A kind of gliclazide-piperazine cocrystal and preparation method thereof
By forming a co-crystal with glizide and piperazine, the problem of poor solubility and stability of glizide in water was solved, and a glizide-piperazine co-crystal with higher solubility and stability was prepared, realizing the drug Effective purification and improve in vivo absorption efficiency.
Patent Information
- Application Number
- CN202310035868.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-01-10
- Publication Date
- 2025-01-14
- Estimated Expiration
- 2043-01-10
AI Technical Summary
Glicit has poor solubility and stability in water, which affects its purification and in vivo absorption.
Glicit and piperazine are used to form eutectics, and a new gllicit-piperazine eutectic is prepared by solvent volatilization or grinding method, with a monoclinic crystal structure and a lower melting point, and is in water. and ethanol significantly improves solubility.
Glicit-piperazine eutectic has higher water solubility and alcohol solubility, which significantly improves the solubility and stability of Glicit and has potential industrial application value.
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Figure CN116162053B_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of cocrystal and gliclazide medicine, in particular to a gliclazide-piperazine cocrystal and a preparation method thereof. Background Art
[0002] Gliclazide, molecular formula is C 15 H 21 N3O3S is an oral antidiabetic drug of the sulfonylurea class. It is white crystals or crystalline powder, odorless and tasteless. Gliclazide is a second-generation oral sulfonylurea hypoglycemic drug with a strong effect. Its mechanism is similar to that of tolbutamide, that is, it selectively acts on pancreatic β cells, promotes insulin secretion, and increases insulin release after eating, inhibiting the production and output of glycogen in the liver, which helps 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. It may be the result of enhanced biological effects after insulin receptors. At the same time, the production and output of glycogen in the liver are also resisted, which makes gliclazide have extrapancreatic receptor or post-receptor effects.
[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 problem of poor solubility and stability of gliclazide in water or other solvents, the present invention aims to provide a gliclazide-piperazine cocrystal 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-piperazine cocrystal is a cocrystal composed of gliclazide and piperazine.
[0008] Preferably, the gliclazide-piperazine cocrystal has the following unit cell parameters: the crystal system is monoclinic; the space group is P21; the unit cell length is a=6.3416(1), b=24.8034(4), c=6.5323(1); unit cell angle (°) α=90, β=100.553(4), γ=90; number of units in the unit cell Z=2; F(000)=440.0.
[0009] Preferably, the gliclazide-piperazine cocrystal 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: 5.92, 7.11, 8.36, 11.86, 13.86, 14.25, 15.58, 16.78, 17.49, 17.79, 19.17, 19.89, 20.81, 21.38, 21.66, 22.59, 23.35, 23.9 2, 25.62, 27.97, 28.77, 29.15, 29.83, 30.40, 30.87, 31.45, 31.97, 32.33, 33.22, 33.77, 34.30, 35.34, 36.03, 36.64, 38.25, 38.76, 40.52, 42.30, 43.09, 43.70, 44.97, 46.01, 47.39, 48.02.
[0010] Preferably, the method for preparing the above-mentioned gliclazide-piperazine cocrystal is carried out by a solvent evaporation method, comprising the following steps: adding gliclazide and piperazine 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-piperazine cocrystals;
[0011] The molar ratio of gliclazide to piperazine is 1:0.8-1.2; the mass volume ratio of gliclazide to acetonitrile is 10-20 mg:1 ml.
[0012] Preferably, the method for preparing the above-mentioned gliclazide-piperazine cocrystal is carried out by a grinding method, comprising the following steps: placing gliclazide and piperazine in a molar ratio of 1:0.8-1.2 in a ball mill, adding ethanol thereto, and then ball milling with a ball mill for 15-30 minutes to obtain a white powder, namely the gliclazide-piperazine cocrystal; wherein the mass ratio of gliclazide to ethanol is 1:0.2-0.5.
[0013] Compared with the prior art, the present invention has the following advantages:
[0014] The gliclazide-piperazine cocrystal of the present invention is a new crystal form completely different from gliclazide and piperazine, has a lower melting point, greatly increases the solubility of gliclazide in water or ethanol, has high water solubility and alcohol solubility, and has potential industrial application value. BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Figure 1 Schematic diagram of the structure of the gliclazide-piperazine cocrystal obtained in Examples 1 to 8;
[0016] Figure 2 Schematic diagram of diffraction peaks of gliclazide, piperazine and gliclazide-piperazine cocrystal;
[0017] Figure 3 is the DSC graph of gliclazide-piperazine cocrystal;
[0018] Figure 4 is the infrared spectrum of gliclazide;
[0019] Figure 5 is the infrared spectrum of piperazine;
[0020] Figure 6 is the infrared spectrum of gliclazide-piperazine cocrystal;
[0021] Figure 7 Schematic diagram of the dissolution rate of gliclazide and gliclazide-piperazine cocrystal;
[0022] In the figure, 1 is gliclazide, 2 is gliclazide-piperazine cocrystal, and 3 is piperazine. DETAILED DESCRIPTION
[0023] The object of the present invention is to provide a gliclazide-piperazine cocrystal and a preparation method thereof. The present invention is further described below in conjunction with specific embodiments.
[0024] Example 1
[0025] 32.3 g of gliclazide and 68.8 g of piperazine were placed in a beaker, 3.23 L of acetonitrile was added thereto, the mixture was stirred to dissolve, and the mixture was filtered. The filtrate was placed in a transparent glass bottle, the bottle mouth was sealed with a sealing film, and small holes were pierced in the film. The glass bottle was transferred to a fume hood and placed at 25°C for crystallization to obtain colorless transparent block crystals, which were filtered and dried to obtain gliclazide-piperazine eutectic.
[0026] Example 2
[0027] 32.3 g of gliclazide and 103.2 g of piperazine were placed in a beaker, 1.62 L of acetonitrile was added thereto, the mixture was stirred to dissolve, and the mixture was filtered. The filtrate was placed in a transparent glass bottle, the bottle mouth was sealed with a sealing film, and small holes were pierced in the film. The glass bottle was transferred to a fume hood and placed at 35°C for crystallization to obtain colorless transparent block crystals, which were filtered and dried to obtain gliclazide-piperazine eutectic.
[0028] Example 3
[0029] 32.3 g of gliclazide and 86 g of piperazine were placed in a beaker, 2.15 L of acetonitrile was added thereto, the mixture was stirred to dissolve, and the mixture was filtered. The filtrate was placed in a transparent glass bottle, the bottle mouth was sealed with a sealing film, and small holes were pierced in the film. The glass bottle was transferred to a fume hood and placed at 30°C for crystallization to obtain colorless transparent block crystals, which were filtered and dried to obtain gliclazide-piperazine eutectic.
[0030] Example 4
[0031] 32.3 g of gliclazide and 90 g of piperazine were placed in a beaker, 2.50 L of acetonitrile was added thereto, the mixture was stirred to dissolve, and the mixture was filtered. The filtrate was placed in a transparent glass bottle, the bottle mouth was sealed with a sealing film, and small holes were pierced in the film. The glass bottle was transferred to a fume hood and placed at 28°C for crystallization to obtain colorless transparent block crystals, which were filtered and dried to obtain gliclazide-piperazine eutectic.
[0032] Example 5
[0033] 32.3 g of gliclazide and 68.8 g of piperazine were placed in a ball mill, 6.46 g of ethanol was added thereto, and then ball milled for 15 minutes to obtain a white powder, which was the gliclazide-piperazine cocrystal.
[0034] Example 6
[0035] 32.3 g of gliclazide and 103.2 g of piperazine were placed in a ball mill, 16.15 g of ethanol was added thereto, and then ball milled for 30 minutes to obtain a white powder, which was the gliclazide-piperazine cocrystal.
[0036] Example 7
[0037] 32.3 g of gliclazide and 86 g of piperazine were placed in a ball mill, 10 g of ethanol was added thereto, and then ball milled for 20 minutes to obtain a white powder, which was the gliclazide-piperazine cocrystal.
[0038] Example 8
[0039] 32.3 g of gliclazide and 85 g of piperazine were placed in a ball mill, 15 g of ethanol was added thereto, and then ball milled for 25 minutes to obtain a white powder, which was the gliclazide-piperazine cocrystal.
[0040] Comparative Example 1
[0041] 32.3 g of gliclazide and 86 g of piperazine were placed in a ball mill, 10 g of methanol was added thereto, and then ball milled for 20 minutes to obtain a white powder, which was the gliclazide-piperazine cocrystal.
[0042] Comparative Example 2
[0043] 32.3 g of gliclazide and 86 g of piperazine were placed in a ball mill, 10 g of dichloromethane was added thereto, and then ball milled for 20 minutes to obtain a white powder, which was the gliclazide-piperazine cocrystal.
[0044] The eutectic structure was determined by a Bruker ApexⅡCCD X-ray diffractometer, and the XRD data were collected by a Japanese RigakuMiniFlex 600 X-ray diffractometer. The tube voltage was 40 kV, the tube current was 15 mA, and the scanning speed was 8° / min. The XRD data of the gliclazide-piperazine cocrystal obtained in Examples 1 to 8 were detected. The characteristic peaks of the XRD spectrum appeared at 7.11°, 13.86°, 23.92° and 25.62°, indicating that the gliclazide-piperazine cocrystal was synthesized.
[0045] The schematic diagram of the structure of the gliclazide-piperazine cocrystal obtained in Examples 1 to 8 is as follows Figure 1 As shown, the diffraction peaks of gliclazide, piperazine and gliclazide-piperazine cocrystal are as follows Figure 2 As shown, it can be seen that the diffraction peaks of gliclazide, piperazine and gliclazide-piperazine cocrystal are obviously different, among which the diffraction peaks of gliclazide-piperazine cocrystal have obvious new peaks at 7.11°, 13.86°, 23.92° and 25.62°. Compared with gliclazide and piperazine, the peaks of gliclazide-piperazine cocrystal between 8 and 12° disappear.
[0046] The crystallographic parameter results of the gliclazide-piperazine cocrystals obtained in Examples 1 to 8 are shown in Table 1, and the X-ray powder diffraction characterization data are shown in Table 2.
[0047] Table 1 Crystallographic parameters of gliclazide-piperazine cocrystals obtained in Examples 1 to 8
[0048]
[0049] Table 2 X-ray powder diffraction characterization data of gliclazide-piperazine cocrystals obtained in Examples 1 to 8
[0050]
[0051]
[0052] The DSC data of gliclazide-piperazine cocrystal are as follows Figure 3 As shown, it can be seen that the melting point of the gliclazide-piperazine eutectic is 149°C, while the melting points of gliclazide and piperazine are 163-169°C and 109-112°C, respectively, and the three are significantly different.
[0053] Infrared spectroscopic analysis of gliclazide, piperazine and gliclazide-piperazine cocrystal was performed. The data were measured by Bruker TENSORII Fourier transform infrared spectrometer with a wave number range of 4000-400 cm -1 ,Depend on Figures 4 to 6 It can be seen that there are differences between the cocrystal and the API. The gliclazide-piperazine cocrystal has a C=O double bond stretching vibration region (1815-1600 cm -1 ) is different, and the C=O double bond stretching vibration frequency of gliclazide is 1710.31cm -1 , while the gliclazide-piperazine cocrystal showed a shift to 1596.91 cm -1 , combined with crystal structure analysis, it can be seen that the difference in the above positions is due to the NH…O hydrogen bond interaction formed between gliclazide and piperazine in the cocrystal, which causes the infrared absorption spectrum of this area to change.
[0054] The solubility of gliclazide, the gliclazide-piperazine cocrystals obtained in Examples 1 to 8, and the gliclazide-piperazine cocrystals obtained in Comparative Examples 1 to 2 in water and ethanol was tested. The results are shown in Table 3.
[0055] Table 3 Solubility data of gliclazide and gliclazide-piperazine cocrystal
[0056]
[0057]
[0058] Gliclazide is a poorly soluble drug, and has the disadvantage of low solubility during the purification process, which leads to the problem of large solvent consumption during the purification process, and for gliclazide, it is difficult to significantly improve its solubility by simply increasing the temperature. As can be seen from the results in Table 3, the solubility of gliclazide in water is very small and cannot be measured, but the solubility after forming a cocrystal with piperazine can be increased to about 0.24g, which greatly improves the solubility of gliclazide in water. The solubility of gliclazide in ethanol is increased by more than 97% after forming a cocrystal with piperazine, so the gliclazide-piperazine cocrystal has higher water solubility and alcohol solubility than gliclazide, which provides a broad prospect for the application of gliclazide.
[0059] Compared with the gliclazide-piperazine cocrystals obtained from comparative documents 1 to 2 and the gliclazide-piperazine cocrystals obtained from Examples 5 to 8, the water solubility and alcohol solubility data are both reduced. This is because the addition of ethanol during the grinding process of gliclazide and piperazine can promote the formation of NH...O hydrogen bonds between gliclazide and piperazine in the cocrystal, thereby making the water solubility and alcohol solubility data of the gliclazide-piperazine cocrystal higher.
[0060] 10 g of each of the gliclazide-piperazine cocrystals obtained in Examples 1 to 4 were mixed evenly to obtain sample 1, and thermal stability (5 g) and photostability tests (5 g) were performed; 10 g of each of the gliclazide-piperazine cocrystals obtained in Examples 5 to 8 were mixed evenly to obtain sample 2, and thermal stability (5 g) and photostability tests (5 g) were performed. The gliclazide-piperazine cocrystals obtained in Comparative Examples 1 to 2 were also subjected to the same test; thermal stability data, test conditions: 60 ° C, 40% humidity, accelerated experiment 10 days after the test purity; photostability data, test conditions: 25 ° C, cold white fluorescent lamp, accelerated experiment 10 days after the test purity, purity detection according to the 2020 edition of the Chinese Pharmacopoeia, General 0512. Determine the content of related substances, 100% minus the content of related substances to obtain the purity value, the results are shown in Table 4.
[0061] Table 4 Light stability and thermal stability test results
[0062]
[0063] For chemical raw materials, it is generally required that the maximum single impurity content does not exceed 1.0%, the total impurity content does not exceed 1.5 or 2.0%, and the single impurity less than 0.1% can be ignored, so for trace impurities, the content of 1.0% is relatively large. Especially for accelerated experiments, after passing through harsh accelerated experimental conditions, the impurity content tends to increase more. It can be seen from the results of Table 4 that the thermal stability and photostability of the gliclazide-piperazine cocrystal obtained by the solvent volatilization method and the grinding method of the present invention are more excellent than the data of the comparative gliclazide crystal, and the gliclazide-piperazine cocrystal of the present invention has better thermal stability and photostability.
[0064] It can be seen from the above experiments that the same gliclazide-piperazine cocrystal can be obtained by both the solvent evaporation method and the grinding method. The dissolution data of the gliclazide-piperazine cocrystal and the gliclazide crystal obtained by the solvent evaporation method are tested as follows:
[0065] Weigh the same mass of gliclazide and gliclazide-piperazine cocrystals and put them into the crystallizer. Then add 200 ml of phosphate buffer (pH = 7.2-7.4) to the conical flask, suspend and stir at 37 ° C, the stirring speed is 100 rpm, and samples are taken at 5, 10, 15, 20, 30, 45, 60, 120, 180, and 300 min. Filter with a 0.22 μm filter membrane, the sample is fixed and diluted, and the 2020 edition of the "Chinese Pharmacopoeia", General Chapter 0512 liquid chromatography quantitative analysis is used. The results are as follows Figure 7 shown.
[0066] Depend on Figure 7It can be seen that the gliclazide-piperazine cocrystal can be dissolved within 5 minutes and the maximum dissolution rate can be reached in 60 minutes. The gliclazide-piperazine cocrystal has a faster dissolution rate than the gliclazide crystal.
Claims
1. A gliclazide-piperazine cocrystal, characterized in that: The eutectic is composed of gliclazide and piperazine; the gliclazide-piperazine eutectic has the following unit cell parameters: the crystal system category is monoclinic; the space group is P21; the unit cell length (Å) a=6.3416(1), b=24.8034(4), c=6.5323(1); the unit cell angle (°) α=90, β=100.553(4), γ=90; the number of units in the unit cell Z=2; F(000)=440.0; The gliclazide-piperazine cocrystal is prepared by a grinding method, which comprises the following steps: placing gliclazide and piperazine 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 using a ball mill to obtain a white powder, namely the gliclazide-piperazine cocrystal; wherein the mass ratio of gliclazide to ethanol is 1:0.2-0.
5.
2. The gliclazide-piperazine cocrystal according to claim 1, characterized in that: The co-crystal has a powder X-ray diffraction pattern expressed in 2θ angle values, wherein the powder X-ray diffraction pattern comprises the following 2θ angle values: 5.92, 7.11, 8.36, 11.86, 13.86, 14.25, 15.58, 16.78, 17.49, 17.79, 19.17, 19.89, 20.81, 21.38, 21.66, 22.59, 23.35, 23.92, 25. 62, 27.97, 28.77, 29.15, 29.83, 30.40, 30.87, 31.45, 31.97, 32.33, 33.22, 33.77, 34.30, 35.34, 36.03, 36.64, 38.25, 38.76, 40.52, 42.30, 43.09, 43.70, 44.97, 46.01, 47.39, 48.02.