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Leflunomide crystal form compound, preparation method and application thereof

A leflunomide and compound technology, applied in organic chemical methods, active ingredients of heterocyclic compounds, drug combinations, etc., can solve problems such as affecting the stability of preparations, affecting the production quality of raw materials and preparations, and instability, and achieving good Formulation processability, good selection, stable properties

Active Publication Date: 2020-04-07
力赛生物医药科技(厦门)有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Both crystal form I and crystal form II are unstable, and most of the raw materials currently on the market are mixed crystals of crystal form I and crystal form II, which not only affects the production quality of raw materials and preparations, but also affects the stability of preparations

Method used

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  • Leflunomide crystal form compound, preparation method and application thereof
  • Leflunomide crystal form compound, preparation method and application thereof
  • Leflunomide crystal form compound, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Heat and dissolve 8 g of leflunomide bulk drug (crystalline form I) in 10 ml of the following solvents, cool to room temperature (about 22° C.), and detect the obtained solid by X-ray powder diffraction. Form IV was obtained in PEG400, as shown in Table 2 below.

[0069] Table 2

[0070] Numbering solvent method crystal form 1 Tween 80 hot melt cold analysis solid not collected 2 Division 20 hot melt cold analysis solid not collected 3 polyethylene glycol 400 hot melt cold analysis Form IV 4 TRANSCUTOL P hot melt cold analysis Form I 5 LABRASOL hot melt cold analysis solid not collected 6 CAPRYOL 90 hot melt cold analysis solid not collected 7 TRANSCUTOL HP hot melt cold analysis solid not collected

Embodiment 2

[0071] Embodiment 2 Preparation of Leflunomide Form IV

[0072] Suspend 8g of leflunomide raw material (form I) in 10ml of PEG 400, heat to 68°C, and completely dissolve leflunomide, stir for 10 hours, cool to room temperature (22°C), and filter to obtain a solid , washed with water for 2-5 times, dried to obtain crystals after washing, X-ray powder diffraction detection and DSC detection, the crystals are crystal form IV, see figure 1 .

Embodiment 3

[0073] Embodiment 3 Preparation of Leflunomide Form IV

[0074] Suspend 1 g of leflunomide raw material (form I) in 5 g of PEG 200, heat to 68°C, and completely dissolve leflunomide, stir for 36 hours, cool to room temperature (22°C), and filter to obtain a solid , washed with water for 2-5 times, dried to obtain crystals after washing, X-ray powder diffraction detection and DSC detection were performed, and the crystals were crystal form IV.

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Abstract

The invention discloses a crystal form compound of leflunomide. In an XRD pattern of the crystal form compound, characteristic diffraction peaks occur when the value of 2theta is 8.04 DEGs + / - 0.2 DEG, 10.83 DEGs + / - 0.2 DEG, 14.29 DEGs + / - 0.2 DEG, 18.72 DEGs + / - 0.2 DEG, 20.48 DEGs + / - 0.2 DEG and 24.92DEGs + / - 0.2 DEG. The novel crystal form of leflunomide has better stability than all the reported crystal forms of leflunomide and has high purity and good reproducibility. The invention also discloses a preparation method for the crystal form compound. The preparation method is simple in process and can be easily implemented. The invention further provides application of the crystal form compound in the fields of preparations and medicines.

Description

technical field [0001] The invention relates to a new crystal form compound of leflunomide, a preparation method and an application thereof, belonging to the field of pharmaceutical crystal forms. Background technique [0002] Leflunomide (Leflunomide), chemical formula: C 12 h 9 f 3 N 2 o 2 , chemical name: N-(4-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide, the structural formula is as follows: [0003] [0004] It is an isazole immunomodulator with anti-proliferative activity, used for the treatment of rheumatoid arthritis, systemic lupus erythematosus, etc. Its active metabolite, terizolamide, has also been developed for multiple sclerosis. There are currently three crystal forms of leflunomide reported, and the patent application CN02104574 reports the crystal form I and the crystal form II. Crystal form I has a specific X-ray diffraction pattern, with strong diffraction peaks at 2θ angles of 16.70°, 18.90°, 23.00°, 23.65° and 29.05°, while at 2θ angl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D261/18A61K31/42A61P37/02A61P29/00A61P19/02
CPCC07B2200/13C07D261/18
Inventor 朱海健周鹏飞苏艺杰林福祥
Owner 力赛生物医药科技(厦门)有限公司