Hydrate of micheliolide dimethylamine fumarate, preparation method and application thereof

Abstract

The invention relates to a hydrate of micheliolide dimethylamine fumarate, a preparation method and application thereof, wherein the hydrate is a crystal form D, is high in crystallinity, smooth in particle surface, free of coalescence, high in bulk density and good in flowability, and has good stability and good reproducibility. The preparation method comprises the following steps: under stirringeffect, adding dimethylamine micheliolide and fumaric acid into a mixed solvent system with a constant temperature of 30-70 DEG C, carrying out reaction crystallization; and filtering after the reaction is finished, and drying the filtered solid at normal pressure to obtain the micheliolide dimethylamine fumarate crystal form D. The preparation method is simple, the product yield is high, and themethod is suitable for later preparation of patent medicines, and is beneficial to large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine crystallization, and in particular relates to a hydrate of mimilactone dimethylamine fumarate, a preparation method and application thereof. Background technique [0002] Parthenolide is a main active ingredient extracted from the Compositae herb Chamomile and Tansy. It is a natural sesquiterpene lactone compound. Traditionally, Parthenolide is mainly used for fever , rheumatoid arthritis, migraine, toothache and other diseases. In recent years, domestic and foreign studies have found that parthenolide also has anti-tumor effects, but this compound is unstable under acidic or alkaline conditions. [0003] In order to improve its stability, the compound parthenolide was modified to obtain Micheliolide. The English name is Micheliolide (MCL), which belongs to the guaiacane-type sesquiterpene lactone compound. There are relevant literature and patent reports on Micheliolide Esters have the effect o...

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Problems solved by technology

[0007] Chinese patent CN103724307B discloses mimilactone dimethylamine fumarate crystal form A and its preparation method. The patent uses XRPD to characterize crystal form A, expressed in 2θ at 7.10°, 7.58°, 11.72°, 12.26° , 13.30°, 14.24°, 15.70°, 16.38°, 17.04°, 19.02°, 19.86°, 20.14°, 20.66°, 21.20°, 21.78°, 22.64°, 23.58°, 23.8°, 24.48°, 25.08°, 26.24 °, 27.08°, 27.60°, 28.40°, 28.94°, 34.48°, 34.82°, 36.12°, 38.72°, and 45° have characteristic peaks, and crystal form A is prepared by recrystallization in ethyl acetate solvent. In this method Natural cooling is used to prepare products, and the crystallization process is controlled by thermodynamics and kinetics at the same time. Natural cooling crystallization conditions fluctuate greatly due to environmental influences, and the cooling rate is difficult to control. The product particle size is small, the main particle size is 35.8 μm, and the bulk density is small. , only reaches 0.270g / mL, the angle of repose is 62°, the fluidity is poor, and the quality of crystal products varies greatly between different batches

At the same time, crystal form A has poor stability and is prone to crystal transformation, and the solid powder also has a strong electrostatic effect, resulting in dust in the production process, which will bring many problems to later processing and handling

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