Crystal form of PCSK9 inhibitor, composition and application

Abstract

The present disclosure provides crystalline forms of a compound of formula (I), as well as pharmaceutically acceptable compositions thereof, methods for their preparation and their use in methods of treating hypercholesteremia and other conditions associated with PCSK9 activity, other conditions such as atherosclerosis, atherosclerotic cardiovascular disease, peripheral arterial disease, cerebrovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome or related cardiovascular and cardiac metabolic conditions.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 371,690, filed on August 17, 2022, and U.S. Provisional Application No. 63 / 384,298, filed on November 18, 2022. The contents of each application are incorporated herein by reference in their entirety. Technical Field

[0003] Provided herein are crystalline forms of compounds of Formula I:

[0004]

[0005] Among them A - The invention relates to a pharmaceutically acceptable anion, a pharmaceutically acceptable composition thereof, a method for preparing the same, and use thereof in methods for treating hypercholesterolemia and other diseases associated with PCSK9 activity (e.g., atherosclerosis, atherosclerotic cardiovascular disease, peripheral arterial disease, cerebrovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome or related cardiovascular diseases and cardiometabolic diseases). Background Art

[0006] When a compound is used for pharmaceutical purposes, the solid state of the compound may be important. The physical properties of a compound may be transformed from one solid form to another solid form, which may affect the suitability of the form for pharmaceutical use. For example, a particular crystalline solid compound may overcome the disadvantages of other solid forms of the compound, such as, for example, instability and / or reduced purity.

[0007] Provided herein are crystalline forms of compounds of Formula I:

[0008]

[0009] Among them A - It is a pharmaceutically acceptable anion. These crystalline forms of the compound of formula I enable effective separation and purification, avoiding the need for expensive operations, such as chromatography and lyophilization. In addition, the advantages of the crystalline forms of the compound of formula I are that they have high purity, high stability and low hygroscopicity, so that they are suitable for use in pharmaceutical preparations. Summary of the invention

[0010] The present disclosure relates to crystalline forms of compounds of formula I:

[0011]

[0012] and a composition comprising the same, a preparation method thereof and a method of using the same, wherein A -is a pharmaceutically acceptable anion and the crystalline form is active as a PCSK9 inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for the amorphous acetate salt 1. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0014] Figure 2 Depicted is an X-ray powder diffraction pattern of the acetate salt 2, showing the range 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0015] Figure 3 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for the acetate salt 3. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0016] Figure 4 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for the acetate salt 4. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0017] Figure 5 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for the acetate salt 5. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0018] Figure 6 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for the acetate salt 6. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0019] Figure 7 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for amorphous decanoate salt 1. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0020] Figure 8 Depicted is an X-ray powder diffraction pattern of the decanoate salt 2, showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0021] Fig. 9Depicted is an X-ray powder diffraction pattern of the decanoate salt 3 showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0022] Fig.10 Depicted is an X-ray powder diffraction pattern of the decanoate salt 4 showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0023] Fig.11 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for the decanoate salt 5. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0024] Fig.12 Depicted is an X-ray powder diffraction pattern of the decanoate salt 6 showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0025] Fig.13 Depicted is an X-ray powder diffraction pattern of the decanoate salt 7 showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0026] Fig.14 Depicted is an X-ray powder diffraction pattern of the decanoate salt 8 showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0027] Fig.15 Depicted is an X-ray powder diffraction pattern of decanoate 9 showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0028] Fig.16 Depicted is an X-ray powder diffraction pattern of decanoate 10 showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0029] Fig.17 Depicted is an X-ray powder diffraction pattern of decanoate salt 11 showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0030] Fig.18Depicted is an X-ray powder diffraction pattern of decanoate 12 showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0031] Fig.19 Depicted is an X-ray powder diffraction pattern of decanoate 13 showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0032] Fig. 20 Depicted is an X-ray powder diffraction pattern of decanoate 14 showing a range of 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0033] Fig.21 Depicted is an X-ray powder diffraction pattern of D-lactic acid 1 showing the range 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0034] Fig. 22 Depicted is an X-ray powder diffraction pattern of D-lactic acid 2 showing the range 2-40 2θ. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0035] Fig.23 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for succinate 1. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0036] Fig.24 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for the succinate salt 2. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0037] Fig.25 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for the L-tartrate salt 1. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0038] Fig.26 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for the L-tartrate salt 2. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0039] Fig. 27 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for the sulfate salt 1. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0040] Fig.28 Depicted is an X-ray powder diffraction pattern showing the range 2-40 2θ for the sulfate salt 2. The graph plots the peak intensity (defined in counts per second) versus the diffraction angle 2 theta (2θ) in degrees.

[0041] Fig.29A The total impurity percentages for Compound A (API chloride amorphous; amorphous form of the chloride salt), acetate 1, decanoate 1, decanoate 3, and decanoate 7 are depicted, showing a range of 3 months.

[0042] Fig.29B The total impurity percentages for acetate 1 (amorphous acetate), decanoate 1 (amorphous decanoate), decanoate 3, and decanoate 7 are depicted, showing a range of 3 months.

[0043] Fig. 30A The adsorption / desorption cycle of acetate 4 is depicted, showing the range of 5-55% relative humidity (RH).

[0044] Fig. 30B Depicted Fig. 30A X-ray powder diffraction patterns of acetate 4 before and after adsorption / desorption cycles.

[0045] Fig.31A The adsorption / desorption cycle of acetate 4 is depicted, showing the range of 5-95% RH.

[0046] Fig.31B Depicted Fig.31A X-ray powder diffraction patterns of acetate 4 before and after adsorption / desorption cycles.

[0047] Fig.32A The adsorption / desorption cycle of decanoate 5 is depicted, showing the range of 5-65% RH.

[0048] Fig.32B Depicted Fig.32A X-ray powder diffraction patterns of decanoate 5 before and after adsorption / desorption cycles.

[0049] Fig.33A The adsorption / desorption cycle of decanoate 5 is depicted, showing the range of 5-95% RH.

[0050] Fig.33B Depicted Fig.33AX-ray powder diffraction patterns of decanoate 5 before and after adsorption / desorption cycles.

[0051] Fig.34A The adsorption / desorption cycle of decanoate 3 is depicted, showing the range of 5-85% RH.

[0052] Fig.34B Depicted Fig.34A X-ray powder diffraction patterns of decanoate 3 before and after adsorption / desorption cycles.

[0053] Fig.35A The adsorption / desorption cycle of the anhydrous decanoate salt 3 is depicted, showing the range of 5-85% RH.

[0054] Fig.35B Depicted Fig.35A X-ray powder diffraction patterns of anhydrous decanoate 3 before and after adsorption / desorption cycles.

[0055] Fig.36A The solid-state C-13 CPMAS NMR spectrum of the decanoate salt 3 is depicted.

[0056] Fig.36B The solid-state C-13 CPMAS NMR spectrum of the decanoate salt 5 is depicted.

[0057] Fig.36C The solid-state C-13 CPMAS NMR spectrum of the decanoate salt 8 is depicted.

[0058] Fig.37 Depicted are selected spectral regions from the decanoate C-13 CPMAS spectra of the decanoate forms that exhibit unique features of the form. From top to bottom, spectral regions for decanoate 8, decanoate 5, and decanoate 3 are shown, respectively. The associated isotropic chemical shifts are expressed in ppm (parts per million). DETAILED DESCRIPTION

[0059] 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 secretory subtilase family; see Seidah et al., 2003 PNAS 100: 928-933. PCSK9 belongs to the mammalian proprotein convertase serine protease family 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 of transcriptional regulation of PCSK9 have shown that it is regulated by sterol regulatory element binding protein ("SREBP"), as are other genes involved in cholesterol metabolism; Maxwell et al., 2003 J. Lipid Res. 44:2109-2119, as are 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 attributed to the cholesterol-lowering effects of the drug; see above. In addition, the PCSK9 promoter has been shown to have two conserved sites involved in cholesterol regulation, a sterol regulatory element and an Sp1 site; see above.

[0060] While in the endoplasmic reticulum, the only catalytic activity of PCSK9 is self-cleavage between residues Gln-152 and Ser-153; see Naureckiene et al., 2003 Arch. Biochem. Biophys. 420:55–67; Seidah et al., 2003 Proc. Natl. Acad. Sci. USA 100:928–933. During subsequent transport through the trans-Golgi network, the prodomain remains tightly associated with the catalytic domain. Maturation through self-cleavage has been shown to be essential for the secretion and subsequent extracellular function of PCSK9 (see Benjannet et al., 2012 J. Biol. Chem. 287:33745–33755). Thus, there are several lines of evidence that PCSK9 specifically reduces the level of hepatic LDLR protein, thereby impairing the liver's ability to clear low-density lipoprotein ("LDL") cholesterol from the circulation.

[0061] Adenovirus-mediated overexpression of PCSK9 in mouse liver leads to accumulation of circulating low-density lipoprotein cholesterol ("LDL-C") due to a dramatic loss of hepatic LDLR protein, without affecting LDLR mRNA levels; Benjannet et al., 2004 J. Biol. Chem. 279:48865-48875; Maxwell & Breslow, 2004 PNAS 101:7100-7105; Park et al., 2004 J. Biol. Chem. 279:50630-50638; and Lalanne et al., 2005 J. Lipid Res. 46:1312-1319. The effect of PCSK9 overexpression on increasing circulating LDL-C levels in mice is completely dependent on LDLR expression, again suggesting that PCSK9 regulation of LDL-C is mediated by downregulating LDLR protein. Consistent with these results, mice lacking PCSK9 or mice in which PCSK9 mRNA has been reduced by antisense oligonucleotide inhibitors have higher levels of liver LDLR protein and a greater 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. In addition, reducing PCSK9 levels in cultured human hepatocytes by siRNA also resulted in higher LDLR protein levels and an enhanced ability to absorb LDL-C; Benjannet et al., 2004 J. Biol. Chem. 279: 48865-48875; and Lalanne et al., 2005 J. Lipid Res. 46: 1312-1319. In summary, these data suggest that PCSK9 acts by reducing LDLR protein levels to increase LDL-C.

[0062] Multiple mutations in the PCSK9 gene have also been clearly associated with autosomal dominant hypercholesterolemia ("ADH"), an inherited metabolic disorder characterized by markedly elevated plasma low-density lipoprotein ("LDL") particles, which can lead to premature cardiovascular failure; see Abifadel et al., 2003 Nature Genetics 34:154-15; Timms et al., 2004 Hum. Genet. 114:349-353; Leren, 2004 Clin. Genet. 65:419-422. A subsequent study published by Abifadel et al. (see above) on the S127R mutation reported that patients carrying such mutations had higher plasma total cholesterol and apoB100 levels, which was attributed 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 reduction in the clearance or turnover of such lipoproteins; Ouguerram et al., 2004 Arterioscler. Thromb. Vasc. Biol. 24:1448-1453.

[0063] Therefore, there is no doubt that PCSK9 plays a role in LDL regulation. The expression or upregulation of PCSK9 is associated with increased plasma LDL cholesterol levels, while the corresponding inhibition or loss of PCSK9 expression is associated with reduced plasma LDL cholesterol levels. It has been found that reduced LDL cholesterol levels associated with PCSK9 sequence variations can prevent coronary heart disease; Cohen, 2006 N. Engl. J. Med. 354: 1264-1272.

[0064] In clinical trials, reductions in LDL cholesterol levels were directly associated with reduced rates of coronary events; Law et al., 2003 BMJ 326:1423-1427. Studies have found that modest lifetime reductions in plasma LDL cholesterol levels are associated with substantial reductions in the rate of coronary events; Cohen et al., 2006 N. Engl. J. Med. 354:1264-1272. This was true even in populations with a high prevalence of non-lipid-related cardiovascular risk factors; see above. Thus, managed control of LDL cholesterol levels can provide substantial benefits.

[0065] Therefore, it is necessary to identify compounds and / or agents that are effective in treating cardiovascular diseases, including antagonizing the role of PCSK9 in LDL regulation; however, in general, because PCSK9 circulates in the blood and has a moderate binding affinity for cell surface LDL receptors, attempts to treat diseases associated with high serum LDL levels using this mechanism have so far focused on the use of large biomolecules, such as antibodies. The therapeutic potential of small peptides or small molecules as drugs against PCSK9 is just beginning to be explored; for example, Tombling et al., Atherosclerosis 330 (2021) 52-60. In addition, there are few compounds suitable for formulation into dosage forms for administration by oral administration, which is very advantageous for treating diseases in which the activity of PCSK9 may play a role.

[0066] WO2019 / 246349 discloses cyclic peptide compounds that can be used to treat cardiovascular diseases and diseases associated with PCSK9 activity. The present disclosure promotes the development of the prior art by providing a crystalline form of a compound of formula I, which can be used to treat hypercholesterolemia and other conditions associated with PCSK9 activity, ideally including oral administration of identified PCSK9 inhibitors. Certain crystalline forms have the following advantages, such as easy processing or handling. Specifically, these forms may exhibit improved physicochemical properties, such as making them particularly suitable for the manufacture of various pharmaceutical dosage forms, including oral dosage forms.

[0067] Thus, provided herein are crystalline forms of salts of compounds of Formula I:

[0068]

[0069] Among them A - is a pharmaceutically acceptable anion. In a further embodiment, A -Selected from acetate, caprate, lactate, tartrate, succinate and sulfate. The term "caprate" is also referred to as "decanoate" in the art and can be used interchangeably. In another embodiment, provided herein is a crystalline form of a 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. Other aspects of this embodiment of the present disclosure provide a specific drug substance comprising at least one form described herein. The presence of a specific crystalline form in a drug substance can be detected by physical methods known to those of ordinary skill 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.

[0070] Compound A is the chloride salt of the compound of Formula I in an amorphous form.

[0071] Compound B is the bicarbonate salt of the compound of formula I.

[0072] Described herein is the acetate salt of the compound of Formula I, shown below, referred to as Compound 1:

[0073]

[0074] Acetate salt 1 is an amorphous form of compound 1.

[0075] In one embodiment, provided herein is a crystalline form of Compound 1.

[0076] 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.

[0077] Also described herein is the decanoate salt of the compound of Formula I shown below, referred to as Compound 2:

[0078]

[0079] The decanoate salt 1 is an amorphous form of compound 2.

[0080] In one embodiment, provided herein is a crystalline form of Compound 2.

[0081] In a further embodiment, provided herein is a crystalline form of Compound 2, wherein the crystalline form is selected from Decanoate 2, Decanoate 3, Decanoate 4, Decanoate 5, Decanoate 6, Decanoate 7, Decanoate 8, Decanoate 9, Decanoate 10, Decanoate 11, Decanoate 12, Decanoate 13 and Decanoate 14.

[0082] Also described herein is a lactic acid salt of the compound of Formula I shown below, referred to as Compound 3:

[0083]

[0084] In one embodiment, provided herein is a crystalline form of Compound 3.

[0085] 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 the D-lactate is shown below:

[0086]

[0087] Also described herein is a succinate salt of a compound of Formula I shown below, referred to as Compound 4:

[0088]

[0089] In one embodiment, provided herein is a crystalline form of Compound 4.

[0090] 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.

[0091] Also described herein is the tartrate salt of the compound of Formula I shown below, referred to as Compound 5:

[0092]

[0093] In one embodiment, provided herein is a crystalline form of Compound 5.

[0094] 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 the L-tartrate salt is depicted as follows:

[0095]

[0096] L-Tartrate is also known as (2R,3R)-tartrate.

[0097] Also described herein is the sulfate salt of the compound of formula I shown below, referred to as compound 6:

[0098]

[0099] In one embodiment, provided herein is a crystalline form of Compound 6.

[0100] 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.

[0101] In an embodiment of the above structure, the stoichiometry of the compound of Formula I to the sulfate anion is 2:1, as shown below:

[0102]

[0103] The specific crystalline forms of the compound of Formula I provided herein have advantageous properties that facilitate the preparation of various pharmaceutical formulations. For example, the specific crystalline form of the compound of Formula I, the decanoate salt 3, is a stable crystalline form. When subjected to varying relative humidity, the decanoate salt 3 can maintain its crystallinity (i.e., is physically stable) (e.g., see Figures 34A-35B The stability of the crystalline form is very important in the preparation, packaging, transportation and storage of pharmaceutical products. The method for preparing the decanoate salt 3 (see, e.g., Examples 12A, 12B, 12C and 19) also results in a higher chemical stability than the amorphous chloride salt, which is an important feature for the preparation and use of pharmaceutical products (see, e.g., Fig.29A and Fig.29B ).

[0104] Characterization of crystalline forms

[0105] In certain embodiments, the crystalline forms provided herein can be identified according to characteristic peaks in X-ray powder diffraction analysis. X-ray powder diffraction (XRPD) is a scientific technique for characterizing the structure of solid materials using X-ray diffraction of powders, crystallites or other solid materials. A description of methods for obtaining certain XRPD patterns associated with the crystalline forms of the present invention can be found in Example 34 (Description of Powder X-ray Diffraction). In one embodiment, the X-ray powder diffraction data provided herein are obtained by a method utilizing Cu Kα radiation.

[0106] Crystalline form of the compound of formula I

[0107] Acetate 2:

[0108] 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 having an X-ray powder diffraction pattern with peaks expressed in 2-θ degrees at angles (± 0.2°) of 4.92, 6.59, 9.82, and 17.91. In a specific aspect, acetate 2 is characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 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 having an X-ray powder diffraction pattern with peaks (expressed in 2-θ degrees at angles ± 0.2°) shown in Table 1.

[0109] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of acetate salt 2, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, acetate salt 2 is essentially characterized by Figure 2 In some aspects of this embodiment, Acetate Salt 2 is substantially characterized by an X-ray powder diffraction pattern as described in Table 1 with one or more characteristics.

[0110] Table 1: X-ray powder diffraction pattern of acetate 2

[0111] 2-θ° Distance between faces, A Relative strength, % 4.92 17.95 100 5.72 15.44 11 6.59 13.41 45 7.53 11.74 10 7.73 11.43 10 8.83 10.01 5 9.82 9.01 27 14.29 6.20 10 14.86 5.96 13 16.14 5.49 28 17.37 5.11 43 17.91 4.95 59 19.01 4.67 49 19.67 4.51 46 20.16 4.40 36

[0112] Acetate 3:

[0113] In another embodiment, provided herein is acetate salt 3, 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 2θ degrees at angles (± 0.2°) of 4.48, 18.17, 18.79, and 19.27. In a specific aspect, acetate salt 3 is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 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 salt 3 is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (±0.2°) of 4.48, 8.97, 9.08, 13.80, 14.51, 16.12, 16.54, 18.17, 18.79, 19.27, 20.64, 20.93, 21.51, 22.18, 22.65, 23.83, 24.29 and 24.57. In another embodiment, the crystalline form of the compound of Formula I is acetate salt 3, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in 2-θ degrees at angles ±0.2°) shown in Table 2.

[0114] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of acetate salt 3, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, acetate salt 3 is essentially characterized by Figure 3 In some aspects of this embodiment, the acetate salt 3 is substantially characterized by an X-ray powder diffraction pattern as described by one or more characteristics described in Table 2.

[0115] Table 2: X-ray powder diffraction pattern of acetate 3:

[0116]

[0117] Acetate 4

[0118] In one embodiment, provided herein is acetate salt 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 2θ at angles (±0.2°) of 8.36, 17.74, 20.29 and 21.35. In particular aspects, the acetate salt 4 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2θ at angles (± 0.2°) of 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 aspect, the acetate salt 4 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2θ at angles (± 0.2°) of 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 the acetate salt 4, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks shown in Table 3 (expressed in 2-theta degrees at angles ±0.2°).

[0119] In aspects of this embodiment, about 10% to about 100% of the compound of formula I in the pharmaceutical composition is in the form of acetate salt 4, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, acetate salt 4 is essentially characterized by Figure 4 In aspects of this embodiment, acetate salt 4 is substantially characterized by an X-ray powder diffraction pattern as described by one or more of the characteristics described in Table 3.

[0120] Table 3: X-ray powder diffraction pattern of acetate 4

[0121]

[0122] Acetate 5:

[0123] In another embodiment, provided herein is acetate salt 5, which is a crystalline form of the acetate salt of the compound of Formula I, characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 5.02, 6.66, 9.89, and 19.84. In a specific aspect, acetate salt 5 is characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 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 aspect, the acetate salt 5 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2θ at angles (± 0.2°) of 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 the acetate salt 5, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks shown in Table 4 (expressed in 2-theta degrees at angles ±0.2°).

[0124] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of acetate salt 5, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, acetate salt 5 is essentially characterized by Figure 5 In aspects of this embodiment, the acetate salt 5 is substantially characterized by an X-ray powder diffraction pattern as described by one or more of the characteristics described in Table 4.

[0125] Table 4: X-ray powder diffraction pattern of acetate 5

[0126]

[0127] Acetate 6:

[0128] In another embodiment, provided herein is acetate salt 6, 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 2θ degrees at angles (± 0.2°) of 7.79, 11.00, 16.24, and 18.89. In a specific aspect, acetate salt 6 is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 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, the acetate salt 6 is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (±0.2°) of 7.79, 9.47, 10.30, 11.00, 13.40, 14.01, 14.70, 15.12, 15.44, 16.24, 17.05, 18.89, 20.34, 20.96 and 21.95. In another embodiment, the crystalline form of the compound of Formula I is the acetate salt 6, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in 2-θ degrees at angles ±0.2°) shown in Table 5.

[0129] In aspects of this embodiment, about 10% to about 100% of the compound of formula I in the pharmaceutical composition is in the form of acetate salt 6, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, acetate salt 6 is essentially characterized by Figure 6 In aspects of this embodiment, acetate salt 6 is substantially characterized by an X-ray powder diffraction pattern as described by one or more of the characteristics described in Table 5.

[0130] Table 5: X-ray powder diffraction pattern of acetate 6

[0131]

[0132] Decanoate 2:

[0133] In another embodiment, provided herein is Decanoate 2, which is a crystalline form of the decanoate salt of the compound of Formula I, characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 4.85, 7.65, 17.16, 18.20, and 19.50. In a specific aspect, Decanoate 2 is characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 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 Decanoate 2, wherein the crystalline form is characterized by having an X-ray powder diffraction pattern with peaks (expressed in 2-θ degrees at angles ± 0.2°) shown in Table 6.

[0134] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 2, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the decanoate salt 2 is essentially characterized by Figure 8 In aspects of this embodiment, the Decanoate Salt 2 is substantially characterized by an X-ray powder diffraction pattern as described by one or more of the characteristics described in Table 6.

[0135] Table 6: X-ray powder diffraction pattern of Decanoate 2

[0136]

[0137] Decanoate 3:

[0138] In another embodiment, provided herein is a decanoate salt 3, which is a crystalline form of the decanoate salt of the compound of formula I, characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 7.92, 17.33, and 19.60. In another embodiment, provided herein is a decanoate salt 3, which is a crystalline form of the decanoate salt of the compound of formula I, characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 7.92, 15.40, 17.33, and 19.60. In a specific aspect, decanoate salt 3 is characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 7.92, 15.40, 17.33, 18.86, 19.60, and 20.79. In a more specific aspect, the decanoate 3 is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 7.92, 12.99, 15.40, 17.33, 18.59, 18.86, 19.07, 19.60, 20.79, and 21.27. In a specific aspect, the decanoate 3 is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 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 aspect, the decanoic acid salt of 3 is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2θ at angles (± 0.2°) of 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 the decanoate salt 3, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks shown in Table 7 (expressed in 2-theta degrees at angles ±0.2°).

[0139] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 3, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In some aspects of this embodiment, the decanoate salt 3 is essentially characterized by Fig. 9In aspects of this embodiment, the decanoic acid salt 3 is substantially characterized by an X-ray powder diffraction pattern as described in one or more of the characteristics described in Table 7.

[0140] Table 7: X-ray powder diffraction pattern of decanoate 3

[0141]

[0142] Decanoate 4:

[0143] In another embodiment, provided herein is a decanoate salt 4, which is a crystalline form of the decanoate salt of the compound of Formula I, characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 4.18, 6.14, 17.51, and 17.68. In a specific aspect, the decanoate salt 4 is characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 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 the decanoate salt 4, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks as shown in Table 8 (expressed in 2-theta degrees at angles ±0.2°).

[0144] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 4, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In some aspects of this embodiment, the decanoate salt 4 is substantially characterized by Fig.10 In some aspects of this embodiment, the decanoic acid salt 4 is substantially characterized by an X-ray powder diffraction pattern as described in Table 8 with one or more characteristics.

[0145] Table 8: X-ray powder diffraction pattern of decanoate 4

[0146]

[0147] Decanoate 5:

[0148] In another embodiment, provided herein is a decanoate salt 5, which is a crystalline form of the decanoate salt of the compound of formula I, characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 7.66, 16.18, 18.26, and 19.11. In a specific aspect, the decanoate salt 5 is characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 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 a decanoate salt 5, wherein the crystalline form is characterized by having an X-ray powder diffraction pattern with peaks (expressed in 2-θ degrees at angles ± 0.2°) shown in Table 9.

[0149] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 5, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In some aspects of this embodiment, the decanoate salt 5 is essentially characterized by Fig.11 In some aspects of this embodiment, the decanoic acid salt 5 is substantially characterized by an X-ray powder diffraction pattern as described in Table 9 with one or more characteristics.

[0150] Table 9: X-ray powder diffraction pattern of decanoate 5

[0151]

[0152] Decanoate 6:

[0153] In another embodiment, provided herein is a decanoate salt 6, which is a crystalline form of the decanoate salt of the compound of Formula I, characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 5.33, 6.97, 19.04, and 21.58. In a specific aspect, the decanoate salt 6 is characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 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 a decanoate salt 6, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in 2-θ degrees at angles ±0.2°) as shown in Table 10. In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of a decanoate salt 6, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the decanoate salt 6 is essentially characterized as follows Fig.12 In aspects of this embodiment, the decanoic acid salt 6 is substantially characterized by an X-ray powder diffraction pattern as described by one or more of the characteristics described in Table 10.

[0154] Table 10: X-ray powder diffraction pattern of decanoate 6

[0155]

[0156] Decanoate 7:

[0157] In another embodiment, provided herein is Decanoate 7, which is a crystalline form of the decanoate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern at 7.73, 17.14, 18.75, and 19.48. In another embodiment, the crystalline form of the compound of Formula I is Decanoate 7, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks shown in Table 11 (expressed in 2-θ degrees at angles ±0.2°).

[0158] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 7, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the decanoate salt 7 is essentially characterized by Fig.13 In aspects of this embodiment, the decanoic acid salt 7 is substantially characterized by an X-ray powder diffraction pattern as described in one or more of the characteristics described in Table 11.

[0159] Table 11: X-ray powder diffraction pattern of decanoate 7

[0160]

[0161] Decanoate 8:

[0162] In another embodiment, provided herein is Decanoate 8, which is a crystalline form of the decanoate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern at 7.45, 17.97, 19.32, and 22.08. In a specific aspect, Decanoate 8 is characterized by an X-ray powder diffraction pattern having a peak at an angle (± 0.2°) of 6.35, 7.45, 14.95, 16.13, 17.46, 17.97, 19.32, 20.62, and 22.08 expressed in 2θ degrees. In another embodiment, the crystalline form of the compound of Formula I is Decanoate 8, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks (expressed in 2-θ degrees at an angle ± 0.2°) shown in Table 12.

[0163] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 8, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the decanoate salt 8 is essentially characterized by Fig.14 In aspects of this embodiment, the decanoic acid salt 8 is substantially characterized by the X-ray powder diffraction pattern as described in Table 12 with one or more of the characteristics described.

[0164] Table 12: X-ray powder diffraction pattern of decanoate 8

[0165]

[0166] Decanoate 9:

[0167] In another embodiment, provided herein is a decanoate salt 9, which is a crystalline form of the decanoate salt of Formula I, characterized by an X-ray powder diffraction pattern at 6.73, 11.95, 18.23, and 19.77. In a specific aspect, the decanoate salt 9 is characterized by having X-ray powder diffraction patterns at 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, 1 14.04, 14.06, 14.08, 15.71, 15.97, 16.10, 17.11, 18.73, 19.81, 20.97, 21.09, 22.10, 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 the decanoate salt 9, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in 2-theta degrees at angles ±0.2°) shown in Table 13.

[0168] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 9, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the decanoate salt 9 is essentially characterized by Fig.15 In aspects of this embodiment, the decanoic acid salt 9 is substantially characterized by an X-ray powder diffraction pattern as described by one or more of the characteristics described in Table 13.

[0169] Table 13: X-ray powder diffraction pattern of decanoate 9

[0170]

[0171] Decanoate 10:

[0172] In another embodiment, provided herein is Decanoate 10, which is a crystalline form of the decanoate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern at 3.50, 7.90, 16.21, and 18.23. In another embodiment, the crystalline form of the compound of Formula I is Decanoate 10, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks shown in Table 14 (expressed in 2-theta degrees at angles ±0.2°).

[0173] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 10, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the decanoate salt 10 is essentially characterized by Fig.16 In aspects of this embodiment, the decanoic acid salt 10 is substantially characterized by the X-ray powder diffraction pattern as described by one or more of the characteristics described in Table 14.

[0174] Table 14: X-ray powder diffraction pattern of decanoate 10

[0175]

[0176] Decanoate 11:

[0177] In another embodiment, provided herein is decanoate 11, which is a crystalline form of the decanoate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern at 3.93, 4.90 and 7.68. In another embodiment, the crystalline form of the compound of Formula I is decanoate 11, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having the peaks shown in Table 15 (expressed in 2-θ degrees at angles ±0.2°).

[0178] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 11, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In some aspects of this embodiment, the decanoate salt 11 is essentially characterized by Fig.17 In aspects of this embodiment, the decanoic acid salt 11 is substantially characterized by an X-ray powder diffraction pattern as shown in Table 15 with one or more of the characteristics described.

[0179] Table 15: X-ray powder diffraction pattern of decanoate 11

[0180]

[0181] Decanoate 12:

[0182] In another embodiment, provided herein is decanoate 12, which is a crystalline form of the decanoate salt of the compound of Formula I, characterized by an X-ray powder diffraction pattern at 6.80, 15.37, 18.22, and 20.63. In a specific aspect, decanoate 12 is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 5.01, 5.58, 6.80, 10.75, 13.44, 13.85, 14.43, 15.37, 16.00, 16.34, 16.68, 17.67, 18.22, 18.50, 19.09, 19.67, 20.27, 20.63, 21.33, 22.30, 23.22, 23.88, 25.39, and 26.02. In another embodiment, the crystalline form of the compound of Formula I is the decanoate salt 12, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in 2-theta degrees at angles ±0.2°) shown in Table 16.

[0183] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 12, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the decanoate salt 12 is essentially characterized by Fig.18 In aspects of this embodiment, the decanoate salt 12 is substantially characterized by the X-ray powder diffraction pattern as described in Table 16 with one or more of the characteristics described.

[0184] Table 16: X-ray powder diffraction pattern of decanoate 12

[0185]

[0186] Decanoate 13:

[0187] In another embodiment, provided herein is a decanoate salt 13, which is a crystalline form of the decanoate salt of the compound of formula I, characterized by an X-ray powder diffraction pattern at 5.02, 6.29, 7.12, and 20.25. In a specific aspect, decanoate salt 13 is characterized by having an X-ray powder diffraction pattern with peaks at angles (± 0.2°) of 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 expressed in 2θ degrees. In another embodiment, the crystalline form of the compound of formula I is decanoate salt 13, wherein the crystalline form is characterized by having an X-ray powder diffraction pattern with peaks (expressed in 2-θ degrees at angles ± 0.2°) shown in Table 17.

[0188] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 13, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the decanoate salt 13 is essentially characterized by Fig.19 In aspects of this embodiment, the decanoic acid salt 13 is substantially characterized by the X-ray powder diffraction pattern as described in Table 17 with one or more of the characteristics described.

[0189] Table 17: X-ray powder diffraction pattern of decanoate 13

[0190]

[0191] Decanoate 14:

[0192] In another embodiment, provided herein is a decanoate salt 14, which is a crystalline form of the decanoate salt of the compound of formula I, characterized by an X-ray powder diffraction pattern at 6.74, 18.16, 19.51 and 20.68. In a specific aspect, decanoate salt 14 is characterized by having an X-ray powder diffraction pattern with peaks at angles (± 0.2°) of 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, expressed in 2θ degrees. In another embodiment, the crystalline form of the compound of formula I is decanoate salt 14, wherein the crystalline form is characterized by having an X-ray powder diffraction pattern with peaks (expressed in 2-θ degrees at angles ± 0.2°) shown in Table 18.

[0193] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the decanoate salt 14, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the decanoate salt 14 is essentially characterized by Fig. 20 In aspects of this embodiment, the decanoic acid salt 14 is substantially characterized by the X-ray powder diffraction pattern as described in Table 18 with one or more of the characteristics described.

[0194] Table 18: X-ray powder diffraction pattern of decanoate 14

[0195]

[0196] D-Lactate 1:

[0197] In another embodiment, provided herein is D-lactate 1, which is a crystalline form of a lactate salt of a compound of formula I, characterized by an X-ray powder diffraction pattern having peaks at angles (± 0.2°) of 18.24, 19.56, 20.07, and 20.45 expressed in 2θ degrees. In a specific aspect, D-lactate 1 is characterized by an X-ray powder diffraction pattern having peaks at angles (± 0.2°) of 17.26, 18.24, 19.56, 20.07, 20.45, 20.89, 21.72, and 22.10 expressed in 2θ degrees. In a more specific aspect, the D-lactate salt 1 is characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 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 the D-lactate salt 1, wherein the crystalline form is characterized by having an X-ray powder diffraction pattern with peaks (expressed in 2-θ degrees at angles ± 0.2°) shown in Table 19.

[0198] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the D-lactate salt 1, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the D-lactate salt 1 is essentially characterized by Fig.21 In aspects of this embodiment, the D-lactate salt 1 is substantially characterized by the X-ray powder diffraction pattern as described in one or more of the characteristics described in Table 19.

[0199] Table 19: X-ray powder diffraction pattern of D-lactate 1

[0200]

[0201] D-Lactate 2:

[0202] In another embodiment, provided herein is D-lactate 2, which is a crystalline form of a lactate salt of a compound of formula I, characterized by having an X-ray powder diffraction pattern with a peak represented by 2θ degrees at an angle (± 0.2°) of 7.38. In a particular aspect, D-lactate 2 is characterized by having an X-ray powder diffraction pattern with a peak represented by 2θ degrees at an angle (± 0.2°) of 7.38 and 19.63. In another embodiment, the crystalline form of the compound of formula I is D-lactate 2, wherein the crystalline form is characterized by having an X-ray powder diffraction pattern with a peak (represented by 2-θ degrees at an angle ± 0.2°) shown in Table 20.

[0203] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the D-lactate salt 2, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the D-lactate salt 2 is essentially characterized by Fig. 22 In aspects of this embodiment, the D-lactate salt 2 is substantially characterized by the X-ray powder diffraction pattern as described in one or more of the characteristics described in Table 20.

[0204] Table 20: X-ray powder diffraction pattern of D-lactate 2

[0205]

[0206] Succinate 1:

[0207] 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 having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 5.98, 7.05, 17.29, and 20.22. In a specific aspect, succinate 1 is characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 5.98, 7.05, 17.29, 18.82, 20.22, and 21.39. In a more specific aspect, succinic acid 1 is characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 4.84, 5.49, 5.98, 7.05, 14.38, 16.79, 17.29, 18.82, 20.22, and 21.39. In another embodiment, the crystalline form of the compound of Formula I is succinate salt 1, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in 2-theta degrees at angles ±0.2°) shown in Table 21.

[0208] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of succinate salt 1, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, succinate salt 1 is essentially characterized by Fig.23 In aspects of this embodiment, Succinate Salt 1 is substantially characterized by an X-ray powder diffraction pattern as described by one or more of the characteristics described in Table 21.

[0209] Table 21: X-ray powder diffraction pattern of succinate 1

[0210]

[0211] Succinate 2:

[0212] In another embodiment, provided herein is Succinate Salt 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 2θ degrees at angles (±0.2°) of 5.15, 6.12, 7.22, and 7.90. In another embodiment, the crystalline form of the compound of Formula I is Succinate Salt 2, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in 2-θ degrees at angles ±0.2°) shown in Table 22.

[0213] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the succinate salt 2, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the succinate salt 2 is essentially characterized by Fig.24 In aspects of this embodiment, Succinate Salt 2 is substantially characterized by the X-ray powder diffraction pattern as described by one or more of the characteristics described in Table 22.

[0214] Table 22: X-ray powder diffraction pattern of succinic acid 2

[0215]

[0216] L-Tartrate 1:

[0217] 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 having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 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 having an X-ray powder diffraction pattern with peaks (expressed in 2-θ degrees at angles ± 0.2°) shown in Table 23.

[0218] In aspects of this embodiment, about 10% to about 100% of the compound of formula I in the pharmaceutical composition is in the form of the L-tartrate salt 1, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the L-tartrate salt 1 is essentially characterized by Fig.25 In aspects of this embodiment, the L-tartrate salt 1 is substantially characterized by the X-ray powder diffraction pattern as described in Table 23 with one or more of the characteristics described.

[0219] Table 23: X-ray powder diffraction pattern of L-tartrate salt 1

[0220]

[0221] L-Tartrate 2:

[0222] In another embodiment, provided herein is L-tartrate 2, which is a crystalline form of the tartrate of the compound of formula I, characterized in that there is an X-ray powder diffraction pattern with a peak at an angle (± 0.2 °) of 7.35, 14.19, 15.86 and 18.70, expressed in 2θ degrees. In a particular aspect, L-tartrate 2 is characterized in that there is an X-ray powder diffraction pattern with a peak at an angle (± 0.2 °) of 7.35, 10.90, 14.19, 15.86, 16.63, 17.58, 18.20, 18.70, 19.79, 20.54 and 20.94, expressed in 2θ degrees. In another embodiment, the crystalline form of the compound of formula I is L-tartrate 2, wherein the crystalline form is characterized in that there is an X-ray powder diffraction pattern with a peak (expressed in 2-θ degrees at an angle ± 0.2 °) shown in Table 24.

[0223] In aspects of this embodiment, about 10% to about 100% of the compound of formula I in the pharmaceutical composition is in the form of the L-tartrate salt 2, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the L-tartrate salt 2 is essentially characterized by Fig.26 In aspects of this embodiment, the L-tartrate salt 2 is substantially characterized by the X-ray powder diffraction pattern as described in Table 24 with one or more of the characteristics described.

[0224] Table 24: X-ray powder diffraction pattern of L-tartrate salt 2

[0225]

[0226] Sulfate 1:

[0227] 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 having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 6.87, 19.48, 20.38, and 20.94. In a specific aspect, Sulfate 1 is characterized by having an X-ray powder diffraction pattern with peaks expressed in 2θ degrees at angles (± 0.2°) of 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, wherein the crystalline form is characterized by having an X-ray powder diffraction pattern with peaks (expressed in 2-θ degrees at angles ± 0.2°) shown in Table 25

[0228] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of the sulfate salt 1, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, the sulfate salt 1 is essentially characterized by Fig. 27 In aspects of this embodiment, Sulfate Salt 1 is substantially characterized by the X-ray powder diffraction pattern as described by one or more of the characteristics described in Table 25.

[0229] Table 25: X-ray powder diffraction pattern of sulfate 1

[0230]

[0231] Sulfate 2:

[0232] In another embodiment, provided herein is Sulfate Salt 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 2θ degrees at angles (±0.2°) of 5.21, 5.75, 6.30, and 7.74. In another embodiment, the crystalline form of the compound of Formula I is Sulfate Salt 2, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks (expressed in 2-θ degrees at angles ±0.2°) shown in Table 26.

[0233] In aspects of this embodiment, about 10% to about 100% of the compound of Formula I in the pharmaceutical composition is in the form of Sulfate Salt 2, such as about 25% to about 98%, about 50% to about 96%, about 75% to about 95%, about 90% to about 94%, or about 92%. In aspects of this embodiment, Sulfate Salt 2 is essentially characterized by Fig.28 In aspects of this embodiment, Sulfate Salt 2 is substantially characterized by the X-ray powder diffraction pattern as described in Table 26 with one or more of the characteristics described.

[0234] Table 26: X-ray powder diffraction pattern of sulfate 2

[0235]

[0236] Another aspect of these embodiments provides a specific drug substance comprising a crystalline form of a compound of Formula I as described herein. "Drug substance" refers to an active pharmaceutical ingredient. The presence of a crystalline form in a drug substance can be detected by physical methods known to those of ordinary skill 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.

[0237] In another aspect of this embodiment, compound 2 is selected from ethers, esters, linear alkanes (C3-C 10 In another 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 ), alcohol and water and mixtures thereof. In some embodiments, compound 2 is crystallized from a solvent system comprising a solvent selected from 2-Me-THF, MTBE, ethyl acetate, n-butanol, 1-propanol and water.

[0238] In the first case, the decanoate salt 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 the decanoate salt 2. Specifically, the decanoate salt 2 is crystallized from a solvent system comprising MTBE, about 30-40% by weight 1-propanol, and 0.5-5% water.

[0239] In subsequent cases, the decanoate salt 2 is filtered and optionally dried. In one embodiment, the decanoate salt 2 is dried to obtain a crystalline form of Formula I, such as the decanoate salt 3. Drying can be performed at room temperature and / or at a relative humidity of about 50%.

[0240] In another case, the decanoate salt 9 is crystallized from a solvent system comprising 1-propanol, MTBE, water, and mixtures thereof. In one embodiment, a solvent system comprising compound 2 is suspended to form the decanoate salt 9. The solvent system may comprise a variety of forms of compound 2. Specifically, the decanoate salt 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, the decanoate salt 9 is filtered and optionally dried. In one embodiment, the decanoate salt 9 is dried to obtain a crystalline form of Formula I, such as the decanoate salt 3. Drying may be performed at room temperature and / or about 50% relative humidity.

[0241] definition

[0242] Specific definitions of certain technical and scientific terms are as follows. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which this disclosure relates. That is, the terms used herein have their ordinary meanings and are independent at each occurrence. Nevertheless and unless otherwise indicated, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures can be used interchangeably to describe the same structure. If both a chemical structure and a chemical name are used to refer to a compound, and there is ambiguity between the structure and the name, the structure shall prevail.

[0243] The terms used herein have their usual meanings, and the meanings of these terms are independent at each occurrence. Nevertheless and unless otherwise indicated, the following definitions apply throughout the specification and claims.

[0244] “FIG” or “FIG.” or “Fig.” or “Fig” or “fig.” or “fig” means “Figure” or “figure” and refers to the corresponding drawing.

[0245] For the numerical values ​​provided herein, the use of the term "about" can include, for example, 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. "About" is used to modify a numerically defined parameter (e.g., a 2θ value of an X-ray powder diffraction pattern measured using CuKα radiation, or a value described herein). 13 C or 15 N chemical shift), means that the parameter may be as much as 10% higher or lower than the stated value of the parameter; where appropriate, the parameter may be rounded to the nearest integer. In addition, the term "or" as used herein indicates alternatives that can be combined where appropriate; that is, the term "or" includes each individually listed alternative as well as their combinations.

[0246] Exemplary methods and materials are described herein, but 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 for illustrative purposes only and are not intended to be limiting.

[0247] "Patient" includes humans and other animals.

[0248] "Mammal" includes humans and other mammals.

[0249] "XPRD" refers to powder X-ray diffraction.

[0250] "Excipient" refers to an essentially inert substance used to impart stability, form, or consistency to a formulation.

[0251] A "diluent" is an excipient that functions primarily as a diluent. A diluent acts to reduce the viscosity of a fluid.

[0252] As used herein, the term "composition" (or "pharmaceutical composition" or "pharmaceutically acceptable composition") is intended to encompass a product comprising specified ingredients in specified amounts, as well as any product resulting directly or indirectly from the combination of specified ingredients in specified amounts. The term is intended to encompass a product comprising an active ingredient and an inert ingredient (if any) constituting a carrier, as well as any product resulting directly or indirectly from the combination, complexation or aggregation of any two or more ingredients, or any product resulting from the dissociation of one or more ingredients, or any product resulting from other types of reactions or interactions of one or more ingredients. Thus, the pharmaceutical compositions of the present invention encompass any composition made by mixing a crystalline form of a compound of Formula I as described herein and 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 harmful to the recipient.

[0253] The term "composition" (or "pharmaceutical composition" or "pharmaceutically acceptable composition") as used herein is also intended to cover bulk compositions and / or individual dosage units. (Such compositions and units may also contain additional active ingredients as described herein.) Bulk compositions and each individual dosage unit may contain a fixed amount of active agent. Bulk compositions are materials that have 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 patients by administering the pharmaceutical compositions of the present invention are also intended to cover the administration of the aforementioned bulk compositions and individual dosage units.

[0254] As used herein, the term "caprate" is also referred to as "decanoate."

[0255] Compounds of the present invention also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the migration of the ensuing proton. Tautomeric forms include proton tautomers, which are homogeneous protonation states with the same empirical formula and total charge. Examples of proton tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or spatially locked into one form by appropriate substitution.

[0256] As used herein, the terms "treat" or "treating" refer to inhibiting or ameliorating a disease, condition, or disorder in a subject who is 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 development of the pathology and / or symptoms of the disease, condition, or disorder. Additionally, ameliorating a disease, condition, or disorder refers, for example, to reversing the pathology and / or symptoms, such as reducing the severity of the disease.

[0257] As used herein, the terms "prevent," "preventing," or "suppressing" include preventing at least one symptom associated with or caused by the disease, condition, or disorder being prevented.

[0258] As used herein, "subject" refers to an animal, preferably a mammal, particularly a human or non-human animal, including livestock and domestic animals, including but not limited to cattle, horses, sheep, pigs, goats, rabbits, cats, dogs and other mammals in need of treatment. In some embodiments, the subject is a human.

[0259] As used herein, the term "administering" and its variants (e.g., "administering") with respect to a compound of Formula I refers to providing the compound to a subject in need of treatment. "Oral" and its variants (e.g., "oral") as used herein refers to administration via the oral cavity, i.e., administering a compound of Formula I through the oral cavity.

[0260] The administration of the compound of formula I to a subject includes self-administration and administration to a subject by another person. A subject may need or desire to treat an existing disease or medical condition, or may need or desire preventive treatment to prevent or reduce the risk of a disease or medical condition. As used herein, a subject "needs" to treat an existing condition or preventive treatment, including both the judgment of a medical professional on the need and the patient's desire for such treatment.

[0261] Technology

[0262] Provided herein are processes or methods for preparing crystalline forms of compounds of formula I:

[0263]

[0264] Among them A - is a pharmaceutically acceptable anion;

[0265] The crystalline form is formed by a process comprising adding an alcohol to a starting material,

[0266] The starting material is selected from compound 1, compound 2, compound 3, compound 4, compound 5 and compound 6.

[0267] 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, decanoate 2, decanoate 3, decanoate 4, decanoate 5, decanoate 6, decanoate 7, decanoate 8, decanoate 9, decanoate 10, decanoate 11, decanoate 12, decanoate 13, decanoate 14, D-lactate 1, D-lactate 2, succinate 1, succinate 2, L-tartrate 1, L-tartrate 2, sulfate 1 and sulfate 2.

[0268] In one embodiment of the process for preparing the 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.

[0269] In one embodiment, the process for preparing the 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 in the range of 0°C to 40°C. In another embodiment, the process comprises aging the slurry / solution in the range of 20°C to 35°C.

[0270] In one embodiment, the process for preparing the 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 an 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.

[0271] In one embodiment, the process for preparing the crystalline form of the compound of formula I comprises adding a mixture comprising an organic solvent. In a further embodiment, an 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.

[0272] In one embodiment, the process for preparing the crystalline form of the compound of formula I comprises washing the starting material with an organic solvent or an 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.

[0273] In one 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 a relative humidity of about 5%, thereby producing 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 a relative humidity of about 50%, thereby obtaining a second crystalline form of the compound of formula I.

[0274] In one embodiment of the process for preparing the crystalline form of the compound of formula I, the organic solvent is selected from ethers, esters and linear 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.

[0275] In one specific embodiment of the process for preparing a crystalline form of a 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 (acetate salt of a compound of formula I).

[0276] In a specific embodiment of the process for preparing a crystalline form of a compound of formula I, the crystalline form of the compound of formula I is selected from decanoate 2, decanoate 3, decanoate 4, decanoate 5, decanoate 6, decanoate 7, decanoate 8, decanoate 9, decanoate 10, decanoate 11, decanoate 12, decanoate 13 and decanoate 14, and the starting material is compound 2 (decanoate salt of a compound of formula I).

[0277] In a specific embodiment of the process for preparing a crystalline form of a 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 (bicarbonate salt of the compound of formula I).

[0278] In one embodiment of the process for preparing a crystalline form of a compound of formula I, the crystalline form of the compound of formula I is D-lactate 2, and the starting material is compound 3 (lactate salt of compound of formula I). ​​In one embodiment, compound 3 is D-lactate 1.

[0279] In one embodiment of the process for preparing a crystalline form of a compound of formula I, the crystalline form of the compound of formula I is succinate 2 and the starting material is compound 4 (succinate salt of a compound of formula I). ​​In one embodiment, compound 4 is succinate 1.

[0280] In one embodiment of the process for preparing a crystalline form of a compound of formula I, the crystalline form of the compound of formula I is L-tartrate 2, and the starting material is compound 5 (tartrate salt of compound of formula I). ​​In one embodiment, compound 5 is L-tartrate 1.

[0281] In one specific embodiment of the process for preparing a crystalline form of a compound of formula I, the crystalline form of the compound of formula I is sulfate 2, and the starting material is compound 6 (sulfate of a compound of formula I). ​​In one embodiment, compound 6 is sulfate 1.

[0282] In another aspect, provided herein is a process or method for preparing a crystalline form of a decanoate salt of a compound of Formula I:

[0283]

[0284] Among them A - It is the decanoate;

[0285] The crystalline form is formed by a process comprising adding an alcohol to the form of the starting material,

[0286] The starting material is compound 2 (decanoate of the compound of formula I).

[0287] In one embodiment of the process for preparing a crystalline form of a decanoate salt of the compound of formula I, the crystalline form prepared by the above process is selected from decanoate 2, decanoate 3, decanoate 4, decanoate 5, decanoate 6, decanoate 7, decanoate 8, decanoate 9, decanoate 10, decanoate 11, decanoate 12, decanoate 13 and decanoate 14.

[0288] In one embodiment, in the process for preparing the 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.

[0289] In one embodiment, the process for preparing a crystalline form of a decanoate salt of a compound of formula I comprises adding an organic solvent to a starting material (compound 2 - decanoate salt of a 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 in the range of 0°C to 40°C. In another embodiment, the process comprises aging the slurry / solution in the range of 20°C to 35°C.

[0290] 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 an 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.

[0291] 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. In a further embodiment, an 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.

[0292] In one embodiment, the method for preparing the crystalline form of the decanoate salt of the compound of formula I comprises washing the starting material (compound 2 - decanoate salt of the compound of formula I) 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.

[0293] In one embodiment, the process for preparing the crystalline form of the decanoate salt of the compound of Formula I further comprises exposing the crystalline form of the decanoate salt of the compound of Formula I to a relative humidity of about 5%, thereby producing a second crystalline form of the decanoate salt of the compound of Formula I. In one embodiment, the process for preparing the crystalline form of the decanoate salt of the compound of Formula I further comprises exposing the crystalline form of the decanoate salt of the compound of Formula I to a relative humidity of about 50%, thereby producing a second crystalline form of the decanoate salt of the compound of Formula I. In one embodiment, the organic solvent of the above process is selected from 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.

[0294] In one embodiment of the process for preparing a crystalline form of the decanoate salt of the compound of Formula I, the starting material is selected from Decanoate 1, Decanoate 2, Decanoate 3, Decanoate 4, Decanoate 5, Decanoate 6, Decanoate 7, Decanoate 8, Decanoate 9, Decanoate 10, Decanoate 11, Decanoate 12, Decanoate 13 and Decanoate 14.

[0295] In one embodiment, the crystalline form of the decanoate salt of the compound of Formula I is decanoate 4 and the starting material is decanoate 1.

[0296] In one embodiment, the crystalline form of the decanoate salt of the compound of Formula I is decanoate 5 and the starting material is decanoate 4.

[0297] In one embodiment, the crystalline form of the decanoate of the compound of formula I is decanoate 2, and the starting material is compound 2. In another embodiment, the crystalline form of the decanoate of the compound of formula I is decanoate 2, and the starting material is decanoate 5. In yet another embodiment, the crystalline form of the decanoate of the compound of formula I is decanoate 2, and the starting material is compound A or compound B. In a further embodiment, the process includes adding a mixture comprising an organic solvent and water. In another embodiment, the process includes 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 consists of MTBE, about 30-40% by weight of 1-propanol and 0.5-5% water. In a further embodiment, the mixture consists of MTBE, about 39% by weight of 1-propanol and 1% water. In another embodiment, the process includes aging the mixture. In a further embodiment, the process includes aging the mixture at 20°C to 30°C.

[0298] In one embodiment, the crystalline form of the decanoate compound of Formula I is decanoate 3, and the starting material is decanoate 2 or decanoate 9. In a further embodiment, the process comprises filtering and optionally drying decanoate 2. In one embodiment, the process comprises drying decanoate 2 to form decanoate 3. In a further embodiment, the process comprises drying decanoate 2 at 20° C. to 30° C. to form decanoate 3. Drying can be performed at room temperature and / or at a relative humidity of about 50%.

[0299] As described above, the caprate salt 3 can be formed by drying a composition comprising the caprate salt 9. Drying can be performed at room temperature and / or at a relative humidity of about 50%.

[0300] In one embodiment, the crystalline form of the decanoate salt of the compound of Formula I is decanoate 4 and the starting material is decanoate 3.

[0301] In one embodiment, the crystalline form of the decanoate salt of the compound of Formula I is decanoate 6, and the starting material is decanoate 1.

[0302] In one embodiment, the crystalline form of the decanoate salt of the compound of Formula I is decanoate 7 and the starting material is decanoate 6.

[0303] In one embodiment, the crystalline form of the decanoate salt of the compound of Formula I is decanoate 8 and the starting material is decanoate 4.

[0304] In one embodiment, the crystalline form of the decanoate salt of the compound of Formula I is selected from decanoate 9 and decanoate 12, and the starting material is a mixture of decanoate 3, decanoate 5 and decanoate 8.

[0305] In one embodiment, the process for preparing a crystalline form of a decanoate salt of a compound of Formula I further comprises exposing a first crystalline form of a compound of Formula I selected from decanoate 3 and decanoate 7 to a relative humidity of about 5% and obtaining a second crystalline form of a decanoate salt of a compound of Formula I selected from decanoate 10 and decanoate 11. In a further embodiment, the first crystalline form of a decanoate salt of a compound of Formula I is decanoate 3, and the second crystalline form of a decanoate salt of a compound of Formula I is decanoate 10. In another embodiment, the first crystalline form of a decanoate salt of a compound of Formula I is decanoate 7, and the second crystalline form of a decanoate salt of a compound of Formula I is decanoate 11.

[0306] In one embodiment, the crystalline form of the decanoate salt of the compound of Formula I is selected from decanoate 13 and decanoate 14, and the starting material is decanoate 3.

[0307] In one embodiment, the process for preparing a crystalline form of a decanoate salt of a compound of Formula I comprises exposing decanoate salt 3 to a vapor comprising an alcohol, and the crystalline form of the compound of Formula I is decanoate salt 13. In another embodiment, the process comprises exposing decanoate salt 3 to a vapor comprising an organic solvent and an alcohol, wherein the crystalline form of the compound of Formula I is decanoate salt 13. In a further embodiment, the organic solvent is MTBE.

[0308] Also provided herein is a process or method for preparing a crystalline form of a compound of formula I:

[0309]

[0310] Among them A - is a pharmaceutically acceptable anion;

[0311] The crystalline form is formed by a process comprising adding an alcohol to a starting material,

[0312] The starting material is compound A (chloride salt of the compound of formula I) or compound B (bicarbonate salt of the compound of formula I).

[0313] In one embodiment, the process for preparing the crystalline compound of Formula I comprises ion exchange.

[0314] In one embodiment, the process for preparing the crystalline compound of Formula I comprises ion exchange, wherein the starting material is Compound A (chloride salt of the compound of Formula I) and the ion exchange comprises reacting the crystalline compound with A. - of ion exchange resins.

[0315] In another embodiment, Compound B (the bicarbonate salt of the compound of Formula I) is formed by a process comprising ion exchange, wherein the starting material is Compound A (the chloride salt of the compound of Formula I) and the ion exchange to form Compound B comprises:

[0316] (1) Ion exchange resins loaded with bicarbonate; or

[0317] (2) Liquid-liquid extraction using an organic solvent and an aqueous bicarbonate solution.

[0318] In a further embodiment, the process for preparing 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 the addition of an acid comprising a pharmaceutically acceptable anion.

[0319] 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, decanoate 2, decanoate 3, decanoate 4, decanoate 5, decanoate 6, decanoate 7, decanoate 8, decanoate 9, decanoate 10, decanoate 11, decanoate 12, decanoate 13, decanoate 14, D-lactate 1, D-lactate 2, succinate 1, succinate 2, L-tartrate 1, L-tartrate 2, sulfate 1 and sulfate 2.

[0320] In one embodiment of the process for preparing the 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.

[0321] In one embodiment, the process for preparing the 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 in the range of about -10°C to about 40°C. In another embodiment, the process comprises aging the slurry / solution in the range of about 20°C to about 35°C. In another embodiment, the process comprises aging the slurry / solution in the range of about -10°C to about 0°C.

[0322] In one embodiment, the process for preparing the 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 an 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.

[0323] In one embodiment, the process for preparing the crystalline form of the compound of formula I comprises adding a mixture comprising an organic solvent. In a further embodiment, an 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.

[0324] In one embodiment, the process for preparing the crystalline form of the compound of formula I comprises washing the starting material with an organic solvent or an 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.

[0325] In one 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 a relative humidity of about 5% to about 50%, thereby obtaining 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%.

[0326] In one embodiment of the process for preparing the crystalline form of the compound of formula I, the organic solvent is selected from ethers, esters and linear 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.

[0327] In one specific embodiment of the process for preparing a crystalline form of a 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 (chloride salt of the compound of formula I). ​​In another embodiment of the process for preparing a crystalline form of a 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 (bicarbonate salt of the compound of formula I).

[0328] In one specific embodiment of the process for preparing a crystalline form of a compound of formula I, the crystalline form of the compound of formula I is selected from decanoate 2, decanoate 3, decanoate 4, decanoate 5, decanoate 6, decanoate 7, decanoate 8, decanoate 9, decanoate 10, decanoate 11, decanoate 12, decanoate 13 and decanoate 14, and the starting material is compound A (chloride salt of the compound of formula I). ​​In another embodiment of the process for preparing a crystalline form of a compound of formula I, the crystalline form of the compound of formula I is selected from decanoate 2, decanoate 3, decanoate 4, decanoate 5, decanoate 6, decanoate 7, decanoate 8, decanoate 9, decanoate 10, decanoate 11, decanoate 12, decanoate 13 and decanoate 14, and the starting material is compound B (bicarbonate salt of the compound of formula I).

[0329] In a specific embodiment of the scheme for preparing a crystalline form of a compound of formula I, wherein 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 (bicarbonate salt of the compound of formula I).

[0330] Treatment

[0331] On the other hand, provided herein is a method of antagonizing PCSK9 function using a PCSK9-specific antagonist compound described herein (e.g., a compound of Formula I); the method is further described below. The term "antagonism" used throughout this application refers to providing a substance to the affected tissue that antagonizes the effects of PCSK9 in the affected tissue, or inhibits, counteracts, neutralizes or weakens one or more functions of PCSK9 in the affected tissue. Inhibition or antagonism of one or more PCSK9-related functional properties can be easily determined according to methods known in the art (see, for example, Barak & Webb, 1981 J. Cell Biol. 90: 595-604; Stephan & Yurachek, 1993 J. Lipid Res. 34: 325-330; and McNamara et al., 2006 Clinica Chimica Acta 369: 158-167) and those methods described herein. Inhibition or antagonism will result in a decrease in PCSK9 activity relative to the activity observed in the absence of the antagonist, or, for example, relative to the activity observed in the presence of a control antagonist of irrelevant specificity. Preferably, a PCSK9-specific antagonist according to the present invention antagonizes PCSK9 function to the extent that a measured parameter (including but not limited to the activity disclosed herein) is reduced by at least 10%, and more preferably, the measured parameter is reduced by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% and 95%. Such inhibition / antagonism of PCSK9 function is particularly effective in cases where PCSK9 function is at least in part responsible for a particular phenotype, disease, disorder or condition that negatively affects the subject.

[0332] In one aspect, the present invention provides a method for antagonizing PCSK9 activity, comprising contacting a cell, cell population, or tissue sample that can be affected by PCSK9 (i.e., expressing and / or comprising an LDL receptor) with a PCSK9 specific antagonist disclosed herein (e.g., a compound of Formula I) under conditions that allow the antagonist to bind to PCSK9 (if present) and inhibit PCSK9's inhibition of cellular LDL uptake. Some embodiments of the present invention include methods in which the cell is a human cell. Additional embodiments of the present invention include methods in which the cell is a mouse cell.

[0333] In one aspect, the invention provides a method of antagonizing PCSK9 activity in a subject, comprising administering to the subject a therapeutically effective amount of a PCSK9-specific antagonist of the invention. In some embodiments, the method for antagonizing PCSK9 function is used to treat a PCSK9-related disease, disorder or condition as defined herein, or alternatively, to provide therapy for a disease, disorder or condition that may benefit from the action of a PCSK9 antagonist.

[0334] Therefore, the present invention contemplates the use of the PCSK9 specific antagonists described herein in various treatment methods that require antagonizing PCSK9 function. The term "treatment method" as used herein relates to a process of action that results in at least one symptom change in a disease state, which may be preventive or therapeutic in nature. In some embodiments, the present invention relates to a method for treating a condition associated with PCSK9 activity and / or attributed to PCSK9 activity or a condition in which PCSK9 function is contraindicated for a particular subject, the method 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 arterial disease, cerebrovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions, or may be a disease state or condition in which PCSK9 activity is contraindicated.

[0335] In one aspect, provided herein is the use of a crystalline form of a compound of Formula I as an active ingredient in a medicament for treating hypercholesterolemia in a subject.

[0336] In one embodiment, provided herein is the use of a pharmaceutical composition comprising a crystalline form of a compound of Formula I as a medicament for treating hypercholesterolemia in a subject.

[0337] 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.

[0338] In yet another embodiment, provided herein is the use of a crystalline form of a compound of Formula I as an active ingredient in a medicament for treating atherosclerotic cardiovascular disease in a subject.

[0339] In one aspect, provided herein is a method of treating hypercholesterolemia comprising administering a therapeutically effective amount of a crystalline form of a compound of Formula I to a patient in need thereof.

[0340] In one aspect, provided herein is the use of a crystalline form of a compound of Formula I as an active ingredient in a medicament for treating peripheral arterial disease in a subject.

[0341] In one embodiment, provided herein is the use of a pharmaceutical composition comprising a crystalline form of a compound of Formula I as a medicament for treating peripheral arterial disease in a subject.

[0342] In one aspect, provided herein is the use of decanoate 3 as an active ingredient in a medicament for treating hypercholesterolemia in a subject.

[0343] In one embodiment, provided herein is a pharmaceutical composition comprising decanoate 3 as a medicament for treating hypercholesterolemia in a subject.

[0344] In another embodiment, provided herein is the use of decanoate 3 as an active ingredient in a medicament for lowering LDL-C in a subject.

[0345] In yet another embodiment, provided herein is the use of decanoate 3 as an active ingredient in a medicament for treating atherosclerotic cardiovascular disease in a subject.

[0346] In one aspect, provided herein is a method of treating hypercholesterolemia comprising administering a therapeutically effective amount of decanoate 3 to a patient in need thereof.

[0347] In one aspect, provided herein is the use of decanoate 3 as an active ingredient in a medicament for treating peripheral arterial disease in a subject.

[0348] In one embodiment, provided herein is a pharmaceutical composition comprising decanoate 3 as a medicament for treating peripheral arterial disease in a subject.

[0349] Pharmaceutical composition

[0350] The treatment method according to the present invention includes administering a therapeutically (or preventively) effective amount of a PCSK9 specific antagonist of the present invention to an individual. The term "therapeutically effective" or "preventively effective" when referring to an amount refers to the amount required to achieve the desired therapeutic and / or preventive effect within the desired time period at the desired dose. The desired effect can be, for example, to alleviate, improve, reduce or stop at least one symptom associated with the treated disorder. As will be appreciated by those skilled in the art, these amounts will vary according to various factors, including but not limited to the disease state, age, sex and weight of the individual, and the ability of the PCSK9 specific antagonist to cause the desired effect in the individual. The response can be recorded by in vitro tests, in vivo non-human animal studies, and / or further supported by clinical trials.

[0351] In some embodiments, it is preferred to administer the PCSK9 antagonist compounds of the present invention in the form of a pharmaceutical composition described herein.

[0352] The dosage of antagonist therapy is well within the capabilities of those skilled 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 depending on a variety of factors, such as, but not limited to, those listed above, including the patient's condition, the area being treated, the route of administration, and the desired treatment, e.g., prophylactic or acute treatment, etc. A physician or veterinarian of ordinary skill can readily determine and prescribe a therapeutically effective amount of the antagonist.

[0353] The subject may need or desire treatment for an existing disease or medical condition. As used herein, a subject's "need" for treatment of an existing condition includes both a determination of need by a medical professional and the subject's desire for such treatment. The term "subject" as used herein refers to a mammal, plant, lower animal, or cell culture. In one embodiment, the subject is a human 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, "administering" and its variants are each understood to include providing the compound or salt thereof and the other agent by separate administration in parallel or simultaneously or over a period of time. When the combined agents are administered simultaneously, they may be administered together in the form of a single composition or may be administered separately. It should be understood that the "combination" of active agents may be a single composition containing all active agents or multiple compositions each containing one or more active agents. For the case of two active agents, the combination may be a single composition containing both agents simultaneously or two separate compositions each containing one agent; for the case of three active agents, the combination may be a single composition containing all three agents or three separate compositions each containing one agent, or two compositions, one of which contains two agents and the other contains a third agent; and so on.

[0354] The compositions and combinations of the present invention are suitable for administration in an effective amount. The term "effective amount" refers to an amount of active compound sufficient to antagonize PCSK9 and thereby induce the response sought (i.e., to induce a therapeutic response in the treatment or management of a condition associated with or affected by PCSK9 function, including but not limited to atherosclerosis, hypercholesterolemia, peripheral arterial disease, cerebrovascular disease, coronary heart disease, metabolic syndrome, acute coronary syndrome, and related cardiovascular and cardiometabolic diseases in animals or humans).

[0355] The actual administration used may vary according to the patient's needs and the severity of the disease being treated. It is within the technical scope of the art to determine the appropriate dosage regimen for a particular situation, for example, as described in standard literature, for example, as described in "Physicians' Desk Reference" (PDR), such as 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA), Physicians' Desk Reference, 56th edition, 2002 (published by Medical Economics company, Inc.), or Physicians' Desk Reference, 57th edition, 2003 (published by Thompson PDR, Montvale, NJ07645-1742); its disclosure is incorporated herein by reference. For convenience, the total daily dose can be divided into several parts and administered in divided doses or continuously as needed within a day.

[0356] PCSK9 specific antagonists can be administered to individuals by any route of administration known in the art, including but not limited to oral administration, injection administration (specific embodiments thereof include intravenous, subcutaneous, intraperitoneal or intramuscular injection) or inhalation administration, intranasal administration or topical administration, alone or in combination with other agents designed to assist in the treatment of individuals. PCSK9 specific antagonists can also be administered by injection devices, injection pens, needle-free devices and subcutaneous patch delivery systems. The route of administration should be determined according to a variety of considerations known to those skilled in the art, including but not limited to the desired physicochemical properties for treatment.

[0357] Dosage and formulation

[0358] Also provided herein is a method of treating hypercholesterolemia in a subject in need of such treatment, comprising orally administering to the subject an amount of a crystalline form of a compound of Formula I:

[0359]

[0360] Among them A - selected from pharmaceutically acceptable anions, and wherein the amount administered is from about 5 mg to about 300 mg of the compound of formula I.

[0361] The dosage regimen is selected based on a variety of factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition being treated; the route of administration; and the patient's renal and liver function. A physician, veterinarian or clinician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0362] The forms of the present disclosure can be formulated and administered in solid dosage forms, such as tablets, pills, capsules, powders or granules, intended for oral administration. Compositions according to the present disclosure can be conveniently formulated by methods known in the art, for example, as described in Remington's Pharmaceutical Sciences, 18th edition, 1990, and Remington: The Science and Practice of Pharmacy, 22nd edition, 2012. In addition, the forms of the present disclosure can be formulated and administered in sterile solutions for enteral (oral), parenteral, intravenous or intramuscular administration.

[0363] In the methods of the present disclosure, the forms described herein can be formulated as active pharmaceutical ingredients and can be administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials), which are appropriately selected according to the intended form of administration and in accordance with conventional pharmaceutical practice, i.e., oral tablets, oral capsules, oral suspensions, oral preparations or sterile solutions for parenteral, intravenous or intramuscular administration.

[0364] For example, for oral administration in the form of tablets or capsules, the forms described herein can be combined with oral, non-toxic, pharmaceutically acceptable inert carriers such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc. For parenteral, intravenous or intramuscular administration in the form of sterile solutions, the forms described herein can be combined with suitable excipients and non-toxic, pharmaceutically acceptable inert carriers into formulations that can be provided as prepared dosage forms in pre-filled injection devices, as lyophilized formulations to be reconstituted for injection, or as sterile liquids to be diluted for injection.

[0365] In one embodiment, the amount administered to the subject is a crystalline form of a compound of formula I of about 5 mg to about 300 mg. Integers and half integers between 5 mg and 300 mg are included in the present invention. In one embodiment, the amount administered is a crystalline form of a compound of formula I of about 10 mg to about 300 mg. In one embodiment, the amount administered is a crystalline form of a compound of formula I of about 10 mg or about 20 mg or about 22 mg. In one embodiment, the amount administered is a crystalline form of a compound of formula I of 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. In one embodiment, the amount administered 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 a crystalline form of a compound of Formula I. In one embodiment, the amount administered is about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about The crystalline form of the compound of Formula I can be 20 mg, about 20.5 mg, about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg, about 23.5 mg, about 24 mg, about 24.5 mg, about 25 mg, about 25.5 mg, about 26 mg, about 26.5 mg, about 27 mg, about 27.5 mg, about 28 mg, about 28.5 mg, about 29 mg, about 29.5 mg, or about 30 mg. In one embodiment, the amount administered is a daily dose of about 5 mg to about 300 mg.In one embodiment, the amount administered is a daily dose of about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg , about 20.5 mg, about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg, about 23.5 mg, about 24 mg, about 24.5 mg, about 25 mg, about 25.5 mg, about 26 mg, about 26.5 mg, about 27 mg, about 27.5 mg, about 28 mg, about 28.5 mg, about 29 mg, about 29.5 mg, about 30 mg, about 35 mg, or about 40 mg of a crystalline form of a compound of Formula I. In one embodiment, the amount administered is a daily dose of 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 22.5 mg, about 24 mg, about 25 mg, or about 30 mg of a crystalline form of a compound of Formula I. In one embodiment, the amount administered is a daily dose of about 10 mg, about 12 mg, about 15 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg, about 25 mg, or about 30 mg of the crystalline form of the compound of Formula I.

[0366] In one embodiment, the amount of Formula I administered to the subject is about 10 mg to about 40 mg of a crystalline form of a compound of Formula I. In one embodiment, the amount of Formula I administered to the subject is about 10 mg to about 30 mg of a crystalline form of a compound of Formula I. In another embodiment, the amount administered to the subject is about 12 mg to about 27 mg of a crystalline form of a compound of Formula I. In yet another embodiment, the amount administered to the subject is about 15 mg to about 25 mg of a crystalline form of a compound of Formula I. In one embodiment, the amount administered to the subject is about 10 mg to about 22.5 mg of a crystalline form of a compound of Formula I. In one embodiment, the amount administered to the subject is about 10 mg to about 20 mg of a crystalline form of a compound of Formula I. In yet another embodiment, the amount administered to the subject is about 15 mg to about 20 mg of a crystalline form of a compound of Formula I.

[0367] In one embodiment, the amount administered to the subject is about 10 mg to about 30 mg of decanoate 3. In another embodiment, the amount administered to the subject is about 12 mg to about 27 mg of decanoate 3. In yet another embodiment, the amount administered to the subject is about 15 mg to about 25 mg of decanoate 3. In one embodiment, the amount administered to the subject is about 10 mg to about 22 mg of decanoate 3. In one embodiment, the amount administered to the subject is about 10 mg to about 20 mg of decanoate 3. In yet another embodiment, the amount administered to the subject is about 15 mg to about 22 mg of decanoate 3. In one embodiment, the amount is about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about 11.5 mg, about 12.5 mg, about 13.5 mg, about 14.5 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about 11.5 mg, about 12 In one embodiment, the amount is about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg, about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg, about 23.5 mg, about 24 mg, about 24.5 mg, about 25 mg, about 25.5 mg, about 26 mg, about 26.5 mg, about 27 mg, about 27.5 mg, about 28 mg, about 28.5 mg, about 29 mg, about 29.5 mg, or about 30 mg of decanoate 3. In one embodiment, the amount is about 15 mg, about 15.5 mg, about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg, about 21 mg, about 21.5 mg, about 22 mg of decanoate 3 per day. 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 decanoate 3. In a further embodiment, the amount administered to a subject in need thereof is about 20 mg or about 22 mg of decanoate 3. In a further embodiment, the amount administered to a subject in need thereof is about 20 mg of decanoate 3. In a further embodiment, the amount administered to a subject in need thereof is about 22 mg of decanoate 3.

[0368] It will be understood that administration of a particular dose of a crystalline form of the compound of Formula I will correspond to administration of the corresponding free form of the compound of Formula I. For example, administration of about 22 mg of the decanoate salt 3 will correspond to administration of about 20 mg of the corresponding free form of the compound of Formula I.

[0369] In one embodiment, oral administration comprises administering a single oral dosage form comprising an amount of a crystalline form of a compound of Formula I. In one embodiment, oral administration comprises administering more than one or more oral dosage forms, each oral dosage form comprising an amount of a crystalline form of a compound of Formula I or a portion thereof. In one embodiment, oral administration comprises administering once daily a single oral dosage form comprising a crystalline form of a compound of Formula I. In one embodiment, oral administration comprises administering once daily more than one or more oral dosage forms, each oral dosage form comprising an amount of a crystalline form of a compound of Formula I or a portion thereof. In one embodiment, oral administration comprises administering more than once a day, for example, twice, three times, or four times a day, a single oral dosage form comprising an amount of a crystalline form of a compound of Formula I. In one embodiment, oral administration comprises administering more than once a day, for example, twice, three times, or four times a day, more than one or more oral dosage forms, each oral dosage form comprising an amount of a crystalline form of a compound of Formula I or a portion thereof. The oral dosage form may be administered in a fasting or non-fasting state, that is, with or without food. In one embodiment, the subject in need of treatment fasts for about 30 minutes prior to administering the crystalline form of the compound of Formula I.

[0370] In one embodiment, a single oral dosage form is administered once daily for at least 14 days. In one embodiment, a single oral dosage form is administered once daily for 14 days. In one embodiment, a single oral dosage form is administered once daily for as long as the subject requires treatment.

[0371] As used herein, "oral dosage form" refers to a pharmaceutical preparation comprising a crystalline form of a compound of formula I and at least one pharmaceutically acceptable excipient suitable for administration through the oral cavity of a subject. The terms "oral dosage form" and "pharmaceutical composition" as used herein are intended to encompass a combination of specified ingredients in specified amounts, as well as any product produced directly or indirectly by a combination of specified ingredients in specified amounts. An oral dosage form may include the entire amount of a crystalline form of a compound of formula I, e.g., from about 5 mg to about 300 mg, which may or may not be a daily dose. An oral dosage form may include a portion of a daily dose of a crystalline form of a compound of formula I.

[0372] Oral dosage forms according to the present disclosure may be solid, semisolid or liquid. Such oral dosage forms include, but are not limited to, powders, dispersed granules, tablets and beads (e.g., for tabletting, encapsulation or direct administration), pills, tablets, lacquered tablets, sugar-coated tablets, hard and soft capsules (including gelatin capsules), lozenges, fast-dissolving tablets, aqueous, alcoholic or oily solutions, gels, syrups, emulsions or suspensions. Oral dosage forms according to the present disclosure may also include one or more coatings that modify the release characteristics, such as coatings that impart delayed release or formulations with sustained release characteristics. The present disclosure also includes formulations that are intended to be converted into suspensions or solutions shortly before use; examples include, but are not limited to, lyophilized formulations and liquid formulations adsorbed into a solid absorption medium. In one embodiment, the oral dosage form is a liquid-filled capsule, for example, for use in A hard gelatin capsule filled with a crystalline form of a compound of Formula I in a combination of propylene glycol and propylene glycol (e.g., in a ratio of 2:1). In one embodiment, the oral dosage form is a liquid-filled capsule, for example, and propylene glycol in a combination (e.g., a ratio of 2:1) and filled with hard gelatin capsules and filled with enteric-coated capsules (e.g., HPMC Enteric-coated capsules( In one embodiment, the oral dosage form is a suspension, for example, a crystalline form of a compound of Formula I suspended in a combination of, for example, OraBlend SF and propylene glycol in a ratio of 2:1. In one embodiment, the oral dosage form is a dry-filled enteric capsule, for example, a dry-filled HPMC Enteric-coated capsules( Lonza). In one embodiment, the oral dosage form is a tablet. In a further embodiment, the oral dosage form is a film-coated tablet.

[0373] In one embodiment, the pharmaceutical composition provided herein contains a diluent selected from polyethylene glycol (molecular weight over 300), microcrystalline cellulose, mannitol, starch, dicalcium phosphate, calcium carbonate, sodium carbonate, lactose or a combination thereof. In one embodiment, the pharmaceutical composition provided herein contains a diluent selected from PEG300, polyethylene glycol (PEG4000)), microcrystalline cellulose, mannitol, lactose or a combination thereof. In a further embodiment, the diluent is selected from PEG300, polyethylene glycol (PEG4000), microcrystalline cellulose or lactose.

[0374] In one embodiment, the pharmaceutical composition provided herein contains a binder selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose or polyvinyl pyrrolidone. In a further embodiment, the binder is hydroxypropyl cellulose. In one embodiment, the binder is used for wet granulation (high shear, twin screw or fluidized bed granulation).

[0375] In one embodiment, the pharmaceutical composition provided herein contains a disintegrant selected from cross-linked sodium carboxymethylcellulose, cross-linked polyvidone or sodium starch glycolate. In a further embodiment, the disintegrant is cross-linked sodium carboxymethylcellulose. In one embodiment, the pharmaceutical composition of the present invention contains 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 composition of the present invention contains a lubricant selected from magnesium stearate or sodium stearyl fumarate or both. In one embodiment, the pharmaceutical composition of the present invention contains a solubilizer selected from propylene glycol, polysorbate 80, sorbitol, polyoxyethylene castor oil (cremophor EL), castor oil, corn oil, cottonseed oil, safflower oil, sesame oil, soybean oil, peppermint oil, olive oil, miglyol, glycerol or a combination thereof. In a further embodiment, the solubilizer is propylene glycol.

[0376] In one embodiment, the oral dosage form further comprises a penetration enhancer. As used herein, a "penetration enhancer" refers to a pharmaceutically acceptable excipient that improves the absorption of an active agent (e.g., a crystalline form of a compound of Formula I) from the gastrointestinal tract. A penetration enhancer promotes the absorption of cell-impermeable compounds by promoting the size-restricted passage of tight junctions between intestinal epithelial cells. (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 decanoate, Salcaprozate sodium (SNAC) and combinations thereof. Also known as caprylocaproyl macrogol-8glyceride, manufactured by Gattefosse, Lyon Saint-Priest, France. In one embodiment, the oral dosage form comprises In one embodiment, the oral dosage form comprises sodium decanoate. When present in the oral dosage form, use a maximum amount of 1800mg, a maximum amount of about 720mg, a maximum amount of about 540mg, a maximum amount of about 360mg, an amount of about 90mg to about 360mg, an amount of about 180 to about 360mg, or a penetration enhancer of 90mg, 180mg or 360mg. In one embodiment provided herein, the oral dosage form comprises a maximum amount of about 360mg, an amount of about 90mg to about 360mg, an amount of about 180 to about 360mg, or a penetration enhancer of 90mg, 180mg or 360mg. In one embodiment, the oral dosage form provided herein comprises a penetration enhancer of 90mg or 180mg or 360mg. In one embodiment, the oral dosage form of the present invention comprises a penetration enhancer of 180mg or 360mg.

[0377] When present in an oral dosage form, sodium decanoate is used in an amount of up to about 360 mg, an amount of about 90 mg to about 360 mg, an amount of about 180 to about 360 mg, or an amount of 90 mg, 180 mg, or 360 mg. In one embodiment, the oral dosage forms provided herein contain an amount of 90 mg, 180 mg, or 360 mg of the penetration enhancer sodium decanoate. In one embodiment, 180 mg of sodium decanoate is used in the oral dosage form. In one embodiment, 360 mg of sodium decanoate is used in the oral dosage form.

[0378] In one embodiment, dry-filled capsules or tablets can be used to administer a crystalline form of a compound of formula I to a subject in need. In the pharmaceutical compositions provided herein, a penetration enhancer may be included. In one embodiment, a penetration enhancer, such as an amount of sodium decanoate, may be in the range of about 1wt% to about 75wt%. As used herein, wt% refers to the weight percentage of an ingredient relative to the gross weight of a pharmaceutical composition. In another embodiment, the amount of the penetration enhancer in the pharmaceutical composition is about 18wt% to about 65wt%. In a further embodiment, the amount of the penetration enhancer in the pharmaceutical composition is about 22wt% to about 36wt%. For tablets, a penetration enhancer, such as an amount of sodium decanoate, may be about 22wt% to about 65wt%. Oral dosage forms may be manufactured by standard methods, including wet and dry granulation.

[0379] Table 27: Examples of Formulations Using Decanoate 3

[0380]

[0381] In one embodiment, provided herein is a pharmaceutical composition comprising a crystalline form of a compound of formula I:

[0382]

[0383] Among them A - In another embodiment, the pharmaceutical composition further comprises a diluent. In a further embodiment, the composition comprises two or more diluents, wherein two or more diluents comprise a combination of microcrystalline cellulose, polyethylene glycol (PEG 4000) and lactose. In a further embodiment, the composition comprises two or more diluents, wherein two or more diluents comprise a combination of microcrystalline cellulose (Avicel PH 102), polyethylene glycol (PEG 4000) and lactose.

[0384] In one embodiment of the present invention, the pharmaceutical composition comprises about 1% to about 8% of the crystalline form of the compound of formula I relative to the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 1% to about 6% by weight of the crystalline form of the compound of formula I relative to 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 relative to the total weight of the pharmaceutical composition.

[0385] In another embodiment of the present invention, the pharmaceutical composition comprises about 22.5% to about 50% of a penetration enhancer relative to the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises about 33% by weight of a penetration enhancer relative to the total weight of the pharmaceutical composition.

[0386] In one embodiment of the invention, the pharmaceutical composition comprises at least one diluent. In one embodiment of the invention, the pharmaceutical composition comprises two diluents. In one embodiment, the diluent or the combination of diluents accounts for about 10% to about 70%, about 20% to about 60%, about 30% to about 50% or about 40% to about 50% weight relative to the gross weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises about 15% to about 72% weight of diluent relative to the gross weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 40% to about 72% weight of diluent relative to the gross weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 58% weight of diluent relative to the gross weight of the pharmaceutical composition.

[0387] In one embodiment of the invention, the pharmaceutical composition comprises a disintegrant. In one embodiment, the pharmaceutical composition comprises about 0% to about 3% by weight of a disintegrant relative to the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises about 3% by weight of a disintegrant relative to the total weight of the pharmaceutical composition.

[0388] In one embodiment of the invention, the pharmaceutical composition comprises a glidant. In one embodiment, the pharmaceutical composition comprises about 0% to about 1% by weight of a glidant relative to the total weight of the pharmaceutical composition. In another embodiment, the pharmaceutical composition comprises about 1% by weight of a glidant relative to the total weight of the pharmaceutical composition.

[0389] In one embodiment of the invention, the pharmaceutical composition comprises a lubricant. In one embodiment, the pharmaceutical composition comprises about 1% to about 1.5% by weight of a lubricant relative to the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises about 1% by weight of a lubricant relative to the total weight of the pharmaceutical composition.

[0390] In one embodiment of the present invention, the pharmaceutical composition comprises: a) about 1% to about 8% by weight of a crystalline form of a compound of formula I, relative to the total weight of the pharmaceutical composition; b) about 1% to about 80% by weight of a penetration enhancer, relative to the total weight of the pharmaceutical composition; c) at least one diluent; d) an optional glidant and / or lubricant. In one embodiment, about 18% to about 74% by weight of a penetration enhancer, relative to the total weight of the pharmaceutical composition, is present in the pharmaceutical composition. In another embodiment of the present invention, the pharmaceutical composition comprises: a) about 1% to about 7% by weight of a crystalline form of a compound of formula I, relative to the total weight of the pharmaceutical composition; b) about 22% to about 67% by weight of a compound selected from sodium decanoate or c) at least one diluent or solubilizer selected from PEG4000, microcrystalline cellulose, propylene glycol and lactose; d) an optional glidant; and e) an optional lubricant. In a further embodiment, the pharmaceutical composition further comprises about 22% to about 36% by weight of a compound selected from sodium caprate or penetration enhancer.

[0391] In one embodiment of the present invention, provided herein is a pharmaceutical composition comprising: a) about 1% to about 8% by weight of a crystalline form of a compound of formula I, relative to the total weight of the pharmaceutical composition; b) about 22.5% to about 80% by weight of a permeation enhancer, relative to the total weight of the pharmaceutical composition, wherein the permeation enhancer is sodium caprate; c) two diluents selected from microcrystalline cellulose and lactose, wherein the combination of the diluents accounts for about 15% to about 72% by weight relative to the total weight of the pharmaceutical composition; d) an optional disintegrant, wherein the pharmaceutical composition comprises about 0% to about 3% by weight of the disintegrant, relative to the total weight of the pharmaceutical composition; e) an optional glidant, wherein the pharmaceutical composition comprises about 0% to about 1% by weight of a glidant, relative to the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; and f) about 1% to about 1.5% by weight of a lubricant, relative to the total weight of the pharmaceutical composition, wherein the lubricant is magnesium stearate.

[0392] 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 a compound of formula I relative to the total weight of the pharmaceutical composition; b) about 22.5% to about 50% by weight of a permeation enhancer relative to the total weight of the pharmaceutical composition, wherein the permeation enhancer is sodium caprate; c) two diluents selected from microcrystalline cellulose and lactose, wherein the combination of the diluents is about 40% to about 72% by weight relative to the total weight of the pharmaceutical composition; d) about 3% by weight of a disintegrant relative to the total weight of the pharmaceutical composition; e) about 1% by weight of a glidant relative to the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; and f) about 1% by weight of a lubricant relative to the total weight of the pharmaceutical composition, wherein the lubricant is magnesium stearate.

[0393] In one embodiment of the present invention, provided herein is a pharmaceutical composition comprising: a) about 4% by weight of a crystalline form of a compound of formula I relative to the total weight of the pharmaceutical composition; b) about 33% by weight of a permeation enhancer relative to the total weight of the pharmaceutical composition, wherein the permeation enhancer is sodium caprate; c) two diluents selected from microcrystalline cellulose and lactose, wherein the combination of the diluents is about 58% by weight relative to the total weight of the pharmaceutical composition; d) about 3% by weight of a disintegrant relative to the total weight of the pharmaceutical composition; e) about 1% by weight of a glidant relative to the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; and f) about 1% by weight of a lubricant relative to the total weight of the pharmaceutical composition, wherein the lubricant is magnesium stearate.

[0394] In one embodiment of the present invention, the pharmaceutical composition comprises: a) about 2% to about 6% by weight of a crystalline form of a compound of formula I, relative to the total weight of the pharmaceutical composition; b) about 18% to about 74% by weight of a permeation enhancer, relative to the total weight of the pharmaceutical composition, wherein the permeation enhancer is sodium caprate; c) at least one diluent selected from PEG4000, microcrystalline cellulose or lactose; d) about 0% to about 3% by weight of a glidant, relative to the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; e) about 0% to about 2% by weight of a lubricant, relative to the total weight of the pharmaceutical composition, wherein the lubricant is magnesium stearate; and f) optionally at least one disintegrant.

[0395] In one embodiment of the above, the diluent is about 10% to about 70%, about 20% to about 60%, about 30% to about 50%, or about 40% to about 50% by weight relative to the total weight of the pharmaceutical composition.

[0396] In another embodiment of the present invention, provided herein is a pharmaceutical composition comprising: a) about 4% by weight of a crystalline form of a compound of formula I relative to the total weight of the pharmaceutical composition; b) about 33% by weight of a penetration enhancer relative to the total weight of the pharmaceutical composition, wherein the penetration enhancer is sodium caprate; c) about 58% by weight of one or more diluents selected from microcrystalline cellulose or lactose relative to the total weight of the pharmaceutical composition; d) about 1% by weight of a glidant relative to the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; e) about 1% by weight of a lubricant relative to the total weight of the pharmaceutical composition, wherein the lubricant is magnesium stearate; and f) about 3% by weight of at least one disintegrant relative to the total weight of the pharmaceutical composition.

[0397] In one embodiment, a pharmaceutical composition is provided herein, 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, polyethylene glycol (PEG 4000) and lactose.

[0398] In one embodiment of the present invention, the pharmaceutical composition comprises: a) about 1% to about 8% by weight of decanoate 3 relative to the total weight of the pharmaceutical composition; b) about 1% to about 75% by weight of a penetration enhancer relative to the total weight of the pharmaceutical composition; c) at least one diluent; d) an optional glidant and / or lubricant. In one embodiment, about 18% to about 74% by weight of the penetration enhancer relative to the total weight of the pharmaceutical composition is present in the pharmaceutical composition. In another embodiment of the present invention, the pharmaceutical composition comprises: a) about 1% to about 8% by weight of decanoate 3 relative to the total weight of the pharmaceutical composition; b) about 22% to about 67% by weight of a diluent selected from sodium decanoate or c) at least one diluent or solubilizer selected from PEG4000, microcrystalline cellulose, propylene glycol and lactose; d) an optional glidant; and e) an optional lubricant.

[0399] In one embodiment of the above, the diluent or solubilizer is 10% to about 70%, about 20% to about 60%, about 30% to about 60% or about 40% to about 60% by weight relative to the total weight of the pharmaceutical composition.

[0400] In one embodiment of the present invention, the pharmaceutical composition comprises: a) about 2% to about 6% by weight of decanoate 3 relative to the total weight of the pharmaceutical composition; b) about 18% to about 74% by weight of a permeation enhancer relative to the total weight of the pharmaceutical composition, wherein the permeation enhancer is sodium decanoate; c) at least one diluent selected from PEG4000, microcrystalline cellulose or lactose; d) 0% to about 3% by weight of a glidant relative to the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; e) 0% to about 2% by weight of a lubricant relative to the total weight of the pharmaceutical composition, wherein the lubricant is magnesium stearate; and f) optionally at least one disintegrant.

[0401] In one embodiment of the above, the diluent or solubilizer is 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 total weight of the pharmaceutical composition.

[0402] In another embodiment of the present invention, provided herein is a pharmaceutical composition comprising: a) about 4% by weight of decanoate 3 relative to the total weight of the pharmaceutical composition; b) about 33% by weight of a penetration enhancer relative to the total weight of the pharmaceutical composition, wherein the penetration enhancer is sodium decanoate; c) about 58% by weight of one or more diluents selected from PEG4000, microcrystalline cellulose or lactose relative to the total weight of the pharmaceutical composition; d) about 1% by weight of a glidant relative to the total weight of the pharmaceutical composition, wherein the glidant is silicon dioxide; e) about 1% by weight of a lubricant relative to the total weight of the pharmaceutical composition, wherein the lubricant is magnesium stearate; and f) about 3% by weight of at least one disintegrant relative to the total weight of the pharmaceutical composition.

[0403] The present disclosure is further illustrated by the following examples and syntheses, but should not be construed as limiting the scope or spirit of the present disclosure. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to produce essentially the same or similar results.

[0404] Example

[0405] Example of Preparation of Crystalline Form of Compound of Formula I

[0406] Synthesis of compounds of formula I

[0407] The compounds of formula I and methods for preparing the same are described in PCT International Patent Application Publication No. WO2019 / 246349, which is incorporated herein by reference in its entirety. As demonstrated in Example 25 of International Patent Application Publication No. WO2019 / 246349, the K of compound A i Plus is 0.01127nm, K i The Ultra is 0.00463 nm as shown in the PCSK9 Alexa FRET Ultra analysis.

[0408] Example 1A: Preparation of Lyophilized Acetate 1 (Amorphous Acetate)

[0409] Macroporous anion exchange resin AGMP-1M (6g, 100-200 mesh, chloride form) is loaded into a 60mL funnel. The filled resin is washed 5 times with a mixture of 9mL of acetonitrile (MeCN) / water (1:1 ratio). The resin is washed with 200mL of 1M sodium hydroxide (NaOH), and then washed with 50mL of 1M acetic acid (AcOH) aqueous solution. The resin is transferred to a 100mL round-bottomed flask containing a solution of compound A (0.3g) in a 1:1 mixture of 6mL of acetonitrile and water. 18mL of MeCN / water (1:1) is added again. The mixture is aged at room temperature for 30 minutes and the resulting mixture is transferred to a 60mL funnel. The filtrate is collected in a 20mL vial, and the resin is washed three times with 10mL of MeCN / water (1 / 1), and the filtrate is collected in a 20mL vial. Fractions containing acetate 1 were combined and concentrated to remove MeCN, and the desired amorphous acetate 1 (0.304 g) was isolated by lyophilization of the solution.

[0410] Example 1B: Alternative Preparation of Acetate Salt 1

[0411] 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 washing fractions were not clear, and the resin was continued to be washed by slurrying and applying vacuum until the eluent was clear). The resin was transferred to an empty solid-loaded column of Redi SepRf (Teledyne ISCO) by gravity elution using 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 into a column. The resulting compound acetate 1 was eluted with water (25 mL). Acetate 1 (0.29 g) was isolated by freeze-drying the solution.

[0412] Example 2: Preparation of lyophilized caprate 1 (amorphous caprate)

[0413] The macroporous anion exchange resin AG MP-1M (6g, 100-200 mesh, chloride form) was loaded into a 60mL funnel. The filled resin was washed five times with a mixture of 9mL of acetonitrile and water (1:1). The resin was washed with 200mL of 1M NaOH and then washed twice with 10mL of water. The resin was transferred to a glass column and washed three times with 10mL of water. The resin was then washed twice with 10mL of ethanol (EtOH), then washed twice with 9mL of 1M capric acid in EtOH solution, and then washed three times with 9mL of EtOH. Compound A (0.3g) was dissolved in 6mL of MeCN / water (1:1) and loaded into a resin-filled column. The filtrate was collected in a 20mL vial. The column was washed three times with 15mL of MeCN and water (1:1) solution, and the filtrate was collected in a 20mL vial. Fractions containing decanoate 1 were combined and concentrated to remove MeCN and then the desired amorphous decanoate 1 (0.29 g) was isolated by lyophilization.

[0414] Example 3: Preparation of Acetate 2

[0415] Acetate 1 (25.5 mg) was added to a vial, and 2-Me-THF (250 uL) was added. The slurry was aged at room temperature. n-Butanol (150 uL) was added, and the mixture was aged until it became uniform. The uniform solution was aged at room temperature for 4 days to obtain a white slurry. The microscope image of the slurry showed that the slurry had needle-shaped crystals (acetate 2).

[0416] Example 4: Preparation of Acetate 3

[0417] In a round bottom flask, acetate 1 (37 g) was dissolved in 3 volumes of 1-propanol (111 ml). The solution was aged at 25°C for 20 minutes. 2-Me-THF (46.7 mL) was added. Acetate 2 seeds were added as a slurry and the mixture was aged for 40 minutes. The remaining seed slurry was added. 2-Me-THF (174 ml) was added at 25°C over 10 hours. After the addition of 2-Me-THF, the mixture was aged for 4 hours to give acetate 3.

[0418] Example 5: Preparation of Acetate 4

[0419] The mixture of Example 4 (acetate 3) was vacuum filtered, and the wet cake was washed with a mixture of n-propanol-2-Me-THF (1:4.3, w / w), followed by a second wash with 2-Me-THF. The solid was dried at ambient temperature with nitrogen (N2) for 4 days to afford acetate 4.

[0420] Example 6: Alternative Preparation of Acetate Salt 1

[0421] Acetate 4 (1.755 g) was added to a vial. Wet MeTHF (2 wt % water in 2-methyltetrahydrofuran (2-MeTHF, 19.99 g)) was added and the resulting slurry was aged at room temperature. The slurry was filtered and the wet cake was dried under vacuum with air purge for 1 hour. Acetate 1 (1.75 g) was obtained as a white solid.

[0422] Example 7: Preparation of Acetate 5

[0423] Acetate 1 (4.787 g) was dissolved in 14.4 mL of nPrOH. While stirring, 2-MeTHF (6.2 mL) was added over 5 minutes. The Karl Fischer (KF) value of the resulting solution was 7628 ppm. 2 mL of 2-MeTHF was also added. Seed crystals of acetate 2 were added as a slurry. The resulting slurry was aged at room temperature for 15 minutes. 2-MeTHF (20.7 mL) was slowly added over 5 hours at room temperature. After the addition was complete, the slurry was aged for another 22 hours. The slurry was filtered and the wet cake was washed twice with 5 mL of 2-MeTHF to obtain acetate 5.

[0424] Example 8: Preparation of Acetate 6

[0425] The wet cake from Example 7 (acetate 5) was dried under vacuum with N2 purge to obtain a white solid, acetate 6.

[0426] Example 9: Preparation of Decanoate 4

[0427] In a glass container, decanoate 1 (40 g) was dissolved in 3 volumes of 1-propanol (120 ml). The solution was aged at 20° C. for 20 minutes. MTBE (14.4 ml) was added to the solution. The mixture was heated to 28-28.5° C. to achieve dissolution. The solution was cooled to 25° C. and the resulting decanoate 4 seeds were added in slurry form. The mixture was aged for 20 minutes, and then MTBE solvent (225.6 ml) was added over 10 hours. The suspension was aged at 25° C. for 8.5 hours to obtain decanoate 4.

[0428] Example 10: Preparation of Decanoate 5

[0429] The suspension of Example 10 (decanoate 4) was filtered and washed with MTBE-20% 1-propanol. The solid was dried under N2 for a long time (about 118 hours) to remove 1-propanol and MTBE to give the decanoate 5.

[0430] Example 11: Preparation of Decanoate 2

[0431] To a vial was added the decanoate salt 5 (1.838 g) followed by a ternary solvent mixture containing methyl tert-butyl ether (MTBE) with 38.3 wt% n-propanol and 0.99 wt% water. The mixture was aged for 3 hours to provide the decanoate salt 2.

[0432] Example 12A: Preparation of Decanoate 3

[0433] The mixture of Example 11 (Decanate 2) was filtered by centrifugation using a centrifugal filter. The filter cake was air-dried at ambient conditions for 2 hours to obtain the Decanoate 3.

[0434] Example 12B: Alternative preparation of decanoate 3

[0435] Compound A (chloride, 700 g) was dissolved in a 4 / 1 acetonitrile-water mixture (8.4 L) at 20° C. and the solution was heated to 35° C. The solution was mixed with the addition of 3.0 M aqueous KHCO3 (7.0 L; the KHCO3 solution was prepared and maintained at 35° C. to prevent precipitation), stirred for 10 minutes, and the layers were separated while maintaining the temperature at 35° C. The organic phase was mixed with a 4 / 1 mixture of acetonitrile-water (0.7 L) and a 3.0 M aqueous KHCO3 solution (7.0 L), stirred for 10 minutes, and the layers were separated while maintaining the temperature at 35° C. The organic phase was mixed again with a 4 / 1 acetonitrile-water mixture (0.7 L) and a 3.0 M aqueous KHCO3 solution (7.0 L), stirred for 10 minutes, and the layers were separated while maintaining the temperature 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 rinsed with 1-propanol (1.4L). Decanoic acid (93g) was added to the combined filtrate, and the mixture was stirred at room temperature for 15 minutes to achieve dissolution. The acetonitrile solvent was replaced with 1-propanol by continuous distillation under vacuum. 1-propanol was added to the concentrated residue until the total volume of 1-propanol reached 2.0L. Water (36mL) was added to bring the content of water relative to 1-propanol to 2.3wt%. The mixture was stirred at room temperature and MTBE (0.984L) (solution #1) was added. MTBE (2.95L) (solution #2) was loaded into another flask.

[0436] In a separate container, a seed bed was prepared by adding 25 g of Decanoate 3 seeds followed by 0.6 L of a 2 / 1 MTBE / l-PrOH solution containing 0.5 wt% water. The resulting slurry was aged at 22°C for 1 hour to obtain a Decanoate 2 seed slurry.

[0437] Solutions #1 and #2 were added simultaneously to the stirred slurry of Decanoate 2 seeds over 6 hours while maintaining the temperature at 22° C. The resulting slurry was aged at 22° C. overnight to provide a Decanoate 2 slurry.

[0438] The decanoate 2 slurry was filtered under nitrogen atmosphere. The wet cake was washed with 1.4 L of 8 / 2 (m:m) MTBE / 1-PrOH solution containing 0.5 wt% water. The cake was dried under nitrogen flow to remove MTBE and part of the 1-PrOH solvent.

[0439] Wet drying was performed using humidified nitrogen (50% RH) to remove residual 1-PrOH and obtain the decanoate 3 (684 g).

[0440] Example 12C: Alternative preparation of decanoate 3

[0441] To a mixture of MTBE (6.75 mL) and n-propanol (3.37 mL) was added water (54 μl) to ensure that the water content of the solution was at least 0.7 wt%. Decanoate 3 seed crystals (120 mg) were added and the slurry was stirred at 22°C for 1 hour to obtain a seed slurry of decanoate 2.

[0442] In a separate mixture, the decanoate salt 3 (5 g, containing 6.7 wt% water) was dissolved in n-propanol (13.8 mL). MTBE (6.9 mL) was added to the solution to dilute it. Decanoic acid (120 mg) was added to the solution.

[0443] At 22 ° C, the two solutions were added to the stirred seed slurry simultaneously over 20 hours. A solution of MTBE (6.13 mL), n-propanol (3.07 mL) and water (49 μL) was used to flush the addition line into the slurry. The resulting slurry of decanoate 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 a filter funnel to surface dry the batch. The batch was then dried under 250 mm Hg and 50% relative humidity of humid nitrogen to obtain decanoate 3 (4.01 g).

[0444] Example 13: Alternative preparation of decanoate 4

[0445] To a vial was added the decanoate salt 3 (101.9 mg) followed by 1-propanol-MTBE (1:1.1) solvent mixture (1 ml). The mixture was stirred and aged at 5 °C overnight to give the decanoate salt 4.

[0446] Example 14: Preparation of Decanoate 6

[0447] Caprate 1 (0.5 g) was added to a vial. Next, n-propanol (1.35 mL) was added to achieve dissolution. Ethyl acetate (7.2 mL) was added and then cooled to below ambient temperature. An additional 2.7 ml of ethyl acetate was added to the solution. The mixture was aged overnight to obtain caprate 6.

[0448] Example 15: Preparation of Decanoate 7

[0449] The suspension of Example 14 (decanoate 6) was vacuum filtered and the wet cake was washed with a 1-propanol-ethyl acetate mixture (1:10). The filter cake was dried in a vacuum oven at 30°C overnight and purged with dry nitrogen to give the decanoate 7.

[0450] Example 16: Preparation of Decanoate 8

[0451] The filter cake of Example 9 (decanoate 4) was vacuum filtered and the wet cake was washed with a mixture of n-propanol-MTBE (1:4, w / w), followed by a second wash with MTBE (120 ml). The solid was dried at ambient temperature with N2 to give the decanoate 8.

[0452] Example 17: Alternative Preparation of Decanoate 1

[0453] The decanoate salt 8 was pressed at 97% RH for at least 3 days and then dried at 40°C under reduced pressure and purged with nitrogen for 1 hour to give the decanoate salt 1.

[0454] Example 18: Preparation of Decanoate 9

[0455] A mixture of decanoate 3, decanoate 5, and decanoate 7 (0.01:1:1) was suspended in a 1-propanol-MTBE (1:12, v / v) solvent mixture at room temperature for at least one week to obtain decanoate 9.

[0456] Example 19: Alternative preparation of decanoate 3

[0457] The wet cake of Example 18 (decanoate salt 9) was vacuum filtered and dried overnight in a vacuum oven with a dry nitrogen purge to afford the decanoate salt 3.

[0458] Example 20: Preparation of Decanoate 10

[0459] Decanoate 3 was exposed to 5% RH for at least 3 hours to obtain Decanoate 10.

[0460] Example 21: Preparation of Decanoate 11

[0461] The decanoate 7 was exposed to 5% RH for at least 3 hours to obtain the decanoate 11.

[0462] Example 22: Preparation of Decanoate 12

[0463] A mixture of decanoate 3, decanoate 5 and decanoate 7 (0.01:1:1) was suspended in a mixture of 1-propanol-MTBE (1:1, v / v) at 5°C for one week to give decanoate 12.

[0464] Example 23: Preparation of Decanoate 13

[0465] The decanoate salt 3 was exposed to 1-propanol solvent vapor for at least three days to obtain the decanoate salt 13.

[0466] Example 24: Preparation of Decanoate 14

[0467] The decanoate salt 3 was exposed to 1-propanol-MTBE solvent vapor for at least three days to obtain the decanoate salt 14.

[0468] Example 25: Preparation of Compound B (Bicarbonate Salt)

[0469] The macroporous anion exchange resin AGMP-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 washing fractions were not clear, and washing was continued by slurrying and applying vacuum until the eluent was clear). The resin in the filter funnel was eluted with 2.5 bed volumes of 5 wt% NaHCO3 aqueous solution (2.5×265 mL) and slurried to a certain extent, thereby converting to the HCO3 anion form. The resin was transferred to an empty solid-loaded column of RediSep Rf (Teledyne ISCO, diameter: 2.42 inches) and gravity eluted using 100 mL of 5 wt% NaHCO3 in water. By gravity elution, the column was eluted with 7.5 bed volumes of 5 wt% NaHCO3 in water (7.5×265 mL). Excess NaHCO3 was removed by gravity elution with 2×265 mL of water. Compound A (10 g, 6.14 mmol) was dissolved in 100 mL of water. The solution of Compound A was loaded into a small column and rinsed with 10 mL of water. The resulting compound, Compound B (bicarbonate), was eluted with water (260 mL).

[0470] Example 26: Preparation of D-lactate 1

[0471] A solution of D-lactic acid (280mg, 3.07mmol) in water is added to a solution of compound B (3.07mmol) in water. The solution is aged at 0°C for 30 minutes. The solution is then frozen and lyophilized overnight in a dry ice-acetone bath to obtain 5.0g of the lyophilized D-lactate of the compound of formula I. The lyophilized D-lactate (5.0g) of the compound of formula I is dissolved in an ethanol / 2-Me-THF mixture (1:1, 20mL). The solution is transferred to a 250mL three-necked round-bottom flask with an overhead stirrer and N2 inlet. The transfer is completed by rinsing the flask with ethanol: 2-Me-THF (1:1, 10mL) and adding the rinse to a 250mL three-necked round-bottom flask. 2-Me-THF (10mL) is added dropwise by a syringe. Stop adding and inoculate with the slurry of seed crystals. After 1 hour, a suitable slurry is formed. An ethanol / 2-Me-THF mixture (1:3) was added followed by 2-Me-THF (20 mL) via a syringe pump over 2.5 hours. The slurry was aged overnight to provide the D-lactate salt 1.

[0472] Example 27: Preparation of D-lactate 2

[0473] Some of the filtrate was used to filter the slurry of D-lactate 1 (~5 g) to complete the transfer. The filter cake was washed with 2-Me-THF:EtOH (3:1, 7 mL), then washed with 2-Me-THF (10 mL), then washed with heptane (20 mL). The solid was dried in vacuo under a nitrogen atmosphere to give D-lactate 2 (3.9 g).

[0474] Example 28: Preparation of Succinate 1

[0475] A solution of succinic acid (362.9 mg, 3.07 mmol) in water is added to a solution of compound B (167 g; 3.07 mmol) in water and aged at room temperature for 1 hour. The solution is then frozen in a dry ice-acetone bath and lyophilized overnight to provide a freeze-dried succinate (5.05 g) of the compound of formula I. A mixture of succinate (3.50 g, 2.097 mmol) and EtOH (17.5 ml) of the compound of formula I is evaporated to a jelly at 15-25 ° C under a nitrogen stream. Under nitrogen, EtOH (17.5 mL) is added, and the mixture is evaporated to a jelly at 45-55 ° C under a nitrogen stream. The residue is dissolved in 75 ° C EtOH (17.5 mL) to obtain a uniform solution. The mixture is cooled to 25 ° C and seed crystals (1 mg) are added, and then the solid slowly crystallizes out. The mixture was stirred for 16 hours and then cooled to 1-3°C for 2 hours to provide the succinate salt 1.

[0476] Example 29: Preparation of Succinate Salt 2

[0477] A suspension of succinate 1 (-3.5 g) was filtered on a 30 cc polypropylene filter funnel with 0-5°C EtOH (10 mL) to transfer the slurry completely to the filter funnel. The filter cake was dried under a stream of nitrogen for 24 hours to give succinate 2 (2.8 g, 1.678 mmol, 80% yield) as a white crystalline solid.

[0478] Example 30: Preparation of L-tartrate 1

[0479] A solution of L-(+)-tartaric acid (460.9mg, 3.07mmol) in water is added to a solution of compound B (167g, 3.07mmol) in water, and aged at room temperature for 1 hour. The solution is then frozen in a dry ice-acetone bath and lyophilized overnight to provide a freeze-dried L-tartrate (5.15g) of a compound of formula I. The freeze-dried L-tartrate (5.0g) and n-propanol (50mL) of the compound of formula I are loaded into a 100mL EasyMax container, which has a nitrogen atmosphere to control humidity. The mixture is stirred and heated to 55°C to dissolve all solids. The solution is cooled to 50°C and seed crystals are added. The slurries are slowly cooled to 45°C, and then several heating and cooling cycles are performed to crystallize the product. In the last cycle, the slurries are heated to 40°C, and cooled to 20°C in 4 hours to obtain L-tartrate 1.

[0480] Example 31: Preparation of L-tartrate 2

[0481] The L-tartrate salt 1 (~5 g) was filtered and the filter cake was washed with n-propanol. The filter cake was placed in an oven and dried at 40°C and purged with nitrogen overnight to give the L-tartrate salt 2 (2.57 g).

[0482] Example 32: Preparation of Sulfate 1

[0483] A solution of sulfuric acid in water (1M, 1.5mL, 1.5mmol) is added to a solution of compound B (167g; 3.07mmol) in water and aged at room temperature for 1 hour. The solution is then frozen in a dry ice-acetone bath and lyophilized overnight to provide a freeze-dried sulfate (4.88g) of the compound of formula I. The freeze-dried sulfate (2.5g) of the compound of formula I is loaded into a 250mL three-necked round-bottom flask equipped with an overhead stirrer. 1-Propanol (40mL) is added to the round-bottom flask and stirred vigorously to dissolve some solids adhering to the flask wall. Crystals are formed before all solids are dissolved. The mixture is continued to be stirred vigorously, and 10mL of heptane is added by a syringe pump within 1 hour, and then aged for 6 hours to obtain sulfate 1.

[0484] Example 33: Preparation of Sulfate 2

[0485] The suspension of sulfate 1 (~4.9 g) was filtered and the filter cake was washed with a mixture of 10 mL of 1-propanol and 20% heptane. The filter cake was then washed with 20 mL of heptane and then 10 mL of heptane was added. The filter cake was vacuum dried overnight under a nitrogen atmosphere to give sulfate 2 (2.21 g).

[0486] Example 34: Description of powder X-ray diffraction studies

[0487] 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 on a Philips Analytical X'Pert PRO X-ray Diffraction System with a PW3040 / 60 console. A PW3373 / 00 ceramic Cu LEFX tube K-Alpha radiation was used as the source. The samples of Examples 1-33 were characterized by XRPD. XRPD analysis showed that acetate 1 ( Figure 1 ) and decanoate 1( Figure 7 ) is amorphous, acetate 2-6 ( Figure 2-Figure 6 ), decanoate 2-14 ( Figure 8-Figure 20 )、D-Lactate 1-2( Figure 21-22 ), succinate 1-2( Figure 23-Figure 24 ), L-tartrate 1-2( Figure 25-26 ) and sulfate 1-2( Figure 27 to Figure 28 ) is crystalline.

[0488] Example 35: Chemical stability of the crystalline salt relative to Compound A (amorphous chloride salt)

[0489] The crystalline forms disclosed herein provide improved chemical purification advantages. In particular, these crystalline forms avoid the use of SFC chromatography and lyophilization necessary for purifying Compound A (chloride salt). This improved strategy reduces the cost of goods and simplifies the process because the number of operating units involved is reduced, which is crucial for commercial feasibility.

[0490] Compared to the purity of the amorphous chloride compound A, the acetate and decanoate salts of Formula I (including the crystalline forms decanoate 3 and decanoate 7) showed satisfactory purity >99% ( Fig.29A ). Fig.29A The graph demonstrates that acetate and decanoate salts have higher chemical stability than chloride salts. In addition, chloride salts require -20°C storage to minimize chemical degradation, while acetate and decanoate salts are less susceptible to degradation at higher temperatures. Fig.29BThe graphs of 20 and 21 demonstrate that under accelerated stability conditions, the acetate and decanoate crystalline salts have greater chemical stability than the amorphous forms of the decanoate and acetate salts, which is particularly evident at the three month time point. The stability of the crystalline form of the compound of Formula I was characterized by XRPD under relative humidity conditions simulating potential storage conditions.

[0491] Adsorption / desorption cycles showed that acetate 4 is hygroscopic, with a weight increase of approximately 9% at 55% RH (see Fig. 30A XRPD analysis showed that the acetate salt 4 retained minimal crystallinity after two adsorption / desorption cycles at 5–55% RH (see Fig. 30B ). Adsorption / desorption cycles showed that acetate 4 is very hygroscopic, with a weight increase of about 40% at 95% RH (see Fig.31A ). Hysteresis was observed during the desorption step. XRPD analysis showed that the acetate salt 4 lost its crystallinity after 5-95-5% RH adsorption / desorption cycles (see Fig.31B ).

[0492] Adsorption / desorption cycles showed that the decanoate salt 5 was hygroscopic, with a weight increase of approximately 7.5% at 65% RH (see Fig.32A Slight hysteresis was observed during the desorption step in the first and second cycles. XRPD analysis showed that the decanoate salt 5 retained some crystallinity after two adsorption / desorption cycles at 5-65% RH (see Fig.32B ). Adsorption / desorption cycles showed that the decanoate salt 5 is very hygroscopic, with a weight increase of about 26% at 95% RH (see Fig.33A ). XRPD analysis showed that the decanoate salt 5 lost its crystallinity after 5-95-5% RH adsorption / desorption cycles (see Fig.33B ).

[0493] Adsorption / desorption cycles showed that the decanoate salt 3 was hygroscopic, with a weight increase of approximately 4.9% at 85% RH (see Fig.34A ). This is similar to the acetate salt 4 (9%; see Fig. 30A ) and decanoate 5 (7.5%; see Fig.32A ) showed a greater weight gain at 55% RH and 65% RH, respectively. XRPD analysis showed that the decanoate 3 maintained its crystallinity after adsorption / desorption cycles from 5 to 85% RH (see Fig.34B ). This is similar to acetate 4 ( Fig. 30B ) and decanoate 5 (see Fig.32B ) is in contrast to the decrease in crystallinity observed after two adsorption / desorption cycles at 5-55% RH and 5-65% RH, respectively.

[0494] The decanoate salt 3 was dried at 40 °C for 3 h under N2 to remove the residue. Adsorption / desorption cycles showed that the anhydrous decanoate salt 3 was hygroscopic, with a weight increase of about 9.4% at 85% RH (see Fig.35A ). This adsorption / desorption cycle shows that the decanoate salt 3 readily absorbs H2O at about 25-35% RH and does not lose H2O until 15% RH. XRPD analysis shows that the anhydrous decanoate salt 3 retains crystallinity after adsorption / desorption cycles at 5-85% RH (see Fig.35B ).

[0495] The behavior of the decanoate salt 3 shows that this crystalline form is highly stable with respect to relative humidity, which is important for further development, especially for withstanding variable storage conditions. This is in contrast to the observed decrease in crystallinity with increasing relative humidity observed for the acetate salt 4 and the decanoate salt 5.

[0496] Example 36: Solid-state NMR studies

[0497] Decanoate 3, Decanoate 5 and Decanoate 8 batches were characterized based on their respective solid-state carbon-13 nuclear magnetic resonance (NMR) spectroscopy. All carbon-13 spectra were recorded on a Bruker AV400 NMR spectrometer operating at a carrier frequency of 400.14 MHz using a Bruker 4mm H / F / X BB triple resonance CPMAS probe. Spectra were collected at 80 kHz using proton / carbon-13 variable amplitude cross polarization (VACP) with a contact time of 3 minutes. Other experimental parameters used for data acquisition were: proton 90 degree pulses at 100 kHz, SPINAL64 decoupling at 100 kHz, pulse delay of 1.5 s, and signal averaging of 50,000 scans. The magic angle spinning (MAS) rate was set to 13 kHz. Lorentzian line broadening of 30 Hz was applied to the spectra before Fourier transformation. The carbonyl carbon of glycine (176.70 ppm) was used as a secondary reference, and chemical shifts are reported on the TMS scale.

[0498] Fig.36A -C shows the individual carbon-13 CPMAS spectra of decanoate 3, decanoate 5, and decanoate 8, respectively. The three decanoate forms exhibit similar carbon-13 CPMAS spectra, and the deviations of the individual spectra for a given form are small. Nevertheless, by comparing specific spectral regions, each form can be clearly identified based on the carbon-13 CPMAS spectrum. Fig.37 Regions of the spectrum that exhibit unique isotropic chemical shifts are shown, along with the relative peak heights and shapes of each form.

Claims

1. A crystalline form of a compound of formula I: Among them A - It is a pharmaceutically acceptable anion.

2. The crystalline form of claim 1, wherein the crystalline form is selected from the group consisting of 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. 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 2θ degrees at angles (± 0.2°) of 4.92, 6.59, 9.82 and 17.

91.

4. The crystalline form of claims 1-2, wherein the crystalline form is the acetate salt 3, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 4.48, 18.17, 18.79 and 19.

27.

5. The crystalline form of claims 1-2, wherein the crystalline form is acetate salt 4, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 8.36, 17.74, 20.29 and 21.

35.

6. The crystalline form of claims 1-2, wherein the crystalline form is the acetate salt 5, wherein the crystalline form is characterized by having an X-ray powder diffraction pattern having peaks expressed in degrees 2θ at angles (± 0.2°) of 5.02, 6.66, 9.89 and 19.

84.

7. The crystalline form of claims 1-2, wherein the crystalline form is the acetate salt 6, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 7.79, 11.00, 16.24 and 18.

89.

8. The crystalline form of claims 1-2, wherein the crystalline form is Decanoate 2, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 4.85, 7.65, 17.16, 18.20, and 19.

50.

9. The crystalline form of claims 1-2, wherein the crystalline form is decanoate 3, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 7.92, 15.40, 17.33, and 19.

60.

10. The crystalline form of claims 1-2, wherein the crystalline form is decanoate 4, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 4.18, 6.14, 17.51 ​​and 17.

68.

11. The crystalline form of claims 1-2, wherein the crystalline form is decanoate 5, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 7.66, 16.18, 18.26 and 19.

11.

12. The crystalline form of claims 1-2, wherein the crystalline form is 6-decanoate, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 5.33, 6.97, 19.04, and 21.

58.

13. The crystalline form of claims 1-2, wherein the crystalline form is decanoate 7, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 7.73, 17.14, 18.75, and 19.

48.

14. The crystalline form of claims 1-2, wherein the crystalline form is decanoate 8, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 7.45, 17.97, 19.32, and 22.

08.

15. The crystalline form of claims 1-2, wherein the crystalline form is decanoate 9, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 6.73, 11.95, 18.23, and 19.

77.

16. The crystalline form of claims 1-2, wherein the crystalline form is decanoate 10, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of about 3.50, 7.90, 16.21, and 18.

23.

17. The crystalline form of claims 1-2, wherein the crystalline form is decanoate 11, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 3.93, 4.90, and 7.

68.

18. The crystalline form of claims 1-2, wherein the crystalline form is decanoate 12, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 6.80, 15.37, 18.22, and 20.

63.

19. The crystalline form of claims 1-2, wherein the crystalline form is decanoate 13, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having peaks expressed in 2θ degrees at angles (± 0.2°) of 5.02, 6.29, 7.12, and 20.

25.

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

68.

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

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

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

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

27. A crystalline form of a compound of formula I: Among them A - is a pharmaceutically acceptable anion; 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.

28. The crystalline form of the compound of formula I according to claim 27: Among them A - It is decanoate; The crystalline form is formed by a process comprising adding an alcohol to a form of Compound 2.

29. The crystalline form of any one of claims 27-28, wherein the crystalline form is selected from the group consisting of 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. The crystalline form of any one of claims 27-29, wherein the alcohol is selected from: ethanol, propanol or butanol.

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

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

33. The crystalline form of claim 32, wherein the crystalline form is decanoate 3, and the method further comprises filtering the solvent system to form a wet cake, and drying the wet cake.

34. A method of inhibiting PCSK9 activity in a subject in need of such treatment, comprising orally administering to the subject an amount of a crystalline form of a compound of formula I according to claim 1: Among them A - is a pharmaceutically acceptable anion, and wherein the amount is from about 5 mg to about 300 mg of the crystalline form of the compound of Formula I.

35. A pharmaceutical composition comprising a crystalline form of a compound of formula I according to claim 1: Among them A - is a pharmaceutically acceptable anion, and wherein the amount is from about 5 mg to about 300 mg of the crystalline form of the compound of formula I, and Penetration enhancers.

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

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

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