CN112538070B - Pymetrozine-p-hydroxybenzoic acid eutectic crystal and preparation method thereof - Google Patents

Abstract

The invention relates to a co-crystal of pymetrozine-p-hydroxybenzoic acid and a preparation method thereof. In the co-crystal of pymetrozine and p-hydroxybenzoic acid, the molar ratio of pymetrozine and p-hydroxybenzoic acid is 1:1; The differential scanning calorimetry spectrum of the co-crystal of keto-p-hydroxybenzoic acid has a characteristic melting peak at 215 ° C ~ 220 ° C; after mixing pymetrozine and p-hydroxy benzoic acid, add a solvent, and use liquid-assisted grinding or slurry Suspension or solvent volatilization crystallization method, after drying to obtain the co-crystal of pymetrozine-p-hydroxybenzoic acid. Compared with the raw material drug of pymetrozine, the co-crystal has better hygrothermal stability and higher water solubility. The insecticidal activity test shows that the co-crystal maintains the good insecticidal activity of pymetrozine. The preparation method is simple, the crystallization process is easy to control, and is suitable for industrial production, and the formation of the eutectic greatly improves the stability of the pesticide and the safety of the use process, and has good industrial application prospects.

Description

Pymetrozine-p-hydroxybenzoic acid co-crystal and preparation method thereof

technical field

The invention belongs to the field of compound cocrystals and the technical field of pesticide chemistry, and specifically relates to a cocrystal of pymetrozine and p-hydroxybenzoic acid and a preparation method thereof.

Background technique

The use effect of drugs or pesticides depends to a large extent on the physical and chemical properties of their active ingredients, such as stability, solubility, etc., and the physical and chemical properties of different solid forms have certain differences. effect plays an important role. Solid forms of drugs/pesticides include salts, co-crystals, solvates and their polymorphic and amorphous forms. Among them, the eutectic is a crystalline compound formed by two or more different molecules or ionic compounds in a certain stoichiometric ratio, which is generally combined through non-covalent bonding. It is possible to change the properties of the compound significantly, and thus it is an effective means to improve the physical and chemical properties of active ingredients of drugs/pesticides. However, the design of co-crystals is more difficult because it involves factors such as steric hindrance caused by different molecules that may have different shapes and sizes during the molecular recognition process.

Pesticides are one of the necessary means of production in agriculture, and play an important role in preventing and controlling crop diseases, insect pests and weeds, and ensuring food security in my country. The annual use of pesticides in my country is as high as one million tons, but the effective utilization rate is less than 30%. A large amount of pesticides are lost into the environment through volatilization, runoff, leakage, etc., which not only causes serious environmental pollution, but also endangers the health of humans and animals. How to improve the utilization rate of pesticides and reduce the amount of pesticides has become a key problem to be solved urgently in the fields of agriculture and environment in my country and even in the world.

In response to this problem, the research on the co-crystal of pesticide API and its physical properties is also increasing year by year. For example CN111187204 A discloses a kind of eutectic about systemic insecticide acetamiprid and its preparation method and application. Using the co-crystal method, without changing the covalent structure of acetamiprid, combine acetamiprid with carboxylic acids such as oxalic acid and malonic acid to prepare acetamiprid co-crystals, which can effectively improve the acetamiprid Physical and chemical properties, improve the water solubility and melting point of acetamiprid, enhance its stability and processability. CN108558761B discloses a co-crystal of the herbicide triazole sulfotrione and salicylic acid, the co-crystal has stable physical and chemical properties, and the drug effect is obviously synergistic.

Pymetrozine (C ₁₀ H ₁₁ N ₅ O, molecular weight 217.2, CAS No. 123312-89-0, structure as shown in Formula 1), also known as pyrazinone, is a non-toxic azinonone developed by Syngenta in 1988. Biocidal insecticides. Pymetrozine has the advantages of high efficiency, low toxicity, high selectivity, and unique toxicological characteristics. It has outstanding control effects on piercing-sucking mouthparts pests, especially aphids, whiteflies, and black-tailed leafhoppers, and has a relatively good effect on natural enemies insects. good selectivity. Can be used both as a foliar spray and as a soil treatment.

Formula 1. Pymetrozine chemical structural formula.

The reported solid form of pymetrozine has a crystal form, a methanolate and a dihydrate. Most of the related research focuses on the mechanism of pymetrozine’s insecticidal action and control effect. The existing patents also mainly focus on the formula In terms of application and application, there are few research reports on the physical properties and activity of the co-crystal of this compound. CN 111374136A discloses a composition of pymetrozine and thiamethoxam, which can increase the duration of the drug effect of the composition of thiamethoxam and pymetrozine, and improve the dispersion uniformity of water-dispersible granules. CN109221191A discloses an insecticidal composition containing dipropacyclofen and pymetrozine, which can synergize against pests and improve the control effect. CN 109006837A discloses a composition containing chlorfenapyr and pymetrozine, which can maintain the excellent control effect on mulberry thrips, and can improve the quick-acting and long-lasting effect compared with the compound composition of the prior art. These patents report the compound of pymetrozine, which is essentially a physical mixture of another component pesticide and pymetrozine, and requires the synergistic effect of various solvents, surfactants, emulsifiers, etc., and the usage is complicated , can not effectively reduce the use of pesticides. However, the existing pymetrozine product is easily converted into the dihydrate of pymetrozine in an environment with a humidity greater than 70%, and has poor hygroscopic stability. At the same time, the water solubility of the product is small, only 0.2335g/L. Pymetrozine requires high storage conditions, and the utilization rate of pesticides is also low.

It has been found through research that pymetrozine contains a pyridine group and a carbonyl group, which can be used as a good hydrogen bond acceptor, so it is expected to interact with compounds containing strong hydrogen bond donors such as carboxyl and hydroxyl groups through hydrogen bonds and other non-covalent interactions Forming a co-crystal, without changing the covalent structure of pymetrozine, changes the arrangement and mode of action of molecules in the crystal to improve the stability and solubility of pymetrozine. After screening, the pymetrozine-p-hydroxybenzoic acid co-crystal was prepared, which significantly improved the stability and water solubility of pymetrozine, and laid the foundation for the further development and application of pymetrozine.

Contents of the invention

The purpose of the present invention is to overcome the inconvenience in the process of preparation and storage of pesticide preparations caused by the lower water solubility and poor moisture absorption stability of pymetrozine in the prior art. At present, the commonly used methods to improve its properties are usually to change the structure, add additives, etc., not only the cost is high, but also part of the way is to change the structure, so that the performance of its practical application is affected. With the support of the National Key Research and Development Program "Natural Green Biopesticide Synthetic Biology and Combination Synthesis Technology" subject six "Natural Biopesticide Manufacturing Process Optimization and Product Promotion Demonstration" (2017YFD0201406), the technical solution of the present invention uses p-hydroxybenzoic acid as (C ₇ H ₆ O ₃ , molecular weight 138.1, CAS number 99-96-7, structure as in formula 2) the co-crystal former forms co-crystals with pymetrozine, and the resulting co-crystals have better hygroscopic stability and higher With the advantages of water solubility, it is suitable for use in the production and application of pesticide preparations. Simultaneously, the method is simple, the production cost is low, and the production cycle is short.

Formula 2. Structural formula of p-hydroxybenzoic acid.

To achieve the above object, the present invention is specifically realized through the following technical solutions:

A co-crystal of pymetrozine-p-hydroxybenzoic acid, wherein the molar ratio of pymetrozine and p-hydroxybenzoic acid in the co-crystal of pymetrozine and p-hydroxybenzoic acid is 1:1.

The X-ray powder diffraction spectrum of the co-crystal of pymetrozine-p-hydroxybenzoic acid is 7.1°±0.2°, 8.7°±0.2°, 10.2°±0.2°, 14.2°±0.2°, 15.8° at 2θ angle There are characteristic peaks at °±0.2°, 16.9°±0.2°, 19.5°±0.2°, 21.0°±0.2, 25.7°±0.2°, 27.4°±0.2°, 29.5°±0.2°. Its powder X-ray diffraction pattern is as shown in accompanying drawing 1.

The differential scanning calorimetry spectrum of the co-crystal of pymetrozine-p-hydroxybenzoic acid has a characteristic melting peak at 215°C-220°C, as shown in Figure 2.

The infrared spectra of the cocrystal of pymetrozine-p-hydroxybenzoic acid are at 3241±1, 1661±1, 1610±1, 1480±1, 1420±1, 1328±1, 1286±1, 1235±1 , 1152±1, 1039±1, 897±1, 849±1cm ^-1 have characteristic peaks, as shown in Figure 3.

轴角α＝90°，β＝90°，γ＝90°。结构式如附图4所示。The eutectic of pymetrozine-p-hydroxybenzoic acid is orthorhombic, the space group is P _bca , and its unit cell parameter is

Shaft angle α=90°, β=90°, γ=90°. The structural formula is shown in Figure 4.

According to another aspect of the present invention, there is provided a method for preparing a co-crystal of pymetrozine-p-hydroxybenzoic acid. After mixing pymetrozine and p-hydroxybenzoic acid, adding a solvent, using liquid-assisted grinding or slurry suspension or The solvent volatilization and crystallization method obtains the co-crystal of pymetrozine-p-hydroxybenzoic acid after drying.

In the method for preparing the co-crystal of pymetrozine-p-hydroxybenzoic acid, the method of liquid-assisted grinding is to grind the mixture of pymetrozine and p-hydroxybenzoic acid in a vibrating ball mill after adding a solvent dropwise. The molar ratio of pymetrozine and p-hydroxybenzoic acid is 1:1, the solvent is selected from one of water, methanol, ethanol, acetonitrile or acetone, the ratio of the total mass of pymetrozine and p-hydroxybenzoic acid mixture to the solvent 11.8-35.5g/mL, grinding conditions: frequency 2-10 times/second, duration 20-80 minutes.

In the method for preparing the co-crystal of pymetrozine-p-hydroxybenzoic acid, the slurry suspension method is: mixing pymetrozine and p-hydroxybenzoic acid, suspending in a solvent, and filtering. The molar ratio of pymetrozine and p-hydroxybenzoic acid is 1:2-2:1, the solvent is one of water, methanol, ethanol, acetonitrile or acetone, the total mass of pymetrozine and p-hydroxybenzoic acid mixture and the solvent The dosage ratio is 0.247-0.355g/mL, and the suspension time is 6-24h.

In the method for preparing the co-crystal of pymetrozine-p-hydroxybenzoic acid, the method for volatilizing the solvent is to completely dissolve the mixture of pymetrozine and p-hydroxybenzoic acid in the solvent, and volatilize until crystals are precipitated. The molar ratio of pymetrozine and p-hydroxybenzoic acid is 1:2-2:1, and the solvent is selected from the mixed solvent of ethanol and methanol or dimethyl sulfoxide with a volume ratio of 1:1-1:3, and the added solvent The volume should be such that the mixture of pymetrozine and p-hydroxybenzoic acid is completely dissolved, and the solvent volatilization time is subject to the precipitation of crystals.

In the method for preparing the co-crystal of pymetrozine-p-hydroxybenzoic acid, the drying conditions are: blast drying, the temperature is 40-60° C., and the time is 8-12 hours.

In the method for preparing the co-crystal of pymetrozine-p-hydroxybenzoic acid described in the present invention, the yield is over 40%, and the highest reaches over 99.0%. Calculate the number of moles of the obtained eutectic against the number of moles of pymetrozine raw material used.

Compared with the accelerated stability test, the co-crystal has better hygrothermal stability than the pymetrozine raw material drug itself. Compared with the dynamic water vapor adsorption test, the co-crystal has better hygroscopic stability. Chromatography was performed to determine the equilibrium water solubility, and the cocrystal has a higher water solubility. The insecticidal activity test shows that the co-crystal maintains the good insecticidal activity of pymetrozine. The preparation method of the pymetrozine-p-hydroxybenzoic acid co-crystal is simple, the crystallization process is easy to control, and is suitable for industrial production, and the formation of the co-crystal greatly improves the stability of the pesticide and the safety of the use process, and has good Industrial application prospects.

The solubility of pymetrozine and the obtained pymetrozine-p-hydroxybenzoic acid cocrystal product in pure water was detected by high performance liquid chromatography. Add excess pymetrozine/eutectic product to 100mL water, stir at 25°C for 12 hours, then let it stand for 12 hours, take the supernatant and filter it through a polytetrafluoroethylene filter membrane and dilute it, then detect the concentration by liquid chromatography. The measured solubility of pymetrozine raw material is 0.2335g/L, and the solubility of pymetrozine in the pymetrozine-p-hydroxybenzoic acid cocrystal obtained in the present invention (calculated by pymetrozine component) is 0.3096g/L. It can be seen that the obtained pymetrozine-p-hydroxybenzoic acid cocrystal has higher water solubility.

The hygroscopic stability of the obtained pymetrozine-p-hydroxybenzoic acid cocrystal product was detected by a dynamic water vapor adsorption instrument. Under the condition of 25±0.1°C, a cycle from 0%-95%-5% relative humidity (RH) was set. The obtained isothermal adsorption/desorption curve is shown in Figure 5. The desorption isotherm of pymetrozine had a large stagnation phenomenon. When the humidity was greater than 70%, the weight of pymetrozine increased significantly, and the change almost did not decrease with the decrease of humidity. The desorption curve of the co-crystal of pymetrozine-p-hydroxybenzoic acid has almost no stagnation phenomenon. The powder X-ray diffraction pattern of the pymetrozine raw material after the dynamic adsorption experiment is shown in Figure 6. Compared with before the dynamic adsorption experiment, the characteristic peaks of the pymetrozine raw material have changed significantly, and the characteristic peaks are consistent with those of the pymetrozine hydrate. The PXRD patterns calculated from the single crystal structure were consistent, indicating that pymetrozine was transformed into dihydrate. The characteristic peaks of the pymetrozine-p-hydroxybenzoic acid cocrystal do not change, as shown in Figure 1. The results show that the co-crystal of pymetrozine-p-hydroxybenzoic acid remains stable in a high-humidity environment, and compared with pymetrozine, its hygroscopic stability is greatly improved.

The fluidity and bulk density of the pymetrozine-p-hydroxybenzoic acid eutectic product obtained in the present invention and the pymetrozine raw material were compared and tested by using a powder property tester. The bulk density of the raw material is: 0.509-0.514g/mL, stop The angle is 41.3-41.5°. The bulk density of the pymetrozine-hydroxybenzoic acid eutectic product is: 0.517-0.521g/mL, and the angle of repose is 40.1-40.3°. The bulk density of eutectic products increases to a certain extent, and the fluidity also improves to a certain extent.

A constant temperature and humidity chamber is used to carry out accelerated stability tests on the products and raw materials prepared by the liquid-phase assisted grinding method of the present invention. Take 3 grams of pymetrozine powder and pymetrozine p-hydroxybenzoic acid eutectic powder respectively, both of which have a particle size of 50- Between 100μm and stored for 30 days at a temperature of 50°C and a relative humidity of 75±5%, the raw material of pymetrozine has relatively serious moisture absorption and coalescence. The D ₅₀ is 176μm, as tested by the Malvern particle size analyzer. The pymetrozine-p-hydroxybenzoic acid co-crystal has a slight coalescence phenomenon, and the D ₅₀ is 104 μm. Samples were taken at 0 days, 5 days, 10 days, 20 days, and 30 days for powder X-ray diffraction experiments to monitor the phase transition of raw materials and eutectics in a hot and humid environment. The diffraction patterns changed significantly, as shown in Figure 6, and then remained unchanged. The co-crystal powder X-ray diffraction pattern of pymetrozine-p-hydroxybenzoic acid has not changed, as shown in Figure 1. The results show that the formation of co-crystals improves the stability of pymetrozine raw materials in high-temperature and high-humidity environments, and at the same time improves the moisture absorption and coalescence of pymetrozine to a certain extent.

The insecticidal activity of pymetrozine and pymetrozine-p-hydroxybenzoic acid co-crystal was carried out on the nymphs of the bean aphid that were reared indoors at the same age. Pymetrozine and pymetrozine-p-hydroxybenzoic acid eutectic were dissolved in water respectively to make a liquid, and diluted to a concentration of 0.001mol/L with an emulsifier, and the broad bean seedlings with aphids (each bean seedling with worms 30 -70 pieces) immersed in the liquid medicine for 10 seconds, and absorb the excess liquid medicine with filter paper. Afterwards, the test worms were transferred to normal conditions for rearing (temperature: 20-28° C., relative humidity: 60-80%, well-ventilated). And set the treatment of pure water without medicament as blank control. After 48 hours, the death of the test insects was investigated. Record the total number of insects and the number of dead insects. The insecticidal activity of pymetrozine and its cocrystals was evaluated based on the mortality of bean aphid nymphs. The experiment was repeated three times, and the average mortality rate of the three experiments is shown in Table 1. It can be seen that the formation of the eutectic did not have a great impact on the activity of pymetrozine, and the insecticidal activity of pymetrozine was basically maintained. The formation of pymetrozine can improve the properties of pymetrozine such as water solubility and heat and humidity stability, and the formation of co-crystal has great potential for the agricultural application of pymetrozine.

Table 1. Insecticidal activity test results

liquid medicine blank control Pymetrozine Pymetrozine-paraben cocrystal Bean aphid nymph mortality (%) 7.4 74.4 73.6-75.0

In summary, the pymetrozine-p-hydroxybenzoic acid co-crystal disclosed in the present invention has higher water solubility and better hygrothermal stability than pymetrozine, and the bulk density is also slightly increased , the fluidity is enhanced, which is beneficial to the subsequent formulation, storage and transportation. The cocrystal and pymetrozine have almost the same insecticidal activity, so they have great prospects for agricultural application.

The invention has the beneficial effects of simple process, strong operability, low equipment requirements, short production cycle, suitable for industrial production, and can prepare pymetrozine-p-hydroxybenzoic acid eutectic for industrial production as required.

Description of drawings

Fig. 1 is the PXRD collection of illustrative plates of the pymetrozine-p-hydroxybenzoic acid cocrystal prepared in embodiment 1 and two kinds of raw materials used in all embodiments, and ordinate is diffraction intensity, unit count (counts); Abscissa is Diffraction angle 2θ, unit degree (°);

Fig. 2 is the DSC collection of illustrative plates of the pymetrozine-p-hydroxybenzoic acid eutectic prepared in embodiment 1 and two kinds of raw materials used in all embodiments, and the ordinate is the heat flow that the substance of unit mass emits, and the unit is ( W/g), upward is exothermic; abscissa is temperature, unit is Celsius (°C);

Fig. 3 is the infrared spectrum of the pymetrozine-p-hydroxybenzoic acid cocrystal prepared in Example 1 and two kinds of raw materials used in all embodiments, and the ordinate is the transmittance, and the unit is (%); is the wave number, in degrees Celsius (cm ^-1 );

Fig. 4 is a structural diagram of the pymetrozine-p-hydroxybenzoic acid co-crystal in Example 1, the molecular formula is C ₁₇ H ₁₇ N ₅ O ₄ ;

Fig. 5 is the dynamic water vapor adsorption and desorption curve of pymetrozine-eutectic at 25°C in Example 7;

Figure 6 is the PXRD spectrum of pymetrozine after the dynamic vapor adsorption experiment in Example 7 and the PXRD spectrum calculated according to the single crystal structure of pymetrozine hydrate;

Detailed ways

In order to deepen the understanding of the present invention, the present invention will be described in further detail below in conjunction with the embodiments and accompanying drawings. The embodiments are only used to explain the present invention, and do not constitute a limitation to the protection scope of the present invention.

Testing instruments and methods:

The single crystal X-ray diffraction measurement is performed by using the X-ray surface detection diffractometer Rapid-RigakuП of Japan Rigaku Co., Ltd., and the MoKα target ray wavelength is 7.103×10 ^-10 m for scanning. The integration and scaling of the intensity data was done using the SAINT procedure. Structures are resolved by direct methods using SHELXS-XT. The SHELXL-XL is used for refinement by the full matrix least squares method, and the hydrogen atom refinement process is obtained by isotropic calculation.

。扫描范围为2-40°(2θ)，扫描步长为0.02°，速率为8°/min。电源设置为40kV，100mA。Powder X-ray diffraction adopts Rigaku D/max-2500 X-ray diffractometer, and the radiation source is Cu/Kα1

. The scanning range is 2-40° (2θ), the scanning step is 0.02°, and the rate is 8°/min. The power supply is set to 40kV, 100mA.

DSC was performed in a Mettler DSC 1 system (STARe, Mettler, Switzerland). A sample weighing 3-5 mg was heated in a standard aluminum pan at a ramp rate of 10 °C/min under a flow of nitrogen at 50 mL/min.

Infrared spectra were collected on an ALPHA II infrared instrument (Bruker, Germany). Each sample was scanned at a resolution of 4 ^cm in the spectral range of 4000–400 ^cm . At least 16 scans were collected and averaged.

The dynamic vapor sorption experiment uses a VTI-SA+ vapor sorption analyzer (TA Instruments) to measure samples at a relative humidity (RH) of 0%-95%-5% at 25°C. If a weight change of less than 0.02% occurs within 5 minutes, proceed to the next humidity point with a maximum hold time of 30 minutes.

The liquid chromatography adopts Agilent Extend C18 chromatographic column (250×4.6mm, 5μm), and is detected at 30°C with a UV detection wavelength of 300nm. The mobile phase was methanol and water (v/v: 70/30) at a flow rate of 1.0 mL/min. The observed retention time of pymetrozine was 2.68 min.

Example 1:

Add 0.217g of pymetrozine and 0.138g of p-hydroxybenzoic acid into the sample tube of the vibrating ball mill, add 30μL of water with a pipette gun, grind at a frequency of 2 times/second, take it out after 80 minutes, and place it in a blast Dry in a drying oven at a temperature of 40° C. for 12 hours to obtain a co-crystal of pymetrozine p-hydroxybenzoic acid with a yield of 99%. The PXRD pattern of the product is shown in Figure 1, and the characteristic peaks (2θ, ±0.2°) are: 7.1°±0.2°, 8.7°±0.2°, 10.2°±0.2°, 14.2°±0.2°, 15.8°±0.2 °, 16.9°±0.2°, 19.5°±0.2°, 21.0°±0.2, 25.7°±0.2°, 27.4°±0.2°, 29.5°±0.2°, consistent with the single crystal structure fitting results; its DSC spectrum is as follows As shown in Figure 2, the characteristic values are: the melting start point is 218.2°C, and the peak value is 219.7°C; There is a characteristic peak at 849cm ^-1 . The solubility is 0.3096g/L (based on pymetrozine component). The bulk density is 0.517g/mL, and the angle of repose is 40.1°. The isothermal adsorption/desorption curve measured by the dynamic water vapor adsorption instrument is shown in Figure 5, and there is almost no stagnation phenomenon. After 30 days of accelerated stability test using a constant temperature and humidity chamber, the XRD pattern does not change, which is consistent with that shown in Figure 1. In the insecticidal activity experiment, the mortality rate of bean aphid nymphs was 74.3%.

Example 2:

Add 0.217g of pymetrozine and 0.138g of p-hydroxybenzoic acid into the sample tube of the vibrating ball mill, add 10μL of methanol with a pipette gun, grind at a frequency of 6 times/second, take it out after 50 minutes, and place it in a blast Dry in a drying oven at a temperature of 40° C. for 12 hours to obtain a co-crystal of pymetrozine p-hydroxybenzoic acid with a yield of 99%. The PXRD spectrum, DSC spectrum, infrared spectrum, isotherm adsorption/desorption curve of this product are similar to Example 1. The solubility is 0.3096g/L (based on pymetrozine component). The bulk density is 0.519g/mL, and the angle of repose is 40.2°. After 30 days of accelerated stability test using a constant temperature and humidity chamber, the XRD pattern does not change, which is consistent with that shown in Figure 1. In the insecticidal activity experiment, the mortality rate of bean aphid nymphs was 74.0%.

Example 3:

Add 0.217g of pymetrozine and 0.138g of p-hydroxybenzoic acid into the sample tube of the vibrating ball mill, add 20μL of ethanol with a pipette gun, grind at a frequency of 10 times/second, take it out after 20 minutes, and place it in a blast Dry in a drying oven at a temperature of 40° C. for 12 hours to obtain a co-crystal of pymetrozine p-hydroxybenzoic acid with a yield of 99%. The PXRD spectrum, DSC spectrum, infrared spectrum, isotherm adsorption/desorption curve of this product are similar to Example 1. The solubility is 0.3096g/L (based on pymetrozine component). The bulk density is 0.521g/mL, and the angle of repose is 40.3°. After 30 days of accelerated stability test using a constant temperature and humidity chamber, the XRD pattern does not change, which is consistent with that shown in Figure 1. In the insecticidal activity experiment, the mortality rate of bean aphid nymphs was 74.4%.

Example 4:

Weigh 2.17g of pymetrozine, add 1.38g of p-hydroxybenzoic acid, add 10ml of acetonitrile, stir at room temperature for 6h, filter, place in a blast drying oven and dry at a temperature of 50°C for 10 hours to obtain pymetrozine Co-crystal of ketone p-hydroxybenzoic acid, yield 86.2%. The PXRD spectrum, DSC spectrum, infrared spectrum, isotherm adsorption/desorption curve of this product are similar to Example 1. The solubility is 0.3096g/L (based on pymetrozine component). The bulk density is 0.520g/mL, and the angle of repose is 40.2°. After 30 days of accelerated stability test using a constant temperature and humidity chamber, the XRD pattern does not change, which is consistent with that shown in Figure 1. In the insecticidal activity experiment, the mortality rate of bean aphid nymphs was 74.8%.

Example 5:

Weigh 2.17g of pymetrozine, add 0.69g of p-hydroxybenzoic acid, add 10ml of acetone, stir at room temperature for 12h, filter, place in a blast drying oven and dry at 60°C for 8 hours to obtain pymetrozine Co-crystal of ketone p-hydroxybenzoic acid, yield 83.8%. The PXRD spectrum, DSC spectrum, infrared spectrum, isotherm adsorption/desorption curve of this product are similar to Example 1. The solubility is 0.3096g/L (based on pymetrozine component). The bulk density is 0.519g/mL, and the angle of repose is 40.2°. After 30 days of accelerated stability test using a constant temperature and humidity chamber, the XRD pattern does not change, which is consistent with that shown in Figure 1. In the insecticidal activity experiment, the mortality rate of bean aphid nymphs was 75.0%.

Embodiment 6:

Weigh 1.09g of pymetrozine, add 1.38g of p-hydroxybenzoic acid, add 10ml of water, stir at room temperature for 24h, filter, place in a blast drying oven and dry at 60°C for 8 hours to obtain pymetrozine A co-crystal of ketone-p-hydroxybenzoic acid with a yield of 85.3%. The PXRD spectrum, DSC spectrum, infrared spectrum, isotherm adsorption/desorption curve of this product are similar to Example 1. The solubility is 0.3096g/L (based on pymetrozine component). The bulk density is 0.520g/mL, and the angle of repose is 40.1°. After 30 days of accelerated stability test using a constant temperature and humidity chamber, the XRD pattern does not change, which is consistent with that shown in Figure 1. In the insecticidal activity experiment, the mortality rate of bean aphid nymphs was 74.0%.

Embodiment 7:

Weigh 10.9 mg of pymetrozine, add 6.9 mg of p-hydroxybenzoic acid, add 10 mL of a mixed solution of ethanol and methanol (V/V=1:2), dissolve and volatilize at room temperature until crystals precipitate, filter, and place in a blast Dry in a drying oven at a temperature of 40° C. for 8 hours to obtain a co-crystal of pymetrozine p-hydroxybenzoic acid with a yield of 52.3%. The PXRD spectrum, DSC spectrum, infrared spectrum, isotherm adsorption/desorption curve of this product are similar to Example 1. The solubility is 0.3096g/L (based on pymetrozine component). The bulk density is 0.521g/mL, and the angle of repose is 40.1°. After 30 days of accelerated stability test using a constant temperature and humidity chamber, the XRD pattern does not change, which is consistent with that shown in Figure 1. In the insecticidal activity experiment, the mortality rate of bean aphid nymphs was 74.6%.

Embodiment 8:

Weigh 21.7 mg of pymetrozine, add 6.9 mg of p-hydroxybenzoic acid, add 10 mL of a mixed solution of ethanol and methanol (V/V=1:3), dissolve and volatilize at room temperature until crystals are precipitated, filter, and place in a blast Dry in a drying oven at a temperature of 40° C. for 8 hours to obtain a co-crystal of pymetrozine p-hydroxybenzoic acid with a yield of 40.3%. The PXRD spectrum, DSC spectrum, infrared spectrum, isotherm adsorption/desorption curve of this product are similar to Example 1. The solubility is 0.3096g/L (based on pymetrozine component). The bulk density is 0.519g/mL, and the angle of repose is 40.2°. After 30 days of accelerated stability test using a constant temperature and humidity chamber, the XRD pattern does not change, which is consistent with that shown in Figure 1. In the insecticidal activity experiment, the mortality rate of bean aphid nymphs was 74.0%.

Embodiment 9:

Weigh 10.9 mg of pymetrozine, add 13.8 mg of p-hydroxybenzoic acid, add 10 mL of a mixed solution of ethanol and dimethyl sulfoxide (V/V=1:1), dissolve and volatilize at room temperature until crystals precipitate, filter, Place it in a blast drying oven and dry it at a temperature of 60° C. for 12 hours to obtain a co-crystal of pymetrozine p-hydroxybenzoic acid with a yield of 53.5%. The PXRD spectrum, DSC spectrum, infrared spectrum, isotherm adsorption/desorption curve of this product are similar to Example 1. The solubility is 0.3096g/L (based on pymetrozine component). The bulk density is 0.521g/mL, and the angle of repose is 40.3°. After 30 days of accelerated stability test using a constant temperature and humidity chamber, the XRD pattern does not change, which is consistent with that shown in Figure 1. In the insecticidal activity experiment, the mortality rate of bean aphid nymphs was 73.6%.

Although the embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variants, the scope of the invention is defined by the appended claims and their equivalents.

Claims (6)

1. a cocrystal of pymetrozine-p-hydroxybenzoic acid is characterized in that the mol ratio of pymetrozine and p-hydroxybenzoic acid in the cocrystal of pymetrozine-p-hydroxybenzoic acid is 1:1; The X-ray powder diffraction pattern of the cocrystal of ketone-p-hydroxybenzoic acid is 7.1°±0.2°, 8.7°±0.2°, 10.2°±0.2°, 14.2°±0.2°, 15.8°±0.2°, 16.9° ±0.2°, 19.5°±0.2°, 21.0°±0.2, 25.7°±0.2°, 27.4°±0.2°, 29.5°±0.2° It has a characteristic peak; its differential scanning calorimetry spectrum has a characteristic melting peak at 215 ° C ~ 220 ° C; There are characteristic peaks at ±1, 1286±1, 1235±1, 1152±1, 1039±1, 897±1, 849±1cm ^-1 ; X-ray single crystal diffraction results are orthorhombic, and the space group is P _bca , its unit cell parameters are

Shaft angle α=90°, β=90°, γ=90°. 2. the method for the eutectic of pymetrozine-p-hydroxybenzoic acid described in claim 1 is characterized in that, after pymetrozine and p-hydroxybenzoic acid are mixed, add solvent, adopt liquid auxiliary grinding or slurry suspension or The solvent volatilization and crystallization method obtains the co-crystal of pymetrozine-p-hydroxybenzoic acid after drying. 3. method according to claim 2, it is characterized in that, the method for liquid assisted grinding is with the mixture of pymetrozine and p-hydroxybenzoic acid, after dripping solvent, grind in vibration ball mill; Wherein, pymetrozine and The molar ratio of p-hydroxybenzoic acid is 1:1, the solvent is selected from one of water, methanol, ethanol, acetonitrile or acetone, and the ratio of the total mass of pymetrozine and p-hydroxybenzoic acid mixture to the solvent is 11.8-35.5 g/mL, the grinding conditions are: frequency 2-10 times/second, duration 20-80 minutes. 4. The method according to claim 2, wherein the slurry suspension method is to mix pymetrozine and p-hydroxybenzoic acid, suspend in a solvent, and filter; wherein pymetrozine and p-hydroxybenzoic acid The molar ratio is 1:2-2:1, the solvent is one of water, methanol, ethanol, acetonitrile or acetone, the total mass of pymetrozine and p-hydroxybenzoic acid mixture and the amount ratio of solvent is 0.247-0.355g /mL, the suspension time is 6-24h. 5. The method according to claim 2, characterized in that, the method of solvent volatilization and crystallization is to completely dissolve the mixture of pymetrozine and p-hydroxybenzoic acid in the solvent, and volatilize until crystals are separated out; wherein, pymetrozine And the mol ratio of p-hydroxybenzoic acid is 1:2-2:1, and solvent is selected from the mixed solvent that the volume ratio of ethanol and methyl alcohol or dimethyl sulfoxide is 1:1-1:3, and the volume of the solvent that adds should be The mixture of pymetrozine and p-hydroxybenzoic acid is completely dissolved, and the solvent volatilization time is subject to the precipitation of crystals. 6 . The method according to claim 2 , characterized in that, the drying conditions are: blast drying at a temperature of 40-60° C. for 8-12 hours.

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