Application of a eutectic solvent in improving solubility of carbamazepine

Abstract

The application discloses application of a eutectic solvent in improving solubility of carbamazepine, wherein the eutectic solvent is prepared by taking castor oil acid or 1,2-propanediol as a hydrogen bond donor, taking menthol or glycerol as a hydrogen bond acceptor, and the molar ratio of the hydrogen bond acceptor to the hydrogen bond donor being 1-7:1-3. The activity coefficient prediction module of the COSMO-RS model is used to screen a suitable hydrogen bond acceptor (HBA) and a hydrogen bond donor (HBD) to construct a eutectic solvent DESs system, so that the problem of low efficiency of a traditional trial-and-error method is solved, and a low-cost and green eutectic solvent DESs is successfully prepared through further systematic optimization. The solubility experiment data show that the prepared DESs can significantly improve the solubility of carbamazepine, and a new way is provided for development of a carbamazepine preparation.

Description

Technical Field

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

[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. Its water solubility at 25°C is approximately 113 μg / mL. This poor solubility poses a significant threat to bioavailability, limiting its clinical application.

[0003] The dissolution of poorly soluble drugs is one of the core challenges in the pharmaceutical industry. Currently, there are many strategies to improve drug solubility, including salt formation, pH adjustment, using solid dispersions, reducing particle size, and using solubilizers such as complexing agents. These traditional methods have limited effectiveness in improving the solubility of CBZ, and existing methods often involve complex compositions and frequently 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, adjustability, and environmental friendliness. DESs, formed by hydrogen bonding between HBD and HBA to create a eutectic system, can significantly alter intermolecular forces in drugs and improve solubility. However, current applications of DESs in drug solubilization largely rely on trial-and-error methods and empirical screening, resulting in low efficiency and high costs. Therefore, it is necessary to research and develop a green and environmentally friendly new technology to efficiently improve the solubility of CBZ. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the purpose of this invention is to provide an application of a eutectic solvent in improving the solubility of carbamazepine. This eutectic solvent can significantly improve the solubility of carbamazepine, providing a new approach for the development of carbamazepine formulations.

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

[0007] The application of a eutectic solvent in improving the solubility of carbamazepine, wherein the eutectic solvent uses ricinoleic acid (RA) or 1,2-propanediol (1,2-PG) as a hydrogen bond donor (HBD) and menthol (Men) or glycerol (Gly) as a hydrogen bond acceptor (HBA), with a molar ratio of hydrogen bond acceptor to hydrogen bond donor of 1-7:1-3.

[0008] As a preferred embodiment of the present invention, the eutectic solvent is a mixture of menthol and 1,2-propanediol in a molar ratio of 1:1-3, a mixture of glycerol and 1,2-propanediol 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 eutectic solvent is a mixture of menthol and 1,2-propanediol in a molar ratio of 1:3, a mixture of glycerol and 1,2-propanediol in a molar ratio of 1:2, or a mixture of menthol and ricinoleic acid in a molar ratio of 5:1.

[0010] The eutectic solvent described in this invention is obtained by screening suitable hydrogen bond acceptors (HBA) and hydrogen bond donors (HBD) through the activity coefficient prediction module of the COSMO-RS model, and then constructing them through ratio optimization, thus avoiding blind experimentation.

[0011] In the eutectic solvent of this invention, hydrogen bond acceptor HBA (such as the hydroxyl group of Men) and hydrogen bond donor HBD (such as the hydroxyl group of 1,2-PG) form a hydrogen bond network. Through polarity matching and hydrogen bonding, the carbonyl and amino groups of carbamazepine are solubilized, thereby improving the solubility of carbamazepine. Increasing the temperature disrupts 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 eutectic solvent, dissolved by ultrasonication, and then pharmaceutically acceptable excipients are added to obtain a carbamazepine formulation.

[0013] In this invention, pharmaceutically acceptable excipients include conventional diluents, excipients, fillers, binders, humectants, disintegrants, absorption promoters, surfactants, adsorbents, lubricants, etc., used in the conventional amounts in the field, and prepared into corresponding formulations by conventional methods known in the field.

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

[0015] Through experimental research, this invention has found that the solubility of carbamazepine in eutectic solvents has a significant temperature dependence. As a preferred technical solution of this invention, the ultrasonic dissolution temperature is 25-65℃.

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

[0017] This invention utilizes the activity coefficient prediction module of the COSMO-RS model (a quantum chemical calculation tool based on a conductor shielding model) to screen suitable hydrogen bond acceptors (HBA) and hydrogen bond donors (HBD) to construct a eutectic solvent DESs system. This solves the problem of low efficiency in traditional trial-and-error methods. Through further system optimization, a low-cost, environmentally friendly eutectic solvent DESs was 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 formulations. Attached Figure Description

[0018] Figure 1 Plot of log activity coefficients at infinite dilution calculated for COSMO-RS;

[0019] Figure 2 Fourier transform infrared spectra of HBA or HBD as individual components;

[0020] Figure 3 The Fourier transform infrared spectrum of DESs;

[0021] Figure 4 The solubility of CBZ in DESs at different temperatures. Detailed Implementation

[0022] 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.

[0023] All chemicals and reagents used in the preparation of DES in this invention embodiment are commercially available.

[0024] 1. Selection of COSMO-RS models

[0025] This study used the COSMO-RS model to systematically perform thermodynamic calculations and evaluations on 306 potential DES systems (see Table 1) consisting of 18 hydrogen bond acceptors (HBAs) and 17 hydrogen bond donors (HBDs). The logarithm (lnγ) of the infinite dilution activity coefficients of each system with carbamazepine (CBZ) was analyzed. ∞ In conjunction with green chemistry principles (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, using carbamazepine as a model solute molecule and each group of NADESs as the extraction solvent, the lnγ of carbamazepine as a solute molecule was analyzed. ∞ The value is calculated as lnγ ∞ A lower value indicates that the solvent system has a stronger ability to dissolve carbamazepine. Ultimately, ricinoleic acid (RA) and 1,2-propanediol (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 DESs in eutectic solvents:

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

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

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

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

[0034] ④ Cooling and standing: Cool the prepared DESs to room temperature. Let it stand at room temperature for one week to observe its stability and whether layering or crystallization occurs. The results are shown in Table 1.

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

[0036] Composition Mole ratio room temperature Menthol: 1,2-Propanediol 1：1 Uniform, transparent, without layering or crystallization Menthol: 1,2-Propanediol 1：2 Uniform, transparent, without layering or crystallization Menthol: 1,2-Propanediol 1：3 Uniform, transparent, without layering or crystallization Glycerin: 1,2-Propanediol 1：1 Uniform, transparent, without layering or crystallization Glycerin: 1,2-Propanediol 1：2 Uniform, transparent, without layering or crystallization Glycerin: 1,2-Propanediol 1：3 Uniform, transparent, without layering or crystallization Menthol: Ricinol 1：1 Turbidity, layering, crystallization Menthol: Ricinol 2：1 Turbidity, layering, crystallization Menthol: Ricinol 3：1 Turbidity, layering, crystallization Menthol: Ricinol 4：1 Turbidity, layering, crystallization Menthol: Ricinol 5：1 Uniform, transparent, without layering or crystallization Menthol: Ricinol 6：1 Uniform, transparent, without layering or crystallization Menthol: Ricinol 7：1 Uniform, transparent, without layering or crystallization

[0037] As shown in Table 1, when the ratio of menthol to ricinoleic acid is 1-4:1, the resulting eutectic solvent exhibits layering or crystallization. Therefore, this invention selects menthol: 1,2-propanediol 1:1-3, glycerol: 1,2-propanediol 1:1-3, and menthol: ricinoleic acid 5-7:1 as eutectic solvents.

[0038] 2.2 Fourier Transform Infrared Spectroscopy (FT-IR) Characterization

[0039] DESs and other components were heated and dried at 100°C for 24 hours. Fourier transform infrared spectroscopy (FTIR) was then performed on the prepared DESs samples using the liquid film method. DESs was then coated onto thin sheets after drying at room temperature. Pure components were mixed with KBr in a specific ratio, pressed into thin sheets, and then subjected to spectral measurements. The spectral scanning range was 600–4000 cm⁻¹. -1 The number of scans was 32, and the spectral resolution was 4 cm⁻¹. -1 Each sample was measured three times.

[0040] Figure 2 Fourier transform infrared spectra of HBA / HBD components alone; infrared spectrum of ricinoleic acid (RA) shows 3009 cm⁻¹. -1 The strong absorption peak at 2924 cm⁻¹ corresponds to the stretching vibration of the OH bond, while the peak at 2924 cm⁻¹ corresponds to the stretching vibration of the OH bond. -1 The nearby absorption peak is attributed to the stretching vibration of the CH bond of the methyl group in the ricinoleic acid molecule. Additionally, the 1708 cm⁻¹ peak... -1 The strong absorption peak at 3325 cm⁻¹ indicates the presence of a C=O bond. In the infrared spectrum of menthol (Men), the peak at 3325 cm⁻¹... -1 The strong absorption peak at 2925 cm⁻¹ also indicates the stretching vibration of the OH bond, while the strong absorption peak at 2925 cm⁻¹ indicates the stretching vibration of the OH bond. -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-propanediol (1,2-PG) is at 3312 cm⁻¹. -1 The vicinity shows stretching vibration characteristics of OH bonds, while 2970 cm⁻¹ -1 and 2930cm -1 The absorption peaks in the region reflect the stretching vibrations of the CH bond. The infrared spectrum of glycerol (Gly) is similar to that of 1,2-propanediol, with a peak at 3281 cm⁻¹. -1 The absorption peak at 2932 cm⁻¹ corresponds to the stretching vibration of the OH bond, while the peak at 2932 cm⁻¹ corresponds to the stretching vibration of the OH bond. -1 The absorption peaks in the region originate from the stretching vibrations of the CH bonds.

[0041] Figure 3 Fourier transform infrared spectra of the combined HBA and HBD show small wavelength deviations and no new absorption peaks, with only simple overlap of some peaks. This indicates that the prepared DESs did not generate new substances but retained the characteristics of the original components. (3600 cm⁻¹) -1 -3000cm -1The presence of broad absorption peaks between them also indicates the possibility of HB formation in DESs. The spectra of menthol and 1,2-propanediol in three different molar ratios show nearly identical patterns. However, as the proportion of 1,2-propanediol increases, the stretching vibration peak of the OH bond shifts to a higher wavelength, from 3321 cm⁻¹. -1 Moved to 3324cm -1 This wavelength shift reflects a change in the strength of hydrogen bonding within DESs, indicating that different ratios of HBA and HBD can affect the tightness and interaction strength of hydrogen bonds in DESs.

[0042] 3. Solubility Experiment

[0043] The CBZ solubility of the following DESs was tested using an ultrasonic-assisted dissolution method combined with UV-Vis spectrophotometry: menthol and 1,2-propanediol (1:1, 1:2, 1:3), glycerol and 1,2-propanediol (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 a constant temperature in a constant temperature water bath at 25℃, 30℃, 45℃, 55℃, and 65℃ respectively. Stir continuously for 6 hours under ultrasonic conditions to ensure that CBZ is fully dissolved.

[0047] (3) Sample extraction and filtration: Every two hours, use a preheated 2.5 mL syringe to draw 1.5 mL of CBZ solution from a round-bottom flask. Filter through a 0.5 mL polytetrafluoroethylene (PTFE) filter to remove undissolved CBZ, obtaining 1 mL of clear sample. (4) UV-Vis spectrophotometry: Use a UV-8000 UV-Vis spectrophotometer to scan the spectrum at 0.5 nm intervals within the wavelength range of 200–400 nm. Use ethanol as a blank solvent to ensure a baseline deviation of less than 0.005 cm⁻¹. -1 Dilute the sample appropriately with ethanol to control the absorbance range between 0.2 and 0.8 Abs, and measure at a wavelength of 285 nm. Each sample should be measured at least three times to ensure data reliability and repeatability.

[0048] (5) Standard Curve Plotting and Solubility Calculation: Five sets of CBZ standard solutions were prepared, dissolved in DESs (1 mL) + ethanol (to 10 mL), diluted 6000 times, and the absorbance at 285 nm was measured (triple parallel). A standard curve for CBZ solutions was plotted based on the absorbance values. 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 show that the prepared DESs exhibit excellent solubility for CBZ. At 25℃, the solubility of CBZ in the Men:1,2-PG = 1:3 system reached 45.25 mg / mL, a significant increase of 400 times compared to pure water, fully demonstrating the advantage of DESs in improving the solubility of poorly soluble drugs. The solubility of DESs showed a clear temperature dependence; as the temperature increased, the solubility of CBZ increased significantly, reaching 124.68 mg / mL in the Men:1,2-PG = 1:3 system at 65℃. This is attributed to the enhanced solubility due to the partial breaking of the hydrogen bond network at high temperatures. Further analysis revealed that the solubility of CBZ increased with the increase of the 1,2-propanediol 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 CBZ showed significantly better solubility in the Men / 1,2-PG system than in the Gly / 1,2-PG and RA / Men systems, which may be related to the differences in intermolecular interactions between CBZ and DESs. Gly / 1,2-PG (1:2) also exhibited excellent solubility at 65℃, while Men / RA (5:1) maintained superior solubility at all test temperatures. These results indicate 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, 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 eutectic solvent in improving the solubility of carbamazepine, characterized in that, The eutectic solvent is a mixture of menthol and 1,2-propanediol in a molar ratio of 1:1-3, a mixture of glycerol and 1,2-propanediol in a molar ratio of 1:1-3, or a mixture of menthol and ricinoleic acid in a molar ratio of 5-7:

1.

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

1.

3. The application of the eutectic solvent according to any one of claims 1-2 in improving the solubility of carbamazepine, characterized in that, Carbamazepine is mixed with a eutectic solvent, dissolved by sonication, and then pharmaceutically acceptable excipients are added to obtain a carbamazepine formulation.

4. The application of the eutectic solvent according to claim 3 in improving the solubility of carbamazepine, characterized in that, The temperature for ultrasonic dissolution is 25-65℃.

5. The application of the eutectic solvent according to claim 3 in improving the solubility of carbamazepine, characterized in that, The carbamazepine formulation is an oral formulation, a transdermal formulation, or an injection.

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