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Crystal form and preparation method of salt formed by bromhexine and fumaric acid

A technology of fumaric acid and bromhexine, which is applied in the crystal form and preparation of salt, can solve the problems of transportation, storage and use restrictions, achieve the effect of improving stability and solubility, and avoiding strong corrosion

Active Publication Date: 2022-03-29
SOUTHEAST UNIV CHENGXIAN COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The concentrated hydrochloric acid used in the formation of hydrochloride is a precursor chemical supervised by the state, and has disadvantages such as strong corrosion, which limits its transportation, storage and use.

Method used

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  • Crystal form and preparation method of salt formed by bromhexine and fumaric acid
  • Crystal form and preparation method of salt formed by bromhexine and fumaric acid
  • Crystal form and preparation method of salt formed by bromhexine and fumaric acid

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preparation example Construction

[0028] The preparation method of the crystal form of the salt formed by the bromhexine and fumaric acid of the foregoing embodiment comprises the following steps:

[0029] Put bromhexine and fumaric acid into a mixed solvent of methanol and organic solvent. The above-mentioned reactant is placed in an ultrasonic generator, and ultrasonically treated at ambient temperature (15-25° C.) for 10-30 min. After filtering and standing for volatilization, colorless and transparent massive crystals are precipitated. After filtering and washing the massive crystals, the crystals of the salt formed by bromhexine and fumaric acid are obtained after drying, which is to obtain the crystal form described in the application of the present invention.

[0030] In the above embodiments, the organic solvent is one or any combination of ethanol, acetonitrile, ethyl acetate and tetrahydrofuran.

[0031] As a preferred example, the molar ratio of bromhexine and fumaric acid is 1:1-2.

[0032] As a ...

Embodiment 1

[0045] At room temperature, weigh 200 mg (0.532 mmol) of bromhexine and 62 mg (0.534 mmol) of fumaric acid into the reactor, add 32 mL of ethyl acetate and 8 mL of methanol, place the above reactants in an ultrasonic generator, and ultrasonically 30min. Filter the solution into a clean and dry 50ml beaker with analytical filter paper, and let it stand at room temperature for volatilization. After about 2 weeks, a colorless transparent block crystal is precipitated, and the crystal form described in the application of the present invention is obtained.

[0046] Adopt the bulk crystal obtained in embodiment 1 to carry out single crystal diffraction experiment, obtain figure 1 . The obtained crystal form is monoclinic P2 1 / n space group, the basic structural unit is composed of a protonated positively charged bromhexine molecule and a deprotonated negatively charged fumaric acid molecule, and the basic structural unit is passed through N-H...O, C-H...O, O-H...O hydrogen bonds...

Embodiment 2

[0048] At room temperature, weigh 100 mg (0.266 mmol) of bromhexine and 34 mg (0.293 mmol) of fumaric acid into a reactor, add 20 mL of acetonitrile and 2 mL of methanol, place the above reactants in an ultrasonic generator, and ultrasonicate for 15 min at ambient temperature. Filter the solution into a clean and dry 50mL beaker with analytical filter paper, and let it stand at room temperature for volatilization. After about 2 weeks, a colorless and transparent block crystal is precipitated. The crystallographic characteristics, PXRD spectrum and thermogravimetric analysis spectrum of the bulk crystal in Example 2 are consistent with the crystal form obtained in Example 1.

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Abstract

The invention discloses a crystal form of a salt formed of bromhexine and fumaric acid and a preparation method thereof. The drug co-crystal uses bromhexine as the active ingredient of the drug and fumaric acid as the reactant to form a salt in a mixed solvent; the obtained crystal form is monoclinic P2 1 / n space group, the basic structural units are composed of a protonated positively charged bromhexine molecule and a deprotonated negatively charged fumaric acid molecule, and the basic structural units are passed through N‑H…O , C‑H…O, O‑H…O hydrogen bonds are combined to form a three-dimensional space structure. The new crystal form of bromhexine fumarate of the present invention can maintain good storage stability, has improved solubility, has no hygroscopicity, and provides convenience for transportation, production, and pharmaceutical preparations.

Description

technical field [0001] The invention relates to a crystal form of a salt and a preparation method thereof, in particular to a crystal form of a salt formed of bromhexine and fumaric acid and a preparation method thereof. Background technique [0002] Bromhexine has a strong mucolytic effect, mainly acting on the mucus-producing cells of the trachea and bronchial mucosa, inhibiting the synthesis of acidic mucopolysaccharide proteins in the sputum, and breaking the mucin fibers in the sputum, thus making the trachea, bronchi The rheological characteristics of bronchial secretion returned to normal, the viscous sputum decreased, and the sputum was diluted and easy to cough up. At home and abroad, bromhexine is widely used in the adjuvant treatment of respiratory diseases. In clinical application, bromhexine is more suitable for chronic obstructive pulmonary diseases such as chronic bronchitis, emphysema, and bronchiectasis, and those with sticky phlegm that is difficult to cou...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C211/52C07C57/15C07C209/00C07C209/84C07C51/41C07C51/43
CPCC07C211/52C07C57/15C07C209/00C07C209/84C07C51/412C07C51/43C07C2601/14C07B2200/13
Inventor 张亚安
Owner SOUTHEAST UNIV CHENGXIAN COLLEGE
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