Azulenesulfonic acid-organic base co-crystals, methods of making and uses thereof

Abstract

The application discloses an azulene sulfonic acid-organic base co-crystal and a preparation method and application thereof, relates to the technical field of medicinal chemistry, and is characterized in that the azulene sulfonic acid-organic base co-crystal is prepared by a salt reaction with sodium azulene sulfonate and an organic base salt as raw materials. The azulene sulfonic acid-organic base co-crystal has good stability under high-temperature, high-humidity and light conditions in a solid form, is not crystallized at low temperature in a solution form, and has good stability under high-temperature and light conditions, so that the stability of sodium azulene sulfonate in storage and preparation is improved, and the purity of sodium azulene sulfonate in the bulk drug and preparations is prevented from being reduced due to the existence of related substances.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to an azulenic acid-organic base cocrystal, its preparation method, and its application. Background Technology

[0002] Sodium azulene sulfonate, also known as sodium guanylate, is a component of amomile. Its chemical name is sodium 1,4-dimethyl-7-isopropylazulene-3-sulfonate. It has good anti-inflammatory and healing-promoting effects on various inflammations, ulcers, and minor wounds occurring in the human digestive system, respiratory system, skin, and conjunctiva. In 1960, Japan first approved Azunol tablets for the treatment of gastric and duodenal ulcers. It also approved the use of water-soluble tablets as a gargle for pharyngitis, tonsillitis, stomatitis, acute gingivitis, glossitis, and oral wounds.

[0003] Studies have found that two impurity peaks appeared in the liquid chromatography of sodium azulene sulfonate raw material after light or heating. Based on the synthetic route and the analysis of degradation products of the sample after light and heating, and after comparison, the related substances were confirmed to be guaiac blue oil, the raw material for the synthesis of sodium azulene sulfonate, and the inorganic salt sodium sulfite or sodium sulfate. Sodium azulene sulfonate is not very stable, especially under heating and light conditions, and is prone to losing sulfonic acid groups (Zhang Zhanhui et al., Determination of sodium azulene sulfonate content and related substances by high performance liquid chromatography, Pharmaceutical Analysis Impurities, 2001, 21(5): 339-341). Summary of the Invention

[0004] To improve the stability of sodium azulene sulfonate raw material, this invention provides a method for preparing azulene sulfonate organic base cocrystal. The azulene sulfonate organic base cocrystal exhibits good stability under high temperature, high humidity, and light conditions in solid form, and does not crystallize at low temperature in solution form, while also exhibiting good stability under high temperature and light conditions.

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

[0006] The first objective of this invention is to provide a method for preparing azulene sulfonic acid organic base co-crystals, comprising the following steps:

[0007] (1) Sodium azulene sulfonate reacts with an organic base salt to form a salt-forming reaction, yielding crude azulene sulfonate organic base eutectic product;

[0008] (2) The crude azusulfonic acid organic base co-crystal was recrystallized to obtain azusulfonic 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, berberine hydrochloride, chlorhexidine hydrochloride, chlorhexidine acetate, chlorhexidine gluconate, ciprofloxacin hydrochloride, and ofloxacin hydrochloride.

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

[0011] Furthermore, the salt formation reaction is carried out at a temperature of 20–40°C for 2–10 hours.

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

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

[0014] A second objective of this invention is to provide an azulenic acid organic base cocrystal prepared by the aforementioned preparation method.

[0015] A third objective of this invention is to provide the application of the aforementioned azusulfonic acid organic base cocrystal in the preparation of anti-inflammatory drugs, antibacterial drugs, and mucosal repair drugs.

[0016] The beneficial effects of this invention are as follows: This invention uses sodium azulene sulfonate and organic base salt as raw materials to prepare azulene sulfonate organic base cocrystal through a salt formation reaction. This azulene sulfonate organic base cocrystal has good stability under high temperature, high humidity and light conditions in solid form, and does not crystallize at low temperature in solution form and has good stability under high temperature and light conditions. This improves the stability of sodium azulene sulfonate during storage and preparation, and avoids the reduction of the purity of sodium azulene sulfonate in the raw material and preparation due to the presence of related substances. Attached Figure Description

[0017] Figure 1 A schematic diagram of the X-ray diffraction structure of the azusulfonic acid-berberine eutectic prepared in Example 1;

[0018] Figure 2 The 1H NMR spectrum of the azusulfonic acid-berberine cocrystal prepared in Example 1;

[0019] Figure 3 The carbon NMR spectrum of the azusulfonic acid-berberine cocrystal prepared in Example 1;

[0020] Figure 4 The 1H NMR spectrum of the azusulfonic acid-ciprofloxacin cocrystal prepared in Example 2;

[0021] Figure 5 The carbon NMR spectrum of the azusulfonic acid-ciprofloxacin cocrystal prepared in Example 2;

[0022] Figure 6The 1H NMR spectrum of the azusulfonic acid-ofloxacin cocrystal prepared in Example 3;

[0023] Figure 7 The carbon NMR spectrum of the azusulfonic acid-ofloxacin cocrystal prepared in Example 3;

[0024] Figure 8 The 1H NMR spectrum of the azusulfonic acid-chlorhexidine cocrystal prepared in Example 4;

[0025] Figure 9 The image shows the carbon NMR spectrum of the azulene sulfonic acid-chlorhexidine cocrystal prepared in Example 4. Detailed Implementation

[0026] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below with reference to specific embodiments and illustrations.

[0027] Example 1

[0028] Sodium azulene sulfonate (0.31 g, 1 mmol) was dissolved in 20 mL of water with stirring, and berberine bisulfate (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, allowed to cool naturally to crystallize, filtered, and dried to obtain crude azulene sulfonate-berberine cocrystals. The crude azulene sulfonate-berberine cocrystals were recrystallized from a 40% aqueous ethanol solution to obtain the azulene sulfonate-berberine cocrystals.

[0029] The 1H and 1C NMR spectra of the azusulfonic acid-berberine eutectic are shown below. Figure 1 , Figure 2 As 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] Crystal data for azulene-berberine eutectic are shown in Table 1.

[0031] Table 1. Crystal data of azusulfonic acid-berberine eutectic.

[0032]

[0033]

[0034]

[0035] Example 2

[0036] Sodium azulene sulfonate (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, the reaction solution was filtered, and dried to obtain crude azulene sulfonate-ciprofloxacin cocrystals. The crude azulene sulfonate-ciprofloxacin cocrystals were recrystallized from a 40% aqueous ethanol solution to obtain azulene sulfonate-ciprofloxacin cocrystals.

[0037] The 1H and 1C NMR spectra of the azusulfonic acid-ciprofloxacin cocrystal are shown below. Figure 4 , Figure 5 As 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 azulene sulfonate (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 crystals were filtered and dried to obtain crude azulene sulfonate-ofloxacin cocrystals. The crude azulene sulfonate-ofloxacin cocrystals were recrystallized from 95% aqueous ethanol solution to obtain azulene sulfonate-ofloxacin cocrystals.

[0040] The 1H NMR and 1C NMR spectra of the azusulfonic acid-ofloxacin cocrystal are shown below. Figure 6 , Figure 7 As 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 azulene sulfonate (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, and the mixture was cooled at 0–4 °C to crystallize. The crystals were filtered, dried, and the crude azulene sulfonate-chlorhexidine cocrystal was obtained. The crude azulene sulfonate-chlorhexidine cocrystal was recrystallized from the crude azulene sulfonate-chlorhexidine cocrystal using a 40% aqueous ethanol solution to obtain the azulene sulfonate-chlorhexidine cocrystal.

[0043] The 1H NMR and 1C NMR spectra of the azusulfonic acid-chlorhexidine eutectic are shown below. Figure 8 , Figure 9 As 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 of the azusulfonic acid-berberine cocrystal, azusulfonic acid-ciprofloxacin cocrystal, azusulfonic acid-ofloxacin cocrystal, and azusulfonic acid-chlorhexidine cocrystal prepared in Examples 1-4 was tested.

[0046] Test results showed that azulene sulfonic acid-berberine cocrystal and azulene sulfonic acid-ofloxacin cocrystal are readily soluble in water, while azulene sulfonic acid-ciprofloxacin cocrystal and azulene sulfonic acid-chlorhexidine cocrystal are poorly soluble in water.

[0047] Example 6

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

[0049] The azulene sulfonic acid-berberine eutectic 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 at 0, 5 and 10 days. The results are shown in Table 2.

[0050] A Waters 2695 high-performance liquid chromatograph was used; the 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 28:72); the flow rate was 1 mL / min; the detection wavelength was 290 nm; the column temperature was 30 ℃; and the injection volume was 20 μL.

[0051] Table 2. Stability test results of azulene-berberine eutectic solid.

[0052]

[0053] As can be seen from Table 2, after the azusulfonic acid-berberine eutectic solid was placed under high temperature, high humidity and light conditions for 10 days, its appearance, purity and content of related substances hardly changed.

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

[0055] 20 mg of the azusulfonic acid-berberine eutectic prepared in Example 1 was placed in a 10 mL transparent volumetric flask, distilled water was added, and the volume was adjusted to the mark. The mixture was shaken well and set aside. The crystals were placed under low temperature, high temperature, and light conditions for 10 days respectively. The appearance, purity, and content of related substances were recorded and tested at 0, 5, and 10 days. The results are shown in Table 3.

[0056] A Waters 2695 high-performance liquid chromatograph was used; the 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 28:72); the flow rate was 1 mL / min; the detection wavelength was 290 nm; the column temperature was 30 ℃; and the injection volume was 20 μL.

[0057] Table 3. Stability test results of azusulfonic acid-berberine eutectic solution

[0058]

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

[0060] Example 7

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

[0062] The azulene sulfonic 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 at 0, 5 and 10 days. The results are shown in Table 4.

[0063] A Waters 2695 high-performance liquid chromatograph was used; the 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 28:72); the flow rate was 1 mL / min; the detection wavelength was 290 nm; the column temperature was 30 ℃; and the injection volume was 20 μL.

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

[0065]

[0066]

[0067] As can be seen from Table 4, after azusulfonic acid-ofloxacin cocrystals were placed under high humidity conditions for 10 days, their appearance, purity and content of related substances remained almost unchanged. However, under high temperature and light conditions, the content of related substances increased, indicating that azusulfonic acid-ofloxacin cocrystals are unstable under high temperature and light conditions.

[0068] Example 8

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

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

[0071] A Waters 2695 high-performance liquid chromatograph was used; the 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 28:72); the flow rate was 1 mL / min; the detection wavelength was 290 nm; the column temperature was 30 ℃; and the injection volume was 20 μL.

[0072] Table 5. Stability test results of azusulfonic acid-chlorhexidine eutectic

[0073]

[0074]

[0075] As can be seen from Table 5, after azusulfonic acid-chlorhexidine cocrystals were placed under high temperature, high humidity and light conditions for 10 days, their appearance, purity and content of related substances remained almost unchanged.

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

Claims

1. A method for preparing azulene sulfonic acid-organic base eutectic, characterized in that, Includes the following steps: (1) Sodium azulene sulfonate reacts with an organic base salt to form a salt, yielding crude azulene sulfonate-organic base eutectic crystals; (2) The crude azusulfonic acid-organic base co-crystal was recrystallized to obtain azusulfonic acid-organic base co-crystal; The organic base salt is at least one of berberine hydrochloride, berberine bisulfate, chlorhexidine hydrochloride, chlorhexidine acetate, chlorhexidine gluconate, ciprofloxacin hydrochloride, and ofloxacin hydrochloride.

2. The preparation method according to claim 1, characterized in that: The molar ratio of sodium azulene sulfonate to organic alkali salt is 1: (0.45~2.05).

3. The preparation method according to claim 1, characterized in that: The salt formation reaction is carried out at a temperature of 20-40℃ for 2-10 hours.

4. The preparation method according to claim 1, characterized in that: The solvent for the salt-forming reaction is water.

5. The preparation method according to claim 1, characterized in that: The solvent for recrystallization is a 30-99% aqueous ethanol solution, by volume fraction.

6. The azulene sulfonic acid-organic base eutectic obtained by the preparation method according to any one of claims 1 to 5.

7. The use of the azulene sulfonic acid-organic base eutectic as described in claim 6 in the preparation of anti-inflammatory drugs, antibacterial drugs, and mucosal repair drugs.

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