阅读说明：本技术 一种非布司他晶型含量检测方法 (Febuxostat crystal form content detection method ) 是由 李川 郝英魁 陈蔚 穆彤 傅琳 于 2021-09-08 设计创作，主要内容包括：本发明提供了一种非布司他晶型A原料药中晶型G含量的检测方法。该方法通过粉末X-射线衍射方法建立相对于2种晶型的质量比的标准曲线,用于测定非布司他晶型A原料药中晶型G的含量。本方法快速简便,准确度较高。(The invention provides a method for detecting the content of a crystal form G in febuxostat crystal form A bulk drug. The method establishes a standard curve of mass ratio relative to 2 crystal forms by a powder X-ray diffraction method, and is used for determining the content of the crystal form G in the febuxostat crystal form A bulk drug. The method is rapid, simple and convenient and has high accuracy.)

1. A method for detecting the content of a crystal form G in a febuxostat crystal form A comprises the following steps:

(1) preparing standard samples of febuxostat crystal form A and crystal form G, and crushing and sieving the samples;

(2) mixing to prepare febuxostat standard samples with different crystal form ratios, performing powder X-ray diffraction measurement on the samples, reading the quantitative characteristic diffraction peak height ratio of febuxostat crystal form A to crystal form G, and establishing a standard curve taking the mass ratio of febuxostat crystal form A to crystal form G as a horizontal coordinate and the characteristic peak height ratio as a vertical coordinate;

(3) and determining the content of the crystal form G in the febuxostat crystal form A and crystal form G samples to be detected with unknown crystal form proportion through a standard curve.

2. The detection method according to claim 1, characterized in that: the ratio of the different crystal forms in the step (2) is that the ratio of the febuxostat crystal form A to the febuxostat crystal form G is from 100:1 to 100: 20.

3. The detection method according to claim 1, characterized in that: the mixing and preparing of the febuxostat standard samples with different crystal form proportions in the step (2) is to place the febuxostat standard samples with different crystal forms in a penicillin bottle, and mix the samples evenly by swirling for 30 min.

4. The detection method according to claim 1, characterized in that: the 2 theta-12.84 +/-0.04 DEG is selected as a quantitative characteristic peak of the febuxostat crystal form A, and the 2 theta-4.81 +/-0.03 DEG is selected as a quantitative characteristic peak of the febuxostat crystal form G.

5. The detection method according to claim 1, characterized in that: when powder X-ray diffraction measurement is carried out, Kalpha rays of a copper target are used as a diffraction source, the working voltage is set to be 40kV, the working current is 40mA, the step length is 0.01 degrees, the scanning speed is 3 degrees/min, the divergence slit is 0.5 degrees, and the width of the receiving slit is 20 mm.

6. The detection method according to claim 1, characterized in that: when the febuxostat crystal form A is measured, the scanning range is 3-14 degrees; when the febuxostat crystal form G is determined, the scanning range is 4-5.2 degrees.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a method for detecting febuxostat crystal form content.

Background

Febuxostat (Febuxostat) is a selective xanthine oxidase/xanthine dehydrogenase inhibitor, and is suitable for long-term treatment of hyperuricemia with gout symptoms. Febuxostat has excellent activity and fewer side effects, is eliminated through double channels of liver and kidney, and has good safety for people with renal insufficiency.

Polymorphism of chemical drug substances may affect bioequivalence and bioavailability of oral drugs. Febuxostat has polymorphism, and the crystal form a is usually used as a raw material drug for preparation development. The crystal form A is a metastable crystal form, is easy to absorb water in the preparation process and is converted into a hemihydrate crystal form G. Form G has a somewhat reduced solubility relative to the main form a, the presence of which affects the quality of the oral formulation. Therefore, the control of the content of the crystal form G in the febuxostat crystal form A is necessary.

The current analysis methods for characterizing polymorphs mainly include X-ray diffraction methods, thermal analysis methods, infrared spectroscopy, microscopic analysis methods, and the like. Among them, X-ray diffraction is the accepted authoritative method for crystal form research and can provide the most accurate crystal structure information. Depending on the sample to be measured by X-ray diffraction, there are single crystal X-ray diffraction and powder X-ray diffraction. A single crystal X-ray diffraction method features that a monochromatic X-ray whose wavelength is same as the primary spacing in crystal is incident on the crystal, the X-rays scattered by different atoms in the crystal interfere with each other to generate strong X-ray diffraction in some specific directions, and the information about size, shape and position of crystal cell can be deduced according to the distribution rule and intensity of the diffraction ray. Different crystals will produce different diffraction signals. However, there is a limitation in use due to the difficulty in preparing single crystals. The powder X-ray diffraction method has lower requirements on samples, and is widely used in the fields of detecting the crystal purity of a compound, the crystal stability, identifying the content of raw materials in a pharmaceutical preparation, identifying crystal form change and the like. The content of the crystal form G in the febuxostat raw material crystal form A is determined by a powder X-ray diffraction method. By optimizing the measuring conditions and controlling the scanning speed and the scanning range, the method can quickly and accurately complete the measurement and has the characteristics of low sensitivity and high accuracy.

Disclosure of Invention

The invention aims to provide a rapid detection method for the content of crystal form G in febuxostat crystal form A.

The purpose of the invention is realized by the following technical scheme:

a method for detecting the content of a crystal form G in a febuxostat crystal form A comprises the following steps:

(1) preparing standard samples of febuxostat crystal form A and crystal form G, and crushing and sieving the samples;

(2) mixing to prepare febuxostat standard samples with different crystal form ratios, performing powder X-ray diffraction measurement on the samples, reading the quantitative characteristic diffraction peak height ratio of febuxostat crystal form A to crystal form G, and establishing a standard curve taking the mass ratio of febuxostat crystal form A to crystal form G as a horizontal coordinate and the characteristic peak height ratio as a vertical coordinate;

(3) and determining the content of the crystal form G in the febuxostat crystal form A and crystal form G samples to be detected with unknown crystal form proportion through a standard curve.

Further, the ratio of the different crystal forms in the step (2) is that the ratio of the febuxostat crystal form A to the febuxostat crystal form G is from 100:1 to 100: 20.

Further, the mixing and preparing of the febuxostat standard samples with different crystal form proportions in the step (2) is to place the febuxostat standard samples with different crystal forms in a penicillin bottle, and uniformly mix the febuxostat standard samples by vortex for 30 min.

Furthermore, in the detection method, 2 theta is 12.84 +/-0.04 degrees and is selected as a quantitative characteristic peak of febuxostat crystal form A, and 2 theta is 4.81 +/-0.03 degrees and is selected as a quantitative characteristic peak of febuxostat crystal form G.

Furthermore, when the powder X-ray diffraction measurement is carried out, the K alpha ray of a copper target is used as a diffraction source, the working voltage is set to be 40kV, the working current is 40mA, the step length is 0.01 degrees, the scanning speed is 3 degrees/min, the divergence slit is 0.5 degrees, and the width of the receiving slit is 20 mm.

Further, when the detection method is used for determining the febuxostat crystal form A, the scanning range is 3-14 degrees; when the febuxostat crystal form G is determined, the scanning range is 4-5.2 degrees.

Drawings

FIG. 1X-ray diffraction diagram of febuxostat crystal form A powder

FIG. 2X-ray diffraction diagram of febuxostat crystal form G powder

FIG. 3 shows characteristic diffraction peaks of a febuxostat crystal form A and a crystal form G after the mixture of the crystal form A and the crystal form G according to the ratio of 100:0.3

FIG. 4 shows characteristic diffraction peaks of a febuxostat crystal form A and a crystal form G after the mixture of the crystal form A and the crystal form G according to a ratio of 100:1

Detailed Description

Example 1:

preparation of samples and characteristic peak selection

(1) Instruments and measurement conditions:

an experimental instrument: rigaku Smartlab 3kW powder X-ray diffractometer;

the instrument parameters are as follows: the working voltage is 40kV, the working current is 40mA, the step length is 0.01 degrees, the scanning speed is 10 degrees/min, the divergence slit is 0.5 degrees, the width of the receiving slit is 20mm, and the scanning range is 3-40 degrees.

(2) Sample preparation: febuxostat crystal form a and crystal form G samples were prepared by tianjintaipu pharmaceuticals, inc. Taking appropriate amount of febuxostat crystal form A and crystal form G samples respectively, crushing, and separating by using a 100-mesh detection sieve.

(3) And (3) spectrogram determination: and spreading the sample on a sample slide, setting instrument parameters, and performing powder X-ray diffraction measurement on the sample.

(4) Selecting a characteristic peak: the acquired spectrums of the febuxostat crystal form A and the febuxostat crystal form G are consistent with the standard sample spectrum, and the febuxostat crystal form A and the febuxostat crystal form G can be used as a standard sample. The powder X-ray diffraction pattern of febuxostat crystal form A is compared with the powder diffraction pattern of febuxostat crystal form G, the highest diffraction peak (2 theta is 12.84 +/-0.04 DEG) of febuxostat crystal form A is not interfered by febuxostat crystal form G, and the X-ray diffraction pattern can be used as a quantitative characteristic peak of febuxostat crystal form A. The G-th order high diffraction peak (2 theta is 4.81 +/-0.03 ℃) of the febuxostat crystal form is not interfered by the febuxostat crystal form A, and can be used as a quantitative characteristic peak of the febuxostat crystal form G.

The optimized scanning speed is 3 degrees/min. The acquisition range of the optimized febuxostat crystal form A is 3-14 degrees, and the acquisition range of the optimized febuxostat crystal form G is 4-5.2 degrees.

Example 2:

detection limit and quantification limit

Weighing febuxostat crystal form A standard sample and febuxostat crystal form G standard sample into a penicillin bottle according to the ratio of 100:0.3, and mixing for 30min in a vortex manner to obtain a mixed sample with the ratio of febuxostat crystal form A to febuxostat crystal form G of 100: 0.3. The sample is laid on a glass slide and placed into an instrument for detection, the working voltage is set to be 40kV, the working current is set to be 40mA, the step length is 0.01 degrees, the scanning speed is 3 degrees/min, the divergence slit is 0.5 degrees, the width of the receiving slit is 20mm, the scanning range is 4-5.2 degrees, and the diffraction peak intensity of the febuxostat crystal form G is 3 times of the intensity of the measured noise. The detection limit of the method is that the content of the febuxostat crystal form G in the sample is 0.3 percent of that of the crystal form A.

Weighing febuxostat crystal form A standard sample and febuxostat crystal form G standard sample into a penicillin bottle according to the ratio of 100:1, and mixing for 30min in a vortex manner to obtain a mixed sample with the ratio of febuxostat crystal form A to febuxostat crystal form G of 100: 1. The sample is laid on a glass slide and placed into an instrument for detection, the working voltage is set to be 40kV, the working current is set to be 40mA, the step length is 0.01 degrees, the scanning speed is 3 degrees/min, the divergence slit is 0.5 degrees, the width of the receiving slit is 20mm, the scanning range is 4-5.2 degrees, and the peak intensity of the diffraction peak of the febuxostat crystal form G is 10 times of the intensity of the measured noise. The quantitative limit of the method is that the content of febuxostat crystal form G in the sample is 1 percent of that of the crystal form A.

Example 3:

drawing of standard curve

Respectively weighing standard samples of the crystal form A and the crystal form G of the febuxostat into a penicillin bottle, controlling the total mass to be the same, and respectively controlling the mass ratio of the crystal form A to the crystal form G to be 100:1, 100:3, 100:5, 100:8, 100:10, 100:15 and 100: 20. Vortex the weighed febuxostat sample for 30min and mix well. The mixed samples are laid on a glass slide and flattened, 3 samples are prepared by mixing the samples according to each proportion, the samples are placed on an X-ray diffractometer for detection, the working voltage is set to be 40kV, the working current is 40mA, the step length is 0.01 degrees, the scanning speed is 3 degrees/min, the divergence slit is 0.5 degrees, the width of the receiving slit is 20mm, the scanning range is 3-14 degrees, and the characteristic diffraction peak intensity of the febuxostat crystal form A is determined. The scanning range is 4-5.2 degrees, and the febuxostat crystal form G characteristic diffraction peak intensity is determined. Taking the mass ratio of the 2 crystal forms as an abscissa and the characteristic peak intensity ratio of the 2 crystal forms as an ordinate, and drawing a standard curve by using a least square method to obtain a linear equation of y-0.3749 x +0.0769, R²The linear relationship was good at 0.997.

Example 4:

repeatability and accuracy survey

Respectively weighing standard samples of the crystal form A and the crystal form G of the febuxostat into a penicillin bottle, and controlling the total mass of the weighed samples to be consistent, wherein the mass ratio of the crystal form A to the crystal form G is 100:3, 100:8 and 100:15 respectively. Vortex for 30min and mix well. The test sample is respectively used as a quality control sample with three mixing ratios of low, medium and high, 6 detection samples are prepared in each ratio, the working voltage is set to be 40kV, the working current is 40mA, the step length is 0.01 degrees, the scanning speed is 3 degrees/min, the divergence slit is 0.5 degrees, the width of the receiving slit is 20mm, febuxostat crystal form A and crystal form G are respectively scanned, the characteristic diffraction peak intensity ratio is obtained by reading and calculating, the measured mass ratio of the crystal form A and the crystal form G is calculated by utilizing a standard linear curve, and the repeatability and the recovery rate are calculated according to the actual weighing mass. The low mixing ratio recovery rate was 113.3% (RSD ═ 13.24%, and n ═ 6), the medium mixing ratio recovery rate was 98.17% (RSD ═ 8.21%, and n ═ 6), and the high mixing ratio recovery rate was 106.8% (RSD ═ 4.34%, and n ═ 6). The recovery rates of the mixture with the low, medium and high proportions are all within 100 +/-15 percent, the RSD is less than 15 percent, and the recovery rate and the repeatability are good.

Example 5:

stability of

The repetitive sample prepared in example 4 was placed in a desiccator, and placed in an X-ray diffractometer for detection 1 day and 2 days after the sample preparation, respectively, with a working voltage of 40kV, a working current of 40mA, a step size of 0.01 °, a scanning speed of 3 °/min, a divergence slit of 0.5 °, a width of a receiving slit of 20mm, and scanning ranges of 3 ° to 14 ° and 4 ° to 5.2 °, respectively. And reading the characteristic diffraction peak intensities of the febuxostat crystal form A and the febuxostat crystal form G, and calculating stability data through a standard curve. Specific results are shown in the following table. It can be seen that the sample is placed in a dryer after being prepared, the recovery rate of the sample with the low, medium and high mixing ratio is changed by no more than 2%, the RSD result is stable, and the stability of the prepared sample is good.

Table 1 stability sample desiccator left for 2 days recovery change