Application of eutectic solvent in improving solubility of carbamazepine

Abstract

The invention discloses an application of a deep-eutectic solvent in improving the solubility of carbamazepine, the deep-eutectic solvent takes ricinoleic acid or 1, 2-propylene glycol as a hydrogen bond donor and menthol or glycerol as a hydrogen bond acceptor, and the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is (1-7): (1-3). Through an activity coefficient prediction module of a COSMO-RS model, appropriate hydrogen bond acceptors (HBA) and hydrogen bond donors (HBD) are screened out to construct the deep eutectic solvent DESs system, the problem that a traditional trial and error method is low in efficiency is solved, the low-cost and environment-friendly deep eutectic solvent DESs is successfully prepared through further system optimization, and solubility experiment data show that the DESs have the advantages of being low in cost, good in stability and good in stability. The prepared DESs can significantly improve the solubility of carbamazepine, and a new way is provided for development of carbamazepine preparations.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug preparation, and particularly relates to application of a deep eutectic solvent in improving the solubility of carbamazepine. Background Art

[0002] Carbamazepine (CBZ) is a first-line drug used to treat epilepsy, trigeminal neuralgia, and other neurological disorders. CBZ is classified as a BCS class II drug with a water solubility of approximately 113 μg / mL at 25°C. Its poor solubility poses a significant threat to bioavailability, limiting its clinical application.

[0003] The solubility of poorly soluble drugs is a core challenge in the pharmaceutical industry. Numerous strategies are currently underway to improve drug solubility, including salt formation, pH adjustment, solid dispersions, particle size reduction, and the use of solubilizers such as complexing agents. These traditional approaches have limited success in improving CBZ solubility. Existing methods are complex and often involve volatile, flammable, and explosive organic solvents, posing potential risks to the environment and operational safety.

[0004] Green solvents (such as DESs) have become a research hotspot due to their low volatility, tunability, and environmental friendliness. DESs, composed of HBD and HBA, form a eutectic system through hydrogen bonding, which can significantly alter the intermolecular forces of drugs and enhance their solubility. However, the application of existing DESs in drug solubilization relies heavily on trial-and-error methods and empirical screening, which is inefficient and costly. Therefore, there is a need to develop a new, green and environmentally friendly technology to efficiently enhance the solubility of CBZ. Summary of the Invention

[0005] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide an application of a deep eutectic solvent in improving the solubility of carbamazepine. The deep eutectic solvent can significantly improve the solubility of carbamazepine, providing a new approach for the development of carbamazepine preparations.

[0006] The present invention is achieved through the following technical solutions:

[0007] A deep eutectic solvent is used to improve the solubility of carbamazepine. The deep eutectic solvent uses ricinoleic acid (RA) or 1,2-propylene glycol (1,2-PG) as a hydrogen bond donor (HBD), menthol (Men) or glycerol (Gly) as a hydrogen bond acceptor (HBA), and the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 1-7:1-3.

[0008] As a preferred technical solution of the present invention, the deep eutectic solvent is a mixture of menthol and 1,2-propylene glycol in a molar ratio of 1:1-3, a mixture of glycerol and 1,2-propylene glycol in a molar ratio of 1:1-3, or a mixture of menthol and ricinoleic acid in a molar ratio of 5-7:1.

[0009] As a further preferred technical solution of the present invention, the deep eutectic solvent is a mixture of menthol and 1,2-propylene glycol in a molar ratio of 1:3, a mixture of glycerol and 1,2-propylene glycol in a molar ratio of 1:2, or a mixture of menthol and ricinoleic acid in a molar ratio of 5:1.

[0010] The deep eutectic solvent of the present invention is obtained by screening suitable hydrogen bond acceptors (HBAs) and hydrogen bond donors (HBDs) through the activity coefficient prediction module of the COSMO-RS model, and then constructing them through ratio optimization, thus avoiding blind experiments.

[0011] In the low eutectic solvent of the present invention, the hydrogen bond acceptor HBA (such as the hydroxyl group of Men) and the hydrogen bond donor HBD (such as the hydroxyl group of 1,2-PG) form a hydrogen bond network, which solvates the carbonyl and amino groups of carbamazepine through polarity matching and hydrogen bonding, thereby improving the solubility of carbamazepine. Increasing the temperature destroys the hydrogen bond network, which can further improve the solubility.

[0012] As a preferred technical solution of the present invention, carbamazepine is mixed with a deep eutectic solvent, dissolved by ultrasonication, and then a pharmaceutically acceptable excipient is added to obtain a carbamazepine preparation.

[0013] In the present invention, pharmaceutically acceptable excipients are conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field, and their amounts are conventional amounts in the field, and the corresponding preparations are prepared by conventional methods known in the art.

[0014] As a preferred technical solution of the present invention, the carbamazepine preparation is an oral preparation (such as a tablet), a transdermal preparation or an injection.

[0015] The present invention has found through experimental research that the solubility of carbamazepine in the deep eutectic solvent has a significant temperature dependence. As a preferred technical solution of the present invention, the temperature of the ultrasonic dissolution is 25-65°C.

[0016] Compared with the prior art, the present invention has the following advantages:

[0017] The present invention uses the activity coefficient prediction module of the COSMO-RS model (a quantum chemical calculation tool based on the conductor shielding model) to screen suitable hydrogen bond acceptors (HBAs) and hydrogen bond donors (HBDs) to construct a deep eutectic solvent (DESs) system, solving the low efficiency problem of the traditional trial-and-error method. Through further system optimization, low-cost, green and environmentally friendly deep eutectic solvents (DESs) are successfully prepared. Solubility experimental data show that the prepared DESs can significantly improve the solubility of carbamazepine, providing a new approach for the development of carbamazepine preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Plot of the logarithmic activity coefficient at infinite dilution calculated for COSMO-RS;

[0019] Figure 2 is the Fourier transform infrared spectrum of the individual components of HBA or HBD;

[0020] Figure 3 is the Fourier infrared spectrum of DESs;

[0021] Figure 4 is the solubility of CBZ in DESs at different temperatures. DETAILED DESCRIPTION

[0022] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. The described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0023] All chemicals and reagents used to prepare DES in the examples of the present invention were purchased from commercial sources.

[0024] 1. Screening of COSMO-RS Model

[0025] In this study, the COSMO-RS model was used to perform a systematic thermodynamic calculation and evaluation of 306 potential DES systems (see Table 1) consisting of 18 hydrogen bond acceptors (HBAs) and 17 hydrogen bond donors (HBDs). The logarithm of the infinite dilution activity coefficient (lnγ ∞ ), and combined with the principles of green chemistry (such as safety, low toxicity and environmental friendliness), suitable hydrogen bond acceptors and hydrogen bond donors are selected.

[0026] Table 1. 18 hydrogen bond acceptors (HBAs) and 17 hydrogen bond donors (HBDs)

[0027]

[0028] The results are as follows Figure 1 As shown in the figure, carbamazepine was used as a model solute molecule, and each group of NADESs was used as the extraction solvent to determine the lnγ ∞ The value is calculated, lnγ ∞ A lower value means that the solvent system has a stronger solubility for carbamazepine. Finally, ricinoleic acid (RA) and 1,2-propylene glycol (1,2-PG) were selected as hydrogen bond donors (HBD), and menthol (Men) and glycerol (Gly) were selected as hydrogen bond acceptors (HBA).

[0029] 2. Preparation and characterization of deep eutectic solvents DESs:

[0030] 2.1 DESs were prepared by the heating and stirring method. The specific experimental steps are as follows:

[0031] ① Raw material preparation: 1,2-propylene glycol (1,2-PG) and ricinoleic acid (RA) were selected as hydrogen bond donors (HBDs), and menthol (Men) and glycerol (Gly) were selected as hydrogen bond acceptors (HBAs);

[0032] ② Weighing and mixing: Accurately weigh each component according to the specified molar ratio (see Table 1);

[0033] ③ Heating and stirring: After mixing the weighed raw materials, place them at 60°C and stir them magnetically. Continue stirring until the solution is completely clear and transparent, ensuring that all components are fully mixed and uniform DESs are formed;

[0034] ④ Cooling and Standing: The prepared DESs were cooled to room temperature and allowed to stand for one week to observe their stability and whether stratification or crystallization occurred. The results are shown in Table 1.

[0035] Table 1 Composition and state of deep eutectic solvents

[0036] Ingredients molar ratio Room temperature Menthol: 1,2-Propanediol 1：1 Uniform, transparent, no stratification or crystallization Menthol: 1,2-Propanediol 1：2 Uniform, transparent, no stratification or crystallization Menthol: 1,2-Propanediol 1：3 Uniform, transparent, no stratification or crystallization Glycerol: 1,2-propylene glycol 1：1 Uniform, transparent, no stratification or crystallization Glycerol: 1,2-propylene glycol 1：2 Uniform, transparent, no stratification or crystallization Glycerol: 1,2-propylene glycol 1：3 Uniform, transparent, no stratification or crystallization Menthol: Ricinoleic acid 1：1 Turbidity, stratification, crystallization Menthol: Ricinoleic acid 2：1 Turbidity, stratification, crystallization Menthol: Ricinoleic acid 3：1 Turbidity, stratification, crystallization Menthol: Ricinoleic acid 4：1 Turbidity, stratification, crystallization Menthol: Ricinoleic acid 5：1 Uniform, transparent, no stratification or crystallization Menthol: Ricinoleic acid 6：1 Uniform, transparent, no stratification or crystallization Menthol: Ricinoleic acid 7：1 Uniform, transparent, no stratification or crystallization

[0037] As shown in Table 1, when the ratio of menthol to ricinoleic acid is 1-4:1, the prepared deep eutectic solvent exhibits stratification or crystallization. Therefore, the present invention selects menthol to 1,2-propylene glycol 1:1-3, glycerol to 1,2-propylene glycol 1:1-3, and menthol to ricinoleic acid 5-7:1 as the deep eutectic solvent.

[0038] 2.2 Fourier transform infrared spectroscopy (FT-IR) characterization

[0039] The DESs and their components were dried at 100°C for 24 hours, and the prepared DESs samples were analyzed by Fourier transform infrared spectroscopy using the liquid film method. The dried KBr was pressed into thin sheets at room temperature, and the DESs were then applied to the sheets. The pure components were mixed with KBr in a specific ratio, pressed into thin sheets, and then the spectra were measured. The spectral scanning range was 600–4000 cm -1 , 32 scans, spectral resolution 4cm -1 , each sample was measured three times.

[0040] Figure 2 This is the Fourier transform infrared spectrum of HBA / HBD single component. The infrared spectrum of ricinoleic acid (RA) shows that 3009cm -1 The strong absorption peak at 2924 cm corresponds to the stretching vibration of the OH bond, while the -1 The absorption peak near 1708cm is attributed to the stretching vibration of the CH bond of the methyl group in the ricinoleic acid molecule. -1 The strong absorption peak at 3325 cm indicates the presence of C=O bond. -1 The strong absorption peak at 2925 cm also indicates the stretching vibration of the OH bond, while the -1 and 2955cm -1 The absorption peak in the region corresponds to the stretching vibration of the CH bond of the methyl group in the menthol molecule. The infrared spectrum of 1,2-propylene glycol (1,2-PG) is at 3312 cm -1 The stretching vibration characteristics of the OH bond are shown near 2970cm -1 and 2930cm -1 The absorption peak in the region reflects the stretching vibration of the C-H bond. The infrared spectrum of glycerol (Gly) is similar to that of 1,2-propylene glycol, with a peak at 3281 cm -1 The absorption peak at 2932 cm corresponds to the stretching vibration of the OH bond, while the absorption peak at 2932 cm -1 The absorption peak in the region comes from the stretching vibration of the C-H bond.

[0041] Figure 3 The Fourier transform infrared spectrum of the combination of HBA and HBD shows that the wavelength deviation is small and no additional new absorption peaks are shown. There are only some simple overlaps of peaks, which also shows that the prepared DESs do not generate new substances but maintain the characteristics of the original components. -1 –3000cm -1The existence of broad absorption peaks between 3 and 4 also indicates the possibility of HB formation in DESs. The spectra of menthol and 1,2-propylene glycol in three different molar ratios show almost identical spectra. However, with the increase of the proportion of 1,2-propylene glycol, the stretching vibration peak of the OH bond shifts to a higher wavelength, from 3321 cm -1 Move to 3324cm -1 This wavelength shift reflects the change in the strength of hydrogen bonds within DESs, indicating that different ratios of HBA and HBD combinations affect the tightness and interaction strength of hydrogen bonds in DESs.

[0042] 3. Solubility Experiment

[0043] Ultrasound-assisted dissolution combined with UV-visible spectrophotometry was used to test the CBZ solubility of the following DESs: menthol and 1,2-propylene glycol (1:1, 1:2, 1:3), glycerol and 1,2-propylene glycol (1:1, 1:2, 1:3), and menthol and ricinoleic acid (5:1, 6:1, 7:1). The solubility of each group of DESs was compared.

[0044] The specific experimental steps are as follows:

[0045] (1) Sample preparation: Add a certain amount of CBZ to a round-bottom flask containing 10 mL of DESs. Seal the round-bottom flask to prevent solvent evaporation or contamination.

[0046] (2) Ultrasonic dissolution: Place the round-bottom flask in an ultrasonic cleaner and maintain constant temperatures at 25°C, 30°C, 45°C, 55°C, and 65°C in a thermostatic water bath. Stir continuously for 6 hours under ultrasonic conditions to ensure that CBZ is fully dissolved.

[0047] (3) Sample extraction and filtration: Every two hours, 1.5 mL of CBZ solution was extracted from the round-bottom flask using a preheated 2.5 mL syringe. Undissolved CBZ was removed by filtration through a 0.5 mL polytetrafluoroethylene (PTFE) filter to obtain 1 mL of clear sample. (4) UV-visible spectrophotometry: A UV-8000 UV-visible spectrophotometer was used to scan the spectrum at 0.5 nm intervals within the wavelength range of 200–400 nm. Ethanol was used as the blank solvent to ensure that the baseline deviation was less than 0.005 cm -1 The sample was diluted with ethanol to a value between 0.2 and 0.8 Abs, and the measurement wavelength was 285 nm. Each sample was measured at least three times to ensure data reliability and repeatability.

[0048] (5) Standard curve drawing and solubility calculation: Five sets of CBZ standard solutions were prepared and dissolved in DESs (1 mL) + ethanol (to 10 mL). After dilution 6000 times, the absorbance at 285 nm was measured (three times in parallel). The standard curve of CBZ solution was drawn based on the absorbance value. The solubility of CBZ in DESs was calculated using the average absorbance of CBZ in the standard curve. The results are shown in Table 4 and Figure 4 As shown:

[0049] Table 4 Solubility (mg / mL) test at different temperatures

[0050] DESs 25℃ 35℃ 45℃ 55℃ 65℃ Men / 1,2-PG (1:1) 28.74 36.87 50.19 74.29 105.57 Men / 1,2-PG (1:2) 32.69 50.50 65.83 88.66 107.65 Men / 1,2-PG (1:3) 45.25 49.16 74.92 94.37 124.68 Gly / 1,2-PG (1:1) 23.5 31.7 33.7 33.7 61.5 Gly / 1,2-PG (1:2) 33.13 34.88 74.06 75.86 112.06 Gly / 1,2-PG (1:3) 12.82 16.69 18.80 28.39 41.17 Men / RA (5:1) 37.0 40.7 41.2 45.1 69.6 Men / RA (6:1) 18.16 30.29 33.43 47.70 55.81 Men / RA (7:1) 17.85 32.80 34.13 45.87 55.37

[0051] The results in the table above demonstrate that all prepared DESs exhibit excellent solubility for CBZ. At 25°C, the solubility of CBZ in a Men:1,2-PG = 1:3 system reached 45.25 mg / mL, a significant 400-fold increase compared to pure water, fully demonstrating the advantages of DESs in improving the solubility of poorly soluble drugs. The solubility of DESs exhibits a clear temperature dependence, with CBZ solubility increasing significantly with increasing temperature, reaching 124.68 mg / mL in a Men:1,2-PG = 1:3 system at 65°C. This is attributed to the enhanced solvation capacity due to the partial disruption of the hydrogen bond network at high temperatures. Further analysis revealed that the solubility of CBZ increased with increasing 1,2-propylene glycol ratio, suggesting that the molar ratio of HBA to HBD has a significant impact on drug solubility.

[0052] A systematic comparison of the solubility of nine DESs revealed that the solubility of CBZ in the Men / 1,2-PG system was significantly superior to that in the Gly / 1,2-PG and RA / Men systems, likely due to differences in the molecular interactions between CBZ and DESs. Gly / 1,2-PG (1:2) also exhibited excellent solubility at 65°C, while Men / RA (5:1) maintained excellent solubility at all tested temperatures. These results suggest that a specific molar ratio of HBA to HBD in DESs can significantly enhance the solubility of CBZ.

[0053] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them. For those skilled in the art, the present application may have various changes and variations. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application should all be included within the protection scope of the present application.

Claims

1. Use of a deep eutectic solvent in improving the solubility of carbamazepine, characterized in that: The deep eutectic solvent uses ricinoleic acid or 1,2-propylene glycol as a hydrogen bond donor, menthol or glycerol as a hydrogen bond acceptor, and the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor is 1-7:1-3.

2. Use of the deep eutectic solvent according to claim 1 in improving the solubility of carbamazepine, characterized in that The deep eutectic solvent is a mixture of menthol and 1,2-propylene glycol in a molar ratio of 1:1-3, a mixture of glycerol and 1,2-propylene glycol in a molar ratio of 1:1-3, or a mixture of menthol and ricinoleic acid in a molar ratio of 5-7:

1.

3. Use of the deep eutectic solvent according to claim 2 in improving the solubility of carbamazepine, characterized in that The deep eutectic solvent is a mixture of menthol and 1,2-propylene glycol in a molar ratio of 1:3, a mixture of glycerol and 1,2-propylene glycol in a molar ratio of 1:2, or a mixture of menthol and ricinoleic acid in a molar ratio of 5:

1.

4. Use of the deep eutectic solvent according to any one of claims 1 to 3 in improving the solubility of carbamazepine, characterized in that The deep eutectic solvent is obtained by screening suitable hydrogen bond acceptors and hydrogen bond donors through the activity coefficient prediction module of the COSMO-RS model, and then constructing them through ratio optimization.

5. Use of the deep eutectic solvent according to any one of claims 1 to 3 in improving the solubility of carbamazepine, characterized in that Carbamazepine is mixed with a low eutectic solvent, dissolved by ultrasonication, and then a pharmaceutically acceptable excipient is added to obtain a carbamazepine preparation.

6. Use of the deep eutectic solvent according to claim 5 in improving the solubility of carbamazepine, characterized in that The temperature of the ultrasonic dissolution is 25-65°C.

7. Use of the deep eutectic solvent according to claim 5 in improving the solubility of carbamazepine, characterized in that The carbamazepine preparation is an oral preparation, a transdermal preparation or an injection.

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