Application of a supramolecular deep eutectic solvent in improving solubility of naproxen

Abstract

The application discloses application of a supramolecular eutectic solvent in improving solubility of naproxen, wherein the supramolecular eutectic solvent is prepared by taking methyl-beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin as a hydrogen bond acceptor and phenethyl alcohol or acetylpiclinic acid as a hydrogen bond donor, and the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 1:25-50.The application takes methyl-beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin as a hydrogen bond acceptor, systematically investigates the influence of different hydrogen bond donors on the solubility of naproxen, and successfully screens and prepares a supramolecular eutectic solvent system which is green, environment-friendly and easy to degrade.The supramolecular eutectic solvent has moderate polarity and viscosity and excellent thermal stability, and the solubility test result shows that the prepared supramolecular eutectic solvent can obviously improve the solubility of naproxen, and the solubility is obviously stronger than that of the reported solvent, so that the defect of poor water solubility of naproxen is effectively improved, and a technical thought and path are provided for research and industrialization of a new type of naproxen preparation.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to the application of a supramolecular eutectic solvent in improving the solubility of naproxen. Background Technology

[0002] Naproxen (NPX) is a propionic acid derivative nonsteroidal anti-inflammatory drug (NSAID) widely used in the treatment of rheumatoid arthritis, osteoarthritis, gout, and dysmenorrhea. However, its solubility in water at 298.15 K is only 15.9 μg / mL. This poor water solubility not only reduces the drug's bioavailability but also limits its widespread clinical application.

[0003] The dissolution of poorly soluble drugs is a common challenge in the pharmaceutical industry. Current strategies for improving drug solubility include using solid dispersions, adjusting pH, forming salts, and utilizing eutectic solvents for solubilization. However, some methods present challenges related to physical stability: for example, solid dispersions may exhibit a tendency to crystallize, thus affecting long-term stability. While eutectic solvents are considered environmentally friendly and have low toxicity, their ability to specifically recognize particular drug molecules is limited, which restricts their application to some extent.

[0004] Supramolecular eutectic solvents (SUPRADES) are constructed using cyclodextrin as a hydrogen bond acceptor and other hydrogen bond donors through a hydrogen bond network. Supramolecular eutectic solvents not only possess the rich hydrogen bond network of traditional eutectic solvents but also have the host-guest inclusion function of cyclodextrin, enabling targeted inclusion and solubilization of poorly soluble drugs. Furthermore, their composition and proportions can be flexibly designed over a wide range, providing space for customized design. Therefore, it is necessary to research and develop a supramolecular eutectic solvent for naproxen to efficiently improve its solubility and thus enhance its bioavailability. Summary of the Invention

[0005] Therefore, the purpose of this invention is to provide an application of a supramolecular eutectic solvent in improving the solubility of naproxen. This supramolecular eutectic solvent has excellent solubility for naproxen, providing a new approach for the development of naproxen solubilizing formulations.

[0006] This invention is achieved through the following technical solution:

[0007] The application of a supramolecular eutectic solvent in improving the solubility of naproxen, wherein the supramolecular eutectic solvent uses methyl-β-cyclodextrin or hydroxypropyl-β-cyclodextrin as hydrogen bond acceptor and phenylethanol or levulinic acid as hydrogen bond donor, and the molar ratio of hydrogen bond acceptor to hydrogen bond donor is 1:25-50.

[0008] The supramolecular eutectic solvent of this invention uses hydrogen bond acceptors and hydrogen bond donors to interact through a hydrogen bond network, solubilizing the carbonyl group of naproxen through polarity matching and hydrogen bonding. Cyclodextrin further enhances the solubility of naproxen through inclusion complexation, thereby significantly improving the solubility of naproxen.

[0009] As a preferred embodiment of the present invention, the supramolecular eutectic solvent is a mixture of methyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:30-40, a mixture of hydroxypropyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:30-39, a mixture of methyl-β-cyclodextrin and levulinic acid at a molar ratio of 1:30-40, or a mixture of hydroxypropyl-β-cyclodextrin and levulinic acid at a molar ratio of 1:26-40.

[0010] As a further preferred technical solution of the present invention, the supramolecular eutectic solvent is a mixture of methyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:40, a mixture of hydroxypropyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:39, a mixture of methyl-β-cyclodextrin and levulinic acid at a molar ratio of 1:40, or a mixture of hydroxypropyl-β-cyclodextrin and levulinic acid at a molar ratio of 1:26.

[0011] As a preferred embodiment of the present invention, the supramolecular eutectic solvent is a mixture of methyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:40 or a mixture of hydroxypropyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:39.

[0012] The supramolecular eutectic solvent of this invention has a polarity in the range of 45-55 kcal / mol and a thermal decomposition initiation temperature >393K, and has both moderate polarity and good thermal stability.

[0013] As a preferred technical solution of the present invention, the application involves mixing naproxen with a supramolecular eutectic solvent, heating and stirring to dissolve, thereby obtaining a naproxen solubilized formulation.

[0014] The present invention found that the solubility of naproxen in supramolecular eutectic solvents is significantly temperature-dependent, with the solubility of naproxen increasing significantly as the temperature rises.

[0015] As a preferred embodiment of the present invention, the heating temperature is 293.15-333.15 K, and the stirring time is 1-3 hours.

[0016] As a preferred embodiment of the present invention, the naproxen solubilizing formulation further includes pharmaceutically acceptable excipients.

[0017] In this invention, pharmaceutically acceptable excipients include, but are not limited to, diluents, excipients, fillers, binders, absorption enhancers, surfactants, adsorbent carriers, and lubricants. Each excipient is used in conventional amounts as known in the art, and the corresponding pharmaceutical formulation is prepared according to conventional processes known in the art.

[0018] As a preferred embodiment of the present invention, the naproxen solubilizing agent is a transdermal preparation or an injection.

[0019] Compared with the prior art, the present invention has the following advantages:

[0020] This invention uses methyl-β-cyclodextrin or hydroxypropyl-β-cyclodextrin as hydrogen bond acceptors to systematically investigate the effects of different hydrogen bond donors on the solubility of naproxen. A green, environmentally friendly, and easily degradable supramolecular eutectic solvent system was successfully screened and prepared. This supramolecular eutectic solvent possesses moderate polarity and viscosity, as well as excellent thermal stability. Solubility test results show that the prepared supramolecular eutectic solvent can significantly improve the solubility of naproxen, and its solubility is significantly stronger than that of previously reported solvents. This effectively improves the poor water solubility of naproxen, providing a technical approach and feasible path for the research and industrialization of novel naproxen formulations. Attached Figure Description

[0021] Figure 1 The Gibbs free energy of dissolution of naproxen in a mixture of methyl-β-cyclodextrin / hydroxypropyl-β-cyclodextrin and hydrogen bond donor (1:40) at 298.15 K;

[0022] Figure 2 Fourier transform infrared spectra of supramolecular eutectic solvent and supramolecular eutectic solvent + naproxen;

[0023] Figure 3 The solubility of naproxen in supramolecular eutectic solvents at different temperatures;

[0024] Figure 4 The density of the supramolecular eutectic solvent at different temperatures;

[0025] Figure 5 The graph shows the viscosity changes of supramolecular eutectic solvents at different temperatures.

[0026] Figure 6 The maximum absorption wavelength of Nile Red in a supramolecular eutectic solvent and the polarity of the supramolecular eutectic solvent;

[0027] Figure 7 Thermogravimetric curves and derivative thermogravimetric curves of supramolecular eutectic solvents at different temperatures are shown. Detailed Implementation

[0028] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. The described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] All chemicals and reagents used in the preparation of supramolecular eutectic solvents in the embodiments of this invention are commercially available.

[0030] 1. Screening of supramolecular eutectic solvents

[0031] The Gibbs free energy of dissolution (-ΔG) of naproxen at 298.15 K in 42 supramolecular eutectic solvent candidates and water was calculated using the COSMO-RS model. sol The supramolecular eutectic solvent uses methyl-β-cyclodextrin (RAMEB) and hydroxypropyl-β-cyclodextrin (HP-β-CD) as hydrogen bond acceptors, and the hydrogen bond donors are listed in Table 1. The molar ratio of cyclodextrin to hydrogen bond donor is 1:40.

[0032] Table 1. Candidate hydrogen bond donors for supramolecular eutectic solvents

[0033] lactic acid bitter n-heptanoic acid glycerin hexanoic acid Thymol Ethylene glycol butyric acid 1-Heptanol Propylene glycol levulinic acid Cyclohexyl methanol 1-Pentanol Isobutanol benzyl alcohol Phenylacetyl alcohol 2-Butanol 1,3-Butanediol

[0034] Figure 1 The Gibbs free energy of dissolution of naproxen in a mixture of methyl-β-cyclodextrin / hydroxypropyl-β-cyclodextrin and hydrogen bond donor (1:40) at 298.15 K is shown. The more negative the Gibbs free energy of dissolution, the stronger the solvent’s ability to dissolve naproxen.

[0035] Depend on Figure 1 It is known that 1,3-butanediol, 2-butanol, and phenethyl alcohol all exhibit strong solubility for naproxen. However, 1,3-butanediol has strong hygroscopicity and mild toxicity; 2-butanol has a low boiling point at normal pressure (372.65K) and is easily lost through volatilization. Considering all factors, phenethyl alcohol combines antibacterial activity with good safety and has obtained FDA GRAS certification, making it widely used in oral, topical, and injectable formulations. Therefore, it was selected as one of the candidate hydrogen bond donors in this study. In addition, levulinic acid also exhibits strong solubility for naproxen, and its molecular structure contains carboxyl and ketone groups, making it an excellent hydrogen bond donor for the construction of supramolecular eutectic solvents. Furthermore, levulinic acid is a biomass-derived platform compound with green, biodegradable, and low-toxicity characteristics, aligning with the development concept of green medicine. Therefore, it was also selected as another candidate hydrogen bond donor in this study.

[0036] 2. Preparation and characterization of supramolecular eutectic solvents

[0037] 1.1 The supramolecular eutectic solvent was prepared by heating and stirring. The specific experimental steps are as follows:

[0038] (1) Raw material preparation: Phenylephrine and levulinic acid were selected as hydrogen bond donors, and methyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin were selected as hydrogen bond acceptors;

[0039] (2) Weighing and mixing: Weigh each component accurately according to the specified molar ratio;

[0040] (3) Heating and stirring: After mixing the weighed raw materials, place them at 333.15K and stir magnetically. Continue stirring until the solution is completely clear and transparent, ensuring that all components are fully mixed and form a homogeneous solvent;

[0041] (4) Cooling and standing: Cool the prepared solvent to room temperature. Let it stand at room temperature for one week and observe its stability and whether layering or crystallization occurs.

[0042] In the construction of supramolecular eutectic solvents, the molar ratio between cyclodextrin and hydrogen bond donors is not simply a dilution, but directly determines the hydrogen bond network density and macroscopic rheological properties within the system. To comprehensively investigate the influence of the ratio on the physical state of the system, this study systematically screened a series of ratios from low to high (1:10-50), the composition and physical state of which are detailed in Table 2.

[0043] Table 2. Composition and physical state of supramolecular eutectic solvents

[0044] SUPRADES2 Hydroxypropyl-β-cyclodextrin:Phenylexic alcohol = 1:39 homogeneous, clear liquid SUPRADES3 Methyl-β-cyclodextrin: levulinic acid = 1:40 homogeneous, clear liquid SUPRADES4 Hydroxypropyl-β-cyclodextrin: levulinic acid = 1:26 homogeneous, clear liquid SUPRADES5 Methyl-β-cyclodextrin: phenylethanol = 1:30 homogeneous, clear liquid SUPRADES6 Methyl-β-cyclodextrin: phenylethanol = 1:50 homogeneous, clear liquid SUPRADES7 Hydroxypropyl-β-cyclodextrin:Phenylexic alcohol = 1:30 homogeneous, clear liquid SUPRADES8 Hydroxypropyl-β-cyclodextrin:Phenylexic alcohol = 1:50 homogeneous, clear liquid SUPRADES9 Methyl-β-cyclodextrin: levulinic acid = 1:30 homogeneous, clear liquid SUPRADES10 Methyl-β-cyclodextrin: levulinic acid = 1:50 homogeneous, clear liquid SUPRADES11 Hydroxypropyl-β-cyclodextrin: levulinic acid = 1:30 homogeneous, clear liquid SUPRADES12 Hydroxypropyl-β-cyclodextrin: levulinic acid = 1:40 homogeneous, clear liquid SUPRADES13 Hydroxypropyl-β-cyclodextrin: levulinic acid = 1:50 homogeneous, clear liquid SUPRADES14 Methyl-β-cyclodextrin: phenylethanol = 1:10 Turbid liquid, containing solid precipitate SUPRADES15 Methyl-β-cyclodextrin: phenylethanol = 1:20 homogeneous, viscous liquid SUPRADES16 Hydroxypropyl-β-cyclodextrin:Phenylexic alcohol = 1:10 Turbid liquid, containing solid precipitate SUPRADES17 Hydroxypropyl-β-cyclodextrin:Phenylexic alcohol = 1:20 homogeneous, viscous liquid SUPRADES18 Methyl-β-cyclodextrin: levulinic acid = 1:10 Turbid liquid, containing solid precipitate SUPRADES19 Methyl-β-cyclodextrin: levulinic acid = 1:20 homogeneous, viscous liquid SUPRADES20 Hydroxypropyl-β-cyclodextrin: levulinic acid = 1:10 Turbid liquid, containing solid precipitate SUPRADES21 Hydroxypropyl-β-cyclodextrin: levulinic acid = 1:20 homogeneous, viscous liquid

[0045] As shown in Table 2, for the four types of supramolecular eutectic solvents, all were turbid liquids containing solid precipitates at a molar ratio of cyclodextrin to hydrogen bond donor of 1:10. This heterogeneous coexistence indicates that the system failed to form a thermodynamically stable true solution or eutectic network, and therefore did not meet the basic conditions for use as a drug delivery solvent, so it was excluded first. Further investigation at higher ratios revealed that the viscosity of the system decreased progressively with the increase of the proportion of hydrogen bond donor, but the phase transition critical points of different combinations differed. Based on a comprehensive trade-off between uniform stability, injectable flowability, and drug affinity microenvironment, this study did not mechanically select the highest dilution (e.g., a ratio of 1:50), but instead precisely anchored the optimal threshold that balances drug loading potential and rheological properties based on the structural characteristics of different cyclodextrin derivatives and hydrogen bond donors, ultimately selecting four ratios of SUPRADES 1-4.

[0046] SUPRADES1 (methyl-β-cyclodextrin: phenylethanol = 1:40): Phenyethanol acts as a molecular diluent to reduce viscosity and enhances the affinity for naproxen through π-π stacking. At a ratio of 1:40, both flowability and naproxen solubility are balanced. Although 1:50 has better flowability, the aromatic ring density is too high, which dilutes the content of methyl-β-cyclodextrin and is not conducive to drug loading.

[0047] SUPRADES2 (hydroxypropyl-β-cyclodextrin: phenylethanol = 1:39): Hydroxypropyl-β-cyclodextrin has better hydrophilic flexibility, and a suitable viscosity can be achieved at a ratio of 1:39. It also retains the hydroxypropyl-β-cyclodextrin concentration to the maximum extent to maintain high solubility and saturation.

[0048] SUPRADES3 (Methyl-β-cyclodextrin:levulinic acid = 1:40): Levulinic acid solubilizes cyclodextrin through hydrogen bonding interactions with the peripheral hydrogen bonding sites of methyl-β-cyclodextrin. Simultaneously, the carbonyl / carboxyl groups of levulinic acid form strong hydrogen-bonded complexes with naproxen, further solubilizing naproxen in conjunction with the inclusion effect of methyl-β-cyclodextrin. A 1:40 ratio achieves a balance between viscosity and naproxen solubility: compared to 1:30, the increased proportion of levulinic acid effectively weakens the hydrogen bonding between methyl-β-cyclodextrin particles, significantly reducing the system viscosity and meeting the operability requirements for injection administration; while compared to 1:50, this ratio retains a higher cyclodextrin concentration, ensuring sufficient inclusion cavities and hydrogen bonding sites, avoiding decreased naproxen solubility or impaired long-term storage stability due to excessive dilution with levulinic acid.

[0049] SUPRADES4 (hydroxypropyl-β-cyclodextrin: levulinic acid = 1:26): The phase transition critical point of this combination is between 1:20 (extremely viscous) and 1:30 (clare). The selection of 1:26 is based on the principle of "minimum effective dilution", that is, while crossing the viscosity barrier, the maximum density of active groups is retained to enhance drug affinity and avoid excessive dilution from damaging the long-term stability of the formulation.

[0050] In summary, the four selected formulations achieved a balance between rheological properties and the drug solubilizing microenvironment, ensuring both the clarity and homogeneity of the supramolecular eutectic solvent and meeting the operability requirements for injection administration.

[0051] 1.2 Fourier Transform Infrared Spectroscopy (FT-IR) Characterization

[0052] Dried potassium bromide was pressed into thin sheets at room temperature, and then a supramolecular eutectic solvent was applied to the sheets before spectral measurements were performed. The spectral scanning range was 600–4000 cm⁻¹. -1 The scan was performed 32 times, with a spectral resolution of 4 cm⁻¹. -1 Each sample was measured three times.

[0053] Figure 2 The Fourier transform infrared (FTIR) spectra of each supramolecular eutectic solvent and the Fourier transform infrared (FTIR) spectra of the corresponding supramolecular eutectic solvent plus naproxen are shown respectively. The red spectra located at the top of the figure are the Fourier transform infrared spectra of the corresponding supramolecular eutectic solvent plus naproxen.

[0054] Observation of the infrared spectra of four supramolecular eutectic solvents without naproxen revealed that at 3400 cm⁻¹... -1 The broad peaks near the peaks are all stretching vibrations of OH bonds, and their peak broadening is due to intermolecular hydrogen bonding.

[0055] In the infrared spectrum of SUPRADES1 without added drug, 2931.92 cm⁻¹ -1 The absorption peak at 1041.77 cm⁻¹ is attributed to the CH stretching vibration of the methylene group corresponding to phenylethanol and the superposition of the CH vibration of the sugar ring skeleton of methyl-β-cyclodextrin with the methoxy group. -1 The strong absorption peak at that point indicates the stretching vibration of the alcohol CO single bond of phenylethanol and the COC glycosidic bond vibration of methyl β-cyclodextrin.

[0056] The infrared spectrum of SUPRADES2 without added drug showed a value of 2933.88 cm⁻¹. -1 The nearby absorption peaks are due to the stretching vibration of the phenylethyl methylene (-CH2-) group and the CH stretching vibration of the cyclodextrin backbone and hydroxypropyl side chain of hydroxypropyl-β-cyclodextrin. Meanwhile, the 1650-1450 cm⁻¹... -1 The vibration at this location is primarily due to the C=C stretching vibration of the benzene ring skeleton of phenylethanol. 1041.02 cm⁻¹ -1 The position belongs to the bending vibration of saturated alkyl CH.

[0057] In the untreated infrared spectra of SUPRADES3 and SUPRADES4, at 2650 cm⁻¹ -1 Nearby is the -OH subpeak of the carboxyl group of levulinic acid, and it is at 1712 cm⁻¹. -1 The vicinity also shows stretching vibrations of the carboxyl group (-COOH) and the ketone carbonyl group (C=O) of levulinic acid. The untreated infrared spectrum of SUPRADES3 is shown at 2932.13 cm⁻¹. -1 The saturated CH stretching vibrations of the methyl and methylene groups of levulinic acid and the saturated CH stretching vibrations of the sugar ring skeleton and methoxy group of methyl-β-cyclodextrin are present at 1405.73 cm⁻¹. -1 1368.78 cm -1 Both locations are dominated by saturated alkyl CH bending vibrations. 1164.17 cm -1 With 1043.37 cm -1All vibrations were CO bond stretching vibrations, primarily originating from the carboxyl CO group of levulinic acid and the skeletal CO group of methyl-β-cyclodextrin. A value of 2930.13 cm⁻¹ was observed in the untreated infrared spectrum of SUPRADES4. -1 The absorption peaks are due to the saturated CH stretching vibrations of the methyl and methylene groups of levulinic acid and the saturated CH stretching vibrations of the sugar ring skeleton and methoxy group of hydroxypropyl-β-cyclodextrin. 1404.77 cm⁻¹ -1 1368.82 cm -1 Both locations are dominated by saturated alkyl CH bending vibrations. 1163.70 cm -1 With 1034.06 cm -1 All of these are CO bond stretching vibrations, mainly originating from the carboxyl CO of levulinic acid and the skeletal CO of hydroxypropyl-β-cyclodextrin.

[0058] contrast Figure 2 Fourier transform infrared (FTIR) spectra of naproxen in both pure supramolecular eutectic solvent and supramolecular eutectic solvent showed small wavelength deviations and no additional new absorption peaks, indicating that the naproxen peaks may be covered by the supramolecular eutectic solvent peaks. Furthermore, the prepared supramolecular eutectic solvent did not react with naproxen, but rather maintained the characteristics of its original components. However, after adding the drug to SUPRADES3 and SUPRADES4, the wavelength deviation at 2650 cm⁻¹ was [not specified]. -1 The characteristic peak disappeared, possibly at 2640 cm⁻¹. -1 The peak is the OH vibration subpeak of the carboxyl dimer of levulinic acid. After the addition of naproxen, the three form hydrogen bonds with each other, and the original carboxyl dimer structure of levulinic acid is destroyed, causing this characteristic peak to disappear.

[0059] 3. Determination of naproxen solubility

[0060] The solubility of naproxen in the following supramolecular eutectic solvents was tested using electromagnetic stirring-assisted dissolution combined with UV-Vis spectrophotometry: methyl-β-cyclodextrin with phenylethanol (1:40), hydroxypropyl-β-cyclodextrin with phenylethanol (1:39), methyl-β-cyclodextrin with levulinic acid (1:40), and hydroxypropyl-β-cyclodextrin with levulinic acid (1:26).

[0061] The specific experimental steps are as follows:

[0062] (1) Standard curve preparation: Prepare 5 groups of 5 mL SUPRADES solutions, add a certain amount of naproxen (0.04 g / 5 mL, 0.08 g / 5 mL, 0.12 g / 5 mL, 0.16 g / 5 mL, 0.2 g / 5 mL) to each group, heat and stir at a constant temperature for 2 hours, then take 1 mL of supramolecular eutectic solvent + a certain amount of ethanol from each group, dilute to 4000 times, and use a UV-Vis spectrophotometer (X-8D) to scan the spectrum at 0.5 nm intervals in the wavelength range of 200-400 nm. The measurement wavelength is 331 nm. Use ethanol to dilute the untreated SUPRADES as a blank solvent to ensure that the baseline deviation is less than 0.005 cm⁻¹. -1 The sample was appropriately diluted with ethanol to ensure the measured absorbance range was between 0.2 and 0.8 Abs (ensuring consistency with the dilution factor of the blank). Based on the Lambert-Beer law, a standard curve for naproxen solution was plotted using the naproxen concentration (y) and absorbance value (x): y = kx + b. The standard curve parameters for the four supramolecular eutectic solvents are shown in Table 3.

[0063] Table 3. Standard curve parameters of naproxen-supramolecular eutectic solvent

[0064] SUPRADES1 7.8861 0.0133 0.9962 SUPRADES2 7.5979 0.0173 0.9970 SUPRADES3 7.6485 0.0191 0.9996 SUPRADES4 7.4508 0.0289 0.9997

[0065] (2) Measurement of solubility

[0066] ① Sample preparation: Add a certain amount of naproxen to a flask containing 10 mL of supramolecular eutectic solvent. Seal the flask to prevent solvent evaporation or contamination.

[0067] ② Stirring and dissolving: Place the flask in a heat-collecting magnetic stirrer and maintain a constant temperature at 298.15 K, 308.15 K, 318.15 K, 328.15 K, and 338.15 K respectively. If naproxen is completely dissolved, continue to add it to ensure that a supersaturated solution of naproxen is prepared. Continue stirring for 2 hours under heating conditions.

[0068] ③ Sample extraction and filtration: Using a preheated 2.5 mL syringe, draw 1.5 mL of solution from the flask. Filter through a 0.5 mL PTFE filter to remove undissolved naproxen, yielding 1 mL of clear sample.

[0069] ④ Ultraviolet-Vis Spectrophotometry: A UV-Vis spectrophotometer was used to scan the spectrum at 0.5 nm intervals within the wavelength range of 200–400 nm. The measurement wavelength was 331 nm. Untreated SUPRADES was diluted with ethanol as a blank solvent to ensure a baseline deviation of less than 0.005 cm⁻¹. -1The sample was appropriately diluted with ethanol to ensure the measured absorbance range was between 0.2 and 0.8 Abs. Finally, the absorbance was measured at different temperature ranges, with each range measured at least three times to ensure data reliability and repeatability.

[0070] (3) Calculation of solubility

[0071] The average absorbance measured for each temperature range was taken and substituted into the corresponding standard curve to determine the solubility at that temperature range. The solubility of naproxen in supramolecular eutectic solvents at different temperatures is shown below. Figure 3 The solubility of naproxen at 298.15 K in the supramolecular eutectic solvent described in this invention and in existing solvents is listed in Table 4.

[0072] Table 4. Comparison of solubility of naproxen at 298.15 K in the supramolecular eutectic solvent of this invention and in existing solvents.

[0073] SUPRADES1 78.214 SUPRADES2 84.339 SUPRADES3 44.689 SUPRADES4 30.621 Hydroxypropyl-β-cyclodextrin:L-valine (1:1) 5.36 Hydroxypropyl-β-cyclodextrin:L-isoleucine (1:1) 5.38 Hydroxypropyl-β-cyclodextrin:L-arginine (1:1) 29.5 Hydroxypropyl-β-cyclodextrin:L-lysine (1:1) 16.0 L-valine 0.18 L-Isoleucine 0.19 L-arginine 14.5 L-Lysine 12.1 Hydroxypropyl-β-cyclodextrin 11.3 Octyl alcohol 25.21 chloroform 66.31 Isopropyl myristate 4.93 Cyclohexane 0.12 Ethylene glycol 12.66 Choline chloride:Propylene glycol (1:3) 11.72

[0074] As shown in Table 4 above, the supramolecular eutectic solvent prepared in this invention exhibits excellent solubility for naproxen. Furthermore, at the same temperature, the solubility of SUPRADES1 and SUPRADES2 is higher than that of solvents disclosed in existing literature. Although naproxen has a solubility of 66.31 mg / mL in chloroform, chloroform has a boiling point of only 334.35 K, making it highly volatile. Moreover, its metabolism in the liver produces toxic intermediates such as phosgene, which can lead to severe hepatocellular necrosis and fatty degeneration. Therefore, its use in pharmaceutical formulations is strictly limited.

[0075] from Figure 3 As can be seen, at 298.15 K, supramolecular eutectic solvents containing phenethyl alcohol exhibit high solubility for naproxen. For example, SUPRADES1 (methyl-β-cyclodextrin:phenethyl alcohol = 1:40) shows a solubility of 78.214 mg / mL for naproxen, nearly twice that of SUPRADES3 (methyl-β-cyclodextrin: levulinic acid = 1:40) at 44.689 mg / mL. The solubility of supramolecular eutectic solvents shows a significant temperature dependence; as the temperature increases, the solubility of naproxen increases significantly. At 338.15 K, the solubility of the SUPRADES1 (methyl-β-cyclodextrin:phenethyl alcohol = 1:40) system reaches 239.510 mg / mL, possibly because the partial breaking of the hydrogen bond network at high temperatures enhances the solubilization ability. A systematic comparison of the solubility of four supramolecular eutectic solvents revealed that SUPRADES1 (methyl-β-cyclodextrin: phenylethanol = 1:40) and SUPRADES2 (hydroxypropyl-β-cyclodextrin: phenylethanol = 1:39) exhibited better solubility for naproxen.

[0076] 4. Determination of density and viscosity

[0077] Density was measured using a U-tube vibrating densitometer (Anton Paar DMA 5000 M) in static mode within the range of atmospheric pressure and 293.15–333.15 K. The instrument was validated before and after measurement with air and three times with deionized water. The analytical uncertainties for density and temperature of this densitometer are ±0.1 kg·m³, respectively. -3 and ±0.001 K.

[0078] Viscosity was measured using a falling ball microvisometer (Anton Paar Lovis 2000 M / ME) at ambient pressure within a temperature range of 293.15–333.15 K. Temperature control accuracy was ±0.005 K, and measurement accuracy was better than 0.02 K. A 1.8 mm inner diameter capillary tube was used, pre-calibrated with standard oil at different temperatures and measurement angles. The overall measurement uncertainty for viscosity was 2%. After each solvent measurement, the apparatus was thoroughly cleaned with anhydrous ethanol to remove any residual solvent, and all ethanol was purged before the next measurement.

[0079] The density and viscosity data of four supramolecular eutectic solvents at different temperatures are shown in Tables 5-6 and 6. Figure 4-5 As shown.

[0080] Table 5. Densities of supramolecular eutectic solvents at different temperatures (kg / m³) 3 )

[0081] 293.15 1082.3 1091.7 1189.2 1224.4 303.15 1074.8 1085 1180.9 1216.4 313.15 1067.4 1077.5 1172.5 1207.7 323.15 1059.9 1070 1164.3 1199.7 333.15 1052.3 1062.4 1156 1191.8

[0082] Table 6. Viscosities (mPa·s) of supramolecular eutectic solvents at different temperatures

[0083] 293.15 93.609 417.172 337.155 4933.780 303.15 49.410 194.575 157.862 1756.537 313.15 28.855 86.048 83.567 626.653 323.15 18.205 44.247 49.091 301.807 333.15 12.223 25.171 31.251 160.263

[0084] The data are now fitted using the corresponding equations. The density (ρ) of the supramolecular eutectic solvent is described using a linear model, as shown in the following equation:

[0085]

[0086] In the formula, T represents the measurement temperature; λ0 and λ1 represent the intercept and slope of the linear fit. The viscosity (η) of the supramolecular eutectic solvent is fitted using the Vogel-Fulcher-Taman (VFT) model, as shown in the following formula:

[0087]

[0088] In the formula, α (mPa·s) represents the limiting high-temperature viscosity; β (K) represents an empirical constant; T0 is the characteristic temperature; and T represents the measurement temperature. The final density-viscosity fitting curves are shown below. Figure 4 and Figure 5 As shown.

[0089] observe Figure 4-5 It was observed that the higher the temperature, the lower the density and viscosity of the supramolecular eutectic solvent. Density and temperature showed an almost linear relationship, but the effect of temperature was not significant. Viscosity showed a curvilinear relationship with temperature; increasing the temperature significantly reduced the solvent viscosity. The density and viscosity of SUPRADES1 (methyl-β-cyclodextrin: phenylethanol = 1:40) were 1082.3 kg / m³. 3 The viscosity of SUPRADES2 (hydroxypropyl-β-cyclodextrin: phenylethanol = 1:39) is 93.609 mPa·s, significantly lower than the other three systems. This gives it optimal fluidity, minimizing injection thrust and patient discomfort, and fully meeting the stringent low viscosity requirements for injectable administration. Although SUPRADES2 has a relatively high viscosity at room temperature (417.172 mPa·s at 293.15 K), its viscosity exhibits a strong temperature dependence, rapidly decreasing to around 100 mPa·s as the temperature rises to near-physiological conditions (310–313 K), remaining within a viscosity window suitable for smooth injection. Simultaneously, its density is only slightly higher than SUPRADES1 among the four systems, also demonstrating good operability. Furthermore, SUPRADES2 also possesses the highest naproxen solubility (84.339 mg·mL). -1 These four supramolecular eutectic solvents achieve an optimal balance between drug loading capacity and administration compliance. SUPRADES3, while maintaining low viscosity, is suitable for systems requiring high injection smoothness or enhanced drug loading through hydrogen bonding, thanks to the strong hydrogen-bonding ability provided by the carbonyl / carboxyl groups of levulinic acid. Although SUPRADES4 has a relatively high viscosity at room temperature, it retains the highest density of cyclodextrin active groups and exhibits a strong temperature dependence on viscosity, significantly improving flowability at near-physiological temperatures or under slight preheating conditions, meeting the operability requirements for injection or local administration. These four supramolecular eutectic solvents complement each other in terms of solubility, rheological properties, temperature responsiveness, and polar microenvironment, providing flexible and controllable carrier options for diverse routes of naproxen administration.

[0090] 5. Polarity Measurement

[0091] Naproxen is a hydrophobic drug, and the cyclodextrin cavity possesses hydrophobic inclusion capacity. Adjusting the polarity can enhance naproxen solubility by moderately aiding dissolution with the help of a solvent while retaining the hydrophobic inclusion capacity. Therefore, polarity measurement is necessary.

[0092] The experimental procedure is as follows: 60 μL of a 1 mmol / L Nile Red solution was pipetted into a vial, followed by 2940 μL of SUPRADES solution. The mixture was thoroughly shaken to ensure homogeneity. The solution was then transferred to a quartz cuvette, and the sample was spectrally scanned using a UV spectrophotometer at wavelengths of 400-700 nm. Each sample was measured twice. After spectral scanning, the maximum absorption wavelength (λmax) of Nile Red in the supramolecular eutectic solvent was obtained. The polarity value (ENR), expressed in kcal / mol, was calculated by substituting this wavelength into the following formula. The results of the polarity measurements in the supramolecular eutectic solvent are shown in Table 7. Figure 6 As shown.

[0093]

[0094] Table 7. Polarity of supramolecular eutectic solvents

[0095] SUPRADES1 562.00 50.874 SUPRADES2 562.50 50.829 SUPRADES3 574.49 49.768 SUPRADES4 573.50 49.854

[0096] Depend on Figure 6 As shown in Table 7, the polarity of the four supramolecular eutectic solvents is between 49 and 51, which is moderate. This moderate polarity is beneficial for enhancing the solubilization and depolymerization of naproxen by utilizing the moderate polar environment of the solvent while retaining the hydrophobic inclusion ability of the cyclodextrin cavity, thereby achieving efficient solubilization of hydrophobic drugs.

[0097] 6. Thermal stability analysis

[0098] Thermogravimetric analysis (TGA) is a thermal analysis technique used to study the thermal stability, decomposition temperature, and component content of materials. It measures the change in mass of a substance over time (or temperature) under programmed temperature control. Thermogravimetric curves (TG) and derivative thermogravimetric curves (DTG) of four supramolecular eutectic solvents as a function of temperature were obtained, and the results are as follows: Figure 7 express.

[0099] Observation of the thermal decomposition curves of four supramolecular eutectic solvents revealed significant differences in their thermal decomposition behaviors, with varying initial thermal decomposition temperatures. This indicates that the combination of hydrogen bond donors and acceptors alters the thermal stability of the supramolecular eutectic solvents. The residual mass fractions of all samples remained low at the high-temperature stage, suggesting that all four supramolecular eutectic solvents could be completely thermally decomposed, indicating low impurity content and good overall purity. The thermal decomposition initiation temperatures of all four supramolecular eutectic solvents were above 393 K, demonstrating good thermal stability. These relatively high thermal decomposition temperatures enable them to withstand the high-temperature operations involved in formulation preparation, such as hot-melt extrusion, terminal sterilization, and drying granulation, providing a broad process window for production.

[0100] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. The application of a supramolecular eutectic solvent in improving the solubility of naproxen, characterized in that, The supramolecular eutectic solvent uses methyl-β-cyclodextrin or hydroxypropyl-β-cyclodextrin as hydrogen bond acceptors and phenylethanol or levulinic acid as hydrogen bond donors, with a molar ratio of hydrogen bond acceptors to hydrogen bond donors of 1:25-50.

2. The application of the supramolecular eutectic solvent according to claim 1 in improving the solubility of naproxen, characterized in that, The supramolecular eutectic solvent is a mixture of methyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:30-40, a mixture of hydroxypropyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:30-39, a mixture of methyl-β-cyclodextrin and levulinic acid at a molar ratio of 1:30-40, or a mixture of hydroxypropyl-β-cyclodextrin and levulinic acid at a molar ratio of 1:26-40.

3. The application of the supramolecular eutectic solvent according to claim 2 in improving the solubility of naproxen, characterized in that, The supramolecular eutectic solvent is a mixture of methyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:40, a mixture of hydroxypropyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:39, a mixture of methyl-β-cyclodextrin and levulinic acid at a molar ratio of 1:40, or a mixture of hydroxypropyl-β-cyclodextrin and levulinic acid at a molar ratio of 1:

26.

4. The application of the supramolecular eutectic solvent according to claim 3 in improving the solubility of naproxen, characterized in that, The supramolecular eutectic solvent is a mixture of methyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:40 or a mixture of hydroxypropyl-β-cyclodextrin and phenylethanol at a molar ratio of 1:

39.

5. The application of the supramolecular eutectic solvent according to any one of claims 1-4 in improving the solubility of naproxen, characterized in that, The supramolecular eutectic solvent has a polarity of 45-55 kcal / mol and a thermal decomposition initiation temperature >393 K.

6. The application of the supramolecular eutectic solvent according to any one of claims 1-4 in improving the solubility of naproxen, characterized in that, The application involves mixing naproxen with a supramolecular eutectic solvent, heating and stirring to dissolve, thereby obtaining a naproxen solubilized formulation.

7. The application of the supramolecular eutectic solvent according to claim 6 in improving the solubility of naproxen, characterized in that, The heating temperature is 293.15-333.15 K, and the stirring time is 1-3 hours.

8. The application of the supramolecular eutectic solvent according to claim 6 in improving the solubility of naproxen, characterized in that, The naproxen solubilizing formulation also includes pharmaceutically acceptable excipients.

9. The application of the supramolecular eutectic solvent according to claim 6 in improving the solubility of naproxen, characterized in that, The naproxen solubilizing agent is a transdermal preparation or an injection.

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