Polymorph of (s)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, and pharmaceutical composition comprising same

Abstract

The present invention provides a polymorph of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, which is an alpha-aminoamide derivative, and a pharmaceutical composition comprising same.

Description

Crystalline polymorphism of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate and pharmaceutical composition containing the same

[0001] The present invention relates to a crystal polymorph of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, which is an alpha-aminoamide derivative, and a pharmaceutical composition containing the same.

[0002]

[0003] (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate is a compound useful as an MAO-B inhibitor for the prevention and / or treatment of Parkinson's disease, as disclosed in Korean Patent Publication No. 10-2016-0039817.

[0004] In addition, according to Korean Patent Publication No. 10-2016-0039817, this substance is an alpha-aminoamide derivative and was developed as a therapeutic agent that inhibits MAO-B through reversible action via non-covalent bonding to alleviate or eliminate the side effects of existing MAO-B inhibitor drugs that exert therapeutic effects by acting irreversibly through covalent bonding with MAO-B.

[0005] Meanwhile, polymorphs refer to crystalline solids that possess the same molecular structure but undergo changes in crystal structure due to variations in molecular packing or molecular conformation. Therefore, polymorphs in a broad sense can be understood as a concept that includes pseudo-polymorphs, hydrates or solvates, salt forms, and co-crystals (Crystal Growth & Design (2011) 11, 887-895; Polymorphism the Pharmaceutical Industry: Wiley-Vch, 2006; pp. 1-19).

[0006] Furthermore, according to polymorphic transformations explained by Ostwald's rule of stage, polymorphs generally preferentially precipitate metastable polymorphs with relatively high thermodynamic energy during the crystallization process. They then possess the characteristic of maintaining thermodynamic stability by transitioning to relatively stable polymorphs in the solution and solid states. Consequently, molecules rearrange through phase transformations within the solvent to form more stable crystal structures, resulting in the generation of polymorphs.

[0007] As such, the crystal polymorphs generated through crystallization possess different thermodynamic energies, which causes changes in the physicochemical properties of metastable and stable crystal polymorphs.

[0008] Although crystal polymorphisms can be explored through conventional crystallization methods, the transitions of the aforementioned crystal polymorphs are not easily controlled. If metastable crystal polymorphs are preferred because they exhibit higher solubility and dissolution rates than stable crystal polymorphs, advanced crystal engineering techniques are required to control the transition rate of metastable crystal polymorphs to stable crystal polymorphs, thereby enabling the acquisition of only metastable crystal polymorphs (Crystal Growth & Design (2011) 11, 887-895, Polymorphism in the Pharmaceutical Industry: Wiley-Vch, 2006; pp. 1-19).

[0009] For example, in the case of clopidogrel bisulphate, as disclosed in Korean Registered Patent No. 10-1567438 and Crystal Growth & Design 2016, 16, 1829-1836, crystalline form 1 is pharmaceutically preferred due to its high solubility, but the crystal polymorphism transition rate to crystalline form 2 does not exceed 5 minutes. Consequently, countless crystal engineering studies have been conducted to control the crystal polymorphism transition rate of crystalline form 1 to obtain it. Obtaining and controlling such metastable crystal polymorphisms requires countless crystal engineering studies and numerous trials and errors.

[0010] Therefore, when designing new crystal polymorphs for active pharmaceutical ingredients (APIs) that have been launched into the market after crystal polymorph discovery, metastable crystal polymorphs are prioritized because they exist as the final stable crystal polymorphs. Furthermore, since all metastable crystal polymorphs transition to stable crystal polymorphs, such research on crystal polymorph design requires countless advanced crystal engineering studies.

[0011] Furthermore, enhancing the reproducibility of novel crystal polymorphs requires a design by an advanced crystal engineer, and a reproducible crystallization process can only be established if it is executed based on chemical engineering knowledge.

[0012] To date, no crystal polymorphisms of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate as an alpha-aminoamide derivative have been presented, so research on this is necessary.

[0013]

[0014] [Prior Art Literature]

[0015] [Patent Literature]

[0016] 1. Korean Published Patent No. 10-2016-0039817

[0017] 2. Korean Published Patent No. 10-2004-0029362

[0018] 3. Korean Published Patent No. 10-2016-0039817

[0019] 4. Korean Published Patent No. 10-2017-0034071

[0020] 5. U.S. Patent No. 5,391,577

[0021] 6. U.S. Patent No. 6,258,851

[0022] 7. U.S. Published Patent No. 2009-0149544

[0023] [Non-patent literature]

[0024] 1. Crystal Growth & Design (2011) 11, 887-895

[0025] 2. Journal of Medicinal Chemistry 1998, Vol.41, pp.579-590

[0026]

[0027] Polymorphism, that is, the occurrence of different crystal forms, is a characteristic of some molecules and molecular complexes. A single molecule can produce various polymorphs with distinct crystal structures and properties, examples of which include melting point, thermal characteristics measured by thermogravimetric analysis (TGA) or differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) patterns, infrared absorption fingerprints, and solid-state nuclear magnetic resonance (NMR) spectra. One or more of the properties measured by these techniques can be used to distinguish different polymorphs of a compound.

[0028] As a result of countless studies and numerous trials and errors regarding the crystal polymorphisms of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, an alpha-aminoamide derivative represented by Chemical Formula 1, the inventors identified two novel crystal forms and one amorphous form.

[0029] By discovering novel polymorphs and solvates of pharmaceutical products, it is possible to provide materials with desirable processing characteristics, such as ease of handling, ease of processing, storage stability, or ease of purification, or materials as desirable intermediate crystalline forms that are easily convertible into other polymorphs. Novel polymorphs and solvates of pharmaceutically useful compounds or their salts may also provide opportunities to improve the performance characteristics of pharmaceutical products.

[0030] At least in this respect, additional solid forms of the free base and the corresponding salt of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate are required.

[0031]

[0032] Therefore, the inventors intend to provide two novel crystalline forms and one amorphous form.

[0033] [Chemical Formula 1]

[0034]

[0035] According to one aspect, the present invention provides a crystalline form 1 of (S)-2-(((4-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate having a PXRD pattern with characteristic peaks at 2θ diffraction angles of 11.477°±0.2°, 12.142°±0.2°, 15.329°±0.2°, 20.035°±0.2°, 20.310°±0.2° and 22.234°±0.2° in PXRD analysis.

[0036] The intensity and peak position of the PXRD showing the first crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to the present invention may be as shown in FIG. 9, but are not limited thereto.

[0037] In addition, the present invention provides a first crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, which is an anhydrous crystalline form in which no mass loss due to solvent is observed at around 100°C as a result of TGA analysis.

[0038] In addition, the present invention provides a crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, in which the endothermic onset temperature appears at 268.39±3 ℃ and the endothermic temperature appears at 269.97±3 ℃ in DSC analysis.

[0039] According to another aspect, the present invention provides a crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate having a PXRD pattern with characteristic peaks at 2θ diffraction angles of 17.309°±0.2°, 17.572°±0.2°, 19.366°±0.2°, 19.546°±0.2°, 22.205°±0.2° and 22.577°±0.2° in PXRD analysis.

[0040] The intensity and peak position of the PXRD showing the second crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to the present invention may be as shown in FIG. 10.

[0041] In addition, the present invention provides a second crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, which is an anhydrous crystalline form that does not show mass loss due to solvent at around 100°C as a result of TGA analysis.

[0042] In addition, the present invention provides a second crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, in which, in DSC analysis, the endothermic onset temperature appears at 152.77±3 ℃ and the endothermic temperature appears at 155.18±3 ℃.

[0043] According to another aspect, the present invention provides an amorphous form of (S)-2-(((4-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate having an amorphous PXRD pattern in PXRD analysis.

[0044] In addition, the present invention provides a pharmaceutical composition for inhibiting MAO-B or for treating or preventing degenerative neurological diseases, comprising one or more selected from crystalline form 1, crystalline form 2, or amorphous form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to the present invention.

[0045] In addition, the present invention provides a pharmaceutical composition for inhibiting GABA production or for treating or preventing obesity, comprising one or more selected from crystalline form 1, crystalline form 2, or amorphous form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to the present invention.

[0046]

[0047] The present invention provides a crystal polymorph of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, which is an alpha-aminoamide derivative, and a pharmaceutical composition containing the same.

[0048] Through this, a crystalline form with significantly or qualitatively different thermal decomposition characteristics, solubility, hygroscopicity, and photostability can be provided.

[0049]

[0050] Figure 1 shows a method for evaluating relative humidity.

[0051] Figure 2 shows the PXRD pattern of the first crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate prepared according to an embodiment of the present invention.

[0052] FIG. 3 shows the thermogravimetric analysis (TGA) results of crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate prepared according to an embodiment of the present invention.

[0053] FIG. 4 shows the differential scanning calorimetry (DSC) analysis calorimetry curve of the first type of crystalline (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate prepared according to an embodiment of the present invention.

[0054] Figure 5 shows the PXRD pattern of the (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate crystalline form 2 prepared according to an embodiment of the present invention.

[0055] FIG. 6 shows the thermogravimetric analysis (TGA) results of crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate prepared according to an embodiment of the present invention.

[0056] FIG. 7 shows the differential scanning calorimetry (DSC) analysis calorimetry curve of the (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate crystalline type 2 prepared according to an embodiment of the present invention.

[0057] FIG. 8 shows the PXRD pattern of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate amorphous prepared according to an embodiment of the present invention.

[0058] Figure 9 shows the intensity and peak position of PXRD of the crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate.

[0059] Figure 10 shows the intensity and peak position of PXRD of the crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate.

[0060] Figure 11 is the Raman spectrum of the crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate before formulation.

[0061] Figure 12 is the Raman spectrum of the crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate after formulation.

[0062]

[0063] The present invention provides a crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, which has a PXRD pattern in PXRD analysis with characteristic peaks at 2θ diffraction angles of 11.477°±0.2°, 12.142°±0.2°, 15.329°±0.2°, 20.035°±0.2°, 20.310°±0.2°, and 22.234°±0.2°.

[0064] In addition, the present invention provides a crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, in which the endothermic onset temperature appears at 268.39±3 ℃ and the endothermic temperature appears at 269.97±3 ℃ in differential scanning calorimetry (DSC) analysis.

[0065] In addition, the present invention provides a crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate in which no mass loss due to solvent is observed at around 100°C in thermogravimetric analysis (TGA).

[0066] In addition, the present invention provides a second crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate having a PXRD pattern with characteristic peaks at 2θ diffraction angles of 17.309°±0.2°, 17.572°±0.2°, 19.366°±0.2°, 19.546°±0.2°, 22.205°±0.2° and 22.577°±0.2° in PXRD analysis.

[0067] In addition, the present invention provides a second crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, in which the endothermic onset temperature appears at 152.77±3 ℃ and the endothermic temperature appears at 155.18±3 ℃ in differential scanning calorimetry (DSC) analysis.

[0068] In addition, the present invention provides a second crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate in which no mass loss due to solvent is observed at around 100°C in thermogravimetric analysis (TGA).

[0069] In addition, the present invention provides an amorphous form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate having an amorphous PXRD pattern as shown in FIG. 8 in PXRD analysis.

[0070] The present invention also provides a pharmaceutical composition for inhibiting MAO-B or inhibiting GABA production comprising one or more selected from (a) to (c) below:

[0071] (a) Crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to various embodiments of the present invention,

[0072] (b) a second crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to various embodiments of the present invention, and

[0073] (c) Amorphous (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to various embodiments of the present invention.

[0074] The present invention also provides a pharmaceutical composition for the treatment or prevention of degenerative neurological diseases such as Parkinson's disease, Alzheimer's disease, epilepsy, and depression, or for the treatment or prevention of obesity, comprising one or more selected from (a) to (c) below:

[0075] (a) Crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to various embodiments of the present invention,

[0076] (b) a second crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to various embodiments of the present invention, and

[0077] (c) Amorphous (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate in various embodiments of the present invention.

[0078]

[0079] The crystalline forms 1, 2, and amorphous of the (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention have higher solubility than the free base crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide and can have a pharmaceutically improved solid form.

[0080]

[0081] The crystalline forms of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention can exhibit significantly lower hygroscopicity compared to the amorphous form.

[0082] In addition, the amorphous form of the (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention may exhibit somewhat low hygroscopicity, but as relative humidity increases, it actually exhibits lower hygroscopicity, thereby showing a unique effect of even superior moisture stability at high relative humidity.

[0083] The crystalline forms (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention, Type 1 and Type 2, have less flexible material that increases after exposure to a light source compared to the amorphous form and possess excellent photostability, which makes them advantageous for handling or storage not only in the manufacturing process but also in the productization process.

[0084] In addition, the crystalline forms 1 and 2 of the (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention possess superior photostability compared to the amorphous form. In particular, the crystalline form 1 showed unexpected results in which no increase in impurities due to photodegradation was observed during the test period. Since the photostability is qualitatively different from that of the crystalline form 2, it can be handled and stored most advantageously during the manufacturing and commercialization processes.

[0085] The first crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention can be stably maintained without phase transition or deformation of the crystal structure before and after formulation, which can be confirmed through Raman spectrum analysis.

[0086] The crystalline form 1 of the (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention exhibits unique resistance to mechanical stress during the manufacturing process, unlike the 2nd form and the amorphous form. Under ball milling conditions (300 rpm, 30 min), the 2nd form becomes significantly amorphous and the amorphous form becomes completely amorphous, whereas the 1st form does not show amorphousness.

[0087] The crystalline form 2 of the (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention exhibits unique reversible stability against changes in humidity, unlike the crystalline form 1 and amorphous forms. As a result of dynamic moisture absorption analysis (DVS), when the relative humidity was changed from 0→90→0% at 25°C, the crystalline form 2 completely recovered to its original state after dehumidification at the maximum absorption rate (residual moisture content: 0.1% of the maximum absorption rate), whereas the crystalline form 1 and amorphous forms showed residual moisture content of 12% and 27% of the maximum absorption rate, respectively.

[0088]

[0089] The present invention is to be explained in more detail through the following examples. These examples are solely for the purpose of explaining the present invention more specifically, and it will be obvious to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the invention.

[0090] Examples

[0091] Example 1: Preparation of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate crystalline form 1

[0092] 1 g of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate was dissolved in 10 mL of methanol. Then, 10 mL of methylene chloride was added and stirred for more than 16 hours. Afterward, 0.85 g of crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate was obtained by vacuum drying at 30 °C for 16 hours after filtering under reduced pressure.

[0093]

[0094] Example 2: Preparation of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate crystalline form 1

[0095] 1 g of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate was dissolved in 10 mL of ethanol. Then, 10 mL of cyclohexane was added and stirred for more than 16 hours. Afterward, 0.78 g of crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate was obtained by vacuum drying at 30 °C for 16 hours after filtering under reduced pressure.

[0096]

[0097] Example 3: Preparation of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate crystalline form 2

[0098] 1 g of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate was dissolved in 10 mL of methanol. Then, the solvent was reduced to about 1 / 3 of its original volume and concentrated under reduced pressure at a water bath temperature of 50 °C. Afterward, 15 mL of ethyl acetate was added and stirred for more than 1 hour, followed by vacuum filtration and vacuum drying at 30 °C for 16 hours to obtain 0.58 g of crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate.

[0099]

[0100] Example 4: Preparation of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate crystalline form 2

[0101] 1 g of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate was dissolved in 10 mL of ethanol. Then, the solvent was concentrated under reduced pressure at a water bath temperature of 50 °C. Afterward, 15 mL of ethyl acetate was added and stirred for more than 1 hour, followed by vacuum filtration and vacuum drying at 30 °C for 16 hours to obtain 0.64 g of crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate.

[0102]

[0103] Example 5: Preparation of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate amorphous

[0104] 1 g of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate was dissolved in 10 mL of methanol. Then, the solution was concentrated under reduced pressure at a water bath temperature of 60 °C until a solid precipitated. Afterward, the solid was obtained to yield 0.81 g of amorphous (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate.

[0105]

[0106] Experimental Example 1: PXRD Analysis

[0107] PXRD analysis was performed on the crystalline, type 1, and amorphous forms of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate as follows, and the results are presented in Figs. 2, 5, and 8, respectively. The analysis was performed on an X-ray powder diffractometer (D8 Advance) using CuKα radiation.

[0108] The apparatus was equipped with tube power, and the current was set to 45 kV and 40 mA. The diverging and scattering slits were set to 1°, and the receiving slit was set to 0.2 mm. A θ-2θ continuous scan was used at a scan speed of 3° / min for 2θ values ​​from 5° to 35°.

[0109]

[0110] Experimental Example 2: Thermogravimetric Analysis (TGA)

[0111] TGA analysis was performed on crystalline forms 1 and 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate as follows, and the results are presented in Figures 3 and 6, respectively. TGA analysis was performed using a DSC Q50 obtained from TA at a scan rate of 10 °C / min from 20 °C to 400 °C in a TGA pan under a nitrogen-purged atmosphere.

[0112]

[0113] Experimental Example 3: Differential Scanning Calorimetry (DSC) Analysis

[0114] DSC analysis was performed on crystalline forms 1 and 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate as follows, and the results are presented in Figures 4 and 7, respectively. Using a DSC Q50 obtained from TA, DSC analysis was performed in a sealed pan in a nitrogen-purged atmosphere from 20 °C to 350 °C at a scan rate of 10 °C / min.

[0115]

[0116] Experimental Example 4: Evaluation of the Solubility of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate Crystalline Polymorphs

[0117] The solubility of the crystalline, type 1, type 2, and amorphous forms of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide free base and (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate was evaluated as follows, and the results are presented in Table 1 below. To compare the solubility of each substance, solubility was evaluated using water and pH 6.8 buffer solution, respectively, from a concentration of 5 μg / mL until maximum dissolution.

[0118] As shown in Table 1 below, which compares the solubility of the crystalline forms of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, it was confirmed that the crystalline forms 1, 2, and amorphous forms of the (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention have higher solubility than the free base crystalline form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide and are pharmaceutically improved solid forms.

[0119] Classification pH 6.8 Free Base Crystalline Form 15 μg / mL or less 18 μg / mL or less Methanesulfonate Crystalline Form Type 1 1 mg / mL or less 1.5 mg / mL or less Methanesulfonate Crystalline Form Type 2 2 mg / mL or less 2 mg / mL or less Methanesulfonate Amorphous Form 3 mg / mL or less 3.5 mg / mL or less

[0120] Experimental Example 5: Evaluation of Hygroscopicity of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate Crystalline Polymorph

[0121] Since solids in the form of salts have an affinity for moisture, their stability may deteriorate or they may deliquite in the presence of moisture, and because they also undergo a phase transition to hydrates, an assessment of their stability regarding hygroscopicity is essential.

[0122] The hygroscopicity of the crystalline Type 1, Type 2, and amorphous materials of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide free base and (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate was evaluated as follows.

[0123] Specifically, a saturated solution containing the inorganic salts in Table 2 below was evaluated for a total of 10 days using the method of Figure 1, and the hygroscopic results in Table 3 were obtained through the Karl Fischer analysis of moisture.

[0124] As shown in the hygroscopic results of Table 3 below, it was confirmed that the crystalline forms of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention exhibit significantly lower hygroscopicity compared to the amorphous form. In particular, in the case of the amorphous form, it was confirmed that the hygroscopicity actually decreases as the relative humidity increases, showing even better moisture stability at high relative humidity.

[0125] P2O5MgCl2Mg(NO3)NaNO2NaClKNO3 Relative humidity 11% 33% 52% 64% 75% 93% Inorganic salts used in hygroscopicity evaluation

[0126] RH 11% RH 33% RH 52% RH 64% RH 75% RH 93% Crystalline Type 1 0.08% 0.12% 0.10% 0.14% 0.14% 0.16% Crystalline Type 2 0.11% 0.11% 0.12% 0.12% 0.15% 0.18% Amorphous 0.24% 0.24% 0.23% 0.23% 0.22% 0.21%

[0127] As such, it has been confirmed that by utilizing the crystalline or amorphous forms of the (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention, the conventional stability issues associated with the salt form due to moisture during storage can be overcome, and it can be utilized as a useful raw material for pharmaceuticals during storage.

[0128] Experimental Example 6: Evaluation of the photostability of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate crystal polymorphs

[0129] The photostability of crystalline type 1, type 2, and amorphous materials of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide free base and (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate was evaluated as follows, and the results are presented in Table 4 below.

[0130] Each sample was placed in a clear glass container and stored in a light-stable chamber for 3 days while exposed to a light source. After 3 days of exposure to the light source, the purity of each sample was analyzed using HPLC, and the results are shown in Table 4 below.

[0131] In this case, a CARON Photostability Chamber Model 6545 was used as the photostability meter, and the light exposure was an overall illumination of 2.4 × 10⁻⁶ 6 lux-hr / m 2 , Near UV is 400 W·hr / m 2 It proceeded under certain conditions.

[0132] As shown in the photostability results in Table 4 below, the crystalline forms (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate of the present invention, Type 1 and Type 2, have less flexible material that increases after exposure to a light source compared to the amorphous form and possess excellent photostability, which can be advantageous for handling and storage not only in the manufacturing process but also in the productization process.

[0133] In addition, crystalline Type 1, in particular, unlike crystalline Type 2, showed no increase in flexible matter due to photodegradation during the test period, demonstrating qualitatively improved photostability. This confirmed that it can be handled or stored most favorably during the manufacturing and commercialization processes.

[0134] Photostability by HPLC purity % Increase in impurities (%) Start (0 days) After 3 days Crystalline Type 1 98.42 98.42 0.00 Crystalline Type 2 98.49 96.14 2.39 Amorphous 97.94 95.90 2.08

[0135] Experimental Example 7: Evaluation of the stability of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate Type 1 after formulation

[0136] (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate type 1 was confirmed to remain consistently stable after formulation through FT-Raman spectroscopy as follows.

[0137] As shown in the Raman spectrum of Fig. 11, which is the result of Raman analysis prior to formulation, (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate type 1 had a value of 1613 cm⁻¹ prior to formulation. -1 It can be confirmed that a strong characteristic peak is observed.

[0138] In addition, as shown in the Raman spectrum of Fig. 12, which is the result of Raman analysis after formulation, (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate type 1 has a value of 1614 cm⁻¹ even after formulation. -1 It can be observed that a strong characteristic peak is shown at.

[0139] In addition, 1532 cm -1 , 1329 cm -1 , 1283 cm -1 , 1201 cm -1, and 1049 cm -1 It can be confirmed that characteristic peaks are commonly observed before and after formulation.

[0140] From these results, it was confirmed that (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate type 1 remains stable without phase transition or deformation of the crystal structure before and after formulation.

[0141] Foregoing, specific parts of the present invention have been described in detail. It is evident to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the actual scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A powder X-ray diffraction (PXRD) analysis showing a powder X-ray diffraction pattern with characteristic peaks at 2θ diffraction angles of 11.477°±0.2°, 12.142°±0.2°, 15.329°±0.2°, 20.035°±0.2°, 20.310°±0.2° and 22.234°±0.2°, which is the crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate.

2. Crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, in which the endothermic onset temperature is 268.39±3 ℃ and the endothermic temperature is 269.97±3 ℃ in differential scanning calorimetry (DSC) analysis.

3. Crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, which does not show mass loss due to solvent at around 100 °C in thermogravimetric analysis (TGA).

4. Crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate having a powder X-ray diffraction pattern with characteristic peaks at 2θ diffraction angles of 17.309°±0.2°, 17.572°±0.2°, 19.366°±0.2°, 19.546°±0.2°, 22.205°±0.2° and 22.577°±0.2° in powder X-ray diffraction (PXRD) analysis.

5. Crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, in which the endothermic onset temperature is 152.77±3 ℃ and the endothermic temperature is 155.18±3 ℃ in differential scanning calorimetry (DSC) analysis.

6. Crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate, which does not show mass loss due to solvent at around 100 °C in thermogravimetric analysis (TGA).

7. Amorphous form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate having an amorphous powder X-ray diffraction pattern as shown in the figure below in powder X-ray diffraction (PXRD) analysis: .

8. A pharmaceutical composition for inhibiting MAO-B comprising one or more selected from (a) to (c) below: (a) Crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to any one of claims 1 to 3, (b) Crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to any one of claims 4 to 6, and (c) Amorphous form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to claim 7.

9. A pharmaceutical composition for the treatment or prevention of degenerative neurological diseases comprising one or more selected from (a) to (c) below: (a) Crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to any one of claims 1 to 3, (b) Crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to any one of claims 4 to 6, and (c) Amorphous form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to claim 7.

10. A pharmaceutical composition for treating or preventing a degenerative nervous system disease according to claim 9, characterized in that the degenerative nervous system disease is selected from Parkinson's disease, Alzheimer's disease, epilepsy, and depression.

11. A pharmaceutical composition for inhibiting GABA production comprising one or more selected from (a) to (c) below: (a) Crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to any one of claims 1 to 3, (b) Crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to any one of claims 4 to 6, and (c) Amorphous form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to claim 7.

12. A pharmaceutical composition for treating or preventing obesity comprising one or more selected from (a) to (c) below: (a) Crystalline form 1 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to any one of claims 1 to 3, (b) Crystalline form 2 of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to any one of claims 4 to 6, and (c) Amorphous form of (S)-2-(((4'-trifluoromethylbiphenyl-4-yl)methyl)amino)propanamide methanesulfonate according to claim 7.

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