Rapid crystal form identification method of probucol

Abstract

The invention discloses a rapid probucol crystal form identification method which comprises the following steps: step 1, taking potassium bromide, drying, and pressing a potassium bromide blank sheet; 2, adding probucol crystal powder to be detected, lightly grinding and uniformly mixing the probucol crystal powder and potassium bromide powder for not more than 2 minutes, and tabletting; step 3, acquiring an infrared spectrum; and comparing with a probucol crystal form infrared spectrum obtained in advance to obtain the crystal form of the probucol crystal to be detected. The inventor finds that infrared spectrum is adopted to detect the crystal form I or the crystal form II of a single probucol crystal, obtained spectrums are obviously different in three positions, and the two crystal forms can be distinguished. Potassium bromide and probucol crystals are mixed and ground, the crystal form I is partially converted into the crystal form II, and the infrared spectrum is different from that of the two crystals and can be distinguished. Based on the discovery, the invention provides two crystal forms of the probucol crystal and a standard infrared spectrum of a mixture of the two crystal forms, so that the probucol crystal forms can be quickly identified.

Description

Technical Field

[0001] The invention relates to a rapid crystal form identification method of probucol. Background Art

[0002] Probucol is a lipid-lowering drug. In recent years, the sales of probucol tablets have exceeded 100 million, and research literature has increased rapidly. Probucol is a BSCII drug and is insoluble in water, resulting in a bioavailability of less than 20% for its tablets. Crystal form is an important factor affecting solubility. According to literature reports, probucol has three crystal forms, among which crystal form III is unstable and mechanically pressure-sensitive, and will transform into crystal form II when placed at room temperature. Therefore, the common crystal forms are crystal form I and crystal form II.

[0003] Although infrared spectroscopy has been used to identify compounds, it is rarely used for crystal analysis of compounds. The reason is that infrared spectroscopy is usually insensitive to the crystal forms of most compounds and cannot distinguish different crystal forms of common compounds. There are currently few literature studies on the crystal forms of probucol, which can be identified by single crystal X-ray diffraction, powder X-ray diffraction and differential scanning calorimetry. However, the above instruments are relatively expensive and have high technical requirements for operation, and lack simple and rapid methods for crystal form identification.

[0004] There is no report on infrared spectroscopy identification of probucol crystal forms. Summary of the invention

[0005] The main purpose of the present invention is to provide a method for rapid crystal form identification of probucol.

[0006] The technical solution adopted by the present invention to solve its technical problem is:

[0007] A method for rapid crystal form identification of probucol comprises the following steps:

[0008] Step 1, taking potassium bromide, drying, removing moisture, grinding into fine powder, and pressing potassium bromide blank tablets;

[0009] Step 2, add the probucol test crystal powder, gently grind and mix with potassium bromide powder for no more than 2 minutes, and compress into tablets;

[0010] Step 3, collecting infrared spectra; comparing with the infrared spectra of the probucol crystal form obtained in advance, obtaining the crystal form of the probucol crystal to be tested; wherein, the absorption peak characteristics of the spectrum of crystal form I are 3627cm -1 , 1151cm -1 、1137cm -1 、1121cm -1 、1098cm -1 , 642cm -1 、604cm -1; Absorption peak characteristics of crystal form II spectrum; respectively 3546cm -1 , 1121cm -1 ,1101cm -1 , 620cm -1 ; The infrared spectrum parameters were set as follows during measurement: spectral range 4000cm -1 ~400cm -1 , scanning resolution 4cm -1 , cumulative amount 15 seconds, if 3546cm -1 There is no absorption peak, which is Form I; if there is 3546cm -1 There is an absorption peak, but there is no 1121cm -1 、1101cm -1 , 620cm -1 If there are two characteristic absorption peaks, it is Form I mixed with Form II; if there is 3546cm -1 , 1121cm -1 、1101cm -1 , 620cm -1 Three characteristic absorption peaks are crystal form II.

[0011] The infrared spectrum of the probucol crystal form obtained in advance in step 3 is obtained by mixing the probucol crystal form I or II with potassium bromide or potassium chloride powder in a mass ratio of 1: (50-200) and detecting the infrared spectrum. The mixing time is no more than 2 minutes (preferably within 1 minute), and the spectral range is 4000cm -1 ~400cm -1 , scanning resolution 4cm -1 , cumulative amount 15 seconds.

[0012] Furthermore, in step 2, the mass ratio of probucol crystals to potassium bromide powder is 1:(50-200).

[0013] Furthermore, in step 2, the grinding time does not exceed 2 minutes.

[0014] Furthermore, the mixing is carried out at room temperature. In the present invention, the "room temperature" refers to the normal ambient temperature, which can be 0°C to 35°C, preferably 5°C to 30°C.

[0015] Compared with the background technology, this technical solution has the following advantages:

[0016] 1. The inventor unexpectedly discovered that the infrared spectrum of Form I or Form II of probucol crystals alone collected by direct measurement method has insufficient resolution and cannot be distinguished; after being pressed into tablets together with potassium bromide, the two forms can be distinguished by infrared spectrum detection. Form I is co-grinded with potassium bromide, and part of Form I is converted into Form II. The infrared spectrum of the mixture is different from the above two forms and can be distinguished. Based on this unexpected discovery, the present invention provides standard infrared spectra of two forms of probucol crystals and a mixed form. Thereby, infrared identification of crystal forms can be performed quickly. Compared with single crystal X-ray diffraction, powder X-ray diffraction and differential scanning calorimeter, infrared identification technology has lower requirements and is easier to operate.

[0017] 2. The mixing ratio of potassium bromide and probucol crystals is within the mass ratio range of 1:(50-200), and the differentiation effect is the best, which can be used as a standard spectrum.

[0018] 3. The present invention also found that the grinding, mixing and detection time with potassium bromide need to be within 2 minutes (preferably within 1 minute), otherwise the crystal form will be transformed, affecting the detection results. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The present invention will be further described below in conjunction with the accompanying drawings and embodiments.

[0020] Figure 1 This is the infrared spectrum of Probucol Form I in Example 1.

[0021] Figure 2 This is the infrared spectrum of Probucol Crystal II in Example 1.

[0022] Figure 3 This is the infrared spectrum of Probucol crystal form I after it is partially converted into crystal II. DETAILED DESCRIPTION

[0023] Raw materials: Probucol crystals were sourced from a domestic manufacturer, and the crystal form was I (the crystal form had been previously identified by data from three instruments).

[0024] The following examples and comparative examples all adopt manual grinding. Instrument: Perkin Elmer FI-IR Spectrometer.

[0025] Example 1

[0026] Take potassium bromide, dry it, remove the water, grind it into fine powder in an agate mortar, and press a potassium bromide blank tablet;

[0027] Add probucol form I crystal powder in a probucol:potassium bromide mass ratio of 1:100, grind gently to mix with potassium bromide powder, the grinding and mixing time shall not exceed 1 minute, and tablets are pressed.

[0028] Add probucol form II crystal powder in a probucol:potassium bromide mass ratio of 1:100, grind gently to mix with potassium bromide powder, the grinding and mixing time should not exceed 1 minute, and press into tablets.

[0029] Collect infrared spectrum. The infrared spectrum parameters are set as follows: spectral range 4000cm -1 ~400cm -1 , scanning resolution 4cm-1, accumulation time 15 seconds.

[0030] The spectrum of Probucol Form I is shown in Figure 2 , Probucol Crystal II see Figure 3 , there is a clear difference between the two.

[0031] Example 2

[0032] Take potassium bromide, dry it, remove the water, grind it into fine powder in an agate mortar, and press a potassium bromide blank tablet;

[0033] Add probucol form I crystal powder in a probucol:potassium bromide mass ratio of 1:50, grind gently and mix with potassium bromide powder for no more than 1 minute, and compress into tablets.

[0034] Add probucol form II crystal powder in a mass ratio of probucol to potassium bromide of 1:50, grind gently and mix with potassium bromide powder for no more than 1 minute, and compress into tablets.

[0035] Collect infrared spectrum. The infrared spectrum parameters are set as follows: spectral range 4000cm -1 ~400cm -1 , scanning resolution 4cm-1, accumulation time 15 seconds.

[0036] There are obvious differences in the spectra between probucol Form I and Form II.

[0037] Example 3

[0038] Take potassium bromide, dry it, remove the water, grind it into fine powder in an agate mortar, and press a potassium bromide blank tablet;

[0039] Add probucol form I crystal powder in a probucol:potassium bromide mass ratio of 1:200, grind gently and mix with potassium bromide powder for no more than 1 minute, and compress into tablets.

[0040] Add probucol form II crystal powder in a probucol:potassium bromide mass ratio of 1:200, grind gently and mix with potassium bromide powder for no more than 1 minute, and compress into tablets.

[0041] Collect infrared spectrum. The infrared spectrum parameters are set as follows: spectral range 4000cm-1 ~400cm -1 , scanning resolution 4cm -1 , cumulative amount 15 seconds.

[0042] There are obvious differences in the spectra between probucol Form I and Form II.

[0043] Example 4

[0044] Take potassium chloride, dry it, remove the water, grind it into fine powder in an agate mortar, and press a blank piece of potassium bromide;

[0045] Add probucol form I crystal powder in a probucol:potassium chloride mass ratio of 1:100, grind gently and mix with potassium bromide powder for no more than 1 minute, and compress into tablets.

[0046] Add probucol form II crystal powder in a probucol:potassium chloride mass ratio of 1:100, grind gently and mix with potassium bromide powder for no more than 1 minute, and compress into tablets.

[0047] Collect infrared spectrum. The infrared spectrum parameters are set as follows: spectral range 4000cm -1 ~400cm -1 , scanning resolution 4cm -1 , cumulative amount 15 seconds.

[0048] There are obvious differences in the spectra between probucol Form I and Form II.

[0049] Comparative Example 1

[0050] The infrared spectra of pure probucol crystal form I and II were collected by direct measurement. The infrared spectra parameters were set as follows: spectral range 4000~400cm -1 , scanning resolution 4cm -1 , 15 seconds of accumulation. The spectrum resolution is not enough to distinguish.

[0051] Comparative Example 2

[0052] Take potassium bromide, dry it, remove the water, grind it into fine powder in an agate mortar, and press a potassium bromide blank tablet;

[0053] Add probucol form I crystal powder in a probucol:potassium bromide mass ratio of 1:20, grind gently and mix with potassium bromide powder for no more than 1 minute, and compress into tablets.

[0054] Add probucol form II crystal powder in a mass ratio of probucol to potassium bromide of 1:20, grind gently and mix with potassium bromide powder for no more than 1 minute, and compress into tablets.

[0055] Collect infrared spectrum. The infrared spectrum parameters are set as follows: spectral range 4000cm -1 ~400cm -1 , scanning resolution 4cm-1, accumulation time 15 seconds.

[0056] There are differences between the spectra of Form I and Form II, but they are not sufficient to serve as standard spectra.

[0057] Comparative Example 3

[0058] Take potassium bromide, dry it, remove the water, grind it into fine powder in an agate mortar, and press a potassium bromide blank tablet;

[0059] Add probucol form I crystal powder in a probucol:potassium bromide mass ratio of 1:300, grind gently and mix with potassium bromide powder for no more than 1 minute, and compress into tablets.

[0060] Add probucol form II crystal powder in a probucol:potassium bromide mass ratio of 1:300, grind gently and mix with potassium bromide powder for no more than 1 minute, and compress into tablets.

[0061] Collect infrared spectrum. The infrared spectrum parameters are set as follows: spectral range 4000cm -1 ~400cm -1 , scanning resolution 4cm-1, accumulation time 15 seconds.

[0062] There are differences between the spectra of Form I and Form II, but they are not sufficient to serve as standard spectra.

[0063] Comparative Example 4

[0064] Take potassium bromide, dry it, remove the water, grind it into fine powder (no graininess) in an agate mortar, and take a portion of the potassium bromide powder to press a potassium bromide blank tablet;

[0065] The probucol crystals were first ground into powder separately, and then the probucol crystal powder was immediately added to another portion of potassium bromide powder in a ratio of probucol to potassium bromide of 1:100, and gently ground to mix the probucol crystal powder and potassium bromide powder. The mixing and grinding time was 2 min, 4 min, 6 min, 8 min, 10 min, 22 min, and 30 min, respectively, and samples were taken and tablets were pressed.

[0066] Collect infrared spectrum. The infrared spectrum parameters are set as follows: spectral range 4000cm -1 ~400cm -1 , scanning resolution 4cm-1, accumulation time 15 seconds.

[0067] After 2 minutes of mixing and grinding, no obvious absorption peak was observed. After 4 minutes of mixing and grinding, the characteristic absorption peak of Form II could be observed. After 4 minutes of mixing and grinding, part of the crystals had been transformed into Form II. The spectrum is shown in the figure. Figure 3 As shown in the figure, from the grinding time, the longer the grinding time, the stronger the signal of Form 2, which means the conversion rate is getting higher and higher.

[0068] See Example 1, the spectrum of Probucol Form I is as follows Figure 1 The spectrum of Probucol Form II is shown in Figure 2 There are three obvious differences between the two: Crystal II has a peak at 3546cm -1 There is one more peak at 1098cm -1 ~1121cm -1 There are only two obvious absorption peaks in the spectrum of crystal form II, while there are four strong absorption peaks in the spectrum of crystal form I; -1 ~643cm -1 In the spectrum of Form II, only 620 cm -1 One peak, while Form I has three absorption peaks, the difference is significant and very easy to identify.

[0069] These two crystal forms can be converted into each other. According to Comparative Example 4, crystal I was ground with potassium bromide. After 4 minutes, part of the crystal was converted into crystal II. The spectrum is as follows: Figure 3 As shown in the figure, compared with the spectrum of crystal Ⅰ, there is an additional 3546cm -1 The absorption peak is consistent with that of crystal Ⅰ elsewhere.

[0070] The above comparative examples and examples illustrate the results.

[0071] Direct determination of Form I or Form II of probucol crystals using infrared spectroscopy detection cannot distinguish between the two forms.

[0072] When potassium bromide and probucol crystals are mixed, the infrared spectra of Form I or Form II are obviously different and can be distinguished.

[0073] The mixing ratio of potassium bromide and probucol crystals is within the mass ratio range of 1:(50-200), and the differentiation effect is the best, which can be used as a standard spectrum.

[0074] If potassium bromide is used to co-grind probucol crystals, the grinding and detection time needs to be within 2 minutes, preferably within 1 minute, otherwise the crystal forms will transform into each other, affecting the test results.

[0075] The above description is only a preferred embodiment of the present invention, and therefore cannot be used to limit the scope of the present invention. That is, equivalent changes and modifications made according to the patent scope of the present invention and the contents of the specification should still fall within the scope of the present invention.

Claims

1. A method for rapid crystal identification of probucol, comprising the following steps: Step 1, taking potassium bromide, drying, removing moisture, grinding into fine powder, and pressing potassium bromide blank tablets; Step 2, add the probucol test crystal powder, grind it gently with potassium bromide powder, mix it evenly, the grinding time does not exceed 2 minutes, and press it into tablets; Step 3, collecting infrared spectrum; comparing with the infrared spectrum of the probucol crystal form obtained in advance, to obtain the crystal form of the probucol crystal to be tested; wherein, The absorption peak characteristics of the spectrum of Form I are 3627cm -1 , 1151cm -1 、1137cm -1 、1121cm -1 、1098cm -1 , 642cm -1 、604cm -1 ; The absorption peak characteristics of the crystal form II spectrum are 3546cm -1 , 1121cm -1 ,1101cm -1 , 620cm -1 ; The infrared spectrum parameters were set as follows during measurement: spectral range 4000cm -1 ~400cm -1 , scanning resolution 4cm -1 , cumulative amount 15 seconds, if 3546cm -1 There is no absorption peak, which is Form I; if there is 3546cm -1 There is an absorption peak, but there is no 1121cm -1 ~1101cm -1 , 620cm -1 If there are two characteristic absorption peaks, it is Form I mixed with Form II; if there is 3546cm -1 , 1121cm -1 ~1101cm -1 , 620cm -1 Three characteristic absorption peaks are crystal form II.

2. The method for rapid crystal form identification of probucol according to claim 1, characterized in that: The infrared spectrum of the probucol crystal form obtained in advance in step 3 is obtained by mixing probucol crystal form I or form II with potassium bromide powder in a mass ratio of 1: (50-200) and then detecting the infrared spectrum.

3. The method for rapid crystal identification of probucol according to claim 1, characterized in that: In step 2, the mass ratio of probucol crystals to potassium bromide powder is 1:(50-200).

4. The method for rapid crystal identification of probucol according to claim 1, characterized in that: In step 2, the grinding time does not exceed 2 minutes.

5. The method for rapid crystal identification of probucol according to claim 1, characterized in that: Mix at room temperature.

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