A toluimidazole crystal form and its preparation method
By preparing a new crystal form D of mebendazole, the solubility and stability issues of crystal form C of mebendazole were resolved, achieving higher solubility and stability and ensuring the sustained efficacy of the drug.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- XI AN JIAOTONG UNIV
- Filing Date
- 2026-04-08
- Publication Date
- 2026-06-30
AI Technical Summary
Different crystal forms of mebendazole have different structures, resulting in differences in their solubility and stability. Crystal form C is insoluble in water and unstable, and is easily converted into the ineffective crystal form A, affecting the efficacy.
A novel crystal form D was prepared by mixing mebendazole raw material with an organic solvent and a volatile solvent, followed by static crystallization. The resulting mebendazole crystal form D with characteristic peaks was obtained. The single crystal structure belongs to the triclinic crystal system, with space group Triclinic P and cell parameters a=6.10 Å, b=15.69 Å, c=20.35 Å, α=94.14°, β=97.22°, γ=90.70°, and V=1926 Å3.
The newly prepared mebendazole crystal form D has higher solubility and stability, solving the problems of poor solubility and instability of crystal form C and ensuring the stability of the drug efficacy.
Smart Images
Figure CN122301780A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical pharmaceuticals, and in particular to a toluene imidazol crystal form and its preparation method. Background Technology
[0002] Toluene-2-benzimidazole, chemically known as methyl 5-benzoyl-2-benzimidazole carbamate, has the molecular formula C2. 16 H 13 N3O3, with a molecular weight of 295.30, has the chemical structure shown below. It appears as a white, off-white, or slightly yellow crystalline powder, odorless; very slightly soluble in acetone, insoluble in water; readily soluble in formic acid, and slightly soluble in glacial acetic acid.
[0003] Mebendazole is a broad-spectrum benzimidazole anthelmintic. Its mechanism of action involves binding to β-tubulin in the parasite, disrupting the dynamic balance between tubulin and microtubules in the centromere region of chromosomes. This leads to changes in all microtubule-related functions at the cellular level (cell division, cell morphology maintenance, cell movement, cell secretion, nutrient uptake, and intracellular transport). In addition, mebendazole reduces glucose uptake by the parasite, ultimately causing it to die from energy depletion due to nutrient ingestion, thus achieving its deworming effect. Clinically, mebendazole is effective against gastrointestinal worms such as pinworms, roundworms, hookworms, and whipworms, as well as some tapeworms and trichinella. It is listed in the WHO's Essential Medicines List as an anti-intestinal worm treatment. Furthermore, it is also effective against common parasites in aquaculture.
[0004] Mebendazole has been found in crystalline forms including crystal forms A, B, and C, and two solvates. Different crystal forms of mebendazole have different structures, and the constituent molecules of the three crystal forms are tautomers. These structural differences lead to differences in the physicochemical and biological properties of the crystal forms. Crystal form B is highly toxic, crystal form A is an ineffective crystal form, and crystal form C is the effective crystal form; however, crystal form C is insoluble in water and unstable. Improper production and storage can cause it to revert to crystal form A. Studies have shown that when the content of crystal form A in the active pharmaceutical ingredient exceeds 30%, the drug will lose its efficacy due to its extremely low solubility. Summary of the Invention
[0005] This invention provides a toluene-imidazol crystal form and its preparation method to improve the problems of poor solubility and instability (crystal form transformation) of toluene-imidazol.
[0006] To solve the above-mentioned technical problems, the present invention provides the following technical solution: The present invention provides a toluimidazole crystal form, and the powder X-ray diffraction pattern of the toluimidazole crystal form using Cu-Kα radiation has three strong peaks at 2θ angles (°) of 6.88°, 17.19° and 24.99°.
[0007] In this invention, based on the existing three crystal forms of mebendazole, namely A, B, and C, a new crystal form is defined as crystal form D.
[0008] In some specific embodiments, the single crystal structure of the tolimidazole crystal belongs to the triclinic crystal system; The space group of the tolmediazole crystal form is Triclinic P; The unit cell parameters of the described mebendazole crystal form are a = 6.10 Å, b = 15.69 Å, c = 20.35 Å; α = 94.14°; β = 97.22°, γ = 90.70°, V = 1926 Å. 3 .
[0009] In some specific embodiments, the X-ray powder diffraction pattern of the tolimidazole crystal form has characteristic peaks at 2θ angle (°) values of 7.37°, 11.28°, 14.80°, 22.28° and 27.15°.
[0010] In some specific embodiments, the DSC curves of the tolmepiride crystal form show endothermic peaks at 108.5℃, 232.9℃, and 326.4℃.
[0011] In some specific embodiments, the TG curves of the tolmepiride crystal form show weight loss at 108.5℃, 232.9℃, and 326.4℃.
[0012] A second aspect of the present invention also provides a method for preparing the above-mentioned tolimidazole crystal form, comprising the following steps: The toluene-methyl active pharmaceutical ingredient (MTPI) and an organic solvent were mixed to obtain a saturated solution. The saturated solution was added to an open container, and a vial was placed in a beaker. A volatile solvent was added to the beaker, which was then sealed and allowed to stand. After crystallization, the mixture was filtered to obtain the toluene-methyl crystal form.
[0013] In this invention, the mebendazole raw material can be purchased, and the crystal form of the mebendazole raw material can be either crystal form A or crystal form C. In some specific embodiments, the organic solvent includes N,N-dimethylformamide and / or N,N-dimethylacetamide.
[0014] In some specific embodiments, the volatile solvent includes at least one of methyl tert-butyl ether, dichloromethane, and acetone.
[0015] In some specific embodiments, the volume ratio of the organic solvent to the volatile solvent is 1:2 to 1:6.
[0016] In some specific embodiments, the crystallization temperature is 15~50℃.
[0017] Compared with the prior art, the present invention has the following beneficial effects: The newly prepared new crystal form of mebendazole may have higher solubility and stability than crystal form C, which can solve the problems of poor solubility and crystal form transformation of mebendazole crystal form C. Attached Figure Description
[0018] The above and other objects, features, and advantages of the invention will be apparent from the following description of preferred embodiments illustrating the gist of the invention and its use, and the accompanying drawings, in which: Figure 1 This is a micrograph of the appearance of toluene-imidazol crystal form D in Example 1.
[0019] Figure 2 This is the powder X-ray diffraction pattern of toluene-imidazolium crystal form D in Example 1.
[0020] Figure 3 The graphs show the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of toluene imidazolium crystal form D in Example 1.
[0021] Figure 4 X-ray diffraction patterns of crystal forms A and C of mebendazole raw material. Detailed Implementation
[0022] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings and embodiments. The embodiments of this application are only examples, and all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0023] Example 1 (a) Crystal form identification method In this invention, the appearance micrographs were acquired using an ECLIPSE LV100N POL polarization microscope.
[0024] In this invention, single-crystal X-ray diffraction data were acquired using a Bruker D8 QUEST single-crystal diffractometer. The method parameters for single-crystal X-ray diffraction are as follows: X-ray diffractometer parameters: Ius 3.0 micro-focal spot X-ray source, CMOSPHOTON 100 detector with fourth-generation XFEL detector technology, target focal spot ≤30 μm, temperature: 153 K, Cu-Kα target (λ = 1.54178 Å).
[0025] In this invention, the powder X-ray diffraction pattern was acquired using a Shimadzu XRD-6100 X-ray diffractometer. The method parameters for powder X-ray diffraction are as follows: X-ray diffractometer parameters: Cu-Kα target, tube voltage: 40 kV, tube current: 30 mA, scanning range 2θ: 5°~30°, scanning speed: 0.2° / min; In this invention, the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves were acquired using a STA 449 F5 TG / DSC thermogravimetric analyzer. The method parameters for thermal analysis are as follows: Scan rate: 10℃ / min; Temperature range: 30~400℃; Nitrogen purging rate: 50 ml / min.
[0026] (ii) Source of raw materials The tolmepiride raw material used in this invention (purity >99%) is crystal form A or C (verified by powder X-ray diffraction pattern, e.g.) Figure 4 , Figure 4 In this example, a: mebendazole crystal form C; b: mebendazole crystal form A), the mebendazole raw material used is crystal form C.
[0027] (III) Preparation method of mebendazole crystal form D Add 5 mL of a saturated N,N-dimethylacetamide solution of tobendazole to a 10 mL glass vial, and place the vial open in a 100 mL beaker. Pour 20 mL of a volatile solvent with poor solubility in tobendazole into the beaker (be careful not to add it to the glass vial), seal the beaker, let it stand, and wait for crystals to precipitate. Filter to obtain white, needle-like crystals, i.e., benzylidene crystal form D.
[0028] The tolmepiride crystal form D obtained in this embodiment has a smooth, elongated shape, approximately 75-100 μm long and 5 μm wide. Figure 1 As shown in Table 1, the single-crystal X-ray diffraction data are as follows. The single-crystal structure belongs to the triclinic crystal system, space group Triclinic P, and the cell parameters are a = 6.10 Å, b = 15.69 Å, c = 20.35 Å, α = 94.14°, β = 97.22°, γ = 90.70°, and V = 1926 Å. 3 Its powder X-ray diffraction pattern is as follows: Figure 2 As shown, characteristic diffraction peaks appear at 2θ values of 6.88°, 7.37°, 11.28°, 14.80°, 17.19°, 22.28°, 24.99°, and 27.15°. The differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves are shown below. Figure 3As shown, there are three endothermic processes in the range of 30 to 400℃. The peak of the first endothermic process occurs at 108.5℃, with a weight loss of 21.1%; the peak of the second endothermic process occurs at 232.9℃, with a weight loss of 10.8%; and the peak of the third endothermic process occurs at 326.4℃, with a weight loss of 9.2%.
[0029] Table 1. X-ray diffraction data of tolimidazole single crystal (crystallographic data and structural refinement parameters)
[0030] In summary, the tolmepiride crystal form D provided by this invention has a single-crystal structure belonging to the triclinic crystal system, with space group Triclinic P and unit cell parameters a = 6.10 Å; b = 15.69 Å; c = 20.35 Å; α = 94.14°; β = 97.22°; γ = 90.70°, V = 1926 Å. 3 The powder X-ray diffraction pattern has characteristic peaks at 2theta values of 6.88°, 7.37°, 11.28°, 14.80°, 17.19°, 22.28°, 24.99°, and 27.15°.
[0031] Although preferred embodiments of the invention have been shown and described, it is conceivable that those skilled in the art can devise various modifications to the invention within the spirit and scope of the appended claims.
Claims
1. A tolueneimidazole crystal form, characterized in that, Using Cu-Kα radiation, the three strongest peaks in the powder X-ray diffraction pattern of the tolueneimidazole crystal form are located at 2θ angles (°) of 6.88°, 17.19°, and 24.99°.
2. The tolmediazole crystal form according to claim 1, characterized in that, The single crystal structure of the mebendazole crystal form belongs to the triclinic crystal system; The space group of the tolmediazole crystal form is Triclinic P; The unit cell parameters of the described mebendazole crystal form are a = 6.10 Å, b = 15.69 Å, c = 20.35 Å; α = 94.14°; β = 97.22°, γ = 90.70°, V = 1926 Å. 3 .
3. The tolmepiride crystal form according to claim 1, characterized in that, The X-ray powder diffraction pattern of the described mebendazole crystal form has characteristic peaks at 2θ angles (°) of 7.37°, 11.28°, 14.80°, 22.28° and 27.15°.
4. The tolmepiride crystal form according to claim 1, characterized in that, The DSC curves of the described mebendazole crystal form show endothermic peaks at 108.5℃, 232.9℃, and 326.4℃.
5. The tolmediazole crystal form according to claim 1, characterized in that, The TG curves of the described mebendazole crystal form show weight loss at 108.5℃, 232.9℃, and 326.4℃.
6. A method for preparing the tolmepiride crystal form according to any one of claims 1 to 5, characterized in that, Includes the following steps: The tolmepiride active pharmaceutical ingredient was mixed with an organic solvent to obtain a saturated solution; Add the saturated solution to an open container, place the vial in a beaker, add volatile solvent to the beaker, seal the beaker, let it stand, and filter after crystallization to obtain the toluene-imidazol crystal form.
7. The method for preparing the tolimidazole crystal form according to claim 6, characterized in that, The organic solvent includes N,N-dimethylformamide and / or N,N-dimethylacetamide.
8. The method for preparing the tolmepiride crystal form according to claim 6, characterized in that, The volatile solvent includes at least one of methyl tert-butyl ether, dichloromethane, and acetone.
9. The method for preparing the tolimidazole crystal form according to claim 6, characterized in that, The volume ratio of the organic solvent to the volatile solvent is 1:2 to 1:
6.
10. The method for preparing the tolimidazole crystal form according to claim 7, characterized in that, The crystallization temperature is 15~50℃.