Salt and crystalline form of compound A, method of producing the same, and its uses

Abstract

The present invention relates to a pharmaceutically acceptable salt of N-(3-chloro-5-(trifluoromethyl)phenyl)-3-((6-(4-hydroxypiperidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethinyl)-2-methylbenzamide, its crystalline form, and a method for producing the same.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutically acceptable salt of N-(3-chloro-5-(trifluoromethyl)phenyl)-3-((6-(4-hydroxypiperidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethinyl)-2-methylbenzamide, its crystalline form, and a method for producing the same. [Background technology]

[0002] Tropomyosin receptor kinases (TRKs) belong to the receptor tyrosine kinase family (RTKs), and their members are TRKA, TRKB, and TRKC, encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. TRKs are transmembrane proteins composed of an extracellular ligand-binding domain, a transmembrane domain (TM), and an intracellular domain, and are primarily activated by binding to neurotrophic factors (NTs). Neurotrophic factors are a group of protein molecules produced by nerve-innervated tissues (e.g., muscles) and astrocytes, and are essential for the growth and survival of nerve cells. Currently, four major neurotrophic factors have been identified: NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), NT-3 (neurotrophic factor 3), and NT-4 (neurotrophic factor 4). NGF can bind to TRKA, BDNF and NT-4 can bind to TRKB, and NT-3 can bind to all three TRK proteins, but it shows a stronger affinity for TRKC. When activated by signal induction, TRK sequentially activates downstream signaling pathways via autodimerization and phosphorylation, expressing diverse cellular physiological functions. Downstream signaling pathways of TRK include MAPK, PI3K / AKT, and PLCγ / PKC pathways, which regulate physiological processes such as cell proliferation, differentiation, migration, and apoptosis. Furthermore, they are involved in a variety of neuronal physiological activities, including synaptic plasticity, growth and repair of nerve dendrites, prevention and repair of neuronal degeneration, and maintenance of sensory neurons.

[0003] Numerous studies have shown that TRK overexpression, gene fusion, and single-nucleotide alterations are closely associated with the development and progression of a wide variety of tumors, including non-small cell lung cancer, breast cancer, colorectal cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma, and mammary gland-like secretory carcinoma. Among the mechanisms of TRK abnormal activation, TRK gene fusion is the most frequent. The first NTRK fusion gene discovered in medical research was the TPM3-NTRK1 fusion gene, identified from a colorectal cancer sample. As research progressed, several other fusion genes, such as CD74-NTRK1, ETV6-NTRK2, QKI-NTRK2, and ETV6-NTRK3, were subsequently discovered. TRK fusion proteins expressed by NTRK fusion genes constitutively activate downstream signaling pathways independently of ligand binding, inducing abnormal cell proliferation and promoting tumor development and progression. For this reason, TRK is considered an effective target for anti-cancer therapy.

[0004] Currently, larotrectinib, a TRK-selective inhibitor developed by LOXO in the United States, received FDA approval in 2018. Entrectinib, a TRK inhibitor developed by Roche, was marketed in Japan in June 2019. Belizatinib, developed by TESARO, is currently in clinical trials. Furthermore, multi-target inhibitors such as cabozantinib, sitravatinib, and altiratinib also exhibit excellent TRK inhibitory activity.

[0005] NTRK gene point mutations resulting from the continued use of TRK inhibitors are a major factor in the acquisition of drug resistance in tumors. Clinical studies have successively identified G595R, G667C, F589L, and G667S mutations in NTRK1, and G623R and G696A mutations in NTRK3. Currently, there are no inhibitors targeting these mutations on the market, and second-generation TRK inhibitors LOXO-195, TPX-0005, and ONO-5390556 are in clinical development.

[0006] N-(3-chloro-5-(trifluoromethyl)phenyl)-3-((6-(4-hydroxypiperidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethinyl)-2-methylbenzamide (named Compound A) is a TRK protein kinase inhibitor that effectively suppresses the activity of TRK protein kinase and inhibits the proliferation, migration, and invasion of various tumor cells. It has particularly excellent pharmacokinetic properties and resistance-suppressing effects, and its structure is shown in structural formula 1 below. [ka] [Overview of the Initiative]

[0007] A first aspect of the present invention relates to a pharmaceutically acceptable salt of N-(3-chloro-5-(trifluoromethyl)phenyl)-3-((6-(4-hydroxypiperidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-2-methylbenzamide. The pharmaceutically acceptable salt is an inorganic or organic acid addition salt commonly used in the art, wherein the inorganic acid addition salt is preferably a hydrochloride, sulfate, or phosphate, and the organic acid addition salt is preferably p-toluenesulfonate, mesylate, benzenesulfonate, oxalate, maleate, L-camphorsulfonate, gentisinate, tartrate, or fumarate. The pharmaceutically acceptable salt of compound A is preferably a phosphate or fumarate, and more preferably a fumarate. In compound A phosphate, the ratio of compound A to phosphoric acid is preferably 1:1. In compound A fumarate, the ratio of compound A to fumaric acid is preferably 1:0.5.

[0008] A second aspect of the present invention relates to the preparation of a pharmaceutically acceptable salt of N-(3-chloro-5-(trifluoromethyl)phenyl)-3-((6-(4-hydroxypiperidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-2-methylbenzamide. The preparation of the compound can be carried out by the usual salt preparation methods of the art, which include contacting compound A with the corresponding acid under conditions suitable for forming the corresponding acid addition salt.

[0009] A third aspect of the present invention relates to various crystalline forms of pharmaceutically acceptable salts of N-(3-chloro-5-(trifluoromethyl)phenyl)-3-((6-(4-hydroxypiperidine-1-yl)imidazo[1,2-b]pyridazin-3-yl)ethynyl)-2-methylbenzamide, and includes the following hydrochloride crystalline forms I and II, sulfate crystalline forms I, II, III and IV, p-toluenesulfonate crystalline forms I, II, III and IV, mesylate crystalline form I, benzenesulfonate crystalline forms I and II, oxalate crystalline form I, maleate crystalline form I, phosphate crystalline forms I, II and III, L-camphorsulfonate crystalline forms I and II, tartrate crystalline form I, and fumarate crystalline form I. Preferably, phosphate crystalline form I and fumarate crystalline form I are used, and more preferably, fumarate crystalline form I is used.

[0010] In compound A phosphate crystal form I, the ratio of compound A to phosphoric acid is preferably 1:1. Compound A phosphate crystal form I has one, more, or all of the following XRPD characteristic peaks at 2θ±0.2°: 4.339°, 6.033°, 6.651°, 7.308°, 8.631°, 10.392°, 10.640°, 12.690°, 12.914°, 14.147°, 14.437°, 15.026°, 17.457°, 17.890°, 18.468°, 19.006°, 19.487°, 19.938°, 20.266°, 20.846°, 21. 619°, 21.987°, 22.604°, 23.640°, 23.875°, 24.484°, 25.113°, 25.388°, 25.979°, 26.438°, 27.252°, 27.580°, 27.976°, 28.434°, 29.326°, 30.441°, 30.914°, 31.363°, 32.269°, 32.556°, 34.144°, 34.722°, 35.890°, 36.732°, 37.404°, 38.730°, 39.149°.

[0011] In one embodiment, the phosphate crystal form I has at least one XRPD feature peak where 2θ is selected from 4.3°±0.2°, 17.4°±0.2°, 21.6°±0.2°, and 21.9°±0.2°. Preferably, the phosphate crystal form I has an XRPD feature peak where 2θ is 4.3°±0.2°, 17.4°±0.2°, 21.6°±0.2°, and 21.9°±0.2°.

[0012] In another embodiment, the phosphate crystal form I has at least one XRPD feature peak where 2θ is selected from 12.9°±0.2°, 14.4°±0.2°, 20.3°±0.2°, and 22.6°±0.2°. Preferably, the phosphate crystal form I has XRPD feature peaks where 2θ is 12.9°±0.2°, 14.4°±0.2°, 20.3°±0.2°, and 22.6°±0.2°.

[0013] In another embodiment, the phosphate crystal form I has at least one XRPD feature peak where 2θ is selected from 12.7°±0.2°, 14.1°±0.2°, 19.9°±0.2°, and 26.4°±0.2°. Preferably, the phosphate crystal form I has XRPD feature peaks where 2θ is 12.7°±0.2°, 14.1°±0.2°, 19.9°±0.2°, and 26.4°±0.2°.

[0014] In another embodiment, the phosphate crystal form I has at least one XRPD feature peak selected from 2θ to be 4.3°±0.2°, 17.4°±0.2°, 21.6°±0.2°, 21.9°±0.2°, 12.9°±0.2°, 14.4°±0.2°, 20.3°±0.2°, 22.6°±0.2°, 12.7°±0.2°, 14.1°±0.2°, 19.9°±0.2°, and 26.4°±0.2°. Preferably, the phosphate crystal form I has XRPD characteristic peaks where 2θ is 4.3°±0.2°, 17.4°±0.2°, 21.6°±0.2°, 21.9°±0.2°, 12.9°±0.2°, 14.4°±0.2°, 20.3°±0.2°, 22.6°±0.2°, 12.7°±0.2°, 14.1°±0.2°, 19.9°±0.2°, and 26.4°±0.2°.

[0015] In another embodiment, the phosphate crystal form I basically has the XRPD diagram shown in Figure 19.

[0016] The present invention also provides a method for preparing the crystalline form I of compound A phosphate, comprising the following steps: Compound A is brought into contact with phosphoric acid in a solvent to form compound A phosphate. Compound A phosphate is precipitated as the crystalline form I of compound A phosphate.

[0017] In the above method, the solvent is isopropanol. In the above method, the solvent is acetonitrile / water, and the ratio of acetonitrile to water is preferably in the range of 15:1 to 25:1, for example, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1. In the above method, the precipitation is carried out at room temperature.

[0018] In compound A fumarate crystal form I, the ratio of compound A to fumaric acid is preferably 1:0.5. Compound A fumarate crystal form I has one, more, or all of the following XRPD characteristic peaks at 2θ±0.2°: 4.703°, 5.234°, 7.100°, 9.515°, 10.561°, 10.864°, 11.566°, 14.336°, 15.324°, 15.926°, 16.625°, 17.834°, 18.671°, 19.193°, 19.904°, 20.972°, 21.320°, 21.607°, 21.908°, 22. 058°, 23.118°, 23.487°, 24.089°, 24.899°, 25.162°, 25.337°, 26.463°, 26.767°, 28.444°, 28.809°, 29.017°, 29.496°, 30.621°, 31.059°, 32.281°, 32.640°, 33.214°, 33.407°, 34.009°, 34.480°, 35.672°, 37.870°, 38.210°, 39.076°, 39.488°.

[0019] In one embodiment, the fumarate crystal form I has at least one XRPD feature peak selected from 2θ = 9.5°±0.2°, 10.5°±0.2°, 14.3°±0.2°, and 21.9°±0.2°. Preferably, the fumarate crystal form I has an XRPD feature peak with 2θ = 9.5°±0.2°, 10.5°±0.2°, 14.3°±0.2°, and 21.9°±0.2°.

[0020] In other embodiments, the fumarate crystalline form I has at least one XRPD characteristic peak selected from 2θ of 15.9° ± 0.2°, 16.6° ± 0.2°, 19.1° ± 0.2° and 22.0° ± 0.2°. Preferably, the fumarate crystalline form I has XRPD characteristic peaks where 2θ is 15.9° ± 0.2°, 16.6° ± 0.2°, 19.1° ± 0.2° and 22.0° ± 0.2°.

[0021] In other embodiments, the fumarate crystalline form I has at least one XRPD characteristic peak selected from 2θ of 4.7° ± 0.2°, 10.8° ± 0.2°, 19.9° ± 0.2°, 21.3° ± 0.2° and 26.7° ± 0.2°. Preferably, the fumarate crystalline form I has XRPD characteristic peaks where 2θ is 4.7° ± 0.2°, 10.8° ± 0.2°, 19.9° ± 0.2°, 21.3° ± 0.2° and 26.7° ± 0.2°.

[0022] In other embodiments, the fumarate crystalline form I has at least one XRPD characteristic peak selected from 2θ of 9.5° ± 0.2°, 10.5° ± 0.2°, 14.3° ± 0.2°, 21.9° ± 0.2°, 15.9° ± 0.2°, 16.6° ± 0.2°, 19.1° ± 0.2°, 22.0° ± 0.2°, 4.7° ± 0.2°, 10.8° ± 0.2°, 19.9° ± 0.2°, 21.3° ± 0.2° and 26.7° ± 0.2°. Preferably, the fumarate crystalline form I has XRPD characteristic peaks where 2θ is 9.5° ± 0.2°, 10.5° ± 0.2°, 14.3° ± 0.2°, 21.9° ± 0.2°, 15.9° ± 0.2°, 16.6° ± 0.2°, 19.1° ± 0.2°, 22.0° ± 0.2°, 4.7° ± 0.2°, 10.8° ± 0.2°, 19.9° ± 0.2°, 21.3° ± 0.2° and 26.7° ± 0.2°.

[0023] In other embodiments, the fumarate crystalline form I basically has the XRPD diagram shown in FIG. 24.

[0024] The present invention also provides a method for preparing the fumarate crystalline form I of the compound A, comprising the following steps: Compound A is brought into contact with fumaric acid in a solvent to form compound A fumarate. Compound A fumarate is precipitated as the crystalline form I of compound A fumarate.

[0025] In the above method, the solvent is isopropanol. In the above method, the solvent is butanone. In the above method, the solvent is 2-methyltetrahydrofuran. In the above method, the solvent is acetonitrile / water, and the ratio of acetonitrile to water is preferably in the range of 15:1 to 25:1 (for example, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1). In the above method, the precipitation is carried out at room temperature.

[0026] Compound A fumarate and its crystalline form I possess superior properties compared to other salts and crystalline forms of Compound A in the following respects: rational acid-base ratio in salt formation, stability of the single crystal form in various crystal systems, crystallinity, solvent-free properties, stability (including solid storage stability, mechanical grinding stability, and tableting stability), hygroscopicity, and absence of polymorphism. This achieves an optimal balance of beneficial properties, allowing Compound A fumarate and its crystalline form I to simplify operations and reduce requirements in the manufacturing and storage processes of Compound A-related pharmaceuticals. For example, it offers advantages such as easier removal of impurities, reduced impact from variations in manufacturing conditions, and relaxed storage requirements.

[0027] A fourth aspect of the present invention provides a pharmaceutical composition comprising the salt or crystalline form and a pharmaceutically acceptable carrier. [Brief explanation of the drawing]

[0028] [Figure 1] Figure 1 shows a polarized light microscope image of free base crystal form I (batch number: A16803-008S3). [Figure 2] Figure 2 shows the XRPD pattern of the starting material free base crystal form I (batch number: A16803-008S3). [Figure 3] Figure 3 shows the DSC and TGA data for free base crystal form I (batch number: A16803-008S3). [Figure 4] Figure 4 shows the DVS weight change curve for free base crystal form I (batch number: A16803-008S3). [Figure 5] Figure 5 shows the DVS isothermal adsorption and desorption curve for free base crystal form I (batch number: A16803-008S3). [Figure 6] Figure 6 shows the XRPD patterns of free base crystal form I before and after DVS analysis. [Figure 7] Figure 7 shows the XRPD overlay pattern of free bases. [Figure 8] Figure 8 shows the DSC and TGA data for free base crystal form II (batch number: A16498-004A). [Figure 9] Figure 9 shows the DSC and TGA data for free base crystal form III (batch number: A16498-004C). [Figure 10] Figure 10 shows the DSC and TGA data for free base crystal form IV (batch number: A16498-004D). [Figure 11] Figure 11 shows the XRPD overlay pattern of the hydrochloride salt. [Figure 12] Figure 12 shows the XRPD overlay pattern of the sulfate. [Figure 13] Figure 13 shows the XRPD overlay pattern of p-toluenesulfonate. [Figure 14] Figure 14 shows the XRPD overlay pattern of mesylate. [Figure 15] Figure 15 shows the XRPD overlay pattern of benzenesulfonate. [Figure 16] Figure 16 shows the XRPD overlay pattern of oxalate. [Figure 17]Figure 17 shows the XRPD overlay pattern of maleate. [Figure 18] Figure 18 shows the XRPD overlay pattern of phosphate. [Figure 19] Figure 19 shows the XRPD overlay pattern of phosphate crystal form I (batch No.: A16498-045A1). [Figure 20] Figure 20 shows the XRPD overlay pattern of L-camphor sulfonate. [Figure 21] Figure 21 shows the XRPD overlay pattern of gentisinate. [Figure 22] Figure 22 shows the XRPD overlay pattern of tartrate. [Figure 23] Figure 23 shows the XRPD overlay pattern of fumarate. [Figure 24] Figure 24 shows the XRPD overlay pattern of fumarate crystal form I (batch number: A16498-045C1). [Figure 25] Figure 25 shows the PLM image of fumarate crystal form I (batch number: A16498-067-B1). [Figure 26] Figure 26 shows the XRPD pattern of fumarate crystal form I (batch number: A16498-067-B1). [Figure 27] Figure 27 shows the DSC and TGA data for fumarate crystal form I (batch number: A16498-067-B1). [Figure 28] Figure 28 shows the 1H-NMR spectrum of fumarate crystal form I (batch number: A16498-067-B1). [Figure 29] Figure 29 shows the XRPD overlay pattern of the crystalline salt (I / II). [Figure 30] Figure 30 shows the XRPD overlay pattern of the crystalline salt (II / II). [Figure 31] Figure 31 shows the XRPD overlay patterns of the anhydrous crystalline form before and after the stability test. [Figure 32]Figure 32 shows the XRPD overlay patterns of mesylate crystal form I before and after stability testing. [Figure 33] Figure 33 shows a polarized light microscope image of phosphate crystal form I (batch number: A16498-045A1). [Figure 34] Figure 34 shows the DSC and TGA diagrams of phosphate crystal form I (batch number: A16498-045A1). [Figure 35] Figure 35 shows the DVS weight change curve for phosphate crystal form I (batch number: A16498-045A1). [Figure 36] Figure 36 shows the DVS adsorption curve for phosphate crystal form I (batch number: A16498-045A1). [Figure 37] Figure 37 shows the XRPD patterns of phosphate crystal form I (batch number: A16498-045A1) before and after DVS analysis. [Figure 38] Figure 38 shows a polarized light microscope image of fumarate crystal form I (batch number: A16498-045C1). [Figure 39] Figure 39 shows the DSC and TGA data for fumarate crystal form I (batch number: A16498-045C1). [Figure 40] Figure 40 shows the DVS weight change curve for fumarate crystal form I (batch number: A16498-045C1). [Figure 41] Figure 41 shows the DVS adsorption curve for fumarate crystal form I (batch number: A16498-045C1). [Figure 42] Figure 42 shows the XRPD patterns of fumarate crystal form I (batch number: A16498-045C1) before and after DVS analysis. [Figure 43] Figure 43 shows plots of biological solvent solubility data for free bases, phosphates, and fumarates. [Figure 44] Figure 44 shows the XRPD overlay pattern of the free base crystalline form I residual solid in water. [Figure 45] Figure 45 shows the XRPD overlay pattern of the free base crystal form I residual solid in SGF. [Figure 46] Figure 46 shows the XRPD overlay pattern of the free base crystalline form I residual solid in FaSSIF. [Figure 47] Figure 47 shows the XRPD overlay pattern of the free base crystal form I residual solid in FeSSIF. [Figure 48] Figure 48 shows the XRPD overlay pattern of residual solid phosphate crystal form I in water. [Figure 49] Figure 49 shows the XRPD overlay pattern of residual phosphate crystal form I in SGF. [Figure 50] Figure 50 shows the XRPD overlay pattern of residual solid phosphate crystal form I in FaSSIF. [Figure 51] Figure 51 shows the DSC and TGA data for phosphate crystal form 3. [Figure 52] Figure 52 shows the XRPD overlay pattern of residual phosphate crystal form I in FeSSIF. [Figure 53] Figure 53 shows the XRPD overlay pattern of the fumarate crystal form I residual solid in water. [Figure 54] Figure 54 shows the XRPD overlay pattern of the fumarate crystal form I residual solid in SGF. [Figure 55] Figure 55 shows the XRPD overlay pattern of the fumarate crystal form I residual solid in FaSSIF. [Figure 56] Figure 56 shows the XRPD overlay pattern of the fumarate crystal form I residual solid in FeSSIF. [Figure 57] Figure 57 shows the XRPD overlay patterns of free base crystal form I before and after stability testing. [Figure 58] Figure 58 shows the HPLC overlay patterns of free base crystal form I before and after the stability test. [Figure 59] Figure 59 shows the XRPD overlay patterns of phosphate crystal form I before and after stability testing. [Figure 60]Figure 60 shows the HPLC overlay patterns of phosphate crystal form I before and after the stability test. [Figure 61] Figure 61 shows the XRPD overlay patterns of fumarate crystal form I before and after stability testing. [Figure 62] Figure 62 shows the HPLC overlay patterns of fumarate crystal form I before and after stability testing. [Figure 63] Figure 63 shows the DVS weight change curve for fumarate crystal form I. [Figure 64] Figure 64 shows the DVS adsorption curve for fumarate crystal form I. [Figure 65] Figure 65 shows the XRPD overlay patterns of fumarate crystal form I before and after grinding. [Figure 66] Figure 66 shows the XRPD overlay patterns of fumarate crystal form I before and after tableting. [Figure 67] Figure 67 shows a simplified solubility histogram of fumarate crystal form I. [Figure 68] Figure 68 shows the XRPD overlay pattern of the evaporation crystallization sample. [Figure 69] Figure 69 shows the XRPD overlay pattern of the cooled crystallized sample. [Figure 70] Figure 70 shows the XRPD overlay pattern of the crystallized sample by antisolvent precipitation. [Figure 71] Figure 71 shows the XRPD overlay pattern of a sample that was treated with trituration at room temperature for 3 days. [Figure 72] Figure 72 shows the XRPD overlay pattern of a sample that underwent tritulation treatment at 50°C for 3 days. [Figure 73] Figure 73 shows the XRPD overlay pattern of a sample that underwent trituration treatment at room temperature for 7 days. [Figure 74] Figure 74 shows the XRPD overlay pattern of a sample treated with tritulation at 50°C for 7 days.

[0029] Abbreviation: Abbreviations for chemical reagents: TIFF2026508813000002.tif76170 Other abbreviations (sorted alphabetically): TIFF2026508813000003.tif91170 [Modes for carrying out the invention]

[0030] Specific Embodiments 1. Characterization of the starting material 1.1 Characterization of Solid Properties The free base of compound A (batch number: A16803-008S3) was fully characterized as a starting material. The characterization data is shown in Figures 1-3. The starting material exhibited aggregated microcrystalline form with moderate crystallinity and was named Free Base Crystal Form I. TGA analysis revealed a weight loss of 0.2% from room temperature to 60°C and another 0.2% from 170°C to 250°C, suggesting dehydration and desolvation of the sample. DSC analysis showed only a single endothermic peak at 245°C due to melting, indicating that Free Base Crystal Form I was an anhydrous crystalline form. As shown in Figures 4-6, DVS results showed that Free Base Crystal Form I was slightly hygroscopic, with increases in moisture absorption of approximately 0.8% and 0.9% under 80%RH and 90%RH conditions, respectively, and the crystal form did not change after the DVS test.

[0031] 1.2 Simple evaluation of solubility A simple solubility test for free base compound A was performed by visual evaluation after adding a solvent, and the results are summarized in Table 1. The substance from this batch was soluble in butanone, tetrahydrofuran, and 2-methyltetrahydrofuran (>50 mg / mL), but sparingly soluble in water, toluene, and n-heptane (<1 mg / mL). During the experiment, solid precipitation was observed in isopropanol and butanone solutions, suggesting the possibility of the formation of new crystalline forms. Table 1 Crude solubility of starting material (Batch number: A16803-008S3) [Table 1]

[0032] 1.3 Research on the trituration of free bases (salt formation blank experiment) As shown in Table 2, three novel crystalline forms of free bases (free base crystalline forms II, III, and IV) were identified by blank experiments. The XRPD overlay patterns are shown in Figure 7, and the DSC and TGA data are shown in Figures 8 and 10. XRPD patterns indicated that free base crystal form II had high crystallinity. 1 ¹H-NMR detected 8.6 wt.% isopropanol residue, and TGA showed an 8.5% weight loss of the sample in the temperature range of 100-150°C (due to desolvation). Multiple endothermic peaks were observed in the DSC curve, leading to the determination that the free base crystal form II was an isopropanol solvent compound. Free base crystal form III showed moderate crystallinity. Two overlapping endothermic peaks (attributed to sample melting) were detected in DSC. 1 ¹H-NMR confirmed the presence of 0.2 wt.% 2-methyltetrahydrofuran. TGA showed a 0.3% weight loss (desorption of 2-methyltetrahydrofuran) in the sample over a temperature range of 100–225°C. Based on the characteristic data, the free base crystalline form III was determined to be the anhydrous crystalline form. Free base crystal form IV was obtained by trituration of the starting material in an acetonitrile / water mixed solvent and exhibited moderate to high crystallinity. 1 ¹H-NMR detected 2.2 wt.% acetonitrile residue, DSC showed three endothermic peaks, and TGA confirmed a 1.9% weight loss in the sample in the 80-150°C range (attributable to acetonitrile elimination). Therefore, free base crystal form IV was determined to be an acetonitrile solvent compound. Table 3 summarizes the characterization data for various free base crystal forms. Free base crystal form I, which has a higher melting point and enthalpy value, was selected, and further research was conducted. Table 2 Preparation of Novel Crystal Forms of Free Bases [Table 2] Table 3 Summary of Free Base Crystalline Form Data [Table 3]

[0033] 2. Preparation of pharmaceutically acceptable salts of compound A: 2.1 Preparation of hydrochloride Two types of hydrochloride crystalline forms (hydrochloride crystalline form I and hydrochloride crystalline form II) were obtained by the salt formation reaction between the free base and hydrochloric acid (the results are shown in Table 4). The XRPD patterns are shown in Figure 11. Table 4 Preparation of hydrochloride salts [Table 4]

[0034] 2.1.1 Hydrochloride crystal form I Hydrochloride crystalline form I can be prepared using two solvent systems: an isopropanol system and an acetonitrile / water (19 / 1,v / v) system. Preparation of hydrochloride crystalline form I (batch No.: A16498-004A1): Approximately 25 mg of the starting material, free base (batch No.: A16803-008S3), was weighed, and 0.5 mL of isopropanol was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to prepare a white suspension. 42 μL of concentrated hydrochloric acid was added to 0.5 mL of isopropanol and mixed uniformly. 55 μL of this mixture (equivalent to 1.1 equivalents of hydrochloric acid) was added to the free base suspension to obtain a clarified solution. After stirring at room temperature for 2 hours, it changed to a suspension. It remained a suspension even after continuing stirring for 18 hours. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. It was identified as hydrochloride crystalline form I by X-ray powder diffraction. Preparation of hydrochloride crystalline form I (batch No.: A16498-004D1): Approximately 25 mg of the starting material, free base (batch No.: A16803-008S3), was weighed, and 0.5 mL of acetonitrile / water (19 / 1,v / v) was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to prepare a white suspension. 42 μL of concentrated hydrochloric acid was added to 0.5 mL of acetonitrile / water (19 / 1,v / v) and homogeneously mixed. 55 μL of this mixture (equivalent to 1.1 equivalents of hydrochloric acid) was added to the free base suspension to obtain a gel-like substance. After stirring at room temperature for 20 hours, it changed to a suspension. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. It was identified as hydrochloride crystalline form I by X-ray powder diffraction.

[0035] 2.1.2 Hydrochloride crystal form II The sample was obtained from hydrochloride crystalline form II (batch No.: A16498-004B1). Approximately 25 mg of the starting material, free base (batch No.: A16803-008S3), was weighed, and 0.5 mL of butanone was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a clarified solution. 42 μL of concentrated hydrochloric acid was added to 0.5 mL of butanone and mixed uniformly. 55 μL of this mixture (equivalent to 1.1 equivalents of hydrochloric acid) was added to the free base suspension to obtain a gel. After stirring at room temperature for 2 hours, it changed to a concentrated suspension. Then, 0.2 mL of butanone was added, and the mixture was stirred for 18 hours to obtain a final suspension. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. It was identified as hydrochloride crystalline form II by X-ray powder diffraction.

[0036] 2.2 Sulfate crystal forms I, II, III, and IV Four different sulfate crystal forms (crystal form I, crystal form II, crystal form III, and crystal form IV) were obtained by salt formation reactions between 1.1 equivalents and 0.55 equivalents of sulfuric acid and free base samples (the results are shown in Tables 5 and 6). The XRPD patterns are shown in Figure 12. Table 5 Preparation of sulfate (1.1 eq. sulfuric acid) [Table 5] Table 6 Preparation of sulfate (0.55 eq. sulfuric acid) [Table 6]

[0037] 2.2.1 Sulfate crystal form I Approximately 25 mg of the starting material free base (batch No.: A16803-008S3), which was sulfate crystal form I (batch No.: A16498-004A2), was weighed, and 0.5 mL of isopropanol was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to prepare a white suspension. 28 μL of concentrated sulfuric acid was added to 0.5 mL of isopropanol and mixed uniformly. 53 μL of this mixture (equivalent to 1.1 equivalents of sulfuric acid) was added to the free base suspension to obtain a clarified solution. The solution remained in a state after stirring at room temperature for 22 hours, but solid precipitation was confirmed upon addition of 1 mL of n-heptane. The mixture was stirred for a further 18 hours to obtain a suspension. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as sulfate crystal form I by X-ray powder diffraction.

[0038] 2.2.2 Sulfate Crystal Form II The sulfate crystal form II (batch No.: A16498-004B2) was prepared by weighing approximately 25 mg of the starting material free base (batch No.: A16803-008S3). 0.5 mL of butanone was added at room temperature (~24°C), and the mixture was stirred for approximately 10 minutes to prepare a clarified solution. 28 μL of concentrated sulfuric acid was added to 0.5 mL of isopropanol and mixed uniformly. 53 μL of this mixture (equivalent to 1.1 equivalents of sulfuric acid) was added to the free base suspension to obtain a solution. After stirring for 2 hours, it transformed into a suspension. The suspension remained even after continued stirring for a further 18 hours. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as sulfate crystal form II by X-ray powder diffraction.

[0039] 2.2.3 Sulfate crystal form III A solution of 2-methyltetrahydrofuran (concentration 60 mg / mL) of sulfate crystal form III (batch No.: A16498-004C2) and free base (batch No.: A16803-008S3) was prepared in advance, and 416 μL of the solution was dispensed into a glass vial. 28 μL of concentrated sulfuric acid was added to 0.5 mL of 2-methyltetrahydrofuran and homogeneously mixed. 53 μL of this mixture (equivalent to 1.1 equivalents of sulfuric acid) was then added to the free base solution to obtain the solution. After stirring for 2 hours, it transformed into a suspension. The suspension state was maintained even after continued stirring for a further 18 hours. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as sulfate crystal form III by X-ray powder diffraction.

[0040] 2.2.4 Sulfate Crystal Form IV For sulfate crystal form IV (batch No.: A16498-004D3), approximately 25 mg of the starting material, free base (batch No.: A16803-008S3), was weighed and 0.5 mL of acetonitrile / water (19 / 1,v / v) was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a white suspension. 28 μL of concentrated sulfuric acid was added to 0.5 mL of acetonitrile / water (19 / 1,v / v) and after homogeneous mixing, 27 μL of this mixture (equivalent to 0.55 equivalents of sulfuric acid) was added to the free base suspension. An oily substance precipitated first and remained so even after stirring for 20 hours. After stirring at 50°C for 7 hours, it transformed into a suspension. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as sulfate crystal form IV by X-ray powder diffraction.

[0041] 2.3 p-toluenesulfonate Four crystalline forms of p-toluenesulfonate (crystal forms I, II, III, and IV) were obtained by salt formation reactions between free base samples and p-toluenesulfonic acid (the results are shown in Table 7). The XRPD patterns are shown in Figure 13. Table 7 Preparation of p-toluenesulfonate [Table 7]

[0042] 2.3.1 p-toluenesulfonate crystalline form I The sample was p-toluenesulfonate crystalline form I (batch No.: A16498-004A4). Approximately 25 mg of the starting material's free base (batch No.: A16803-008S3) was weighed, and 0.5 mL of isopropanol was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to prepare a white suspension. 8.6 mg (1.1 equivalents) of p-toluenesulfonate solid was added to obtain a clarified solution. After stirring at room temperature for 2 hours, it changed to a concentrated suspension. 0.2 mL of isopropanol was added, and the mixture was stirred for 18 hours to obtain a suspension. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. By X-ray powder diffraction, the sample was identified as p-toluenesulfonate crystalline form I.

[0043] 2.3.2 p-toluenesulfonate crystalline form II The sample was p-toluenesulfonate crystalline form II (batch No.: A16498-004B4). Approximately 25 mg of the starting material's free base (batch No.: A16803-008S3) was weighed, and 0.5 mL of butanone was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to prepare a clarified solution. 8.6 mg (1.1 equivalents) of solid p-toluenesulfonate was weighed and added to the free base solution to obtain a solution. Solid precipitation was confirmed after stirring for 2 hours, and the suspension state was maintained after stirring for 18 hours. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. By X-ray powder diffraction, the sample was identified as p-toluenesulfonate crystalline form II.

[0044] 2.3.3 p-toluenesulfonate crystal form III A solution of p-toluenesulfonate crystalline form III (batch No.: A16498-004C4) and free base (batch No.: A16803-008S3) in 2-methyltetrahydrofuran (concentration 60 mg / mL) was prepared in advance, and 416 μL of the solution was dispensed into a glass vial. 8.6 mg (1.1 equivalents) of p-toluenesulfonate solid was weighed and added to the free base solution to obtain a solution. After stirring for 2 minutes, solid precipitation was confirmed, and the suspension state was maintained after stirring for 20 hours. After filtration with a syringe equipped with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as p-toluenesulfonate crystalline form III by X-ray powder diffraction.

[0045] 2.3.4 p-toluenesulfonate crystal form IV The sample was p-toluenesulfonate crystalline form IV (batch No.: A16498-004D4). Approximately 25 mg of the starting material, free base (batch No.: A16803-008S3), was weighed, and 0.5 mL of acetonitrile / water (19 / 1, v / v) was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a white suspension. 8.6 mg (1.1 equivalents) of solid p-toluenesulfonic acid was weighed and added to the free base solution. After stirring at room temperature for 2 hours, the solution changed to a dilute suspension. After stirring for 18 hours, a suspension was obtained. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. By X-ray powder diffraction, the sample was identified as p-toluenesulfonate crystalline form IV.

[0046] 2.4 Mesylate Crystal Form I Using free base as a starting material, a salt formation reaction with 1.1 equivalents of mesylic acid yielded mesylate crystalline form I (the results are shown in Table 8). The XRPD pattern is shown in Figure 14. Table 8 Preparation of Mesylates [Table 8]

[0047] For the mesylate crystalline form I (batch number: A16498-004A5), approximately 25 mg of the starting material free base (batch number: A16803-008S3) was weighed, and 0.5 mL of isopropanol was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a white suspension. 48 mg of methanesulfonic acid was weighed out and added to 0.5 mL of isopropanol. After dissolution, 55 μL of the mixture (containing 1.1 equivalents of methanesulfonic acid) was added to the suspension of free base. A solution was obtained first, and it remained a solution after stirring for 20 hours. When 1 mL of n-heptane was added, oil precipitated, and the mixture was then stirred at 50°C for 7 hours to obtain a suspension. After filtration with a syringe equipped with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. By X-ray powder diffraction, the sample was identified as mesylate crystalline form I.

[0048] For the mesylate crystalline form I (batch number: A16498-004B5), approximately 25 mg of the starting material's free base (batch number: A16803-008S3) was weighed, and 0.5 mL of butanone was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a clarified solution. 48 mg of methanesulfonic acid was weighed out and added to 0.5 mL of butanone. After dissolution, 55 μL of the mixture (containing 1.1 equivalents of methanesulfonic acid) was added to the free base solution to obtain a solution. After stirring for 2 hours, solid precipitation was observed, and the suspension remained stable even after stirring for a further 18 hours. This suspension was filtered through a syringe with a 0.22 μm micropore filter to obtain a solid sample. The obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. X-ray powder diffraction identified it as mesylate crystalline form I.

[0049] 2.5 Benzenesulfonate Two crystalline forms of benzenesulfonate (besylate) were obtained by salt formation between a free base and benzenesulfonic acid, and were named benzenesulfonate crystalline form I and benzenesulfonate crystalline form II, respectively (the results are shown in Table 9). The XRPD patterns are shown in Figure 15. Table 9 Preparation of benzenesulfonates [Table 9]

[0050] 2.5.1 Benzene sulfonate crystalline form I Benzenesulfonic acid crystalline form I can be obtained using two types of organic solvent systems: isopropanol and butanone. Approximately 25 mg of the starting material free base (batch No.: A16803-008S3) was weighed from benzenesulfonate crystalline form I (batch No.: A16498-004A6). 0.5 mL of isopropanol was added at room temperature (~24°C), and the mixture was stirred for approximately 10 minutes to prepare a white suspension. 9.2 mg (1.1 equivalents) of benzenesulfonic acid solid was added to the free base suspension to obtain a clarified solution. After stirring at room temperature for 2 hours, the solution remained a solution, and after stirring for 18 hours, the solution changed to a suspension. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as benzenesulfonic acid crystalline form I by X-ray powder diffraction. The sample was benzenesulfonate crystalline form I (batch number: A16498-004B6). Approximately 25 mg of the starting material, free base (batch number: A16803-008S3), was weighed, and 0.5 mL of butanone was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a clarified solution. 9.2 mg (1.1 equivalents) of solid benzenesulfonic acid was weighed and added to the free base solution to obtain a solution. After stirring for 2 hours, a solid precipitate was observed, and the solution remained a suspension after stirring for 18 hours. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. By X-ray powder diffraction, the sample was identified as benzenesulfonate crystalline form I.

[0051] 2.5.2 Benzene sulfonate crystalline form II The sample was benzenesulfonic acid crystalline form II (batch number: A16498-004D6). Approximately 25 mg of the starting material, free base (batch number: A16803-008S3), was weighed, and 0.5 mL of acetonitrile / water (19 / 1,v / v) was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a white suspension. 9.2 mg (1.1 equivalents) of benzenesulfonic acid solid was weighed and added to the free base suspension to obtain a nearly clear solution. After stirring at room temperature for 2 hours, it changed to a concentrated suspension. Further 0.2 mL of acetonitrile / water (19 / 1,v / v) was added, and the mixture was stirred for 18 hours to obtain a suspension. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. By X-ray powder diffraction, the sample was identified as benzenesulfonate crystalline form II.

[0052] 2.6 Oxalate crystal form I One type of oxalate crystal was obtained by salt formation between the free base and oxalic acid (the results are shown in Table 10). The XRPD pattern is shown in Figure 16. Table 10 Preparation of oxalates [Table 10]

[0053] For oxalate crystalline form I (batch No.: A16498-004B7), approximately 25 mg of the starting material free base (batch No.: A16803-008S3) was weighed, and 0.5 mL of butanone was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a clarified solution. 4.5 mg (1.1 equivalents) of solid oxalate was weighed and added to the free base solution. A colloidal substance was initially obtained, and it remained colloidal even after stirring at room temperature for 20 hours. This was transferred to a 50°C environment to obtain a solution, and after adding 1 mL of n-heptane, the mixture was stirred for 7 hours to obtain a suspension. This suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as oxalate crystalline form I by X-ray powder diffraction.

[0054] 2.7 Maleate crystal form I Salt formation between the free base and maleic acid yielded one type of maleate crystalline form, which was named maleate crystalline form I. Maleate crystalline form I could be obtained in butanone, 2-methyltetrahydrofuran, or acetonitrile / water (19 / 1,v / v) solvent systems (results are shown in Table 11). The XRPD pattern is shown in Figure 17. Table 11 Preparation of maleates [Table 11]

[0055] The sample was maleate crystalline form I (batch No.: A16498-004B8). Approximately 25 mg of the starting material's free base (batch No.: A16803-008S3) was weighed, and 0.5 mL of butanone was added at room temperature (~24°C). A clarified solution was obtained by stirring for approximately 10 minutes. 5.8 mg (1.1 equivalents) of maleic acid solid was weighed and added to the free base solution to obtain a suspension. The suspension remained stable after stirring for 20 hours. The obtained suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as maleate crystalline form I by X-ray powder diffraction.

[0056] A 2-methyltetrahydrofuran solution of maleate crystalline form I (batch No.: A16498-004C8) and free base (batch No.: A16803-008S3) was pre-prepared at a concentration of 60 mg / mL, and 416 μL of the solution was dispensed into a glass vial. 5.8 mg (1.1 equivalents) of maleic acid solid was weighed and added to the free base solution. Initially, it remained in solution, but after stirring for 2 minutes, solid precipitation was observed, and the suspension state persisted even after stirring for 20 hours. The obtained suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as maleate crystalline form I by X-ray powder diffraction.

[0057] The sample was maleate crystalline form I (batch No.: A16498-004D8). Approximately 25 mg of the starting material's free base (batch No.: A16803-008S3) was weighed, and 0.5 mL of acetonitrile / water (19 / 1, v / v) was added at room temperature (~24°C). A white suspension was obtained by stirring for approximately 10 minutes. 5.8 mg (1.1 equivalents) of maleic acid solid was weighed and added to the free base suspension, resulting in a suspension. The suspension remained stable after stirring for 20 hours. The obtained suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as maleate crystalline form I by X-ray powder diffraction.

[0058] 2.8 Phosphate Using free base as a starting material, three types of phosphate crystal forms (crystal form I, crystal form II, and crystal form III) were obtained by salt formation with 1.1 equivalents of phosphate (the results are shown in Table 12). The XRPD patterns are shown in Figure 18. Table 12 Preparation of phosphates [Table 12]

[0059] 2.8.1 Phosphate Crystal Form I For phosphate crystal form I (batch number: A16498-004D9), approximately 25 mg of the starting material free base (batch No.: A16803-008S3) was weighed, and 0.5 mL of acetonitrile / water (19 / 1, v / v) was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a white suspension. 58 mg of phosphoric acid was added to 0.5 mL of acetonitrile / water (19 / 1, v / v), and after homogeneous mixing, 56 μL (equivalent to 1.1 equivalents of phosphoric acid) was added to the free base suspension. Initially, a cotton-like solid precipitated, but after stirring for 2 hours, a concentrated suspension was obtained. A further 0.2 mL of solvent was added, and the mixture was stirred for 18 hours to obtain a suspension. The obtained suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as phosphate crystal form I by X-ray powder diffraction.

[0060] 2.8.2 Phosphate Crystal Form II The sample was obtained from phosphate crystal form II (batch number: A16498-004B9). Approximately 25 mg of the starting material, free base (batch No.: A16803-008S3), was weighed, and 0.5 mL of butanone was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a clarified solution. 58 mg of phosphoric acid was dissolved in 0.5 mL of butanone and homogeneously mixed. 56 μL (equivalent to 1.1 equivalents of phosphoric acid) was then added to the free base solution to obtain a suspension. After stirring at room temperature for 20 hours, the suspension was maintained. The obtained suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as phosphate crystal form II by X-ray powder diffraction.

[0061] 2.8.3 Phosphate Crystal Form III A solution of 2-methyltetrahydrofuran (phosphate crystal form III, batch number: A16498-004C9) and free base (batch number: A16803-008S3) was pre-prepared at a concentration of 60 mg / mL, and 416 μL of the solution was dispensed into a glass vial. 58 mg of phosphoric acid was dissolved in 0.5 mL of 2-methyltetrahydrofuran and homogeneously mixed. 56 μL (equivalent to 1.1 equivalents of phosphoric acid) was then added to the free base solution to obtain the solution. The solution remained stable after stirring for 2 hours, and a suspension was obtained after stirring for 18 hours. The obtained suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as phosphate crystal form III by X-ray powder diffraction.

[0062] 2.8.4 Scale-up production of phosphate crystalline form I Approximately 350 mg of free base (batch number: A16803-008S3) was weighed, and 7 mL of acetonitrile / water (19 / 1, v / v) was added. The mixture was then stirred at room temperature (~21°C) to obtain a suspension. To this, 1.1 equivalents of phosphoric acid solution (81 mg of phosphoric acid diluted in 2 mL of acetonitrile / water (19 / 1, v / v)) was added. Initially, the suspension was almost clear, but after stirring for 10 minutes, it became a concentrated suspension, and an additional 6 mL of acetonitrile / water (19 / 1, v / v) was added. Finally, after stirring at room temperature for 16 hours, a suspension was obtained. The obtained suspension was filtered by vacuum pump, and the solid was recovered. This solid was vacuum-dried at 40°C for 4 hours to obtain sample A16498-045A1 in 93% yield. By X-ray powder diffraction (Figure 19), the substance was identified as phosphate crystalline form I.

[0063] 2.9 L-Camphor sulfonate Two crystalline forms (L-camphor sulfonate crystalline form I and L-camphor sulfonate crystalline form II) were obtained by the salt formation reaction between the free base and L-camphor sulfonic acid (the results are shown in Table 13). The XRPD patterns are shown in Figure 20. Table 13 Preparation of L-camphor sulfonates [Table 13]

[0064] 2.9.1 L-Camphor Sulfonate Crystalline Form I The L-camphor sulfonate crystalline form I (batch number: A16498-004A10) was prepared by weighing approximately 25 mg of the starting material, free base (batch number: A16803-008S3), adding 0.5 mL of isopropanol at room temperature (~24°C), and stirring for approximately 10 minutes to obtain a white suspension. 11.6 mg (1.1 equivalents) of L-camphor sulfonate solid was weighed and added to the suspension of the active pharmaceutical ingredient (the free base). A colloidal substance was initially formed, and after stirring at room temperature for 20 hours, it was maintained in that state. Further, 0.4 mL of isopropanol was added, and after stirring at 50°C for 7 hours, a suspension was obtained. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. By X-ray powder diffraction, the sample was identified as L-camphor sulfonate crystalline form I.

[0065] 2.9.2 L-Camphor Sulfonate Crystalline Form II L-camphor sulfonate crystalline form II can be obtained using butanone, 2-methyltetrahydrofuran, or acetonitrile / water (19 / 1,v / v) solvents. The sample was L-camphor sulfonate crystalline form II (batch number: A16498-004B10). Approximately 25 mg of the starting material, free base (batch number: A16803-008S3), was weighed, and 0.5 mL of butanone was added at room temperature (~24°C). The mixture was then stirred for approximately 10 minutes to obtain a clarified solution. 11.6 mg (1.1 equivalents) of L-camphor sulfonate solid was weighed and added to the solution to obtain a colloidal substance. The colloidal state was maintained even after stirring at room temperature for 20 hours. Further, 0.4 mL of butanone was added, and the mixture was stirred at 50°C for 7 hours to obtain a suspension. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. By X-ray powder diffraction, the sample was identified as L-camphor sulfonate crystalline form II. A sample of L-camphor sulfonate crystalline form II (batch number: A16498-004C10) was prepared by first preparing a 2-methyltetrahydrofuran solution with a free base concentration of 60 mg / mL (batch number: A16803-008S3). 416 μL of this solution was dispensed into a glass vial. 11.6 mg (1.1 equivalents) of L-camphor sulfonate solid was weighed and added to the solution. Initially in solution form, it transformed into a colloidal substance after 2 hours of stirring. After stirring at room temperature for 18 hours, the mixture was maintained in its original state. 0.6 mL of 2-methyltetrahydrofuran was then added, and the mixture was stirred at 50°C for 7 hours to obtain a suspension. After filtration using a syringe with a 0.22 μm micropore filter, the obtained solid was vacuum-dried at 40°C for 5 hours to obtain the sample. X-ray powder diffraction identified this sample as L-camphor sulfonate crystalline form II. The L-camphor sulfonate crystalline form II sample (batch number: A16498-004D10) was prepared by weighing approximately 25 mg of the starting material, free base (batch number: A16803-008S3). 0.5 mL of acetonitrile / water (19 / 1,v / v) was added at room temperature (~24°C), and the mixture was stirred for approximately 10 minutes to obtain a white suspension. 11.6 mg (1.1 equivalents) of L-camphor sulfonic acid was then added, and a colloidal substance was initially formed, which remained in this state even after stirring at room temperature for 20 hours. Further addition of 0.6 mL of acetonitrile / water (19 / 1,v / v) was performed, and the mixture was stirred at 50°C for 7 hours to obtain a suspension. After filtration using a syringe with a 0.22 μm micropore filter, the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. X-ray powder diffraction identified this sample as L-camphor sulfonate crystalline form II.

[0066] 2.10 Gentisidine salt We attempted to form a salt with gentisic acid using free base as a starting material, but we were unable to obtain gentisic acid salt. Detailed information and results are summarized in Table 14 and Figure 21. Table 14 Preparation of gentisic acid salts [Table 14]

[0067] 2.11 Tartrate crystal form I A salt formation reaction between the free base and tartaric acid yielded one crystalline form (tartrate crystal form I) (the results are shown in Table 15). The XRPD pattern is shown in Figure 22. Table 15 Preparation of tartrates [Table 15]

[0068] This describes a method for preparing tartrate crystalline form I (batch number: A16498-004D12). Approximately 25 mg of the starting material, free base (batch number: A16803-008S3), was weighed, and 0.5 mL of acetonitrile / water (19 / 1, v / v) was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a white suspension. 7.5 mg (1.1 equivalents) of solid tartrate was weighed and added to the suspension. Initially, it was in a suspension state, but after stirring for 2 hours, it changed to a concentrated suspension. 0.2 mL of acetonitrile / water (19 / 1, v / v) was added, and stirring was continued for a further 18 hours to obtain the final suspension. The obtained suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as tartrate crystalline form I by X-ray powder diffraction.

[0069] 2.12 Fumarate crystal form I The crystalline form obtained by the salt formation reaction between the free base and 1.1 equivalents of fumaric acid was named fumarate crystal form I. All fumarates obtained in four different solvent systems—isopropanol, butanone, 2-methyltetrahydrofuran, and acetonitrile / water (19 / 1, v / v)—were crystal form I, indicating that the fumarate of compound A forms a single crystalline form even under multiple crystallization conditions (the results are shown in Table 16). The XRPD pattern is shown in Figure 23. Table 16 Preparation of fumarates [Table 16]

[0070] Preparation of fumarate crystalline form I (batch number: A16498-004A13): Approximately 25 mg of the starting material, free base (batch number: A16803-008S3), was weighed, and 0.5 mL of isopropanol was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a white suspension. To the suspension of the active pharmaceutical ingredient, 5.8 mg (1.1 equivalents) of solid fumarate was weighed and added. Initially, it was a suspension, but after stirring for 2 hours, the suspension became more concentrated. 0.2 mL of isopropanol was added, and stirring was continued at room temperature for 18 hours to obtain a final suspension. The obtained suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. By X-ray powder diffraction, the sample was identified as fumarate crystalline form I.

[0071] Preparation of fumarate crystalline form I (batch number: A16498-004B13): Approximately 25 mg of the starting material, free base (batch number: A16803-008S3), was weighed, and 0.5 mL of butanone was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a clarified solution. To this drug substance solution, 5.8 mg (1.1 equivalents) of solid fumarate was weighed and added. Initially, it was in a solution state, but after 2 minutes, precipitation of the solid was observed. After continuing stirring for 2 hours, the suspension became concentrated, and 0.2 mL of butanone was added. After stirring for a further 18 hours, a final suspension was obtained. The obtained suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain a sample. By X-ray powder diffraction, this sample was identified as fumarate crystalline form I.

[0072] Preparation of fumarate crystalline form I (batch number: A16498-004C13): A 2-methyltetrahydrofuran solution of free base (batch number: A16803-008S3) at a concentration of 60 mg / mL was prepared in advance, and 416 μL of the drug solution was dispensed into a glass vial. 5.8 mg (1.1 equivalents) of solid fumarate was weighed and added to this drug solution. Initially, it was in a solution state, but then the solid precipitated. After stirring for 2 hours, the suspension became concentrated, and 0.2 mL of 2-methyltetrahydrofuran was added. After stirring for a further 18 hours, a final suspension was obtained. The obtained suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as fumarate crystalline form I by X-ray powder diffraction.

[0073] Preparation of fumarate crystalline form I (batch number: A16498-004D13): Approximately 25 mg of the starting material, free base (batch number: A16803-008S3), was weighed, and 0.5 mL of acetonitrile / water (19 / 1, v / v) mixed solvent was added at room temperature (~24°C). The mixture was stirred for approximately 10 minutes to obtain a white suspension. When 5.8 mg (1.1 equivalents) of solid fumarate was added, the suspension became more concentrated. 0.6 mL of acetonitrile / water (19 / 1, v / v) mixed solvent was added, and stirring was continued for 20 hours to obtain a final suspension. The obtained suspension was filtered using a syringe with a 0.22 μm micropore filter, and the resulting solid was vacuum-dried at 40°C for 5 hours to obtain the sample. The sample was identified as fumarate crystalline form I by X-ray powder diffraction.

[0074] Scale-up production of fumarate crystal form I Approximately 350 mg of free base (batch number: A16803-008S3) was weighed and dissolved in 7 mL of butanone at room temperature (~21°C). 1.1 equivalents of solid fumarate (82 mg) were added. The mixture was first stirred for 2 minutes to obtain a solution. Seed crystals of fumarate crystal form I were added, and a concentrated suspension was obtained by stirring for approximately 3 minutes. Subsequently, 2 mL of butanone was added, and the mixture was stirred at room temperature for 16 hours to obtain a suspension. The obtained suspension was filtered by vacuum pump, and the solid was recovered. This solid was vacuum-dried at 40°C for 4 hours to obtain the sample (batch number: A16498-045C1). The sample, obtained in 85% yield, was identified as fumarate crystal form I by X-ray powder diffraction (Figure 24).

[0075] Under room temperature conditions, 3 g of free base form I was added to MEK (80 mL) to obtain a clarified solution. Then, fumaric acid (1.1 equivalents) and seed crystals (fumarate form I, batch number: A16498-045C1) were added, and the mixture was stirred at room temperature for 20 hours. The resulting solid was collected by filtration, and it was confirmed that an excess amount of fumaric acid remained. This solid was re-added to MEK (40 mL), stirred at room temperature for 4 hours, and then the suspension was filtered. The obtained filter cake was dried at 40°C for 3 hours, successfully preparing fumarate crystalline form I in a yield of 81.5% (2.7 g). Characterization data is shown in Figure 25-28.

[0076] 3. Related properties of pharmaceutically acceptable salts of compound A Compound A (defined as free base crystal form I) is an anhydrous crystalline form with a melting point of 245°C. Salt form screening was performed, yielding 11 crystalline salts and 22 crystal forms. These include hydrochloride crystal forms I / II, sulfate crystal forms I / II / III / IV, p-toluenesulfonate crystal forms I / II / III / IV, mesylate crystal form I, benzenesulfonate crystal form I / II, oxalate crystal form I, maleate crystal form I, phosphate crystal forms I / II / III, L-camphorsulfonate crystal form I / II, tartrate crystal form I, and fumarate crystal form I. Characteristic data for the anhydrous crystalline form and possible anhydrous crystalline form samples are shown in Table 16, Figure 29, and Figure 30. Table 16 Summary of Solid-Phase Properties Data for Free Bases and Crystalline Salts [Table 16] TIFF2026508813000021.tif255170TIFF2026508813000022.tif198170a) Salt formation ratio: The salt formation ratio of inorganic salts is measured by ion chromatography, and the salt formation ratio of organic salts is 1 Analysis by H-NMR b) m / d: Melting accompanied by decomposition

[0077] 3.1 Short-term physical stability test of anhydrous crystalline form Mesylate crystal form I, benzenesulfonate crystal form I, oxalate crystal form I, phosphate crystal form I, L-camphorsulfonate crystal form II, and fumarate crystal form I were left in a high-humidity environment (40°C / 75%RH, open) for one day. The short-term physical stability results of these anhydrous crystalline forms are shown in Table 17 and Figure 31. Except for mesylate crystal form I, the other anhydrous crystalline forms were stable under high-humidity conditions. As shown in Figure 32, a new form of mesylate was identified, indicating that mesylate crystal form I is unstable and that a crystal transition occurred after being left standing for one day under high-humidity conditions. Table 17 Results of short-term physical stability evaluation [Table 17]

[0078] Since phosphate crystalline form I, L-camphor sulfonate crystalline form II, and fumarate crystalline form I exhibited appropriate solid-state properties, each was scaled up to 350 mg for hygroscopic evaluation. DVS measurements confirmed that phosphate crystalline form I and L-camphor sulfonate crystalline form II showed slight hygroscopicity, while fumarate crystalline form I exhibited almost no hygroscopicity. However, colloid formation was observed during the preparation of L-camphor sulfonate crystalline form II, which became a potential risk factor in the manufacturing process. Conclusion: The above test results show that phosphate crystal form I and fumarate crystal form I have superior solid-state properties, exhibiting favorable characteristics in terms of the rationality of the acid acid formation ratio, crystallinity, solvent-free properties, and hygroscopicity. Furthermore, it was revealed that fumarate crystal form I also has the advantage of maintaining a single crystal form under various crystallization conditions.

[0079] Therefore, phosphate crystalline form I and fumarate crystalline form I were selected as candidate salt forms, and their solid stability and solubility in biological solvents and water were investigated. Biological solvent solubility tests and stability tests were conducted for phosphate crystalline form I and fumarate crystalline form I, and compared with the data for free base crystalline form I (the results are shown in Table 18 and Figures 33-62). Table 18 Comparison of data between free base crystal form I and dominant candidate salt form [Table 18] a) Salt formation ratio: The salt formation ratio of inorganic salts is measured by ion chromatography, and the salt formation ratio of organic salts is 1 Analysis was performed using 1H-NMR. b) Sample processing: The experiment was conducted using duplicated samples (n=2), and the data represents the mean of the experimental values. LOQ) = 0.002 mg / mL c) m / d: Melting accompanied by decomposition

[0080] 3.2 Scale-up production of the dominant salt form and solubility and stability testing thereof Based on solid-state properties and production feasibility, phosphate crystal form I, fumarate crystal form I, and free base crystal form I were selected as targets for scale-up preparation, and biological solvent solubility tests and solid-state stability tests were conducted. 3.2.1 Scale-up preparation of phosphate crystal form I Phosphate crystal form I was prepared in 350 mg quantities (see section 2.8.4 for experimental details). As shown in Figures 19 and 33, the obtained solid (batch No.: A16498-045A1) consisted of aggregated, irregularly shaped crystals with high crystallinity, consistent with phosphate crystal form I. The DSC curve in Figure 34 showed two superimposed endothermic peaks due to melting accompanied by decomposition. The TGA showed a weight loss of 0.2% from room temperature to 50°C. 1 No significant solvent residue was detected by 1H-NMR, and the acid acid stoichiometric ratio detected by IC was 1:1. Therefore, phosphate crystal form I was successfully prepared in 93% yield. DVS results (Figures 35-37) showed that phosphate crystal form I exhibited mild hygroscopicity (weight increase due to 1.3% absorption at 80% RH and 1.6% absorption at 90% RH), and no change in crystal form was observed after DVS analysis. 3.2.2 Scale-up preparation of fumarate crystal form I Fumarate crystal form I (batch No.: A16498-045C1) was prepared in a 350 mg batch according to the method described in section 2.12. As shown in Figure 38-42, high-crystallinity crystals were obtained, consistent with fumarate crystal form I. The size of fumarate crystal form I was microcrystals less than 5 μm. 1 ¹H-NMR analysis confirmed that the base:acid stoichiometric ratio was 1:0.5. A single endothermic peak was observed in the DSC curve due to melting accompanied by decomposition, and TGA showed a weight loss of 1.0% in the temperature range of 180°C to 235°C. Fumarate crystal form I was successfully prepared with a yield of 85%. From the DVS results in Figures 39-41, fumarate crystal form I was substantially non-hygroscopic (weight increase due to moisture absorption of 0.15% at 80% RH and 0.20% at 90% RH), and the crystal form did not change after DVS analysis.

[0081] 3.3 Solubility tests in biological solvents and water Solubility tests were conducted on free base crystalline form I (batch No.: A16803 - 008S3), phosphate crystalline form I (batch No.: A16498 - 045A1), and fumarate crystalline form I (batch No.: A16498 - 045C1) in biological solvents (SGF, FaSSIF, FeSSIF) and water. The target concentration was set at 5 mg / mL and the temperature at 37 °C, and the results are shown in Table 19 and Figures 43 - 56. Compound A had low solubility in SGF and water (<LOD), and showed a certain solubility in FeSSIF (0.2 - 1.9 mg / mL). The solubility in FaSSIF and FeSSIF was in the order of phosphate crystalline form I > fumarate crystalline form I ≥ free base crystalline form I. As shown in Figures 44 - 47, the free base crystalline form I did not change in water, FaSSIF, and FeSSIF, but amorphousized after 2 hours in SGF. As shown in Figures 48 - 52, an additional peak at 16° (2θ) was confirmed in the XRPD pattern of the solid residue of phosphate crystalline form I in water. Phosphate crystalline form I amorphousized after shaking in SGF for 2 hours. New form 1 was generated after shaking in FaSSIF and FeSSIF for 0.5 hours, and new form 2 was generated in FaSSIF after 24 hours. Forms 1 and 2 were unstable and changed to amorphous and form 3 respectively after drying. The PO4 3- As a result of IC analysis of the content in the residual solid (Table 20), phosphate crystalline form I dissociated into the free base in FaSSIF and FeSSIF. Form 3 showed medium to moderately high crystallinity by XRPD, 1 no obvious residual organic solvent was detected by 1H - NMR. Multiple endothermic peaks were detected by DSC, and a 0.4% weight loss was shown at 130 - 180 °C by TGA, but no obvious PO4 3- was detected by IC, suggesting that form 3 might be a new anhydrous crystalline form of the free base. As shown in Figures 53 - 56, no change was observed in fumarate crystalline form I in biological solvents and water. Table 19 Solubility test results in biological solvents and water

Table 19

[0082] 3.4 Solid phase stability study Free base crystal form I, phosphate crystal form I, and fumarate crystal form I were left for 14 days at 60°C (closed) and 40°C / 75%RH (open), and their solid state stability was evaluated by performing XRPD analysis and purity analysis over time. The results are shown in Table 21 and Figures 57 to 62. Free base crystal form I, phosphate crystal form I, and fumarate crystal form I were all physically and chemically stable under the above test conditions. Table 21 Stability Evaluation Results [Table 21]

[0083] 4. Related properties of compound A fumarate The fumarate crystalline form was obtained by salt formation with a free base and 1.1 equivalents of fumaric acid, and was named fumarate crystalline form I (synthesis method is described in section 2.12, batch No.: A16498-067-B1). The fumarate crystal form I was characterized as follows: XRPD characteristic peaks were at 2θ: 4.703°, 5.234°, 7.100°, 9.515°, 10.561°, 10.864°, 11.566°, 14.336°, 15.324°, 15.926°, 16.625°, 17.834°, 18.671°, 19.193°, 19.904°, 20.972°, 21.320°, 21.607°, 21.908°, 22.058°, 23.11°. It was observed at 8°, 23.487°, 24.089°, 24.899°, 25.162°, 25.337°, 26.463°, 26.767°, 28.444°, 28.809°, 29.017°, 29.496°, 30.621°, 31.059°, 32.281°, 32.640°, 33.214°, 33.407°, 34.009°, 34.480°, 35.672°, 37.870°, 38.210°, 39.076°, and 39.488°. 1 ¹H-NMR revealed an acid-to-base molar ratio of 0.5:1. DSC showed an endothermic peak indicating the melting point at 251°C, and TGA results showed no significant weight loss below 200°C, indicating it is an anhydrous compound. It is essentially non-hygroscopic. It was physicochemically stable for 7 days under 60°C / closed and 40°C / 75%RH conditions. See Figures 25-28 and 61-64.

[0084] 4.1 Research on the storage stability of solids 4.1.1 Solid stability at 60°C / closed and 40°C / 75%RH The solid stability of fumarate crystal form I was evaluated for 7 days under 60°C / closed and 40°C / 75%RH conditions. No change in crystal form was observed, and the chemical purity remained unchanged. Therefore, crystal form I was confirmed to be physicochemically stable for 7 days under these conditions. The experimental results are shown in Figures 61 and 62. 4.1.2 Mechanical grinding An appropriate amount of fumarate crystalline form I (batch No. A16498-067-B1) was ground in a mortar for 5 minutes, and samples were taken at 2 minutes and 5 minutes to perform XRPD measurements. There was no change in the crystalline form after grinding, and no significant decrease in crystallinity was observed. The experimental results are shown in Figure 65. 4.1.3 Tablet compression test An appropriate amount of fumarate crystal form I (batch No. A16498-067-B1) was weighed into a mold, manually compressed (40 MPa, 1 minute), and then XRPD analysis was performed. The crystal form did not change after tableting, and although the crystallinity decreased slightly, the experimental results are shown in Figure 66.

[0085] 4.2 Polycrystalline Form Screening 4.2.1 Simple Measurement of Solubility Under room temperature conditions, 5 mg of fumarate crystalline form I (batch No. A16498-067-B1) was weighed into a sample vial. Solubility (mg / mL) was then calculated by gradually adding solvent dropwise until the drug was completely dissolved and a clear solution was obtained, or until 1600V was reached. The results are summarized in Table 22 and Figure 67. Fumarate crystalline form I showed high solubility in DMSO (>167 mg / mL), but extremely low solubility in water and most other organic solvents (<5.0 mg / mL). Table 22 Simple measurement results of solubility of fumarate crystal form I [Table 22] 1. Measured values ​​were rounded to the nearest integer, and "<" was used to indicate undissolved substances, while ">" was used to indicate dissolved substances.

[0086] 4.2.2 Evaporation Crystallization Test 10 mg of fumarate crystalline form I (batch No. A16498-067-B1) was dissolved in a solvent (1.0 mL) at room temperature or 50°C to prepare a clarified solution. This solution was divided into two equal parts; one was rapidly dried by nitrogen gas blowing, and the other was slowly dried by evaporation under perforated film at room temperature. However, no new fumarate crystalline forms were obtained. However, new free base crystalline forms (free base form 1 and free base crystalline form V) were formed. Free base form 1 may be in a metastable state and changes to free base crystalline form V after drying. No new crystalline forms of compound A fumarate were confirmed. The results are shown in Table 23 and Figure 68. Table 23 Results of Evaporation Crystallization Test [Table 23]

[0087] 4.2.3 Cooling Crystallization Test 30 mg of fumarate crystal form I (batch No. A16498-067-B1) was weighed into a sample vial, and after adding the solvent at 50°C, the mixture was stirred for 30 minutes. The solution was filtered through a microfilter and transferred to a clear vial. This filtrate was divided into two equal parts; one was rapidly cooled in a refrigerator (5°C), and the other was allowed to naturally cool to room temperature in a heated metal module with the power off. If a solid precipitate formed, the corresponding characterization was performed, but no novel crystal forms were obtained. In methanol solution, fumarate crystal form I dissociated into free base form 1 upon rapid cooling and into free base form 2 upon slow cooling. After drying, forms 1 and 2 transformed into free base crystal form V and free base crystal form VI, respectively. The results are shown in Table 24 and Figure 69. However, no novel crystal forms of compound A fumarate were confirmed. Table 24 Experimental results of cooling crystallization [Table 24]

[0088] 4.2.4 Reverse Solvent Precipitation Test An appropriate amount of fumarate crystal form I (batch A16498-067-B1) was dissolved in 0.2-0.4 mL of MeOH, THF, or DMSO at room temperature, and filtered to obtain a clarified solution. The reverse solvent was gradually added to this solution, and the process was continued until a solid precipitate formed or the solvent volume reached 10V. If no precipitate formed, the solution was cooled to 5°C, stirred for 40 hours, filtered, and the resulting filtration cake was analyzed by XRPD. No new crystal forms were obtained. However, a new free base crystal form (free base crystal form VII) was formed. The results are shown in Table 25 and Figure 70. Note that no new crystal forms of compound A fumarate were identified. Table 25 Results of reverse solvent precipitation test [Table 25]

[0089] 4.2.5 Tritulation Test 30 mg of fumarate crystal form I (batch A16498-067-B1) was weighed into a sample vial, and a solvent was added to prepare a suspension with a concentration of 30 mg / mL. This suspension was stirred at room temperature or 50°C for 3 or 7 days. The solid was collected by filtration, and the filtration cake was characterized by XRPD. No novel fumarate crystal forms were found. Fumarate crystal form I dissociated to free base crystal form VII in alcohols, water, 2-Me-THF, MTBE, and acetone. The results are shown in Tables 26-27 and Figures 71-74. No novel crystal forms of compound A fumarate were identified. Table 26 Results of the 3-Day Tritulation Test [Table 26] Table 27 Experimental results of 7-day trituration [Table 27] In conclusion, polymorphic screening was performed using fumarate crystal form I as a starting material, employing various methods including volatile crystallization, tritulation, reverse solvent precipitation, refrigeration crystallization, and mechanical grinding. However, no new fumarate crystal forms of compound A were generated. This result suggests that compound A fumarate crystal form I is likely the only crystal form of compound A fumarate. In summary, fumarate crystal form I exhibits acceptable properties and is considered suitable for further development.

[0090] 5 Analysis method 5.1 Polarizing Microscope (PLM) PLM analysis was performed using a polarizing microscope (model: ECLIPSE LV100POL, Nikon, Japan). A small amount of sample was placed on a glass slide, cedar wood oil was added to disperse the sample, and then the slide was covered with a coverslip. Observation and photography were performed using objective lenses with magnifications of 4 to 20x.

[0091] 5.2 X-ray Powder Diffraction (XRPD) Solid samples were analyzed using an X-ray powder diffractometer. The samples were placed on a zero-background silicon surface and lightly pressed to flatten them. The measurement conditions for the X-ray powder diffractometer are shown in Table 28. Table 28 Parameters of the XRPD measurement method [Table 28]

[0092] 5.3 Thermogravimetric analysis (TGA) The thermogravimetric analyzer used was a TGA 55 (TA Instruments, USA). 1–5 mg of sample was placed in a zero-adjusted aluminum sample pan, and measurements were performed using the temperature program shown in Table 29. The obtained data were analyzed using TRIOS software. Table 29 TGA Test Method Parameters [Table 29]

[0093] 5.4 Differential Scanning Calorimetry (DSC) The differential scanning calorimeter used was a DSC 250 (TA Instruments, USA). 1-3 mg of sample was placed in a perforated DSC sample pan, and heating tests were performed according to the measurement conditions shown in Table 30. The obtained data were analyzed using TRIOS software. Table 30 DSC Test Method Parameters [Table 30]

[0094] 5.5 Dynamic Moisture Adsorption Device (DVS) Water vapor adsorption / desorption data for the samples were collected using a dynamic moisture adsorption apparatus (proUmid GmbH&Co.KG, Germany). Approximately 50-70 mg of the sample was placed in a zero-point adjusted sample pan, and the sample weight was accurately measured. The measurement conditions for the anhydrous crystalline form are shown in Table 31. Table 31 Parameters for DVS analysis of anhydrous crystalline form [Table 31]

[0095] 5.6 Hydrogen nuclear magnetic resonance ( 1 (H-NMR) Hydrogen spectral information of the samples was collected using a Bruker 400MHz instrument. The samples were prepared by dissolving them in DMSO-d6 solvent, and measurements were performed under the conditions shown in Table 32. The obtained data were analyzed using MestReNova software. Table 32 1 H-NMR analysis method parameters [Table 33]

[0096] 5.7 High-Performance Liquid Chromatography (HPLC) HPLC analysis was performed using an Agilent HPLC 1260 series instrument. The HPLC analysis conditions used for solubility and stability tests are shown in Tables 33 and 34, respectively. Table 33 HPLC analysis method for solubility tests [Table 33] Table 34 HPLC analysis method for stability testing [Table 34]

[0097] 5.8 Ion Chromatography (IC) IC analysis of salts was performed using a Thermo ICS-6000 instrument. The IC instrument and analytical conditions used are shown in Tables 35 and 36. Table 35 IC Devices (Anions) [Table 35] Table 36 IC Analysis Method Parameters (Anions) [Table 36]

Claims

1. A pharmaceutically acceptable salt of compound A, Compound A has the following structure, 【Chemistry 1】 A pharmaceutically acceptable salt of compound A, characterized in that the pharmaceutically acceptable salt is a hydrochloride, sulfate, phosphate, p-toluenesulfonate, mesylate, benzenesulfonate, oxalate, maleate, L-camphorsulfonate, gentisidine, tartrate, or fumarate.

2. A pharmaceutically acceptable salt of compound A according to claim 1, characterized in that the pharmaceutically acceptable salt is a phosphate salt.

3. The phosphate is crystalline form I of compound A phosphate, A pharmaceutically acceptable salt of compound A according to claim 2, characterized in that it has at least one XRPD characteristic peak selected from 4.3°±0.2°, 17.4°±0.2°, 21.6°±0.2°, and 21.9°±0.2° as 2θ.

4. A pharmaceutically acceptable salt of compound A according to claim 1, characterized in that the pharmaceutically acceptable salt is a fumarate.

5. The fumarate is crystalline form I of compound A fumarate, A pharmaceutically acceptable salt of compound A according to claim 4, characterized in that it has at least one XRPD characteristic peak selected from 9.5°±0.2°, 10.5°±0.2°, 14.3°±0.2°, and 21.9°±0.2° as 2θ.

6. A method for producing the crystalline form I of compound A phosphate according to claim 3, A step of contacting compound A with phosphoric acid in a solvent to form compound A phosphate, A method for producing compound A phosphate, characterized by comprising the step of precipitating the compound A phosphate as crystalline form I of compound A phosphate.

7. A method for producing the crystalline form I of compound A fumarate according to claim 5, A step of reacting compound A with fumaric acid in a solvent to produce compound A fumarate, A manufacturing method characterized by comprising the step of precipitating compound A fumarate as the compound A fumarate crystal form I.

8. A pharmaceutical composition characterized by comprising a pharmaceutically acceptable salt of compound A as described in any one of claims 1 to 5.

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