A co-crystal drug and a preparation method and application thereof

Abstract

The application discloses a co-crystal medicine and a preparation method and application thereof, relates to the technical field of organic chemical synthesis, and forms a co-crystal medicine through intermolecular hydrogen bond action of two medicines. The prepared co-crystal medicine has the advantages of good solubility, strong stability and enhanced curative effect, solves the defects of poor solubility, poor stability and poor curative effect of original medicines, and thus improves clinical application.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, specifically to a co-crystal drug and its preparation method and application. Background Technology

[0002] Statistics show that over 40% of currently marketed drugs are poorly soluble. In recent years, with the continuous development of new chemical entities, the proportion of poorly soluble drugs has been steadily increasing. Therefore, improving the solubility and dissolution rate of poorly soluble drugs has always been a research hotspot in pharmaceuticals. However, current drug formulation development typically still employs traditional experimental methods, which are time-consuming and expensive. Currently, numerous formulation technologies exist for improving the solubility and dissolution rate of poorly soluble drugs, including micronization, micellar solubilization, inclusion technology, nanotechnology, and solid dispersion technology. As widely used excipients in pharmaceuticals, polymers also have numerous applications in solubilizing poorly soluble drugs. Commonly used polymers include hydroxypropyl methylcellulose, povidone, polyethylene glycol, and poloxamer. These formulation technologies require expensive formulation equipment and high-molecular-weight excipients, directly increasing the formulation threshold and cost.

[0003] The basic flavonoid core (benzopyranone) possesses a large conjugated system, with a tight molecular arrangement and high lattice energy, requiring a significant amount of energy to escape from the lattice and enter the aqueous phase. The carbonyl group at the C-4 position of flavonoids readily forms intramolecular hydrogen bonds with the ortho-phenolic hydroxyl group (such as at the C-3 or C-5 position), further enhancing molecular stability and hydrophobicity. Although many flavonoids contain phenolic hydroxyl groups, exhibiting some hydrophilicity, they are generally more lipophilic, especially when the hydroxyl groups are poorly methylated or glycosylated (e.g., flavonoid aglycones), resulting in extremely poor water solubility. The lipid-water partition coefficient is typically high, hindering dissolution in aqueous media.

[0004] Dihydroflavonoids are a unique class of flavonoids, characterized by the saturation of the double bond at the C2-C3 position of the parent ring, forming a non-planar semi-chair conformation and thus creating a chiral center. Due to their non-planar structure, dihydroflavonoids exhibit slightly better water solubility than planar flavonoids, but their water solubility is also lower.

[0005] Flavonoids or dihydroflavonoids are a class of plethora of natural drug lead compounds with various effects, including antioxidant, antitumor, anti-inflammatory, antibacterial, and antiviral properties, and low toxicity. They show great promise in the treatment of cardiovascular and cerebrovascular diseases, metabolic diseases, neurodegenerative diseases, and as adjuvant therapy for tumors. Studies have found that at pH 7.4-8.0, the flavonoid nucleus rapidly undergoes ring-opening to form chalcones in alkaline solutions. Therefore, flavonoids are extremely unstable in alkaline solutions, and their stability decreases further at pH values ​​greater than 3, increasing the difficulty of formulation production and storage. Furthermore, the poor water solubility of flavonoids leads to low oral bioavailability, which in turn affects efficacy and limits their application. Therefore, developing flavonoid active ingredients that improve solubility, stability, and bioavailability is of great significance. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a method for preparing a co-crystal drug, in which two drugs form a co-crystal drug through intermolecular hydrogen bonding, which can significantly improve the solubility and bioavailability of the drug, thereby enhancing the therapeutic effect.

[0007] The technical problem to be solved by this invention is achieved by the following technical solution:

[0008] One of the objectives of this invention is to provide a method for preparing a co-crystal drug, in which two drugs are formed into a co-crystal drug through intermolecular hydrogen bonding.

[0009] Furthermore, the drug includes, but is not limited to, two of the following: flavonoids, organic bases, acetylcysteine, purines, and drugs containing hydroxyl, carboxyl, or sulfhydryl groups.

[0010] Furthermore, the drugs include, but are not limited to, two of the following: baicalin, quercetin, naringin, naringenin, tromethamine, ambroxol, pentoxyverine, acetylcysteine, doxophylline, and terbutaline.

[0011] Furthermore, the molar ratio of the two drugs is 1:(1~2), preferably 1:(1~1.5). An excess of one drug allows the other drug to react as completely as possible, thereby improving the conversion rate of raw materials and the yield of products.

[0012] Furthermore, the intermolecular hydrogen bonds are formed at 20–60°C, preferably 25–35°C. The eutectic drug is prepared under ambient temperature or heating conditions.

[0013] Furthermore, the drug uses water, an organic solvent, or a water / organic solvent as a solvent. The organic solvent can be a single organic solvent or a mixture of two organic solvents; water / organic solvent refers to a mixture of water and an organic solvent.

[0014] Furthermore, the organic solvent includes, but is not limited to, at least one of methanol, ethanol, acetone, ethyl acetate, dimethyl sulfoxide, and N,N-dimethylformamide.

[0015] The second objective of this invention is to provide a cocrystal drug prepared by the aforementioned preparation method.

[0016] Furthermore, the cocrystal drugs include, but are not limited to, baicalin-tromethamine cocrystals, baicalin-ambroxol cocrystals, baicalin-pentoxyverine cocrystals, baicalin-acetylcysteine ​​cocrystals, baicalin-doxophylline cocrystals, baicalin-terbutaline cocrystals, quercetin-tromethamine cocrystals, quercetin-ambroxol cocrystals, quercetin-pentoxyverine cocrystals, quercetin-acetylcysteine ​​cocrystals, and quercetin-terbutaline cocrystals. Naringin-tromethamine cocrystal, naringin-ambroxol cocrystal, naringin-pentoxyverine cocrystal, naringin-acetylcysteine ​​cocrystal, naringin-terbutaline cocrystal, naringin-doxophylline cocrystal, naringin-tromethamine cocrystal, naringin-ambroxol cocrystal, naringin-pentoxyverine cocrystal, naringin-acetylcysteine ​​cocrystal, naringin-terbutaline cocrystal, naringin-doxophylline cocrystal.

[0017] Taking flavonoids and acetylcysteine ​​as examples, the preparation principle of the cocrystal drug of the present invention is as follows:

[0018] Flavonoids contain hydroxyl and carboxyl groups in their molecules, which readily interact with cocrystallizing agents containing amino, hydroxyl, or thiol groups to form cocrystallizations through hydrogen bonding. The cocrystallization structure is stabilized by a network of multiple hydrogen bonds, thereby improving the solubility and dissolution rate of flavonoids, enhancing bioavailability, improving stability, and maintaining or enhancing their pharmacological activity.

[0019] Acetylcysteine ​​contains thiol and carboxyl groups, which readily interact with cocrystallizing agents containing amino or hydroxyl groups to form cocrystallizations through hydrogen bonding. The cocrystallization structure is stabilized by a network of multiple hydrogen bonds, thereby improving the stability of acetylcysteine ​​and maintaining or enhancing its pharmacological activity.

[0020] A third objective of this invention is to provide the application of the cocrystallized drug in the preparation of anti-inflammatory drugs, antiviral drugs, antitumor drugs, antioxidant drugs, or hepatoprotective drugs.

[0021] The beneficial effects of this invention are: This invention uses two drugs to form a co-crystal drug through intermolecular hydrogen bonding. The prepared co-crystal drug has the advantages of good solubility, strong stability and high bioavailability, which solves the shortcomings of poor solubility and stability and low bioavailability of the original drugs, thereby improving the therapeutic effect. Attached Figure Description

[0022] Figure 1The high-performance liquid chromatogram of the baicalin-tromethamine cocrystal prepared in Example 1 is shown below.

[0023] Figure 2 The 1H NMR spectrum of the baicalin-aminobutyric acid cocrystal prepared in Example 1;

[0024] Figure 3 The infrared spectra of the baicalin-tromethorphan cocrystal, baicalin, tromethorphan, and baicalin-tromethorphan mixture prepared in Example 1 are shown below.

[0025] Figure 4 The crystal structure diagram of the baicalin-aminobutyric acid eutectic prepared in Example 1 is shown.

[0026] Figure 5 The high-performance liquid chromatogram of the quercetin-acetylcysteine ​​cocrystal prepared in Example 10;

[0027] Figure 6 The 1H NMR spectrum of the quercetin-acetylcysteine ​​cocrystal prepared in Example 10;

[0028] Figure 7 Infrared spectra of the quercetin-acetylcysteine ​​cocrystal, quercetin, acetylcysteine, and quercetin-acetylcysteine ​​mixture prepared in Example 10;

[0029] Figure 8 The high-performance liquid chromatogram of the naringin-ambroxol cocrystal prepared in Example 14 is shown below.

[0030] Figure 9 The 1H NMR spectrum of the naringin-ambroxol cocrystal prepared in Example 14;

[0031] Figure 10 Infrared spectra of the naringin-ambroxol cocrystal, naringin, ambroxol, and naringin-ambroxol mixture prepared in Example 14;

[0032] Figure 11 The high-performance liquid chromatogram of the naringenin-doxophylline cocrystal prepared in Example 23 is shown below.

[0033] Figure 12 The 1H NMR spectrum of the naringenin-doxophylline cocrystal prepared in Example 23;

[0034] Figure 13 Infrared spectra of the naringenin-doxothecoline cocrystal, naringenin, doxothecoline, and naringenin-doxothecoline mixture prepared in Example 23;

[0035] Figure 14 The effect of the tested compounds on the levels of TNF-α and IL-6 proteins in an LPS-induced RAW264.7 inflammation model. Detailed Implementation

[0036] 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.

[0037] Example 1: Synthesis of baicalin-tromethamine cocrystal

[0038]

[0039] Baicalin (13.38 g, 0.03 mol), tromethamine (3.63 g, 0.03 mol), and 200 mL of water were added to a reaction flask. The mixture was stirred at 65 °C for 2 h, concentrated under reduced pressure to 50 mL, and then 400 mL of anhydrous ethanol was added. The mixture was stirred for 2 h, filtered while hot, and the filter cake was dried at 55 °C to obtain 15.11 g of baicalin-tromethamine eutectic, with a yield of 88.81%.

[0040] The contents of baicalin and tromethamine in the baicalin-tromethamine cocrystal were analyzed by high performance liquid chromatography (HPLC), and the results are shown in the figure. Figure 1 The baicalin content was 64.7% (theoretical value 64.9%). Calculations showed that the molar ratio of baicalin in the eutectic molecules was consistent with the theoretical value.

[0041] The 1H NMR spectrum analysis of the baicalin-tromethamine cocrystal is shown in the figure. Figure 2 . 1 H NMR (400 MHz, DMSO-d6) δ 8.12 – 8.03 (m, 2H), 7.65 – 7.55 (m, 3H), 7.05 (s, 1H), 7.00 (s,1H), 5.10 (brs, 1H), 5.04 (d, J = 7.2 Hz, 1H), 3.68 (d, J = 9.7 Hz, 1H), 3.45 (s, 6H), 3.35 (dt, J = 18.3, 8.9 Hz, 3H), 3.31 – 3.23 (m, 2H).

[0042] Fourier transform infrared spectroscopy analysis was performed on the baicalin-tromethamine cocrystal, and the results are shown in the figure. Figure 3 . IR(KBr) 3371.57, 2925.62, 1664.39, 1611.82, 1585.48, 1492.29, 1483.28, 1450.20,1411.34, 1357.74, 1295.52, 1245.49, 1193.32, 1068.45cm -1.

[0043] Take 0.5 g of baicalin-tromethorphan eutectic, dissolve it in 50% methanol-water, and let it crystallize at room temperature in an open container. After 6 days, a pale yellow transparent needle-like single crystal is obtained. Diffraction intensity data are collected using a Single Crystal X-ray Diffractometer, and the crystal structure is analyzed by the direct method (SHELXS-97). After refinement, the final reliability factor is R=0.0305(4899), wR2=0.0832(5020), and S=1.088. Detection results: Monoclinic crystal system, space group P21, cell parameters: a=7.49439(7), b=14.98025(13), c=22.9234(2), a=γ=90°, β=90°, cell volume V=2573.56(4), number of asymmetric units in the cell Z=4. From Figure 4 It can be seen that the structure is a eutectic formed by one molecule of baicalin, one molecule of tromethamine, and one molecule of water through hydrogen bonds.

[0044] Example 2: Synthesis of baicalin-ambroxol eutectic

[0045]

[0046] Baicalin (13.38 g, 0.03 mol), ambroxol (11.34 g, 0.03 mol), 400 mL of methanol and 50 mL of water were added to a reaction flask. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure to 40 mL, and 200 mL of isopropanol was added. The mixture was heated to 40 °C and stirred for 1 h, then cooled to 10 °C and stirred for 1 h. The mixture was filtered, and the filter cake was dried at 55 °C to obtain baicalin-ambroxol eutectic with a yield of 90.12%.

[0047] HPLC analysis of the baicalin-ambroxol cocrystal revealed a baicalin content of 53.7% (theoretical value 54.1%) and an ambroxol content of 44.9% (theoretical value 44.5%). Calculations showed that the molar ratio of baicalin to ambroxol in the cocrystal was consistent with the theoretical value.

[0048] The results of 1H NMR analysis of the baicalin-ambroxol cocrystal are as follows: 1H NMR (400 MHz, DMSO-d6) δ 8.07 (dd, J = 7.9, 1.8 Hz, 2H), 7.65 – 7.55 (m, 3H), 7.51 (d, J = 2.3Hz, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.05 (s, 1H), 6.99 (s, 1H), 5.16 (d, J =7.2 Hz, 1H), 3.97 – 3.88 (m, 1H), 3.83 (s, 2H), 3.47 – 3.30 (m, 4H), 2.60 (s,1H), 1.96 (d, J = 11.1 Hz, 2H), 1.82 (d, J = 10.4 Hz, 2H), 1.31 – 1.07 (m,4H).

[0049] Fourier transform infrared spectroscopy (FTIR) analysis of the baicalin-ambroxol cocrystal was performed, and the results are as follows: IR (KBr) 3355.63, 2936.62, 1613.62, 1586.29, 1465.00, 1409.55, 1357.17, 1296.40, 1244.64, 1190.69, 1073.49, 1023.49 cm⁻¹ -1 .

[0050] Example 3: Synthesis of baicalin-pentoxyverine cocrystal

[0051]

[0052] Baicalin (2.23 g, 5 mmol), pentoxyverine (1.90 g, 5.7 mmol), 50 mL of water and 50 mL of methanol were added to a reaction flask. The mixture was stirred at room temperature for 1 h, concentrated to dryness under reduced pressure, 10 mL of isopropanol was added, 25 mL of ethyl acetate was added dropwise, and the mixture was stirred for 2 h. The mixture was filtered, and the filter cake was dried at 55 °C to obtain the baicalin-pentoxyverine cocrystal with a yield of 96.41%.

[0053] HPLC analysis of the baicalin-pentoxyverine cocrystal revealed a baicalin content of 57.1% (theoretical value 57.3%) and a pentoxyverine content of 42.5% (theoretical value 42.7%). Calculations showed that the molar ratio of baicalin to pentoxyverine in the cocrystal was consistent with the theoretical value.

[0054] The results of 1H NMR analysis of the baicalin-pentoxyverine cocrystal are as follows: 1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 8.11 – 8.03 (m, 2H), 7.64 – 7.55 (m, 3H), 7.31 (d,J = 4.3 Hz, 4H), 7.23 (q, J = 4.2 Hz, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 5.14(d, J = 7.1 Hz, 1H), 4.16 – 4.04 (m, 2H), 3.91 – 3.82 (m, 1H), 3.54 – 3.46(m, 4H), 3.38 (h, J = 8.7, 8.1 Hz, 3H), 2.83 (t, J = 5.5 Hz, 2H), 2.78 (q, J= 7.1 Hz, 4H), 2.57 – 2.52 (m, 1H), 1.83 (dt, J = 12.3, 6.1 Hz, 2H), 1.72 –1.55 (m, 4H), 1.06 – 1.00 (m, 7H).

[0055] Fourier transform infrared spectroscopy (FTIR) analysis of the baicalin-pentoxyverine cocrystal was performed, and the results are as follows: IR (KBr) 3396.95, 2954.01, 2874.51, 1723.07, 1614.82, 1587.19, 1464.52, 1450.26, 1403.79, 1358.13, 1296.91, 1243.41, 1184.98, 1073.95, 1022.74 cm⁻¹ -1 .

[0056] Example 4: Synthesis of baicalin-acetylcysteine ​​cocrystal

[0057]

[0058] Baicalin (4.46 g, 0.01 mol), acetylcysteine ​​(1.63 g, 0.01 mol), 10 mL of water and 50 mL of acetone were added to a reaction flask. The mixture was stirred at 50 °C for 2 h, concentrated to dryness under reduced pressure, and then 60 mL of ethyl acetate and 20 mL of n-hexane were added. The mixture was stirred to induce crystallization for 2 h, filtered, and the filter cake was dried at 55 °C to obtain the baicalin-acetylcysteine ​​cocrystal with a yield of 76.3%.

[0059] HPLC analysis of the baicalin-acetylcysteine ​​cocrystal revealed a baicalin content of 77.1% (theoretical value 73.2%) and an acetylcysteine ​​content of 22.5% (theoretical value 26.8%). Calculations showed that the molar ratio of baicalin to pentoxyverine in the cocrystal was inconsistent with the theoretical value, indicating that the cocrystal was not 1:1.

[0060] Example 5: Synthesis of baicalin-doxophylline cocrystal

[0061]

[0062] Baicalin (1.12 g, 2.5 mmol), doxorubicin (0.67 g, 2.5 mmol), and 20 mL of acetone were added to the reaction flask. The mixture was stirred at 45 °C for 2 h, concentrated under reduced pressure to dryness, and the resulting solid was dried at 55 °C to obtain baicalin-doxorubicin eutectic with a yield of 75.4%.

[0063] HPLC analysis of the baicalin-theophylline cocrystal revealed a baicalin content of 98.1% (theoretical value 62.6%) and an undetectable theophylline content (theoretical value 37.4%). Calculations showed that the molar ratio of baicalin to theophylline in the cocrystal was inconsistent with the theoretical value, indicating that the cocrystal ratio was not fixed and not 1:1.

[0064] Example 6: Synthesis of baicalin-terbutaline cocrystal

[0065]

[0066] Baicalin (2.23 g, 5 mmol), terbutaline (1.12 g, 5 mmol), 30 mL of water and 20 mL of methanol were added to a reaction flask. The mixture was stirred at 45 °C for 2 h, concentrated to dryness under reduced pressure, and then 20 mL of isopropanol, 40 mL of ethyl acetate and 20 mL of n-hexane were added. The mixture was stirred to induce crystallization, filtered, and the filter cake was dried at 55 °C to obtain the baicalin-terbutaline cocrystal with a yield of 80.6%.

[0067] HPLC analysis of the baicalin-terbutaline cocrystal revealed a baicalin content of 57.3% (theoretical value 66.5%) and a terbutaline content of 23.2% (theoretical value 42.7%). Calculations showed that the molar ratio of baicalin to terbutaline in the cocrystal was inconsistent with the theoretical value, indicating that the cocrystal ratio was not fixed and not 1:1.

[0068] Example 7: Synthesis of Quercetin-Glamethoxazole Cocrystal

[0069]

[0070] Quercetin (15 g, 0.05 mol), tromethamine (6 g, 0.05 mol), acetone (250 mL), and water (50 mL) were added to a reaction flask. The mixture was stirred at 50 °C for 3 h, concentrated to dryness under reduced pressure, and then ethyl acetate (60 mL) and n-hexane (30 mL) were added. The mixture was stirred to induce crystallization for 2 h, filtered, and the filter cake was dried at 55 °C to obtain the quercetin-tromethamine cocrystal with a yield of 72.0%.

[0071] HPLC analysis of the quercetin and tromethamine cocrystal revealed a quercetin content of 66.5% (theoretical value 71.4%). Calculations showed that the molar ratio of quercetin to tromethamine in the cocrystal was inconsistent with the theoretical value, indicating that the measured ratio was not constant and not 1:1.

[0072] Example 8: Synthesis of quercetin-ambroxol eutectic

[0073]

[0074] Quercetin (11.18 g, 0.037 mol), ambroxol (14.00 g, 0.037 mol), 50 mL of water, 200 mL of methanol, and 20 mL of DMF were added to a reaction flask. The mixture was stirred at 50 °C for 3 h, concentrated to dryness under reduced pressure, 120 mL of water was added, and the mixture was stirred for 1 h. The mixture was filtered, and the filter cake was dried at 55 °C to obtain a quercetin-ambroxol eutectic with a yield of 99.70%.

[0075] HPLC analysis of the quercetin-ambroxol cocrystal revealed a quercetin content of 43.1% (theoretical value 44.4%) and an ambroxol content of 54.3% (theoretical value 55.6%). Calculations showed that the molar ratio of quercetin to ambroxol in the cocrystal was consistent with the theoretical value.

[0076] The 1H NMR spectrum analysis of the quercetin-ambroxol cocrystal yielded the following results: 1H NMR (400 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.56 (dd, J = 8.5, 2.2 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.24 (s, 1H), 6.90 (d, J = 8.5 Hz, 1H), 6.41 (s, 1H), 6.19 (d, J = 2.0 Hz,1H), 5.66 (s, 2H), 3.69 (s, 2H), 3.38 (tt, J = 9.9, 4.1 Hz, 1H), 2.33 (qd, J= 7.1, 4.9, 3.6 Hz, 1H), 1.98 – 1.67 (m, 4H), 1.28 – 0.94 (m, 4H).

[0077] Fourier transform infrared (FTIR) spectroscopy analysis of the quercetin-ambroxol cocrystal was performed, and the results are as follows: IR (KBr) 3404.30, 2927.05, 2851.42, 1654.26, 1630.22, 1610.83, 1560.57, 1522.23, 1465.35, 1450.31, 1407.66, 1381.88, 1356.91, 1320.17, 1262.78, 1199.33, 1168.52, 1130.97, 1113.93, 1014.51 cm⁻¹ -1 .

[0078] Example 9: Synthesis of quercetin-pentoxyverine eutectic

[0079]

[0080] Quercetin (1.53 g, 5 mmol), pentoxyverine (1.67 g, 5 mmol), 10 mL of water and 50 mL of acetone were added to a reaction flask. The mixture was stirred at 50 °C for 2 h, concentrated to dryness under reduced pressure, and then 40 mL of ethyl acetate and 20 mL of n-hexane were added. The mixture was stirred to induce crystallization for 2 h, filtered, and the filter cake was dried at 55 °C to obtain the quercetin-pentoxyverine eutectic with a yield of 90.3%.

[0081] HPLC analysis of the baicalin and quercetin content in the quercetin-pentoxyverine cocrystal revealed a quercetin content of 57.6% (theoretical value 47.5%) and a pentoxyverine content of 40.5% (theoretical value 52.5%). Calculations showed that the molar ratio of quercetin to pentoxyverine in the cocrystal was inconsistent with the theoretical value, indicating that the detection ratio was not fixed and not 1:1.

[0082] Example 10: Synthesis of quercetin-acetylcysteine ​​cocrystal

[0083]

[0084] Quercetin (15.12 g, 0.05 mol), acetylcysteine ​​(8.15 g, 0.05 mol), 50 mL of water and 200 mL of acetone were added to a reaction flask. The mixture was stirred at 45 °C for 3 h, concentrated to dryness under reduced pressure, 50 mL of isopropanol was added, and 100 mL of n-hexane was added dropwise. The mixture was stirred for 2 h, filtered, and the filter cake was dried at 55 °C to obtain quercetin-acetylcysteine ​​cocrystal with a yield of 96.98%.

[0085] HPLC analysis was performed on the contents of quercetin and acetylcysteine ​​in the quercetin-acetylcysteine ​​cocrystal. The results are shown in the figure. Figure 5 The quercetin content was 64.7% (theoretical value 64.9%), and the acetylcysteine ​​content was 34.9% (theoretical value 35.0%). Calculations showed that the molar ratio of quercetin to acetylcysteine ​​in the cocrystal molecule was consistent with the theoretical value.

[0086] The quercetin-acetylcysteine ​​cocrystal was analyzed by 1H NMR spectroscopy, and the results are shown in the figure. Figure 6 . 1 H NMR (400MHz, DMSO-d6) δ 12.50 (s, 1H), 9.35 (s, 1H), 8.18 (s, 1H), 7.70 (d, J = 2.2Hz, 1H), 7.56 (dd, J = 8.5, 2.2 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.43 (d, J= 2.0 Hz, 1H), 6.21 (d, J = 2.0 Hz, 1H), 4.40 (m, 1H), 2.80 (m, 2H), 2.44(brs, 1H), 1.90 (s, 3H).

[0087] Fourier transform infrared spectroscopy analysis was performed on the quercetin-acetylcysteine ​​cocrystal, and the results are shown in the figure. Figure 7 . IR (KBr) 3409.60,1664.16, 1611.51, 1562.04, 1522.28, 1450.02, 1408.80, 1382.59,1319.72, 1263.10, 1199.11,1168.86, 1131.40,1014.70 cm -1 .

[0088] Example 11: Synthesis of quercetin-doxophylline eutectic

[0089]

[0090] Quercetin (1.54 g, 5 mmol), doxorubicin (1.35 g, 5 mmol) and 50 mL of acetone were added to the reaction flask. The mixture was stirred at 40 °C for 3 h, concentrated under reduced pressure to dryness, and the resulting solid was dried at 55 °C to obtain quercetin-doxorubicin eutectic with a yield of 91.81%.

[0091] HPLC analysis of the quercetin and doxophylline content in the quercetin-doxophylline cocrystal revealed a quercetin content of 52.8% (theoretical value 53.2%) and a doxophylline content of 46.6% (theoretical value 46.8%). Calculations showed that the molar ratio of quercetin to doxophylline in the cocrystal molecule was consistent with the theoretical value.

[0092] The 1H NMR spectroscopy analysis of the quercetin-doxophylline cocrystal yielded the following results: 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 10.76 (s, 1H), 9.57 (s, 1H), 9.34 (s, 1H), 9.28 (s, 1H), 8.00 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 8.5, 2.2 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 6.18 (d, J = 2.0 Hz, 1H), 5.20 (t, J = 4.2 Hz, 1H), 4.43 (d, J = 4.2 Hz, 2H), 3.89–3.77 (m, 4H), 3.43 (s, 3H), 3.22 (s, 3H), 2.09 (s, 4H).

[0093] Fourier transform infrared (FTIR) spectroscopy analysis of the quercetin-doxophylline cocrystal was performed, and the results are as follows: IR (KBr) 3316.87, 3146.95, 2963.06, 2890.99, 1690.82, 1639.96, 1601.77, 1555.16, 1512.34, 1475.42, 1406.44, 1374.09, 1317.44, 1246.24, 1223.24, 1186.00, 1160.76, 1132.38, 1102.45, 1087.52, 1031.25, 1004.88 cm⁻¹ -1 .

[0094] Example 12: Synthesis of quercetin-terbutaline eutectic

[0095]

[0096] Quercetin (1.51 g, 5 mmol), terbutaline (1.15 g, 5 mmol), and 40 mL of acetone were added to a reaction flask. The mixture was stirred at 45 °C for 2 h, concentrated to dryness under reduced pressure, and then 20 mL of ethyl acetate and 30 mL of n-hexane were added. The mixture was stirred to induce crystallization for 2 h, filtered, and the filter cake was dried at 55 °C to obtain the quercetin-terbutaline cocrystal with a yield of 86.8%.

[0097] HPLC analysis of the quercetin and terbutaline cocrystals revealed a quercetin content of 52.8% (theoretical value 57.3%) and a terbutaline content of 31.3% (theoretical value 42.7%). Calculations showed that the molar ratio of quercetin to terbutaline in the cocrystal was inconsistent with the theoretical value, indicating that the detection ratio was not fixed and not 1:1.

[0098] Example 13: Synthesis of naringin-tromethamine cocrystal

[0099]

[0100] Naringin (23.2 g, 0.04 mol), tromethamine (4.8 g, 0.04 mol), and 250 mL of methanol were added to a reaction flask. The mixture was stirred at room temperature for 3 h, concentrated to dryness under reduced pressure, 75 mL of acetone was added, and 30 mL of n-hexane was added dropwise. The mixture was stirred for 2 h, filtered, and the filter cake was dried at 55 °C to obtain the naringin-tromethamine eutectic with a yield of 94.31%.

[0101] HPLC analysis of the naringin and tromethamine cocrystals revealed a naringin content of 82.4% (theoretical value 82.7%). Calculations showed that the molar ratio of naringin to tromethamine in the cocrystal was consistent with the theoretical value.

[0102] The results of 1H NMR analysis of the naringin-tromethamine cocrystal are as follows: 1H NMR (400 MHz, DMSO-d6) δ 7.33 (dd, J = 8.7, 3.2 Hz, 2H), 6.80 (dd, J = 8.5 Hz, 1.2 Hz, 2H), 6.12 (t, J = 2.0 Hz, 1H), 6.09 (t, J = 2.5 Hz, 1H), 5.50 (td, J = 13.2, 2.9Hz, 1H), 5.29 (brs, 1H), 5.17–5.06 (m, 3H), 4.77–4.37 (m, 6H), 3.75–3.58 (m,3H), 3.51–3.39 (m, 4H), 3.39–3.27 (m, 5H), 3.24 (s, 6H), 3.22–3.12 (m, 2H), 2.78–2.66 (m, 1H), 1.15 (d, J = 6.3 Hz, 3H).

[0103] Fourier transform infrared spectroscopy (FTIR) analysis of the naringin-tromethorphan cocrystal was performed, and the results are as follows: IR (KBr) 3405.47, 2921.52, 1644.17, 1577.41, 1519.83, 1446.76, 1403.34, 1340.19, 1293.47, 1197.22, 1176.42, 1134.77, 1087.72 cm⁻¹ -1 .

[0104] Example 14: Synthesis of naringin-ambroxol cocrystal

[0105]

[0106] Naringin (23.3 g, 0.04 mol), ambroxol (15.18 g, 0.04 mol), and 300 mL of methanol were added to the reaction flask. The mixture was stirred at 35 °C for 4 h, concentrated under reduced pressure to dryness, and the resulting solid was dried at 55 °C to obtain the naringin-ambroxol eutectic with a yield of 96.91%.

[0107] HPLC analysis was performed on the contents of naringin and ambroxol in the naringin-ambroxol cocrystal. The results are shown in the figure. Figure 8 The content of naringin was 60.1% (theoretical value 60.5%), and the content of ambroxol was 39.9% (theoretical value 39.7%). Calculations showed that the molar ratio of naringin to ambroxol in the cocrystal molecule was consistent with the theoretical value.

[0108] The 1H NMR spectrum analysis of the naringin-ambroxol cocrystal is shown in the figure. Figure 9 . 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.33 (dd, J = 8.6, 3.2 Hz, 2H), 7.23 (d, J = 2.3 Hz, 1H), 6.80 (dd, J = 8.5, 1.5 Hz, 2H), 6.11 (dt, J =11.8, 2.3 Hz, 2H), 5.64 (s, 2H), 5.50 (td, J = 13.3, 2.9 Hz, 1H), 5.30 (d, J= 5.0 Hz, 1H), 5.19 – 5.05 (m, 3H), 4.68 (dd, J = 23.6, 4.5 Hz, 2H), 4.61 –4.53 (m, 2H), 4.46 (d, J = 5.2 Hz, 2H), 3.77 – 3.65 (m, 6H), 3.52 – 3.39 (m,4H), 3.39 – 3.28 (m, 6H), 3.26 – 3.08 (m, 4H), 2.73 (ddd, J = 17.1, 9.0, 3.0Hz, 1H), 2.36 – 2.21 (m, 1H), 1.95 – 1.71 (m, 4H), 1.16 (d, J = 6.1 Hz, 3H), 1.14 – 0.98 (m, 4H).

[0109] Fourier transform infrared spectroscopy analysis was performed on the naringin-ambroxol cocrystal, and the results are shown in the figure. Figure 10 . IR(KBr) 3413.94, 2930.86, 1640.46,1577.81,1519.37, 1456.72, 1374.91, 1294.67,1271.66, 1199.66, 1176.08,1132.16,1088.21 cm -1 .

[0110] Example 15: Synthesis of naringin-pentoxyverine cocrystal

[0111]

[0112] Naringin (17.51 ​​g, 0.03 mol), pentoxyverine (10.02 g, 0.03 mol), and 250 mL of methanol were added to the reaction flask. The mixture was stirred at 35 °C for 4 h, concentrated under reduced pressure to dryness, and the resulting solid was dried at 55 °C to obtain the naringin-pentoxyverine eutectic with a yield of 97.41%.

[0113] HPLC analysis of the naringin-pentoxyverine cocrystal revealed a naringin content of 63.2% (theoretical value 63.5%) and a pentoxyverine content of 36.4% (theoretical value 36.5%). Calculations showed that the molar ratio of naringin to pentoxyverine in the cocrystal was consistent with the theoretical value.

[0114] The results of 1H NMR analysis of the naringin-pentoxyverine cocrystal are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 9.60 (s, 1H), 7.36 – 7.30 (m, 6H), 7.26 – 7.19 (m,1H), 6.80 (dd, J = 8.5, 1.5 Hz, 2H), 6.11 (dt, J = 11.9, 2.3 Hz, 2H), 5.50 (td, J = 13.3, 2.9 Hz, 1H), 5.30 (d, J = 5.1 Hz, 1H), 5.17 – 5.07 (m, 3H), 4.67 (dd, J = 23.8, 4.5 Hz, 2H), 4.56 (s, 1H), 4.46 (d, J = 5.7 Hz, 1H), 4.13– 4.05 (m, 2H), 3.76 – 3.63 (m, 3H), 3.52 – 3.39 (m, 6H), 3.39 – 3.27 (m,7H), 3.25 – 3.14 (m, 2H), 2.73 (ddd, J = 17.1, 9.1, 3.0 Hz, 1H), 2.59 – 2.52(m, 2H), 2.49 – 2.41 (m,6H), 1.88 – 1.78 (m, 2H), 1.73 – 1.59 (m, 4H), 1.16(d, J = 6.2 Hz, 3H), 0.92 (t, J = 7.1 Hz, 6H).

[0115] Fourier transform infrared spectroscopy (FTIR) analysis of the naringin-pentoxyverine cocrystal was performed, and the results are as follows: IR (KBr) 3422.10, 2968.94, 2875.10, 1726.45, 1640.56, 1577.36, 1519.73, 1497.00, 1448.94, 1376.40, 1343.85, 1294.86, 1256.16, 1176.77, 1131.71, 1088.85 cm⁻¹ -1 .

[0116] Example 16: Synthesis of naringin-acetylcysteine ​​cocrystal

[0117]

[0118] Naringin (23.3 g, 0.04 mol), acetylcysteine ​​(6.53 g, 0.04 mol), and 250 mL of methanol were added to the reaction flask. The mixture was stirred at room temperature for 4 h, concentrated under reduced pressure to dryness, and the resulting solid was dried at 55 °C to obtain the naringin-acetylcysteine ​​cocrystal with a yield of 94.33%.

[0119] HPLC analysis of the naringin and acetylcysteine ​​cocrystals revealed a naringin content of 78.0% (theoretical value 78.1%) and an acetylcysteine ​​content of 21.8% (theoretical value 21.9%). Calculations showed that the molar ratio of naringin to acetylcysteine ​​in the cocrystal molecules was consistent with the theoretical values.

[0120] The results of 1H NMR analysis of the naringin-acetylcysteine ​​cocrystal are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (d, J = 2.7 Hz, 1H), 9.60 (s, 1H), 8.17 (d, J = 7.9 Hz, 1H), 7.33 (dd, J = 8.6, 3.2 Hz, 2H), 6.80 (dd, J = 8.6, 1.5 Hz, 2H), 6.12 (t, J =2.1 Hz, 1H), 6.09 (t, J = 2.5 Hz, 1H), 5.50 (td, J = 13.2, 2.9 Hz, 1H), 5.30(s, 1H), 5.21–5.07 (m, 3H), 4.68 (d, J = 23.4 Hz, 2H), 4.56 (s, 1H), 4.38(td, J = 7.6, 4.7 Hz, 1H), 3.77–3.61 (m, 3H), 3.55–3.29 (m, 9H), 3.25–3.12(m, 2H), 2.90–2.79 (m, 1H), 2.80–2.67 (m, 2H), 2.43 (brs, 1H), 1.88 (s, 3H), 1.16 (d, J = 6.0 Hz, 3H).

[0121] Fourier transform infrared spectroscopy (FTIR) analysis of the naringin-acetylcysteine ​​cocrystal was performed, and the results are as follows: IR (KBr) 3414.05, 2932.58, 1640.49, 1577.48, 1519.97, 1448.54, 1377.54, 1346.88, 1295.64, 1270.00, 1200.95, 1176.08, 1132.26, 1075.12 cm⁻¹ -1 .

[0122] Example 17: Synthesis of naringin-doxophylline cocrystal

[0123]

[0124] Naringin (2.92 g, 5 mmol), doxorubicin (1.34 g, 5 mmol), and 30 mL of acetone were added to the reaction flask. The mixture was stirred at 40 °C for 2 h, concentrated under reduced pressure to dryness, and the resulting solid was dried at 55 °C to obtain the naringin-doxorubicin eutectic, with a yield of 76.5%.

[0125] HPLC analysis of the naringin and doxophylline cocrystals revealed a naringin content of 73.0% (theoretical value 68.6%) and a doxophylline content of 27.4% (theoretical value 31.4%). Calculations showed that the molar ratio of naringin to doxophylline in the cocrystals did not conform to the theoretical value, indicating that the detection ratio was not fixed and not 1:1.

[0126] Example 18: Synthesis of naringin-terbutaline cocrystal

[0127]

[0128] Terbutaline (4.52 g, 0.02 mol), naringin (11.61 g, 0.02 mol), 150 mL of methanol and 10 mL of water were added to the reaction flask. The mixture was stirred at room temperature for 3 h, filtered, and the filtrate was concentrated to dryness under reduced pressure. The resulting solid was dried at 55 °C to obtain the naringin-terbutaline cocrystal with a yield of 98.61%.

[0129] HPLC analysis of the naringin-terbutaline cocrystal revealed a naringin content of 71.7% (theoretical value 72.0%) and a terbutaline content of 27.8% (theoretical value 28.0%). Calculations showed that the molar ratio of naringin to terbutaline in the cocrystal was consistent with the theoretical value.

[0130] The results of 1H NMR analysis of the naringin-terbutaline cocrystal are as follows: 1H NMR (400 MHz, DMSO-d6) δ 7.33 (dd, J = 8.7, 3.1 Hz, 2H), 6.80 (dd, J = 8.6, 1.5 Hz, 2H), 6.20 (d, J = 2.2 Hz, 2H), 6.12 (t, J = 2.1 Hz, 1H), 6.09 (t, J = 2.5 Hz, 1H), 6.06 (t, J = 2.2 Hz, 1H), 5.50 (td, J = 13.2, 2.9 Hz, 1H), 5.30 (s, 1H), 5.18– 5.08 (m, 3H), 4.77–4.42 (m, 4H), 4.33 (dd, J = 8.3, 4.1 Hz, 1H), 3.74–3.63(m, 3H), 3.39–3.28 (m, 3H), 3.19 (q, J = 9.3 Hz, 2H), 2.73 (ddd, J = 17.1,8.9, 3.0 Hz, 1H), 2.58–2.52 (m, 1H), 1.16 (d, J = 6.2 Hz, 3H), 1.02 (s, 9H).

[0131] Fourier transform infrared spectroscopy (FTIR) analysis of the naringin-terbutaline cocrystal was performed, and the results are as follows: IR (KBr) 3385.82, 2975.54, 1640.86, 1519.12, 1501.21, 1449.11, 1380.45, 1344.15, 1295.75, 1270.94, 1200.84, 1171.29, 1133.33, 1087.12 cm⁻¹ -1 .

[0132] Example 19: Synthesis of naringin-tromethamine cocrystal

[0133]

[0134] Naringenin (10.88 g, 0.04 mol), tromethamine (4.87 g, 0.04 mol), and 200 mL of acetone were added to the reaction flask. The mixture was stirred at 35 °C for 3 h, concentrated under reduced pressure to dryness, and the resulting solid was dried at 55 °C to obtain naringenin-tromethamine eutectic with a yield of 91.12%.

[0135] HPLC analysis of the naringenin and tromethamine cocrystal content revealed a naringenin content of 69.0% (theoretical value 69.2%). Calculations showed that the molar ratio of naringenin in the cocrystal was consistent with the theoretical value.

[0136] The results of 1H NMR analysis of the naringenin-tromethamine cocrystal are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 5.71 – 5.67(m, 2H), 5.35 (dd, J = 12.6, 3.0 Hz, 1H), 3.33 (s, 6H), 3.14 (dd, J = 17.0,12.6 Hz, 1H), 2.60 (dd, J = 17.0, 3.1 Hz, 1H).

[0137] Fourier transform infrared (FTIR) spectroscopy analysis of the naringenin-tromethorphan cocrystal was performed, and the results are as follows: IR (KBr) 3348.47, 3057.89, 2940.33, 1640.38, 1552.67, 1519.47, 1498.26, 1348.76, 1313.09, 1278.47, 1248.72, 1212.54, 1158.01, 1085.92, 1064.73 cm⁻¹ -1 .

[0138] Example 20: Synthesis of naringenin-ambroxol eutectic

[0139]

[0140] Naringenin (5.47 g, 0.02 mol), ambroxol (7.58 g, 0.02 mol), and 150 mL of methanol were added to the reaction flask. The mixture was stirred at 35 °C for 3 h, concentrated under reduced pressure to dryness, and the resulting solid was dried at 55 °C to obtain naringenin-ambroxol eutectic with a yield of 93.94%.

[0141] HPLC analysis of the naringenin-ambroxol cocrystal revealed a naringenin content of 41.7% (theoretical value 41.8%) and an ambroxol content of 57.9% (theoretical value 58.2%). Calculations showed that the molar ratio of naringenin to ambroxol in the cocrystal was consistent with the theoretical value.

[0142] The results of 1H NMR analysis of the naringenin-ambroxol cocrystal are as follows: 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.23(d, J = 2.3 Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H), 5.87 (s, 2H), 5.65 (s, 2H), 5.43 (dd, J = 12.8, 3.0 Hz, 1H), 3.42–3.32 (m, 1H), 3.25 (dd, J = 17.1, 12.8Hz, 1H), 2.67 (dd, J = 17.1, 3.0 Hz, 1H), 2.31 (t, J = 3.7 Hz, 1H), 1.93–1.74(m, 4H), 1.20–0.98 (m, 4H).

[0143] Fourier transform infrared spectroscopy (FTIR) analysis of the naringenin-ambroxol cocrystal was performed, and the results are as follows: IR (KBr) 3290.32, 2928.30, 2852.54, 1633.04, 1603.19, 1519.54, 1497.65, 1462.76, 1341.44, 1312.39, 1249.72, 1181.16, 1157.51, 1110.24, 1083.41, 1064.23, 1013.71 cm⁻¹ -1 .

[0144] Example 21: Synthesis of naringenin-pentoxyverine eutectic

[0145]

[0146] Naringenin (1.40 g, 5 mmol), pentoxyverine (1.71 g, 5 mmol) and 20 mL of methanol were added to the reaction flask. The mixture was stirred at 40 °C for 2 h, concentrated under reduced pressure to dryness, and the resulting solid was dried at 55 °C to obtain naringenin-pentoxyverine eutectic with a yield of 72.8%.

[0147] HPLC analysis of the naringenin-pentoxyverine cocrystal revealed a naringenin content of 56.3% (theoretical value 45.0%) and a pentoxyverine content of 41.5% (theoretical value 55.0%). Calculations showed that the molar ratio of naringenin to pentoxyverine in the cocrystal was inconsistent with the theoretical value, indicating that the detection ratio was not fixed and not 1:1.

[0148] Example 22: Synthesis of naringenin-acetylcysteine ​​cocrystal

[0149]

[0150] Naringenin (10.90 g, 0.04 mol), acetylcysteine ​​(6.52 g, 0.04 mol), and 200 mL of acetone were added to a reaction flask. The mixture was stirred at 30 °C for 3 h, concentrated under reduced pressure to dryness, and the resulting solid was dried at 55 °C to obtain naringenin-acetylcysteine ​​cocrystal with a yield of 97.33%.

[0151] HPLC analysis of the naringenin-acetylcysteine ​​cocrystal revealed a naringenin content of 62.3% (theoretical value 62.5%) and an acetylcysteine ​​content of 37.3% (theoretical value 37.5%). Calculations showed that the molar ratio of naringenin to acetylcysteine ​​in the cocrystal molecule was consistent with the theoretical value.

[0152] The results of 1H NMR analysis of the naringenin-acetylcysteine ​​cocrystal are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 12.15 (s, 1H), 10.76 (s, 1H), 9.57 (s, 1H), 8.17(d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 5.88 (s, 2H), 5.44 (dd, J = 12.8, 3.0 Hz, 1H), 4.38 (td, J = 7.5, 4.6 Hz, 1H), 3.26 (dd, J = 17.1, 12.8 Hz, 1H), 2.85 (ddd, J = 13.2, 8.3, 4.7 Hz, 1H), 2.79–2.63 (m, 2H), 2.43 (t, J = 8.4 Hz, 1H), 1.88 (s, 3H).

[0153] Fourier transform infrared spectroscopy (FTIR) analysis of the naringenin-acetylcysteine ​​cocrystal was performed, and the results are as follows: IR (KBr) 3375.68, 3292.81, 3117.30, 3036.00, 2918.79, 2832.45, 2547.78, 1717.87, 1601.92, 1520.02, 1498.13, 1463.11, 1413.84, 1388.89, 1338.06, 1312.10, 1250.96, 1181.31, 1157.34, 1110.34, 1083.43, 1064.26, 1013.86 cm⁻¹-1 .

[0154] Example 23: Synthesis of naringenin-doxophylline eutectic

[0155]

[0156] Naringenin (1.40 g, 5 mmol), doxorubicin (1.34 g, 5 mmol) and 30 mL of acetone were added to the reaction flask. The mixture was stirred at 40 °C for 3 h, concentrated under reduced pressure to dryness, and the resulting solid was dried at 55 °C to obtain naringenin-doxorubicin eutectic with a yield of 91.13%.

[0157] HPLC analysis was performed on the contents of naringenin and doxophylline in the naringenin-doxophylline cocrystal. The results are shown in the figure. Figure 11 The content of naringenin was 50.1% (theoretical value 50.5%), and the content of doxophylline was 49.1% (theoretical value 49.5%). Calculations showed that the molar ratio of naringenin to doxophylline in the eutectic molecule was consistent with the theoretical value.

[0158] The 1H NMR spectrum analysis of the naringenin-doxophylline cocrystal is shown in the figure below. Figure 12 . 1 H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.76 (s, 1H), 9.57 (s, 1H), 8.01 (s, 1H), 7.34–7.28 (m, 2H), 6.83–6.75 (m, 2H), 5.88 (s, 2H), 5.44 (dd, J = 12.9, 3.0 Hz, 1H), 5.20 (t, J = 4.2 Hz, 1H), 4.43 (d, J = 4.2 Hz, 2H), 3.90 – 3.78 (m, 4H), 3.43 (s, 3H), 3.31–3.25 (m, 1H), 3.22 (s, 3H), 2.68 (dd, J = 17.1, 3.1 Hz, 1H).

[0159] Fourier transform infrared spectroscopy analysis was performed on the naringenin-doxophylline cocrystal, and the results are shown in the figure. Figure 13. IR(KBr) 3334.63, 2952.89, 1689.57, 1647.23, 1594.77, 1551.52, 1519.04, 1468.62,1406.96, 1379.39, 1344.84, 1312.92, 1253.38, 1217.97, 1180.22, 1165.93,1086.95, 1060.37, 1023.27 cm -1 .

[0160] Example 24: Synthesis of naringenin-terbutaline eutectic

[0161]

[0162] Terbutaline (2.30 g, 10 mmol), naringenin (2.73 g, 10 mmol), 10 mL of water and 20 mL of methanol were added to the reaction flask. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, extracted with dichloromethane and water, and the organic phase was concentrated to dryness under reduced pressure. The resulting solid was dried at 55 °C to obtain the naringenin-terbutaline cocrystal with a yield of 89.7%.

[0163] HPLC analysis of the naringenin-terbutaline cocrystal revealed a naringenin content of 70.1% (theoretical value 54.7%) and a terbutaline content of 38.8% (theoretical value 45.3%). Calculations showed that the molar ratio of naringenin to terbutaline in the cocrystal was inconsistent with the theoretical value, indicating that the detection ratio was not fixed and not 1:1.

[0164] Example 25: Determination of the solubility of eutectic compounds

[0165] Compounds that have passed through a 100-mesh sieve were added to a certain volume of water and sonicated for 5 minutes at room temperature. Complete dissolution was considered achieved when no visible solute particles or droplets remained. The solubility results of baicalin, quercetin, naringin, naringenin, and the cocrystals prepared in Examples 1-24 are shown in Table 1.

[0166] Table 1

[0167] Compound Name Water solubility (mg / mL) in conclusion baicalin 0.16 soluble Quercetin - Insoluble Naringin 1 soluble Naringin - Insoluble Baicalin-Atromethamine Cocrystal ＞800 Very soluble Baicalin-Ambroxol Cocrystal 100 Easily soluble Baicalin-pentoxyverine cocrystal 50 Easily soluble Quercetin-ambroxol eutectic 10 soluble Quercetin-acetylcysteine ​​cocrystal 5 soluble Quercetin-Doxophylline Cocrystal 2 soluble Naringin-Gastrotyl Cocrystal 500 Very soluble Naringin-Ambroxol Cocrystal 10 soluble Naringin-pentoxyverine cocrystal 10 soluble Naringin-acetylcysteine ​​cocrystal 50 Easily soluble Naringin-terbutaline cocrystal 10 soluble Naringin-Gastrotyl Cocrystal 10 soluble Naringin-Ambroxol Cocrystal 5 soluble Naringenin-acetylcysteine ​​cocrystal 5 soluble Naringenin-Doxophylline Cocrystal 2 soluble

[0168] As shown in Table 1:

[0169] The solubility of baicalin is 0.16 mg / mL. Its solubility increases after forming cocrystals with other drugs. For example, the solubility of baicalin-tromethorphan cocrystal is greater than 800 mg / mL, which is more than 5,000 times that of baicalin.

[0170] Quercetin is insoluble in water, but its solubility increases when it forms cocrystals with other drugs. For example, the solubility of quercetin-ambroxol cocrystal is greater than 10 mg / mL, and it is soluble in water.

[0171] Naringin has low solubility in water, only 1 mg / mL. However, its solubility increases when it forms cocrystals with other drugs. For example, the solubility of naringin-tromethorphan cocrystal is 500 mg / mL, which is more than 500 times that of naringin.

[0172] Naringen is insoluble in water, but its solubility increases when it forms cocrystals with other drugs. For example, the solubility of naringen-tromethorphan cocrystal is greater than 10 mg / mL, and it is soluble in water.

[0173] Baicalin and quercetin belong to class IV in the BCS classification, while naringin and naringenin belong to class II, all of which are classified as having low solubility. However, the cocrystal developed in this invention can significantly improve their solubility, making them easier to absorb and thus improving bioavailability.

[0174] Example 26: Investigating the effect of the cocrystal on improving a lipopolysaccharide (LPS)-induced inflammation model in RAW264.7 monocytes and macrophages.

[0175] The CO2 cell incubator was purchased from Thermo Fisher Scientific, model 3111; the clean bench was purchased from Suzhou Antai Air Technology Co., Ltd., model SW-CJ-1FD; the benchtop low-speed centrifuge was purchased from Xiangli Scientific Instruments Co., Ltd., model Cenlee 4K; the inverted microscope was purchased from NIKON, model TS2; the imaging system was purchased from NIKON, model MDX10; the microplate reader was purchased from Thermo Fisher Scientific (Shanghai) Instruments Co., Ltd., model Thermo Scientific Multiskan FC; and the electric thermostatic water bath was purchased from Tianjin Test Instruments Co., Ltd., model DK-98-Ⅱ.

[0176] The test compounds are shown in Table 2. All experiments included a blank control group, a model control group, and a drug administration group.

[0177] Table 2

[0178] code name compound HF001 Baicalin-Atromethamine Cocrystal HF002 Baicalin-Ambroxol Cocrystal HF003 Baicalin-pentoxyverine cocrystal HF004 Quercetin-ambroxol eutectic HF005 Quercetin-acetylcysteine ​​cocrystal HF008 Naringin-Gastrotyl Cocrystal HF009 Naringin-acetylcysteine ​​cocrystal HF010 Naringin-Ambroxol Cocrystal HF011 Naringin-pentoxyverine cocrystal HF012 Naringin-terbutaline cocrystal HF013 Naringin-Gastrotyl Cocrystal HF014 Naringin-Ambroxol Cocrystal HF015 Naringenin-acetylcysteine ​​cocrystal HF016 Quercetin-Doxophylline eutectic HF017 Naringenin-Doxophylline Cocrystal HF019 baicalin HF020 Quercetin HF021 Naringin HF022 Naringin HF023 Ambroxol Hydrochloride HF024 Budneid

[0179] When RAW264.7 cells in logarithmic growth phase reached 90% confluence, they were seeded into 12-well plates according to cell passage procedures. Except for the control group, all other cell groups were treated with the corresponding concentration of LPS to induce cell modeling. Simultaneously, the treated groups were administered low, medium, and high concentrations of the test compound, respectively. Twenty-four hours after drug administration, cells were lysed using cell lysis buffer, and total cellular protein was collected. Total cellular protein was quantified using a BCA protein quantification kit. The protein levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the cells were detected using an ELISA kit. The results are shown below. Figure 14 As shown.

[0180] from Figure 14 It can be seen that the cocrystals of HF001, HF003, HF005, HF008, HF009, HF013, and HF017 exhibit superior anti-inflammatory effects on RAW264.7 cells compared to the single compounds HF020-HF024. Therefore, these cocrystals are potential anti-inflammatory drugs. RAW264.7 cells are macrophages, and their cell surface highly expresses key proteins in the inflammatory response process, such as the LPS recognition receptor TLR4 and NADPH oxidase. Upon stimulation by LPS, they rapidly secrete large amounts of inflammatory mediators such as TNF-α, IL-6, and NO. The anti-inflammatory effects of some compounds on RAW264.7 cells may be due to their direct action on the TLR4 receptor or on inflammatory mediators.

[0181] 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 a eutectic drug, characterized in that: Two drugs form a eutectic drug through intermolecular hydrogen bonding.

2. The method for preparing the eutectic drug according to claim 1, characterized in that: The drug is selected from two of the following: flavonoids, organic bases, acetylcysteine, purines, and drugs containing hydroxyl, carboxyl, or thiol groups.

3. The method for preparing the eutectic drug according to claim 1, characterized in that: The drug is selected from two of the following: baicalin, tromethamine, ambroxol, pentoxyverine, quercetin, acetylcysteine, naringin, terbutaline, naringenin, and doxophylline.

4. The method for preparing the eutectic drug according to claim 1, characterized in that: The molar ratio of the two drugs is 1:(1~2), preferably 1:(1~1.5).

5. The method for preparing the eutectic drug according to claim 1, characterized in that: The intermolecular hydrogen bonds are formed at 20~60℃, preferably 25~35℃.

6. The method for preparing the eutectic drug according to claim 1, characterized in that: The drug uses water, organic solvents, or a combination of both as a solvent.

7. The method for preparing the eutectic drug according to claim 6, characterized in that: The organic solvent is at least one of methanol, ethanol, acetone, ethyl acetate, dimethyl sulfoxide, and N,N-dimethylformamide.

8. A cocrystal drug prepared by the method for preparing a cocrystal drug according to any one of claims 1 to 7.

9. The eutectic drug according to claim 8, characterized in that: The cocrystal drugs include baicalin-tromethamine cocrystal, baicalin-ambroxol cocrystal, baicalin-pentoxyverine cocrystal, quercetin-acetylcysteine ​​cocrystal, quercetin-theophylline cocrystal, quercetin-ambroxol cocrystal, naringin-tromethamine cocrystal, naringin-ambroxol cocrystal, naringin-pentoxyverine cocrystal, naringin-terbutaline cocrystal, naringin-tromethamine cocrystal, naringin-ambroxol cocrystal, and naringin-acetylcysteine ​​cocrystal.

10. The use of the eutectic drug according to claim 8 or 9 in the preparation of anti-inflammatory drugs, antiviral drugs, antitumor drugs, antioxidant drugs or hepatoprotective drugs.

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