Quantitative determination method of crystal form B for cyprodinil pesticide

Abstract

The invention discloses an X-ray powder diffraction technology-based quantitative determination method for the content of a crystal form B in a crystal form for a cyprodinil pesticide, and compared with a cyprodinil crystal form quantitative determination method disclosed in the prior art, the method has the advantages that the crystal form B influencing the stability of a preparation is directly and quantitatively analyzed, the influence of impurities and amorphous form is effectively avoided, and the accuracy of the quantitative determination method is improved. The method provided by the invention has the advantages of reduced system error, improved accuracy, rapidness and convenience, can effectively control the quality of the cyprodinil pesticide, and provides favorable support for ensuring the quality of the cyprodinil pesticide.

Description

Technical Field

[0001] This invention relates to a method for quantitative determination of the crystal form of a compound, and in particular to a method for quantitative determination of the content of crystal form B in the crystal form of pyrimethanil pesticide based on X-ray powder diffraction technology. Background Technology

[0002] Cyprodinil, also known as 4-cyclopropyl-6-methyl-N-phenylpyrimidine-2-amine, is an organic compound with the chemical formula C. 14 H 15 N3 is a broad-spectrum phenylamine fungicide that inhibits the biosynthesis of methionine in plant pathogenic fungi. Azoxystrobin inhibits methionine biosynthesis and hydrolytic enzyme activity in pathogenic cells, interfering with the fungal life cycle, inhibiting pathogen penetration, and disrupting mycelial growth in plants. It has excellent control effects against gray mold and leaf spot caused by deuteromycetes and ascomycetes.

[0003] Generally, different crystal forms of the same drug exhibit varying degrees of solubility, leading to significant differences in solubility and efficacy, especially for poorly water-soluble drugs, where crystal form has a greater impact on solubility. Furthermore, different crystal forms of azoxystrobin also show variations in formulation stability. Azoxystrobin often contains mixed crystals of crystal form A and crystal form B. Therefore, studying the purity of azoxystrobin crystal forms is crucial for better controlling its solubility, efficacy, and formulation stability. Consequently, developing analytical methods that can directly and accurately determine the content of specific crystal forms of azoxystrobin is essential. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a method for the quantitative determination of crystal form B in the crystalline form of pyraclostrobin pesticide. This method can quickly and conveniently detect the content of crystal form B in pyraclostrobin with high accuracy and ease of application.

[0005] The specific technical solution of this invention is as follows:

[0006] A method for quantitative determination of crystal form B in pyraclostrobin pesticide crystal form is disclosed. This method uses X-ray powder diffraction to determine the content of pyraclostrobin crystal form B. The peak value of 2θ = 19.26 ± 0.2° is used as the quantitative characteristic peak of pyraclostrobin crystal form B. A standard curve is established comparing the content of pyraclostrobin crystal form B with the intensity of the quantitative characteristic peak, using the absolute intensity of this peak as the quantitative parameter. The content of crystal form B in the pyraclostrobin sample is then determined based on this standard curve.

[0007] Furthermore, the present invention uses the quantitative characteristic peak of pyraclostrobin crystal form B as a quantitative parameter, and the 2θ of the quantitative characteristic peak is 19.26±0.2°.

[0008] In a preferred embodiment, the process of constructing the standard curve of the present invention includes:

[0009] 1) Take pyraclostrobin crystal form A standard and pyraclostrobin crystal form B standard respectively, grind them thoroughly and sieve them;

[0010] 2) Mix the ground and sieved azoxystrobin crystal form A standard and azoxystrobin crystal form B standard to obtain a series of mixtures with different mass percentages of azoxystrobin crystal form B;

[0011] 3) Perform X-ray diffraction tests on the mixture from step (2) to obtain the quantitative characteristic peak intensity of pyrimethanil cycloamine crystal form B;

[0012] 4) Establish a standard curve with the mass percentage of pyrimethanil cycloamine crystal form B as the x-axis and the intensity of the quantitative characteristic peak as the y-axis.

[0013] Preferably, in step 1), both the ground azoxystrobin crystal form A standard and the azoxystrobin crystal form B standard pass through an 80-mesh sieve.

[0014] Preferably, the mass percentage of pyraclostrobin crystal form B in the mixture in step 2) is selected from 20-95 wt%.

[0015] In a preferred embodiment, the mass percentages of pyraclostrobin crystal form B in the mixture of step 2) are 20.04 wt%, 29.99 wt%, 35.12 wt%, 39.86 wt%, 44.82 wt%, 50.02 wt%, 55.04 wt%, 59.95 wt%, 69.8 wt%, 74.58 wt%, 79.96 wt%, 84.8 wt%, 86.91 wt%, 89.84 wt%, and 94.83 wt%.

[0016] Preferably, step 3) uses an X-ray powder diffractometer with Cu rays as the diffraction source, λ = 0.154 nm, working voltage of 40 kV, working current of 15 mA, scanning angle range of 10-35°, scanning step size of 0.01°, and scanning speed of 1° / min.

[0017] Preferably, the linear equation of the standard curve constructed in step 4) is y = 450.72x - 115.31.

[0018] Beneficial effects of this invention:

[0019] This invention employs X-ray powder diffraction analysis to study the content of crystal form B in the crystalline form of pyraclostrobin pesticide. Compared to existing methods for quantitative analysis of pyraclostrobin crystal forms, this method directly quantifies crystal form B, which affects formulation stability, effectively avoiding the influence of impurities and amorphous substances, reducing systematic errors, and improving accuracy. Furthermore, this invention uses the absolute intensity method of X-ray powder diffraction analysis to study the content of crystal form B in the crystalline form of pyraclostrobin pesticide. Compared to methods using relative intensity methods for quantifying pyraclostrobin crystal forms, this absolute intensity method is more accurate and stable. This invention's method offers high accuracy, speed, and convenience in determining the content of crystal form B in the crystalline form of pyraclostrobin pesticide, effectively controlling the quality of pyraclostrobin pesticide and providing strong support for quality assurance of pyraclostrobin pesticide. Attached Figure Description

[0020] Figure 1 X-ray powder diffraction pattern of pyrimethanil cycloamine crystal form A.

[0021] Figure 2 Differential scanning calorimetry curve of pyrimethanil cycloamine crystal form A.

[0022] Figure 3 X-ray powder diffraction pattern of pyrimethanil cycloamine crystal form B.

[0023] Figure 4 Differential scanning calorimetry curve of pyrimethanil cycloamine crystal form B.

[0024] Figure 5 The standard curve is a correlation between the content of pyrimethanil cycloamine crystal form B and the absolute intensity of the quantitative characteristic peak.

[0025] Figure 6 The standard curve of the content of pyrimethanil cycloamine crystal form B and the relative intensity of the quantitative characteristic peak is shown. Detailed Implementation

[0026] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely for illustrative purposes and not for limiting the present invention. Therefore, any simple modifications to the present invention based on the method of the present invention are within the scope of protection claimed by the present invention.

[0027] There are no particular restrictions on the source of any raw materials used in this invention; they can be purchased from the market or prepared using conventional methods known to those skilled in the art.

[0028] Example 1

[0029] Sample preparation and selection of characteristic peaks:

[0030] 1) Instruments and testing conditions used: X-ray powder diffractometer, with Cu rays as the diffraction source, λ=0.154nm, Cu(40 kV, 15mA) (initial angle 2θ=10°, ending angle 2θ=35°, step 0.01°, scanning speed 1° / min); Differential scanning calorimetry (DSC) instrument: Mettler DSC3 differential thermal analyzer, temperature range: 30-300℃, heating rate: 10℃ / min.

[0031] 2) Sample Preparation: Take sample A (provided by Shandong Weifang Runfeng Chemical Co., Ltd.), grind it thoroughly until uniform, and pass it through an 80-mesh sieve. Collect the sieved sample to reduce detection errors caused by preferred orientation. Perform PXRD analysis on this sample. A characteristic peak at 13.600±0.2° is obvious, and there are no other diffraction peaks interfering with this peak at the corresponding position in the diffraction pattern of sample B (see [reference]). Figure 1 DSC detection showed only one absorption peak near 71.61℃ (see...). Figure 2 This sample was used as the standard for pure pyraclostrobin crystal form A. A pyraclostrobin crystal form B sample (provided by Shandong Weifang Runfeng Chemical Co., Ltd.) was taken, thoroughly ground until homogeneous, and passed through an 80-mesh sieve. The sieved sample was collected to reduce detection errors caused by preferred orientation. PXRD analysis was performed on this sample; a characteristic peak was clearly observed at 19.26±0.2°. Figure 3 DSC detection showed only one absorption peak near 76.33℃ (see...). Figure 4 This sample was used as a standard for pure pyrimethanil cycloamine crystal form B.

[0032] 3) Selection of characteristic peaks: Figure 1 X-ray diffraction pattern of pyrimethanil cycloamine crystal form A and Figure 3 By comparing the X-ray diffraction patterns of pyraclostrobin crystal form B, it was found that the characteristic peak of pyraclostrobin crystal form B at 2θ position of 19.26 ± 0.2° had no interference from other diffraction peaks at the corresponding position in the X-ray diffraction pattern of pyraclostrobin crystal form A, and this peak was the strongest diffraction peak of pyraclostrobin crystal form B. Therefore, 2θ = 19.26 ± 0.2° was selected as the quantitative characteristic peak of pyraclostrobin crystal form B, and the absolute intensity of this quantitative characteristic peak was used as the quantitative parameter.

[0033] Example 2

[0034] Plotting the standard curve:

[0035] Fourteen samples were prepared by adding azoxystrobin crystal form B to azoxystrobin crystal form A standard using an incremental method (containing 20.04 wt%, 29.99 wt%, 35.12 wt%, 39.86 wt%, 50.02 wt%, 55.04 wt%, 59.95 wt%, 69.8 wt%, 74.58 wt%, 79.96 wt%, 84.8 wt%, 86.91 wt%, 89.84 wt%, and 94.83 wt% of azoxystrobin crystal form B, respectively). After mixing by shaking in a ball mill, each sample was placed in a sample tray, and X-ray powder diffraction was measured. The mass percentage of azoxystrobin crystal form B was plotted on the x-axis, and the absolute peak intensity of the diffraction peak at 2θ position of 19.26 ± 0.2° was plotted on the y-axis (specific values ​​are shown in Table 1). A standard curve was plotted according to the least squares method, and the linear equation was obtained as y = 450.72x - 115.31 (R² = 0.9792), see Figure 5 The fact that R² is close to 1 indicates that the crystal content and intensity of this invention have a good linear relationship and high accuracy.

[0036] Table 1

[0037]

[0038] Example 3

[0039] Determination of detection limit and quantitation limit

[0040] Five samples (containing 0%, 0.4%, 0.8%, 1%, and 3% of azoxystrobin crystal form B, respectively) were prepared by adding azoxystrobin crystal form B to crystal form A using an equal incremental method. After mixing with a ball mill, the samples were prepared and X-ray powder diffraction was measured. The results showed that when the content of azoxystrobin crystal form B was less than 1%, no characteristic peak was detected. Therefore, the detection limit was 1% and the quantitation limit was 1%.

[0041] Comparative Example 1

[0042] Relative intensity quantitative determination method:

[0043] 1) Selection of characteristic peaks: The X-ray diffraction pattern of pyrimethanil cycloamine crystal form A (see...) Figure 1 X-ray diffraction patterns of ) and pyrimethanil cycloamine crystal form B (see) Figure 3 By comparison, it was found that the characteristic peak of pyraclostrobin crystal form B at 2θ position of 19.26±0.2° had no interference from other diffraction peaks at the corresponding position in the X-ray diffraction pattern of pyraclostrobin crystal form A, and this peak was the strongest diffraction peak of pyraclostrobin crystal form B. Therefore, 2θ=19.26±0.2° was selected as the quantitative characteristic peak of pyraclostrobin crystal form B, and the absolute intensity of this quantitative characteristic peak was used as the quantitative parameter.

[0044] 2) Selection of reference characteristic peaks: The X-ray diffraction pattern of pyrimethanil cycloamine crystal form A (see...) Figure 1 X-ray diffraction patterns of ) and pyrimethanil cycloamine crystal form B (see) Figure 3 By comparison, it was found that the characteristic peak of pyrimethanil cycloamine crystal form A at 2θ position of 13.600±0.2° had no interference from other diffraction peaks at the corresponding position in the X-ray diffraction pattern of pyrimethanil cycloamine crystal form B, and this peak was the strongest diffraction peak of pyrimethanil cycloamine crystal form A. Therefore, this characteristic peak was selected as the reference characteristic peak.

[0045] 3) Construction of the standard curve: Five samples were prepared by adding azoxystrobin crystal form B to azoxystrobin crystal form A standard using the equal incremental method (containing azoxystrobin crystal form B at concentrations of 83.01 wt%, 85.15 wt%, 87.23 wt%, 89.04 wt%, and 91.3 wt%, respectively). After mixing using a ball mill, each sample was placed in a sample tray, and the X-ray powder diffraction was measured. The relative intensity was calculated using the following formula: B Ⅱ = A Ⅱ / (A Ⅱ + A Ⅰ ), where B Ⅱ The relative intensity of crystal form B; A Ⅱ and A Ⅰ The absolute intensities of crystal form B at 2θ = 19.26 ± 0.2° and crystal form A at 2θ = 13.600 ± 0.2°, expressed as peak height, are respectively; the relative peak intensities of the diffraction peak at 2θ = 19.26 ± 0.2° are given by plotting the mass percentage of pyrimethanil crystal form B on the x-axis. Ⅱ Using the ordinate as the vertical axis, a standard curve is plotted according to the least squares method, yielding the linear equation y = 0.016x - 0.5542. (R0) 2 =0.9597), see Figure 6 R-squared of the fitted curve 2 The value was 0.9597, which is much lower than 0.9792, indicating a poor linear relationship between crystal form content and relative intensity, resulting in low accuracy. Parallel analysis of multiple sample preparations and tests on the same batch of samples with the same crystal form content showed unstable results and poor repeatability, making it impossible to provide limits of quantitation and detection.

Claims

1. A method for quantitatively determining crystal form B of a crystal form of cyprodinil pesticide, characterized by: The content of azoxycarb 1 crystal form B is determined by X-ray powder diffraction method, 2θ = 19.26 ± 0.2° is used as the quantitative characteristic peak of azoxycarb 1 crystal form B, the absolute intensity of the quantitative characteristic peak is used as the quantitative parameter, the standard curve of the content of azoxycarb 1 crystal form B and the intensity of the quantitative characteristic peak is established, and the content of azoxycarb 1 crystal form B in the sample is determined according to the standard curve.

2. The quantitative determination method according to claim 1, wherein The construction process of the standard curve includes: 1) azoxycarb 1 crystal form A standard and azoxycarb 1 crystal form B standard are taken respectively, and are fully ground and sieved; 2) the ground and sieved azoxycarb 1 crystal form A standard and azoxycarb 1 crystal form B standard are mixed to obtain a series of mixtures with different mass percentages of azoxycarb 1 crystal form B; 3) the mixtures in step (2) are respectively subjected to X-ray diffraction test to obtain the intensity of the quantitative characteristic peak of azoxycarb 1 crystal form B; 4) the standard curve is established with the mass percentage of azoxycarb 1 crystal form B as the abscissa and the intensity of the quantitative characteristic peak as the ordinate.

3. The quantitative assay method according to claim 2, wherein The ground azoxycarb 1 crystal form A standard and azoxycarb 1 crystal form B standard in step 1) are sieved through an 80-mesh sieve.

4. The quantitative determination method according to claim 2, characterized by The mass percentage of azoxycarb 1 crystal form B in the mixture in step 2) is selected from 20-95wt%.

5. The quantitative determination method according to claim 2, wherein The mass percentages of azoxycarb 1 crystal form B in the mixture in step 2) are 20.04wt%, 29.99wt%, 35.12wt%, 39.86wt%, 44.82wt%, 50.02wt%, 55.04wt%, 59.95wt%, 69.8wt%, 74.58wt%, 79.96wt%, 84.8wt%, 86.91wt%, 89.84wt%, and 94.83wt%, respectively.

6. The quantitative determination method according to claim 2, wherein In step 3), an X-ray powder diffractometer is used for testing, Cu ray is used as the diffraction source, λ = 0.154 nm, the working voltage is 40 kV, the working current is 15 mA, the angle range is 10-35°, the scanning step is 0.01°, and the scanning speed is 1° / min.

7. The quantitative measurement method according to claim 1 or 2, wherein The linear equation of the standard curve of the content of azoxycarb 1 crystal form B and the intensity of the quantitative characteristic peak is y = 450.72x-115.31.

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