Novel bisacoridine crystal form as well as preparation and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and discloses a novel bisacodine crystal form and preparation and application thereof, and an XRPD (X-ray powder diffraction) pattern of the novel bisacodine crystal form has characteristic peaks at the following 2 theta angle positions: 14.40 + / -0.2 degrees, 16.53 + / -0.2 degrees, 17.96 + / -0.2 degrees, 18.93 + / -0.2 degrees, 19.79 + / -0.2 degrees, 21.77 + / -0.2 degrees and 22.37 + / -0.2 degrees. The novel bisacodine crystal form provided by the invention has excellent storage stability and preparation stability, a preparation of the novel bisacodine crystal form can well solve the problems of drug purity decline and the like caused by factors such as temperature and humidity, the risk of curative effect decline is effectively reduced, and the novel bisacodine crystal form is suitable for industrial production and has good economic value and application value.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a new crystal form of bisacodyl and a preparation method and application thereof. Background Art

[0002] Bisacodyl is a white or nearly white organic compound with the chemical formula C 22 H 19 NO4, and the structural formula is as follows: .

[0003] Bisacodyl is a stimulant laxative sold in the form of enteric-coated tablets and suppositories. Bisacodyl acts on the large intestine and is mainly used clinically for acute or chronic constipation. It can also be used for intestinal X-ray examinations, colonoscopy, and intestinal cleansing before abdominal surgery.

[0004] The document Solubility of bisacodyl in fourteen mono solvents and N-methyl-2-pyrrolidone + water mixed solvents at different temperatures, and its application for nanosuspension formation using liquid antisolvent precipitation (Seon-Kwang Lee ea tl. Journal of Molecular Liquids 310 (2020) 113264) introduces a new bisacodyl crystal (denoted as crystal form A), whose powder X-ray diffraction pattern has characteristic peaks at 2θ angles of 9.05°, 14.63°, 16.92°, 19.47°, 20.61°, 21.38°, and 23.29° (the error of 2θ angle is ±0.2°, using Cu-Kα radiation). However, the inventors found in previous studies that the stability of the crystal sample is slightly low, especially after being prepared into suppositories, it has poor resistance to environmental factors such as high temperature, high humidity, and light, which is not conducive to storage. Summary of the invention

[0005] In view of this, the present invention aims to develop a new bisacodyl crystal form with greater stability to improve the storage stability of bisacodyl preparations.

[0006] In order to achieve the above object, the technical solution of the present invention is as follows: In a first aspect, the present invention provides a new crystal form of bisacodyl (denoted as crystal form B), which, using Cu-Kα radiation, has an XRPD spectrum with characteristic peaks at the following 2θ angle positions: 14.40±0.2°, 16.53±0.2°, 17.96±0.2°, 18.93±0.2°, 19.79±0.2°, 21.77±0.2° and 22.37±0.2°.

[0007] Preferably, for the above-mentioned bisacodyl crystal form B, using Cu-Kα radiation, its XRPD spectrum has characteristic peaks at the following 2θ angle positions: 6.25±0.2°, 14.20±0.2°, 14.40±0.2°, 15.63±0.2°, 16.53±0.2°, 17.96±0.2°, 18.93±0.2°, 19.08±0.2°, 19.79±0.2°, 21.44±0.2°, 21.71±0.2°, 21.91±0.2°, 22.23±0.2°. °, 22.37±0.2°, 22.89±0.2°, 23.43±0.2°, 24.33±0.2°, 24.68±0.2°, 24.95±0.2°, 25.33±0.2°, 25.94±0.2°, 26.64±0.2°, 26.81±0.2°, 27.08±0.2°, 27.55±0.2°, 28.60±0.2°, 28.85±0.2°, 29.11±0.2°, 29.46±0.2°, and 30.70±0.2°.

[0008] More preferably, the bisacodyl crystal form B has Figure 1 In some embodiments of the present invention, the bisacodyl crystal form B has characteristic X-ray powder diffraction peak data as shown in Table 1.

[0009] Table 1 Characteristic peak data of X-ray powder diffraction of bisacodyl form B

[0010] The second aspect of the present invention provides a method for preparing sabcotidine crystal form B, comprising the following steps: S1. Add the bisacodyl raw material into an alcohol solvent at 20-40°C and heat it to 60-80°C to dissolve the solid; S2. Cool down to 0-30°C under stirring to precipitate; S3, after filtering, washing the filter cake with the alcohol solvent, and vacuum drying the filter cake to obtain.

[0011] In the above preparation method, the bisacodyl raw material is a crude bisacodyl.

[0012] Preferably, in step S1 of the above preparation method, the alcohol solvent is one or more of ethanol, methanol and isopropanol, and the mass volume ratio of the bisacodyl raw material to the alcohol is 1 g:(4-15 ml).

[0013] Preferably, in step S2 of the above preparation method, the cooling time is 2 to 10 h, and after cooling to 0 to 30° C., the mixture still needs to be kept warm and stirred for 0.5 to 1.5 h.

[0014] Preferably, in step S3 of the above preparation method, the vacuum is specifically 10 -2 ~10 -4 Pa, and the drying temperature is 40~80℃.

[0015] The third aspect of the present invention provides a method for preparing a bisacodyl suppository, comprising the following steps: (1) Mix the powder of bisacodyl crystal form B with the matrix, heat to 60-80°C and mix well, then add the isatis root extract powder and stir for 0.5-1.5 h; (2) Cool down to 30~50℃ and inject into the mold; (3) After demoulding, the bisacodyl suppository is obtained.

[0016] Preferably, in the above preparation method, the matrix is ​​fatty acid glyceride. For example, in some embodiments of the present invention, the matrix is ​​specifically 36 / 38 (1:1, m / m) mixed fatty acid glyceride.

[0017] Preferably, in step (1) of the above preparation method, the stirring speed is 100-400 rpm.

[0018] Preferably, in step (2) of the above preparation method, the cooling time is 2 to 5 h.

[0019] Preferably, in step (3) of the above preparation method, the demoulding temperature is -10~20°C.

[0020] A fourth aspect of the present invention provides a bisacodyl suppository, which contains bisacodyl crystal form B as an active ingredient.

[0021] Compared with the prior art, the present invention has the following beneficial effects: The new crystal form of bisacodyl prepared by the method of the present invention is verified to be a single crystal form, and experimental data show that the crystal form is completely different from the existing reported crystal forms and is a new crystal form; moreover, compared with the existing crystal forms (such as crystal form A), it has more stable storage stability and preparation stability, and its preparation can well resist changes caused by environmental factors such as high temperature, high humidity, and light. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1The present invention discloses an X-ray powder diffraction pattern of the bisacodyl crystal form B prepared in the present invention.

[0023] Figure 2 This is the X-ray powder diffraction pattern of bisacodyl Form A.

[0024] Figure 3 This is the X-ray powder diffraction pattern of bisacodyl mixed crystals.

[0025] Figure 4 This is the HPLC purity chart of bisacodyl Form B. DETAILED DESCRIPTION

[0026] The following embodiments of the technical solution of the present invention are described in detail in conjunction with the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solution of the present invention, and are therefore only used as examples, and cannot be used to limit the protection scope of the present invention.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. The term "comprises" and any variations thereof in the specification and claims of the present invention are intended to cover non-exclusive inclusions.

[0028] Some specific examples are listed below. It should be noted that the examples described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in this field or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be obtained commercially.

[0029] In the following examples, the temperature is room temperature (15-35° C.) unless otherwise specified, and the ratios of the components in the mixed solvent are volume ratios unless otherwise specified.

[0030] In the following examples, the XRD analysis method is: using Cu Kα1 radiation (40 kV, 40 mA), a θ-2θ goniometer, a Ge monochromator and a LynxEye detector, collecting X-ray powder diffraction patterns on a Bruker AXS D8 diffractometer, testing and collecting representative XRPD patterns under room temperature conditions, and the scanning parameters are shown in Table 2.

[0031] Table 2 XRD analysis scanning parameters

[0032] In the following examples, the purity of bisacodyl was tested by HPLC.

[0033] Example 1 This example provides a method for preparing bisacodyl crystal form B, comprising the following steps: (1) Add 80 mL of ethanol (preheated to 30°C) and 10.0 g of crude bisacodyl into a four-necked round-bottom flask and heat the mixture to 70°C to dissolve the solid.

[0034] (2) While stirring, gradually cool the mixture to 25°C (cooling time is 2 h), and then stir for 1 h.

[0035] (3) Filter and wash the filter cake with ethanol (10 mL); -2 Pa) for 10 h, and then at 60 °C in vacuum (10 -2 Pa) for 10 h and finally at 80 °C in vacuum (10 -2 Pa) and dried for 10 h.

[0036] In this case, a total of 8.6 g of bisacodyl product was obtained, which contained 0.13% H2O, 99.9% related substances, and a yield of 86%. Its XRPD pattern was consistent with Figure 1 The specific data are shown in Table 1.

[0037] Example 2 This example provides a method for preparing bisacodyl crystal form B, which specifically comprises the following steps: (1) Add 60 mL of methanol (preheated to 30°C) and 10.0 g of crude bisacodyl into a four-necked round-bottom flask and heat the mixture to 60°C to dissolve the solid.

[0038] (2) While stirring, gradually cool the mixture to 18°C ​​(cooling time is 3 h), and then stir for 1 h.

[0039] (3) Filter and wash the filter cake with methanol (10 mL); -2 The mixture was dried for 10 h at 60 °C in a vacuum oven (10 -2 Pa) for 10 h and finally at 80 °C in vacuum (10 -2 Pa) for 10 hours.

[0040] In this example, 7.8 g of bisacodyl product was obtained, which contained 0.10% H2O, 99.9% related substances, and a yield of 78%. Its XRPD spectrum is as follows: Figure 1 shown.

[0041] Comparative Example 1 In this example, Bisacodyl Crystal Form A was prepared by the following process: (1) Add 50 mL of acetone (preheated to 30°C) and 10.0 g of crude bisacodyl into a four-necked round-bottom flask and warm the mixture to 50°C to dissolve the solid.

[0042] (2) While stirring, gradually cool the mixture to 15°C (cooling time is 3 h) and stir for 1 h. Then slowly add 50 ml of purified water and stir at 15°C for 1 hour.

[0043] (3) Filter and wash the filter cake with acetone (10 mL); -2 The mixture was dried for 10 h at 60 °C in a vacuum oven (10 -2 Pa) for 10 h and finally at 80 °C in vacuum (10 -2 Pa) for 10 hours.

[0044] In this example, 8.8 g of bisacodyl product was obtained, the crystal form was A, and its XRPD spectrum was as follows: Figure 2 As shown; it contains 0.15% H2O, 99.9% related substances, and the yield is 88%.

[0045] The stability test was conducted on the two crystal forms of bisacodyl A and B. The specific method was as follows: the bisacodyl B crystal form prepared in Example 1 and the bisacodyl A crystal form prepared in Comparative Example 1 were placed under high humidity (92.5% RH), high temperature (60°C) and light conditions for 30 days, and their appearance, purity and X-ray diffraction patterns were measured. The test results are shown in Table 3: Table 3 Stability analysis of bisacodyl A and B crystal forms

[0046] As shown in Table 3, crystal form A is not particularly stable under high humidity and light, and its crystal form and purity have some changes. The crystal form of crystal A changes to Figure 3 The crystal form shown in the figure is mostly A crystal, and a small part of the crystal form has changed, which is presumed to be a mixed crystal; Crystal form B is stable, and its content and crystal form have not changed after being placed under high humidity and high temperature conditions for 30 days and under light conditions for 30 days (HPLC spectrum as shown in Figure 4 ), the appearance has not changed.

[0047] Example 3 This example uses a bisacodyl crystal form B sample to provide a suppository, and the preparation method thereof comprises the following steps: (1) Take a sample of bisacodyl crystal form B, grind it into powder and pass it through a 200-mesh sieve, mix it with type 36 / type 38 (1:1, m / m) mixed fatty acid glycerides, and heat it in a 70°C water bath to melt; then add the prescribed amount of Radix Isatidis extract powder, and stir (mechanical stirring, 300 rpm) while keeping warm for 1 hour.

[0048] (2) Gradually cool down to 40℃ (cooling time is 2 h) and inject into the mold.

[0049] (3) After 30 min, slowly cool down to 5°C (about 2 h), keep at 5°C for 30 min, and demold to obtain bisacodyl crystal form B suppository (referred as suppository B).

[0050] Comparative Example 2 Different from Example 3, in this example, the bisacodyl crystal form A sample was used to replace the bisacodyl crystal form B sample to prepare a bisacodyl crystal form A suppository (referred to as suppository A).

[0051] Suppository A and Suppository B were evaluated as follows: 1. Properties: The suppository is milky white and bullet-shaped, with uniform, smooth and delicate color. It has good formability at room temperature. Both AB suppositories meet the requirements.

[0052] 2. Quality difference: Three consecutive batches of products were selected, 10 suppositories were randomly selected from each batch, the mass of each suppository was accurately weighed, the total mass and average mass were calculated, and the quality difference of AB suppositories met the limit requirements. 3. Stability: Take an appropriate amount of sample and place it under light, high temperature (60°C), and high humidity (92.5% RH) for 30 days. Take samples on the 5th and 30th days to inspect the appearance and content of the suppository.

[0053] Table 4 Stability evaluation of suppositories A and B

[0054] As shown in Table 4, the purity of the suppositories made of the bisacodyl crystal form B provided by the present invention did not change significantly after 30 days of high temperature, high humidity or light exposure, and there was no significant difference in purity from the 0th day; however, the suppositories produced from the A crystal had a slight decrease in purity on the 5th day under high temperature, high humidity or light exposure, from 99.8% on the first 0 days to about 99.5%, and basically decreased to about 98.1% on the 30th day. The reagents listed in the present invention, as well as the upper and lower limits and interval values ​​of the reagents of the present invention, and the upper and lower limits and interval values ​​of the process parameters can all realize the present invention, and the embodiments are not listed one by one here.

[0055] In summary, the bisacodyl crystal form B provided by the present invention has good preparation stability and storage stability, and its preparation can well resist the content changes caused by factors such as changes in temperature and humidity.

[0056] It should be noted that the present invention is not limited to the above-mentioned embodiments. The above-mentioned embodiments are only examples, and the embodiments having the same structure as the technical idea and exerting the same effect within the scope of the technical solution of the present invention are all included in the technical scope of the present invention. In addition, without departing from the scope of the main purpose of the present invention, various modifications that can be thought of by those skilled in the art to the embodiments and other methods of combining some of the constituent elements in the embodiments are also included in the scope of the present invention.

Claims

1. A new crystal form of bisacodyl, characterized in that: Using Cu-Kα radiation, its XRPD pattern has characteristic peaks at the following 2θ angle positions: 14.40±0.2°, 16.53±0.2°, 17.96±0.2°, 18.93±0.2°, 19.79±0.2°, 21.77±0.2° and 22.37±0.2°.

2. The new bisacodyl crystal according to claim 1, characterized in that: Using Cu-Kα radiation, its XRPD pattern has characteristic peaks at the following 2θ angle positions: 6.25±0.2°, 14.20±0.2°, 14.40±0.2°, 15.63±0.2°, 16.53±0.2°, 17.96±0.2°, 18.93±0.2°, 19.08±0.2°, 19.79±0.2°, 21.44±0.2°, 21.71±0.2°, 21.91±0.2°, 22.23±0.2°, 22.37±0.2°. 0.2°, 22.89±0.2°, 23.43±0.2°, 24.33±0.2°, 24.68±0.2°, 24.95±0.2°, 25.33±0.2°, 25.94±0.2°, 26.64±0.2°, 26.81±0.2°, 27.08±0.2°, 27.55±0.2°, 28.60±0.2°, 28.85±0.2°, 29.11±0.2°, 29.46±0.2°, and 30.70±0.2°.

3. A method for preparing the new bisacodyl crystal form according to claim 1, characterized in that: The following steps are involved: S1. Mix bisacodyl and alcohol solvent and heat to 60-80°C; S2, cooling down to 0~30℃ under stirring; S3, after filtering, washing the filter cake with the alcohol solvent, and vacuum drying the filter cake to obtain.

4. The method according to claim 3, characterized in that The alcohol solvent is one or more of ethanol, methanol and isopropanol, and the mass volume ratio of bisacodyl to alcohol is 1:(4-15).

5. The method according to claim 3, characterized in that The cooling time in step S2 is 2 to 10 hours.

6. The method according to claim 3, characterized in that The vacuum is specifically 10 -2 ~10 -4 Pa, and the drying temperature is 40-80°C.

7. A method for preparing bisacodyl suppositories, characterized in that: The following steps are involved: (1) The powder of the new crystal form of bisacodyl according to claim 1 or 2 and the matrix are heated to 60-80°C and mixed evenly, and then the isatis root extract powder is added and stirred for 0.5-1.5 hours at the same temperature; (2) Cool down to 30~50℃ and inject into the mold; (3) After demoulding, the bisacodyl suppository is obtained.

8. The preparation method according to claim 7, characterized in that: The matrix is ​​fatty acid glyceride.

9. The preparation method according to claim 7, characterized in that: The cooling time in step (2) is 2 to 5 hours, and the demoulding temperature in step (3) is -10 to 20°C.

10. A bisacodyl suppository, characterized in that: Obtained according to the preparation method according to any one of claims 7 to 9.

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