New crystal forms of 3-(4-(benzyloxy)phenyl)hex-4-ynoic acid derivatives

Abstract

The present invention relates to a novel crystalline form of a 3-(4-(benzyloxy)phenyl)hex-4-ynoic acid derivative, a method for preparing the same, and a pharmaceutical composition containing the same. Crystalline Form I of the compound of Formula 1 according to the present invention exhibits significantly superior physicochemical properties in terms of thermal stability, electrostatic potential, compressibility, etc. compared to the amorphous form and crystalline Form II, and is particularly useful for formulation and long-term storage. [Figure 1] TIFF2022535778000013.tif220170

Description

[Technical field]

[0001] The present invention relates to a novel crystalline form of a 3-(4-(benzyloxy)phenyl)hex-4-ynoic acid derivative represented by the following chemical formula 1:

[0002] [ka] [Background technology]

[0003] Various crystalline or amorphous forms can exhibit various solid-state physical properties, such as hygroscopicity, behavior upon compression, stability during storage, and flowability of milled solids. Such properties further affect the suitability of a particular solid state as an active pharmaceutical substance for commercial production. For example, flowability affects the ease with which a substance can be handled during processing into a pharmaceutical product. If the particles of a powdered compound do not flow easily past one another, the formulation specialist must take that fact into account when developing a tablet or capsule formulation, which may require the use of a lubricant, such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate.

[0004] Different crystalline or amorphous forms of the same drug may also have substantial differences in important pharmacologic properties, such as dissolution rate and bioavailability. Dissolution rate is not only a consideration for preparing syrups, elixirs and other liquid medicines, but may also lead to different therapeutic outcomes. For example, the dissolution rate of an active ingredient in a patient's gastric juices will lead to different therapeutic outcomes, since it places an upper limit on the rate at which an orally administered active ingredient can reach the patient's bloodstream.

[0005] 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 L-lysine salt, is a compound disclosed in International Patent Publication WO2014-171762, and is a substance that activates free fatty acid receptor 1 (FFAR1) / G-protein coupled receptor (GPR40) to increase intracellular calcium concentration and exhibit excellent blood glucose lowering effects.

[0006] The present inventors have continuously studied the crystal form of the compound of Chemical Formula 1 during the product development process of the compound of Chemical Formula 1. As a result, the present inventors have confirmed that the compound of Chemical Formula 1 has two crystal forms, Form I and Form II, and Form I has superior physicochemical properties compared to Form II or amorphous. Summary of the Invention [Problem to be solved by the invention]

[0007] An object of the present invention is to provide crystalline Form I of the compound of Chemical Formula 1, which has superior physicochemical properties compared to the amorphous and crystalline Form II of the compound of Chemical Formula 1.

[0008] The present invention also provides a method for preparing crystalline Form I of the compound of Formula 1.

[0009] The present invention also provides a pharmaceutical composition comprising crystalline Form I of the compound of Chemical Formula 1 as an active ingredient. [Means for solving the problem]

[0010] The present invention provides crystalline Form I of the compound of Chemical Formula 1, which has superior physicochemical properties compared to the amorphous and crystalline Form II of the compound of Chemical Formula 1.

[0011] According to powder X-ray diffraction (PXRD) analysis, crystalline Form I and crystalline Form II have different crystal structures.

[0012] According to one embodiment of the present invention, crystalline Form I of the compound of formula 1 is characterized by an X-ray powder diffraction pattern having 4 or more, e.g., 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.

[0013] In particular, the X-ray powder diffraction pattern is characterized by having 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.

[0014] More specifically, crystalline Form I of the compound of Formula 1 is characterized by an X-ray powder diffraction pattern having peak positions consistent with the peak positions listed in Table 1 below.

[0015] [Table 1]

[0016] On the other hand, the crystal form II of the compound of formula 1 had the following values: 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 and is characterized by being identified by an X-ray powder diffraction pattern having four or more, for example, four, five, six, seven, eight, nine, ten or more, diffraction peaks at 2[θ] values ​​selected from among 20.2, 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.

[0017] In particular, the X-ray powder diffraction pattern is characterized by having 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.

[0018] More specifically, crystalline Form II of the compound of Formula 1 is characterized by an X-ray powder diffraction pattern having peak positions consistent with the peak positions listed in Table 2 below.

[0019] [Table 2]

[0020] The present invention also provides a method for preparing crystalline Form I of Chemical Formula 1, comprising dissolving (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)benzyloxy)phenyl)hex-4-ynoic acid and L-lysine salt in methanol, adding isopropyl acetate, and obtaining crystalline Form I of the compound of Chemical Formula 1 from the reaction product. The present invention also provides a pharmaceutical composition for preventing or treating a metabolic disease, comprising the crystalline form of the compound of Chemical Formula 1 and a pharma- ceutical acceptable carrier.

[0021] The compound of formula 1 is known to activate the GPR40 enzyme. GPR40 is a G protein-coupled receptor (GPCR) that is primarily expressed in insulin-secreting cells of the pancreas, and the GPR40 expression profile has potential utility for the treatment of a variety of metabolic diseases, including obesity and diabetes.

[0022] The compound of formula 1 according to the present invention has an excellent effect of activating GPR40 protein, and therefore has an excellent insulin secretion promoting effect, can be administered in combination with other drugs, and has an excellent effect of activating GPR40 protein in the body. Therefore, a composition containing the compound as an active ingredient can be usefully used as a pharmaceutical composition for preventing or treating metabolic diseases such as obesity, type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X.

[0023] The compound of formula 1 according to the present invention can be administered in various oral and parenteral dosage forms in clinical administration, and when formulated, it is prepared using a diluent or excipient such as a commonly used filler, extender, binder, wetting agent, disintegrant, surfactant, etc.

[0024] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, lozenges, etc., and such solid preparations are prepared by mixing one or more compounds of the present invention with at least one or more excipients, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, oral liquids, emulsions, syrups, etc., and may contain various excipients, such as wetting agents, sweeteners, flavorings, preservatives, etc., in addition to water and liquid paraffin, which are frequently used simple diluents.

[0025] Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, etc. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. As bases for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin, etc. can be used.

[0026] In addition, the effective dosage of the compound of the present invention represented by Chemical Formula 1 to the human body may vary depending on the age, weight, sex, dosage form, health condition and disease level of the patient, and is generally about 0.001 to 100 mg / kg / day, preferably 0.01 to 35 mg / kg / day. Based on an adult patient weighing 70 kg, the dosage is generally 0.07 to 7000 mg / day, preferably 0.7 to 2500 mg / day, and can be administered once or several times a day at regular intervals according to the judgment of a doctor or pharmacist. Effect of the Invention

[0027] The crystalline form I of the compound of Chemical Formula 1 according to the present invention exhibits exceptionally superior physicochemical properties in terms of thermal stability, electrostatic induction ability, compressibility, etc., compared with the amorphous form and the crystalline form II, and is particularly useful for formulation and long-term storage. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 shows the X-ray powder diffraction pattern of crystalline Form I of the compound of Chemical Formula 1. [Diagram 2] FIG. 1 shows the X-ray powder diffraction pattern of crystalline Form II of the compound of Chemical Formula 1. [Diagram 3] FIG. 1 shows an amorphous X-ray powder diffraction pattern of the compound of formula 1. [Figure 4] FIG. 2 is a diagram showing the difference in heat flow with time and temperature for crystalline form I of the compound of Chemical Formula 1. [Diagram 5] FIG. 2 is a diagram showing the physical properties of a substance or reaction products of crystalline Form I of the compound of Chemical Formula 1 according to a change in temperature, measured as a function of temperature or time. [Figure 6] FIG. 2 is a diagram showing the difference in heat flow with temperature and time for crystalline form II of compound of formula 1. [Figure 7] FIG. 2 is a diagram showing the physical properties of a substance or reaction products of a crystalline form II of the compound of Chemical Formula 1 according to a change in temperature, measured as a function of temperature or time. [Figure 8] FIG. 2 is a graph showing the difference in heat flow with time and temperature for the amorphous form of the compound of Chemical Formula 1. [Figure 9] FIG. 2 is a graph showing the physical properties of a material or reaction products of an amorphous compound of Formula 1 as a function of temperature or time according to a change in temperature. [Figure 10] 1 is a photograph showing changes in properties related to thermal stability of crystalline forms I, II, and amorphous of the compound of formula 1 under harsh thermal conditions. [Figure 11] 1 is a graph showing the change in the XRD pattern of crystalline form I before (bottom, black) and after (top, orange) a thermal stress stability test. [Figure 12] 1 is a graph showing the difference in XRD patterns between crystalline form I (bottom, black) and crystalline form II (top, orange) before and after thermal stress stability testing. [Figure 13]1 is a graph showing the change in the XRD pattern of crystalline form II before (bottom, black) and after (top, orange) a thermal stress stability test. [Figure 14] 1 is a graph comparing the difference between the XRD pattern of crystalline Form I before heat stress stability testing (bottom, black) and the XRD pattern of crystalline Form II after heat stress stability testing (top, orange). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The advantages and features of the present invention, as well as the methods for achieving them, will become apparent from the following detailed description of the embodiments. However, the present invention is not limited to the embodiments disclosed below, and may be embodied in various different forms. The embodiments are provided solely to fully disclose the present invention and to fully inform those skilled in the art of the present invention of the scope of the invention, and the present invention is only defined by the scope of the claims.

[0030] [Example] Example 1: Preparation of Crystalline Form I of the Compound of Formula 1 (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)benzyloxy)phenyl)hex-4-ynoic acid and L-lysine were added to methanol and stirred. After stirring at 60°C for 30 minutes, the mixture was gradually cooled. Isopropyl acetate was added in small portions at 35°C. After the solid was generated, the mixture was stirred for 30 minutes and further isopropyl acetate was added. After stirring at 25°C for 1 hour, the mixture was filtered. The mixture was dried to obtain the crystalline form of the compound of Chemical Formula 1.

[0031] As a result of powder X-ray diffraction analysis, it was confirmed that the compound had the XRD pattern shown in FIG. 1, and this was designated as crystalline form I.

[0032] XRD (X-Ray Diffractometer) conditions 1) Model: D8 Advance (Bruker) 2) Current / Voltage / 2 Theta range / Rate: 40Ma / 40KV / 3-45 / 6deg / min*7

[0033] Example 2: Preparation of Crystalline Form II of the Compound of Formula 1 (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)benzyloxy)phenyl)hex-4-ynoic acid L-lysine salt was dissolved in isopropyl alcohol and purified water. The solution was filtered through a membrane filter and cooled. The resulting solid was scraped out and filtered. The solid was dried to obtain the crystalline form of the compound of Chemical Formula 1.

[0034] As a result of powder X-ray diffraction analysis, it was confirmed that the compound had the XRD pattern shown in FIG. 2, and this was designated as crystalline form II.

[0035] Example 3: Preparation of amorphous compound of formula 1 (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)benzyloxy)phenyl)hex-4-ynoic acid L-lysine salt was dissolved in methanol and isopropyl alcohol by heating at 60°C. The solution was filtered through a membrane filter and cooled. The resulting solid was scraped and filtered. The solid was dried to obtain a powder of the compound of Chemical Formula 1. Powder X-ray diffraction analysis confirmed that the compound had the XRD pattern shown in Figure 3, and this was designated as amorphous.

[0036] Experimental Example 1: DSC analysis of crystalline form I of the compound of formula 1 The crystalline form I obtained in Example 1 was analyzed by temperature modulated differential scanning calorimetry (MDSC). The MDSC analysis results are shown in FIG.

[0037] MDSC (Auto Modulated Differential Scanning Calorimeter) Conditions 1) Model: Q-1000(TA) 2) Temperature range: 40℃~210℃ 3) Speed: 20℃ / min

[0038] Experimental Example 2: TGA / SDT analysis of crystalline form I of the compound of formula 1 The crystalline form I obtained in Example 1 was analyzed by a thermal analyzer (TGA / SDT).

[0039] TGA / SDT (Thermal Analyzer) conditions 1) Model: TGA Q5000 IR / SDT Q600(TA) 2) Temperature range: 40℃~400℃ 3) Speed: 20℃ / min

[0040] The results of the TGA / SDT analysis are shown in FIG.

[0041] Experimental Example 3: DSC analysis of crystalline form II of the compound of formula 1 The crystalline form II obtained in Example 2 was analyzed by temperature modulated differential scanning calorimetry (MDSC).

[0042] MDSC (Auto Modulated Differential Scanning Calorimeter) Conditions 1) Model: Q-1000(TA) 2) Temperature range: 40℃~210℃ 3) Speed: 20℃ / min

[0043] The MDSC analysis results are shown in FIG.

[0044] Experimental Example 4: TGA / SDT analysis of crystalline form II of the compound of formula 1 The crystalline form II obtained in Example 2 was analyzed by a thermal analyzer (TGA / SDT).

[0045] TGA / SDT (Thermal Analyzer) conditions 1) Model: TGA Q5000 IR / SDT Q600(TA) 2) Temperature range: 40℃~400℃ 3) Speed: 20℃ / min

[0046] The results of the TGA / SDT analysis are shown in FIG.

[0047] Experimental Example 5: Amorphous DSC analysis of the compound of formula 1 The amorphous material obtained in Example 3 was analyzed by modulated temperature differential scanning calorimetry (MDSC).

[0048] MDSC (Auto Modulated Differential Scanning Calorimeter) Conditions 1) Model: Q-1000(TA) 2) Temperature range: 40℃~210℃ 3) Speed: 20℃ / min

[0049] The MDSC analysis results are shown in FIG.

[0050] Experimental Example 6: TGA / SDT analysis of amorphous compound of formula 1 The amorphous material obtained in Example 3 was analyzed by a thermal analyzer (TGA / SDT).

[0051] TGA / SDT (Thermal Analyzer) conditions 1) Model: TGA Q5000 IR / SDT Q600(TA) 2) Temperature range: 40℃~400℃ 3) Speed: 20℃ / min

[0052] The results of the TGA / SDT analysis are shown in FIG.

[0053] Experimental Example 7: Thermal stability test The thermal stability test was carried out on the crystalline form I, crystalline form II and amorphous samples of the compound of formula 1.

[0054] 0.3g of each sample was placed in a 20mL vial (0.3g*3ea was prepared for each sample), the vial was closed, and the vial was placed in an oven at 80℃. After 6 days, 14 days, and 1 month, the samples were taken out to investigate the properties, purity, and changes in XRD patterns before and after the thermal stress conditions.

[0055] The purity was measured by HPLC under the following conditions. Column: YMC-Pack Pro C18, 5um, 4.6×150mm Column temperature: 35℃ Flow rate: 1.0mL / min Injection volume: 5uL Wavelength: 220nm Mobile Phase A: 0.1%TFA in H2O / MeOH=60 / 40 Mobile Phase B:MeOH / 0.1%TFA in ACN=60 / 40 Gradient: [ka] Diluent: H2O / ACN=80 / 20 Run time: 40 minutes Sample concentration: 0.7mg / mL

[0056] As a result, as can be seen from FIG. 10, the properties of crystalline forms I and II did not change significantly even after one month of the thermal stress test, whereas the amorphous samples had already turned yellow after six days of the thermal stress test, indicating that they had significantly poor thermal stability.

[0057] Similarly, as can be seen from Table 3, after one month of heat stress test conditions, the purity of the amorphous form was clearly inferior, while the purity of crystalline forms I and II was maintained at a high level.

[0058] [Table 3]

[0059] FIG. 11 is a graph showing the change in the XRD pattern of crystalline form I before (bottom, black) and after (top, orange) a thermal stress stability test.

[0060] FIG. 12 is a graph showing the difference in XRD patterns between crystalline form I (lower row, black) and crystalline form II (upper row, orange) before and after the thermal stress stability test.

[0061] FIG. 13 is a graph showing the change in the XRD pattern of crystalline form II before (bottom, black) and after (top, orange) a thermal stress stability test.

[0062] FIG. 14 is a graph comparing the difference in the XRD pattern of crystalline Form I before heat stress stability testing (bottom, black) and that of crystalline Form II after heat stress stability testing (top, orange).

[0063] While no significant change in the XRD pattern peaks was observed in the case of crystalline form I, in the case of crystalline form II, a specific peak shift was observed, indicating that crystalline form II was converted to crystalline form I by heat.

[0064] Experimental Example 8: Compressibility test Drugs with severe static electricity induction are difficult to handle and difficult to compress and tablet during formulation, making it very difficult to realize a formulation with a uniform drug content. Therefore, we investigated the compression ratio of each formulation containing three types of crystalline forms I, II, and amorphous in relation to their static electricity induction ability and fluidity.

[0065] Carr's Index is used as an index showing the compressibility of a formulation, which is related to the convenience during formulation, i.e., electrostatic inducibility and flowability, and ensuring uniformity of drug content.

[0066] Carr's Index (CI) is calculated as follows: CI = 100 × (1-BD / TD) BD: bulk density (BD), TD: tapped density (TD)

[0067] The Hausner ratio (Hr) is also an index related to the flowability of a powder or particulate drug. The Hausner ratio (Hr) is calculated as follows: Hr=TD / BD

[0068] As a result of the test, the bulk density and tapped density of crystalline forms I, II, and amorphous were obtained and summarized in Table 4. Through this, the Carr's Index (CI) and Hausner ratio (Hr) were obtained, and the evaluation results regarding Carr's Index (CI), Hausner ratio (Hr), and fluidity are shown in Table 6 based on the criteria in Table 5.

[0069] [Table 4]

[0070] [Table 5]

[0071] [Table 6]

[0072] Although there was no significant difference between crystalline forms I and II in the thermal stress stability test, in the compressibility test, crystalline form II showed very poor compressibility test results because of very severe electrostatic induction, making it difficult to even fill the die for tableting.

[0073] Experimental Example 9: Storage stability test When formulating the crystalline form I, crystalline form II, and amorphous form of the compound of chemical formula 1, in order to confirm the stability, 50 mg of each sample was mixed with 149 mg of microcrystalline cellulose and 1 mg of hard anhydrous silicic acid, the powder was placed in a brown glass bottle, and left in a stability chamber under conditions of 60°C and 75% RH. After 2 weeks, 4 weeks, and 8 weeks, samples were taken out to confirm the purity of the compound of chemical formula 1 over time.

[0074] At the end of the storage period for each storage condition, 35 mg of the compound of Formula 1 was taken from each sample, placed in a 50 mL volumetric flask, dissolved in an appropriate amount of diluent, and marked. The solution was placed in a glass centrifuge tube and centrifuged at 3,000 rpm and 5°C for 10 minutes. Samples were taken using a glass pipette and placed in HPLC vials for analysis.

[0075] As a result, as can be seen from Table 7, the purity of the compound of Chemical Formula 1 decreased in the order of crystalline form I, crystalline form II, and amorphous, and it was confirmed that crystalline form I was the most stable compound.

[0076] [Table 7]

[0077] In conclusion, it was confirmed that crystalline form I has exceptionally superior physicochemical properties in terms of thermal stability, static electricity induction ability, compressibility, storage stability, etc., compared to amorphous and crystalline form II.

Claims

1. A type I crystal of the compound of formula 1, 【Chemistry 1】 The I-type crystal is characterized by being identified by an X-ray powder diffraction pattern having four 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. The I-type crystal of chemical formula 1.

2. 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. The I-type crystal of formula 1 according to claim 1.

3. Form I crystal of formula 1 according to claim 1, characterized by an X-ray powder diffraction pattern having peak positions consistent with the peak positions listed in the table below: 【Table 1】 。

4. 2. A method for preparing the crystal of formula I according to claim 1, comprising dissolving (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-yl)benzyloxy)phenyl)hex-4-ynoic acid and L-lysine salt in methanol, adding isopropyl acetate, and obtaining the crystal of formula I from the reaction product.

5. A pharmaceutical composition for preventing or treating a metabolic disease, comprising the type I crystal of Chemical Formula 1 according to any one of claims 1 to 3 and a pharma- ceutically acceptable carrier.

6. 6. The pharmaceutical composition for preventing or treating a metabolic disease according to claim 5, wherein the metabolic disease is any one selected from the group consisting of obesity, type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.

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