Albendazole-acesulfame potassium salt crystal form A as well as preparation method and application thereof
By preparing albendazole-acesulfame potassium salt crystal form A, the water solubility and flowability issues of albendazole were solved, improving solubility and bioavailability, simplifying the preparation process, and making it suitable for large-scale production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- WUHAN UNIV OF SCI & TECH
- Filing Date
- 2026-01-26
- Publication Date
- 2026-04-24
AI Technical Summary
Albendazole suffers from poor water solubility, low oral bioavailability, and extremely poor powder flowability, which affects the clinical efficacy of the drug and the stability of formulation production.
Albendazole-acesulfame potassium salt crystal form A was prepared by liquid-phase assisted grinding of albendazole and acesulfame potassium in a 1:1 molar ratio in the presence of an organic solvent, followed by drying, to form crystal form A with characteristic peaks, thereby improving its solubility and flowability.
It significantly improves the solubility and powder flowability of albendazole, enhances bioavailability, simplifies the preparation process, reduces costs, and is suitable for large-scale production.
Smart Images
Figure CN121914036A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug crystal forms, specifically relating to a method for preparing albendazole-acesulfame potassium salt crystal form A and its application. Background Technology
[0002] Albendazole (Formula II), chemically named [5-(propylthio)-1H-benzimidazole-2-yl]carbamate, was developed and manufactured by GlaxoSmithKline. It is a broad-spectrum antiparasitic drug with high activity against nematodes, trematodes, tapeworms, and hookworms.
[0003]
[0004] Formula (II)
[0005] Albendazole, as a drug with significant application value, suffers from technical defects such as poor water solubility and low oral bioavailability. Its oral bioavailability in humans is typically below 5%, severely restricting the full realization of its clinical efficacy. Furthermore, in formulation development and production practice, it has been found that albendazole raw material powder has extremely poor flowability, easily leading to uneven mixing and dosage deviations during formulation, significantly negatively impacting the quality stability and large-scale production of the finished product. To address these technical problems, some improvement schemes have been proposed in the existing technology. For example, the literature "Crystal Growth and Design, 2019, Vol. 19, pp. 4538-4545" reports a technique to improve the water solubility of albendazole hydrochloride by preparing the drug. However, this technique only focuses on improving solubility, and the improvement is limited; at pH 6.8, the solubility of albendazole hydrochloride is only 6.2 μg / mL. In addition, no research has addressed improving the flowability of albendazole powder. Therefore, developing a technical solution that can simultaneously improve the dissolution performance and powder flowability of albendazole, thereby achieving comprehensive optimization of its solid-state properties, and thus enhancing the oral bioavailability of the drug and ensuring the stability of formulation production, has crucial clinical application value and industrialization prospects. Summary of the Invention
[0006] This invention aims to provide an albendazole-acesulfame potassium salt crystal form A. Crystal form A not only improves solubility but also exhibits better flowability, which compensates for the shortcomings of existing albendazole raw materials and possesses good application value. Furthermore, the preparation method of crystal form A is simple, reproducible, low-cost, and environmentally friendly.
[0007] This invention provides an albendazole-acesulfame potassium salt crystal form A, wherein the molar ratio of albendazole cation to acesulfame potassium anion in albendazole-acesulfame potassium salt crystal form A is 1:1. The structural formula is shown in formula (I).
[0008]
[0009] Formula (I)
[0010] Furthermore, the albendazole-acesulfame potassium salt crystal form A of the present invention is characterized in that the powder X-ray diffraction pattern of crystal form A has characteristic peaks at 2θ angles of 6.9±0.2°, 20.3±0.2°, 22.9±0.2°, 25.5±0.2° and 26.3±0.2°.
[0011] Furthermore, the albendazole-acesulfame potassium salt crystal form A of the present invention is characterized in that the powder X-ray diffraction pattern of crystal form A has characteristic peaks at 2θ angles of 6.9±0.2°, 11.2±0.2°, 13.9±0.2°, 17.3±0.2°, 18.4±0.2°, 20.3±0.2°, 22.9±0.2°, 25.5±0.2°, 26.3±0.2° and 29.5±0.2°.
[0012] Furthermore, the albendazole-acesulfame potassium salt crystal form A of the present invention is characterized in that, at a test temperature of 273.15 K, the cell parameters are: a=7.9456(4) Å, b=9.7042(5) Å, c=12.7033(6) Å, α=90.754(4)°, β=94.046(4)°, γ=97.080(4)°, and the space group is P-1.
[0013] Furthermore, the albendazole-acesulfame potassium salt crystal form A of the present invention is characterized in that its differential scanning calorimetry curve has an endothermic peak at a peak value of 156±5 °C.
[0014] The present invention also relates to a method for preparing albendazole-acesulfame potassium salt crystal form A, specifically: the molar ratio of albendazole and acesulfame potassium is 1:1, and liquid-phase assisted grinding is performed in the presence of an aqueous or anhydrous organic solvent; the resulting mixture is then dried to obtain the albendazole-acesulfame potassium salt crystal form A.
[0015] Furthermore, the organic solvent is methanol.
[0016] Furthermore, the ratio of water to methanol is ≤30%.
[0017] This invention relates to albendazole-acesulfame potassium salt crystal form A, which is mainly used for the treatment of various types of parasitic diseases.
[0018] The beneficial effects of this invention are as follows:
[0019] 1. Compared with albendazole raw material, the albendazole-acesulfame potassium salt crystal form A prepared in this invention has significantly improved solubility and bioavailability.
[0020] 2. Compared with albendazole raw material, the albendazole-acesulfame potassium salt crystal form A prepared by this invention has significantly improved powder flowability, which facilitates process handling.
[0021] 3. The preparation method of albendazole-acesulfame potassium salt crystal form A prepared by the present invention is simple, reproducible, low in cost and environmentally friendly. Attached Figure Description
[0022] Figure 1 The image shows the powder X-ray diffraction pattern of albendazole-acesulfame potassium salt crystal form A prepared in Example 1.
[0023] Figure 2 The image shows the differential scanning calorimetry (DSC) curve of albendazole-acesulfame potassium salt crystal form A prepared in Example 1.
[0024] Figure 3 This is an asymmetric unit diagram of the single crystal structure of albendazole-acesulfame potassium salt crystal form A prepared in Example 4.
[0025] Figure 4 Apparent equilibrium solubility diagram of albendazole raw material and albendazole-acesulfame potassium salt crystal form A prepared in Example 1 in phosphate buffer at pH 6.8. Specific implementation methods
[0026] The following detailed description of the present application is provided in conjunction with embodiments, but is not intended to limit the present application. Any equivalent substitutions made in the art based on the disclosure of the present application shall fall within the protection scope of the present application.
[0027] 1. Powder X-ray diffraction
[0028] Powder XRD analysis was performed using a Bruker D8 Advance X-ray powder diffractometer, which employed Cu-Kα radiation (λ = 1.5418 Å) and an array detector. The X-ray generator operated at 40 kV and 40 mA. Diffraction patterns were recorded at room temperature in the range of 3–40° with a scan rate of 0.02 steps and 0.1 seconds per step.
[0029] 2. Single crystal structure determination
[0030] Single-crystal X-ray diffraction data of the albendazole-acesulfame K salt crystal form A prepared in Example 4 were obtained using a Gemini diffractometer equipped with an Atlas CCD detector. The testing conditions were: Mo-Kα rays (λ = 0.71073 Å) at 273.15 K. The obtained crystal structure was analyzed using the direct method (SHELXT program) on the OLEX2 software platform.
[0031] 3. Differential scanning calorimetry analysis
[0032] The thermal behavior was determined using a DSC-3 differential scanning calorimeter. The measurement conditions were as follows: approximately 5 mg of sample was weighed and placed in a standard aluminum crucible, which was then sealed with a pre-perforated cap. Under nitrogen protection at a flow rate of 50 mL / min, the temperature was programmed to rise from 25 °C to 175 °C at a rate of 10 °C / min for scanning.
[0033] Example 1
[0034] Weigh 132.6 mg of albendazole and 81.5 mg of acesulfame potassium, place them in a ball mill jar, and dry-mill for 3 minutes to mix thoroughly. Then, add 20 μL (V) 甲醇 :V 水 A 7:3 mixture of solvents was used as an auxiliary solvent, and ball milling continued for 15 minutes. After the reaction was complete, the resulting solid powder was dried at 50 °C to obtain the albendazole-acesulfame potassium salt crystal form A described in this invention. The obtained sample was subjected to powder XRD analysis using Cu-Kα radiation, and the results are as follows: Figure 1 As shown, the X-ray diffraction pattern exhibits characteristic peaks at 2θ angles of 6.9±0.2°, 11.2±0.2°, 13.9±0.2°, 17.3±0.2°, 18.4±0.2°, 20.3±0.2°, 22.9±0.2°, 25.5±0.2°, 26.3±0.2°, and 29.5±0.2°. The differential scanning calorimetry (DSC) chromatogram of the sample powder is shown below. Figure 2 As shown, its peak melting point is 156±5 ℃.
[0035] Example 2
[0036] Weigh 132.6 mg of albendazole and 81.5 mg of acesulfame potassium, place them in a ball mill jar, and dry-mill for 3 minutes to mix thoroughly. Then, add 20 μL (V) 甲醇 :V 水A 4:1 mixed solvent was used as an auxiliary solvent, and ball milling continued for 15 minutes. After the reaction was completed, the resulting solid powder was dried at 50 °C to obtain the albendazole-acesulfame potassium salt crystal form A of the present invention. The obtained sample was subjected to powder XRD analysis using Cu-Kα rays, and its powder XRD pattern was basically consistent with that of Example 1.
[0037] Example 3
[0038] Weigh 132.6 mg of albendazole and 81.5 mg of acesulfame potassium, place them in a ball mill jar, and dry ball mill them for 3 minutes to ensure homogeneity. Then, add 20 μL of methanol as an auxiliary solvent and continue ball milling for 15 minutes. After the reaction is complete, dry the resulting solid powder at 50 °C to obtain the albendazole-acesulfame potassium salt crystal form A of this invention. The obtained sample was subjected to powder XRD analysis using Cu-Kα radiation, and its powder XRD pattern was basically consistent with that of Example 1.
[0039] Example 4
[0040] Albendazole-acesulfame potassium salt crystal form A was dissolved in 5 mL of toluene and sonicated until completely dissolved. The solution was filtered through a 0.22 μm polytetrafluoroethylene membrane filter and allowed to evaporate slowly at room temperature. After about 5 days, plate-like crystals precipitated, yielding a single crystal of abendazole-acesulfame potassium salt crystal form A. The obtained crystal was subjected to single-crystal testing at 273.15 K. The asymmetric unit cell diagram of the crystal structure is shown below. Figure 3 As shown, its crystallographic data and structural refinement parameters are summarized in Table 1.
[0041] Table 1. Crystallographic data and structural refinement parameters of albendazole–acesulfame potassium salt crystal form A
[0042] Name ALB-AH Formula <![CDATA[C 16 H 20 N4O6S2]]> Formula weight 428.48 Temperature / K 273.15 Crystal system triclinic Space group P-1 a / Å 7.9456(4) b / Å 9.7042(5) c / Å 12.7033(6) α / ° 90.754(4) β / ° 94.046(4) γ / ° 97.080(4) <![CDATA[Volume / Å 3 ]]> 969.37(9) Z 2 <![CDATA[D / g cm –3 ]]> 1.468 Total no. of reflns 13613 Unique no. of reflns 4454 No. of parameters 253 <![CDATA[R int ]]> 0.0437 GOF 1.037 <![CDATA[μ / mm –1 ]]> 0.316 F(000) 448.0 θ range / ° 2.948 to 27.485 <![CDATA[R1[I >2σ(I)] / R1]]> 0.0517 / 0.0875 <![CDATA[wR2[I >2σ(I)] / wR2]]> 0.1164 / 0.1321
[0043] Experimental Example 1: Solubility Test
[0044] To verify and compare solubility, albendazole raw material was used as a control, and the salt described in this invention was tested under the same conditions. The specific method is as follows: 10.0 mg of commercially available albendazole raw material and 16.2 mg of albendazole-acesulfame potassium salt crystal form A were weighed and added to 3 mL of phosphate buffer solution at pH 6.8, respectively. The solutions were then shaken and equilibrated at a constant temperature for 72 hours. After equilibration, samples were taken, filtered, and the concentration was determined by high-performance liquid chromatography (HPLC). The chromatographic conditions were: LC-2050 HPLC system, ChromSep® C18-KPH column (4.6 mm × 250 mm, 5 μm), UV detector wavelength 296 nm, and mobile phase flow rate 0.8 mL / min. The results showed that the apparent solubility of albendazole-acesulfame potassium salt crystal form A in this medium was significantly higher than that of albendazole raw material.
[0045] according to Figure 4 The solubility test results show that, in phosphate buffer at pH 6.8, the equilibrium solubility of commercially available albendazole active pharmaceutical ingredient (API) is 1.23 μg / mL, while the equilibrium solubility of albendazole-acesulfame potassium salt crystal form A described in this invention is 56.67 μg / mL. This comparison demonstrates that the salt increases the solubility of albendazole in this medium to approximately 46.07 times that of the API. The albendazole-acesulfame potassium salt crystal form A described in this invention also shows a 9-fold increase compared to the reported albendazole hydrochloride (6.2 μg / mL, Crystal Growth and Design, 2019, Vol. 19, pp. 4538-4545). This significant increase in solubility facilitates the dissolution and absorption of albendazole in vivo, thus providing an important basis for improving its bioavailability.
[0046] Experimental Example 2: Flowability Test of Albendazole-Acesulfame K Salt Crystal Form A
[0047] Flowability is a key powder property affecting the processing performance of pharmaceutical formulations. To evaluate and compare the powder flowability of albendazole-acesulfame potassium salt crystal form A described in this invention and commercially available albendazole active pharmaceutical ingredient, the bulk density and tap density of both were tested.
[0048] The specific test method is as follows: Accurately weigh 500 mg of sample powder and slowly and evenly fill it into a calibrated 5 mL graduated cylinder, recording the volume occupied by the powder at this point. Then, use a tapping method to vibrate the powder at a frequency of 55 ± 5 times per minute for 10 minutes, recording the final volume of the powder after compaction. By comparing the bulk density, tap density, and their changes between the two samples, the difference in powder flowability can be assessed.
[0049] According to powder science standards (see *Theory and Fundamentals of Crystalline Drug Development*, Chemical Industry Press, 2019, p. 246), powder flowability can be assessed using the Hausner Ratio, calculated as: Hausner Ratio = Tap Density / Bulk Density. A higher ratio indicates poorer powder flowability. Typically, a Hausner Ratio between 1.00 and 1.11 indicates very good powder flowability, while a ratio greater than 1.60 indicates extremely poor flowability.
[0050] Based on the aforementioned standards and test results, the Hauss-Na ratio of commercially available albendazole raw material is calculated to be 1.92, indicating extremely poor flowability. In contrast, the Hauss-Na ratio of albendazole-acesulfame potassium salt crystal form A described in this invention is 1.06, indicating very good flowability. This result directly confirms that the albendazole-acesulfame potassium salt crystal form A exhibits significantly improved powder properties compared to the raw material.
[0051] Table 2. Liquidity Parameter Evaluation Results
[0052] name Bulk density (g / mL) Tap density (g / mL) Hausnabi Liquidity Albendazole 0.20 0.38 1.90 Range Albendazole – Acesulfame K Salt Crystal Form A 0.63 0.67 1.06 very good
[0053] In summary, the albendazole-acesulfame potassium salt crystal form A provided by this invention exhibits significantly higher solubility in phosphate buffer at pH 6.8 than the active pharmaceutical ingredient (up to 46.07 times), potentially fundamentally improving the low bioavailability of albendazole due to its poor solubility. Furthermore, the significantly optimized powder flowability of albendazole-acesulfame potassium salt crystal form A greatly enhances its industrial processability, facilitating large-scale production processes. Simultaneously, acesulfame potassium, as an artificial sweetener and an approved food additive, has relatively complete toxicological data, which can assist albendazole in improving its flavor. Moreover, the preparation process of the salt is simple, mild, and requires low amounts of organic solvents, meeting the requirements of green production.
[0054] It will be apparent to those skilled in the art that various modifications and variations can be made to the compounds and their preparation methods without departing from the spirit or scope of this application. Therefore, the scope of protection of this application covers various modifications and variations made to this application, as long as the modifications or variations are within the scope covered by the claims and their equivalent embodiments.
Claims
1. An albendazole-acesulfame potassium salt crystal form A having the structure of formula (I), characterized in that, The molar ratio of albendazole cation to acesulfame K anion in crystal form A is 1:
1.
2.
3. Formula (I).
4. The albendazole-acesulfame potassium salt crystal form A as described in claim 1, characterized in that, The powder X-ray diffraction pattern of crystal form A has characteristic peaks at 2θ angles of 6.9±0.2°, 20.3±0.2°, 22.9±0.2°, 25.5±0.2° and 26.3±0.2°.
5. The albendazole-acesulfame potassium salt crystal form A as described in claim 1, characterized in that, The powder X-ray diffraction pattern of crystal form A has characteristic peaks at 2θ angles of 6.9±0.2°, 11.2±0.2°, 13.9±0.2°, 17.3±0.2°, 18.4±0.2°, 20.3±0.2°, 22.9±0.2°, 25.5±0.2°, 26.3±0.2°, and 29.5±0.2°.
6. The albendazole-acesulfame potassium salt crystal form A according to claim 1, characterized in that, When the test temperature is 273.15 K, the cell parameters are: a=7.9456(4) Å, b=9.7042(5) Å, c=12.7033(6) Å, α=90.754(4)°, β=94.046(4)°, γ=97.080(4)°, and the space group is P-1.
7. The albendazole-acesulfame potassium salt crystal form A according to claim 1, characterized in that, The differential scanning calorimetry curve shows an endothermic peak at a peak of 156±5 ℃.
8. The method for preparing albendazole-acesulfame potassium salt crystal form A according to any one of claims 1 to 5, characterized in that, Albendazole and acesulfame potassium were mixed at a predetermined molar ratio and subjected to liquid-phase assisted milling in the presence of an aqueous or anhydrous organic solvent; the resulting mixture was then dried to obtain the albendazole-acesulfame potassium salt crystal form A.
9. The method for preparing albendazole-acesulfame potassium salt crystal form A as described in claim 6, characterized in that, The organic solvent is methanol. The ratio of water to methanol is ≤30%.
10. Albendazole-acesulfame potassium salt crystal form A according to any one of claims 1 to 6 is mainly used for the treatment of various types of parasitic diseases.