Gemigliptin maleate crystal as well as preparation method and application thereof

Abstract

The invention provides a gemigliptin maleate crystal and a preparation method and application thereof, the gemigliptin maleate crystal has higher thermal stability, better fluidity, better stability and the like, and the preparation method is simple and suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a gemagliptin maleate crystal and a preparation method and application thereof. Background Art

[0002] Gelagliptin, chemical name: (S)-1-(2-amino-4-(2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-D]pyrimidin-7(6H)-yl)-4-oxobutyl)-5,5-difluoropiperidin-2-one, its structural formula was first disclosed in patent KR20090068156A, and its application in the preparation of diabetes or obesity drugs was disclosed. Gelagliptin is a DPP-IV inhibitor that can activate incretin to show a stable decrease in blood sugar levels, and it does not have the disadvantages of conventional oral antidiabetic drugs, such as hypoglycemia and weight gain, and shows a low risk of cardiovascular diseases, making it a very ideal drug for treating diabetes or obesity.

[0003] In order to find the most suitable form of active ingredients for medicinal use, a series of salts of active ingredients are usually studied during the drug development process. Specifically, for carboxylic acid ester compounds to which ollisartan medoxomil belongs, the salts formed at the tetrazole position usually have better solubility in polar solvents. In addition, the salts of active ingredients may also have unpredictable advantages in physical and chemical properties such as stability and hygroscopicity.

[0004] Patent CN103189375A discloses gemagliptin tartrate, hydrate and crystal form. The 1.5 hydrate of the tartrate of compound 1 obtained by the developed crystal form is superior to similar crystal forms in terms of stability, especially storage stability. It can be used to prepare a pharmaceutical composition containing compound 1 as an active ingredient, so a product with a uniform standard can usually be obtained during storage and preparation, and the error in quality control is very small. Although the prior art provides a variety of gemagliptin salts, the crystal form most suitable for pharmaceutical use is not screened, so it is very necessary to develop a new crystal form of gemagliptin salt with better stability and more suitable for pharmaceutical use. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a gemagliptin maleate crystal and a preparation method and application thereof. The gemagliptin maleate crystal provided by the present invention has obvious advantages over the gemagliptin salt disclosed in the prior art in at least one aspect, such as solubility, stability (thermal stability, light stability, hygroscopicity, etc.), and fluidity, and is more suitable for pharmaceutical use in comprehensive evaluation.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] The first object of the present invention is to provide a gemagliptin maleate crystal, wherein the diffraction angle 2θ of the gemagliptin maleate crystal on the powder XPRD spectrum is 9.24, 12.42, 16.62, 18.61, 19.04, 20.28, 24.23, and the error range is ±0.2°;

[0008] Furthermore, the diffraction angle 2θ of the gemagliptin maleate crystals on the powder XPRD spectrum is 11.57, 14.24, 14.65, 16.86, 17.13, 20.60, 21.83, 23.93, 24.67, 25.65, with an error range of ±0.2°;

[0009] Furthermore, the relative peak intensity at the 2θ angle of 9.24 ± 0.2° is the strongest;

[0010] Further, the DSC spectrum of the gemagliptin maleate crystals has an endothermic peak at 169.2±5°C; preferably, the DSC spectrum of the gemagliptin maleate crystals has an endothermic peak at 169.2±3°C;

[0011] Further, the TG spectrum of the gemagliptin maleate crystals shows that the mass change from 0 to 120°C is 0.51%±0.1%; preferably, the TG spectrum of the gemagliptin maleate crystals shows that the mass change from 0 to 120°C is 0.51%±0.05%;

[0012] Furthermore, the HPLC purity of the gemagliptin maleate crystals is greater than or equal to 91.5%; preferably, the HPLC purity of the gemagliptin maleate crystals is greater than or equal to 99.6%.

[0013] The second object of the present invention is a method for preparing gemagliptin maleate crystals, characterized in that the preparation method comprises the following steps:

[0014] Step (1): weighing gemagliptin free base, and then adding polar solvent A to obtain solution 1;

[0015] Step (2): adding maleic acid to solution 1, and then adding a non-polar solvent B to obtain solution 2;

[0016] Step (3): performing solid-liquid separation on solution 2 and collecting the filtrate;

[0017] Step (4): evaporating the filtrate to dryness, adding a polar solvent A / non-polar solvent B mixed solvent to obtain solution 3;

[0018] Step (5): heating and cooling the solution 3 at 50-5°C for about 6 hours, separating the solid from the liquid, collecting the solid, and drying to obtain gemagliptin maleate crystals;

[0019] Furthermore, in the step (1), the mass volume ratio of the gemagliptin free base to the polar solvent A is 1 g: 4-6 mL;

[0020] Further, the molar ratio of the gemagliptin free base to the maleic acid is 1:1.0-1.2;

[0021] Furthermore, in the step (2), the mass volume ratio of the gemagliptin free base to the non-polar solvent B is 1 g: 1.5-2.5 mL;

[0022] Furthermore, in the step (4), the mass volume ratio of the gemagliptin free base to the polar solvent A / non-polar solvent B mixed solvent is 1 g: 6-8 mL;

[0023] Further, in the step (4), the volume ratio of polar solvent A to non-polar solvent B in the polar solvent A / non-polar solvent B mixed solvent is 5:1-3; specifically, the volume ratio of polar solvent A to non-polar solvent B can be 5:1, 5:2, or 5:3;

[0024] Further, the polar solvent A includes R1-COO-R2, wherein R1 and R2 are independently selected from one of methyl, ethyl, and propyl; specifically, the polar solvent A can be methyl formate, ethyl formate, ethyl acetate, methyl acetate, etc.;

[0025] Further, the non-polar solvent B includes one or more of C5-C8 alkanes, benzene, toluene, ethylbenzene, and xylene; specifically, the polar solvent A can be n-pentane, n-hexane, n-heptane, n-octane, benzene, toluene, ethylbenzene, xylene, etc.;

[0026] Furthermore, in step (3), the temperature is raised from 50 to 5°C for about 6 hours, and the procedure is as follows: the temperature is raised from 20°C to 50°C within 0.5 hours, and kept at a constant temperature for 2 hours, and then dropped to 5°C within 1.5 hours, and kept at a constant temperature of 5°C for 2 hours.

[0027] The third object of the present invention is to provide a pharmaceutical composition or pharmaceutical preparation, characterized in that it comprises the gemagliptin maleate crystals according to any one of claims 1-6.

[0028] The fourth object of the present invention is to provide use of gemagliptin maleate crystals or the aforementioned pharmaceutical composition or pharmaceutical preparation in treating or preventing diseases associated with DPP-IV.

[0029] Beneficial effects of the present invention:

[0030] The gemagliptin maleate crystals provided in the present application have higher thermal stability, better fluidity, better stability, etc., and the preparation method thereof is simple and suitable for industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The hydrogen spectrum of the gemagliptin maleate crystal prepared in Example 1

[0032] Figure 2 DSC-TGA spectrum of gemagliptin maleate crystals prepared in Example 1

[0033] Figure 3 XPRD spectrum of gemagliptin maleate crystals prepared in Example 1 DETAILED DESCRIPTION

[0034] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by technicians in the technical field of the present invention, and the terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. In the description of the present application, it should be understood that "and / or" describes the association relationship of associated objects, indicating that three relationships may exist, for example, A and / or B can represent: A exists alone, A and B exist at the same time, and B exists alone, where A and B can be singular or plural.

[0036] Example 1

[0037]

[0038] This embodiment provides a gemagliptin maleate crystal and a preparation method thereof, and the specific steps are as follows:

[0039] Step (1): 10 g of gilagliptin free base was weighed and dissolved in 50 mL of ethyl acetate to obtain a clear solution 1;

[0040] Step (2): add 2.40 g of maleic acid solid to the clear solution 1, stir and react for 30 min, then add 10 mL of n-heptane under stirring to form solution 2;

[0041] Step (3): performing solid-liquid separation on solution 2 and collecting the filtrate;

[0042] Step (4): evaporate the filtrate to dryness, and add 70 mL of a mixed solvent of ethyl acetate / n-heptane (5:2, v / v);

[0043] Step (5): heating and cooling at 50-5°C for about 6 hours, solid-liquid separation, collecting the solid, and drying to obtain gemagliptin maleate, with a yield of 54%;

[0044] The 50-5°C temperature rise and fall procedure is as follows: the temperature is raised from 20°C to 50°C within 0.5h, and kept constant for 2h, then dropped to 5°C within 1.5h, and kept constant at 5°C for 2h.

[0045] The purity of the product gemagliptin maleate was determined by HPLC. The test equipment was Agilent 1260 equipped with a DAD detector; the chromatographic column was Xtimate C18, 3.0 mm x 150 mm, 3 pm; the mobile phase was 0.1% H3PO4 aqueous solution and acetonitrile, the flow rate was 1.0 ml / min, the column temperature was 35 ° C, and the gradient elution method (gradient conditions see Table 1) was used to analyze the purity of the product. The test results are shown in Table 2:

[0046] Table 1 Gradient conditions

[0047]

[0048]

[0049] Table 2 HPLC test results

[0050] #Peak RRT Area(%) #Peak RRT Area(%) 1 0.81 0.05 6 1.29 0.03 2 0.87 0.03 7 1.35 0.03 3 0.90 0.07 8 1.42 0.02 4 0.94 0.09 9 1.43 0.08 5 1.00 99.60

[0051] As can be seen from Table 1, the liquid phase (HPLC) purity test results of gemagliptin maleate show that the purity of gemagliptin maleate is greater than 99.60%, and the purity of each impurity is less than 0.1%.

[0052] The hydrogen spectrum data of the product is (see attached figure Figure 1 ): 1HNMR (400MHz, DMSO-d6): δ10.29(s,1H),6.02(s,2H),4.93~5.01(m,2H),4.49~4.87(m,1H),4.0 0~4.07(m,1H),3.77~3.88(m,4H),3.54~3.59(m,1H),3.16(m,1H),2.68~3.02(m,4H),2.34(m,2H).

[0053] Example 2

[0054] This embodiment provides a gemagliptin maleate crystal and a preparation method thereof, and the specific steps are as follows:

[0055] Step (1): 10 g of gilagliptin free base was weighed and dissolved in 50 mL of ethyl acetate to obtain a clear solution 1;

[0056] Step (2): add 2.40 g of maleic acid solid to the clear solution 1, stir and react for 30 min, then add 10 mL of n-hexane under stirring to form solution 2;

[0057] Step (3): performing solid-liquid separation on solution 2 and collecting the filtrate;

[0058] Step (4): evaporate the filtrate to dryness, and add 70 mL of a mixed solvent of ethyl acetate / n-hexane (5:2, v / v);

[0059] Step (5): heating and cooling at 50-5°C for about 6 hours, solid-liquid separation, collecting the solid, and drying to obtain gemagliptin maleate type A with a yield of 56%; wherein the heating and cooling program at 50-5°C is as follows: heating to 50°C within 0.5 hours and keeping the temperature constant for 2 hours, then reducing the temperature to 5°C within 1.5 hours and keeping the temperature constant at 5°C for 2 hours.

[0060] The product obtained in Example 2 was tested according to the HPLC test conditions in Example 1. The test results showed that the purity of gemagliptin maleate was greater than 99.7%, and the single impurity was less than 0.1%.

[0061] The hydrogen spectrum data of the product are: 1HNMR (400MHz, DMSO-d6)δ10.28(s,1H),6.01(s,2H),4.81~5.01(m,2H),4.50~4.53(m,1H),4.03~4.06(m,1H),3.80~3.86(m,4H),3.53~3.58(m,1H),3.15(m,1H),2.68~3.02(m,4H),2.33(m,2H).

[0062] Example 3

[0063] This embodiment provides a gemagliptin maleate crystal and a preparation method thereof, and the specific steps are as follows:

[0064] Step (1): 10 g of gilagliptin free base was weighed and dissolved in 50 mL of ethyl acetate to obtain a clear solution 1;

[0065] Step (2): add 2.40 g of maleic acid solid to the clear solution 1, stir and react for 30 min, then add 10 mL of toluene under stirring to form solution 2;

[0066] Step (3): performing solid-liquid separation on solution 2 and collecting the filtrate;

[0067] Step (4): evaporate the filtrate to dryness, and add 70 mL of a mixed solvent of ethyl acetate / toluene (5:2, v / v);

[0068] Step (5): heating and cooling at 50-5°C for about 6 hours, solid-liquid separation, collecting the solid, and drying to obtain gemagliptin maleate type A with a yield of 48%; wherein the heating and cooling program at 50-5°C is as follows: heating to 50°C within 0.5 hours and maintaining the temperature for 2 hours, then reducing the temperature to 5°C within 1.5 hours and maintaining the temperature at 5°C for 2 hours.

[0069] The product obtained in Example 2 was tested according to the HPLC test conditions in Example 1. The test results showed that the purity of gemagliptin maleate was about 91.5%.

[0070] The hydrogen spectrum data of the product are: 1HNMR (400MHz, DMSO-d6)δ10.29(s,1H),6.02(s,2H),4.82~5.01(m,2H),4.51~4.57(m,1H),4.00~4.07(m,1H),3.77~3.88(m,4H),3.54~3.59(m,1H),3.16(m,1H),2.68~3.03(m,4H),2.34(m,2H).

[0071] Detection and analysis

[0072] (1) TGA / DSC Test Differential Scanning Calorimetry (DSC) was performed using a TADiscovery DSC 2500 / DSC 250 differential scanning calorimeter. About 2.5 mg of the sample was placed in an aluminum pan, and its weight was accurately recorded. The pan was covered with a lid and a hole was poked in the lid. The pan was mounted on the instrument and heated from 25°C to 210°C at a rate of 10°C / min under nitrogen ventilation. Indium metal was used as a calibration standard. The test results of the product in Example 1 are shown in Figure 2 ;

[0073] Thermogravimetric analysis (TGA) was performed using a Discovery TGA 5500 / TGA 550 thermogravimetric analyzer. Approximately 4.5 mg of sample was placed in an aluminum pan. The pan was mounted on the instrument and then heated from 25°C to 210°C at a rate of 10°C / min under nitrogen flow. Nickel and Aluminum TM were used as calibration standards. The test results of the product in Example 1 are shown in Figure 2 .

[0074] Depend on Figure 2It can be seen that the product prepared in Example 1 of the present application loses only 0.51% of its weight when heated to 120°C, and the product has an endothermic peak at 169.2°C (peak temperature), which shows that the product prepared in the present application has very good thermal stability.

[0075] (2) XRPD test test conditions are shown in Table 3 below, and the results are shown in Figure 3 ;

[0076] Table 3

[0077] XRPD Testing Parameters

[0078] XRPD data were collected on an X-ray powder diffractometer from PANalytical.

[0079]

[0080] It can be seen that the diffraction angle 2θ of the gemagliptin maleate crystals prepared in Example 1 of the present application on the powder XPRD spectrum is 9.24, 12.42, 16.62, 18.61, 19.04, 20.28, and 24.23, with an error range of ±0.2°. This group of absorption peaks is a peak with a relative intensity of more than 30%, and its probability of recurrence is extremely high. It appears in repeated detections between different batches and within the same batch, and can be used as the characteristic peaks of the new crystal form.

[0081] In addition, the diffraction angle 2θ of the gemagliptin maleate crystals prepared in Example 1 of the present application on the powder XPRD spectrum is 11.57, 14.24, 14.65, 16.86, 17.13, 20.60, 21.83, 23.93, 24.67, and 25.65, with an error range of ±0.2°. This group of absorption peaks is a peak with a relative intensity of 20-30%, and its probability of recurrence is also very high. It also appears in repeated detections between different batches and within the same batch, and can also be further used as the characteristic peaks of the new crystal form.

[0082] (3) Fluidity Test Take appropriate amounts of the corresponding solid samples of Examples 1-3 respectively, and measure the angle of repose of the powders by the fixed funnel method; and measure the bulk density of the powders by the graduated cylinder tapping method. The results are shown in Table 4:

[0083] Table 4

[0084] Angle of repose Bulk density Example 1 40° 0.65g / mL Example 2 41° 0.68g / mL Example 3 48° 0.45g / mL

[0085] It can be seen that the crystals prepared in this application all have good fluidity.

[0086] (4) Stability

[0087] a. High temperature experiment: About 10 mg of the corresponding solid samples of Examples 1-3 were weighed into 1.5 ml HPLC vials, and the sample vials under 25°C / 60% RH and 40°C / 70% RH conditions were sealed with sealing film, pierced with about 20 small pinholes and stored. After one week, samples were taken for HPLC testing (the testing method was the same as in Example 1). The results are shown in Table 5.

[0088] Table 5

[0089]

[0090] b. High humidity test: Weigh 5 portions of the products of Examples 1-3, each weighing 1 g, and place them naked in a culture dish, placed in a constant temperature and humidity chamber at RH92.5% (temperature 25±1°C), and sample them for HPLC testing after 0 day, 1 day, 7 days, and 14 days (the testing method is the same as in Example 1). The results are shown in Table 6.

[0091] Table 6

[0092] Day 0 1 day 7 days 14 days Example 1 99.6％ 99.5％ 99.4％ 99.3％ Example 2 99.7％ 99.6％ 99.6％ 98.4％ Example 3 91.5％ 91.2％ 91.0％ 90.3％

[0093] It can be seen from the above results that the product prepared in this application shows good stability under high temperature and high humidity conditions.

[0094] Specific examples are used herein to illustrate the principles and implementation methods of the present application. The description of the above embodiments is only used to help understand the method of the present application and its core idea. At the same time, for those skilled in the art, according to the idea of ​​the present application, there will be changes in the specific implementation methods and application scope. In summary, the content of this specification should not be understood as a limitation on the present application, and the scope of protection of the present invention shall be based on the scope defined by the claims. For those of ordinary skill in the art, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as the scope of protection of the present invention. Those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A gemagliptin maleate crystal, characterized in that: The diffraction angles 2θ of the gemagliptin maleate crystals in the powder XPRD spectrum are 9.24, 12.42, 16.62, 18.61, 19.04, 20.28, and 24.23, with an error range of ±0.2°.

2. The gemagliptin maleate crystal according to claim 1, characterized in that The diffraction angles 2θ of the gemagliptin maleate crystals in the powder XPRD spectrum are 11.57, 14.24, 14.65, 16.86, 17.13, 20.60, 21.83, 23.93, 24.67, and 25.65, with an error range of ±0.2°.

3. The gemagliptin maleate crystal according to any one of claims 1 to 2, characterized in that Among them, the relative peak intensity at the 2θ angle of 9.24±0.2° is the strongest.

4. The gemagliptin maleate crystal according to claim 3, characterized in that The DSC spectrum of the gemagliptin maleate crystals has an endothermic peak at 169.2±5°C; And / or, the TG spectrum of the gemagliptin maleate crystals shows that the mass change from 0 to 120° C. is 0.51%±0.1%.

5. The gemagliptin maleate crystal according to claim 4, characterized in that The HPLC purity of the gemagliptin maleate crystals is greater than or equal to 91.5%.

6. A method for preparing gemagliptin maleate crystals, characterized in that: The preparation method comprises the following steps: Step (1): weighing gemagliptin free base, and then adding polar solvent A to obtain solution 1; Step (2): adding maleic acid to solution 1, and then adding a non-polar solvent B to obtain solution 2; Step (3): performing solid-liquid separation on solution 2 and collecting the filtrate; Step (4): evaporating the filtrate to dryness, adding the polar solvent A / the non-polar solvent B mixed solvent to obtain solution 3; Step (5): the solution 3 is heated and cooled at 50-5°C for about 6 hours, the solid-liquid separation is performed, the solid is collected, and the solid is dried to obtain gemagliptin maleate crystals.

7. The method for preparing gemagliptin maleate crystals according to claim 6, characterized in that: In the step (1), the mass volume ratio of the free base of gemagliptin to the polar solvent A is 1 g:4-6 mL; and / or the molar ratio of the free base of gemagliptin to the maleic acid is 1:1.0-1.2; And / or, in the step (2), the mass volume ratio of the gemagliptin free base to the non-polar solvent B is 1 g: 1.5-2.5 mL; And / or, in the step (4), the mass volume ratio of the gemagliptin free base to the polar solvent A / non-polar solvent B mixed solvent is 1 g: 6-8 mL; And / or, in the step (4), the volume ratio of the polar solvent A to the non-polar solvent B in the polar solvent A / non-polar solvent B mixed solvent is 5:1-3; And / or, the polar solvent A comprises R1-COO-R2, wherein R1 and R2 are independently selected from one of methyl, ethyl and propyl; And / or, the non-polar solvent B includes one or more of C5-C8 alkanes, benzene, toluene, ethylbenzene, and xylene.

8. The method for preparing gemagliptin maleate crystals according to claim 6, characterized in that: In the step (3), the temperature is raised from 50 to 5°C for about 6 hours, and the procedure is as follows: the temperature is raised from 20°C to 50°C within 0.5 hours, and the temperature is kept constant for 2 hours, and then the temperature is lowered to 5°C within 1.5 hours, and the temperature is kept constant at 5°C for 2 hours.

9. A pharmaceutical composition or pharmaceutical preparation, characterized in that: The invention comprises the gemagliptin maleate crystal according to any one of claims 1 to 5.

10. Use of the gemagliptin maleate crystal according to any one of claims 1 to 5 or the pharmaceutical composition or pharmaceutical preparation according to claim 9 in treating or preventing diseases associated with DPP-IV.

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