NOVEL CRYSTAL FORM OF 3-(4-(BENZYLOXY)PHENYL)HEX-4-INOIC ACID DERIVATIVE

Abstract

The present invention relates to a novel crystal form of a 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, a preparation method therefore and a pharmaceutical composition comprising same. A crystal form I of a compound of chemical formula 1, according to the present invention, exhibits more excellent physicochemical properties such as thermal stability, static electricity-inducing capability, compressibility, etc. compared to an amorphous form or a crystal form II, and thus is especially useful for preparation and long-term storage.

Claims

1. A crystal form I of a compound of Chemical Formula 1, ##STR00002## wherein the crystal form exhibits an X-ray powder diffraction pattern having 4 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.

2. The crystal form of claim 1, wherein 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.

3. The crystal form of claim 1, wherein the crystal form exhibits an X-ray powder diffraction pattern where the positions of peaks match the peak positions listed in the following table: TABLE-US-00009 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

4. A method of preparing the crystal form I of Chemical Formula 1 according to claim 1, the method comprising 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.

5. A pharmaceutical composition for preventing or treating a metabolic disease, comprising the crystal form I of Chemical Formula 1 according to claim 1 and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition of 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.

7. A pharmaceutical composition for preventing or treating a metabolic disease, comprising the crystal form I of Chemical Formula 1 according to claim 2 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7, 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.

9. A pharmaceutical composition for preventing or treating a metabolic disease, comprising the crystal form I of Chemical Formula 1 according to claim 3 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9, 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.

11. A pharmaceutical composition for preventing or treating a metabolic disease, comprising the crystal form I of Chemical Formula 1 according to claim 4 and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, 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.

Description

DESCRIPTION OF DRAWINGS

[0025] FIG. 1 shows an X-ray powder diffraction pattern of a crystal form I of a compound of Chemical Formula 1.

[0026] FIG. 2 shows an X-ray powder diffraction pattern of a crystal form II of a compound of Chemical Formula 1.

[0027] FIG. 3 shows an X-ray powder diffraction pattern of an amorphous form of a compound of Chemical Formula 1.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] FIG. 8 shows the heat flow change of an amorphous form of a compound of Chemical Formula 1 according to temperature and elapsed time.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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

[0039] 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

[0040] (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.

[0041] 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.

[0042] X-ray diffractometer (XRD) conditions

[0043] 1) Model: D8 Advance (Bruker)

[0044] 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

[0045] (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.

[0046] 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

[0047] (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

[0048] 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.

[0049] Auto modulated differential scanning calorimeter (MDSC) conditions

[0050] 1) Model: Q-1000 (TA)

[0051] 2) Temperature range: 40° C.˜210° C.

[0052] 3) Rate: 20° C./min

Experimental Example 2: TGA/SDT Analysis of Crystal Form I of Compound of Chemical Formula 1

[0053] The crystal form I obtained in Example 1 was analyzed using a thermal analyzer (TGA/SDT).

[0054] Thermal analyzer (TGA/SDT) conditions

[0055] 1) Model: TGA Q5000 IR/SDT Q600 (TA)

[0056] 2) Temperature range: 4° C.˜400° C.

[0057] 3) Rate: 20° C./min

[0058] TGA/SDT analysis results are shown in FIG. 5.

Experimental Example 3: DSC Analysis of Crystal Form II of Compound of Chemical Formula 1

[0059] The crystal form II obtained in Example 2 was analyzed using an auto modulated differential scanning calorimeter (MDSC).

[0060] Auto modulated differential scanning calorimeter (MDSC) conditions

[0061] 1) Model: Q-1000 (TA)

[0062] 2) Temperature range: 40° C.˜210° C.

[0063] 3) Rate: 20° C./min

[0064] MDSC analysis results are shown in FIG. 6.

Experimental Example 4: TGA/SDT Analysis of Crystal Form II of Compound of Chemical Formula 1

[0065] The crystal form II obtained in Example 2 was analyzed using a thermal analyzer (TGA/SDT).

[0066] Thermal analyzer (TGA/SDT) conditions

[0067] 1) Model: TGA Q5000 IR/SDT Q600 (TA)

[0068] 2) Temperature range: 40° C.˜400° C.

[0069] 3) Rate: 20° C./min

[0070] TGA/SDT analysis results are shown in FIG. 7.

Experimental Example 5: DSC Analysis of Amorphous Form of Compound of Chemical Formula 1

[0071] The amorphous form obtained in Example 3 was analyzed using an auto modulated differential scanning calorimeter (MDSC).

[0072] Auto modulated differential scanning calorimeter (MDSC) conditions

[0073] 1) Model: Q-1000 (TA)

[0074] 2) Temperature range: 40° C.˜210° C.

[0075] 3) Rate: 20° C./min

[0076] MDSC analysis results are shown in FIG. 8.

Experimental Example 6: TGA/SDT Analysis of Amorphous Form of Compound of Chemical Formula 1

[0077] The amorphous form obtained in Example 3 was analyzed using a thermal analyzer (TGA/SDT).

[0078] Thermal analyzer (TGA/SDT) conditions

[0079] 1) Model: TGA Q5000 IR/SDT Q600 (TA)

[0080] 2) Temperature range: 40° C.˜400° C.

[0081] 3) Rate: 20° C./min

[0082] TGA/SDT analysis results are shown in FIG. 9.

Experimental Example 7: Thermal Stability Test

[0083] 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.

[0084] 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.

[0085] Purity was measured under the following conditions using a HPLC.

[0086] Column: YMC-Pack Pro C18, 5 um, 4.6×150 mm

[0087] Column temperature: 35° C.

[0088] Flow rate: 1.0 mL/min

[0089] Injection volume: 5 uL

[0090] Wavelength: 220 nm

[0091] Mobile Phase A: 0.1% TFA in H.sub.2O/MeOH=60/40

[0092] Mobile Phase B: MeOH/0.1% TFA in ACN=60/40

[0093] Gradient:

TABLE-US-00003 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

[0094] Diluent: H.sub.2O/ACN=80/20

[0095] Run time: 40 min

[0096] Sample concentration: 0.7 mg/mL

[0097] 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.

[0098] 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-US-00004 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

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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).

[0103] 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

[0104] 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.

[0105] 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.

[0106] The Carr Index (CI) is calculated as follows.

CI=100×(1−BD/TD)

[0107] BD: bulk density, TD: tapped density

[0108] The Hausner ratio (Hr) is also an indication related to the flowability of a powder or granular drug.

[0109] The Hausner ratio (Hr) is calculated as follows.

Hr=TD/BD

[0110] 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-US-00005 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-US-00006 TABLE 5 Carr's compressibility index (%) Hausner ratio Description of flow <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 >40 >1.60 Very. very poor

TABLE-US-00007 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

[0111] 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

[0112] 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.

[0113] 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.

[0114] 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-US-00008 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

[0115] 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.