Azulene sulfonic acid-organic base eutectic and preparation method and application thereof

Abstract

The invention discloses an azulene sulfonic acid-organic alkali eutectic and a preparation method and application thereof, and relates to the technical field of medicinal chemistry. Sodium azulene sulfonate and organic alkali salt are used as raw materials, and the azulene sulfonic acid-organic alkali eutectic is prepared through a salt forming reaction. The azulene sulfonic acid-organic base eutectic has good stability under high temperature, high humidity and illumination conditions in a solid state, does not crystallize at low temperature in a solution state and has good stability under high temperature and illumination conditions, so that the stability of sodium azulene sulfonate in storage and preparation processes is improved; the phenomenon that the purity of sodium gualenate in the raw material medicine and the preparation is reduced due to the existence of related substances is avoided.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to an azulenesulfonic acid-organic base co-crystal and a preparation method and application thereof. Background Art

[0002] Sodium azulenesulfonate, also known as sodium guarenate, is also known in English as Sodium Azulene Sulfonate. Its chemical name is sodium 1,4-dimethyl-7-isopropylazulene-3-sulfonate. It is the active ingredient in chamomile and has excellent anti-inflammatory and healing properties for various inflammations, ulcers, and minor wounds in the digestive and respiratory systems, skin, and conjunctiva. Azunol tablets were first approved for marketing in Japan in 1960 for the treatment of gastric and duodenal ulcers. The tablets were also approved for gargling in water to treat pharyngitis, tonsillitis, stomatitis, acute gingivitis, glossitis, and oral wounds.

[0003] Studies have found that two impurity peaks appear in the liquid chromatography of sodium azulenesulfonate raw materials after exposure to light or heating. Based on the synthesis route and the analysis of degradation products of samples exposed to light and heated, and after comparison, the related substances were confirmed to be guaiazulene, the synthetic raw material of sodium azulenesulfonate, and inorganic salts such as sodium sulfite or sodium sulfate. Sodium azulenesulfonate is not very stable, especially under heating and light conditions, and is easily desulfonated (Zhang Zhanhui et al., Determination of the content of sodium guarenate and related substances by high performance liquid chromatography, Pharmaceutical Analysis Impurities, 2001, 21(5): 339-341). Summary of the Invention

[0004] In order to improve the stability of sodium azulenesulfonate raw materials, the present invention provides a method for preparing an azulenesulfonic acid organic base co-crystal. The azulenesulfonic acid organic base co-crystal has good stability to high temperature, high humidity and light conditions in solid form, does not crystallize at low temperature and has good stability to high temperature and light conditions in solution form.

[0005] The technical problem to be solved by the present invention is achieved by adopting the following technical solutions:

[0006] The first object of the present invention is to provide a method for preparing an azulenesulfonic acid organic base co-crystal, comprising the following steps:

[0007] (1) sodium azulenesulfonate reacts with an organic base salt to form a salt, thereby obtaining a crude azulenesulfonic acid organic base co-crystal;

[0008] (2) Recrystallizing the crude azulenesulfonic acid organic base co-crystal to obtain azulenesulfonic acid organic base co-crystal.

[0009] Furthermore, the organic base salt includes but is not limited to at least one of berberine hydrochloride, berberine bisulfate, palmatine hydrochloride, chlorhexidine hydrochloride, chlorhexidine acetate, chlorhexidine gluconate, ciprofloxacin hydrochloride, and ofloxacin hydrochloride.

[0010] Furthermore, the molar ratio of the sodium azulenesulfonate to the organic base salt is 1:(0.45-2.05).

[0011] Furthermore, the reaction temperature of the salt-forming reaction is 20-40° C., and the reaction time is 2-10 h.

[0012] Furthermore, the solvent for the salt-forming reaction is water.

[0013] Furthermore, the solvent for the recrystallization is 30-99% ethanol aqueous solution, calculated by volume fraction.

[0014] The second object of the present invention is to provide an azulenesulfonic acid organic base co-crystal prepared by the aforementioned preparation method.

[0015] The third object of the present invention is to provide the use of the aforementioned azulenesulfonic acid organic base co-crystal in the preparation of anti-inflammatory drugs, antibacterial drugs, and mucosal repair drugs.

[0016] The beneficial effects of the present invention are as follows: the present invention uses sodium azulenesulfonate and an organic base salt as raw materials to prepare an azulenesulfonic acid organic base co-crystal through a salt-forming reaction; the azulenesulfonic acid organic base co-crystal has good stability under high temperature, high humidity and light conditions in a solid form; does not crystallize at low temperature in a solution form and has good stability under high temperature and light conditions; thus, the stability of the sodium azulenesulfonate during storage and preparation is improved, and the reduction in the purity of the sodium azulenesulfonate in the raw material and preparation due to the presence of related substances is avoided. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Schematic diagram of the X-ray diffraction structure of the azulenesulfonic acid-berberine co-crystal prepared in Example 1;

[0018] Figure 2 This is the H NMR spectrum of the azulenesulfonic acid-berberine co-crystal prepared in Example 1;

[0019] Figure 3 This is the C NMR spectrum of the azulenesulfonic acid-berberine co-crystal prepared in Example 1;

[0020] Figure 4 This is the H NMR spectrum of the azulenesulfonic acid-ciprofloxacin cocrystal prepared in Example 2;

[0021] Figure 5 This is the C NMR spectrum of the azulenesulfonic acid-ciprofloxacin cocrystal prepared in Example 2;

[0022] Figure 6This is the H NMR spectrum of the azulenesulfonic acid-ofloxacin cocrystal prepared in Example 3;

[0023] Figure 7 This is the C NMR spectrum of the azulenesulfonic acid-ofloxacin cocrystal prepared in Example 3;

[0024] Figure 8 This is the H NMR spectrum of the azulenesulfonic acid-chlorhexidine cocrystal prepared in Example 4;

[0025] Figure 9 This is the NMR carbon spectrum of the azulenesulfonic acid-chlorhexidine cocrystal prepared in Example 4. DETAILED DESCRIPTION

[0026] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is further described below with reference to specific embodiments and illustrations.

[0027] Example 1

[0028] Sodium azulenesulfonate (0.31 g, 1 mmol) was dissolved in 20 mL of water, and berberine hydrogen sulfate (0.38 g, 0.88 mmol) was added. The mixture was stirred at 30°C for 8 h. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. The solution was cooled naturally to crystallize, filtered, and dried to obtain crude azulenesulfonic acid-berberine cocrystals. The crude azulenesulfonic acid-berberine cocrystals were recrystallized from 40% aqueous ethanol to obtain azulenesulfonic acid-berberine cocrystals.

[0029] The H NMR spectrum and C NMR spectrum of azulenesulfonic acid-berberine cocrystal are as follows: Figure 1 、 Figure 2 shown. 1H-NMR (400MHz, DMSO-d6)δ:9.86(s,1H,ArH),8.90(s,1H,CH),8.16-8.19(d,J=8.8Hz,1H,ArH),8.07-8.08(d,J=1.6Hz,1H ,ArH),7.96-7.98(d,J=8.8Hz,1H,ArH),7.89(s,1H,ArH),7.77(s,1H,ArH),7.39-7.42(dd,J=8.8,1.6Hz,1H,ArH),7.07( s,1H,ArH),7.01-7.03(d,J=10.8Hz,1H,ArH),6.17(s,2H,CH2),4.90-4.93(t,J=6.0Hz,2H,CH2),4.08(s,3H,CH3),4.06( s,3H,CH3),3.31(s,3H,CH3),3.17-3.20(t,J=6.0Hz,2H,CH2),3.02-3.08(m,1H,CH),1.30(s,3H,CH3),1.28(s,3H,CH3). 13 C-NMR(100MHz,DMSO-d6)δ:150.8,150.2,148.1,148.1,145.9,144.0,140.9,140.0,137.8,137.6,135.6,134.5,134.1,133.3,13 1.5,131.1,128.6,127.1,124.0,121.8,121.4,120.8,120.6,108.8,105.8,102.5,62.3,57.4,55.6,37.1,27.6,26.7,24.8,13.1.

[0030] The crystal data of azulenesulfonic acid-berberine co-crystal are shown in Table 1.

[0031] Table 1 Crystal data of azulenesulfonic acid-berberine cocrystal

[0032]

[0033]

[0034]

[0035] Example 2

[0036] Sodium azulenesulfonate (0.31 g, 1 mmol) was dissolved in 20 mL of water with stirring, and ciprofloxacin hydrochloride (0.37 g, 1 mmol) was added. The mixture was stirred at 30°C for 8 h. The reaction was stopped, and the reaction solution was filtered and dried to obtain crude azulenesulfonic acid-ciprofloxacin co-crystals. The crude azulenesulfonic acid-ciprofloxacin co-crystals were recrystallized from 40% aqueous ethanol to obtain azulenesulfonic acid-ciprofloxacin co-crystals.

[0037] The H NMR spectrum and C NMR spectrum of azulenesulfonic acid-ciprofloxacin cocrystal are shown as follows: Figure 4 、 Figure 5 shown. 1 H-NMR(400MHz,DMSO-d6)δ:15.1(s,1H,COOH),8.90(s,2H,H + ),8.66(d,J=0.8Hz,1H,ArH),8.09(d,J=2.0Hz,1H,ArH),7.95,7.92,7.98(d and s,J=0.8Hz,2H,ArH),7.59(d,J=7.8Hz,1H,ArH),7.44(d,J=1.6Hz,1H,ArH),7.43(dd,J=8.8,1.6Hz,1H,ArH ),7.06(d,J=11.2Hz,1H,ArH),3.83-3.85(m,1H,CH),3.51-3.53(m,4H,2*CH2),3.32-3.35(m,7H,2*CH2and CH3),3.02-3.09(m,1H,CH),2.49(s,3H,CH3),1.28-1.30(m,8H,CH3and 2CH),1.17(s,2H,CH2). 13 C-NMR(100MHz,DMSO-d6)δ:176.8,166.3,152.0,148.6,148.1,144.5,144.4,140.8,140.2,139.4,137.7,135.7 ,134.2,131.5,128.8,121.5,111.7,111.5,107.4,107.2,46.8,46.8,43.1,36.4,27.6,24.8,24.8,13.1,8.07.

[0038] Example 3

[0039] Sodium azulenesulfonate (0.31 g, 1 mmol) was dissolved in 20 mL of water with stirring, and ofloxacin hydrochloride (0.2 g, 0.5 mmol) was added. The mixture was stirred at 30°C for 6 h. The reaction was stopped, and the reaction solution was concentrated under reduced pressure. 20 mL of anhydrous ethanol was added, and the mixture was cooled to crystallize. The mixture was filtered and dried to obtain crude azulenesulfonic acid-ofloxacin cocrystals. The crude azulenesulfonic acid-ofloxacin cocrystals were recrystallized from 95% aqueous ethanol to obtain azulenesulfonic acid-ofloxacin cocrystals.

[0040] The H NMR spectrum and C NMR spectrum of azulenesulfonic acid-ofloxacin cocrystal are shown as follows: Figure 6 、 Figure 7 shown. 1 H-NMR(400MHz,D2O)δ:15.1(s,1H,COOH),10.8(s,H,H + ),8.10-8.11(d,J=2.0Hz,2H,ArH),7.94(s,2H,ArH),7.59-7.62(d,J=2.0Hz,1H,ArH),7.45(d,J=0.8H z,2H,ArH),7.42(d,J=1.6Hz,1H,ArH),7.06-7.08(d,J=11.8Hz,2H,ArH),4.91-4.96(m,1H,CH),4.58- 4.60(m,1H,CH),4.38-4.40(m,1H,CH),3.56(m,2H,2*CH2),3.39(s,4H,2*CH2),3.33(s,6H,2*CH3),3. 03-3.10(m,2H,2*CH),2.83(s,3H,CH3),1.44-1.45(d,J=6.4Hz,1H,CH3),1.28-1.30(ds,12H,4*CH3). 13 C-NMR(100MHz,DMSO-d6)δ:176.84,176.81,166.4,156.9,154.5,148.1,146.8,140.9,140.2,137.7,135.7,134.2, 133.9,131.5,128.8,125.1,121.5,107.2,103.7,103.5,68.7,55.3,53.5,47.5,42.8,37.2,27.6,24.8,18.4,13.1

[0041] Example 4

[0042] Sodium azulenesulfonate (0.31 g, 1 mmol) was dissolved in 20 mL of water with stirring, and chlorhexidine acetate (0.31 g, 0.5 mmol) was added. The mixture was stirred at 30°C for 4 h. The reaction was stopped, cooled at 0-4°C to separate crystals, filtered, and dried to obtain crude azulenesulfonic acid-chlorhexidine cocrystals. The crude azulenesulfonic acid-chlorhexidine cocrystals were recrystallized from 40% aqueous ethanol to obtain azulenesulfonic acid-chlorhexidine cocrystals.

[0043] The H NMR spectrum and C NMR spectrum of azulenesulfonic acid-chlorhexidine cocrystal are as follows: Figure 8 、 Figure 9 shown. 1 H-NMR(400MHz,CD3OD)δ:8.24(d,J=0.8Hz,1H,ArH),8.09(d,J=2.0Hz,1H,ArH),8.11(s,1H,ArH),7.51 -7.54(dd,J=10.8,1.6Hz,1H,ArH),7.21-7.32(m,5H,ArH),3.43(s,3H,CH3),3.08-3.13(m,3H,CH2and CH),2.56(s,3H,CH3),1.35-1.37(m,10H,2*CH3and 2*CH2). 13 C-NMR (100MHz, CD3OD) δ: 147.8, 141.9, 140.0, 138.7, 135.8, 134.1, 132.5, 129.8, 128.3, 127.7, 121.9, 37.46, 26.75, 23.5, 11.5.

[0044] Example 5

[0045] The water solubility test of the azulenesulfonic acid-berberine co-crystal, azulenesulfonic acid-ciprofloxacin co-crystal, azulenesulfonic acid-ofloxacin co-crystal and azulenesulfonic acid-chlorhexidine co-crystal prepared in Examples 1-4 was performed.

[0046] The test results showed that azulenesulfonic acid-berberine cocrystals and azulenesulfonic acid-ofloxacin cocrystals were easily soluble in water, while azulenesulfonic acid-ciprofloxacin cocrystals and azulenesulfonic acid-chlorhexidine cocrystals were poorly soluble in water.

[0047] Example 6

[0048] 1. Stability test of azulenesulfonic acid-berberine cocrystal solid under high temperature, high humidity and light conditions:

[0049] The azulenesulfonic acid-berberine co-crystal prepared in Example 1 was placed in a transparent open bottle (diameter = 3.2 cm) and placed under high temperature, high humidity, and light conditions for 10 days. Its appearance, purity, and content of related substances were recorded and tested on days 0, 5, and 10. The results are shown in Table 2.

[0050] A Waters 2695 high performance liquid chromatograph was used; the chromatographic column was a C18 column (150 mm × 4.6 mm × 5 μm); the mobile phase was acetonitrile-0.02 mol / L ammonium acetate solution (volume ratio of 28:72); the flow rate was 1 mL / min; the detection wavelength was 290 nm; the column temperature was 30°C; and the injection volume was 20 μL.

[0051] Table 2 Stability test results of azulenesulfonic acid-berberine cocrystal solid

[0052]

[0053] As can be seen from Table 2, after the azulenesulfonic acid-berberine co-crystal solid was placed under high temperature, high humidity and light conditions for 10 days, its appearance, purity and content of related substances remained almost unchanged.

[0054] 2. Stability test of azulenesulfonic acid-berberine eutectic solution under low temperature, high temperature and light conditions:

[0055] Place 20 mg of the azulenesulfonic acid-berberine cocrystal prepared in Example 1 in a 10 mL transparent volumetric flask. Add distilled water, dilute to volume, shake well, and set aside. The flask was then placed under low and high temperature conditions under light for 10 days. The appearance, purity, and content of related substances were recorded and tested on days 0, 5, and 10. The results are shown in Table 3.

[0056] A Waters 2695 high performance liquid chromatograph was used; the chromatographic column was a C18 column (150 mm × 4.6 mm × 5 μm); the mobile phase was acetonitrile-0.02 mol / L ammonium acetate solution (volume ratio of 28:72); the flow rate was 1 mL / min; the detection wavelength was 290 nm; the column temperature was 30°C; and the injection volume was 20 μL.

[0057] Table 3 Stability test results of azulenesulfonic acid-berberine cocrystal solution

[0058]

[0059] As can be seen from Table 3, after the azulenesulfonic acid-berberine eutectic solution was placed under low temperature, high temperature and light conditions for stability test for 10 days, its appearance, purity and content of related substances were almost unchanged.

[0060] Example 7

[0061] Stability test of azulenesulfonic acid-ofloxacin cocrystal solid under high temperature, high humidity and light conditions:

[0062] The azulenesulfonic acid-ofloxacin cocrystal prepared in Example 3 was placed in a transparent open bottle (diameter = 3.2 cm) and placed under high temperature, high humidity and light conditions for 10 days. Its appearance, purity and content of related substances were recorded and tested on days 0, 5 and 10. The results are shown in Table 4.

[0063] A Waters 2695 high performance liquid chromatograph was used; the chromatographic column was a C18 column (150 mm × 4.6 mm × 5 μm); the mobile phase was acetonitrile-0.02 mol / L ammonium acetate solution (volume ratio of 28:72); the flow rate was 1 mL / min; the detection wavelength was 290 nm; the column temperature was 30°C; and the injection volume was 20 μL.

[0064] Table 4 Stability test results of azulenesulfonic acid-ofloxacin cocrystal

[0065]

[0066]

[0067] As can be seen from Table 4, after the azulenesulfonic acid-ofloxacin co-crystal was placed under high humidity conditions for 10 days, its appearance, purity and related substance content remained almost unchanged. However, under high temperature and light conditions, the content of its related substances increased, that is, the azulenesulfonic acid-ofloxacin co-crystal was unstable to high temperature and light.

[0068] Example 8

[0069] Stability test of azulenesulfonic acid-chlorhexidine eutectic solid under high temperature, high humidity and light conditions:

[0070] The azulenesulfonic acid-chlorhexidine cocrystal prepared in Example 4 was placed in a transparent open bottle (diameter = 3.2 cm) and placed under high temperature, high humidity, and light conditions for 10 days. Its appearance, purity, and content of related substances were recorded and tested on days 0, 5, and 10. The results are shown in Table 5.

[0071] A Waters 2695 high performance liquid chromatograph was used; the chromatographic column was a C18 column (150 mm × 4.6 mm × 5 μm); the mobile phase was acetonitrile-0.02 mol / L ammonium acetate solution (volume ratio of 28:72); the flow rate was 1 mL / min; the detection wavelength was 290 nm; the column temperature was 30°C; and the injection volume was 20 μL.

[0072] Table 5 Stability test results of azulenesulfonic acid-chlorhexidine cocrystal

[0073]

[0074]

[0075] As can be seen from Table 5, after the azulenesulfonic acid-chlorhexidine co-crystal was placed under high temperature, high humidity and light conditions for 10 days, its appearance, purity and content of related substances remained almost unchanged.

[0076] The basic principles, main features, and advantages of the present invention are shown and described above. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and modifications are intended to fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing an azulenesulfonic acid-organic base eutectic, characterized in that: The following steps are involved: (1) sodium azulenesulfonate reacts with an organic base salt to form a salt, thereby obtaining a crude azulenesulfonic acid-organic base eutectic; (2) Recrystallizing the crude azulenesulfonic acid-organic base eutectic to obtain azulenesulfonic acid-organic base eutectic.

2. The preparation method according to claim 1, wherein: The organic base salt is at least one of berberine hydrochloride, berberine bisulfate, palmatine hydrochloride, chlorhexidine hydrochloride, chlorhexidine acetate, chlorhexidine gluconate, ciprofloxacin hydrochloride, and ofloxacin hydrochloride.

3. The preparation method according to claim 1, wherein: The molar ratio of the sodium azulenesulfonate to the organic base salt is 1:(0.45-2.05).

4. The preparation method according to claim 1, wherein: The reaction temperature of the salt-forming reaction is 20-40° C., and the reaction time is 2-10 hours.

5. The preparation method according to claim 1, wherein: The solvent for the salt-forming reaction is water.

6. The preparation method according to claim 1, wherein: The solvent for the recrystallization is 30-99% ethanol aqueous solution, calculated by volume fraction.

7. An azulenesulfonic acid-organic base co-crystal prepared by the preparation method according to any one of claims 1 to 6.

8. Use of the azulenesulfonic acid-organic base co-crystal according to claim 7 in the preparation of anti-inflammatory drugs, antibacterial drugs, and mucosal repair drugs.

Images