilisin-kexin type 9 (hereinafter referred to as "PCSK9"), also known as neuronal apoptosis-regulating 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, a prodomain, a catalytic domain, and a 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 PCSK9 is regulated by sterol regulatory element-binding protein ("SREBP"), as seen in other genes involved in cholesterol metabolism (Maxwell et al., 2003 J. Lipid Res. 44:2109-2119) and, as is typical for other genes involved in lipoprotein metabolism (Dubuc et al., 2004 Arterioscler. Thromb. Vasc. Biol. 24:1454-1459). Statins have been shown to upregulate PCSK9 expression in a manner that is attributed to the cholesterol-lowering effects of the drug. Furthermore, the PCSK9 promoter has been shown to contain two conserved sites involved in cholesterol regulation: a sterol regulatory element and an Sp1 site; see above.

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

[0009] Adenovirus-mediated overexpression of PCSK9 in mouse liver results in the accumulation of circulating low-density lipoprotein cholesterol ("LDL-C") due to a dramatic loss of hepatic LDLR protein, but does not affect 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 completely dependent on LDLR expression, again indicating that PCSK9 regulation of LDL-C occurs via downregulation of LDLR protein. Consistent with these findings, mice lacking PCSK9 or in which PCSK9 mRNA is reduced with antisense oligonucleotide inhibitors have higher hepatic LDLR protein levels and an increased ability to clear 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 by siRNA similarly increases LDLR protein levels and the ability to uptake LDL-C; Benjannet et al., 2004 J. Biol. Chem. 279:48865-48875 and Lalanne et al., 2005 J. Lipid Res. 46:1312-1319. Together, these data indicate that the action of PCSK9 leads to increased LDL-C by reducing LDLR protein levels.

[0010] Many mutations in the PCSK9 gene have also been conclusively associated with autosomal dominant hypercholesterolemia ("ADH"), an inherited metabolic disorder characterized by marked elevation of plasma low-density lipoprotein ("LDL") particles that 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; Leren, 2004 Clin. Genet. 65:419-422. A subsequent study by Abifadel et al. (supra) on the S127R mutation reported that patients with such mutations have elevated plasma total cholesterol and apoB100 due to (1) overproduction of apoB100-containing lipoproteins, such as low-density lipoproteins ("LDL"), very-low-density lipoproteins ("VLDL"), and intermediate-density lipoproteins ("IDL"), and (2) a concomitant decrease in clearance or conversion of these lipoproteins; Ouguerram et al., 2004 Arterioscler. Thromb. Vasc. Biol. 24:1448-1453.

[0011] Therefore, there is no doubt that PCSK9 is involved in the regulation of LDL. Expression or upregulation of PCSK9 is associated with elevated LDL cholesterol plasma levels, and corresponding inhibition or lack of expression of PCSK9 is associated with reduced LDL cholesterol plasma levels. Reductions in LDL cholesterol levels associated with sequence variants of PCSK9 have been found to protect against coronary heart disease; Cohen, 2006 N. Engl. J. Med. 354:1264-1272.

[0012] In clinical trials, lowering LDL cholesterol levels has been directly associated with a reduced incidence of coronary events; Law et al., 2003 BMJ 326:1423-1427. Moderate reductions in plasma LDL cholesterol levels over a lifetime have 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 a high prevalence of non-lipid-related cardiovascular risk factors. Thus, there is significant benefit to be gained from managed control of LDL cholesterol levels.

[0013] Therefore, identifying compounds and / or drugs effective in treating cardiovascular disease, 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 exploit this mechanism in the treatment of 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 molecules as drugs targeting PCSK9 is only beginning to be explored; see, for example, Tombling et al., Atherosclerosis 330 (2021) 52-60. Furthermore, few compounds can be formulated into dosage forms that utilize the oral route of administration, which is a highly desirable route for providing treatment for conditions in which modulating PCSK9 activity may play a role.

[0014] WO2019 / 246349 discloses cyclic peptide compounds useful in the treatment of cardiovascular disease and conditions associated with PCSK9 activity. This disclosure represents the state of the art by providing crystalline forms of the compound represented by Formula I, which can be used to treat hypercholesterolemia and other conditions associated with PCSK9 activity, preferably through 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, making them particularly suitable for the manufacture of various pharmaceutical dosage forms, including oral dosage forms.

[0015] Thus, provided herein are compounds of formula I: [ka] [In the ceremony, A - is a pharmaceutically acceptable anion. In a further embodiment, A is a crystalline form of a salt of a compound represented by the formula: -is selected from acetate, caprate, lactate, tartrate, 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 is a crystalline form of the compound of Formula I, wherein the crystalline form 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-tartrate 1, L-tartrate 2, sulfate 1, and sulfate 2. An additional aspect of this embodiment of the present disclosure provides a particular drug substance comprising at least one of the forms described herein. The presence of a particular 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 (XRPD), single crystal X-ray diffraction, nuclear magnetic resonance (NMR) spectroscopy, or nitrogen-15 CPMAS NMR spectroscopy.

[0016] Compound A is an amorphous form of the chloride salt of the compound of Formula I.

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

[0018] Described herein is the acetate salt of a compound of formula I shown below, designated Compound 1: [ka]

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

[0020] In one embodiment, provided herein is a crystalline form of Compound 1.

[0021] In a further embodiment, provided herein is a crystalline form of Compound 1, wherein the crystalline form is selected from acetate 2, acetate 3, acetate 4, acetate 5, and acetate 6.

[0022] Also described herein is the caprate salt of a compound of Formula I, as seen below, designated Compound 2: [ka]

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

[0024] In one embodiment, provided herein is a crystalline form of Compound 2.

[0025] In a further embodiment, provided herein is a crystalline form of Compound 2, wherein 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] Also described herein is the lactate salt of a compound of formula I, as seen below, designated Compound 3: [ka]

[0027] In one embodiment, provided herein is a crystalline form of Compound 3.

[0028] In a further embodiment, provided herein is a crystalline form of Compound 3, wherein the crystalline form is selected from D-lactate 1 and D-lactate 2. The structure of D-lactate is shown below: [ka]

[0029] Also described herein is the succinate salt of the compound of formula I, as seen below, designated Compound 4: [ka]

[0030] In one embodiment, provided herein is a crystalline form of Compound 4.

[0031] In a further embodiment, provided herein is a crystalline form of Compound 4, wherein the crystalline form is selected from succinate 1 and succinate 2.

[0032] Also described herein is the tartrate salt of a compound of formula I, as seen below, designated Compound 5: [ka]

[0033] In one embodiment, provided herein is a crystalline form of Compound 5.

[0034] In a further embodiment, provided herein is a crystalline form of Compound 5, wherein the crystalline form is selected from L-tartrate 1 and L-tartrate 2. The structure of L-tartrate is shown below: [ka]

[0035] L-tartrate may also be referred to as (2R,3R)-hydrogen tartrate.

[0036] Also described herein is the sulfate salt of the compound of formula I, as seen below, designated Compound 6: [ka]

[0037] In one embodiment, provided herein is a crystalline form of Compound 6.

[0038] In a further embodiment, provided herein is a crystalline form of Compound 6, wherein the crystalline form is selected from Sulfate 1 and Sulfate 2.

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

[0040] The specific crystalline form of the compound of Formula I provided herein has advantageous properties that are useful for preparing various drug formulations. For example, Caprate 3, a specific crystalline form of the compound of Formula I, is a stable crystalline form. Caprate 3 maintains its crystallinity (i.e., is physically stable) even when relative humidity changes (see, e.g., Figures 34A-35B). A crystalline form with good stability is important in the processes of preparing, packaging, shipping, and storing pharmaceutical products. The manufacturing process of Caprate 3 (see, e.g., Examples 12A, 12B, 12C, and 19) also provides improved chemical stability over the amorphous chloride salt, an important feature for preparing and using pharmaceutical products (see, e.g., Figures 29A and 29B).

[0041] Characterization of crystal morphology In certain embodiments, the crystalline forms provided herein can be distinguished 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 characterize the structural properties of solid materials. A description of the method used to obtain specific XRPD patterns associated with the crystalline forms of the present invention can be found in Example 34, "X-ray Powder Diffraction Description." In one embodiment, the X-ray powder diffraction data provided herein is obtained by a method utilizing Cu Kα radiation.

[0042] Crystalline Forms of the Compound of Formula I Acetate 2: In one embodiment, provided herein is acetate 2, which is a crystalline form of the acetate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 4.92, 6.59, 9.82, and 17.91. In a particular aspect, acetate 2 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following 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 of Formula I is acetate 2, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees -2-θ at angles ±0.2°) as set forth in Table 1.

[0043] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of acetate 2. In aspects of this embodiment, acetate 2 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 2. In aspects of this embodiment, acetate 2 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 1.

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

[0045] Acetate 3: In another embodiment, provided herein is acetate 3, which is a crystalline form of the acetate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern with peaks at the following angles (±0.2°) expressed in degrees -2-θ: 4.48, 18.17, 18.79, and 19.27. In a particular aspect, acetate 3 is characterized by an X-ray powder diffraction pattern with peaks at the following angles (±0.2°) expressed in degrees -2-θ: 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 aspect, acetate 3 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following 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, a crystalline form of the compound of Formula I is acetate 3, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees -2-θ at angles ±0.2°) as set forth in Table 2.

[0046] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of acetate 3. In aspects of this embodiment, acetate 3 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 3. In aspects of this embodiment, acetate 3 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 2.

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

[0048] Acetate 4: In one embodiment, provided herein is acetate 4, which is a crystalline form of the acetate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 8.36, 17.74, 20.29, and 21.35. In certain embodiments, acetate 4 is characterized by an X-ray powder diffraction pattern having peaks expressed in 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 expressed in degrees-2-theta 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 of Formula I is acetate 4, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks shown in Table 3 (expressed in degrees -2-θ at angles ±0.2°).

[0049] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of acetate 4. In aspects of this embodiment, acetate 4 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 4. In aspects of this embodiment, acetate 4 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 3.

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

[0051] Acetate 5: In another embodiment, provided herein is acetate 5, which is a crystalline form of the acetate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 5.02, 6.66, 9.89, and 19.84. In a particular aspect, acetate 5 is characterized by an X-ray powder diffraction pattern having peaks expressed in 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 expressed in 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 of Formula I is acetate 5, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks shown in Table 4 (expressed in degrees -2-θ at angles ±0.2°).

[0052] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of acetate 5. In aspects of this embodiment, acetate 5 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 5. In aspects of this embodiment, acetate 5 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 4.

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

[0054] Acetate 6: In another embodiment, provided herein is acetate 6, which is a crystalline form of the acetate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern with peaks expressed in degrees -2-θ at the following angles (±0.2°): 7.79, 11.00, 16.24, and 18.89. In a particular aspect, acetate 6 is characterized by an X-ray powder diffraction pattern with peaks expressed in 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 aspect, acetate 6 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following 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, a crystalline form of the compound of Formula I is acetate 6, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees -2-θ at angles ±0.2°) as set forth in Table 5.

[0055] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of acetate 6. In aspects of this embodiment, acetate 6 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 6. In aspects of this embodiment, acetate 6 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 5.

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

[0057] Caprate 2: In another embodiment, provided herein is caprate 2, which is a crystalline form of the caprate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 4.85, 7.65, 17.16, 18.20, and 19.50. In a particular aspect, caprate 2 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following 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 of Formula I is caprate 2, characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees -2-θ at angles ±0.2°) as set forth in Table 6.

[0058] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of Caprate 2. In aspects of this embodiment, Caprate 2 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 8. In aspects of this embodiment, Caprate 2 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 6.

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

[0060] Caprate 3: In another embodiment, provided herein is caprate 3, which is a crystalline form of the caprate salt of the compound represented by Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 7.92, 17.33, and 19.60. In another embodiment, provided herein is caprate 3, which is a crystalline form of the caprate salt of the compound represented by Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 7.92, 15.40, 17.33, and 19.60. In a particular aspect, caprate 3 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 7.92, 15.40, 17.33, 18.86, 19.60, and 20.79. In a more specific embodiment, Cuprate 3 is characterized by an X-ray powder diffraction pattern having peaks expressed in 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 particular embodiment, Cuprate 3 is characterized by an X-ray powder diffraction pattern having peaks expressed in 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, Cuprate 3 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees-2-theta 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 of Formula I is caprate 3, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks shown in Table 7 (expressed in degrees -2-θ at angles ±0.2°).

[0061] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of Caprate 3. In aspects of this embodiment, Caprate 3 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 9. In aspects of this embodiment, Caprate 3 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 7.

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

[0063] Caprate 4: In another embodiment, provided herein is caprate 4, which is a crystalline form of the caprate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 4.18, 6.14, 17.51, and 17.68. In certain aspects, caprate 4 is characterized by an X-ray powder diffraction pattern having peaks expressed in 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 of Formula I is caprate 4, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks shown in Table 8 (expressed in degrees -2-θ at angles ±0.2°).

[0064] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of caprate 4. In aspects of this embodiment, caprate 4 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 10. In aspects of this embodiment, caprate 4 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 8.

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

[0066] Caprate 5: In another embodiment, provided herein is caprate 5, which is a crystalline form of the caprate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 7.66, 16.18, 18.26, and 19.11. In a particular aspect, caprate 5 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±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 of Formula I is caprate 5, characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees -2-θ at angles ±0.2°) set forth in Table 9.

[0067] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of caprate 5. In aspects of this embodiment, caprate 5 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 11. In aspects of this embodiment, caprate 5 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 9.

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

[0069] Caprate 6: In another embodiment, provided herein is caprate 6, which is a crystalline form of the caprate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 5.33, 6.97, 19.04, and 21.58. In certain aspects, caprate 6 is characterized by an X-ray powder diffraction pattern having peaks expressed in 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 of Formula I is caprate 6, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks shown in Table 10 (expressed in degrees -2-θ at angles ±0.2°).

[0070] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of caprate 6. In aspects of this embodiment, caprate 6 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 12. In aspects of this embodiment, caprate 6 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 10.

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

[0072] Caprate 7: In another embodiment, provided herein is caprate 7, which is a crystalline form of the caprate salt of the compound of Formula I, characterized by the following X-ray powder diffraction pattern: 7.73, 17.14, 18.75, and 19.48. In another embodiment, the crystalline form of the compound of Formula I is caprate 7, characterized by an X-ray powder diffraction pattern having the peaks set forth in Table 11 (expressed in degrees -2-θ at angles ±0.2°).

[0073] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of caprate 7. In aspects of this embodiment, caprate 7 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 13. In aspects of this embodiment, caprate 7 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 11.

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

[0075] Caprate 8: In another embodiment, provided herein is caprate 8, which is a crystalline form of the caprate salt of the compound of Formula I, characterized by the following X-ray powder diffraction pattern: 7.45, 17.97, 19.32, and 22.08. In certain aspects, caprate 8 is characterized by an X-ray powder diffraction pattern having peaks at the following angles (±0.2°) expressed in degrees -2-θ: 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 of Formula I is caprate 8, characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees -2-θ at angles ±0.2°) set forth in Table 12.

[0076] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of caprate 8. In aspects of this embodiment, caprate 8 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 14. In aspects of this embodiment, caprate 8 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 12.

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

[0078] Caprate 9: In another embodiment, provided herein is caprate 9, which is a crystalline form of caprate salt represented by Formula I, characterized by the following X-ray powder diffraction pattern: 6.73, 11.95, 18.23, and 19.77. In certain aspects, caprate 9 is characterized by an X-ray powder diffraction pattern having peaks at the following angles (±0.2°), expressed in degrees -2-θ: 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 of Formula I is cuprate 9, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks set forth in Table 13 (expressed in degrees -2-θ at angles ±0.2°).

[0079] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of caprate 9. In aspects of this embodiment, caprate 9 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 15. In aspects of this embodiment, caprate 9 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 13.

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

[0081] Caprate 10: In another embodiment, provided herein is Caprate 10, which is a crystalline form of the caprate salt of the compound of Formula I, characterized by the following X-ray powder diffraction pattern: 3.50, 7.90, 16.21, and 18.23. In another embodiment, the crystalline form of the compound of Formula I is Caprate 10, characterized by an X-ray powder diffraction pattern having the peaks set forth in Table 14 (expressed in degrees -2-θ at angles ±0.2°).

[0082] In an aspect of 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 of Formula I in the pharmaceutical composition is in the form of caprate 10. In an aspect of this embodiment, caprate 10 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 16. In an aspect of this embodiment, caprate 10 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 14.

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

[0084] Caprate 11: In another embodiment, provided herein is caprate 11, which is a crystalline form of the caprate salt of the compound of Formula I, characterized by the following X-ray powder diffraction pattern: 3.93, 4.90, and 7.68. In another embodiment, the crystalline form of the compound of Formula I is caprate 11, characterized by an X-ray powder diffraction pattern having the peaks set forth in Table 15 (expressed in degrees -2-θ at angles ±0.2°).

[0085] In an aspect of 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 of Formula I in the pharmaceutical composition is in the form of caprate 11. In an aspect of this embodiment, caprate 11 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 17. In an aspect of this embodiment, caprate 11 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 15.

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

[0087] Caprate 12: In another embodiment, provided herein is caprate 12, which is a crystalline form of the caprate salt of the compound of Formula I, characterized by the following X-ray powder diffraction pattern: 6.80, 15.37, 18.22, and 20.63. In certain aspects, Kaprete 12 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 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, a crystalline form of the compound of Formula I is Kaprete 12, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees -2-θ at angles ±0.2°) as set forth in Table 16.

[0088] In an aspect of 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 of Formula I in the pharmaceutical composition is in the form of caprate 12. In an aspect of this embodiment, caprate 12 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 18. In an aspect of this embodiment, caprate 12 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 16.

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

[0090] Caprate 13: In another embodiment, provided herein is caprate 13, which is a crystalline form of the caprate salt of the compound of Formula I, characterized by the following X-ray powder diffraction pattern: 5.02, 6.29, 7.12, and 20.25. In certain aspects, caprate 13 is characterized by an X-ray powder diffraction pattern having peaks expressed in 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 of Formula I is caprate 13, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks set forth in Table 17 (expressed in degrees -2-θ at angles ±0.2°).

[0091] In an aspect of 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 of Formula I in the pharmaceutical composition is in the form of caprate 13. In an aspect of this embodiment, caprate 13 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 19. In an aspect of this embodiment, caprate 13 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 17.

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

[0093] Caprate 14: In another embodiment, provided herein is caprate 14, which is a crystalline form of the caprate salt of the compound of Formula I, characterized by the following X-ray powder diffraction pattern: 6.74, 18.16, 19.51, and 20.68. In certain aspects, caprate 14 is characterized by an X-ray powder diffraction pattern having peaks expressed in 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 of Formula I is caprate 14, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks set forth in Table 18 (expressed in degrees -2-θ at angles ±0.2°).

[0094] In an aspect of 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 of Formula I in the pharmaceutical composition is in the form of caprate 14. In an aspect of this embodiment, caprate 14 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 20. In an aspect of this embodiment, caprate 14 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 18.

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

[0096] TIFF2025527471000032.tif26152

[0097] D-lactate 1: In another embodiment, provided herein is D-lactate 1, which is a crystalline form of the lactate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern with peaks at the following angles (±0.2°) expressed in degrees -2-θ: 18.24, 19.56, 20.07, and 20.45. In a particular aspect, D-lactate 1 is characterized by an X-ray powder diffraction pattern with peaks at the following angles (±0.2°) expressed in degrees -2-θ: 17.26, 18.24, 19.56, 20.07, 20.45, 20.89, 21.72, and 22.10. In a more specific aspect, D-lactate 1 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following 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 of Formula I is D-lactate 1, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks (expressed in degrees -2-θ at angles ±0.2°) set forth in Table 19.

[0098] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of D-lactate 1. In aspects of this embodiment, the D-lactate 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 21. In aspects of this embodiment, the D-lactate 1 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 19.

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

[0100] D-Lactate 2: In another embodiment, provided herein is D-lactate 2, which is a crystalline form of the lactate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern with peaks expressed in degrees -2-θ at the following angles (±0.2°): 7.38. In a particular aspect, D-lactate 2 is characterized by an X-ray powder diffraction pattern with peaks expressed in degrees -2-θ at the following angles (±0.2°): 7.38 and 19.63. In another embodiment, the crystalline form of the compound of Formula I is D-lactate 2, characterized by an X-ray powder diffraction pattern with peaks (expressed in degrees -2-θ at angles ±0.2°) set forth in Table 20.

[0101] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of D-lactate 2. In aspects of this embodiment, the D-lactate 2 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 22. In aspects of this embodiment, the D-lactate 2 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 20.

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

[0103] Succinate 1 : In another embodiment, provided herein is succinate 1, which is a crystalline form of the succinate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks at the following angles (±0.2°) expressed in degrees -2-θ: 5.98, 7.05, 17.29, and 20.22. In certain aspects, succinate 1 is characterized by an X-ray powder diffraction pattern having peaks at the following angles (±0.2°) expressed in degrees -2-θ: 5.98, 7.05, 17.29, 18.82, 20.22, and 21.39. In a more specific aspect, succinate 1 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following 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, a crystalline form of the compound of Formula I is succinate 1, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks (expressed in degrees -2-θ at angles ±0.2°) set forth in Table 21.

[0104] In an aspect of 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 of Formula I in the pharmaceutical composition is in the form of succinate 1. In an aspect of this embodiment, succinate 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 23. In an aspect of this embodiment, succinate 1 is characterized by an X-ray powder diffraction pattern substantially as 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] Succinate 2: In another embodiment, provided herein is succinate 2, which is a crystalline form of the succinate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 5.15, 6.12, 7.22, and 7.90. In another embodiment, a crystalline form of the compound of Formula I is succinate 2, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees -2-θ at angles ±0.2°) as set forth in Table 22.

[0107] In an aspect of 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 of Formula I in the pharmaceutical composition is in the form of succinate 2. In an aspect of this embodiment, succinate 2 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 24. In an aspect of this embodiment, succinate 2 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 22.

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

[0109] L-Tartrate 1: In another embodiment, provided herein is L-tartrate 1, which is a crystalline form of the tartrate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -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 of Formula I is L-tartrate 1, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees -2-θ at angles ±0.2°) set forth in Table 23.

[0110] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of L-tartrate 1. In aspects of this embodiment, L-tartrate 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 25. In aspects of this embodiment, L-tartrate 1 is characterized by an X-ray powder diffraction pattern substantially as 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 a crystalline form of the tartrate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern with peaks expressed in degrees -2-θ at the following angles (±0.2°): 7.35, 14.19, 15.86, and 18.70. In certain aspects, L-tartrate 2 is characterized by an X-ray powder diffraction pattern with peaks expressed in 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 of Formula I is L-tartrate 2, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks set forth in Table 24 (expressed in degrees -2-θ at angles ±0.2°).

[0113] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of L-tartrate 2. In aspects of this embodiment, the L-tartrate 2 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 26. In aspects of this embodiment, the L-tartrate 2 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 24.

[0114] Table 24: X-ray powder diffraction pattern of L-tartrate 2 [Table 24]

[0115] Sulfate 1: In another embodiment, provided herein is Sulfate 1, which is a crystalline form of the sulfate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at the following angles (±0.2°): 6.87, 19.48, 20.38, and 20.94. In a particular aspect, Sulfate 1 is characterized by an X-ray powder diffraction pattern having peaks expressed in 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 of Formula I is Sulfate 1, characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees -2-θ at angles ±0.2°) set forth in Table 25.

[0116] In an aspect of 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 of Formula I in the pharmaceutical composition is in the form of sulfate 1. In an aspect of this embodiment, sulfate 1 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 27. In an aspect of this embodiment, sulfate 1 is characterized by an X-ray powder diffraction pattern substantially as 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 a crystalline form of the sulfate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -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 of Formula I is Sulfate 2, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in degrees -2-θ at angles ±0.2°) set forth in Table 26.

[0119] In aspects of 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 of Formula I in the pharmaceutical composition is in the form of sulfate 2. In aspects of this embodiment, sulfate 2 is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 28. In aspects of this embodiment, sulfate 2 is characterized by an X-ray powder diffraction pattern substantially as described by one or more of the properties listed in Table 26.

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

[0121] A further aspect of such embodiments provides certain drug substances comprising the crystalline form of the compound of Formula I described herein. "Drug substance" means an active pharmaceutical ingredient. The presence of the 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-polarization magic angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectroscopy, and nitrogen-15 CPMAS NMR spectroscopy.

[0122] In a further aspect of this embodiment, compound 2 may be substituted with ethers, esters, straight chain alkanes (C3-C 10 In a further aspect of this embodiment, compound 2 is crystallized from a solvent system comprising a solvent selected from ethers, esters, straight chain alkanes (C3-C 10 In some embodiments, compound 2 is crystallized from a solvent system comprising a solvent selected from the group consisting of 2-Me-THF, MTBE, ethyl acetate, n-butanol, 1-propanol, and water.

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

[0124] In subsequent examples, caprate 2 is filtered and optionally dried. In one embodiment, caprate 2 is dried to provide 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 containing Compound 2 is suspended to form caprate 9. The solvent system can contain multiple forms of Compound 2. Specifically, caprate 9 is crystallized from a solvent system comprising MTBE, about 5-40% by weight of 1-propanol, and 0.5-5% water. In one embodiment, caprate 9 is filtered and optionally dried. In one embodiment, caprate 9 is dried to provide 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%.

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

[0127] Terms used in this specification have their ordinary meanings, and the meaning of such terms is independent at each occurrence of the term. Nevertheless, and unless otherwise stated, the following definitions apply throughout the specification and claims.

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

[0129] Numerical values ​​provided herein, and the use of the term "about," can 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 ​​in an X-ray powder diffraction pattern measured using CuKα radiation or the like) can be used to describe any of the parameters described herein. 13 C or 15 "About," when used to modify a parameter (e.g., the chemical shift of N), means that the parameter in question may vary by 10% below or above the numerical value listed for that parameter; where appropriate, the listed parameter may be rounded to the nearest integer. Additionally, as used herein, the term "or" indicates alternatives that may be combined, where appropriate; that is, the term "or" includes each listed alternative separately as well as combinations thereof.

[0130] Although exemplary methods and materials are described herein, methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0131] "Patient" includes both humans and other animals.

[0132] "Mammal" includes humans and other mammalian animals.

[0133] "XPRD" stands for X-ray powder diffraction.

[0134] "Excipient" means an essentially inert substance used to give stability, form, or consistency to a formulation.

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

[0136] As used herein, the term "composition" (or "pharmaceutical composition" or "pharmaceutically acceptable composition") is intended to encompass a product containing the specified ingredients in the specified amounts, and any product that results directly or indirectly from combining the specified ingredients in the specified amounts. The term is intended to encompass a product containing the active ingredients and the inactive ingredients (if present) that constitute the carrier, as well as any product that results directly or indirectly from the combination, complexation, or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Thus, a pharmaceutical composition of the present invention encompasses any composition made by admixing the crystalline form of the compound of Formula I described herein with a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

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

[0138] As used herein, the term "caprate" is also known as "decanoate."

[0139] The compounds of the present invention also include tautomers. Tautomers arise when a single bond swaps with an adjacent double bond, resulting in the migration of a proton. Tautomers include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position on a heterocyclic ring system (e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, 1H- and 2H-pyrazole). Tautomers can exist in equilibrium or be sterically locked into one form by appropriate substitution.

[0140] As used herein, the terms "treating" or "treatment" refer to inhibiting or ameliorating a disease, condition, or disorder in a subject experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder. For example, inhibiting a disease, condition, or disorder refers to preventing further progression of the pathology and / or symptoms of the disease, condition, or disorder. Furthermore, ameliorating a disease, condition, or disorder refers to reversing the pathology and / or symptoms, e.g., reducing the severity of the disease.

[0141] As used herein, the terms "prevent," "preventing," or "prevention" include the prevention of at least one symptom associated with or resulting from the disease, condition, or disorder being prevented.

[0142] As used herein, "subject" refers to an animal, preferably a mammal, particularly a human, or a non-human animal such as a livestock or domestic animal (including, but not limited to, cows, horses, sheep, pigs, goats, rabbits, cats, and dogs), in need of treatment. In some embodiments, the subject is a human.

[0143] As used herein, the term "administration" and variations thereof (e.g., "administering") in reference to a compound of Formula I means providing the compound to a subject in need of treatment. As used herein, "orally" and variations thereof (e.g., "oral") means administration via the mouth, i.e., administration of a compound of Formula I via the mouth.

[0144] Administration of a compound of Formula I to a subject includes both self-administration and administration by another person to the subject. The subject may be in need of or desiring treatment for an existing disease or medical condition, or may be in need of or desiring prophylactic treatment to prevent or reduce the risk of developing the disease or medical condition. As used herein, a subject "in need" of treatment for an existing condition or prophylactic treatment includes both a determination of need by a medical professional and the patient's desire for such treatment.

[0145] process Provided herein are compounds of formula I: [ka] [In the ceremony, A - is a pharmaceutically acceptable anion. 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 of 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-tartrate 1, L-tartrate 2, sulfate 1, and sulfate 2.

[0147] In one embodiment of the process for preparing a crystalline form of the compound of 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, the process for preparing a crystalline form of the compound of Formula I comprises adding an organic solvent to the compound to form a slurry / solution. In a further embodiment, the process comprises aging the slurry / solution. In one embodiment, the process comprises aging the slurry / solution at a temperature ranging from 0°C to 40°C. In a further embodiment, the process comprises aging the slurry / solution at a temperature ranging from 20°C to 35°C.

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

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

[0151] In one embodiment, the process for preparing a crystalline form of the compound of Formula I comprises washing the starting material with an organic solvent or 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 comprises drying the wet cake. In one embodiment, the process comprises 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 of formula I further comprises exposing the crystalline form of the compound of formula I to about 5% relative humidity to provide a second crystalline form of the compound of formula I. In another embodiment, the process for preparing the crystalline form of the compound of formula I further comprises exposing the crystalline form of the compound of formula I to about 50% relative humidity to provide a second crystalline form of the compound of formula I.

[0153] In one embodiment of the process for preparing a crystalline form of the compound of Formula I, the organic solvent is selected from the group consisting of ethers, esters, and straight-chain alkanes (C3-C 10 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 certain embodiments of the process for preparing a crystalline form of the compound of Formula I, the crystalline form of the compound of Formula I is selected from acetate 2, acetate 3, acetate 4, acetate 5, and acetate 6, and the starting material is compound 1 (the acetate salt of the compound of Formula I).

[0155] In certain embodiments of the process for preparing a crystalline form of the compound of Formula I, the crystalline form of the compound of 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 caprate salt of the compound of Formula I).

[0156] In certain embodiments of the process for preparing a crystalline form of the compound of Formula I, the crystalline form of the compound of Formula I is selected from D-lactate 1, succinate 1, L-tartrate 1, and sulfate 1, and the starting material is Compound B (the bicarbonate salt of the compound of Formula I).

[0157] In certain embodiments of the process for preparing a crystalline form of the compound of Formula I, the crystalline form of the compound of Formula I is D-lactate 2, and the starting material is compound 3 (the lactate salt of the compound of Formula I). ​​In one embodiment, compound 3 is D-lactate 1.

[0158] In certain embodiments of the process for preparing a crystalline form of the compound of Formula I, the crystalline form of the compound of Formula I is succinate 2, and the starting material is compound 4 (the succinate salt of the compound of Formula I). ​​In one embodiment, compound 4 is succinate 1.

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

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

[0161] In another aspect, provided herein are compounds of formula I: [ka] [In the ceremony, A - is the caprate anion. wherein the crystalline form is formed by a process comprising adding an alcohol to a starting material form, wherein the starting material is Compound 2 (the caprate salt of the compound represented by Formula I).

[0162] In one embodiment of the process for preparing a crystalline form of the caprate salt of the compound of Formula I, the crystalline form prepared by the 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 the process for preparing a crystalline form of the caprate salt of the compound of 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, the process for preparing a crystalline form of the caprate salt of the compound of Formula I comprises adding an organic solvent to the starting material (Compound 2—the caprate salt of the compound of Formula I) to form a slurry / solution. In a further embodiment, the process comprises aging the slurry / solution. In one embodiment, the process comprises aging the slurry / solution at a temperature ranging from 0° C. to 40° C. In a further embodiment, the process comprises aging the slurry / solution at a temperature ranging from 20° C. to 35° C.

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

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

[0167] In one embodiment, the process for preparing a crystalline form of the caprate salt of the compound of Formula I comprises washing the starting material (Compound 2—the caprate salt of the compound of 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 comprises drying the wet cake. In one embodiment, the process comprises drying the wet cake with nitrogen at 20° C. to 40° C.

[0168] In one embodiment, the process for preparing a crystalline form of caprate salt of the compound represented by formula I further comprises exposing the crystalline form of caprate salt of the compound represented by formula I to about 5% relative humidity to provide a second crystalline form of caprate salt of the compound represented by formula I. In one embodiment, the process for preparing a crystalline form of caprate salt of the compound represented by formula I further comprises exposing the crystalline form of caprate salt of the compound represented by formula I to about 50% relative humidity to provide a second crystalline form of caprate salt of the compound represented by formula I. In one embodiment, the organic solvent for the process is selected from the group consisting of ethers, esters, and straight chain alkanes (C3-C 10 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 the process for preparing a crystalline form of the caprate salt of the compound of 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 caprate salt of the compound of Formula I is caprate 4, and the starting material is caprate 1.

[0171] In one embodiment, the crystalline form of the caprate salt of the compound of Formula I is caprate 5, and the starting material is caprate 4.

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

[0173] In one embodiment, the crystalline form of the caprate salt compound of Formula I is caprate 3, and the starting material is caprate 2 or caprate 9. In a further embodiment, the process comprises filtering and optionally drying caprate 2. In one embodiment, the process comprises drying caprate 2 to form caprate 3. In a further embodiment, the process comprises 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 a relative humidity of about 50%.

[0174] As described above, the caprate 3 can be formed by drying a composition comprising the caprate 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 caprate salt of the compound of Formula I is caprate 4, and the starting material is caprate 3.

[0176] In one embodiment, the crystalline form of the caprate salt of the compound of Formula I is caprate 6, and the starting material is caprate 1.

[0177] In one embodiment, the crystalline form of the caprate salt of the compound of Formula I is caprate 7, and the starting material is caprate 6.

[0178] In one embodiment, the crystalline form of the caprate salt of the compound of Formula I is caprate 8, and the starting material is caprate 4.

[0179] In one embodiment, the crystalline form of the caprate salt of the compound of 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 a crystalline form of caprate salt of the compound of Formula I further comprises exposing a first crystalline form of the compound of Formula I selected from caprate 3 and caprate 7 to about 5% relative humidity to produce a second crystalline form of the compound of Formula I selected from caprate 10 and caprate 11. In a further embodiment, the first crystalline form of the compound of Formula I caprate salt is caprate 3, and the second crystalline form of the compound of Formula I caprate salt is caprate 10. In another embodiment, the first crystalline form of the compound of Formula I caprate salt is caprate 7, and the second crystalline form of the compound of Formula I caprate salt is caprate 11.

[0181] In one embodiment, the crystalline form of the caprate salt of the compound of 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 a crystalline form of the caprate salt of the compound of Formula I comprises exposing caprate 3 to vapors containing the alcohol, and the crystalline form of the compound of Formula I is caprate 13. In another embodiment, the process comprises exposing caprate 3 to vapors containing an organic solvent and the alcohol, and the crystalline form of the compound of Formula I is caprate 13. In a further embodiment, the organic solvent is MTBE.

[0183] Also provided herein are compounds of formula I: [ka] [In the ceremony, A - is a pharmaceutically acceptable anion. wherein the crystalline form is formed by a process comprising adding an alcohol to a starting material, wherein the starting material is Compound A (the chloride salt of the compound of Formula I) or Compound B (the bicarbonate salt of the compound of Formula I).

[0184] In one embodiment, the process for preparing the crystalline compound of Formula I comprises ion exchange.

[0185] In one embodiment, the process for producing the crystalline compound of Formula I comprises ion exchange, wherein the starting material is Compound A (the chloride salt of the compound of Formula I), and the ion exchange is carried out by subjecting A - The ion exchange resin is charged with

[0186] In another embodiment, compound B (the bicarbonate salt of the compound of Formula I) is formed by a process comprising ion exchange, where the initial material is compound A (the chloride salt of the compound of Formula I), and the ion exchange to form compound B is: (1) an ion exchange resin charged with bicarbonate anions; or (2) liquid-liquid extraction with organic solvents and aqueous bicarbonate anion; Includes.

[0187] In a further embodiment, the process for making the crystalline compound of Formula I comprises ion exchange, wherein the starting material is Compound B (the bicarbonate salt of the compound of Formula I), and the ion exchange comprises adding an acid comprising a pharmaceutically acceptable anion.

[0188] In one embodiment, the crystalline form of the compound of 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-tartrate 1, L-tartrate 2, sulfate 1, and sulfate 2.

[0189] In one embodiment of the process for preparing a crystalline form of the compound of 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, the process for preparing a crystalline form of the compound of Formula I comprises adding an organic solvent to the compound to form a slurry / solution. In a further embodiment, the process comprises aging the slurry / solution. In one embodiment, the process comprises aging the slurry / solution at a temperature ranging from about -10°C to about 40°C. In a further embodiment, the process comprises aging the slurry / solution at a temperature ranging from about 20°C to about 35°C. In another embodiment, the process comprises aging the slurry / solution at a temperature ranging from about -10°C to about 0°C.

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

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

[0193] In one embodiment, the process for preparing a crystalline form of the compound of Formula I comprises washing the 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 comprises drying the wet cake. In one embodiment, the process comprises 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 of Formula I further comprises exposing the crystalline form of the compound of Formula I to a relative humidity of about 5% to about 50% to provide a second crystalline form of the compound of 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 the process for preparing a crystalline form of the compound of Formula I, the organic solvent is selected from the group consisting of ethers, esters, and straight-chain alkanes (C3-C 10 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 certain embodiments of the process for preparing a crystalline form of the compound of Formula I, the crystalline form of the compound of Formula I is selected from acetate 2, acetate 3, acetate 4, acetate 5, and acetate 6, and the starting material is Compound A (the chloride salt of the compound of Formula I). ​​In other embodiments of the process for preparing the crystalline form of the compound of Formula I, the crystalline form of the compound of Formula I is selected from acetate 2, acetate 3, acetate 4, acetate 5, and acetate 6, and the starting material is Compound B (the bicarbonate salt of the compound of Formula I).

[0197] In certain embodiments of the process for preparing a crystalline form of the compound of Formula I, the crystalline form of the compound of 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 (the chloride salt of the compound of Formula I). ​​In other embodiments of the process for preparing the crystalline form of the compound of Formula I, the crystalline form of the compound of 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 (the bicarbonate salt of the compound of Formula I).

[0198] In certain embodiments of the process for preparing a crystalline form of the compound of Formula I, the crystalline form of the compound of Formula I is selected from D-lactate 1, succinate 1, L-tartrate 1, and sulfate 1, and the starting material is Compound B (the bicarbonate salt of the compound of Formula I).

[0199] Treatment method In another aspect, provided herein are methods of using the PCSK9-specific antagonist compounds described herein (e.g., compounds of Formula I) to antagonize PCSK9 function; the methods are further described below. Throughout this application, use of the term "antagonizing" refers to providing an agent to an affected tissue that antagonizes, inhibits, prevents, neutralizes, or suppresses one or more functions of PCSK9 in the affected tissue. Inhibition or antagonism of one or more functional properties associated with PCSK9 can be readily determined according to methodologies known in the art (see, e.g., 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 seen in the absence of the antagonist, or compared to the activity observed in the presence of, for example, a control antagonist of irrelevant specificity. Preferably, PCSK9-specific antagonists according to the present invention antagonize PCSK9 function to the point where there is at least a 10% reduction in a measured parameter (which includes, but is not limited to, the activities disclosed herein), and more preferably at least a 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 95% reduction in a measured parameter. Such inhibition / antagonism of PCSK9 function is particularly effective when PCSK9 function contributes, at least in part, to a particular phenotype, disease, disorder, or condition adversely affecting a subject.

[0200] In one aspect, the invention provides a method for antagonizing the activity of PCSK9, comprising contacting a cell, cell population, or tissue sample that can be affected by PCSK9 (i.e., expressing and / or containing an LDL receptor) with a PCSK9-specific antagonist (e.g., a compound of Formula I) disclosed herein under conditions that allow the antagonist to bind to PCSK9, if present, and inhibit PCSK9 from inhibiting the uptake of cytoplasmic LDL. Some embodiments of the invention include such methods wherein the cell is a human cell. Further embodiments of the invention include such methods wherein the cell is a mouse cell.

[0201] In one aspect, the invention provides a method for antagonizing the activity of PCSK9 in a subject, the method comprising administering to the subject a therapeutically effective amount of a PCSK9-specific antagonist of the 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 treatment for a disease, disorder, or condition that can benefit from the effects of a PCSK9 antagonist.

[0202] Accordingly, the present invention contemplates the use of the PCSK9-specific antagonists described herein in a variety of therapeutic methods in which antagonizing the function of PCSK9 is desirable. As used herein, the term "method of treatment" refers to a course of action that results in an alteration of at least one symptom of a disease state, which may be preventative or therapeutic in nature. In some embodiments, the present invention relates to a method of treating a condition associated with and / or caused by PCSK9 activity, or a condition in which PCSK9 function is contraindicated in a particular subject, comprising administering to the subject a therapeutically effective amount of a PCSK9-antagonist compound of 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 may be a disease state or condition in which PCSK9 activity is contraindicated.

[0203] In one aspect, provided herein is the use of a crystalline form of the compound of Formula I as an active ingredient in a medicament for treating hypercholesterolemia in a subject.

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

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

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

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

[0208] In one aspect, provided herein is the use of a crystalline form of the compound of Formula I as an active ingredient in a medicament for treating peripheral arterial disease in a subject.

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

[0210] In one aspect, provided herein is the use of caprate 3 as an active ingredient in a medicament for treating hypercholesterolemia in a subject.

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

[0212] In another embodiment, provided herein is the use of caprate 3 as an active ingredient in a medicament 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 medicament for treating atherosclerotic cardiovascular disease in a subject.

[0214] In one aspect, provided herein is a method of treating hypercholesterolemia, wherein the method comprises administering a therapeutically effective amount of caprate 3 to a patient in need of treatment for hypercholesterolemia.

[0215] In one aspect, provided herein is the use of caprate 3 as an active ingredient in a medicament for treating peripheral arterial disease in a subject.

[0216] In one embodiment, provided herein is a pharmaceutical composition comprising Caprate 3 as a medicament for treating peripheral arterial disease in a subject.

[0217] Pharmaceutical Composition Therapeutic methods according to the present invention involve administering to an individual a therapeutically (or prophylactically) effective amount of a PCSK9-specific antagonist of the present invention. The use of the terms "therapeutically effective" or "prophylactically effective" in relation to quantity refers to the amount necessary at the intended dosage to achieve the desired therapeutic and / or prophylactic effect for a desired period of time. The desired effect may be, for example, the alleviation, amelioration, reduction, or cessation of at least one symptom associated with the treated condition. As will be appreciated by those skilled in the art, these amounts will vary depending on a variety of factors, including, but not limited to, the individual's condition, age, sex, and weight, and the ability of the PCSK9-specific antagonist to elicit the desired effect in the individual. 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 compounds of the present invention are preferably administered in the form of a pharmaceutical composition as described herein.

[0219] Dosing of antagonist therapeutic agents is within the skill of one in the art (see, e.g., Lederman et al., 1991 Int. J. Cancer 47:659-664; Bagshawe et al., 1991 Antibody, Immunoconjugates and Radiopharmaceuticals 4:915-922) and will vary based on numerous factors (including, but not limited to, those factors described above, such as the patient's condition, the area to be treated, the route of administration, and the desired treatment, e.g., prophylactic or acute treatment). A physician or veterinarian of ordinary skill can readily determine and prescribe the effective therapeutic amount of the antagonist.

[0220] A subject may be in need of or desire treatment for an existing disease or medical condition. As used herein, a subject "in need" of treatment for an existing condition encompasses both the determination of need by a medical professional and the subject's desire for such treatment. As used herein, the term "subject" refers to a mammal, plant, lower animal, or cell culture. In one embodiment, the subject is a human patient or other animal patient in need of treatment. When a compound or salt thereof is provided in combination with one or more other active agents, "administration" and variations thereof are understood to include providing the compound or salt thereof and the other agent(s) contemporaneously or simultaneously, or in the course of separate administrations over a period of time, respectively. When agents of a combination are administered simultaneously, they can be administered together in a single composition, or they can be administered separately. It is understood that a "combination" of active agents can be a single composition containing all of the active agents or multiple compositions, each containing one or more of the active agents. For example, in the case of two active agents, the combination can be a single composition containing both active agents, or it can be two separate compositions each containing one active agent; in the case of three active agents, the combination can be a single composition containing all three active agents, or it can be three separate compositions each containing one active agent, or it can be two compositions, one containing two active agents and the other containing a third active agent; etc.

[0221] The compositions and combinations of the present invention are suitably administered in an effective amount. The term "effective amount" refers to an amount of active compound sufficient to antagonize PCSK9 and thereby elicit the desired response (i.e., induce a therapeutic response in the treatment or management of conditions associated with or affected by PCSK9 function, such as, but not limited to, atherosclerosis, hypercholesterolemia, peripheral artery disease, cerebrovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome, and related cardiovascular and cardiometabolic diseases in animals or humans).

[0222] The actual dosage employed may vary depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art, as described, for example, in standard references, such as the 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); the disclosures of which are incorporated herein by reference. For convenience, the total daily dosage may be divided and administered in multiple doses during the day or may be administered continuously as required.

[0223] The PCSK9-specific antagonist, alone or in combination with other drugs designed to aid in the treatment of an individual, can be administered to an individual by any administration route recognized in the art, including, but not limited to, oral administration, administration by injection (specific embodiments of which include intravenous, subcutaneous, intraperitoneal, or intramuscular injection), administration by 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 administration route should be determined based on many considerations recognized by those skilled in the art, including, but not limited to, the desired physicochemical properties of the treatment.

[0224] Dosage and Formulation Also provided herein is a method of treating hypercholesterolemia in a subject in need thereof, comprising administering to the subject an amount of a compound of formula I: [ka] [In the ceremony, A - is selected from pharmaceutically acceptable anions. wherein the particular amount administered is from about 5 mg to about 300 mg of the compound of Formula I.

[0225] The dosage regimen is selected according to various factors (e.g., the type, species, age, weight, sex, and condition of the patient; the severity of the condition being treated; the route of administration; and the patient's renal and hepatic function). An ordinarily skilled physician, veterinarian, or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0226] Forms of the present disclosure can be formulated and administered in solid dosage forms (e.g., tablets, pills, capsules, powders, or granules) intended for oral administration. Formulation of compositions according to the present disclosure can be conveniently 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." Additionally, 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 the present disclosure, the forms described herein can be formulated as active pharmaceutical ingredients and administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to herein as "carrier" materials) appropriately selected with respect to the intended mode of administration and consistent with customary pharmaceutical practice (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 a tablet or capsule, the forms described herein can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier (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 suitable excipients and non-toxic, pharmaceutically acceptable inert carriers to form a formulation that can be provided as a prepared dosage form in a pre-filled injection device, as a lyophilized preparation to be reconstituted for injection, or as a sterile liquid to be diluted for injection.

[0229] In one embodiment, the dosage administered to a subject is about 5 mg to about 300 mg of the crystalline form of the compound of Formula I. Integers and half-integers between 5 mg and 300 mg are encompassed by the present invention. In one embodiment, the dosage is about 10 mg to about 300 mg of the crystalline form of the compound of Formula I. In one embodiment, the dosage is about 10 mg, about 20 mg, or about 22 mg of the crystalline form of the compound of Formula I. In one embodiment, the dosage is about 5 mg, about 6 mg, about 10 mg, about 12 mg, about 15 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, or about 100 mg of the crystalline form of the compound of Formula I. In one embodiment, the dosage is about 10 mg, about 12 mg, about 15 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 30 mg, or about 40 mg of the crystalline form of the compound of formula I. In one embodiment, the dosage is 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 of the crystalline form of the compound of Formula I. In one embodiment, the dosage is a daily dose of about 5 mg to about 300 mg. In one embodiment, the dosage is 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, about 30 mg, about 35 mg, or about 40 mg of the crystalline form of the compound of Formula I per day.In one embodiment, the dosage is about 5, about 6, about 10, about 12, about 15, about 18, about 20, about 22, about 22.5, about 24, about 25, or about 30 mg daily of the crystalline form of the compound of Formula I. In one embodiment, the dosage is about 10, about 12, about 15, about 18, about 20, about 22, about 24, about 25, or about 30 mg daily of the crystalline form of the compound of Formula I.

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

[0231] In one embodiment, the amount administered to the subject is about 10 mg to about 30 mg of caprate 3. In another embodiment, the amount administered to the subject is about 12 mg to about 27 mg of caprate 3. In yet another embodiment, the amount administered to the subject is about 15 mg to about 25 mg of caprate 3. In one embodiment, the amount administered to the subject is about 10 mg to about 22 mg of caprate 3. In one embodiment, the amount administered to the subject is about 10 mg to about 20 mg of caprate 3. In yet another embodiment, the amount administered to the subject is about 15 mg to about 22 mg of caprate 3. In one embodiment, the amount is a daily dose 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 of Caprate 3. In one embodiment, the amount is a daily dose 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 of caprate 3. In yet another embodiment, the amount administered to a subject in need thereof is about 15 mg, about 17.5 mg, 18 mg, about 20 mg, or about 22 mg of caprate 3. In a further embodiment, the amount administered to a subject in need thereof is about 20 mg or about 22 mg of caprate 3. In a further embodiment, the amount administered to a subject in need thereof is about 20 mg of caprate 3. In a further embodiment, the amount administered to a subject in need thereof is about 22 mg of caprate 3.

[0232] It is understood that administration of a particular dosage of a crystalline form of the compound of Formula I corresponds to administration of the corresponding free form of the compound of Formula I. For example, administration of about 22 mg of Caprate 3 corresponds to administration of about 20 mg of the corresponding free form of the compound of Formula I.

[0233] In one embodiment, oral administration comprises administering a single oral dosage form containing the amount of the crystalline form of the compound of Formula I. In one embodiment, oral administration comprises administering two or more or multiple oral dosage forms, each containing the amount of the crystalline form of the compound of Formula I or a portion thereof. In one embodiment, oral administration comprises administering a single oral dosage form containing the amount of the crystalline form of the compound of Formula I once per day. In one embodiment, oral administration comprises administering two or more or multiple oral dosage forms, each containing the amount of the crystalline form of the compound of Formula I or a portion thereof, once per day. In one embodiment, oral administration comprises administering a single oral dosage form containing the amount of the crystalline form of the compound of Formula I two or more times per day (e.g., two, three, or four times per day). In one embodiment, oral administration comprises administering two or more or multiple oral dosage forms, each containing the amount of the crystalline form of the compound of Formula I or a portion thereof, two or more times per day (e.g., two, three, or four times per day). The oral dosage forms can be administered with or without fasting, i.e., with or without food. In one embodiment, the subject in need of treatment fasts about 30 minutes prior to administration of the crystalline form of the compound of Formula I.

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

[0235] As used herein, "oral dosage form" refers to a pharmaceutical formulation containing a crystalline form of the compound of Formula I and at least one pharmaceutically acceptable excipient, suitable for oral administration to a subject. As used herein, the terms "oral dosage form" and "pharmaceutical composition" are intended to encompass both the combination of the specified ingredients in the specified amounts and any product resulting directly or indirectly from the combination of the specified ingredients in the specified amounts. An oral dosage form may contain the entire amount (e.g., about 5 mg to about 300 mg) of the crystalline form of the compound of Formula I, which may or may not be a daily dose. An oral dosage form may contain a portion of the daily dose of the crystalline form of the compound of Formula I.

[0236] Oral dosage forms according to the present disclosure can be solid, semisolid, or liquid. Examples of 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, dragees, hard and soft capsules (e.g., gelatin capsules), lozenges, rapidly dissolving tablets, aqueous, alcoholic, or oily solutions, gels, syrups, emulsions, or suspensions. Oral dosage forms according to the present disclosure may further comprise one or more coatings to modify their release characteristics (e.g., coatings imparting delayed release) or formulations with sustained-release properties. Furthermore, the present disclosure also encompasses formulations intended to be converted to suspensions or solutions immediately prior to use; examples include, but are not limited to, lyophilized formulations and liquid formulations absorbed onto solid absorption media. In one embodiment, the oral dosage form is a liquid-filled capsule, e.g., a hard gelatin capsule filled with the crystalline form of the compound of Formula I in a combination of Labrasol® and propylene glycol, e.g., in a 2:1 ratio. In one embodiment, the oral dosage form is a liquid-filled capsule, e.g., a hard gelatin capsule filled with the crystalline form of the compound of Formula I in a combination of Labrasol® and propylene glycol, e.g., in a 2:1 ratio, overencapsulated with an enteric-coated capsule, e.g., HPMC Vcaps® Enteric capsule (Capsugel®, Lonza). In one embodiment, the oral dosage form is a suspension, e.g., the crystalline form of the compound of Formula I suspended in a combination of OraBlend SF and propylene glycol, e.g., in a 2:1 ratio. In one embodiment, the oral dosage form is a dry-filled enteric-coated capsule, e.g., dry-filled HPMC Vcaps® Enteric capsule (Capsugel®, Lonza). In one embodiment, the oral dosage form is a tablet. In a further embodiment, the oral dosage form is a film-coated tablet.

[0237] In one embodiment, the pharmaceutical compositions provided herein comprise a diluent selected from polyethylene glycol (polyethylene glycols of various molecular weights above 300), microcrystalline cellulose, mannitol, starch, dicalcium phosphate, calcium carbonate, sodium carbonate, lactose, or a combination thereof. In one embodiment, the pharmaceutical compositions provided herein comprise a diluent selected from PEG 300, macrogol (PEG 4000), microcrystalline cellulose, mannitol, lactose, or a combination thereof. In a further embodiment, the diluent is selected from PEG 300, macrogol (PEG 4000), microcrystalline cellulose, or lactose.

[0238] In one embodiment, the pharmaceutical compositions provided herein comprise a binder selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, or polyvinylpyrrolidone. In a further embodiment, the binder is hydroxypropyl cellulose. 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 compositions provided herein comprise 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 compositions of the present invention comprise a glidant selected from silicon dioxide, starch, talc, magnesium stearate, or tricalcium phosphate. In a further embodiment, the glidant is selected from silicon dioxide or tricalcium phosphate. In one embodiment, the pharmaceutical compositions of the present invention comprise a lubricant selected from magnesium stearate, sodium stearyl fumarate, or both. In one embodiment, the pharmaceutical compositions of the present invention comprise a solubilizer selected from propylene glycol, polysorbate 80, sorbitol, Cremophor EL, castor oil, corn oil, cottonseed oil, safflower oil, sesame oil, soybean oil, peppermint oil, olive oil, miglyol, glycerin, or a combination thereof. In a further embodiment, the solubilizer is propylene glycol.

[0240] In one embodiment, the oral dosage form further comprises a penetration enhancer. As used herein, "penetration enhancer" refers to a pharmaceutically acceptable excipient that improves absorption of an active agent (e.g., the crystalline form of the compound of Formula I) from the gastrointestinal tract. Penetration enhancers facilitate size-restricted transport through tight junctions between intestinal epithelial cells, thereby resulting in the absorption of cell-impermeable compounds. (DJ Drucker, Advances in Oral Peptide Therapeutics, Nat Rev Drug Discov, 19, pp. 277-289 (2020)). Suitable penetration enhancers include, but are not limited to, sodium caprate, Labrasol®, sulcaprozate sodium (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 dosage form, penetration enhancers are used in amounts up to 1800 mg, up to about 720 mg, up to about 540 mg, up to about 360 mg, in an amount ranging from about 90 mg to about 360 mg, in an amount ranging from about 180 mg to about 360 mg, or in an amount of 90 mg, 180 mg, or 360 mg. In embodiments provided herein, the oral dosage form comprises a penetration enhancer in an amount up to about 360 mg, in an amount ranging from about 90 mg to about 360 mg, in an amount ranging from about 180 mg to about 360 mg, or in an amount of 90 mg, 180 mg, or 360 mg. In one embodiment, the oral dosage form provided herein comprises a penetration enhancer in an amount of 90 mg, 180 mg, or 360 mg. In one embodiment, the oral dosage form of the present invention comprises a penetration enhancer in an amount of 180 mg or 360 mg.

[0241] When present in the oral dosage form, sodium caprate is used in an amount up to about 360 mg, in an amount ranging from about 90 mg to about 360 mg, in an amount ranging from about 180 mg to about 360 mg, or in an amount of 90 mg, 180 mg, or 360 mg. In one embodiment, the oral dosage form provided herein contains the penetration enhancer sodium caprate in an amount of 90 mg, 180 mg, or 360 mg. 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, dry-fill capsules or tablets can be used to administer the crystalline form of the compound of Formula I to a subject in need thereof. A penetration enhancer can be included in the pharmaceutical compositions provided herein. In one embodiment, the amount of penetration enhancer, such as sodium caprate, can range from about 1% to about 75% by weight. As used herein, "% by weight" refers to the weight percent of the component relative to the total weight of the pharmaceutical composition. In another embodiment, the amount of penetration enhancer in the pharmaceutical composition is from about 18% to about 65% by weight. In a further embodiment, the amount of penetration enhancer in the pharmaceutical composition is from about 22% to about 36% by weight. For tablets, the amount of penetration enhancer, such as sodium caprate, can range from about 22% to about 65% by weight. Oral dosage forms can be manufactured using standard methods, such as wet granulation and dry granulation.

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

[0244] In one embodiment, provided herein is a compound of formula I: [ka] [In the ceremony, A - is 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 comprise a combination of microcrystalline cellulose, macrogol (PEG 4000), and lactose. In a further embodiment, the composition comprises two or more diluents, wherein the two or more diluents comprise a combination of microcrystalline cellulose (Avicel PH 102), macrogol (PEG 4000), and lactose.

[0245] In one embodiment of the invention, the pharmaceutical composition comprises from about 1% to about 8% by weight of the crystalline form of the compound of Formula I, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises from about 1% to about 6% by weight of the crystalline form of the compound of Formula I, based on the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises about 4% by weight of the crystalline form of the compound of Formula I, based on the total weight of the pharmaceutical composition.

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

[0247] In one embodiment of the present invention, the pharmaceutical composition comprises at least one diluent. In one embodiment, the pharmaceutical composition comprises two diluents. In one embodiment, the diluent or combination of diluents comprises about 10% to about 70%, about 20% to about 60%, about 30% to about 50%, or about 40% to about 50% by weight of the diluent, based on 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 is present in the pharmaceutical composition at about 40% to about 72% by weight, based on the total weight of 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 of the present invention, the pharmaceutical composition comprises a disintegrant. In one embodiment, the pharmaceutical composition comprises from about 0% to about 3% by weight of a disintegrant, based on the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises about 3% by weight of a disintegrant, based on the total weight of the pharmaceutical composition.

[0249] In one embodiment of the present invention, the pharmaceutical composition comprises a glidant. In one embodiment, the pharmaceutical composition comprises from about 0% to about 1% by weight of the glidant, based on the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises about 1% by weight of the glidant, based on the total weight of the pharmaceutical composition.

[0250] In one embodiment of the present invention, the pharmaceutical composition comprises a lubricant. In one embodiment, the pharmaceutical composition comprises about 1% by weight to about 1.5% by weight of the lubricant, based on the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 1% by weight of the lubricant, based on the total weight of the pharmaceutical composition.

[0251] In an embodiment of the present invention, the pharmaceutical composition comprises: (a) about 1% to about 8% by weight of the crystalline form of the compound of 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; and (d) optionally, a glidant and / or lubricant. In one embodiment, the penetration enhancer is present in the pharmaceutical composition at about 18% to about 74% by weight, 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 the crystalline form of the compound of 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 PEG 4000, microcrystalline cellulose, propylene glycol, and lactose; (d) optionally, a glidant; and (e) optionally, a lubricant. In a further embodiment, the pharmaceutical composition further comprises about 22% to about 36% by weight of a penetration enhancer selected from sodium caprate or Labrasol®, based on the total weight of the pharmaceutical composition.

[0252] In one embodiment of the present invention, provided herein is a pharmaceutical composition, comprising: (a) from about 1% to about 8% by weight of a crystalline form of the compound of Formula I, based on the total weight of the pharmaceutical composition; (b) from about 22.5% to about 80% by weight of a penetration enhancer, based on the total weight of the pharmaceutical composition, wherein the penetration enhancer is sodium caprate; (c) two diluents selected from microcrystalline cellulose and lactose, where the combination of diluents is from about 15% to about 80% by weight of the total weight of the pharmaceutical composition. (d) optionally, a disintegrant, wherein the pharmaceutical composition comprises from about 0% to about 3% by weight of a disintegrant, based on the total weight of the pharmaceutical composition; (e) optionally, a glidant, wherein the pharmaceutical composition comprises from about 0% to about 1% by weight of a glidant, based on the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; and (f) from about 1% to about 1.5% by weight of a lubricant, based on 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) about 1% to about 6% by weight of a crystalline form of the compound of Formula I, based on the total weight of the pharmaceutical composition; (b) about 22.5% to about 50% by weight of a penetration enhancer, based on the total weight of the pharmaceutical composition, wherein the penetration enhancer is sodium caprate; (c) two diluents selected from microcrystalline cellulose and lactose, where the combination of diluents constitutes about 40% to about 72% by weight of diluent, based on the total weight of the pharmaceutical composition; (d) about 3% by weight of a disintegrant, based on the total weight of the pharmaceutical composition; (e) about 1% by weight of a glidant, based on the total weight of the pharmaceutical composition, where the glidant is silicon dioxide; and (f) about 1% by weight of a lubricant, based on the total weight of the pharmaceutical composition, where the lubricant is magnesium stearate.

[0254] In one embodiment of the present invention, provided herein is a pharmaceutical composition comprising: (a) about 4 wt.% of a crystalline form of the compound of Formula I, based on the total weight of the pharmaceutical composition; (b) about 33 wt.% of a penetration enhancer, based on 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 constitutes about 58 wt.% of diluents, based on the total weight of the pharmaceutical composition; (d) about 3 wt.% of a disintegrant, based on the total weight of the pharmaceutical composition; (e) about 1 wt.% of a glidant, based on the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; and (f) about 1 wt.% of a lubricant, based on 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) about 2% to about 6% by weight of the crystalline form of the compound of Formula I, based on the total weight of the pharmaceutical composition; (b) about 18% to about 74% by weight of a penetration enhancer, based on the total weight of the pharmaceutical composition, wherein the penetration enhancer is sodium caprate; (c) at least one diluent selected from PEG 4000, microcrystalline cellulose, or lactose; (d) about 0% to about 3% by weight of a glidant, based on the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; (e) about 0% to about 2% by weight of a lubricant, based on the total weight of the pharmaceutical composition, wherein the lubricant is magnesium stearate; and (f) optionally, at least one disintegrant.

[0256] In one embodiment of the above, the diluent constitutes 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.

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

[0258] In one embodiment, provided herein is a pharmaceutical composition comprising 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 comprise a combination of microcrystalline cellulose, macrogol (PEG 4000), 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, based on the total weight of the pharmaceutical composition; (b) about 1% to about 75% by weight of a penetration enhancer, based on the total weight of the pharmaceutical composition; (c) at least one diluent; and (d) optionally, a glidant and / or lubricant. In one embodiment, the penetration enhancer is present in the pharmaceutical composition in an amount of about 18% to about 74% by weight, 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 8% by weight of Caprate 3, 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 PEG 4000, microcrystalline cellulose, propylene glycol, and lactose; (d) optionally, a glidant; and (e) optionally, a lubricant.

[0260] In one embodiment of the above, the diluent or solubilizer comprises about 10% to about 70% by weight, about 20% to about 60% by weight, about 30% to about 60% by weight, or about 40% to about 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, based on the total weight of the pharmaceutical composition; (b) about 18% to about 74% by weight of a penetration enhancer, based on the total weight of the pharmaceutical composition, wherein the penetration enhancer is sodium caprate; (c) at least one diluent selected from PEG 4000, microcrystalline cellulose, or lactose; (d) 0% to about 3% by weight of a glidant, based on the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; (e) 0% to about 2% by weight of a lubricant, based on the total weight of the pharmaceutical composition, wherein the lubricant is magnesium stearate; and (f) optionally, at least one disintegrant.

[0262] In one embodiment of the above, the diluent or solubilizer constitutes 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.

[0263] In another embodiment of the present invention, provided herein is a pharmaceutical composition comprising: (a) about 4% by weight of caprate 3, based on the total weight of the pharmaceutical composition; (b) about 33% by weight of a penetration enhancer, based on 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 PEG 4000, microcrystalline cellulose, or lactose, based on the total weight of the pharmaceutical composition; (d) about 1% by weight of a glidant, based on the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; (e) about 1% by weight of a lubricant, based on the total weight of the pharmaceutical composition, wherein the lubricant is magnesium stearate; and (f) about 3% by weight of at least one disintegrant, based on the total weight of the pharmaceutical composition.

[0264] This disclosure is further illustrated by the following examples and syntheses, which are not to be construed as limiting the scope or spirit of the disclosure. One of ordinary skill in the art will readily recognize a variety of non-critical parameters that can be changed or modified to yield essentially the same or similar results. [Example]

[0265] Example Examples of preparation of crystalline forms of compounds of formula I Synthesis of Compounds of Formula I The compound of Formula I and methods for making it are exemplified in PCT International Patent Application Publication No. WO2019 / 246349, the entirety of which is incorporated herein by reference. As demonstrated in Example 25 of PCT International Patent Application Publication No. WO2019 / 246349, Compound A has a Ki Plus of 0.01127 nm and a Ki Ultra of 0.00463 nm as shown in a PCSK9 Alexa FRET Ultra assay.

[0266] Example 1A: Preparation of Lyophilized Acetate 1 (Amorphous Acetate Salt) Macroporous anion exchange resin AG MP-1M (6 g, 100-200 mesh, chloride form) was packed into a 60 mL funnel. The packed resin was washed five times with 9 mL of a 1:1 acetonitrile (MeCN) / water mixture. The resin was washed with 200 mL of 1 M sodium hydroxide (NaOH) and then with 50 mL of 1 M acetic acid (AcOH) in water. The resin was transferred to a 100 mL round-bottom flask containing a solution of compound A (0.3 g) dissolved in 6 mL of a 1:1 acetonitrile / water mixture. An additional 18 mL of 1:1 MeCN / water was added. The mixture was aged at room temperature for 30 minutes, and the resulting mixture was transferred to a 60 mL funnel. The filtrate was collected in a 20 mL vial, the resin was washed three times with 10 mL of 1:1 MeCN / water, and the filtrate was collected in a 20 mL vial. Fractions containing acetate 1 were combined and concentrated to remove MeCN, and the solution was then lyophilized to isolate the desired 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 loaded into a 100 mL filter funnel. The resin was washed with water (UPLC LC-MS grade, 5 × 12.5 mL; the first three wash fractions were not clear, so the resin was slurried and vacuum was applied to wash the resin until the eluate was clear). The resin was transferred to an empty solid-loading cartridge of Redi Sep Rf (Teledyne ISCO) by gravity elution with 10 mL of water. Compound A (0.3 g, 0.189 mmol) was dissolved in 3 mL of water. The solution of compound A was loaded onto the cartridge. The resulting compound, acetate 1, was eluted with water (25 mL). The solution was lyophilized to isolate acetate 1 (0.29 g).

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

[0269] Example 3: Preparation of acetate 2 Acetate 1 (25.5 mg) was placed in 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, resulting in a white slurry. Microscopic images of the slurry showed that it contained needle-like 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 for 20 minutes at 25° C. 2-Me-THF (46.7 mL) was charged. 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 give acetate 3.

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

[0272] Example 6: Alternative preparation of acetate 1 Acetate 4 (1.755 g) was added to a vial. Wet MeTHF (2 wt% water in 2-methyltetrahydrofuran (2-MeTHF, 19.99 g)) was charged and the resulting slurry was aged at room temperature. The slurry was filtered and the wet cake was dried under vacuum with an air sweep for 1 hour. 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. With stirring, 2-MeTHF (6.2 mL) was charged over 5 minutes. The Karl Fischer (KF) of the resulting solution was 7628 ppm. An additional 2 mL of 2-MeTHF was charged. Seed crystals of acetate 2 were charged as a slurry. The resulting slurry was aged at room temperature for 15 minutes. 2-MeTHF (20.7 mL) was slowly charged over 5 hours at room temperature. After the addition was complete, the slurry was aged for an additional 22 hours. The slurry was filtered, and the wet cake was washed twice with 5 mL of 2-MeTHF to give acetate 5.

[0274] Example 8: Preparation of acetate 6 The wet cake from Example 7 (acetate 5) was dried under vacuum with a N sweep to give a white solid as acetate 6.

[0275] Example 9: Preparation of Caprate 4 In a glass vessel, Caprate 1 (40 g) was dissolved in 3 volumes of 1-propanol (120 mL). The solution was aged at 20°C for 20 minutes. MTBE was added to the solution (14.4 mL). The mixture was heated to 28-28.5°C to effect dissolution. The solution was cooled to 25°C, and seed crystals of Caprate 4 were added as a slurry. The mixture was aged for 20 minutes, after which MTBE solvent (225.6 mL) was added over 10 hours. The suspension was aged at 25°C for 8.5 hours to yield Caprate 4.

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

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

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

[0279] Example 12B: Alternative Preparation of Caprate 3 Compound A (chloride salt, 700 g) was dissolved in a 4 / 1 mixture of acetonitrile and water (8.4 L) at 20°C, and the solution was warmed to 35°C. The solution was mixed with 3.0 M aqueous KHCO (7.0 L; the KHCO solution was prepared at 35°C and maintained at 35°C to prevent precipitation), stirred for 10 minutes, and the layers were separated while the temperature was maintained at 35°C. The organic phase was combined with a 4 / 1 mixture of acetonitrile and water (0.7 L) and 3.0 M aqueous KHCO (7.0 L), stirred for 10 minutes, and the layers were separated while the temperature was maintained at 35°C. The organic phase was again combined with a 4 / 1 mixture of acetonitrile and water (0.7 L) and 3.0 M aqueous KHCO (7.0 L), stirred for 10 minutes, and the layers were separated while the temperature was maintained at 35°C. The resulting 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 combined filtrate was added to decanoic acid (93 g), 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 was 2.0 L. Water (36 mL) was added to achieve a water to 1-propanol ratio of 2.3 wt%. The mixture was stirred at room temperature, and MTBE (0.984 L) was added (Solution #1). MTBE (2.95 L) was charged to a separate flask (Solution #2).

[0280] In a separate vessel, 25 g of Caprate 3 crystal seeds were added, followed by 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 a Caprate 2 crystal seed slurry.

[0281] Solutions #1 and #2 were added simultaneously over 6 hours to the stirred Caprate 2 seed slurry while maintaining the temperature at 22° C. The resulting slurry was aged overnight at 22° C. to give Caprate 2 slurry.

[0282] The Caprate 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 stream of nitrogen to remove some of the MTBE and 1-PrOH solvent.

[0283] Residual 1-PrOH was removed by humidified drying with humidified nitrogen (50% RH) to give Caprate 3 (684 g).

[0284] Example 12C: Alternative Preparation of Caprate 3 Water (54 μL) was added to a mixture of MTBE (6.75 mL) and n-propanol (3.37 mL) to give a solution with a water content of at least 0.7 wt %. Caprate 3 seeds (120 mg) were added, and the slurry was stirred at 22°C for 1 hour to give a Caprate 2 seed slurry.

[0285] In a separate mixture, Caprate 3 (5 g, containing 6.7 wt % water) was dissolved in n-propanol (13.8 mL). The solution was diluted with MTBE (6.9 mL). Capric acid (120 mg) was added to the solution.

[0286] Both solutions were added simultaneously to the stirred seed slurry over 20 hours at 22°C. A solution of MTBE (6.13 mL), n-propanol (3.07 mL), and water (49 μL) was used to rinse the addition lines into the slurry. The resulting slurry of Caprate 2 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 the filter funnel to surface dry the batch. The batch was then dried under humidified nitrogen at 250 mmHg and 50% relative humidity to yield Caprate 3 (4.01 g).

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

[0288] Example 14: Preparation of Caprate 6 To a vial was added Caprate 1 (0.5 g). Then, n-propanol (1.35 mL) was added and dissolved. Ethyl acetate (7.2 mL) was added, followed by cooling to below room temperature. An additional 2.7 mL of ethyl acetate was added to the solution. The mixture was aged overnight to give Caprate 6.

[0289] Example 15: Preparation of Caprate 7 The suspension of Example 14 (Caprate 6) was vacuum filtered 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 a dry nitrogen sweep to give Caprate 7.

[0290] Example 16: Preparation of Caprate 8 The cake of Example 9 (Caprate 4) was vacuum filtered and the wet cake was washed with n-propanol-MTBE mixture (1:4, w / w), followed by a second wash with MTBE (120 mL). The solid was dried with N at ambient temperature to give Caprate 8.

[0291] Example 17: Alternative preparation of Caprate 1 Caprate 8 was stressed at 97% RH for at least 3 days and then dried under vacuum at 40° C. with a nitrogen sweep for 1 hour to give Caprate 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 1 week to obtain Caprate 9.

[0293] Example 19: Alternative preparation of Caprate 3 The wet cake of Example 18 (Caprate 9) was vacuum filtered and dried overnight in a vacuum oven with a dry nitrogen sweep to give Caprate 3.

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

[0295] Example 21: Preparation of Caprate 11 Caprate 7 was exposed to 5% RH for at least 3 hours to give 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 1 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 give 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 give 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 loaded into a 500 mL filter funnel. The resin was washed with water (UPLC LC-MS grade, 5 × 264 mL; the first three wash fractions were not clear, so the resin was slurried and vacuum was applied to continue washing until the eluate was clear). The resin in the filter funnel was converted to the HCO anion form by eluting with 2.5 bed volumes of 5 wt% NaHCO (somewhat slurried) in water (2.5 × 265 mL). The resin was transferred to an empty solid-load cartridge of Redi Sep Rf (Teledyne ISCO, diameter: 2.42 inches) by gravity elution with 100 mL of 5 wt% aqueous NaHCO. The cartridge was gravity eluted with 7.5 bed volumes of 5 wt% aqueous NaHCO (7.5 × 265 mL). Excess NaHCO was washed away by gravity elution with 2 x 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 onto the cartridge and rinsed with 10 mL of water. The resulting compound, Compound B (bicarbonate), was 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 lyophilized overnight to yield 5.0 g of the lyophilized D-lactate salt of Compound I. The lyophilized D-lactate salt of Compound I (5.0 g) was dissolved in a 1:1 mixture of ethanol and 2-Me-THF (20 mL). The solution was transferred to a 250 mL three-neck round-bottom flask equipped with an overhead stirrer and a N2 inlet. The transfer was completed by rinsing the flask with 10 mL of ethanol:2-Me-THF and adding the rinse to the 250 mL three-neck round-bottom flask. 10 mL of 2-Me-THF was added dropwise via syringe. The addition was stopped and the mixture was seeded with a crystal seed slurry. After 1 hour, a suitable slurry had formed. A mixture of ethanol / 2-Me-THF (1:3) was added, followed by the addition of 2-Me-THF (20 mL) over 2.5 h via syringe pump. The slurry was aged overnight to give D-lactate 1.

[0301] Example 27: Preparation of D-lactate 2 The slurry of D-lactate 1 (approximately 5 g) was filtered with a portion of the filtrate to complete the transfer. The cake was washed with 2-Me-THF:EtOH (3:1, 7 mL), followed by 2-Me-THF (10 mL), followed by heptane (20 mL). The solid was dried under vacuum under a nitrogen blanket to give 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 lyophilized overnight to give the lyophilized succinate salt of Compound of Formula I (5.05 g). A mixture of the succinate salt of Compound of Formula I (3.50 g, 2.097 mmol) and EtOH (17.5 mL) was evaporated to a gum at 15-25 °C under a nitrogen stream. EtOH (17.5 mL) was added under nitrogen, and the mixture was evaporated to a gum at 45-55 °C under a nitrogen stream. The residue was dissolved in EtOH (17.5 mL) at 75 °C to give a homogeneous solution. The mixture was cooled to 25 °C, seeded (1 mg), and a solid slowly crystallized. The mixture was stirred for 16 h and then cooled to 1-3° C. for 2 h to give succinate 1.

[0303] Example 29: Preparation of succinate 2 A suspension of succinate 1 (approximately 3.5 g) was filtered through a 30 cc polypropylene filter funnel with EtOH (10 mL) at 0-5 °C to completely transfer the slurry to the filter funnel. The filter cake was dried under a stream of nitrogen for 24 h to afford 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 L-(+)-tartaric acid (460.9 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 lyophilized overnight to yield the lyophilized L-tartrate salt of compound of Formula I (5.15 g). Lyophilized L-tartrate salt of compound of Formula I (5.0 g) 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 seeded. 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 yield L-tartrate 1.

[0305] Example 31: Preparation of L-tartrate 2 L-tartrate 1 (approximately 5 g) was filtered and the cake was washed with n-propanol. The cake was dried in an oven at 40° C. overnight with a nitrogen sweep to give L-tartrate 2 (2.57 g).

[0306] Example 32: Preparation of sulfate 1 Aqueous sulfuric acid (1 M, 1.5 mL, 1.5 mmol) was added to a solution of compound B (167 g; 3.07 mmol) in water and aged for 1 hour at room temperature. The solution was then frozen in a dry ice-acetone bath and lyophilized overnight to yield the lyophilized sulfate salt of compound of Formula I (4.88 g). A 250 mL three-neck round-bottom flask equipped with an overhead stirrer was charged with the lyophilized sulfate ester salt of compound of Formula I (2.5 g). 1-Propanol (40 mL) was added to the round-bottom flask and stirred vigorously to dissolve some solids adhering to the walls of the flask. Crystals formed before all the solids dissolved. The mixture was stirred vigorously, and 10 mL of heptane was added via syringe pump over 1 hour. The mixture was then aged for 6 hours to yield sulfate 1.

[0307] Example 33: Preparation of sulfate 2 The 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 vacuum overnight under a nitrogen blanket to give sulfate 2 (2.21 g).

[0308] Example 34: Description of X-ray powder diffraction studies 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 tube with Kα radiation was used as the radiation source. The samples of Examples 1 to 33 were characterized by XRPD. XRPD analysis shows that acetate 1 (Figure 1) and caprate 1 (Figure 7) are amorphous, and that 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-tartrate 1-2 (Figures 25-26), and sulfate 1-2 (Figures 27-28) are crystalline.

[0309] Example 35: Chemical stability of crystalline salt over Compound A (amorphous chloride salt) The crystalline forms disclosed herein offer the advantage 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 reduces the cost of goods and simplifies the process by reducing the number of operating units involved, which is important for commercial viability.

[0310] The acetate and caprate salts of Formula I (including the crystalline forms Caprate 3 and Caprate 7) exhibited satisfactory purity of >99% at 40°C and 75% RH for 3 months (Figure 29A), in contrast to the purity of the amorphous chloride salt of Compound A. The graph in Figure 29A demonstrates that the acetate and caprate salts have improved chemical stability over the chloride salt. Furthermore, while the chloride salt requires storage at -20°C to minimize chemical degradation, the acetate and caprate salts are resistant to degradation even at relatively high temperatures. The graph in Figure 29B demonstrates that the crystalline acetate and caprate salts exhibit improved chemical stability over the amorphous forms of caprate and acetate under accelerated stability conditions, particularly evident at 3 months. The stability of the crystalline forms of Compound I was characterized by XRPD under relative humidity conditions that simulate potential storage conditions.

[0311] Adsorption / desorption cycling indicates that acetate 4 is hygroscopic, increasing in weight by approximately 9% at 55% RH (see Figure 30A). XRPD analysis indicates that acetate 4 maintains minimal crystallinity upon two adsorption / desorption cycles from 5-55% RH (see Figure 30B). Adsorption / desorption cycling indicates that acetate 4 is highly hygroscopic, increasing in weight by approximately 40% at 95% RH (see Figure 31A). Hysteresis is observed during the desorption step. XRPD analysis indicates that acetate 4 loses crystallinity after two adsorption / desorption cycles from 5-95-5% RH (see Figure 31B).

[0312] Adsorption / desorption cycling indicates that Cuprate 5 is hygroscopic, increasing in weight by approximately 7.5% at 65% RH (see Figure 32A). Slight hysteresis is observed during the desorption phase of cycle 1 and cycle 2. XRPD analysis indicates that Cuprate 5 retains some crystallinity during two adsorption / desorption cycles from 5 to 65% RH (see Figure 32B). Adsorption / desorption cycling indicates that Cuprate 5 is highly hygroscopic, increasing in weight by approximately 26% at 95% RH (see Figure 33A). XRPD analysis indicates that Cuprate 5 loses crystallinity after adsorption / desorption cycles from 5 to 95 to 5% RH (see Figure 33B).

[0313] Adsorption / desorption cycling indicates that Caprate 3 is hygroscopic, increasing in weight by approximately 4.9% at 85% RH (see Figure 34A). This contrasts with the larger weight gains observed for Acetate 4 (9%; see Figure 30A) and Caprate 5 (7.5%; see Figure 32A) at 55% and 65% RH, respectively. XRPD analysis indicates that Caprate 3 maintains crystallinity upon adsorption / desorption cycling from 5 to 85% RH (see Figure 34B). This contrasts with the decrease in crystallinity observed for Acetate 4 (Figure 30B) and Caprate 5 (Figure 32B) upon two adsorption / desorption cycles from 5 to 55% RH and 5 to 65% RH, respectively.

[0314] Caprate 3 was dried under N2 at 40°C for 3 hours to remove residues. Adsorption / desorption cycling indicates that water-free Caprate 3 is hygroscopic, increasing in weight by approximately 9.4% at 85% RH (see Figure 35A). This adsorption / desorption cycling indicates that Caprate 3 readily absorbs HO at approximately 25-35% RH and does not lose HO up to 15% RH. XRPD analysis indicates that water-free Caprate 3 retains its crystallinity upon adsorption / desorption cycling from 5-85% RH (see Figure 35B).

[0315] The behavior of Caprate 3 indicates the high stability of this crystalline form to relative humidity, which is important for further development and, in particular, for withstanding fluctuating storage conditions. This contrasts with the decrease in crystallinity observed in Acetate 4 and Caprate 5 with increasing relative humidity.

[0316] Example 36: Solid-state NMR studies Batches of Caprate 3, Caprate 5, and Caprate 8 were characterized based on their respective solid-state carbon-13 nuclear magnetic resonance (NMR) spectra. All carbon-13 spectra were recorded on a Bruker AV400 NMR spectrometer operating at a carrier frequency of 400.14 MHz using a Bruker 4 mm H / F / X BB triple-resonance CPMAS probe. The spectra were collected at 80 kHz with a 3-minute contact time using proton / carbon-13 variable amplitude cross polarization (VACP). Other experimental parameters used for data collection were a 100 kHz proton 90-degree pulse, SPINAL64 decoupling at 100 kHz, a 1.5-second pulse delay, and signal averaging of 50,000 scans. The magic-angle spinning (MAS) rate was set to 13 kHz. A 30 Hz Lorentzian line broadening was applied to the spectra before Fourier transformation. Chemical shifts are reported on the 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 Cuprate 3, Cuprate 5, and Cuprate 8, respectively. The three Cuprate forms exhibit similar carbon-13 CPMAS spectra, and the deviations in each spectrum for a given form are small. Nevertheless, each form can be clearly distinguished by its carbon-13 CPMAS spectrum based on comparison of specific spectral regions. Figure 37 shows the spectral regions exhibiting characteristic isotropic chemical shifts, as well as the relative peak heights and shapes, for each form.

Claims

1. Formula I: 【Chemical 1】 [In the formula, A － is a pharmaceutically acceptable anion. The crystalline form of the compound represented by formula (I).

2. 2. The crystalline form of claim 1, wherein the crystalline form 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-tartrate 1, L-tartrate 2, sulfate 1, and sulfate 2.

3. 3. The crystalline form of claims 1-2, wherein the crystalline form is Acetate 2, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 4.92, 6.59, 9.82, and 17.91 (±0.2°).

4. 3. The crystalline form of claims 1-2, wherein the crystalline form is acetate 3, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 4.48, 18.17, 18.79, and 19.27 (±0.2°).

5. 3. The crystalline form of claims 1-2, wherein the crystalline form is acetate 4, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 8.36, 17.74, 20.29, and 21.35 (±0.2°).

6. 3. The crystalline form of claims 1-2, wherein the crystalline form is acetate 5, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 5.02, 6.66, 9.89, and 19.84 (±0.2°).

7. 3. The crystalline form of claims 1-2, wherein the crystalline form is acetate 6, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 7.79, 11.00, 16.24, and 18.89 (±0.2°).

8. 3. The crystalline form of claims 1-2, wherein the crystalline form is Caprate 2, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 4.85, 7.65, 17.16, 18.20 and 19.50 (±0.2°).

9. 3. The crystalline form of claims 1-2, wherein the crystalline form is Caprate 3, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 7.92, 15.40, 17.33 and 19.60 (±0.2°).

10. 3. The crystalline form of claims 1-2, wherein the crystalline form is cuprate 4, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 4.18, 6.14, 17.51 ​​and 17.68 (±0.2°).

11. 3. The crystalline form of claims 1-2, wherein the crystalline form is Caprate 5, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 7.66, 16.18, 18.26 and 19.11 (±0.2°).

12. 3. The crystalline form of claims 1-2, wherein the crystalline form is cuprate 6, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 5.33, 6.97, 19.04 and 21.58 (±0.2°).

13. 3. The crystalline form of claims 1-2, wherein the crystalline form is Caprate 7, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 7.73, 17.14, 18.75 and 19.48 (±0.2°).

14. 3. The crystalline form of claims 1-2, wherein the crystalline form is cuprate 8, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 7.45, 17.97, 19.32 and 22.08 (±0.2°).

15. 3. The crystalline form of claims 1-2, wherein the crystalline form is cuprate 9, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 6.73, 11.95, 18.23 and 19.77 (±0.2°).

16. 3. The crystalline form of claims 1-2, wherein the crystalline form is Caprate 10, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles of about 3.50, 7.90, 16.21, and 18.23 (±0.2°).

17. 3. The crystalline form of claims 1-2, wherein the crystalline form is Caprate 11, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 3.93, 4.90 and 7.68 (±0.2°).

18. 3. The crystalline form of claims 1-2, wherein the crystalline form is Cuprate 12, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 6.80, 15.37, 18.22 and 20.63 (±0.2°).

19. 3. The crystalline form of claims 1-2, wherein the crystalline form is Caprate 13, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees -2-θ at angles 5.02, 6.29, 7.12 and 20.25 (±0.2°).

20. 3. The crystalline form of claims 1-2, wherein the crystalline form is Cuprate 14, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in degree-2-theta radiation at angles 6.74, 18.16, 19.51 and 20.68 (±0.2°).

21. A pharmaceutical composition comprising at least one crystalline form according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier.

22. Use of the crystalline form of any one of claims 1 to 20 as an active ingredient in a medicament for treating hypercholesterolemia in a subject.

23. Use of the crystalline form of any one of claims 1 to 20 as an active ingredient in a medicament for treating hypercholesterolemia in a subject.

24. 21. Use of the crystalline form of any one of claims 1 to 20 as an active ingredient in a medicament for lowering LDL-C in a subject.

25. Use of the crystalline form of any one of claims 1 to 20 as an active ingredient in a medicament for treating atherosclerotic cardiovascular disease in a subject.

26. 21. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of the crystalline form of any one of claims 1 to 20.

27. 2. A compound of formula I: 【Chemistry 2】 [In the formula, A － is a pharmaceutically acceptable anion. wherein the starting material is selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6.

28. 2, formed by a process comprising adding an alcohol to a form of compound 2, of formula I: 【Chemistry 3】 [In the formula, A － is a cap rate.

28. The crystalline form of claim 27, of a compound represented by:

29. 29. The crystalline form of any one of claims 27 to 28, wherein 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.

30. 30. The crystalline form of any one of claims 27 to 29, wherein the alcohol is selected from ethanol, propanol, or butanol.

31. 31. The crystalline form of any one of claims 27-30, wherein the process comprises adding a solvent system to compound 2, wherein the solvent system comprises MTBE, water, and the alcohol.

32. 32. The crystalline form of claim 31, wherein the solvent system is comprised of MTBE, about 30-40% by weight 1-propanol, and 0.5-5% water.

33. 33. The crystalline form of claim 32, wherein the crystalline form is Caprate 3 and the process further comprises filtering the solvent system to result in the formation of a wet cake and drying the wet cake.

34. 1. A method of inhibiting PCSK9 activity in a subject in need of treatment, comprising administering to said subject an amount of a compound of Formula I: 【Chemistry 4】 [In the formula, A － is a pharmaceutically acceptable anion. orally administering to said subject a crystalline form of the compound of formula I according to claim 1, wherein said specified amount is from about 5 mg to about 300 mg of said crystalline form of the compound of formula I.

35. Formula I: 【Chemistry 5】 [In the formula, A － is a pharmaceutically acceptable anion.

10. A pharmaceutical composition comprising the crystalline form of the compound of formula I according to claim 1, wherein the amount is from about 5 mg to about 300 mg of said crystalline form of the compound of formula I, and a penetration enhancer.

36. 36. The pharmaceutical composition of claim 35, wherein the penetration enhancer is sodium caprate.

37. The pharmaceutical composition according to any one of claims 35 to 36, wherein the crystalline form of the compound of formula I is caprate 3.

Images