A co-crystal formed by gliclazide and 2-methylimidazole and a preparation method thereof

Abstract

The invention discloses a cocrystal formed by gliclazide and 2-methylimidazole and a preparation method thereof, and relates to the fields of medicine and crystal technology. The gliclazide-2-methylimidazole cocrystal has the following unit cell parameters: the crystal system category is monoclinic system; the space group is P21, the unit cell length b=21.6819(9), c=13.4019(6); the unit cell angle (°) α=90, β=104.325(4), γ=90, etc. The gliclazide-2-methylimidazole cocrystal can be obtained by a solvent volatilization method and a grinding method. The gliclazide-2-methylimidazole cocrystal of the invention is a new crystal form different from gliclazide and 2-methylimidazole, has better water solubility and alcohol solubility than gliclazide, and has greatly improved thermal stability and light stability, thereby expanding the application prospect of gliclazide.

Description

Technical Field

[0001] The invention relates to the field of medicine and crystal technology, in particular to a cocrystal formed by gliclazide and 2-methylimidazole and a preparation method thereof. Background Art

[0002] Gliclazide, molecular formula is C 15 H 21 N3O3S is a white crystal or crystalline powder, odorless and tasteless, and is an oral antidiabetic drug of the sulfonylurea class. Gliclazide is a second-generation oral sulfonylurea hypoglycemic drug with a strong effect. Its mechanism is similar to that of tolbutamide, that is, it can selectively act on pancreatic β cells, promote insulin secretion, and increase insulin release after eating, so that the production and output of glycogen in the liver are inhibited, which helps to prevent and treat diabetic microangiopathy. In recent years, studies have also found that gliclazide also has a strong extrapancreatic therapeutic effect, which enhances the effect of insulin on surrounding tissues. This may be the result of the enhanced biological effect after the insulin receptor, while the production and output of glycogen in the liver are also resisted, so that gliclazide has an extrapancreatic receptor or post-receptor effect.

[0003] The solubility of gliclazide in water, methanol and ethanol is very low, especially the solubility of gliclazide in water is almost unmeasurable, which has an adverse effect on the purification and absorption of the drug in the body; cocrystals are crystals with specific physical and chemical properties formed by two or more neutral molecules microscopically combined in the same crystal lattice through intermolecular forces. Cocrystals can change the crystal morphology, stability, hygroscopicity and water solubility, etc., and therefore become an effective way to improve the water solubility of gliclazide.

[0004] Therefore, developing co-crystals of gliclazide and other substances to improve the solubility and stability of gliclazide in water or other solvents is an urgent problem to be solved. Summary of the invention

[0005] In order to solve the above problems, the object of the present invention is to provide a co-crystal formed by gliclazide and 2-methylimidazole and a preparation method thereof.

[0006] In order to achieve the above object, the present invention is implemented through the following technical solutions:

[0007] A gliclazide-2-methylimidazole cocrystal formed by gliclazide and 2-methylimidazole has the following unit cell parameters: the crystal system category is monoclinic; the space group is P21, the unit cell length (Å) is a=7.3501(3), b=21.6819(9), c=13.4019(6); the unit cell angle (°) is α=90, β=104.325(4), γ=90; the number of units in the unit cell is Z=4; F(000)=864.0.

[0008] Preferably, the co-crystal has a powder X-ray diffraction pattern expressed as 2θ angle values, wherein the powder X-ray diffraction pattern comprises the following 2θ angle values ​​(°): 8.10, 10.57, 12.46, 13.31, 13.58, 14.17, 15.02, 15.82, 16.09, 17.56, 18.01, 19.77, 20.17, 20.58, 20.98, 21.38, 21.98, 22.70, 23.80, 24.3 6, 25.38, 25.95, 26.25, 26.76, 27.22, 29.44, 29.82, 31.14, 31.91, 32.44, 32.84, 33.40, 34.10, 34.50, 35.28, 35.76, 36.54, 37.78, 38.86, 40.49, 41.10, 41.58, 42.51, 42.98, 43.77, 44.60, 46.68, 47.65.

[0009] The present invention also includes a method for preparing the above-mentioned gliclazide-2-methylimidazole cocrystal, which is carried out by a solvent volatilization method, comprising the following steps: adding gliclazide and 2-methylimidazole to acetonitrile, stirring and filtering, placing the filtrate at 25-35° C. for evaporation and crystallization to obtain colorless transparent block crystals, filtering, and drying to obtain the gliclazide-2-methylimidazole cocrystal;

[0010] The molar ratio of gliclazide to 2-methylimidazole is 1:0.8-1.2; the mass ratio of gliclazide to acetonitrile is 1:90-110.

[0011] The present invention also includes a method for preparing the above-mentioned gliclazide-2-methylimidazole cocrystal, which is carried out by a grinding method, comprising the following steps: placing gliclazide and 2-methylimidazole in a molar ratio of 1:0.8-1.2 in a ball mill, adding ethanol thereto, and then ball milling for 15-30 minutes with a ball mill to obtain a white powder, namely the gliclazide-2-methylimidazole cocrystal;

[0012] The mass volume ratio of gliclazide to ethanol is 4~6g:1ml.

[0013] Compared with the prior art, the present invention has the following advantages:

[0014] The gliclazide-2-methylimidazole cocrystal formed by gliclazide and 2-methylimidazole of the present invention is a new crystal form different from gliclazide and 2-methylimidazole, has better water solubility and alcohol solubility than gliclazide, and has greatly improved thermal stability and light stability, thereby expanding the application prospects of gliclazide. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 This is the single crystal structure diagram of gliclazide-2-methylimidazole;

[0016] Figure 2 is the XRD spectra of gliclazide, 2-methylimidazole and gliclazide-2-methylimidazole cocrystal;

[0017] Figure 3 is the DSC-TG graph of gliclazide-2-methylimidazole cocrystal;

[0018] Figure 4 is the infrared spectrum of gliclazide;

[0019] Figure 5 is the infrared spectrum of 2-methylimidazole;

[0020] Figure 6 is the infrared spectrum of gliclazide-2-methylimidazole cocrystal;

[0021] Figure 7 Schematic diagram of the dissolution rate of gliclazide-2-methylimidazole cocrystal and gliclazide crystal;

[0022] In the figure, 1, gliclazide, 2, gliclazide-2-methylimidazole cocrystal, 3, 2-methylimidazole. DETAILED DESCRIPTION

[0023] The object of the present invention is to provide a co-crystal formed by gliclazide and 2-methylimidazole and a preparation method thereof, which is achieved by the following technical scheme:

[0024] A gliclazide-2-methylimidazole cocrystal formed by gliclazide and 2-methylimidazole has the following unit cell parameters: the crystal system category is monoclinic; the space group is P21, the unit cell length (Å) is a=7.3501(3), b=21.6819(9), c=13.4019(6); the unit cell angle (°) is α=90, β=104.325(4), γ=90; the number of units in the unit cell is Z=4; F(000)=864.0.

[0025] Preferably, the co-crystal has a powder X-ray diffraction pattern expressed as 2θ angle values, wherein the powder X-ray diffraction pattern comprises the following 2θ angle values ​​(°): 8.10, 10.57, 12.46, 13.31, 13.58, 14.17, 15.02, 15.82, 16.09, 17.56, 18.01, 19.77, 20.17, 20.58, 20.98, 21.38, 21.98, 22.70, 23.80, 24.3 6, 25.38, 25.95, 26.25, 26.76, 27.22, 29.44, 29.82, 31.14, 31.91, 32.44, 32.84, 33.40, 34.10, 34.50, 35.28, 35.76, 36.54, 37.78, 38.86, 40.49, 41.10, 41.58, 42.51, 42.98, 43.77, 44.60, 46.68, 47.65.

[0026] The present invention also includes a method for preparing the above-mentioned gliclazide-2-methylimidazole cocrystal, which is carried out by a solvent volatilization method, comprising the following steps: adding gliclazide and 2-methylimidazole to acetonitrile, stirring and filtering, placing the filtrate at 25-35° C. for evaporation and crystallization to obtain colorless transparent block crystals, filtering, and drying to obtain the gliclazide-2-methylimidazole cocrystal;

[0027] The molar ratio of gliclazide to 2-methylimidazole is 1:0.8-1.2; the mass ratio of gliclazide to acetonitrile is 1:90-110.

[0028] The present invention also includes a method for preparing the above-mentioned gliclazide-2-methylimidazole cocrystal, which is carried out by a grinding method, comprising the following steps: placing gliclazide and 2-methylimidazole in a molar ratio of 1:0.8-1.2 in a ball mill, adding ethanol thereto, and then ball milling for 15-30 minutes with a ball mill to obtain a white powder, namely the gliclazide-2-methylimidazole cocrystal;

[0029] The mass volume ratio of gliclazide to ethanol is 4~6g:1ml.

[0030] The present invention is further described below in conjunction with specific embodiments. Example

[0031] The invention discloses a preparation method of gliclazide-2-methylimidazole cocrystal, which adopts a solvent volatilization method and comprises the following steps: 32.3g of gliclazide and 65.6g of 2-methylimidazole are placed in a beaker, 2.9kg of acetonitrile is added thereto, the mixture is stirred and dissolved, filtered, the filtrate is placed in a transparent glass bottle, the bottle mouth is sealed with a sealing film, and small holes are pierced in the film, the glass bottle is transferred to a fume hood, and placed at 25°C for crystallization to obtain colorless transparent block crystals, filtered, and dried to obtain the gliclazide-2-methylimidazole cocrystal. Example

[0032] The invention discloses a preparation method of gliclazide-2-methylimidazole cocrystal, which adopts a solvent volatilization method and comprises the following steps: 32.3g of gliclazide and 98.4g of 2-methylimidazole are placed in a beaker, 3.23kg of acetonitrile is added thereto, the mixture is stirred and dissolved, and the mixture is filtered, the filtrate is placed in a transparent glass bottle, the bottle mouth is sealed with a sealing film, and small holes are pierced in the film, the glass bottle is transferred to a fume hood, and the mixture is placed at 35°C for crystallization to obtain colorless transparent block crystals, and the crystals are filtered and dried to obtain the gliclazide-2-methylimidazole cocrystals. Example

[0033] The invention discloses a preparation method of gliclazide-2-methylimidazole cocrystal, which adopts a solvent volatilization method and comprises the following steps: 32.3g of gliclazide and 82.0g of 2-methylimidazole are placed in a beaker, 3.04kg of acetonitrile is added thereto, the mixture is stirred and dissolved, filtered, the filtrate is placed in a transparent glass bottle, the bottle mouth is sealed with a sealing film, and small holes are pierced in the film, the glass bottle is transferred to a fume hood, and placed at 28°C for crystallization to obtain colorless transparent block crystals, filtered, and dried to obtain the gliclazide-2-methylimidazole cocrystals. Example

[0034] A preparation method of gliclazide-2-methylimidazole cocrystal adopts a solvent volatilization method, comprising the following steps: 32.3g of gliclazide and 85.0g of 2-methylimidazole are placed in a beaker, 3.10kg of acetonitrile is added thereto, the mixture is stirred and dissolved, filtered, the filtrate is placed in a transparent glass bottle, the bottle mouth is sealed with a sealing film, and small holes are pierced in the film, the glass bottle is transferred to a fume hood, and placed at 30°C for crystallization to obtain colorless transparent block crystals, filtered, and dried to obtain the gliclazide-2-methylimidazole cocrystal. Example

[0035] A preparation method of gliclazide-2-methylimidazole cocrystal is carried out by a grinding method, comprising the following steps: 32.3 g of gliclazide and 65.6 g of 2-methylimidazole are placed in a ball mill, 5.4 ml of ethanol is added thereto, and then ball milled for 15 minutes using a ball mill to obtain a white powder, namely the gliclazide-2-methylimidazole cocrystal. Example

[0036] A preparation method of gliclazide-2-methylimidazole cocrystal is carried out by a grinding method, comprising the following steps: 32.3 g of gliclazide and 98.4 g of 2-methylimidazole are placed in a ball mill, 8 ml of ethanol is added thereto, and then ball milled for 30 minutes using a ball mill to obtain a white powder, namely the gliclazide-2-methylimidazole cocrystal. Example

[0037] A preparation method of gliclazide-2-methylimidazole cocrystal is carried out by a grinding method, comprising the following steps: 32.3 g of gliclazide and 82.0 g of 2-methylimidazole are placed in a ball mill, 6 ml of ethanol is added thereto, and then ball milled for 20 minutes using a ball mill to obtain a white powder, namely the gliclazide-2-methylimidazole cocrystal. Example

[0038] A preparation method of gliclazide-2-methylimidazole cocrystal is carried out by a grinding method, comprising the following steps: 32.3 g of gliclazide and 85.0 g of 2-methylimidazole are placed in a ball mill, 7 ml of ethanol is added thereto, and then ball milled for 25 minutes using a ball mill to obtain a white powder, namely the gliclazide-2-methylimidazole cocrystal.

[0039] The structure of the gliclazide-2-methylimidazole cocrystal obtained in Examples 1 to 8 was determined using a Bruker Apex II CCDX-ray diffractometer. The results are as follows: Figure 1 As shown, its single crystal data are shown in Table 1, and the XRD data are collected by a Japanese RigakuMiniFlex 600 X-ray diffractometer, Cu-Kα (λ=1.54056Å), tube voltage 40kV, tube current 15mA, scanning speed 8° / min, and the results are shown in Table 2.

[0040] Table 1 Crystallographic parameters of gliclazide-2-methylimidazole cocrystal

[0041] Molecular formula <![CDATA[C 19 H 27 N5O3S]]> <![CDATA[Relative molecular mass / (g·mol -1 ).]]> 405.51 Crystal system Monoclinic system Space group P 21 / c a / Å 7.3501(3) b / Å 21.6819(9) c / Å 13.4019(6) α / ° 90 β / ° 104.325(4) γ / ° 90 The number of elements in the unit cell (Z) 4 F (000) 864.0 <![CDATA[Density (g·cm -3 )]]> 1.302

[0042] Table 2 X-ray powder diffraction characterization data of gliclazide-2-methylimidazole cocrystal

[0043] Serial number 2-Theta / ° strength / % Serial number 2-Theta / ° strength / % 1 8.101 35.3 25 27.220 10.1 2 10.578 12.1 26 29.440 4.7 3 12.461 40.7 27 29.821 5.5 4 13.319 8.2 28 31.142 1.7 5 13.580 7.8 29 31.917 5.6 6 14.178 9.6 30 32.440 2.2 7 15.021 20.6 31 32.840 3.3 8 15.821 5.7 32 33.401 0.8 9 16.099 14 33 34.101 3.8 10 17.560 100 34 34.500 2.4 11 18.019 23 35 35.281 4.7 12 19.779 11.2 36 35.761 3.5 13 20.174 1.1 37 36.540 1.7 14 20.581 13.8 38 37.780 1.9 15 20.980 13.8 39 38.861 0.9 16 21.380 10.3 40 40.497 1.8 17 21.980 54.2 41 41.101 1.4 18 22.700 9.3 42 41.582 0.9 19 23.800 25.2 43 42.519 0.6 20 24.361 6 44 42.980 0.7 21 25.380 8.1 45 43.778 2.5 22 25.959 24.2 46 44.601 1.3 23 26.259 2.8 47 46.680 1 24 26.763 1.2 48 47.659 2

[0044] The diffraction peaks of gliclazide, 2-methylimidazole and gliclazide-2-methylimidazole cocrystal are as follows: Figure 2As shown, the gliclazide-2-methylimidazole cocrystal has XRD characteristic peaks at 8.101°, 12.461°, 13.580°, 23.800° and 24.361°, which are not involved in gliclazide and 2-methylimidazole. Therefore, the diffraction peaks of the three are obviously different, indicating that gliclazide-2-methylimidazole is a new cocrystal that is completely different from gliclazide and 2-methylimidazole.

[0045] The melting point of gliclazide is 163~169℃, and the melting point of 2-methylimidazole is 142~143℃. The gliclazide-2-methylimidazole cocrystal was subjected to TG-DSC analysis, measured by Swiss METTLER TOLEDO TGA / DSC 3+, with a heating rate of 10℃ / min. DSC is differential scanning calorimetry, which determines the melting point; TG is thermal gravimetry, which determines the decomposition temperature. The results are as follows: Figure 3 As shown, the DSC line shows that the melting point of the gliclazide-2-methylimidazole cocrystal is 136°C.

[0046] Infrared spectroscopic examination of gliclazide, 2-methylimidazole and gliclazide-2-methylimidazole cocrystal was performed using a Bruker TENSOR II Fourier transform infrared spectrometer with a wave number range of 4000-400 cm -1 , Figure 4~Figure 6 The infrared spectra of gliclazide, 2-methylimidazole and gliclazide-2-methylimidazole cocrystal are shown in Figure 1. By comparison, it can be seen that the gliclazide-2-methylimidazole cocrystal and the raw materials (gliclazide and 2-methylimidazole) have different NH bending vibrations (1650-1500cm -1 ) is different, the bending vibration frequency of NH is 1596.29cm -1 The offset is 1624.98cm -1 Combined with the crystal structure analysis, it can be seen that the difference in the above position is due to the NH···N hydrogen bond interaction formed between gliclazide and 2-methylimidazole in the cocrystal, which leads to changes in the infrared absorption spectrum of this area.

[0047] The XRD, DSC and IR spectra of the gliclazide-2-methylimidazole cocrystals obtained by the solvent evaporation method and the grinding method are basically the same.

[0048] The water solubility and alcohol solubility data of the gliclazide-2-methylimidazole cocrystals obtained in Examples 1 to 8 were tested, and the results are shown in Table 3.

[0049] Table 3 Solubility data of gliclazide and gliclazide-2-methylimidazole cocrystal

[0050] name Solubility in water at 25°C (g / 100ml) Solubility in ethanol at 25°C (g / 100ml) Gliclazide -- 0.9626 Example 1 0.2745 2.0438 Example 2 0.2768 2.0447 Example 3 0.2790 2.0465 Example 4 0.2835 2.0473 Example 5 0.3263 1.8977 Example 6 0.3285 1.8992 Example 7 0.3330 1.9004 Example 8 0.3308 1.8995

[0051] Gliclazide belongs to poorly soluble drugs, and there is the disadvantage of low solubility in the purification process, which leads to the problem of large solvent consumption in the purification process. For gliclazide, it is difficult to significantly improve its solubility by simply increasing the temperature. As can be seen from the results of Table 3, gliclazide is almost insoluble in water, and the value of solubility cannot be measured, but after gliclazide forms a eutectic with 2-methylimidazole, the solubility in water and ethanol is greatly improved. The solubility in water is increased to more than 0.27g / 100ml, and the solubility in ethanol is increased by more than 97% compared with gliclazide crystals, which greatly reduces the consumption of solvent in the purification process.

[0052] 10 g of each of the gliclazide-2-methylimidazole cocrystals obtained in Examples 1 to 4 were mixed evenly to obtain sample 1, and the thermal stability (5 g) and photostability tests (5 g) were tested; 10 g of each of the gliclazide-2-methylimidazole cocrystals obtained in Examples 5 to 8 were mixed evenly to obtain sample 2, and the thermal stability (5 g) and photostability tests (5 g) were tested; thermal stability data: accelerated test at 60°C, 40% humidity, 10 days; photostability data: accelerated test at 25°C, cool white fluorescent lamp, 10 days to test the purity, the purity test was based on the 2020 edition of the "Chinese Pharmacopoeia", General Chapter 0512, the content of related substances was determined, and the purity value was obtained by subtracting the content of related substances from 100%, and the results are shown in Table 4.

[0053] Table 4 Light stability and thermal stability test results

[0054] Purity at 0 day (%) 60℃, 40% humidity, accelerated test for 10 days Purity (%) 25℃, cool white fluorescent lamp, accelerated test for 10 days Purity (%) Gliclazide 99.8 98.0 98.4 Sample 1 99.8 99.3 99.4 Sample 2 99.8 98.9 99.3

[0055] For chemical raw materials, it is generally required that the maximum single impurity content does not exceed 1.0%, and the total impurity content does not exceed 1.5 or 2.0%. The single impurity less than 0.1% can be ignored, so for trace impurities, 1.0% content is relatively large. Especially for accelerated experiments, after passing through harsh accelerated experimental conditions, the impurity content tends to increase more. As can be seen from the results of Table 4, after gliclazide and 2-methylimidazole form eutectic, thermal stability and light stability are improved, so gliclazide-2-methylimidazole eutectic of the present invention has better thermal stability and light stability effect. And the gliclazide-2-methylimidazole eutectic obtained by solvent evaporation method and grinding method has consistent properties, which is the same crystal.

[0056] The dissolution rate test of gliclazide crystals and gliclazide-2-methylimidazole cocrystals was carried out. The measurement method was as follows: gliclazide and gliclazide-2-methylimidazole cocrystals of equal mass were weighed and put into the crystallizer, and then 200 ml of phosphate buffer (pH = 7.2~7.4) was added to the conical flask, suspended and stirred at 37°C, the stirring speed was 100 rpm, and samples were taken at 5, 10, 15, 20, 30, 45, 60, 120, 180, and 300 min. The samples were filtered with a 0.22 μm filter membrane, the samples were diluted to a fixed solution, and quantitative analysis was performed according to the Chinese Pharmacopoeia General Chapter 0512 liquid chromatography. The results are as follows Figure 7 shown.

[0057] Depend on Figure 7 It can be seen from the results that the gliclazide-2-methylimidazole cocrystal of the present invention can reach a maximum value within 5 minutes and a maximum within 50 minutes, and its dissolution rate is much greater than that of the gliclazide crystal.

Claims

1. A gliclazide-2-methylimidazole eutectic formed by gliclazide and 2-methylimidazole, characterized in that: It has the following unit cell parameters: the crystal system category is monoclinic; the space group is P21, the unit cell length a=7.3501(3), b=21.6819(9), c=13.4019(6), the unit of the unit cell length is Å; the unit cell angle α=90, β=104.325(4), γ=90, the unit of the unit cell angle is °; the number of units in the unit cell Z=4; F(000)=864.0; The co-crystal has a powder X-ray diffraction pattern expressed in terms of 2θ angle values, wherein the powder X-ray diffraction pattern comprises the following 2θ angle values: 8.10, 10.57, 12.46, 13.31, 13.58, 14.17, 15.02, 15.82, 16.09, 17.56, 18.01, 19.77, 20.17, 20.58, 20.98, 21.38, 21.98, 22.70, 23.80, 24.36, 25.38, 25.95, 26.25, 26.76, 27.22, The unit of the 2θ angle value is °.

2. A method for preparing the gliclazide-2-methylimidazole cocrystal according to claim 1, characterized in that: The solvent evaporation method is adopted, which includes the following steps: adding gliclazide and 2-methylimidazole to acetonitrile, stirring and filtering, placing the filtrate at 25-35° C. for evaporation and crystallization to obtain colorless transparent block crystals, filtering, and drying to obtain gliclazide-2-methylimidazole cocrystals; The molar ratio of gliclazide to 2-methylimidazole is 1:0.8-1.2; the mass ratio of gliclazide to acetonitrile is 1:90-110.

3. A method for preparing the gliclazide-2-methylimidazole cocrystal according to claim 1, characterized in that: The method is carried out by a grinding method, which comprises the following steps: placing gliclazide and 2-methylimidazole in a molar ratio of 1:0.8-1.2 in a ball mill, adding ethanol thereto, and then ball milling for 15-30 minutes with a ball mill to obtain a white powder, which is the gliclazide-2-methylimidazole cocrystal; The mass volume ratio of gliclazide to ethanol is 4~6g:1ml.

Images