New crystalline form of inavogliflozin and method for producing same

Abstract

The present invention relates to a novel crystalline form of inavogliflozin and a method for producing the same. The novel crystalline form of inavogliflozin according to the present invention has superior thermodynamic stability, improved hygroscopicity, and superior long-term storage and pharmaceutical stability compared to conventionally reported crystalline forms of inavogliflozin. Furthermore, compared to conventionally reported crystalline forms of inavogliflozin, the time to reach Cmax is shorter and the drug effect can be rapidly demonstrated, making it useful.

Description

[Technical Field]

[0001] The present invention relates to a novel crystalline form of inavogliflozin and a method for producing the same. [Background technology]

[0002] The selection of pharmaceutically acceptable salt forms, co-crystals, and their polymorphs has a significant impact on the development of manufacturing processes for raw drug substances and the design and formulation of finished drug substances.

[0003] Specifically, the salts, cocrystals, and their crystalline polymorphs of raw drug substances affect the recrystallization yield, process speed, and even purity during the final stage of drug substance production, i.e., the recrystallization and purification process. The crystal size and shape affect the rate of crystallization, which affects productivity and manufacturing costs.

[0004] In pharmaceutical terms, physicochemical properties such as hygroscopicity, stability, solubility, particle fluidity, and dissolution rate are affected by salts, cocrystals, and their polymorphs, which are factors that determine the production process, production and storage conditions, and expiration date of the finished drug.

[0005] On the other hand, when the bioavailability of a drug is affected by the physicochemical properties of the raw drug, more attention is required in the selection of salts, cocrystals, and their polymorphs. Therefore, optimized salts, cocrystals, and their polymorphs are very important in terms of technology development and approval.

[0006] An object of the present invention is to search for novel crystalline polymorphs of inavogliflozin, analyze their physicochemical characteristics, develop crystalline forms that can maximize pharmacological activity, and provide crystalline forms that are more advantageous than conventional crystalline forms.

[0007] SGLT-2 (sodium glucose cotransporter 2) is a transporter that, together with SGLT-1 (sodium glucose cotransporter 1), is responsible for the reabsorption of excess blood glucose in the kidney, with SGLT-2 playing most of the role. Therefore, when SGLT-2 inhibitors inhibit the SGLT-2 transporter, the amount of blood glucose excreted in the urine increases, ultimately lowering blood glucose levels, and the calories contained in blood glucose are excreted, resulting in weight loss.

[0008] One of the drugs developed as an SGLT-2 inhibitor that can be useful as a therapeutic agent for type 2 diabetes due to such effects is enavogliflozin, which is represented by the following structural formula (Chemical Formula 1), and is disclosed in Korean Patent Publication No. 2014-0022086 (Patent Document 1).

[0009] [ka]

[0010] Furthermore, Korean Patent Publication No. 2017-0142904 (Patent Document 2) discloses a crystalline inavogliflozin and a manufacturing method for manufacturing the crystalline inavogliflozin.

[0011] On the other hand, the criteria for selecting a superior crystalline form depend on the most important physicochemical properties required by the drug. However, the selection of the optimized crystalline form may vary depending on the purpose, such as selecting the most thermodynamically stable one, selecting one optimized for the manufacture of pharmaceutical raw materials and formulations, or improving the solubility and dissolution rate of the drug.

[0012] Therefore, the present inventors have continuously conducted research to select a crystalline form suitable for product development of inavogliflozin. As a result, they have discovered that there exists a crystalline form E that is different from the four crystalline forms disclosed in Korean Patent Publication No. 2017-0142904 (Patent Document 2), and that crystalline form E does not change in crystalline form, is thermodynamically more stable than conventional crystalline forms, and has lower hygroscopicity, thereby completing the present invention. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] Korean Patent Publication No. 2014-0022086 [Patent Document 2] Korean Patent Publication No. 2017-0142904 Summary of the Invention [Problem to be solved by the invention]

[0014] An object of the present invention is to provide a novel crystalline form of inavogliflozin that is thermodynamically stable and has low hygroscopicity, and a method for producing the same. Another object of the present invention is to provide a pharmaceutical composition containing the novel crystalline form of inavogliflozin as an active ingredient. [Means for solving the problem]

[0015] The present invention provides a novel crystalline form of inavogliflozin represented by the following structural formula (Chemical Formula 1) and a method for producing the same.

[0016] [ka]

[0017] According to powder X-ray diffraction (PXRD) analysis, the novel crystalline form has a different crystalline structure from the four crystalline forms disclosed in Korean Patent Publication No. 2017-0142904 (Patent Document 2).

[0018] One embodiment of the present invention provides a crystalline form of inavogliflozin (hereinafter also referred to as crystalline form E) characterized by being identified by an X-ray powder diffraction pattern having four or more, for example, four, five, six, seven, eight or more diffraction peaks at 2[θ] values ​​selected from 4.93±0.2, 6.12±0.2, 7.43±0.2, 8.89±0.2, 9.74±0.2, 14.79±0.2, 15.79±0.2, 16.11±0.2, 19.79±0.2, and 22.83±0.2, in powder X-ray diffraction (PXRD) analysis.

[0019] In particular, the X-ray powder diffraction pattern is characterized by having diffraction peaks at 2[θ] values ​​selected from 7.43±0.2, 14.79±0.2, 15.79±0.2, 16.11±0.2 and 19.79±0.2.

[0020] More specifically, the crystalline form E of inavogliflozin is characterized by being identified by an X-ray powder diffraction pattern in which the peak positions match those listed in Table 1 below.

[0021] [Table 1]

[0022] In another embodiment of the present invention, the novel crystalline form E of inavogliflozin is characterized by exhibiting an endothermic peak with an endothermic onset temperature of 170.58°C±3°C and an endothermic temperature of 174.06°C±3°C in differential scanning calorimetry (DSC) analysis.

[0023] Another embodiment of the present invention provides a method for preparing the novel crystalline form of inavogliflozin.

[0024] Without being limited thereto, crystalline form E of inavogliflozin is prepared by a process including adding water to inavogliflozin, heating and stirring, filtering and drying to obtain a crystalline form of inavogliflozin.

[0025] The process of the present invention for preparing the novel crystalline form of inavogliflozin is described in detail step by step as follows.

[0026] (a) Adding water to inavogliflozin First, the method of the present invention includes a step of adding water to solid inavogliflozin. The physicochemical form of inavogliflozin used to prepare crystalline form E is not particularly limited. For example, inavogliflozin used to prepare crystalline form E may be inavogliflozin crystalline form A, crystalline form B, crystalline form C, crystalline form D, or amorphous inavogliflozin, which has been reported to have the following X-ray diffraction spectrum in Experimental Example 4 of Korean Patent Publication No. 2017-0142904.

[0027] Crystalline form A: A crystalline form having an X-ray diffraction (XRD) spectrum containing peaks at 2[θ] values ​​selected from 6.2°±0.2°, 7.2°±0.2°, 8.8°±0.2°, 17.6°±0.2°, 19.0°±0.2°, 22.5°±0.2°, and 25.1°±0.2°. Crystalline form B: A crystalline form having an X-ray diffraction (XRD) spectrum containing peaks at 2[θ] values ​​selected from 7.0°±0.2°, 14.9°±0.2°, 17.7°±0.2°, 18.8°±0.2°, 20.6°±0.2°, 21.8°±0.2°, and 23.5°±0.2°. Crystalline form C: A crystalline form having an X-ray diffraction (XRD) spectrum containing peaks at 2[θ] values ​​selected from 5.6°±0.2°, 7.3°±0.2°, 15.7°±0.2°, 17.2°±0.2°, 18.9°±0.2°, 21.2°±0.2°, and 21.9°±0.2°. Crystalline form D: A crystalline form having an X-ray diffraction (XRD) spectrum containing peaks at 2[θ] values ​​selected from 5.5°±0.2°, 7.2°±0.2°, 15.3°±0.2°, 17.2°±0.2°, 17.6°±0.2°, 18.9°±0.2°, and 21.1°±0.2°. The crystalline forms A, B, C and D can each be identified by an X-ray diffraction spectrum having four or more, e.g., four, five, six, seven, eight or more, peaks at the 2[θ] values ​​listed above.

[0028] According to one embodiment of the present invention, the water in step (a) may be used in a volume that is 6 times or more the weight of inavogliflozin, for example, 6 to 50 times, for example, 7 times, 8 times, 9 times, 10 times, 12 times, 15 times, 18 times, 20 times, 22 times, 25 times, 28 times, 30 times, 40 times, or 50 times the weight of inavogliflozin.

[0029] (b) heating and stirring the product The method of the present invention then includes the step of heating and stirring the product of step (a).

[0030] According to another embodiment of the present invention, the heating in step (b) can be carried out at a temperature of 50°C or higher, for example, but not limited to, 50 to 80°C, such as 50 to 60°C, 60 to 70°C, or 70 to 80°C.

[0031] According to another embodiment of the present invention, the stirring in step (b) may be carried out for 8 hours or more, but is not limited to, for example, 8 to 48 hours, for example, 8 to 10 hours, 10 to 14 hours, 12 to 16 hours, 16 to 20 hours, 20 to 24 hours, 24 to 30 hours, 30 to 36 hours, or 36 to 48 hours, and may be appropriately changed depending on the amount of water used, the heating temperature, etc.

[0032] (c) Drying the product and obtaining an inavogliflozin crystalline form Finally, the process of the present invention involves filtering and drying the product of step (b) to obtain novel crystalline form E of inavogliflozin.

[0033] According to another embodiment of the present invention, the drying in step (c) may be, for example, vacuum drying, and may be carried out at a temperature of 30 to 65°C for 8 to 24 hours. More preferably, the vacuum drying is carried out at a temperature of 45 to 55°C.

[0034] This method makes it possible to produce a new crystalline form of inavogliflozin, which can be used as a treatment for type 2 diabetes that regulates blood glucose by suppressing blood glucose reabsorption in the kidney as an SGLT-2 inhibitor and excreting blood glucose in the urine.

[0035] The present invention also provides a pharmaceutical composition comprising the novel crystalline form E of inavogliflozin as an active ingredient and a pharmaceutically acceptable carrier.

[0036] The pharmaceutical composition may be for, but is not limited to, treating or preventing diabetes.

[0037] The novel crystalline form of inavogliflozin according to the present invention may be administered in various oral and parenteral dosage forms in clinical administration, and when formulated, it is produced using a commonly used diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, or surfactant. [Effects of the Invention]

[0038] The novel crystalline form of inavogliflozin according to the present invention has superior thermodynamic stability, improved hygroscopicity, and excellent long-term storage and pharmaceutical stability compared to the previously reported crystalline forms of inavogliflozin. Furthermore, the Tmax is 1.25 times faster than that of the previously reported crystalline form A of inavogliflozin, and the novel crystalline form of inavogliflozin according to the present invention can exhibit rapid efficacy, and therefore can be usefully utilized for various indications and in the development of dosage forms. [Brief explanation of the drawings]

[0039] [Figure 1] 1 shows the powder X-ray diffraction (PXRD) pattern results of a novel crystalline form of inavogliflozin prepared according to an embodiment of the present invention. [Figure 2] 1 shows the differential scanning calorimetry (DSC) calorimetry curve results of a novel crystalline form of inavogliflozin prepared according to an embodiment of the present invention. [Figure 3]FIG. 1 shows the results of differential scanning calorimetry (DSC) analysis of a novel crystalline form of inavogliflozin prepared according to an embodiment of the present invention and inavogliflozin crystalline forms A and B prepared according to an embodiment of Korean Patent Publication No. 2017-0142904. DETAILED DESCRIPTION OF THE INVENTION

[0040] The advantages and features of the present invention, as well as 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. These embodiments are provided so that the disclosure of the present invention will be complete and will fully convey the scope of the present invention to those skilled in the art. The present invention is defined only by the scope of the claims.

[0041] [Production Example 1] Production of Inavogliflozin Crystalline Form A Crystalline form A of inavogliflozin reported in Experimental Example 4 of Korean Patent Publication No. 2017-0142904 was prepared.

[0042] Ethyl acetate (15 times the weight of the crude inavogliflozin) was added to crude inavogliflozin, dissolved by refluxing and stirring, and cooled to room temperature. After a suspension was formed at room temperature, the mixture was stirred for an additional 30 minutes. Isopropyl ether (15 times the weight of the crude inavogliflozin) was added dropwise to the resulting mixture over 30 minutes, and the mixture was stirred for an additional 30 minutes at room temperature. The resulting precipitate was filtered, washed with ethyl acetate (2 times the weight of the crude inavogliflozin) at 0°C, and then dried in a vacuum oven (50°C, 12 hours) to obtain white crystals (yield: 88.3%).

[0043] [Production Example 2] Production of amorphous inavogliflozin 100 mg of inavogliflozin was completely dissolved in 3 mL of tetrahydrofuran, and the solvent was then completely concentrated using a rotary evaporator to obtain solid amorphous inavogliflozin.

[0044] [Production Example 3] Production of a new crystalline form using Inavogliflozin crystalline form A 100 mg of inavogliflozin crystalline form A was added to 3 ml of water to form a suspension, which was then stirred for 24 hours at 60°C. After cooling to room temperature, the suspension was filtered under reduced pressure and dried in vacuo at 50°C for 12 hours to obtain a novel crystalline form of inavogliflozin in a yield of 91%.

[0045] [Production Example 4] Production of a new crystalline form using amorphous inavogliflozin A suspension was prepared by adding 3 ml of water to 100 mg of amorphous inavogliflozin and stirring it at 60°C for 24 hours. After cooling to room temperature, the suspension was filtered under reduced pressure and dried in vacuo at 50°C for 12 hours to obtain a novel crystalline form of inavogliflozin in 86% yield.

[0046] [Experimental Example 1] Powder X-ray diffraction (PXRD) The crystalline inavogliflozin obtained in Production Examples 3 and 4 were subjected to PXRD measurement using a Bruker PXRD (30 kV, 10 mA, Cu target). Scanning was performed from 5 to 40° 2θ with a step size of 0.02°, and the results shown in Figure 1 were obtained. The main peaks are summarized in Table 2 below.

[0047] [Table 2]

[0048] The results of the powder X-ray diffraction (PXRD) are different from those of crystalline forms A to D of inavogliflozin reported in the conventional Patent Document 2, and this was named novel crystalline form E of inavogliflozin.

[0049] [Experimental Example 2] Differential Scanning Calorimetry (DSC) DSC measurements were carried out using a DSC Q20 from TA Co. under nitrogen gas at a scan rate of 10°C from 20°C to 250°C.

[0050] As a result, as shown in Figure 2, the novel crystalline form E of inavogliflozin showed an endothermic peak with an endothermic onset temperature of 170.58°C ± 3°C and an endothermic temperature of 174.06°C ± 3°C in differential scanning calorimetry (DSC) analysis.

[0051] The melting point of novel crystalline form E was confirmed to be approximately 171°C, the highest among known crystalline forms of inavogliflozin (see Figure 2).

[0052] [Experimental Example 3] Evaluation of moisture absorption 60 mg of each of the publicly known inavogliflozin crystalline form A disclosed in Korean Patent Publication No. 2017-0142904 and the inavogliflozin crystalline form E was placed in desiccators at relative humidity of 11%, 33%, 54%, 75%, and 93% for at least two days, respectively, to absorb moisture, and then the change in weight was measured. The results are shown in Table 3 below.

[0053] [Table 3]

[0054] As shown in Table 3, both the known inavogliflozin crystalline form A and the inavogliflozin crystalline form E of the present invention did not absorb moisture, but it was confirmed that novel inavogliflozin crystalline form E has improved hygroscopicity.

[0055] [Experimental Example 4] Evaluation of severe stability In order to confirm the commercializability of novel inavogliflozin crystalline form E of the present invention, a severe stability test was carried out using inavogliflozin crystalline form A of Korean Patent Publication No. 2017-0142904 as a control, and the test was analyzed using a liquid chromatography (HPLC) qualitative analysis method. The results are shown in Tables 4 and 5.

[0056] Table 4 shows the results of an 8-week evaluation of heat (60°C) stress stability.

[0057] [Table 4]

[0058] Table 5 shows the evaluation results of the harsh stability against moisture (93% RH) for 4 weeks.

[0059] [Table 5]

[0060] As shown in Tables 4 and 5, it was confirmed that novel crystalline form E of inavogliflozin of the present invention was stably maintained at 60°C for 8 weeks and at 93% RH for 4 weeks without being affected by purity and without any change in crystalline form.

[0061] [Experimental Example 5] Study on setting the temperature range for producing E-type crystals 300 mg of inavogliprozin crystalline form A was added to 9 mL of water and stirred for 24 hours at various temperatures ranging from 40 to 80° C. The crystals were filtered and dried in vacuo, and the crystalline form was confirmed using DSC.

[0062] [Table 6]

[0063] As shown in Table 6, at temperatures between 40 and 50° C., a mixture of crystalline form A was obtained. Therefore, it was confirmed that the crystallization temperature is preferably 50° C. or higher.

[0064] [Experimental Example 6] Study on setting the crystallization time range for producing crystalline form E 300 mg of inavogliprozin crystalline form A was added to 9 mL of water and stirred for 1 to 24 hours at 60° C. The crystals were filtered and dried, and then the crystalline form was confirmed using DSC.

[0065] [Table 7]

[0066] As can be seen from Table 7, under the given conditions, it was confirmed that the crystallization time must be 8 hours or more for the crystal to be converted to crystalline form E. Therefore, it was confirmed that the stirring time for crystallization to obtain crystalline form E is preferably at least 8 hours or more.

[0067] [Experimental Example 7] Study on setting the amount of water added to produce crystal form E 100 mg of inavogliprozin crystalline form A was added to 0.5 mL, 1 mL, and 2 mL of water, respectively, and stirred for 24 hours at 60° C. The crystals were filtered and dried, and then the crystalline form was confirmed using DSC.

[0068] [Table 8]

[0069] The minimum amount of water required for crystallization was confirmed, and as a result, as shown in Table 8, it was confirmed that at least 6 times the weight of water as compared with that of inavogliflozin crystalline form A was required to obtain crystalline form E.

[0070] [Experimental Example 8] Pharmacokinetic study of novel crystalline form E in beagle dogs The pharmacokinetic profiles of inavogliflozin crystalline form A and novel crystalline form E in beagle dogs were investigated. Inavogliflozin crystalline form A was used as the control group, and novel crystalline form E was used as the comparison group. Inavogliflozin crystalline form A and novel crystalline form E were orally administered at a dose of 1 mg / kg to male beagle dogs, and blood samples were taken before administration (0 hour), and at 0.083, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours (a total of 13 times). Blood drug concentrations were analyzed by LC-MS / MS using plasma separated from the collected samples, and pharmacokinetic parameters such as maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were calculated using WinNonlin 5.0.1 program. last and AUC inf ), time versus maximum observed plasma concentration (Tmax), half-life (T 1 / 2 ) was calculated and analyzed.

[0071] The results are summarized in Table 9 below.

[0072] [Table 9]

[0073] As shown in Table 9, the time to maximum observed plasma concentration (Tmax) of novel crystalline form E of the present invention is 1.25 times or more faster than that of inavogliflozin crystalline form A, and the AUC last and AUC inf It was also confirmed that the Tmax of the novel crystalline form E of the present invention was increased. Therefore, it was confirmed that the novel crystalline form E of the present invention reaches the maximum blood concentration (Tmax) earlier than the conventional crystalline form A and exhibits a faster onset of efficacy (faster onset time). Therefore, the novel crystalline form E can exert the effect of lowering blood glucose more quickly than the conventional crystalline form A of inavogliflozin.

Claims

1. A crystalline form of inavogliflozin characterized by being identified by an X-ray powder diffraction pattern having four or more diffraction peaks at 2[θ] values ​​selected from the group consisting of 4.93±0.2, 6.12±0.2, 7.43±0.2, 8.89±0.2, 9.74±0.2, 14.79±0.2, 15.79±0.2, 16.11±0.2, 19.79±0.2, and 22.83±0.2 in X-ray diffraction (PXRD) analysis.

2. 2. The crystalline form of inavogliflozin according to claim 1, wherein the X-ray powder diffraction pattern has diffraction peaks at 2[θ] values ​​selected from 7.43±0.2, 14.79±0.2, 15.79±0.2, 16.11±0.2 and 19.79±0.

2.

3. The crystalline form of inavogliflozin according to claim 1, characterized in that it is identified by an X-ray powder rotation pattern whose peak positions coincide with the peak positions listed in the table below. 【Table 1】

4. 2. The crystalline form of inavogliflozin according to claim 1, which exhibits an endothermic onset temperature of 170.58°C ± 3°C and an endothermic peak at 174.06°C ± 3°C in differential scanning calorimetry (DSC) analysis.

5. 2. A method for producing the crystalline form of inavogliflozin according to claim 1, comprising adding water to solid inavogliflozin, heating and stirring the mixture, filtering and drying the mixture to obtain the crystalline form of inavogliflozin.

6. 6. The method for producing crystalline inavogliflozin according to claim 5, wherein water is added in an amount of 6 times or more by volume relative to the weight of solid inavogliflozin.

7. The method for producing crystalline inavogliflozin according to claim 5, wherein the heating is carried out at 50°C or higher.

8. The method for producing crystalline inavogliflozin according to claim 5, wherein the stirring is carried out for 8 hours or more.

9. 10. A pharmaceutical composition comprising the inavogliflozin crystalline form according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier.

10. 10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is for treating or preventing diabetes.

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