Patent Publication Number: US-2022213051-A1

Title: Novel crystal form of 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative

Description:
TECHNICAL FIELD 
     The present invention relates to a novel crystal form of a 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative of the following Chemical Formula 1. 
     
       
         
         
             
             
         
       
     
     BACKGROUND ART 
     Various crystal or amorphous forms are able to exhibit various physical properties of a solid state, such as hygroscopicity, behavior against compression, stability during storage, and flowability of the milled solid. These properties in turn affect the suitability of a certain solid state as an active pharmaceutical substance for commercial production. For example, flowability affects the ease of handling a substance during processing into a pharmaceutical product. When the particles of the powdered compound do not readily flow past each other, the formulation expert will have to take that fact into account when developing a tablet or capsule preparation, and this may require the use of a glidant such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate. 
     Different crystal or amorphous forms of the same drug may have substantial differences in pharmaceutically important properties such as a dissolution rate and bioavailability. The dissolution rate is not only considered when formulating syrups, elixirs, and other liquid medicaments, but may also vary the outcome of treatment. For example, the rate of dissolution of an active ingredient in a patient&#39;s gastric juice will vary the outcome of treatment as it places an upper limit on the rate at which an orally-administered active ingredient can reach the patient&#39;s bloodstream. 
     Meanwhile, the compound of Chemical Formula 1, (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)benzyloxy)phenyl)hex-4-inoic acid and an L-lysine salt, which is disclosed in International Patent Publication No. WO2014-171762, is a substance that activates free fatty acid receptor 1 (FFAR1)/a G-protein coupled receptor (GPR40) to increase the intracellular calcium concentration and exhibit an excellent blood sugar lowering effect. 
     The inventors of the present invention have continuously conducted research on the crystal form of the compound of Chemical Formula 1 during development of a product of the compound of Chemical Formula 1. As a result, the inventors of the present invention have found that a crystal form I and a crystal form II are present as the crystal forms of the compound of Chemical Formula 1 and the crystal form I exhibits excellent physicochemical properties compared to the crystal form II or an amorphous form. 
     DISCLOSURE 
     Technical Problem 
     The present invention is directed to providing a crystal form I of a compound of Chemical Formula 1 which exhibits excellent physicochemical properties compared to an amorphous form and crystal form II of the compound of Chemical Formula 1. 
     The present invention is also directed to providing a method of preparing the crystal form I of the compound of Chemical Formula 1. 
     The present invention is also directed to providing a pharmaceutical composition including the crystal form I of the compound of Chemical Formula 1 as an active ingredient. 
     Technical Solution 
     One aspect of the present invention provides a crystal form I of a compound of Chemical Formula 1 which exhibits excellent physicochemical properties compared to an amorphous form and crystal form II of the compound of Chemical Formula 1. 
     According to powder X-ray diffraction (PXRD) analysis, the crystal form I and the crystal form II have different crystal structures. 
     According to an embodiment of the present invention, the crystal form I of the compound of Chemical Formula 1 exhibits an X-ray powder diffraction pattern having 4 or more diffraction peaks, for example, 4, 5, 6, 7, 8, 9, 10 or more diffraction peaks, at 2[θ] values selected from 4.61±0.2, 5.49±0.2, 6.84±0.2, 11.74±0.2, 12.05±0.2, 13.74±0.2, 16.50±0.2, 16.94±0.2, 18.45±0.2, 19.11±0.2, 20.13±0.2, 20.42±0.2, 20.87±0.2, 21.57±0.2, 23.04±0.2, and 25.02±0.2. 
     Particularly, the X-ray powder diffraction pattern has diffraction peaks at 2[θ] values selected from 4.61±0.2, 6.84±0.2, 11.74±0.2, 16.50±0.2, 16.94±0.2, 20.42±0.2, and 20.87±0.2. 
     More specifically, the crystal form I of the compound of Chemical Formula 1 exhibits an X-ray powder diffraction pattern where the positions of peaks match the peak positions listed in the following Table 1. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                   
                 Angle 
                 d value 
                 Intensity 
                 Intensity % 
               
               
                 Caption 
                 2-Theta ° 
                 Angstrom 
                 Count 
                 % 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 d = 19.14506 
                 4.612 
                 19.14506 
                 4735 
                 89.4 
               
               
                 d = 16.07776 
                 5.492 
                 16.07776 
                 2226 
                 42 
               
               
                 d = 12.91070 
                 6.841 
                 12.9107 
                 3738 
                 70.6 
               
               
                 d = 7.53027 
                 11.743 
                 7.53027 
                 5231 
                 98.8 
               
               
                 d = 7.33717 
                 12.053 
                 7.33717 
                 5296 
                 100 
               
               
                 d = 6.44222 
                 13.735 
                 6.44222 
                 4485 
                 84.7 
               
               
                 d = 5.36804 
                 16.501 
                 5.36804 
                 5215 
                 98.5 
               
               
                 d = 5.22939 
                 16.941 
                 5.22939 
                 4947 
                 93.4 
               
               
                 d = 4.80573 
                 18.447 
                 4.80573 
                 4289 
                 81 
               
               
                 d = 4.64015 
                 19.112 
                 4.64015 
                 4100 
                 77.4 
               
               
                 d = 4.40719 
                 20.132 
                 4.40719 
                 4188 
                 79.1 
               
               
                 d = 4.34614 
                 20.418 
                 4.34614 
                 4519 
                 85.3 
               
               
                 d = 4.25406 
                 20.865 
                 4.25406 
                 4692 
                 88.6 
               
               
                 d = 4.11754 
                 21.565 
                 4.11754 
                 3688 
                 69.6 
               
               
                 d = 3.85747 
                 23.038 
                 3.85747 
                 3021 
                 57 
               
               
                 d = 3.55665 
                 25.016 
                 3.55665 
                 2478 
                 46.8 
               
               
                   
               
            
           
         
       
     
     Meanwhile, a crystal form II of the compound of Chemical Formula 1 exhibits an X-ray powder diffraction pattern having 4 or more diffraction peaks, for example, 4, 5, 6, 7, 8, 9, 10 or more diffraction peaks, at 2[θ] values selected from 4.71±0.2, 5.47±0.2, 7.17±0.2, 8.21±0.2, 10.56±0.2, 10.99±0.2, 11.23±0.2, 13.75±0.2, 14.20±0.2, 15.01±0.2, 15.19±0.2, 15.74±0.2, 16.24±0.2, 17.32±0.2, 18.37±0.2, 19.33±0.2, 20.54±0.2, 20.86±0.2, 21.20±0.2, 21.49±0.2, 22.05±0.2, 22.76±0.2, 23.26±0.2, 23.64±0.2, 24.94±0.2, 25.80±0.2, and 27.13±0.2. 
     Particularly, the X-ray powder diffraction pattern has diffraction peaks at 2[θ] values selected from 5.47±0.2, 8.21±0.2, 10.99±0.2, 13.75±0.2, 16.24±0.2, 19.33±0.2, 22.05±0.2, 23.26±0.2, and 24.94±0.2. 
     More specifically, the crystal form II of the compound of Chemical Formula 1 exhibits an X-ray powder diffraction pattern where the positions of peaks match the peak positions listed in the following Table 2. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                   
                 Angle 
                 d value 
                 Intensity 
                 Intensity % 
               
               
                 Caption 
                 2-Theta ° 
                 Angstrom 
                 Count 
                 % 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 d = 18.76189 
                 4.706 
                 18.76189 
                 2391 
                 4.5 
               
               
                 d = 16.14857 
                 5.468 
                 16.14857 
                 53225 
                 100 
               
               
                 d = 12.32326 
                 7.168 
                 12.32326 
                 2162 
                 4.1 
               
               
                 d = 10.76005 
                 8.211 
                 10.76005 
                 6871 
                 12.9 
               
               
                 d = 8.36753 
                 10.564 
                 8.36753 
                 3725 
                 7 
               
               
                 d = 8.04414 
                 10.99 
                 8.04414 
                 4743 
                 8.9 
               
               
                 d = 7.87443 
                 11.228 
                 7.87443 
                 4518 
                 8.5 
               
               
                 d = 6.43328 
                 13.754 
                 6.43328 
                 5358 
                 10.1 
               
               
                 d = 6.23107 
                 14.202 
                 6.23107 
                 4632 
                 8.7 
               
               
                 d = 5.89634 
                 15.013 
                 5.89634 
                 4846 
                 9.1 
               
               
                 d = 5.82937 
                 15.187 
                 5.82937 
                 4655 
                 8.7 
               
               
                 d = 5.62647 
                 15.738 
                 5.62647 
                 4364 
                 8.2 
               
               
                 d = 5.45309 
                 16.241 
                 5.45309 
                 4588 
                 8.6 
               
               
                 d = 5.11531 
                 17.322 
                 5.11531 
                 4097 
                 7.7 
               
               
                 d = 4.82690 
                 18.366 
                 4.8269 
                 4278 
                 8 
               
               
                 d = 4.58880 
                 19.327 
                 4.5888 
                 4591 
                 8.6 
               
               
                 d = 4.31979 
                 20.544 
                 4.31979 
                 3784 
                 7.1 
               
               
                 d = 4.25466 
                 20.862 
                 4.25466 
                 3887 
                 7.3 
               
               
                 d = 4.18814 
                 21.197 
                 4.18814 
                 3951 
                 7.4 
               
               
                 d = 4.13240 
                 21.486 
                 4.1324 
                 3606 
                 6.8 
               
               
                 d = 4.02748 
                 22.053 
                 4.02748 
                 4152 
                 7.8 
               
               
                 d = 3.90318 
                 22.764 
                 3.90318 
                 2799 
                 5.3 
               
               
                 d = 3.82080 
                 23.262 
                 3.8208 
                 3260 
                 6.1 
               
               
                 d = 3.76015 
                 23.642 
                 3.76015 
                 2557 
                 4.8 
               
               
                 d = 3.56797 
                 24.936 
                 3.56797 
                 2831 
                 5.3 
               
               
                 d = 3.45025 
                 25.801 
                 3.45025 
                 2478 
                 4.7 
               
               
                 d = 3.28407 
                 27.131 
                 3.28407 
                 2309 
                 4.3 
               
               
                   
               
            
           
         
       
     
     Another aspect of the present invention provides a method of preparing the crystal form I of the compound of Chemical Formula 1, which comprises dissolving (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)benzyloxy)phenyl)hex-4-inoic acid and an L-lysine salt in methanol, adding isopropyl acetate, and obtaining a crystal form I of a compound of Chemical Formula 1 from the reaction product. Still another aspect of the present invention provides a pharmaceutical composition for preventing or treating a metabolic disease, which comprises the crystal form of the compound of Chemical Formula 1 and a pharmaceutically acceptable carrier. 
     The compound of Chemical Formula 1 is known to activate the GPR40 enzyme. GPR40 is a G-protein coupled receptor (GPCR) mainly expressed in the insulin-secreting cells of the pancreas, and the GPR40 expression profile is potentially useful for the treatment of various metabolic diseases including obesity and diabetes. 
     The compound of Chemical Formula 1 according to the present invention has an excellent insulin secretion promoting effect due to having an excellent effect of activating the GPR40 protein, is able to be administered in combination with other drugs, and has a very good effect of activating the GPR40 protein in vivo. Therefore, a composition containing the compound as an active ingredient can be usefully used as a pharmaceutical composition for preventing or treating a metabolic disease such as obesity, type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, syndrome X, and the like. 
     The compound of Chemical Formula 1 according to the present invention may be administered in various oral and parenteral formulations upon clinical administration. For formulation, the compound may be prepared using a commonly used diluent or excipient such as a filler, an extending agent, a binding agent, a wetting agent, a disintegrating agent, a surfactant, and the like. 
     A solid preparation for oral administration includes a tablet, a pill, a powder, a granule, a capsule, a troche, and the like, and such a solid preparation is prepared by mixing one or more compounds according to the present invention with one or more excipients, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like. Also, in addition to the simple excipient, a lubricant such as magnesium stearate, talc, and the like is used. A liquid preparation for oral administration includes a suspension, a liquid for internal use, an emulsion, a syrup, and the like. In this case, in addition to a commonly used simple diluent such as water and liquid paraffin, various excipients such as a wetting agent, a sweetening agent, an aromatic, a preservative, and the like may be included. 
     A preparation for parenteral administration includes a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized preparation, and a suppository, and the like. As the non-aqueous solvent and the suspension, propylene glycol, polyethylene glycol, a vegetable oil (such as olive oil), an injectable ester (such as ethyl oleate), and the like may be used. As a suppository base, Witepsol, Macrogol, Tween 61, cacao butter, laurin fat, glycerol, gelatin, and the like may be used. 
     In addition, the effective dose of the compound of Chemical Formula 1 of the present invention to the human body may vary depending on the age, weight, and sex of a patient, dosage form, health status, and disease level, and is generally about 0.001 to 100 mg/kg/day, and preferably, 0.01 to 35 mg/kg/day. Based on an adult patient weighing 70 kg, the effective dose is generally 0.07 to 7000 mg/day, and preferably, 0.7 to 2500 mg/day, and may be administered once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist. 
     Advantageous Effects 
     A crystal form I of a compound of Chemical Formula 1 according to the present invention exhibits more excellent physicochemical properties in terms of thermal stability, static electricity-inducing capability, compressibility, and the like compared to an amorphous form or a crystal form II and thus is particularly useful for formulation and long-term storage. 
    
    
     
       DESCRIPTION OF DRAWINGS 
         FIG. 1  shows an X-ray powder diffraction pattern of a crystal form I of a compound of Chemical Formula 1. 
         FIG. 2  shows an X-ray powder diffraction pattern of a crystal form II of a compound of Chemical Formula 1. 
         FIG. 3  shows an X-ray powder diffraction pattern of an amorphous form of a compound of Chemical Formula 1. 
         FIG. 4  shows the heat flow change of a crystal form I of a compound of Chemical Formula 1 according to temperature and elapsed time. 
         FIG. 5  shows the physical properties of a crystal form I of a compound of Chemical Formula 1 according to temperature or the properties of a reaction product as measured by a function of temperature or time. 
         FIG. 6  shows the heat flow change of a crystal form II of a compound of Chemical Formula 1 according to temperature and elapsed time. 
         FIG. 7  shows the physical properties of a crystal form II of a compound of Chemical Formula 1 according to temperature or the properties of a reaction product as measured by a function of temperature or time. 
         FIG. 8  shows the heat flow change of an amorphous form of a compound of Chemical Formula 1 according to temperature and elapsed time. 
         FIG. 9  shows the physical properties of an amorphous form of a compound of Chemical Formula 1 according to temperature or the properties of a reaction product as measured by a function of temperature or time. 
         FIG. 10  is a photograph showing the change in properties related to the thermal stability of the crystal form I, crystal form II, and amorphous form of a compound of Chemical Formula 1 under thermal stress conditions. 
         FIG. 11  is a graph showing the change in the XRD pattern of a crystal form I before (bottom, black) and after (top, orange) a stability test under thermal stress conditions. 
         FIG. 12  is a graph showing the difference in the XRD pattern between a crystal form I (bottom, black) and a crystal form II (top, orange) before a stability test under thermal stress conditions. 
         FIG. 13  is a graph showing the change in the XRD pattern of a crystal form II before (bottom, black) and after (top, orange) a stability test under thermal stress conditions. 
         FIG. 14  is a graph of comparing the difference between the XRD pattern of a crystal form I before a stability test under thermal stress conditions (bottom, black) and the XRD pattern of a crystal form II after a stability test under thermal stress conditions (top, orange). 
     
    
    
     MODES OF THE INVENTION 
     Advantages and features of the present invention and methods for achieving the same will be apparent by the exemplary embodiments described below in detail. However, the present invention is not limited to the exemplary embodiments described below and may be implemented in various different forms. Rather, the exemplary embodiments have been provided to make the disclosure of the present invention thorough and complete and to fully inform the scope of the present invention to those of ordinary skill in the art to which the present invention pertains, and the present invention is defined only by the scope of the claims. 
     EXAMPLES 
     Example 1: Preparation of Crystal Form I of Compound of Chemical Formula 1 
     (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)benzyloxy)phenyl)hex-4-inoic acid and L-lysine were added to methanol and then stirred. After the stirring at 60° C. for 30 minutes, the resultant was slowly cooled. A small amount of isopropyl acetate was added at 35° C. to form a solid. After stirring for 30 minutes after solid formation, more isopropyl acetate was added. After stirring at 25° C. for an hour, filtration was performed. The resultant was dried to obtain a crystal form of a compound of Chemical Formula 1. 
     As a result of powder X-ray diffraction analysis, the crystal form was confirmed to have the XRD pattern of  FIG. 1  and was referred to as crystal form I. 
     X-ray diffractometer (XRD) conditions 
     1) Model: D8 Advance (Bruker) 
     2) Current/voltage/2 theta range/Rate: 40 Ma/40 KV/3-45/6 deg/min*7 
     Example 2: Preparation of Crystal Form II of Compound of Chemical Formula 1 
     (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)benzyloxy)phenyl)hex-4-inoic acid and an L-lysine salt were dissolved in isopropyl alcohol and purified water. The resultant was filtered through a membrane filter and cooled. The resulting solid was scraped and then filtered. The resultant was dried to obtain a crystal form of a compound of Chemical Formula 1. 
     As a result of powder X-ray diffraction analysis, the crystal form was confirmed to have the XRD pattern of  FIG. 2  and was referred to as crystal form II. 
     Example 3: Preparation of Amorphous Form of Compound of Chemical Formula 1 
     (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)benzyloxy)phenyl)hex-4-inoic acid and an L-lysine salt were dissolved in methanol and isopropyl alcohol by heating at 60° C. The resultant was filtered through a membrane filter and cooled. The resulting solid was scraped and then filtered. The resultant was dried to obtain a powder of a compound of Chemical Formula 1. As a result of powder X-ray diffraction analysis, the powder was confirmed to have the XRD pattern of  FIG. 3  and was referred to as an amorphous form. 
     Experimental Example 1: DSC Analysis of Crystal Form I of Compound of Chemical Formula 1 
     The crystal form I obtained in Example 1 was analyzed using an auto modulated differential scanning calorimeter (MDSC). MDSC analysis results are shown in  FIG. 4 . 
     Auto modulated differential scanning calorimeter (MDSC) conditions 
     1) Model: Q-1000 (TA) 
     2) Temperature range: 40° C.˜210° C. 
     3) Rate: 20° C./min 
     Experimental Example 2: TGA/SDT Analysis of Crystal Form I of Compound of Chemical Formula 1 
     The crystal form I obtained in Example 1 was analyzed using a thermal analyzer (TGA/SDT). 
     Thermal analyzer (TGA/SDT) conditions 
     1) Model: TGA Q5000 IR/SDT Q600 (TA) 
     2) Temperature range: 4° C.˜400° C. 
     3) Rate: 20° C./min 
     TGA/SDT analysis results are shown in  FIG. 5 . 
     Experimental Example 3: DSC Analysis of Crystal Form II of Compound of Chemical Formula 1 
     The crystal form II obtained in Example 2 was analyzed using an auto modulated differential scanning calorimeter (MDSC). 
     Auto modulated differential scanning calorimeter (MDSC) conditions 
     1) Model: Q-1000 (TA) 
     2) Temperature range: 40° C.˜210° C. 
     3) Rate: 20° C./min 
     MDSC analysis results are shown in  FIG. 6 . 
     Experimental Example 4: TGA/SDT Analysis of Crystal Form II of Compound of Chemical Formula 1 
     The crystal form II obtained in Example 2 was analyzed using a thermal analyzer (TGA/SDT). 
     Thermal analyzer (TGA/SDT) conditions 
     1) Model: TGA Q5000 IR/SDT Q600 (TA) 
     2) Temperature range: 40° C.˜400° C. 
     3) Rate: 20° C./min 
     TGA/SDT analysis results are shown in  FIG. 7 . 
     Experimental Example 5: DSC Analysis of Amorphous Form of Compound of Chemical Formula 1 
     The amorphous form obtained in Example 3 was analyzed using an auto modulated differential scanning calorimeter (MDSC). 
     Auto modulated differential scanning calorimeter (MDSC) conditions 
     1) Model: Q-1000 (TA) 
     2) Temperature range: 40° C.˜210° C. 
     3) Rate: 20° C./min 
     MDSC analysis results are shown in  FIG. 8 . 
     Experimental Example 6: TGA/SDT Analysis of Amorphous Form of Compound of Chemical Formula 1 
     The amorphous form obtained in Example 3 was analyzed using a thermal analyzer (TGA/SDT). 
     Thermal analyzer (TGA/SDT) conditions 
     1) Model: TGA Q5000 IR/SDT Q600 (TA) 
     2) Temperature range: 40° C.˜400° C. 
     3) Rate: 20° C./min 
     TGA/SDT analysis results are shown in  FIG. 9 . 
     Experimental Example 7: Thermal Stability Test 
     The crystal form I, crystal form II, and amorphous form samples of a compound of Chemical Formula 1 were subjected to a thermal stability test. 
     0.3 g of each sample was input into a 20 mL vial (prepared 0.3 g*3 ea for each sample), and the vial was sealed by closing a lid and then allowed to stand in an oven set at 80° C. Afterward, the sample was taken out after 6 days, 14 days, and 1 month had elapsed, and the changes in properties, purity, and XRD pattern before and after thermal stress conditions were examined. 
     Purity was measured under the following conditions using a HPLC. 
     Column: YMC-Pack Pro C18, 5 um, 4.6×150 mm 
     Column temperature: 35° C. 
     Flow rate: 1.0 mL/min 
     Injection volume: 5 uL 
     Wavelength: 220 nm 
     Mobile Phase A: 0.1% TFA in H 2 O/MeOH=60/40 
     Mobile Phase B: MeOH/0.1% TFA in ACN=60/40 
     Gradient: 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Time (min) 
                 Mobile Phase A(%) 
                 Mobile Phase B(%) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 0 
                 80 
                 20 
               
               
                 3 
                 80 
                 20 
               
               
                 25 
                 10 
                 90 
               
               
                 30 
                 10 
                 90 
               
               
                 30.10 
                 80 
                 20 
               
               
                 40 
                 80 
                 20 
               
               
                   
               
            
           
         
       
     
     Diluent: H 2 O/ACN=80/20 
     Run time: 40 min 
     Sample concentration: 0.7 mg/mL 
     As a result, as shown in  FIG. 10 , the crystal forms I and II showed no significant change in properties even after 1 month of the thermal stress test, whereas all of the amorphous form samples had already turned yellow after 6 days of the thermal stress test, indicating that thermal stability was significantly degraded. 
     In addition, as shown in Table 3, the purity of the amorphous form after 1 month of the thermal stress test was significantly degraded, whereas the purity of the crystal forms I and II were maintained at high levels. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Purity change before and after thermal stress test 
               
            
           
           
               
               
               
            
               
                   
                   
                 Purity 
               
               
                   
                   
                 change (%) 
               
               
                   
                 Purity (%) 
                 Month 1 − 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No. 
                 Sample 
                 Initial 
                 Day 6 
                 Day 14 
                 Month 1 
                 Initial 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1 
                 Crystal 
                 99.40 
                 98.67 
                 97.91 
                 95.75 
                 −3.65 
               
               
                   
                 form I 
               
               
                 2 
                 Crystal 
                 99.53 
                 98.73 
                 97.80 
                 95.78 
                 −3.75 
               
               
                   
                 form II 
               
               
                 3 
                 Amorphous 
                 99.33 
                 96.76 
                 94.35 
                 87.64 
                 −11.69 
               
               
                   
                 form 
               
               
                   
               
            
           
         
       
     
       FIG. 11  is a graph showing the change in the XRD pattern of a crystal form I before (bottom, black) and after (top, orange) a stability test under thermal stress conditions. 
       FIG. 12  is a graph showing the difference in the XRD pattern between a crystal form I (bottom, black) and a crystal form II (top, orange) before a stability test under thermal stress conditions. 
       FIG. 13  is a graph showing the change in the XRD pattern of a crystal form II before (bottom, black) and after (top, orange) a stability test under thermal stress conditions. 
       FIG. 14  is a graph of comparing the difference between the XRD pattern of a crystal form I before a stability test under thermal stress conditions (bottom, black) and the XRD pattern of a crystal form II after a stability test under thermal stress conditions (top, orange). 
     The crystal form I showed no significant change in XRD pattern peak, whereas the crystal form II showed the shifting of specific peaks. That is, it was shown that the crystal form II was converted to the crystal form I due to heat. 
     Experimental Example 8: Compressibility Test 
     Since a drug that causes a lot of static electricity has difficulty in handling and compressing to form a tablet when formulated, it is very difficult to implement a preparation with a uniform drug content. Accordingly, in relation to the static electricity-inducing capability and flowability of the three types of crystal form I, crystal form II, and the amorphous form, the compressibility of each preparation containing these drugs was examined. 
     The Carr index is used as an indication of the compressibility of a preparation and is related to convenience in formulation, that is, static electricity-inducing capability, flowability, and uniformity of drug content. 
     The Carr Index (CI) is calculated as follows. 
       CI=100×(1−BD/TD)
 
     BD: bulk density, TD: tapped density 
     The Hausner ratio (Hr) is also an indication related to the flowability of a powder or granular drug. 
     The Hausner ratio (Hr) is calculated as follows. 
       Hr=TD/BD 
     As a result of the test, the bulk density and tapped density of the crystal form I, the crystal form II, and the amorphous form were obtained and summarized in Table 4, through which the Carr Index (CI) and Hausner ratio (Hr) were obtained, and based on the criteria in Table 5, the evaluation results for the Carr Index (CI), Hausner ratio (Hr), and flowability are shown in Table 6. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Bulk density and tapped density 
               
            
           
           
               
               
               
            
               
                   
                 Bulk density 
                 Tapped density 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                   
                 Weight 
                 Weight of 
                 Weight 
                   
                 Weight 
                 Weight of 
                 Weight 
                   
               
               
                 Crystal 
                 of empty 
                 container filled 
                 of 
                   
                 of empty 
                 container filled 
                 of 
               
               
                 forms 
                 container 
                 with substance 
                 substance 
                 BD 
                 container 
                 with substance 
                 substance 
                 TD 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 I 
                 22.46 
                 26.27 
                 3.81 
                 0.381 
                 22.46 
                 26.86 
                 4.4 
                 0.44 
               
               
                 II 
                 22.45 
                 23.81 
                 1.36 
                 0.136 
                 22.45 
                 25.41 
                 2.96 
                 0.296 
               
               
                 Amorphous 
                 21.97 
                 25.5 
                 3.53 
                 0.353 
                 21.03 
                 25.36 
                 4.33 
                 0.433 
               
               
                 form 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE 5 
               
               
                   
                   
               
               
                   
                 Carr&#39;s compressibility  
                   
                   
               
               
                   
                 index (%) 
                 Hausner ratio 
                 Description of flow 
               
               
                   
                   
               
             
            
               
                   
                 &lt;10 
                 1.00-1.11 
                 Excellent 
               
               
                   
                 11-15 
                 1.12-1.18 
                 Good 
               
               
                   
                 16-20 
                 1.19-1.25 
                 Fair 
               
               
                   
                 21-25 
                 1.26-1.34 
                 Passable 
               
               
                   
                 26-31 
                 1.35-1.45 
                 Poor 
               
               
                   
                 32-39 
                 1.46-1.59 
                 Very Poor 
               
               
                   
                 &gt;40 
                 &gt;1.60 
                 Very. very poor 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Carr Index (CI) and Hausner ratio (Hr) 
               
            
           
           
               
               
               
               
            
               
                 Crystal forms 
                 CI 
                 Hr 
                 Description of flow 
               
               
                   
               
               
                 I 
                 13.41 
                 1.15 
                 Good 
               
               
                 II 
                 54.05 
                 2.18 
                 Very, very poor 
               
               
                 Amorphous form 
                 18.48 
                 1.23 
                 Fair 
               
               
                   
               
            
           
         
       
     
     There was no significant difference between the crystal forms I and II in the thermal stress stability test, but in the compressibility test, the crystal form II excessively caused static electricity, and thus it was difficult to even fill a die for tableting, and it showed very poor compressibility test results. 
     Experimental Example 9: Storage Stability Test 
     In order to confirm stability when the crystal form I, crystal form II, and amorphous form of a compound of Chemical Formula 1 were formulated, powder obtained by mixing 50 mg of each sample, 149 mg of microcrystalline cellulose, and 1 mg of light anhydrous silicic acid was input into a brown glass bottle and allowed to stand in a stability chamber set under conditions of 60° C. and 75% RH, and the sample was taken out after 2 weeks, 4 weeks, 8 weeks had elapsed to confirm the purity of the compound of Chemical Formula 1 over time. 
     When the storage period for each storage condition was reached, 35 mg of the compound of Chemical Formula 1 was taken from each sample, input into a 50 mL volumetric flask, dissolved with an appropriate amount of diluent, and marked. The resulting solution was input into a glass centrifuge tube and centrifuged at 3,000 rpm and 5° C. for 10 minutes. The sample was taken using a glass pipette and input into a HPLC vial for analysis. 
     As a result, as shown in Table 7, it was confirmed that the purity of the compound of Chemical Formula 1 was decreased in the order of the crystal form I, the crystal form II, and the amorphous form, and thus the crystal form I of the compound was the stablest. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Test for confirming storage stability 
               
            
           
           
               
               
               
            
               
                   
                   
                 Purity 
               
               
                   
                   
                 change (%) 
               
               
                   
                 Purity (%) 
                 Week 8 − 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 No. 
                 Sample 
                 Initial 
                 Week 2 
                 Week 4 
                 Week 8 
                 Initial 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1 
                 Crystal 
                 100.2 
                 101.8 
                 100.9 
                 99.9 
                 −0.3 
               
               
                   
                 form I 
               
               
                 2 
                 Crystal 
                 99.1 
                 96.2 
                 92.3 
                 88 
                 −11.1 
               
               
                   
                 form II 
               
               
                 3 
                 Amorphous 
                 100.6 
                 91.5 
                 86.8 
                 77.5 
                 −23.1 
               
               
                   
                 form 
               
               
                   
               
            
           
         
       
     
     In conclusion, it was confirmed that the crystal form I exhibited more excellent physicochemical properties in terms of thermal stability, static electricity-inducing capability, compressibility, storage stability, and the like compared to the amorphous form or the crystal form II.