Crystal form transformation method of probucol
By mixing the Probuco crystals and potassium bromide, the Probuco crystal form I was successfully converted into the Probuco crystal form II, which solved the problem of low bioavailability of Probuco tablets and significantly improved its solubility.
Patent Information
- Application Number
- CN202411517080.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-29
- Publication Date
- 2025-02-07
AI Technical Summary
Probuco tablets have low bioavailability, mainly because they are insoluble in water, which leads to an important impact on solubility. It is difficult for the prior art to effectively transform its unstable crystal form III and uncommon crystal form II.
By mixing the Probuco crystal with potassium bromide, the specific steps include mixing the Probuco crystal with potassium bromide powder in a certain proportion at room temperature and grinding for 4 to 30 minutes, the Probuco crystal can be grounded in a certain proportion at room temperature, Form I is converted to Form II.
This method effectively improves the solubility and bioavailability of Probuco. Through infrared spectroscopy, it can be clearly seen that the crystal form changes from I to II, and the conversion rate increases with the increase of grinding time.
Smart Images
Figure CN119390629A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a crystal form conversion 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. Summary of the invention
[0003] The main purpose of the present invention is to provide a method for crystal transformation of probucol.
[0004] The technical solution adopted by the present invention to solve its technical problem is:
[0005] A method for converting the crystal form of probucol: Probucol crystals are mixed with potassium bromide and ground for a sufficient time, so that the probucol crystal form I can be converted into the crystal form II.
[0006] Furthermore, the potassium bromide is powder.
[0007] Furthermore, the mass ratio of probucol crystals to potassium bromide powder is 1:(50-200).
[0008] Further, the potassium bromide powder is dried before mixing.
[0009] 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.
[0010] Furthermore, the mixing and grinding time is 4 min to 30 min, preferably 10 min to 30 min.
[0011] The present invention also provides the use of potassium bromide in the crystal form transformation of probucol, wherein the crystal form transformation is to transform the probucol crystal form I into the crystal form II.
[0012] Furthermore, the probucol crystals are mixed and ground with potassium bromide to convert the probucol crystal form I into the crystal form II.
[0013] The grinding described in the present invention is preferably manual grinding.
[0014] Compared with the background technology, this technical solution has the following advantages:
[0015] The inventor unexpectedly discovered that by mixing potassium bromide and probucol crystals and grinding them together, probucol crystal form I can be converted to crystal form II. The characteristic absorption peak of crystal form II can be seen after 4 minutes of mixing and grinding, indicating that the crystal form begins to change from crystal form I to crystal form II. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The present invention will be further described below in conjunction with the accompanying drawings and embodiments.
[0017] Figure 1 This is the infrared spectrum of Probucol Form I.
[0018] Figure 2 This is the infrared spectrum of Probucol Crystal II.
[0019] Figure 3 This is the infrared spectrum of Probucol crystal form I after it is partially converted into crystal II.
[0020] Figure 4 The infrared spectra of Probucol Form I and potassium bromide at different grinding and mixing times are shown in Figure 1. A to G are 2 min, 4 min, 6 min, 8 min, 10 min, 22 min, and 30 min, respectively. DETAILED DESCRIPTION
[0021] Raw materials: Probucol crystals are sourced from a domestic manufacturer, and the crystal form is Type I (the crystal form has been identified in advance by data from three instruments).
[0022] The following examples and comparative examples all adopt manual grinding. Instrument: Perkin Elmer FI-IR Spectrometer.
[0023] Example 1
[0024] 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;
[0025] The probucol crystals were first ground into powder separately, and then the probucol crystal powder was immediately added to another part of the ground potassium bromide powder in a probucol:potassium bromide mass ratio 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 the samples were taken and tableted.
[0026] 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.
[0027] Example 2
[0028] 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;
[0029] The probucol crystals were first ground into powder separately, and then the probucol crystal powder was immediately added to another part of the ground potassium bromide powder in a probucol:potassium bromide mass ratio of 1:50. The powder was gently ground to mix the probucol crystal powder and the 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 the samples were taken and tableted.
[0030] 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.
[0031] Example 3
[0032] 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;
[0033] The probucol crystals were first ground into powder separately, and then the probucol crystal powder was immediately added to another part of the ground potassium bromide powder at a probucol:potassium bromide mass ratio of 1:200. The powder was gently ground to mix the probucol crystal powder and the 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 the samples were taken and tableted.
[0034] Collect infrared spectrum. The infrared spectrum parameters are set as follows: spectral range 4000~400cm -1 , scanning resolution 4cm -1 , cumulative amount 15 seconds.
[0035] The spectrum of Probucol Form I is as follows Figure 1 The spectrum of Probucol Form II is shown in Figure 2 Compared with the two, there are three obvious differences in absorption: Crystal II at 3546cm -1 One more absorption 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 Strong absorption peak, while Form I has three absorption peaks, with significant differences, which is very easy to identify.
[0036] The two crystal forms can be mutually converted. According to Example 1, Crystal I was mixed and ground with potassium bromide to form tablets. After mixing and grinding for 2 minutes, samples were taken. The results were 3546 cm -1 There is no obvious absorption peak at 3546cm, and after 4 minutes of mixing and grinding, the absorption peak at 3546cm -1 A small absorption peak at 3546 cm-1 after 6 minutes of mixing and grinding -1 The peak intensity is higher, and part of crystal I has been transformed into crystal II. Figure 3 As shown in the figure, from the grinding time, the longer the grinding time, the higher the peak value of Form II at 3546cm -1 The stronger the signal, the higher the conversion rate.
[0037] Comparative Example 1
[0038] Probucol crystals in Form I were gently ground into powder, and samples were taken after grinding for different times and pressed into tablets.
[0039] 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.
[0040] Sampling was performed every 2 minutes, and the spectrum did not change until 30 minutes, which means that Form I did not transform into Form II when ground alone.
[0041] 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 converting the crystal form of probucol, characterized in that: Probucol Form I can be converted into Form II by mixing and grinding probucol crystals with potassium bromide.
2. The method for crystal transformation of probucol according to claim 1, characterized in that: The potassium bromide is powder.
3. The method for crystal transformation of probucol according to claim 2, characterized in that: The mass ratio of probucol crystals to potassium bromide powder is 1:(50-200).
4. The method for crystal transformation of probucol according to claim 3, characterized in that: Potassium bromide powder was dried before mixing.
5. The method for crystal transformation of probucol according to claim 1, characterized in that: The mixing and grinding is carried out at room temperature.
6. The method for crystal transformation of probucol according to claim 1, characterized in that: The mixing and grinding time is 4 minutes to 30 minutes.
7. The method for crystal transformation of probucol according to claim 1, characterized in that: The mixing and grinding time is 10 min to 30 min.
8. Use of potassium bromide in the crystal form transformation of probucol, wherein the crystal form transformation is to transform probucol crystal form I into crystal form II.
9. The use according to claim 8, characterized in that: Probucol Form I can be converted into Form II by mixing and grinding probucol crystals with potassium bromide.