Stable 4-(aminomethyl)-6-(phenylpyrazolyl) phthalazinone composition and preparation method thereof

Abstract

A particulate composition of 2-(4-(4-(aminomethyl)-1-oxo-1, 2-dihydrophthalazin-6-yl)-1-methyl-1h-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile comprising: a crystalline form of said compound comprising: a first chiral crystalline form present in an amount of at least 85 wt%, based on the weight of said crystalline form; and a filler. The present invention relates to a pharmaceutical composition comprising a crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1, 2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile comprising at least 95 wt% of a first chiral crystalline form, a process for preparing said composition, the process comprising: providing a crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1, 2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile comprising at least 95 wt% of a first chiral crystalline form; providing a filler; mixing the crystalline form and the filler in a weight ratio of at least 1: 10; subjecting the mixture to a granulation process selected from fluidized bed granulation, high or low shear granulation and dry granulation to obtain a particulate composition; wherein the particulate composition has an amorphous form of not more than 10 wt% of 2-(4-(4-(aminomethyl)-1-oxo-1, 2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile, and wherein the particulate composition has an amorphous form of not more than 5 wt% of 2-(4-(4-(aminomethyl)-1-oxo-1, 2-dihydrophthalazin-6-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile, and wherein the particulate composition has an amorphous form of not more than 5 wt% of 2-(4-(4-(aminomethyl)-1-oxo-1, 2-dihydrophthalazin-6-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile. The present invention relates to a second chiral form of 4-chloro-6-cyclopropoxy-3-fluorobenzonitrile in the form of 4-(2, 2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzonitrile.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 583,775, filed September 19, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0003] Invention Field

[0004] This invention relates to particulate compositions of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1h-pyrazole-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile, pharmaceutical compositions comprising said particulate compositions, and methods for preparing the same. The particulate compositions can be used to treat and / or prevent diseases and / or conditions involving cell proliferation, such as cancer. In particular, the particulate compositions provide therapeutic benefits as an MTA-co-inhibitor of protein arginine N-methyltransferase 5 (PRMT5). Background of the Invention

[0006] Protein arginine N-methyltransferase (PRMT5) is a type II arginine methyltransferase that catalyzes the transfer of a methyl group from S-adenosyl-L-methionine (SAM) to the ω-nitro group of the L-arginine residue in a protein (ω-monomethylation), and the transfer of a second methyl group to another ω-nitro group to generate symmetric dimethylarginine (sDMA). PRMT5 forms a complex with MEP50 (methylsomal protein 50), which is essential for substrate recognition and orientation, and is also essential for PRMT5-catalyzed histone 2A and histone 4 methyltransferase activities (see, for example, Ho et al., (2013) PLOS ONE 8(8):10.1371 / annotation / e6b5348e-9052-44ab-8f06-90d01dc88fc2).

[0007] Homozygous deletions of p16 / CDKN2a are prevalent in cancers, and these mutations often involve the co-deletion of adjacent genes, including the gene encoding methylthioadenosine phosphatase (MTAP). It is estimated that approximately 15% of all human cancers have homozygous deletions of the MTAP gene (see, for example, Firestone & Schramm (2017) J. Am. Chem Soc. 139(39):13754-13760. doi: 10.1021 / jacs.7b05803. e.g., 20 September 2017).

[0008] Cells lacking MTAP activity exhibit elevated levels of the MTAP substrate methionine (MTA), a potent inhibitor of PRMT5. Inhibition of PRMT5 activity leads to decreased methylation activity and increased sensitivity of cell proliferation to PRMT5 depletion or loss of activity. Therefore, loss of MTAP activity reduces PRMT5 methylation activity, making cells selectively dependent on PRMT5 activity.

[0009] Therefore, MTA-synergistic inhibition of PRMT5 activity in MTAP-deficient cancers could provide therapeutic benefits for a variety of cancers. The compounds of this invention provide this therapeutic benefit as MTA-synergistic inhibitors of PRMT5, negatively regulating the activity of MTA-bound PRMT5 in cells, particularly in MTAP-deficient cells, or for the treatment of various forms of MTAP-related cancers.

[0010] In particular, 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1h-pyrazole-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile is a potent and selective inhibitor of PRMT5 and has been found to possess pharmacological activity. Therefore, particulate compositions of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1h-pyrazole-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile have been found to be suitable for pharmaceutical compositions. Invention Overview

[0012] In one aspect, this disclosure provides a particulate composition of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1h-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile of Compound 1 as shown below and hereinafter.

[0013]

[0014] Therefore, in one aspect, this disclosure provides a particulate composition of compound 1, comprising:

[0015] 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1h-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile in crystalline or solid form, comprising:

[0016] The first chiral crystalline form is present in an amount of at least 85 wt%, based on the weight of the crystalline or solid form;

[0017] An optional secondary chiral form (e.g., crystalline or amorphous) is present in an amount not exceeding 5 wt%, based on the weight of the crystalline or solid form; and

[0018] An optional amorphous form, present in an amount not exceeding 10 wt%, based on the weight of the crystalline or solid form;

[0019] filler; and

[0020] Optional organic acids.

[0021] In some embodiments, the first chiral crystalline form is the crystalline form of the compound of formula (I):

[0022] .

[0023] In some embodiments, the second chiral form is either the crystalline or amorphous form of the compound of formula (II):

[0024] .

[0025] In another aspect, this disclosure provides pharmaceutical compositions comprising the particulate composition as described herein.

[0026] In another aspect, this disclosure provides a method for preparing the particulate composition as described herein. The method includes:

[0027] Provided in crystalline form 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1h-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile, comprising at least 95 wt% of the first chiral crystalline form;

[0028] Provide fillers;

[0029] The crystalline form and the filler are mixed at a weight ratio of at least 1:10;

[0030] The mixture is subjected to a granulation method selected from fluidized bed granulation, high or low shear granulation and dry granulation to obtain a particulate composition;

[0031] The particulate composition contains no more than 10 wt% of an amorphous form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1h-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile; and

[0032] The particulate composition therein has a secondary chiral form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1h-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile, not exceeding 5 wt%. Brief description of the attached diagram

[0034] The accompanying drawings are included to provide a further understanding of the methods of this disclosure, and are incorporated in and form part of this specification. The drawings are not necessarily drawn to scale, and the dimensions of several elements may be distorted for clarity. The drawings illustrate one or more embodiments of this disclosure and, together with this specification, serve to explain the principles and operation of this disclosure.

[0035] Figure 1 This is a graph showing the dissolution % of the drug in the capsule composition of compound 1 as described herein as a function of time.

[0036] Figure 2 This is a flowchart of the dry granulation method as described in this article.

[0037] Figure 3A This is a graph showing the compressibility of the dry granulation composition of Compound 1 as described herein.

[0038] Figure 3B This is a graph showing the compressibility of the dry granulation composition of Compound 1 as described herein.

[0039] Figure 3C This is a graph showing the formability of the dry granulation composition of Compound 1 as described herein.

[0040] Figure 4A This is a graph showing the particle size distribution of the particulate composition of compound 1 as described herein.

[0041] Figure 4B This is a graph showing the particle size distribution of the particulate composition of compound 1 as described herein.

[0042] Figure 4C This is a graph showing the particle size distribution of the particulate composition of compound 1 as described herein.

[0043] Figure 4D This is a graph showing the particle size distribution of the particulate composition of compound 1 as described herein.

[0044] Figure 5A A graph showing the compressibility of the particulate composition of Compound 1 as described herein.

[0045] Figure 5B This is a graph showing the compressibility of the particulate composition of Compound 1 as described herein.

[0046] Figure 5C This is a graph showing the formability of the particulate composition of Compound 1 as described herein.

[0047] Figure 6A A graph showing the compressibility of the final blend of compound 1 as described herein.

[0048] Figure 6B This is a graph showing the compressibility of the final blend of compound 1 as described herein.

[0049] Figure 6C This is a graph showing the formability of the final blend of compound 1 as described herein.

[0050] Figure 7A A graph showing the compressibility of tablets of compound 1 with different tensile strengths.

[0051] Figure 7B A graph showing the compressibility of tablets of compound 1 with different tensile strengths.

[0052] Figure 8A This is a graph showing the compressibility of the acidified composition of Compound 1 as described herein.

[0053] Figure 8B This is a graph showing the compressibility of the acidified composition of Compound 1 as described herein.

[0054] Figure 8C This is a graph showing the formability of the acidified composition of Compound 1 as described herein.

[0055] Figure 9 This is a graph showing the particle size distribution of compound 1 as described herein.

[0056] Figure 10A The figure shows the dissolution curve of the granular composition of compound 1 as a 50 mg coated tablet.

[0057] Figure 10B The figure shows the dissolution curve of the granular composition of compound 1 as a 200 mg coated tablet.

[0058] Figure 11 This is a graph showing the dissolution curves of the particulate composition of compound 1 as a coated tablet.

[0059] Figure 12 This is a graph showing the particle size distribution of compound 1 as described herein.

[0060] Figure 13 This is a graph showing the dissolution curves of the particulate composition of compound 1 as a coated tablet.

[0061] Figure 14This is a graph showing the dissolution curves of the particulate composition of compound 1 as a coated tablet.

[0062] Figure 15A The graph shows the dissolution curves of compound 1 in its crystalline and amorphous forms.

[0063] Figure 15B The graph shows the dissolution curves of compound 1 in its crystalline and amorphous forms.

[0064] Figure 16 This is a diagram showing the expected formation of chiral impurities in tablets of the granular composition described herein.

[0065] Figure 17 The graph shows the amorphous content of compound 1 in powder form when compressed under 1 kN and 6 kN compressive forces.

[0066] Figure 18 The graph shows the chiral growth of particulate compositions of compound 1 with different drug loadings under compression at 2 kN, 6 kN and 16 kN.

[0067] Figure 19 The graph shows the chiral growth of particulate compositions of compound 1 with different fillers under compression at 2 kN, 6 kN and 16 kN.

[0068] Figure 20A This is a diagram showing the chiral growth of granules, capsules, and tablets of compound 1 granular compositions prepared by different methods.

[0069] Figure 20B This is a diagram showing the chiral growth of capsules and tablets of granular compositions of compound 1 prepared by different granulation methods. Invention Details

[0071] This disclosure relates to particulate compositions of Compound 1 and methods for preparing the same. As previously described, Compound 1 is an effective and selective PRMT5 inhibitor and has been found to possess pharmacological activity. However, not all forms of Compound 1 possess the same degree of pharmacological activity. In particular, the first chiral crystalline form of Compound 1, as described herein, is the most effective form, while the second chiral form is 250-fold less effective. The amorphous form of Compound 1 has similar efficacy to the first chiral crystalline form, but tends to rapidly convert to the second chiral form (which may be amorphous or crystalline) compared to the first chiral crystalline form; this conversion leads to a decrease in the efficacy of the amorphous material. Therefore, it is advantageous to provide particulate compositions with low to no amorphous form and chiral impurities. It has been found that the granulation method has a significant effect on the amount of chiral impurities present in the particulate composition. Furthermore, as mentioned above, it has been surprisingly found that the presence of the amorphous form of Compound 1 can lead to the subsequent growth of the second chiral form. Accordingly, it has been found that low-stress granulation methods provide particulate compositions with high chiral purity.

[0072] Therefore, in one embodiment, this disclosure provides a particulate composition of compound 1 comprising a crystalline or solid form of the compound, a filler, and optionally an organic acid. The crystalline or solid form of compound 1 in the particulate composition as described herein includes: a first chiral crystalline form present in an amount of at least 85 wt% based on the weight of said crystalline or solid form; an optional second chiral form present in an amount not exceeding 5 wt% based on the weight of said crystalline or solid form; and an optional amorphous form present in an amount not exceeding 10 wt% based on the weight of said crystalline or solid form.

[0073] As described above, compound 1 can be present in the composition in crystalline or solid form. In some embodiments described herein, compound 1 is in crystalline form as a hydrochloride salt. In some other embodiments described herein, compound 1 is in crystalline form as a free base. These crystalline forms have previously been described in published international applications WO / 2024 / 173207 and WO / 2024 / 173215, the contents of which are incorporated herein by reference in their entirety. In other embodiments, compound 1 is present in solid form. Solid forms of compound 1 include crystalline, amorphous, or combinations thereof.

[0074] Compound 1, in its crystalline or solid form, may be present in the particulate composition in various amounts. In some embodiments described herein, the crystalline form is present in an amount of at least 10 wt%, based on the weight of the particulate composition. For example, in several embodiments, the crystalline form is present in an amount of at least 20 wt%, at least 30 wt%, at least 40 wt%, or at least 50 wt%, based on the weight of the particulate composition. In some embodiments described herein, the crystalline form is present in an amount ranging from 10 to 90 wt%, based on the weight of the particulate composition. For example, in several embodiments described herein, the crystalline form is present in an amount ranging from 10 to 70 wt%, or 10 to 50 wt%, or 30 to 90 wt%, or 30 to 70 wt%, or 30 to 50 wt%, based on the weight of the particulate composition.

[0075] As described above, the particulate composition also includes a filler. The filler may be selected from any suitable pharmaceutical carrier, diluent, excipient, adjuvant, or combination thereof, which facilitates the processing of Compound 1 into a pharmaceutically usable formulation. For example, in several embodiments as described herein, the filler is selected from colloidal silica, croscarmellose sodium, polyvinylpyrrolidone, dibasic calcium phosphate, sodium dodecyl sulfate, hydroxypropyl cellulose (e.g., hydroxypropyl methylcellulose), lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, pregelatinized starch, crospovidone, sodium starch glycolate, sodium stearoyl fumarate, or combinations thereof.

[0076] The filler may be present in the particulate composition in varying amounts. In some embodiments as described herein, the filler is present in an amount of at least 10 wt% based on the weight of the particulate composition. For example, in several embodiments, the filler is present in an amount of at least 20 wt%, at least 30 wt%, at least 40 wt%, or at least 50 wt% based on the weight of the particulate composition. In some embodiments as described herein, the filler is present in a range of 10-90 wt% based on the weight of the particulate composition. For example, in several embodiments as described herein, the filler is present in a range of 10-70 wt%, 10-50 wt%, 30-90 wt%, 30-70 wt%, or 30-50 wt% based on the weight of the particulate composition.

[0077] In some embodiments described herein, the filler comprises microcrystalline cellulose, mannitol, croscarmellose sodium, sodium lauryl sulfate, colloidal silica, and magnesium stearate. In some embodiments described herein, the filler comprises microcrystalline cellulose, and the amount of microcrystalline cellulose present may be at least 20 wt% based on the weight of the particulate composition. For example, in several embodiments described herein, the amount of microcrystalline cellulose present is at least 30 wt%, at least 40 wt%, or at least 50 wt% based on the weight of the particulate composition. In some embodiments described herein, the filler comprises mannitol, and the amount of mannitol present is at least 10 wt% based on the weight of the particulate composition. For example, in several embodiments described herein, the amount of microcrystalline cellulose present is at least 15 wt% or at least 20 wt% based on the weight of the particulate composition. In some embodiments as described herein, the filler comprises croscarmellose sodium, sodium dodecyl sulfate, colloidal silica, and magnesium stearate, wherein the amounts of croscarmellose sodium, sodium dodecyl sulfate, colloidal silica, and magnesium stearate do not exceed 15 wt%, based on the weight of the particulate composition. For example, in several embodiments as described herein, the amounts of croscarmellose sodium, sodium dodecyl sulfate, colloidal silica, and magnesium stearate do not exceed 12 wt%, 10 wt%, or 8 wt%, based on the weight of the particulate composition. Accordingly, in some embodiments, the particulate composition comprises the following components in the amounts described in the table below:

[0078]

[0079] In some other embodiments as described herein, the filler comprises microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate. In some embodiments, the filler comprises microcrystalline cellulose in an amount of at least 5 wt% based on the weight of the particulate composition. For example, in several embodiments as described herein, the microcrystalline cellulose is present in an amount of at least 10 wt%, at least 15 wt%, at least 20 wt%, or at least 25 wt% based on the weight of the particulate composition. In some embodiments, the filler comprises croscarmellose sodium in an amount of at least 4 wt% based on the weight of the particulate composition. For example, in several embodiments as described herein, the microcrystalline cellulose is present in an amount of at least 6 wt% or at least 8 wt% based on the weight of the particulate composition. In some embodiments, the filler comprises hydroxypropyl methylcellulose and magnesium stearate in an amount not exceeding 10 wt% based on the weight of the particulate composition. For example, in several embodiments as described herein, the amounts of hydroxypropyl methylcellulose and magnesium stearate do not exceed 5 wt%, based on the weight of the particulate composition. Accordingly, in some embodiments, the particulate composition comprises the following components in amounts as described in the table below:

[0080]

[0081] In some embodiments as described herein, the filler comprises microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, and magnesium stearate. In some embodiments, the filler comprises microcrystalline cellulose in an amount of at least 5 wt% based on the weight of the particulate composition. For example, in several embodiments as described herein, the microcrystalline cellulose is present in an amount of at least 10 wt%, at least 15 wt%, at least 20 wt%, or at least 25 wt% based on the weight of the particulate composition. In some embodiments, the filler comprises croscarmellose sodium in an amount of at least 4 wt% based on the weight of the particulate composition. For example, in several embodiments as described herein, the microcrystalline cellulose is present in an amount of at least 6 wt% or at least 8 wt% based on the weight of the particulate composition. In some embodiments, the filler comprises polyvinylpyrrolidone and magnesium stearate in an amount not exceeding 10 wt% based on the weight of the particulate composition. For example, in several embodiments as described herein, the amounts of polyvinylpyrrolidone and magnesium stearate do not exceed 5 wt%, based on the weight of the particulate composition. Accordingly, in some embodiments, the particulate composition comprises the following components in amounts as described in the table below:

[0082]

[0083] In some embodiments as described herein, the weight ratio of the crystalline form of compound 1 to the filler is at least 1:10. For example, in several embodiments as described herein, the weight ratio of the crystalline form to the filler is 1:10-10:1, 1:10-5:1, 1:10-2:1, 1:10-1:1, 1:5-10:1, 1:5-5:1, 1:5-2:1, 1:5-1:1, 2:1-10:1, 2:1-5:1, 2:1-2:1, or 2:1-1:1.

[0084] As described above, compound 1 is present in a first chiral crystalline form in an amount of at least 85 wt%, based on the weight of the crystalline form. In some embodiments as described herein, the first chiral crystalline form is a compound of formula (I):

[0085] .

[0086] This first chiral crystalline form exhibits particularly high pharmaceutical activity, especially when compared with other chiral forms of compound 1. Accordingly, the presence of a significant amount of the first chiral crystalline form in the particulate composition is particularly advantageous. Thus, in some embodiments, the first chiral crystalline form is present in an amount of at least 90 wt%, based on the weight of the crystalline form. For example, in several embodiments as described herein, the first chiral crystalline form is present in an amount of at least 92 wt%, at least 94 wt%, or at least 96 wt%, based on the weight of the crystalline form.

[0087] In some embodiments as described herein, the crystalline form of compound 1 may optionally include a second chiral form, present in an amount not exceeding 5 wt% based on the weight of the crystalline form. In some embodiments, the second chiral form is present, and the second chiral form is a compound of formula (II):

[0088] .

[0089] This second chiral form is a transisomer of the first chiral crystalline form, generated by rotation of the C / C bond connecting the N-methylpyrazole and the benzene ring. It has been found that the second chiral form is 250 times less potent than the first chiral crystalline form. Furthermore, it has been found that any amorphous form present in the composition is more readily converted to the second chiral form, resulting in a composition with lower overall potency. Accordingly, it is advantageous to provide compositions having a low amount (or none) of the second chiral form. Thus, in some embodiments, the amount of the second chiral form present does not exceed 3 wt%, based on the weight of the crystalline form. For example, in several embodiments as described herein, the amount of the second chiral form present does not exceed 2 wt% or 1 wt%, based on the weight of the crystalline form. The second chiral form can be present in crystalline, amorphous, or a combination thereof. For example, in some embodiments as described herein, the second chiral form is present in crystalline form. In other embodiments, the second chiral form is present in amorphous form.

[0090] As described above, the crystalline form of compound 1 may optionally include an amorphous form, present in an amount not exceeding 10 wt% based on the weight of the crystalline form. As described above, the amorphous form of compound 1 has similar performance to the first chiral crystalline form, but tends to convert more rapidly to the second chiral form; this conversion results in the amorphous material becoming less effective. Therefore, it is advantageous to provide compositions having a low amount (or no amount) of the amorphous form. For example, in several embodiments as described herein, the amorphous form is present in an amount not exceeding 8 wt%, not exceeding 5 wt%, or not exceeding 3 wt% based on the weight of the crystalline form.

[0091] In some embodiments described herein, the particulate composition comprises an organic acid. It has been found that the inclusion of an organic acid can advantageously improve the in vitro dissolution of the composition in a neutral medium. In some embodiments described herein, the organic acid is selected from citric acid, fumaric acid, DL-tartaric acid, maleic acid, DL-malic acid, or succinic acid. When the organic acid is present in the particulate composition, its presence may be at least 5 wt%, based on the weight of the particulate composition. For example, in several embodiments described herein, the organic acid is present in an amount of at least 10 wt%, at least 12 wt%, or at least 15 wt%, based on the weight of the particulate composition. In several embodiments described herein, the organic acid is present in an amount ranging from 5-30 wt%, 5-25 wt%, 5-20 wt%, 10-30 wt%, 10-25 wt%, or 10-20 wt%, based on the weight of the particulate composition.

[0092] The particulate compositions described herein can be prepared to provide desired porosity and pore size, thereby achieving desired composition dissolution. In some embodiments described herein, the particulate compositions have a porosity in the range of 5-40%. For example, in several embodiments, the particulate compositions have a porosity in the range of 5-35%, 5-30%, 10-40%, 10-35%, or 10-30%. In some embodiments described herein, the particulate compositions have a porosity of 28%. In some other embodiments, the particulate compositions have a porosity of 11%. The porosity ε can be calculated using the following equation:

[0093]

[0094] Where ρ 真实 This is the true density of the material, obtained via a helium hydrometer or calculated from its room-temperature crystal structure. For helium hydrometer measurements, a helium hydrometer (Ultrapyc 1200e or AccuPyc) can be used, with the sample filling approximately 75% of the sample cell volume. After introducing helium gas into the sample chamber to a pressure of ~17 Pa, the system is allowed to stabilize for 300 seconds. Then, the valve is opened to allow helium to diffuse into the expansion chamber, establishing a new pressure. The volume of the solid sample can be calculated from the pressure before and after helium expansion. This process can be repeated until the volume standard deviation (VSD) of the last five runs is less than 0.005% or a total of 100 runs have been completed. The average of the last five values ​​can be taken as the sample volume, which can be used to calculate the true density using the sample weight.

[0095] In several embodiments as described herein, the particulate composition has an average particle size of at least about 250 µm, and typically between about 250 µm and about 1 mm. Suitable average particle sizes are about 250 µm, about 300 µm, about 400 µm, about 500 µm, about 600 µm, about 700 µm, about 800 µm, about 900 µm, and about 1000 µm. Suitable particulate compositions may have a narrow average particle size distribution or a relatively wide average particle size distribution in the range of about 250 µm to about 1 mm. As used herein, “particle size” refers to the maximum size of the particles. Conventional methods known in the art can be used to measure the particle size distribution of the composition.

[0096] Another aspect of this disclosure provides a pharmaceutical composition comprising a particulate composition as described herein. The pharmaceutical composition comprising the particulate composition of compound 1 can be prepared by a variety of granulation methods.

[0097] In the specific embodiments described herein, the pharmaceutical composition is in a form suitable for oral administration. For oral administration, the pharmaceutical composition may be in the form of lozenges, tablets, or capsules prepared by conventional methods with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium dodecyl sulfate). Tablets may be coated using methods well known in the art, such as sugar coating, film coating, or enteric coating.

[0098] In some embodiments described herein, the pharmaceutical composition is in tablet form. In some other embodiments, the tablet is a coated tablet. When the pharmaceutical composition is in the form of a coated tablet, the granular composition described herein is present as the core composition of the tablet. A coating agent can be applied to the core composition of the tablet to obtain a coated tablet. The coating agent can be selected from a variety of reagents known in the art. For example, the coating agent can be selected from hydroxypropyl methylcellulose, titanium dioxide, polydextrose, talc, maltodextrin, medium-chain triglycerides, polyethylene glycol (PEG), caprylic / capric monoglyceride, caprylic / capric diglyceride, polyvinyl alcohol, carmine, iron oxide, or combinations thereof. In some embodiments described herein, the coating agents are listed in the following table:

[0099]

[0100] In some embodiments as described herein, the coating agents are as listed in the table below:

[0101]

[0102] The coating agent can be applied to the tablet core composition (e.g., the granular composition of Compound 1 as described herein) in varying amounts. For example, in some embodiments described herein, the coating agent is present in the tablet at a level of at least 1 wt%, based on the weight of the tablet. For example, in several embodiments described herein, the coating agent is present in an amount of at least 2 wt%, at least 3 wt%, or at least 5 wt%, based on the weight of the tablet. In several embodiments described herein, the coating agent is present in an amount ranging from 1-50 wt%, 1-45 wt%, 1-40 wt%, 3-50 wt%, 3-45 wt%, or 3-50 wt%, based on the weight of the tablet.

[0103] If desired, the pharmaceutical composition may be provided in a packaging or dispenser device, which may contain one or more unit dosage forms containing the compound. The packaging may, for example, contain metal or plastic foil, such as blister packs. Instructions for use may be included with the packaging or dispenser device.

[0104] Another aspect of this disclosure provides a method for preparing a particulate composition as described herein. The method includes providing a crystalline form of compound 1 comprising at least 95 wt% of a first chiral crystalline form; providing a filler; mixing the crystalline form and the filler at a weight ratio of at least 1:10; subjecting the mixture to a granulation method selected from fluidized bed granulation, high- or low-shear granulation, and dry granulation to obtain a particulate composition; wherein the particulate composition has no more than 10 wt% of an amorphous form of compound 1; and wherein the particulate composition has no more than 5 wt% of a second chiral form of compound 1.

[0105] Conventional methods such as fluidized bed granulation, high- or low-shear granulation, and dry granulation can be used to provide particulate compositions. However, as mentioned above, it may be advantageous to use granulation methods that avoid high stress to prevent the amorphization of Compound 1 and the growth of chiral impurities. Therefore, in some embodiments as described herein, the granulation method is fluidized bed granulation. In some other embodiments, the granulation method is shear granulation. In some other embodiments, the granulation method involves low-shear granulation, such as low-shear granulation using a planetary mixer.

[0106] As described above, it is advantageous for the particulate composition to contain small amounts of chiral impurities. The particulate composition and its preparation method provide a composition that maintains its chiral purity over time. In some embodiments, the crystalline form in the particulate composition comprises a second chiral form, which, after storage at 55°C for 2 weeks, is present in an amount not exceeding 5 wt%, 2 wt%, or 1 wt%, based on the weight of the crystalline form. In some embodiments, the crystalline form in the particulate composition comprises a second chiral form, which, after storage at 40°C and 75% relative humidity for 3 months, is present in an amount not exceeding 5 wt%, 2 wt%, or 1 wt%, based on the weight of the crystalline form. In some embodiments, the crystalline form in the particulate composition comprises an amorphous form, which, after storage at 55°C for 2 weeks, is present in an amount not exceeding 10 wt%, 8 wt%, or 6 wt%, based on the weight of the crystalline form. In some embodiments, the crystalline form in the particulate composition includes an amorphous form, which, after being stored at 40°C and 75% relative humidity for 3 months, comprises no more than 10 wt%, no more than 8 wt%, or no more than 6 wt%, based on the weight of the crystalline form.

[0107] The particulate compositions described herein are typically used in amounts that effectively achieve the desired results, such as in amounts that effectively treat or prevent the specific disease being treated. A therapeutic benefit refers to the eradication or improvement of one or more underlying disorders being treated and / or the eradication or improvement of one or more symptoms associated with the underlying disorder, resulting in the patient reporting improvement in feeling or condition, although the patient may still have the underlying disorder. A therapeutic benefit also typically includes halting or slowing the progression of the disease, regardless of whether improvement is achieved.

[0108] In another aspect, the present invention provides a method for inhibiting PRMT5 activity in cells, the method comprising contacting cells in vitro for which PRMT5 activity is desired to be inhibited with an effective amount of a crystalline form of compound 1 as described herein, or a pharmaceutical composition comprising a crystalline form of compound 1 as described herein. In one embodiment, the cells are MTAP-deficient cells.

[0109] The compositions and methods provided herein are particularly considered for use in inhibiting PRMT5 activity in cells in vivo. In one embodiment, cells for which PRMT5 activity is to be inhibited are contacted in vivo with a therapeutically effective amount of a crystalline form of compound 1 as described herein, or a pharmaceutical composition comprising a crystalline form of compound 1 as described herein. In one embodiment, the cells are MTAP-deficient cells. In one embodiment, negative regulation of PRMT5 activity occurs in the presence of bound MTA.

[0110] These methods aim to inhibit PRMT5 activity to block cell proliferation by negatively regulating PRMT5 activity, particularly in cells lacking MTAP activity. Depending on the specific treatment regimen, cells can be exposed to a single or multiple doses to influence the desired negative regulation of PRMT5. In the presence and absence of MTA, well-known methods, including those described below in Example B, can be used to monitor the degree of PRMT5 inhibition of the enzyme in vitro to assess the effectiveness of the treatment and dosage.

[0111] In another aspect, methods of treating cancer include administering to a patient suffering from cancer a therapeutically effective amount of the crystalline form of compound 1 as described herein, or a pharmaceutical composition comprising the crystalline form of compound 1 as described herein. In one embodiment, the cancer is MTAP-related cancer.

[0112] The compositions and methods provided herein can be used to treat a variety of cancers, including tumors such as prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, and testicular cancer. More specifically, cancers that can be treated with the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma. More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial protocarcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal carcinoma). Adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, viroma); Small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma); Large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Urogenital tract: Kidney (adenocarcinoma, Wilms' tumor, lymphoma, leukemia); Bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma); Prostate (adenocarcinoma, sarcoma); Testis (seminoma, teratoma, embryonal carcinoma). Fetal cancer, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma; Liver: hepatocellular carcinoma, bile duct epithelial carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct: gallbladder cancer, ampullary cancer, bile duct epithelial carcinoma; Bone: osteoblastic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis). Warts), benign chondromas, chondroblastomas, chondromyofibromas, osteoid osteomas, and giant cell tumors; Nervous system: Skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pineal tumors), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal cord neurofibromas, meningiomas, gliomas, sarcomas;Gynecology: Uterus (endometrial cancer), Cervix (cervical cancer, precancerous cervical dysplasia), Ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenoma, unclassified carcinoma), granulosa tunica cell carcinoma, Sertoli-Leydig cell carcinoma, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), Fallopian tube (cancer); Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevus (e.g., nevi), lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal: neuroblastoma. In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0113] In one implementation, the cancer is an MTAP-related cancer selected from hepatocellular carcinoma, breast cancer, skin cancer, bladder cancer, liver cancer, pancreatic cancer, and head and neck cancer.

[0114] The concentration and route of administration to the patient vary depending on the cancer being treated. Particulate compositions of Compound 1 as described herein, or pharmaceutical compositions comprising particulate compositions of Compound 1 as described herein, may also be administered co-administered with other antitumor compounds such as chemotherapeutic agents, or in combination with other treatments such as radiotherapy or surgical intervention, as adjuvant therapy before or after surgery.

[0115] Example

[0116] The following examples illustrate specific embodiments of the compositions and methods of this disclosure. They are for illustrative purposes only and should not be considered as limiting the scope of this disclosure.

[0117] Example 1. Drug in capsule formulation

[0118] Five drug capsule formulations of compound 1 were formed, and their dissolution was tested. The amount of compound 1, whether free base or HCl salt, was corrected for its chiral purity and filled into suitable capsules (size 00-4) with a unit dose strength ranging from 10 mg to 300 mg. Hydroxypropyl methylcellulose was used as the capsule material, but gelatin or κ-carrageenan could also be used. The drugs in the capsule formulations are shown in Table 1.

[0119] Table 1.

[0120]

[0121] Using USP <711> The Type II device was used to assess drug dissolution in capsules over the first 30 minutes in simulated fasting gastric fluid with stirring at 50 rpm, followed by a 90-minute pH change to pH 6.8 to simulate fasting intestinal fluid. Drug dissolution in the capsule formulation was also assessed in simulated fasting intestinal fluid for comparison. These results are as follows: Figure 1 As shown. Figure 1 As shown, when pH changed from 1.2 (FaSSGF) to 6.8 (FaSSIF), both the free base and HCl salt in the capsule formulation of Compound 1 exhibited a significant parachute effect (slower precipitation). Additionally, all tested capsules disintegrated within 6 minutes in DI water at 37°C.

[0122] Example 2. Dry granulation formulation

[0123] Preparation of dry granulation formulations

[0124] Three tablet formulations of the free base of compound 1 were prepared using a dry granulation method, and their physical properties were evaluated. The dry granulation method is as follows: Figure 2 As shown in Table 2, the main difference between these three formulations lies in the drug loading (DL). Dry granulation tablet formulations are shown in Table 2. Two dosages, 50 mg and 200 mg, were prepared for each formulation and are labeled "A" or "B" in the table below, respectively.

[0125] Table 2.

[0126]

[0127] Preparation and characterization of intraparticle blends

[0128] In-particle (IG) blends of formulations 1, 2, and 3 were prepared, and their compressibility, tablet compressibility, and formability were determined. IG blends were prepared by weighing the required amounts of each component and mixing them at 49 rpm using a Turbula mixer (Glen Mills Inc., Clifton, NJ). Mixing was first performed for 10 minutes on all components except magnesium stearate, followed by mixing magnesium stearate with the mixture of all other components for 2 minutes. This was to avoid excessive lubrication by magnesium stearate, which could reduce the formability of the blends. During mixing, the mixing container was maintained at 1 / 3–1 / 2 headspace.

[0129] The compressibility, tablet compressibility, and formability curves are as follows: Figure 3A , 3B As shown in 3C, changes in drug load will only cause minor changes in these properties.

[0130] Preparation and characterization of particles using dry granulation

[0131] Compressive stresses of 50–200 MPa were found to be suitable for preparing strips of formulations 1 (DL 20%) and 3 (DL 50%) with different tensile strengths and porosities of 28% and 11%, respectively. For both formulations, strips with 28% and 11% porosity were subsequently prepared. The strips were manufactured using a heavy-impact technique.

[0132] Strips (16 × 9 mm rectangular) were prepared using a force-controlled cycle at 2% speed using a compression simulator (Styl'One Evolution; MedelPharm, Beynost, France). ~450 mg strips were milled in the pelletizing unit of an Alexanderwerk WP 120 (Germany) roller compressor with sieve sizes of 3.15 mm and 1.25 mm. Alternatively, roller compressors such as the Alexanderwerk WP120 or WP200, or Gereis Mini Pactor, or Macropactor, or Fitzpatrick Chilsonator, or similar devices could be used to fabricate the strips to obtain the desired porosity. The strips were milled using an Alexanderwerk WP120 roller compressor and passed through two sieves to obtain the desired particle size distribution. The particle size distribution (PSD), compressibility, tableting ability, and formability were measured. Particle size distribution was obtained using an acoustic sieve (AdvanTech, New Berlin, WI) equipped with US sieves of sizes 25, 35, 45, 60, 80, 120, 170, and 230 (710, 500, 354, 250, 177, 125, 88, and 63 µm opening). The powder was sieved in a sieving / pulse mode with an amplitude of 4 and a duration of 5 minutes. The residue on the sieve and the portion with excessively small particle size were weighed to determine the particle size distribution. The particle size distribution results are shown below. Figures 4A-4D As shown, the compressibility, compressibility, and formability properties are respectively as follows: Figure 5A , 5B As shown in 5C.

[0133] In addition, the flowability of these particles was evaluated using shear unit testing and Foldex testing. For shear unit testing, flow characteristics were measured using an RST-XS annular shear tester (Dietmar Schulze, Wolfenbüttel, Germany) equipped with an XS-Mr unit (~30 mL) at a pre-shear normal stress of 3 kPa. Powder was overfilled, and the excess powder was gently scraped off with a spatula without compressing the powder to obtain a flat surface flush with the upper edge of the shear unit. The shear strength of the powder was tested at five progressively increasing normal stresses (0.23, 1, 1.5, 2, 2.5, 0.23 kPa) to construct yield trajectories. Mohr circles were plotted to obtain the unconfined yield strength (fc) and principal stress (σn) for each yield trajectory. The powder flowability index was calculated as ffc = σn / fc. For the Fledex test, the minimum orifice diameter through which the powder could fall was determined using the Fledex (Teledyne Hanson Research, Chatsworth, CA). The Fledex consists of a loading funnel, a cylindrical assembly with replaceable stainless steel discs and orifices of different diameters at the center, and an opener / closer covering the orifices. The sample was first loaded into the cylinder through the funnel with the closed closure. After filling the stainless steel cylinder, the powder bed was allowed to settle before the closure was opened. The powder bed was observed from above to determine if any orifices were visible. The test was repeated using stainless steel discs with different opening sizes, and the minimum orifice diameter (dmin) allowing powder to pass through was recorded (n = 1). The intraparticle co-components and particle flowability of Formulations 1 and 3, as determined by the shear unit test and the Fledex test, are shown in Tables 3 and 4, respectively.

[0134] Table 3.

[0135]

[0136] Table 4.

[0137]

[0138] For both formulations, granules prepared from tapes with 28% porosity contained more fine particles than those with 11% porosity, significantly impacting their flowability. Drug loading was identified as a key factor in flowability, and the granulation process improved the flowability of both formulations.

[0139] Preparation and characterization of the final blend

[0140] As described above, final blends were prepared using particles of Formulations 1 and 3 with porosities of 11% and 28%, respectively. The particles were mixed with an extragranular mixture of microcrystalline cellulose, magnesium stearate, colloidal silica, and croscarmellose sodium. These blends were prepared as described for intragranular blends. The flowability, forming properties, and disintegration of these final blends were evaluated. The disintegration time of all final blends did not exceed 5 minutes. Flowability was measured using shear unit tests and Foldex tests as described above. These results are shown in Tables 5 and 6, respectively.

[0141] Table 5.

[0142]

[0143] Table 6.

[0144]

[0145] After mixing with the excipients, all blends exhibited good flowability based on their flowability index. Values ​​between 4 and 10 indicate easy flowability, while values ​​greater than 10 indicate free flowability. Specifically, blends containing particles with 11% porosity showed better flowability than those with 28% porosity, consistent with the varying flowability of the respective particles.

[0146] The final results for the compressibility, tablet compressibility, and formability of the blend are as follows: Figure 6A , 6B As shown in Tables 1 and 6C. Similar to what was observed in IG particles, for both formulations, the final blend using particles with 11% porosity exhibited lower compressibility than particles prepared using 11% porosity. Based on the compressibility, compressibility, and formability of the final blend, the porosity and tensile strength of tablets under different compression forces are readily apparent. Therefore, tablets with different tensile strengths were selected for further characterization. Tablets with tensile strengths of 1.75, 2.0, and 2.25 MPa were prepared from formulations 1 and 3 at two different compressive stresses (35 MPa and 210 MPa) for further analysis. These results are shown in Tables 7 and 6C. Figure 7A and 7B As shown in the image.

[0147] Table 7.

[0148]

[0149] The tablet friability and disintegration time of these tablets indicated that all tablets exhibited <1.0% friability, and all tablets disintegrated within 5 minutes in DI water at 37°C. The tablet friability characteristics of each formulation were determined using an accelerated method, namely, tablet weight loss as a function of compressive force. A batch of tablets prepared under different compressive forces was individually coded and then loaded into a friability analyzer. Tablets were weighed before and after testing to calculate the percentage weight loss (%friability) of an individual tablet, which was plotted against compressive force. The disintegration time (DT) of the tablets was measured using a USP disintegration tester (Di 200; Pharma Alliance Group, Valencia, CA) (Pharmacopoeia). For each formulation, the DT of three tablets was recorded. Tablets were placed individually into each tube of the disintegration apparatus, which was then immersed in a beaker containing 900 mL of DI water. The temperature of the apparatus was maintained at 37°C.

[0150] Subsequently, drug loading and granulation parameters (roller force, roller speed, grinding speed, etc.) were optimized in subsequent formulations to prepare particles with the desired flowability and compressibility. The optimized formulation had no undesirable flowability or compressibility parameters.

[0151] Example 3. Acidifying agent

[0152] Preparation and characterization of acidifying agents

[0153] To improve in vitro dissolution in neutral media, 15% of the free base form of compound 1 in formulation 3 was replaced with an organic acid. Citric acid, DL-malic acid, and succinic acid were selected to cover the full range of compressibility for organic acids. These formulations were prepared using a dry granulation method as described above, and their physical properties were evaluated. These acidified formulations are shown in Table 8.

[0154] Table 8.

[0155]

[0156] The compressibility, tablet compressibility, and formability of formulations 4, 5, and 6 are as follows: Figure 8A , 8B As shown in 8C.

[0157] Example 4. Dry granulation formulation with coating

[0158] Preparation of coated dry granulation formulations

[0159] Two tablet formulations of the free base of compound 1 were prepared using a dry granulation method with a coating agent, and their physical properties were evaluated. The coated dry-granulated tablet formulations are shown in Table 9. Two dosages, 50 mg and 200 mg, were prepared for each formulation and are labeled "A" and "B" in the table below.

[0160] Table 9.

[0161]

[0162] Intraparticle blending was performed using a blending / de-blending method. De-blending was performed using a Comil U5 with a 024R (610 µm) sieve and a circular impeller at 1750 rpm to break up agglomerates and produce a homogeneous blend. The pre-blended material was rolled using an Alexanderwerk WP120 roller compressor at 3 MPa, a 2.0 mm gap, and a 5 rpm roller speed. The prepared strips were milled on two different sieves (2.0 mm and 1.0 mm), and the bulk density, tap density, angle of repose, and particle size distribution were characterized by sieve analysis. The Karl Fischer index and Hausner ratio of the pre-blended material and particles were calculated. These results are shown in Table 10. Particle size distribution results are as follows. Figure 9 As shown in the image.

[0163] Table 10.

[0164]

[0165] Based on this result, the flowability of the blend was significantly improved by rolling. Comparing the PSD results between formulation 7 and formulation 8, although the proportion of particles larger than 500 micrometers in formulation 8 was higher than that in formulation 7, there was no significant difference in flowability.

[0166] The final blends were compressed using a Korsch XL100 with two active stations. The tablet hardness, thickness, weight, disintegration, and friability were characterized. Tablet friability and disintegration time showed that all tablets exhibited <0.5% friability, and all tablets disintegrated within 5 minutes in DI water at 37°C. Opadry II 85F18422 white was used as the coating material for 50 mg and 200 mg tablets using a Vector LDCS-Plus coating machine assembled with a 4 L pan. The coated tablets showed an elegant appearance, and no scratches were observed. Dissolution tests were performed using a USP Type II dissolution apparatus in a surfactant-containing buffer medium at pH 6.8 at 37°C and 75 RPM. The dissolution parameters used are shown in Table 11, and the dissolution profiles for formulations 7 and 8 of the 50 mg (A) and 200 mg (B) coated tablets are shown in Table 11. Figure 10A and 10B As shown in the image.

[0167] Table 11.

[0168]

[0169] More than 75% of the drug was released from both formulations within 45 minutes. No difference in dissolution was observed between the 50 and 200 mg dose intensities.

[0170] Example 5. The role of surfactants in formulation

[0171] To evaluate the effect of surfactants on formulations as described herein, sodium lauryl sulfate-free formulations were prepared using dry granulation. Additionally, the granulator screens were reduced from 2.0 mm and 1.0 mm to 1.6 mm and 0.8 mm to reduce particle size. Table 12 describes these formulations of 50 mg and 200 mg tablets, labeled “A” and “B” in the table below, respectively.

[0172] Table 12.

[0173]

[0174] As described above, the dissolution rates of formulations 9A and 9B were evaluated. The dissolution test results are shown in Table 13, and the dissolution profiles are as follows: Figure 11 As shown in the image.

[0175] Table 13.

[0176]

[0177] Over 75% of the drug was released from formulation 9 within 15 minutes, significantly faster than formulations 7 and 8. Dissolution can be optimized by varying the particle size. Effective control of the particle size after rolling minimizes the need for surfactants.

[0178] Example 6. The Role of Particle Size

[0179] By changing the screen size during the rolling process, the particle size of formulation 8 as described above can be reduced. 50 mg and 200 mg coated tablets were prepared. These reduced-size particles of the 50 mg and 200 mg tablets are designated formulations 10A and 10B, respectively. The characteristics of formulation 10 are shown in Table 14.

[0180] Table 14.

[0181]

[0182] The particle size distribution of formulation 10 is as follows: Figure 12 As shown in the figure, and the dissolution rates of formulations 10A and 10B are as follows: Figure 13As shown in the diagram. The slower dissolution observed in formulation 8 was not observed in formulation 10, indicating that optimal dissolution can be achieved by varying the particle size. Significantly, the flowability of the blend remained unchanged despite the reduction in particle size.

[0183] Example 7. Effects of mannitol on pharmaceutical preparations

[0184] In the aforementioned formulations described in the examples, it was observed that the composition adhered to the rollers, and the amount of mannitol (fragile filler) in the formulation was proportional to the degree of adhesion. To test the effect of mannitol on the formulation, mannitol was completely removed from formulation 10. Table 15 describes the formulations of 50 mg and 200 mg tablets, respectively labeled "A" and "B".

[0185] Table 15.

[0186]

[0187] Formulations containing only 5% mannitol were also prepared in three strengths (50 mg, 200 mg, and 300 mg) with two different coating agents. The dissolution and stability risks of these formulations were assessed. Table 16 describes these formulations, and... Figure 14 The dissolution rates of formulations with different coatings were shown.

[0188] Table 16.

[0189]

[0190] Example 8. Amorphous solid dispersion formulation

[0191] The amorphous solid dispersion of compound 1 was evaluated using spray drying technology. The amorphous solid dispersion was prepared by dissolving the drug substance and a stabilizing polymer in a suitable solvent to form a feed solution, which was then spray-dried using an nebulizer to form a powdered amorphous solid dispersion. This technique, which converts the crystalline form into an amorphous form and stabilizes it on the polymer, was evaluated to overcome the problem of slow dissolution in the intestinal medium.

[0192] Examples of suitable solvents include dichloromethane (DCM), chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water, or mixtures thereof. A mixture of dichloromethane and ethanol is preferred. Examples of polymers include hydroxypropyl methyl cellulose phthalate (also known as HPMCP and / or hydroxypropyl methyl cellulose phthalate), cellulose acetate (also known as CAP), hydroxypropyl methyl cellulose acetate succinate (also known as HPMCAS), hydroxypropyl methyl cellulose (HPMC), and polymeric polymethyl methacrylates such as EUDRAGIT RL 100 and Eudragit L100.

[0193] Visual dissolution was performed using various solvents and mixtures thereof. A DCM:methanol ratio of 80:20 was chosen due to its low boiling point and ability to dissolve commonly used spray-dried polymers. The crystalline form of Compound 1 was prepared in a 1:1 ratio with a mixture of different polymers (HPMCAS (LG grade), HPMCAS (HG grade), HPMC E3, and PPVVA64) to form 5% solids in a DCM:methanol solvent mixture. The resulting solution was sprayed using a ProCepT 4M8-Trix pharmaceutical spray dryer. The polymer was dissolved in the solvent system, and then the crystalline form was added.

[0194] The quantitative solubility of crystalline and amorphous solid dispersions in FaSSIF medium at 37°C was determined. It was observed that, in the presence of the polymer, the solubility of the amorphous dispersion ranged from 0.3 to 0.7 mg / mL, higher than the solubility of the crystalline dispersion at 0.19 mg / mL. All samples were found to maintain physical stability after being stored at 40°C for one week.

[0195] Dissolution (SSKD) studies were performed on all samples, including crystalline forms, using a Pion µDISS Profiler. These studies were conducted using two different two-stage dissolution media, with the pH of the media switched to intestinal pH (6.8 after 30 minutes). However, the initial pH differed between the two studies (pH 1.2 simulating fasting conditions and pH 5.0 simulating feeding conditions). Figure 15A and 15B The results of the dissolution study are shown.

[0196] from Figure 15A and 15BIt can be seen that all spray-dried dispersions exhibit the well-established spring and parachute effects typical of amorphous solid dispersions. However, HPMC E3 exhibits the least parachute effect and settles more rapidly at pH 6.5. Significantly, the crystalline form also exhibits supersaturation (solubility higher than its theoretical solubility) in FaSSIF medium when pre-dissolved at pH 1.2 and pH 5.0, similar to that of amorphous solid dispersions. This is extremely rare and is an inherent characteristic of the free base of compound 1.

[0197] Example 9. Chiral impurities in tablets

[0198] background

[0199] In the development of tablet drug products, when the prototype is subjected to accelerated stress, amorphous material is formed during the preparation process, and enantiomeric impurities are subsequently grown during storage.

[0200] Typically, Compound 1 contains a chiral (transisomer) impurity at a current level of 1-2%. The crystalline form and capsule formulation of Compound 1 did not show significant growth of the chiral impurity at room temperature and at 40°C and 75% relative humidity. However, the tablet product showed growth during storage at 25°C / 60% relative humidity and 40°C / 75% relative humidity, but no growth was observed at 2-8°C.

[0201] Further investigation revealed that while the crystalline form of compound 1 exhibited a lower chiral conversion rate, the amorphous form of compound 1 showed a significantly higher chiral conversion rate, particularly at higher temperatures. This suggests that some of the crystalline compound 1 may undergo amorphization during pharmaceutical preparation, which in turn can transform into chiral impurities during high-temperature storage. Figure 16 A proposed hypothesis regarding the generation of chiral impurities observed in tablets is described.

[0202] Solid-state NMR analysis of the final blend and tablet samples revealed an amorphous content of ~3% in the final blend before compression and ~6% in the finished tablet product prepared using dry granulation. The drug product preparation involved dry granulation followed by compression. The 3% amorphous content in the final blend indicates that the drug substance underwent some degree of amorphization during rolling, and that this level increased to 6% during compression.

[0203] Methodology

[0204] Different common blends were prepared using dry granulation, high-shear wet granulation, and fluidized bed granulation with similar formulation compositions to evaluate the effects of processing conditions on amorphization and subsequent chiral growth. Common blends were filled into capsules and tablets to differentiate the effects of granulation and tableting unit operations. Samples were also stored at 55°C for 2 weeks and at 40°C / 75% for 3 months to establish the correlation between amorphous content and chiral growth. These results are shown in Tables 17 and 18.

[0205] Table 17.

[0206]

[0207] Table 18.

[0208]

[0209] Effect of compressive force on amorphous content

[0210] Using the Styl'One™ compression simulator, the effect of compression force was evaluated by compressing 150 mg of crystalline free base with an 8 mm circular planar tool at 1 kN and 6 kN, which is sufficiently correlated with the compressive stress that APIs typically experience during tableting.

[0211] Because tablet pharmaceutical products contain low levels of amorphous matter, the crystallinity percentage cannot be quantified using conventional XRPD technology; instead, a more precise method is used. 19 F SSNMR.

[0212] To assess the amorphous content using SSNMR, one tablet was removed, placed in a clean mortar and pestle, and moderately ground into powder. The powder was then loaded into a 4 mm rotor for analysis. The minimum force required to grind the tablet was used. The sample was not ground. The remaining tablet material was stored in a new 20 mL scintillation vial.

[0213] Acquired using a 400 MHz BrukerAvance NEO spectrometer equipped with a Revolution NMR HF probe and a 4 mm Magic Angle Rotation (MAS) module. 19 Solid-state NMR experiments were conducted using cross-polarization (CP) assays. 19 The F-spectrum is used, and it can distinguish between sharp resonances (-117 to -118 ppm) from crystalline materials and broad resonances (-122 ppm) from amorphous materials. Amorphous content determination utilizes spectral subtraction to determine the percentage of amorphous matter present in the sample. The measured amorphous content is reported in [the relevant section]. Figure 17 middle.

[0214] It was observed that forces as low as 1 kN increased the amorphous content in the formulation, while a compressive force of 6 kN increased the amorphous content to nearly 3.6%.

[0215] Effects of drug loading on amorphous content and subsequent chiral growth

[0216] During stability studies, the growth of chiral impurities in tablet and drug-containing capsule samples was evaluated using a validated high-performance liquid chromatography (HPLC) method. To determine whether impurity growth was caused by stress-induced amorphization, Styl'One was used. TM A compression simulator (Korsch America) was used to compress crystalline compound 1 under different compression forces, and the amorphous content of the samples was evaluated.

[0217] The crystalline form of compound 1 was also co-compressed with different fillers to understand the effects of filler and drug loading. Physical mixtures of the crystalline form and MCC were evaluated in three different ratios, with the free base crystalline form used as a control. The prepared physical mixtures were thoroughly mixed to ensure homogeneity, and Styl'One was used. TM Compression was performed using a compression simulator (Korsch America) at three different compressive forces (2 kN, 6 kN, and 16 kN). The 16 kN force was used as an extreme case to understand the extent of amorphization and subsequent chiral transformation. After compression, the samples were stored at 55 °C for two weeks to establish a correlation between amorphous content and chiral growth. These results are as follows: Figure 18 As shown in the image.

[0218] from Figure 18 As can be seen, when subjected to physical stress, the chiral conversion in the 100% crystalline form is the lowest, while the drug loading is the highest. Even forces as low as 2 kN appear to produce amorphous content, which is evident from the degree of chiral growth. However, it is noteworthy that these values ​​do not increase significantly from 6 to 16 kN. Optimized drug loading and compressive force were identified as key to minimizing chiral conversion, especially at higher temperatures.

[0219] The role of filler type

[0220] The type of filler also affects the chiral conversion of plastic fillers such as microcrystalline cellulose, which is less effective than brittle fillers such as mannitol or lactose.

[0221] To further evaluate the effect of the fillers, Compound 1 was also compressed with different grades of microcrystalline cellulose with different compressibility and particle size to understand the influence of microcrystalline cellulose grade. A 50:50 physical mixture of Compound 1 and different grades of microcrystalline cellulose, along with other fillers, was evaluated. The prepared physical mixtures were thoroughly mixed to ensure homogeneity, and Styl'One was used. TM A compression simulator (Korsch America) was used to compress samples at three different compressive forces (2 kN, 6 kN, and 16 kN). The 16 kN force was used as an extreme case to understand the extent of amorphization and subsequent chiral transformation. After compression, the samples were stored at 55°C for 2 weeks to establish a correlation between amorphous content and chiral growth. Figure 19 These results are shown. It is worth noting that certain grades of microcrystalline cellulose may have a lower impact on amorphous transformation than other materials due to their particle size and compressibility.

[0222] Example 10. High-shear wet granulation and fluidized bed granulation

[0223] To obtain an effective pharmaceutical formulation, crystalline compound 1 must be granulated because the crystalline form has poor flowability. Although dry granulation can be used, amorphization was observed even during the rolling process (however, at a level lower than that discussed in the compression study of Example 9).

[0224] High-shear wet granulation and fluidized bed granulation have been evaluated as alternative granulation technologies to avoid stress-induced amorphization. Wet granulation technologies primarily include high-shear wet granulation (HSWG), low-shear wet granulation using planetary mixers, twin-screw granulation (TSG), fluidized bed granulation (FBG), and fluidized bed melt granulation. Among these methods, HSWG is one of the most widely used technologies for particle product development.

[0225] Methodology

[0226] Tables 19 and 20 list the formulation compositions for high-shear wet granulation and fluidized bed granulation. These compositions are similar to those for dry granulation formulations with a 40% drug loading, except for the addition of a binder, such as poly(vinylpyrrolidone) or HPMC, and the use of water as a wet granulation aid.

[0227] For high-shear wet granulation, granulation was carried out in a 1 L high-shear unit (Vector GMXB Lab Micro Granumest). The mixer blade speed was low (710 rpm) during the premixing (5 min) and water delivery steps (3 min), and higher (1100 rpm) during the high-shear step (2 min). A shredder was run at low speed for the high-shear step. The resulting wet material was then dried in air at 65°C using a fluidized bed dryer until the product moisture content was close to 5%.

[0228] For fluidized bed granulation, granulation was performed in a VFC Lab Mini Flo coating machine (0.8 L). The premix was initially fluidized and heated to 65°C, after which water was gradually atomized using a top spray gun at a spray rate of 2 g / min and an atomization pressure of 5 psi from an 8” distance from the tablet bed. After adding water, the inlet air was increased, and the resulting material was dried until the moisture content of the product was close to 5%.

[0229] Table 19.

[0230]

[0231] Table 20.

[0232]

[0233] Particles obtained from high-shear granulation and fluidized bed granulation were milled using a suitable sieve and then added to an extra-particle component including a lubricant to form a final blend. The final blend was encapsulated in 00 capsules at a unit dose strength of 200 mg and also compressed into tablets at the same unit dose strength. The amorphous content of the capsules and tablets was then assessed using solid-state NMR, and the tablets were stored at 55°C for 2 weeks and at 40°C / 75%RH for 3 months to assess chiral growth. The SSNMR method used was the same as described in Example 9. The results were compared with those of tablets and capsules prepared using dry granulation. These results are shown in Table 21 and... Figure 20A and 20B As shown in the image.

[0234] Table 21.

[0235]

[0236] These results show that all formulations exhibited chiral growth during accelerated storage, albeit at varying levels. Among all techniques evaluated post-granulation, fluidized bed granulation showed the least chiral growth. No change in chiral growth was observed between particles and capsules, indicating that encapsulation had no effect on amorphous content. The combination of high-shear granulation with higher drug loading can be used to prepare capsules and tablets with lower amorphous content. HSWG and fluidized bed granulation are influenced by various formulation and method parameters, which can be optimized to reduce amorphous content. The final blend can be filled into capsules instead of tablets, and the lower amorphous content in capsules reduces the growth of chiral impurities.

[0237] Although the invention has been described in conjunction with specific embodiments thereof, it should be understood that the invention is capable of further modifications, and this application is intended to cover any variations, uses or modifications of the invention that generally follow the principles of the invention and include deviations from this disclosure that are known or customary in the field to which the invention pertains and that may be applied to the basic features described above and within the scope of the appended claims.

Claims

1. 2-(4-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1h-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile, comprising: The crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1h-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile, comprising: The first chiral crystalline form is present in an amount of at least 85 wt%, based on the weight of the crystalline form; The optional second chiral form, present in amounts not exceeding 5 wt%, based on the weight of the crystalline form; and The optional amorphous form, which exists in an amount not exceeding 10 wt%, is based on the weight of the crystalline form; filler; and Optional organic acids.

2. The particulate composition according to claim 1, wherein the crystalline form is a hydrochloride salt.

3. The particulate composition according to claim 1, wherein the crystalline composition is a free alkali.

4. The particulate composition according to any one of claims 1-3, wherein the crystalline form is present in an amount of at least 10 wt% (e.g., at least 20 wt%, at least 30 wt%, at least 40 wt%, or at least 50 wt%), based on the weight of the particulate composition.

5. The particulate composition according to any one of claims 1-4, wherein the crystalline form is present in an amount ranging from 10-90 wt% (e.g., 10-70 wt%, 10-50 wt%, 30-90 wt%, 30-70 wt%, or 30-50 wt%), based on the weight of the particulate composition.

6. The particulate composition according to any one of claims 1-5, wherein the filler is selected from colloidal silica, croscarmellose sodium, polyvinylpyrrolidone, dibasic calcium phosphate, sodium dodecyl sulfate, hydroxypropyl cellulose (e.g., hydroxypropyl methyl cellulose), lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, sodium stearoyl fumarate, or combinations thereof.

7. The particulate composition according to any one of claims 1-6, wherein the filler comprises microcrystalline cellulose, mannitol, croscarmellose sodium, sodium dodecyl sulfate, colloidal silica and magnesium stearate.

8. The particulate composition of claim 7, wherein the amount of microcrystalline cellulose present is at least 20 wt% (e.g., at least 30 wt%, at least 40 wt%, or at least 50 wt%), based on the weight of the particulate composition.

9. The particulate composition according to claim 7 or claim 8, wherein the amount of mannitol present is at least 10 wt% (e.g., at least 15 wt% or at least 20 wt%), based on the weight of the particulate composition.

10. The particulate composition according to any one of claims 7-91, wherein the amounts of cross-linked sodium carboxymethyl cellulose, sodium dodecyl sulfate, colloidal silica and magnesium stearate are not more than 15 wt% (e.g., not more than 12 wt%, not more than 10 wt%, or not more than 8 wt%), based on the weight of the particulate composition.

11. The particulate composition according to any one of claims 1-6, wherein the filler comprises microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate.

12. The particulate composition of claim 11, wherein the amount of microcrystalline cellulose present is at least 5 wt% (e.g., at least 10 wt%, at least 15 wt%, at least 20 wt%, or at least 25 wt%), based on the weight of the particulate composition.

13. The particulate composition according to claim 11 or claim 12, wherein the amount of crosslinked sodium carboxymethyl cellulose present is at least 4 wt% (e.g., at least 6 wt% or at least 8 wt%), based on the weight of the particulate composition.

14. The particulate composition according to any one of claims 11-13, wherein the amount of hydroxypropyl methylcellulose and magnesium stearate is not more than 10 wt% (e.g., not more than 5 wt%).

15. The particulate composition according to any one of claims 1-6, wherein the filler comprises microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, and magnesium stearate.

16. The particulate composition of claim 15, wherein the amount of microcrystalline cellulose present is at least 5 wt% (e.g., at least 10 wt%, at least 15 wt%, at least 20 wt%, or at least 25 wt%), based on the weight of the particulate composition.

17. The particulate composition according to claim 15 or claim 16, wherein the amount of crosslinked sodium carboxymethyl cellulose present is at least 4 wt% (e.g., at least 6 wt% or at least 8 wt%), based on the weight of the particulate composition.

18. The particulate composition according to any one of claims 15-17, wherein the amount of polyvinylpyrrolidone and magnesium stearate is not more than 10 wt% (e.g., not more than 5 wt%), based on the weight of the particulate composition.

19. The particulate composition according to any one of claims 1-18, wherein the filler is present in an amount of at least 10 wt% (e.g., at least 20 wt%, at least 30 wt%, at least 40 wt%, or at least 50 wt%), based on the weight of the particulate composition.

20. The particulate composition according to any one of claims 1-19, wherein the filler is present in an amount ranging from 10 to 90 wt% (e.g., 10 to 70 wt%, 10 to 50 wt%, 30 to 90 wt%, 30 to 70 wt%, or 30 to 50 wt%), based on the weight of the particulate composition.

21. The particulate composition according to any one of claims 1-20, wherein the weight ratio of the crystalline form to the filler is at least 1:

10.

22. The particulate composition according to any one of claims 1-21, wherein the weight ratio of the crystalline form to the filler is in the range of 1:10-10:1 (e.g., in the range of 1:10-5:1, 1:10-2:1, 1:10-1:1, 1:5-10:1, 1:5-5:1, 1:5-2:1, 1:5-1:1, 2:1-10:1, 2:1-5:1, 2:1-2:1, or 2:1-1:1).

23. The particulate composition according to any one of claims 1-22, wherein the first chiral crystalline form is a compound having formula (I): 。 24. The particulate composition according to any one of claims 1-23, wherein the first chiral crystalline form is present in an amount of at least 90 wt% (e.g., at least 92 wt%, at least 94 wt%, or at least 96 wt%), based on the weight of the crystalline form.

25. The particulate composition according to any one of claims 1-24, wherein the second chiral form is a compound having formula (II): 。 26. The particulate composition according to any one of claims 1-25, wherein the second chiral form is present in an amount not exceeding 3 wt% (e.g., not exceeding 2 wt% or not exceeding 1 wt%), based on the weight of the crystalline form.

27. The particulate composition according to any one of claims 1-26, wherein the second chiral form is present in crystalline form.

28. The particulate composition according to any one of claims 1-26, wherein the second chiral form is present in an amorphous form.

29. The particulate composition according to any one of claims 1-28, wherein the amorphous form is present in an amount not exceeding 8 wt% (e.g., not exceeding 5 wt% or not exceeding 3 wt%), based on the weight of the crystalline form.

30. The particulate composition according to any one of claims 1-29, wherein it comprises an organic acid.

31. The particulate composition according to claim 30, wherein the organic acid is selected from citric acid, fumaric acid, DL-tartaric acid, maleic acid, DL-malic acid, or succinic acid.

32. The particulate composition according to claim 30 or claim 31, wherein the organic acid is present in an amount of at least 5 wt% (e.g., at least 10 wt%, at least 12 wt%, or at least 15 wt%), based on the weight of the particulate composition.

33. The particulate composition according to any one of claims 1-32, having a porosity in the range of 5-40% (e.g., 5-35% or 5-30% or 10-40% or 10-35% or 10-30%).

34. The particulate composition according to any one of claims 1-33, having a porosity of 28%.

35. The particulate composition according to any one of claims 1-34, having a porosity of 11%.

36. The particulate composition according to any one of claims 1-35, having an average particle size of at least about 250 µm.

37. The particulate composition according to any one of claims 1-36, having an average particle size of at least about 300 µm.

38. A pharmaceutical composition (e.g., a tablet) comprising the granular composition according to any one of claims 1-37.

39. A method for preparing the particulate composition according to any one of claims 1-34, the method comprising: Provided in crystalline form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile, comprising at least 95 wt% of the first chiral crystalline form; Provide fillers; The crystalline form and the filler are mixed at a weight ratio of at least 1:10; The mixture is subjected to a granulation method selected from fluidized bed granulation, high or low shear granulation and dry granulation to obtain a particulate composition; The particulate composition contains no more than 10 wt% of an amorphous form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile; and The particulate composition contains no more than 5 wt% of the secondary chiral form of 2-(4-(4-(aminomethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-methyl-1H-pyrazol-5-yl)-4-chloro-6-cyclopropoxy-3-fluorobenzyl nitrile.

40. The method according to claim 39, wherein the granulation method is fluidized bed granulation.

41. The method according to claim 39, wherein the granulation method is high-shear granulation.

42. The method of claim 39, wherein the granulation method is low-shear granulation.

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