CN116041246A - Eutectic formed by gliclazide and 2-methylimidazole and preparation method thereof - Google Patents

Eutectic formed by gliclazide and 2-methylimidazole and preparation method thereof Download PDF

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CN116041246A
CN116041246A CN202310038374.1A CN202310038374A CN116041246A CN 116041246 A CN116041246 A CN 116041246A CN 202310038374 A CN202310038374 A CN 202310038374A CN 116041246 A CN116041246 A CN 116041246A
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gliclazide
methylimidazole
eutectic
crystal
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薛富民
于帅
王子豪
高绪洁
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Shandong Analysis and Test Center
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The invention discloses a co-crystal formed by gliclazide and 2-methylimidazole and a preparation method thereof, and relates to the technical fields of medicines and crystals; the gliclazide-2-methylimidazole eutectic has the following unit cell parameters: the crystal system is monoclinic; space group P21, unit cell length
Figure DDA0004049019730000011
b= 21.6819 (9), c= 13.4019 (6); unit cell angle (°) α=90, β= 104.325 (4), γ=90, etc.; the gliclazide-2-methylimidazole eutectic can be obtained by a solvent volatilization method and a grinding method; the gliclazide-2-methylimidazole eutectic crystal is a novel crystal form different from gliclazide and 2-methylimidazole, has better water solubility and alcohol solubility compared with gliclazide, greatly improves thermal stability and light stability, and expands the application prospect of gliclazide.

Description

Eutectic formed by gliclazide and 2-methylimidazole and preparation method thereof
Technical Field
The invention relates to the technical field of medicines and crystals, in particular to a eutectic formed by gliclazide and 2-methylimidazole and a preparation method thereof.
Background
Gliclazide (G)liclazide) of formula C 15 H 21 N 3 O 3 S is white crystal or crystalline powder, is odorless and tasteless, and is a sulfonylurea oral antidiabetic. Gliclazide is a second-generation oral sulfonylurea hypoglycemic agent, has strong acting force, has a mechanism similar to that of tolbutamide, can selectively act on islet beta cells, promote insulin secretion, improve the release of insulin after eating, inhibit hepatic glycogen generation and output, and is favorable for preventing and treating diabetic microangiopathy. In recent years, gliclazide has also been found to have a powerful exopancreatic therapeutic effect, which enhances the insulin action of surrounding tissues. This may be a consequence of enhanced biological effects following insulin receptor, while hepatic glucose production and output are also counteracted, making gliclazide characteristic extrapancreatic receptors or post-receptor effects.
The solubility of gliclazide in water, methanol and ethanol is very small, and especially the solubility of gliclazide in water is almost undetectable, which has adverse effects on the purification and in vivo absorption of the medicament; the eutectic crystal is a crystal with specific physicochemical properties formed by microcosmically combining two or more neutral molecules in the same crystal lattice through intermolecular forces, and can change the morphology, stability, hygroscopicity, water solubility and the like of the crystal, so that the eutectic crystal becomes an effective way for improving the solubility of the glibenches Ji Teshui.
Therefore, developing a co-crystal of gliclazide and other substances to improve the solubility and stability of gliclazide in water or other solvents is a current urgent problem to be solved.
Disclosure of Invention
In order to solve the problems, the invention aims to provide a eutectic crystal formed by gliclazide and 2-methylimidazole and a preparation method thereof.
The invention aims to achieve the aim, and the aim is achieved by the following technical scheme:
a gliclazide-2-methylimidazole co-crystal formed by gliclazide and 2-methylimidazole, which has the following unit cell parameters: the crystal system is monoclinic; the space group is defined as P21,
Figure BDA0004049019710000011
b= 21.6819 (9), c= 13.4019 (6); unit cell angle (°) α=90, β= 104.325 (4), γ=90; the number of units in the unit cell z=4; f (000) = 864.0.
Preferably, 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, 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.
The invention also comprises a method for preparing the gliclazide-2-methylimidazole eutectic according to claim 1, which is carried out by adopting a solvent volatilization method and comprises the following steps of: adding gliclazide and 2-methylimidazole into acetonitrile, stirring and filtering, placing filtrate at 25-35 ℃ for evaporative crystallization to obtain colorless transparent blocky crystals, filtering and drying to obtain gliclazide-2-methylimidazole eutectic;
wherein the mol ratio of gliclazide to 2-methylimidazole is 1:0.8-1.2; the mass ratio of gliclazide to acetonitrile is 1:90-110.
The invention also comprises a method for preparing the gliclazide-2-methylimidazole eutectic, which is carried out by adopting a grinding method and comprises the following steps of: placing gliclazide and 2-methylimidazole with the molar ratio of 1:0.8-1.2 into a ball milling tank, adding ethanol into the mixture, and then ball milling the mixture for 15-30 minutes by using a ball mill to obtain white powder, namely gliclazide-2-methylimidazole eutectic;
wherein the mass volume ratio of gliclazide to ethanol is 4-6 g/1 ml.
Compared with the prior art, the invention has the following advantages:
the gliclazide-2-methylimidazole eutectic formed by gliclazide and 2-methylimidazole is a novel crystal form different from gliclazide and 2-methylimidazole, has better water solubility and alcohol solubility compared with gliclazide, greatly improves thermal stability and light stability, and expands the application prospect of gliclazide.
Drawings
FIG. 1 is a single crystal structure diagram of gliclazide-2-methylimidazole;
FIG. 2 is an XRD spectrum of gliclazide, 2-methylimidazole and gliclazide-2-methylimidazole co-crystals;
FIG. 3 is a DSC-TG plot of gliclazide-2-methylimidazole cocrystal;
FIG. 4 is an infrared spectrum of gliclazide;
FIG. 5 is an infrared spectrum of 2-methylimidazole;
FIG. 6 is an infrared spectrum of gliclazide-2-methylimidazole co-crystal;
FIG. 7 is a graph showing the dissolution rates of gliclazide-2-methylimidazole co-crystal and gliclazide crystals;
in the figure, 1, gliclazide, 2, gliclazide-2-methylimidazole eutectic and 3, 2-methylimidazole are shown.
Detailed Description
The invention aims to provide a co-crystal formed by gliclazide and 2-methylimidazole and a preparation method thereof, and the co-crystal is realized by the following technical scheme:
a gliclazide-2-methylimidazole co-crystal formed by gliclazide and 2-methylimidazole, which has the following unit cell parameters: the crystal system is monoclinic; the space group is defined as P21,
Figure BDA0004049019710000031
b= 21.6819 (9), c= 13.4019 (6); unit cell angle (°) α=90, β= 104.325 (4), γ=90; the number of units in the unit cell z=4; f (000) = 864.0.
Preferably, 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, 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.
The invention also comprises a method for preparing the gliclazide-2-methylimidazole eutectic according to claim 1, which is carried out by adopting a solvent volatilization method and comprises the following steps of: adding gliclazide and 2-methylimidazole into acetonitrile, stirring and filtering, placing filtrate at 25-35 ℃ for evaporative crystallization to obtain colorless transparent blocky crystals, filtering and drying to obtain gliclazide-2-methylimidazole eutectic;
wherein the mole ratio of gliclazide to 2-methylimidazole is 1:0.8 to 1.2; the mass ratio of gliclazide to acetonitrile is 1:90-110.
The invention also comprises a method for preparing the gliclazide-2-methylimidazole eutectic, which is carried out by adopting a grinding method and comprises the following steps of: placing gliclazide and 2-methylimidazole with the molar ratio of 1:0.8-1.2 into a ball milling tank, adding ethanol into the mixture, and then ball milling the mixture for 15-30 minutes by using a ball mill to obtain white powder, namely gliclazide-2-methylimidazole eutectic;
wherein the mass volume ratio of gliclazide to ethanol is 4-6 g/1 ml.
The invention is further described below in connection with specific embodiments.
Example 1
The preparation method of gliclazide-2-methylimidazole eutectic is carried out by adopting a solvent volatilization method, and comprises the following steps of: placing 32.3g of gliclazide and 65.6g of 2-methylimidazole into a beaker, adding 2.9kg of acetonitrile into the beaker, stirring for dissolution, filtering, placing the filtrate into a transparent glass bottle, sealing the bottle mouth by a sealing film, pricking small holes on the film, transferring the glass bottle into a fume hood, standing for crystallization at 25 ℃ to obtain colorless transparent blocky crystals, filtering and drying to obtain the gliclazide-2-methylimidazole eutectic.
Example 2
The preparation method of gliclazide-2-methylimidazole eutectic is carried out by adopting a solvent volatilization method, and comprises the following steps of: placing 32.3g of gliclazide and 98.4g of 2-methylimidazole into a beaker, adding 3.23kg of acetonitrile into the beaker, stirring for dissolution, filtering, placing the filtrate into a transparent glass bottle, sealing the bottle mouth by a sealing film, pricking small holes on the film, transferring the glass bottle into a fume hood, standing for crystallization at 35 ℃ to obtain colorless transparent blocky crystals, filtering and drying to obtain the gliclazide-2-methylimidazole eutectic.
Example 3
The preparation method of gliclazide-2-methylimidazole eutectic is carried out by adopting a solvent volatilization method, and comprises the following steps of: placing 32.3g of gliclazide and 82.0g of 2-methylimidazole into a beaker, adding 3.04kg of acetonitrile into the beaker, stirring for dissolution, filtering, placing the filtrate into a transparent glass bottle, sealing the bottle mouth by a sealing film, pricking small holes on the film, transferring the glass bottle into a fume hood, standing for crystallization at 28 ℃ to obtain colorless transparent blocky crystals, filtering and drying to obtain the gliclazide-2-methylimidazole eutectic.
Example 4
The preparation method of gliclazide-2-methylimidazole eutectic is carried out by adopting a solvent volatilization method, and comprises the following steps of: placing 32.3g of gliclazide and 85.0g of 2-methylimidazole into a beaker, adding 3.10kg of acetonitrile into the beaker, stirring for dissolution, filtering, placing the filtrate into a transparent glass bottle, sealing the bottle mouth by a sealing film, pricking small holes on the film, transferring the glass bottle into a fume hood, standing for crystallization at 30 ℃ to obtain colorless transparent blocky crystals, filtering and drying to obtain the gliclazide-2-methylimidazole eutectic.
Example 5
The preparation method of gliclazide-2-methylimidazole eutectic is carried out by adopting a grinding method and comprises the following steps of: placing 32.3g of gliclazide and 65.6g of 2-methylimidazole into a ball milling tank, adding 5.4ml of ethanol into the mixture, and then ball milling the mixture for 15 minutes by using a ball mill to obtain white powder, namely gliclazide-2-methylimidazole eutectic.
Example 6
The preparation method of gliclazide-2-methylimidazole eutectic is carried out by adopting a grinding method and comprises the following steps of: placing 32.3g of gliclazide and 98.4g of 2-methylimidazole into a ball milling tank, adding 8ml of ethanol into the mixture, and then ball milling the mixture for 30 minutes by using a ball mill to obtain white powder, namely gliclazide-2-methylimidazole eutectic.
Example 7
The preparation method of gliclazide-2-methylimidazole eutectic is carried out by adopting a grinding method and comprises the following steps of: placing 32.3g of gliclazide and 82.0g of 2-methylimidazole into a ball milling tank, adding 6ml of ethanol into the mixture, and then ball milling the mixture for 20 minutes by using a ball mill to obtain white powder, namely gliclazide-2-methylimidazole eutectic.
Example 8
The preparation method of gliclazide-2-methylimidazole eutectic is carried out by adopting a grinding method and comprises the following steps of: placing 32.3g of gliclazide and 85.0g of 2-methylimidazole into a ball milling tank, adding 7ml of ethanol into the mixture, and then ball milling the mixture for 25 minutes by using a ball mill to obtain white powder, namely gliclazide-2-methylimidazole eutectic.
As a result of measurement of the structure of gliclazide-2-methylimidazole co-crystals obtained in examples 1 to 8 by using a Bruce Apex II CCD X-ray diffractometer, the results are shown in FIG. 1, single crystal data are shown in Table 1, XRD data are collected by using a Rigaku MiniFlex 600 ray diffractometer, japan, cu-K.alpha.
Figure BDA0004049019710000052
The tube voltage was 40kV, the tube current was 15mA, the scanning speed was 8 DEG/min, and the results are shown in Table 2.
TABLE 1 crystallographic parameters of gliclazide-2-methylimidazole cocrystal
Figure BDA0004049019710000051
Figure BDA0004049019710000061
TABLE 2X-ray powder diffraction characterization data for gliclazide-2-methylimidazole cocrystals
Figure BDA0004049019710000062
Figure BDA0004049019710000071
Diffraction peaks of gliclazide, 2-methylimidazole and gliclazide-2-methylimidazole eutectic are shown in fig. 2, the gliclazide-2-methylimidazole eutectic has XRD characteristic peaks in 8.101 degrees, 12.461 degrees, 13.580 degrees, 23.800 degrees and 24.361 degrees, and the characteristic peaks are not related in gliclazide and 2-methylimidazole, so that diffraction peaks of the gliclazide, the 2-methylimidazole and the gliclazide-2-methylimidazole are obviously different, and the gliclazide-2-methylimidazole is a novel eutectic completely different from the gliclazide and the 2-methylimidazole.
The melting point of gliclazide is 163-169 ℃, the melting point of 2-methylimidazole is 142-143 ℃, TG-DSC analysis is carried out on gliclazide-2-methylimidazole eutectic, the temperature rising speed is 10 ℃/min as measured by Switzerland METTLER TOLEDO TGA/DSC < 3+ >, DSC is differential scanning heat, and the melting point is determined; TG is thermal weight loss, and the decomposition temperature is determined, and the result is shown in FIG. 3, and DSC line shows that the melting point of gliclazide-2-methylimidazole eutectic is 136 ℃.
Infrared spectrum detection is carried out on gliclazide, 2-methylimidazole and gliclazide-2-methylimidazole eutectic, the detection instrument is a Bruce TENSOR II type Fourier transform infrared spectrometer, and the wave number range is 4000-400 cm -1 Figures 4-6 are infrared spectra of gliclazide, 2-methylimidazole and gliclazide-2-methylimidazole co-crystals, respectively. As can be seen by comparison, gliclazide-2-methylimidazole eutectic and raw materials (gliclazide and 2-methylimidazole) are mixed in an N-H bending vibration region (1650-1500 cm) -1 ) There was a difference in that the flexural vibration frequency of N-H was 1596.29cm -1 Offset to 1624.98cm -1 In this connection, the difference in the above-mentioned positions is attributed to the N-H … N hydrogen bond interaction between gliclazide and 2-methylimidazole in the co-crystal, and the infrared absorption spectrum of the region is changed.
XRD, DSC and infrared spectrograms of gliclazide-2-methylimidazole eutectic crystals obtained by a solvent volatilization method and a grinding method are basically the same.
The water solubility and alcohol solubility data of gliclazide-2-methylimidazole cocrystals obtained in examples 1 to 8 were examined, and the results are shown in Table 3.
TABLE 3 gliclazide and gliclazide-2-methylimidazole eutectic solubility data
Figure BDA0004049019710000072
Figure BDA0004049019710000081
Gliclazide belongs to insoluble drugs, and has the defect of low solubility in the purification process, so that the problem of high solvent consumption in the purification process is caused. For gliclazide, it is difficult to significantly increase its solubility simply by increasing the temperature. As can be seen from the results of Table 3, gliclazide is hardly dissolved in water, and the solubility value cannot be measured, but the solubility of gliclazide in water and ethanol is greatly improved after the gliclazide forms eutectic with 2-methylimidazole. The solubility in water is improved to more than 0.27g/100ml, and the solubility in ethanol is improved by more than 97% compared with gliclazide crystals, so that the consumption of solvents in the purification process is greatly reduced.
Uniformly mixing 10g of gliclazide-2-methylimidazole eutectic crystals obtained in examples 1-4 to obtain a sample 1, and testing the thermal stability (5 g) and the photostability (5 g); 10g of gliclazide-2-methylimidazole eutectic crystals obtained in examples 5-8 are uniformly mixed to obtain a sample 2, and the sample 2 is subjected to test of thermal stability (5 g) and photostability (5 g); thermal stability data: accelerating the experiment for 10 days at 60 ℃ and 40% humidity; photostability data: the purity was measured at 25℃under accelerated test for 10 days by cold white fluorescent lamps according to the rule 0512 of the 2020 edition of Chinese pharmacopoeia, and the purity was measured by subtracting the content of the relevant substances by 100% to obtain the purity value, and the results are shown in Table 4.
TABLE 4 light stability and thermal stability test results Table
Figure BDA0004049019710000082
For chemical raw materials, the maximum single impurity content is generally required to be not more than 1.0%, the total impurity content is required to be not more than 1.5 or 2.0%, and single impurities less than 0.1% are negligible, so that the content of 1.0% is relatively large for trace impurities. Particularly for accelerated experiments, the impurity content tends to increase more after passing the severe accelerated experimental conditions. From the results in table 4, it can be seen that the thermal stability and the light stability of the gliclazide-2-methylimidazole eutectic crystal are improved after the gliclazide and the 2-methylimidazole form the eutectic crystal, so that the gliclazide-2-methylimidazole eutectic crystal has better thermal stability and light stability effects. And the gliclazide-2-methylimidazole eutectic properties obtained by adopting a solvent volatilization method and a grinding method are consistent, and are the same crystals.
The dissolution rate of gliclazide crystal and gliclazide-2-methylimidazole eutectic is tested, and the measurement method comprises the following steps: respectively weighing gliclazide and gliclazide-2-methylimidazole eutectic crystal with the same mass, putting into a crystallizer, then adding 200ml of phosphate buffer (pH=7.2-7.4) into a conical flask, suspending and stirring at 37 ℃ at a stirring speed of 100rpm, sampling at time points of 5, 10, 15, 20, 30, 45, 60, 120, 180 and 300min, filtering with a 0.22 mu m filter membrane, dissolving and diluting the sample, and carrying out quantitative analysis according to the liquid chromatography of the general rule 0512 of Chinese pharmacopoeia, wherein the result is shown in figure 7.
From the results of fig. 7, it can be seen that the gliclazide-2-methylimidazole eutectic of the present invention can reach a larger value within 5 minutes, and reach the maximum within 50 minutes, and the dissolution rate is far greater than that of gliclazide crystals.

Claims (4)

1. The gliclazide-2-methylimidazole eutectic formed by gliclazide and 2-methylimidazole is characterized in that: has the following unit cell parameters: the crystal system is monoclinic; space group P21, unit cell length
Figure FDA0004049019700000011
a＝7.3501(3)，b＝21.6819(9)，c＝13.4019 (6); unit cell angle (°) α=90, β= 104.325 (4), γ=90; the number of units in the unit cell z=4; f (000) = 864.0.
2. The gliclazide-2-methylimidazole co-crystal formed by gliclazide and 2-methylimidazole as claimed in claim 1, wherein: the co-crystal has a powder X-ray diffraction pattern expressed in terms of 20 angular values, wherein the powder X-ray diffraction pattern comprises the following 2θ angular 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, 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.
3. A method for preparing gliclazide-2-methylimidazole eutectic according to claim 1, which is characterized in that: the method is carried out by adopting a solvent volatilization method and comprises the following steps: adding gliclazide and 2-methylimidazole into acetonitrile, stirring and filtering, placing filtrate at 25-35 ℃ for evaporative crystallization to obtain colorless transparent blocky crystals, filtering and drying to obtain gliclazide-2-methylimidazole eutectic;
wherein the mol ratio of gliclazide to 2-methylimidazole is 1:0.8-1.2; the mass ratio of gliclazide to acetonitrile is 1:90 to 110.
4. A method for preparing gliclazide-2-methylimidazole eutectic according to claim 1, which is characterized in that: the grinding method is adopted, and comprises the following steps: placing gliclazide and 2-methylimidazole with the molar ratio of 1:0.8-1.2 into a ball milling tank, adding ethanol into the mixture, and then ball milling the mixture for 15-30 minutes by using a ball mill to obtain white powder, namely gliclazide-2-methylimidazole eutectic;
wherein the mass volume ratio of gliclazide to ethanol is 4-6 g/1 ml.
CN202310038374.1A 2023-01-10 2023-01-10 Eutectic formed by gliclazide and 2-methylimidazole and preparation method thereof Pending CN116041246A (en)

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