Crystalline form of nirogacestat hydrobromide, method of preparation thereof, and uses

Abstract

Novel crystalline forms of nirogacestat hydrobromide and methods for preparing the same, pharmaceutical compositions containing the crystalline form, and applications for preparing γ-secretase inhibitor pharmaceuticals and desmoid tumor treatments using the crystalline form.

Description

Technical Field

[0001] The present disclosure belongs to the field of chemical crystallography, and particularly relates to a novel crystal form of nirogacestat dihydrobromide, as well as its preparation method and uses.

Background Art

[0002] Desmoid tumors (also known as aggressive fibromatosis) are rare soft tissue tumors that locally infiltrate and grow slowly. Although considered benign because they do not have the ability to metastasize, there is an urgent need for effective drug treatment due to the significant morbidity and sometimes mortality they cause in patients.

[0003] As a promising development, there is the γ-secretase inhibitor nirogacestat developed by SpringWorks Therapeutics, which has received marketing approval in the United States and is used in the treatment of desmoid tumors. Nirogacestat has been clinically shown to contribute to the treatment of desmoid tumors by binding to γ-secretase and inhibiting the protease activation of the Notch receptor. Previous clinical research data have shown that Notch signaling plays an important role in cancer development. Therefore, inhibiting Notch signaling is an important strategy for desmoid tumor treatment.

[0004] The chemical name of nirogacestat is (S)-2-(((S)-)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide (referred to as "Compound I"), and the structure of its dihydrobromide salt is shown below.

Chemical Formula

[0005] As is well known, drug polymorphism is a common phenomenon in the development of small molecule drugs and is an important factor affecting drug quality. A crystalline form is a solid substance in which constituent units are arranged in a highly regular manner, forming a crystal lattice in all directions. Polymorphism refers to the phenomenon in which a compound exists in multiple crystalline forms. A compound may exist in one or more crystalline forms, but it is not possible to reliably predict their existence or properties.

[0006] Different crystalline forms of active ingredients (APIs) possess varying physicochemical properties, such as chemical stability and solubility, which affect dissolution and absorption in the body, and to some extent, influence clinical efficacy and safety. Furthermore, different solid forms of APIs result in differences in manufacturability, including compressibility, crushing behavior, and stability under pressure during tableting, impacting the pharmaceutical production process and handling. Therefore, each solid form of an API possesses unique characteristics, offering an opportunity to improve formulation performance.

[0007] Prior art WO2021029854A1 discloses multiple crystalline forms of compound I hydrobromide. Example 6 of WO2021029854A1 shows that crystalline form A is the most stable and preferred crystalline form. However, the inventors of this disclosure have found that crystalline form A exhibits low solubility.

[0008] The possibility of improving drug efficacy by exploring novel solid forms has led the inventors of this disclosure to surprisingly obtain a novel crystalline form of compound I hydrobromide. This crystalline form is superior in at least one respect, including solubility, hygroscopicity, purity, stability, adhesion, compressibility, fluidity, in vitro and in vivo solubility, and bioavailability. In particular, the crystalline form of compound I hydrobromide of this disclosure has good solubility, high density, good compressibility, and stability, solving the problems of the prior art and having great significance for the development of pharmaceuticals containing compound I hydrobromide. [Overview of the project]

[0009] This disclosure aims to provide a novel crystalline form of compound I hydrobromide, a method for preparing it, and a pharmaceutical composition containing said crystalline form.

[0010] In accordance with the purposes of this disclosure, the crystalline form CSV of compound I hydrobromide (hereinafter referred to as "crystalline form CSV") is provided.

[0011] In one embodiment provided herein, the X-ray powder diffraction pattern of crystalline CSV includes characteristic peaks at 2θ values ​​of 6.1°±0.2°, 9.6°±0.2°, and 13.6°±0.2° when using Cu-Kα rays.

[0012] Furthermore, the X-ray powder diffraction pattern of crystalline CSV, when using Cu-Kα rays, includes one, two, or three characteristic peaks at 2θ values ​​of 4.5°±0.2°, 16.1°±0.2°, and 18.6°±0.2°. Preferably, the X-ray powder diffraction pattern of crystalline CSV includes characteristic peaks at 2θ values ​​of 4.5°±0.2°, 16.1°±0.2°, and 18.6°±0.2°.

[0013] Furthermore, the X-ray powder diffraction pattern of crystalline CSV, when using Cu-Kα rays, includes one, two, or three characteristic peaks at 2θ values ​​of 12.7°±0.2°, 21.5°±0.2°, and 23.0°±0.2°. Preferably, the X-ray powder diffraction pattern of crystalline CSV includes characteristic peaks at 2θ values ​​of 12.7°±0.2°, 21.5°±0.2°, and 23.0°±0.2°.

[0014] In yet another embodiment, the X-ray powder diffraction pattern of crystalline CSV, when using Cu-Kα rays, includes three, four, five, six, seven, eight, or nine characteristic peaks at 2θ values ​​of 6.1°±0.2°, 9.6°±0.2°, 13.6°±0.2°, 4.5°±0.2°, 16.1°±0.2°, 18.6°±0.2°, 12.7°±0.2°, 21.5°±0.2°, and 23.0°±0.2°.

[0015] This is not a limitation, and the XRPD patterns of crystalline CSV are essentially shown in Figure 1.

[0016] This is not a limitation, but the TGA curve for the crystalline form CSV is substantially shown in Figure 2, and it shows a weight loss of 0.04% when heated to approximately 100°C.

[0017] This is not a limitation, but the DSC curve for crystalline CSV is substantially shown in Figure 3, exhibiting an endothermic peak with an onset temperature of approximately 259°C and a peak temperature of approximately 263°C.

[0018] This does not imply any limitation; the crystalline form CSV is anhydrous.

[0019] A method for producing crystalline CSV is also provided in accordance with the purposes of this disclosure. The method includes: Compound I hydrobromide is dissolved in a mixed solvent of ether and acid, evaporated to obtain a solid, and then heated to obtain the crystalline form CSV.

[0020] The crystalline form CSV of this disclosure exhibits the following unforeseen technical effects: (1) Compared to the prior art, the crystalline form of CSV of this disclosure has better compressibility. The good compressibility of the crystalline form of CSV avoids problems such as failure in hardness / abrasion tests and tablet breakage, thereby increasing the reliability of the manufacturing process, improving the appearance of the product, and enhancing product quality and production efficiency. (2) Compared to the prior art, the crystalline form of CSV of this disclosure has a higher density. Experimental results show that the bulk density and tap density of crystalline form CSV are superior to those of crystalline form A of the prior art. The high density of crystalline form CSV is advantageous for large-scale production. Furthermore, the high density of crystalline form CSV contributes to a reduction in dust and a reduction in occupational hazards. (3) The crystalline form CSV of this disclosure has good stability. Crystalline CSV remained unchanged after storage for at least 6 months under conditions of 25°C / 60%RH and 40°C / 75%RH, with virtually no change in chemical purity during storage. Furthermore, it remained unchanged after storage for at least 2 months under 60°C / 75%RH, with virtually no change in chemical purity during storage. These results demonstrate that crystalline CSV exhibits good stability under long-term, accelerated, and stress conditions.

[0021] The crystalline form of CSV has good stability against mechanical forces. The crystalline form of CSV does not change even after grinding and under different compression forces.

[0022] Seasonal variations, regional climate differences, and high humidity conditions due to environmental factors can affect the storage, transportation, and manufacture of APIs. Also, in pharmaceutical processing, grinding and milling of APIs are often required. The crystalline form of CSV has good stability and helps to avoid the impact on drug quality due to crystal transition during storage, transportation, and manufacture. Furthermore, it reduces the risk of decreased crystallinity and undesirable polymorphic transitions during pharmaceutical processing. As a result, the quality of the API can be consistently controlled, minimizing quality variations, changes in bioavailability, and toxicity caused by crystal transition.

[0023] In accordance with the objectives of the present disclosure, a crystalline form CSVI of Compound I dihydrobromide (hereinafter referred to as "crystalline form CSVI") is also provided.

[0024] In one aspect provided herein, the X-ray powder diffraction pattern of the crystalline form CSVI, when using Cu-Kα radiation, includes characteristic peaks at 2θ values of 8.8° ± 0.2°, 10.4° ± 0.2°, 19.4° ± 0.2°, and 20.9° ± 0.2°.

[0025] Furthermore, the X-ray powder diffraction pattern of the crystalline form CSVI, when using Cu-Kα radiation, includes one or two or three characteristic peaks at 2θ values of 22.9° ± 0.2°, 26.8° ± 0.2°, and 25.9° ± 0.2°. Preferably, it includes all three of these.

[0026] In yet another aspect, the X-ray powder diffraction pattern of the crystalline form CSVI, when using Cu-Kα radiation, includes four or five or six or seven or eight or nine characteristic peaks at 2θ values of 8.8° ± 0.2°, 10.4° ± 0.2°, 19.4° ± 0.2°, 20.9° ± 0.2°, 22.9° ± 0.2°, 26.8° ± 0.2°, 25.9° ± 0.2°, 6.3° ± 0.2°, and 12.7° ± 0.2°.

[0027] This is not a limitation, but the XRPD patterns of crystalline CSVI are substantially shown in Figures 7, 8, or 10.

[0028] This is not a limitation, but the TGA curve for crystalline CSVI is substantially shown in Figure 9, showing a weight loss of 1.1% when heated to approximately 80°C and a weight loss of 0.6% when heated from 80°C to 110°C.

[0029] This is not a limitation, but the crystalline form of CSVI is a hydrate, preferably a 0.25-hydrate.

[0030] A method for producing crystalline CSVI is also provided for the purposes of this disclosure. The method includes: Compound I hydrobromide is dissolved in alcohol, the solution is filtered, toluene is added to the filtrate, and the solid is allowed to precipitate by standing at -20°C. The solid is separated and vacuum-dried under moisture compensation to obtain crystalline CSVI.

[0031] Furthermore, the alcohol is preferably methanol. The volume ratio of the alcohol to toluene is preferably 1:5. The drying temperature is preferably between room temperature and 80°C. The crystalline form CSVI of this disclosure exhibits the following unforeseen technical effects: (1) Compared to the prior art, the crystalline form CSVI of this disclosure has better solubility. Nilogacestat is a poorly soluble drug in water and belongs to BCS class II. Compared to the crystalline form A of the prior art, the crystalline form CSVI exhibits higher solubility in FaSSIF and FeSSIF, which is beneficial for enhancing drug absorption in the body and improving bioavailability. (2) Compared to the prior art, the crystalline form of CSVI of this disclosure has better compressibility. The good compressibility of the crystalline form of CSVI can avoid problems such as failure in hardness / abrasion tests and tablet breakage, increase the reliability of the manufacturing process, improve product appearance, and enhance product quality and production efficiency. (3) The crystalline form of CSVI of this disclosure has good stability. Crystalline CSVI remained unchanged for at least 8 months under 25°C / 60%RH and 40°C / 75%RH conditions, and also remained unchanged for at least 2 months under 60°C / 75%RH conditions. These results demonstrate that crystalline CSVI exhibits good stability under long-term, accelerated, and stress conditions.

[0032] Crystalline CSVI exhibits good stability against mechanical forces. Crystalline CSVI remains unchanged after grinding and under different compressive forces.

[0033] High humidity conditions due to seasonal variations, regional climatic differences, and environmental factors can affect the storage, transport, and manufacturing of APIs. Furthermore, grinding and milling of APIs are often required during formulation. Crystalline CSVI offers good stability and helps avoid the impact on drug quality due to crystallization during storage, transport, and manufacturing. It also reduces the risk of crystallinity degradation and undesirable polymorphic transformations during formulation. As a result, API quality can be consistently controlled, minimizing quality variations, changes in bioavailability, and toxicity caused by crystallization. In accordance with the purposes of this disclosure, this disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline CSV, or crystalline CSVI, or a combination thereof, and a pharmaceutically acceptable excipient. In accordance with the purposes of this disclosure, this disclosure provides applications for the preparation of γ-secretase inhibitor pharmaceuticals using crystalline CSV, crystalline CSVI, or a combination thereof.

[0034] In accordance with the purposes of this disclosure, this disclosure provides applications for the preparation of desmoid tumor therapeutics using crystalline CSV, crystalline CSVI, or a combination thereof. [Brief explanation of the drawing]

[0035] [Figure 1] Figure 1 shows the XRPD pattern of the crystalline form of CSV. [Figure 2] Figure 2 shows the TGA curve for the crystalline form CSV. [Figure 3] Figure 3 shows the DSC curve for the crystalline form of CSV. [Figure 4] Figure 4 shows the overlay of the XRPD pattern of the crystalline CSV (from top to bottom: initial, after 6 months of storage at 25°C / 60%RH, after 6 months of storage at 40°C / 75%RH, and after 2 months of storage at 60°C / 75%RH). [Figure 5] Figure 5 shows the overlay of the XRPD patterns of crystalline CSV before and after tableting (from top to bottom: before tableting, after tableting at 5kN, 10kN, and 20kN). [Figure 6] Figure 6 shows the overlay of the XRPD patterns of crystalline CSV before and after grinding (from top to bottom: before grinding, after grinding). [Figure 7] Figure 7 shows the XRPD pattern of crystalline CSVI. [Figure 8] Figure 8 shows the XRPD pattern of crystalline CSVI. [Figure 9] Figure 9 shows the TGA curve for the crystalline form of CSVI. [Figure 10] Figure 10 shows the XRPD pattern of crystalline CSVI. [Figure 11] Figure 11 shows the overlay of the XRPD pattern of crystalline CSVI (from top to bottom: initial, after 8 months of storage at 25°C / 60%RH, after 8 months of storage at 40°C / 75%RH, and after 2 months of storage at 60°C / 75%RH). [Figure 12] Figure 12 shows the overlay of the XRPD patterns of crystalline CSVI before and after tableting (from top to bottom: before tableting, after tableting at 5kN, 10kN, and 20kN). [Figure 13] Figure 13 shows the overlay of XRPD patterns before and after grinding of crystalline CSVI (from top to bottom: before grinding, after grinding). [Modes for carrying out the invention]

[0036] This disclosure is further illustrated by the following examples, which describe in detail the preparation and use of the crystalline forms of this disclosure. It will be obvious to those skilled in the art that modifications in materials and methods can be carried out without departing from the scope of this disclosure.

[0037] The following is an explanation of the abbreviations used in this disclosure: XRPD: X-ray Powder Diffraction DSC: Differential Scanning Calorimetry TGA: Thermo Gravimetric Analysis 1 1H NMR: Proton Nuclear Magnetic Resonance HPLC: High-Performance Liquid Chromatography FeSSIF: Fed State Simulated Intestinal Fluid FaSSIF:Fasted State Simulated Intestinal Fluid RH: Relative Humidity RT: Room Temperature

[0038] The equipment and methods used for data collection are as follows:

[0039] The XRPD patterns were acquired using a Bruker D8 ADVANCE X-ray powder diffractometer. The measurement conditions for X-ray powder diffraction were as follows: X-ray source:Cu,Kα Kα1(Å):1.54060 Kα2(Å):1.54439 Kα2 / Kα1 intensity ratio: 0.50 Voltage: 40kV Current: 40mA Scanning range (2θ): 4.0°~40.0°

[0040] DSC data was acquired using TA Q2000. The DSC measurement conditions are as follows: Heating rate: 10℃ / min Purge gas: Nitrogen

[0041] TGA data was acquired using TA Q500. The TGA measurement conditions are as follows: Heating rate: 10℃ / min Purge gas: Nitrogen

[0042] 1 ¹H NMR data were acquired using a Bruker Avance II DMX 400MHz NMR spectrometer. 1–5 mg of the sample was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to obtain solutions with concentrations of 2–10 mg / mL.

[0043] The detection conditions for the related substances are shown in Table 1.

[0044] [Table 1]

[0045] The measurement conditions for dynamic solubility are shown in Table 2.

[0046] [Table 2]

[0047] "Evaporation" refers to methods well known in the field, such as slow evaporation or rapid evaporation. Slow evaporation is performed in a container covered with a pinhole sealing film. Rapid evaporation is performed in an open container.

[0048] "Vacuum drying under moisture compensation" is carried out by methods well known in the field. The drying temperature is above room temperature, preferably room temperature to about 60°C, but conditions down to 50°C or 40°C are also acceptable. The drying time is 2 to 48 hours, or overnight. Typically, vacuum drying is performed by placing a cup of water inside a vacuum oven.

[0049] A "characteristic peak" refers to a representative diffraction peak used to identify a crystal, and when using Cu-Kα lines, it can have a deviation of ±0.2°.

[0050] An anhydrous substance refers to a solid form that does not contain water of crystallization or a solvent.

[0051] A "hydrate" refers to a solid form that contains water of crystallization.

[0052] In this disclosure, “crystal” or “crystal form” means a crystal or crystal form identified by the X-ray diffraction pattern shown herein. Those skilled in the art will understand that the X-ray powder diffraction pattern depends on the apparatus conditions, sample preparation, and sample purity. Furthermore, the relative intensity of the diffraction peaks can vary depending on the experimental conditions, so the order of peak intensities cannot be considered the sole or decisive factor. In practice, the diffraction peak intensities are related to the orientation of the crystal, and the values ​​shown are illustrative. Therefore, the crystal forms in this disclosure do not need to be exactly identical to the illustrative diffraction patterns. Crystal forms having diffraction patterns with identical or similar characteristic peaks are included within the scope of this disclosure.

[0053] In some embodiments of this disclosure, the crystalline form CSV or CSVI is pure and substantially free of other crystalline forms. "Substantially free" means that the content of other crystalline forms is less than 20% (w / w), specifically less than 10%, more specifically less than 5%, and more preferably less than 1%.

[0054] "Approximately" means that the measured values ​​such as weight, time, and temperature include a range of ±10%, ±5%, ±1%, ±0.5%, and even ±0.1%.

[0055] Unless otherwise specified, the following examples were carried out at room temperature. "Room temperature" refers to a range of 10 to 30°C, not a specific value.

[0056] Compound I used as a raw material in this disclosure includes, but is not limited to, a solid (crystalline or amorphous), an oil, a liquid, or a solution. Preferably, Compound I is used as a raw material in solid form.

[0057] The starting materials for compound I used in the following examples were prepared by the method disclosed in WO2021029854A1. [Examples]

[0058] [Example 1] Preparation of crystalline CSV Approximately 85 mg of compound I hydrobromide solid was weighed into a vial. 2.0 mL of a mixed solvent of 2-methyltetrahydrofuran / formic acid (1:1, v / v) was added, and after dissolution and filtration, a clear solution was obtained. This solution was evaporated at room temperature for approximately 3 days to obtain a solid. The obtained solid was heated to 160°C under a nitrogen atmosphere, held for 10 minutes, and then cooled to room temperature. Subsequently, it was heated to 200°C, held for 60 minutes, and then cooled to room temperature to obtain a crystalline solid.

[0059] The obtained solid was confirmed to be crystalline CSV, and its XRPD pattern is substantially shown in Figure 1, with the data listed in Table 3.

[0060] The TGA curve is shown in Figure 2, and it showed a weight loss of approximately 0.04% at 100°C.

[0061] The DSC curve is shown in Figure 3 and exhibits an endothermic peak with an onset temperature of approximately 259°C and a peak temperature of approximately 263°C.

[0062] [Table 3] JPEG2026508907000006.jpg83166

[0063] [Example 2] Compressibility of crystalline CSV Tablets were prepared using an ENERPAC manual tablet press. Approximately 60 mg each of crystalline form CSV and crystalline form A of the prior art were added to a Φ6 mm round punch and formed into tablets under a pressure of 3 kN. The tablets were left at room temperature for 24 hours to allow for complete elastic recovery, after which the diameter and thickness were measured and the fracture strength was measured using a hardness tester. As a result, the average tensile strength of crystalline form CSV was 0.55 MPa, and that of crystalline form A was 0.37 MPa, indicating that CSV showed superior compressibility.

[0064] [Example 3] Density of crystalline CSV Approximately 500 mg of the sample was gently placed into a 5 mL graduated cylinder to measure the bulk volume, and the tap volume was recorded after 1250 taps using a ZS-2E tap density tester. The calculated bulk and tap densities showed that crystalline form CSV had a higher density than crystalline form A (see Table 4).

[0065] [Table 4]

[0066] [Example 4] Stability of crystalline CSV Crystalline CSV was sealed in airtight containers and stored under conditions of 25°C / 60%RH, 40°C / 75%RH, and 60°C / 75%RH. Analysis by XRPD and HPLC (Table 5) showed that crystalline CSV was stable for at least 6 months at 25°C / 60%RH and 40°C / 75%RH, and stable for 2 months at 60°C / 75%RH.

[0067] [Table 5]

[0068] [Example 5] Stability of crystalline CSV under mechanical force XRPD measurements were performed after compressing crystalline CSV at different pressures (5kN, 10kN, and 20kN). The results are shown in Table 6, and the overlay patterns are shown in Figure 5. As a result, no change in crystallinity was observed at any of the pressures.

[0069] Furthermore, when crystalline CSV was ball-milled at 500 rpm for 5 minutes and then subjected to XRPD measurement, no change in crystallinity was observed before and after grinding, indicating good stability against mechanical forces (see Figure 6).

[0070] [Table 6]

[0071] [Example 6] Preparation of crystalline CSVI 0.64 g of compound I hydrobromide was dissolved in 8 mL of methanol, and 45 mL of toluene was added. The mixture was stirred at -20°C for approximately 18 hours to precipitate. The mixture was filtered at room temperature, and the wet cake was dried at 35°C, followed by vacuum drying at 80°C for 9.5 hours to obtain a crystalline solid. The obtained solid was confirmed to be crystalline CSVI, and its XRPD pattern is shown in Figure 7.

[0072] [Example 7] Preparation of crystalline CSVI 200 mg of compound I hydrobromide was dissolved in 2.5 mL of methanol, and 12.5 mL of toluene was added, followed by the addition of a small amount of seed crystal. The mixture was allowed to stand at -20°C for approximately 16 hours to precipitate. After filtration, the wet cake was dried at 25°C for 4 hours, and then vacuum-dried at 70°C for 6 hours under moisture compensation to obtain a crystalline solid.

[0073] The obtained solid was confirmed to be crystalline CSVI, and its XRPD pattern is shown in Figure 8. TGA measurements showed a weight loss of 1.1% at 80°C and 0.6% between 80 and 110°C, which corresponds to 0.25 equivalents of crystal water.

[0074] Crystalline form of CSVI 1 The 1H NMR data is as follows: 1 H NMR(400MHz,DMSO-d6)δ11.29(s,1H),9.30(brs,2H),7.93(brs,2H),7.75(s,1H),7.54(s, 1H),7.08(td,J=9.8,2.4Hz,1H),6.90(d,J=9.3Hz,1H),4.22(s,1H),3.51(s,2H),3.30-3.1 9(m,2H),3.00-2.88(m,1H),2.87-2.69(m,2H),2.61-2.52(m,2H),2.29-2.14(m,1H),2.04 -1.73(m,3H),1.64(d,J=7.6Hz,6H),1.41-1.25(m,2H),0.91(t,J=7.3Hz,3H),0.85(s,9H). 1 1H NMR analysis revealed no residual solvent.

[0075] [Example 8] Preparation of crystalline CSVI 200 mg of compound I hydrobromide was dissolved in 2.5 mL of methanol, and 12.5 mL of toluene was added, followed by a small amount of seed crystal. The mixture was allowed to stand at -20°C for approximately 16 hours to precipitate. After filtration, the wet cake was dried at 25°C for 4 hours, and then vacuum-dried at 70°C for 6 hours under moisture compensation. Further humidity cycling treatment from 0% to 60% to 0% RH was performed to obtain a crystalline solid.

[0076] The obtained solid was confirmed to be crystalline CSVI, its XRPD pattern is shown in Figure 10, and the data is listed in Table 7.

[0077] [Table 7]

[0078] [Example 9] Preparation of crystalline CSVI 0.1934 g of compound I hydrobromide solid was weighed and dissolved in 2.5 mL of methanol. 12.5 mL of toluene was added to the resulting clear solution. The mixture was allowed to stand at -20°C for approximately 16 hours to precipitate. The resulting suspension was filtered at room temperature. The wet cake was dried at 35°C for approximately 6 hours, and then vacuum-dried at 60°C for approximately 3 hours under moisture compensation to obtain a crystalline solid. The obtained crystalline solid was confirmed to be the crystalline form CSVI of this disclosure.

[0079] [Example 10] Solubility of crystalline CSVI When predicting the in vivo performance of a drug using solubility tests, it is crucial to simulate in vivo conditions as closely as possible. For oral drugs, in vivo conditions can be simulated and the effects of food can be predicted by using FaSSIF (fasting simulated intestinal fluid) and FeSSIF (feeding simulated intestinal fluid). The solubility in these media is close to the solubility in vivo.

[0080] Appropriate amounts of crystalline CSVI were suspended in FaSSIF and FeSSIF and maintained at 37°C. After 0.5 hours of equilibration, the suspensions were filtered, and the concentration of compound I (mg / mL) in each filtrate was measured by HPLC. The results are shown in Table 8, revealing that crystalline CSVI exhibits higher solubility in both FaSSIF and FeSSIF compared to crystalline form A of the prior art.

[0081] [Table 8]

[0082] [Example 11] Compressibility of crystalline CSVI Tablets were prepared using an ENERPAC manual tablet press. Approximately 60 mg of crystalline form CSVI and crystalline form A of the prior art were each placed in a Φ6 mm round punch, and tablets were formed under a pressure of 3 kN. The tablets were left at room temperature for 24 hours to allow them to fully recover their elasticity. Subsequently, the diameter (D) and thickness (L) were measured using calipers, and the fracture strength (hardness, H) was measured using a hardness tester. The tensile strength (T) of the powder was calculated using the following formula: T = 2H / πDL. The test results showed that the average tensile strength of crystalline form CSVI was 0.907 MPa, while that of the prior art crystalline form A was 0.37 MPa. Since a higher tensile strength under the same force indicates better compressibility, it was shown that crystalline form CSVI has superior compressibility compared to crystalline form A.

[0083] [Example 12] Stability of crystalline CSVI Appropriate amounts of crystalline CSVI were sealed in airtight containers and stored under conditions of 25°C / 60%RH, 40°C / 75%RH, and 60°C / 75%RH, respectively. The crystalline forms were analyzed by XRPD. The results are shown in Table 9, and the XRPD overlays are shown in Figure 11. As a result, the crystalline form of CSVI was stable for at least 8 months under conditions of 25°C / 60%RH and 40°C / 75%RH, demonstrating good stability under long-term storage and accelerated conditions. Furthermore, it was stable for at least 2 months under 60°C / 75%RH conditions, confirming good stability even under stress conditions.

[0084] [Table 9]

[0085] [Example 13] Stability of crystalline CSVI under mechanical force Appropriate amounts of crystalline CSVI were compressed into tablets using a Φ6 mm round punch under different pressures (5 kN, 10 kN, and 20 kN), and XRPD measurements were taken before and after compression. The test results are shown in Table 10, and the overlay patterns are shown in Figure 12. As a result, it was confirmed that crystalline CSVI is stable under all pressures.

[0086] Furthermore, crystalline CSVI was ground using a ball mill at 500 rpm for 5 minutes. XRPD measurements were performed before and after grinding, and the overlay shown in Figure 13 was observed, with no change in crystallinity. This demonstrates that crystalline CSVI has good stability against mechanical forces.

[0087] [Table 10]

[0088] The above embodiments are intended to illustrate the technical ideas and features of the Disclosure and to enable those skilled in the art to understand and implement the Disclosure. Therefore, they do not limit the scope of protection of the Disclosure. Any equivalent variations or modifications based on the spirit of the Disclosure should be included within the scope of protection of the Disclosure.

Claims

1. The crystalline form CSV of compound I hydrobromide, wherein the X-ray powder diffraction pattern, when using Cu-Kα rays, includes characteristic peaks at 2θ values ​​of 6.1°±0.2°, 9.6°±0.2°, and 13.6°±0.2°. 【Chemistry 1】

2. The crystalline form CSV of compound I hydrobromide according to claim 1, wherein the X-ray powder diffraction pattern, when using Cu-Kα rays, includes at least one characteristic peak at 2θ values ​​of 4.5°±0.2°, 16.1°±0.2°, and 18.6°±0.2°.

3. The crystalline form CSV of compound I hydrobromide according to claim 1, wherein the X-ray powder diffraction pattern, when using Cu-Kα rays, includes at least one characteristic peak at 2θ values ​​of 12.7°±0.2°, 21.5°±0.2°, and 23.0°±0.2°.

4. The crystalline form CSV of compound I hydrobromide according to claim 2, wherein the X-ray powder diffraction pattern, when using Cu-Kα rays, includes at least one characteristic peak at 2θ values ​​of 12.7°±0.2°, 21.5°±0.2°, and 23.0°±0.2°.

5. The crystalline form CSV of compound I hydrobromide according to claim 1, wherein the X-ray powder diffraction pattern, when using Cu-Kα rays, is substantially the pattern shown in Figure 1.

6. The crystalline form CSVI of compound I hydrobromide, wherein the X-ray powder diffraction pattern, when using Cu-Kα rays, includes characteristic peaks at 2θ values ​​of 8.8°±0.2°, 10.4°±0.2°, 19.4°±0.2°, and 20.9°±0.2°. 【Chemistry 2】

7. The crystalline form CSVI of compound I hydrobromide according to claim 6, wherein the X-ray powder diffraction pattern, when using Cu-Kα rays, includes at least one characteristic peak at 2θ values ​​of 22.9°±0.2°, 26.8°±0.2°, and 25.9°±0.2°.

8. The crystalline form CSVI of compound I hydrobromide according to claim 6, wherein the X-ray powder diffraction pattern, when using Cu-Kα rays, is substantially the pattern shown in Figure 7, Figure 8, or Figure 10.

9. A pharmaceutical composition comprising a crystalline form CSV of compound I hydrobromide according to claim 1, or a crystalline form CSVI of compound I hydrobromide according to claim 6, or a combination thereof, and a pharmaceutically acceptable excipient.

10. A method for preparing a γ-secretase inhibitor pharmacopoeia, using the crystalline form CSV of compound I hydrobromide according to claim 1, or the crystalline form CSVVI of compound I hydrobromide according to claim 6, or a combination thereof.

11. A method for preparing a therapeutic agent for desmoid tumors, comprising using the crystalline form CSV of compound I hydrobromide according to claim 1, or the crystalline form CSVVI of compound I hydrobromide according to claim 6, or a combination thereof.

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