Bromhexine hydrochloride crystal as well as preparation method and application of crystal

A kind of technology of bromhexine hydrochloride and crystal, applied in the field of bromhexine hydrochloride crystal and its preparation and use, can solve problems such as unfavorable impurities

Active Publication Date: 2013-02-13
SHIJIAZHUANG DONGFANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The 2010 edition of the Chinese Pharmacopoeia has improved the standards for related substances of bromhexine hydrochloride. The crystallization method based on the existing technology is not conducive to the removal of impurities. During production, it is necessary to undergo multiple crystallization operations to obtain bromhexine hydrochloride products that meet the requirements of the Pharmacopoeia.

Method used

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  • Bromhexine hydrochloride crystal as well as preparation method and application of crystal
  • Bromhexine hydrochloride crystal as well as preparation method and application of crystal
  • Bromhexine hydrochloride crystal as well as preparation method and application of crystal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1 : the preparation method of bromhexine hydrochloride

[0063]

[0064] (1) Synthesis of 2-amino-3,5-dibromobenzyl alcohol

[0065] Suspend 11.2g (0.04mol) of 2-amino-3,5-dibromobenzaldehyde in 20ml of ethanol, below 25°C (cooled in an ice-water bath), add 0.95g (0.025mol) of sodium borohydride solid in batches within 15min After the addition, stir at room temperature for 1.5h, add 50ml of distilled water to dilute, adjust the pH value to 6 with 6% hydrochloric acid at room temperature, and stir vigorously for 0.5h. Filter, wash with distilled water (20ml×3), suck dry, and dry (2h at 70°C) to obtain off-white solid 2-amino-3,5-dibromobenzyl alcohol.

[0066] (2) Synthesis of 2,4-dibromo-6-chloromethylaniline

[0067] Cooled in an ice-water bath (5-25 degrees), within 10 minutes, add 30ml SOCl 2 10 g (0.0357 mol) of 2-amino-3,5-dibromobenzyl alcohol was added in batches to the mixture, and after the addition was complete, it was stirred overnight at room...

Embodiment 2

[0073] Example 2 : prepare bromhexine hydrochloride crystallization according to disclosed technical scheme (DE2411848A1, example 3)

[0074] Operated by Example 1, the ethyl acetate solution of bromhexine base obtained in Example 1 was concentrated to dryness under reduced pressure, added 40ml of 17% HCl ethanol solution and 2ml of distilled water, stirred at 70°C for 1.5h, stopped heating, Add 25 ml of ethanol and stir to cool and crystallize, and filter to obtain 10 g of bromhexine hydrochloride crystals, batch number: 110101-a. Through X-diffraction and infrared measurement, the X-diffraction pattern of bromhexine hydrochloride crystal 110101-a and image 3 Consistent with the infrared absorption spectrum and Figure 4 Consistent, thus judging that the crystal form prepared by this method is consistent with crystal form I.

Embodiment 3

[0075] Example 3 : prepare bromhexine hydrochloride crystallization according to disclosed technical scheme (DE2411848A1, example 1)

[0076] According to the operation of Example 1, the ethyl acetate solution of bromhexine base obtained in Example 1 was concentrated to dryness under reduced pressure, the residue was dissolved in 80ml of absolute ethanol, and 6ml of concentrated hydrochloric acid was slowly added dropwise, and there were solids in the dropwise addition process Precipitation, dropwise, filter. The filter cake was recrystallized with 330 ml of absolute ethanol to obtain 8.9 g of bromhexine hydrochloride crystals. Batch number: 110101-b. Through X-diffraction and infrared measurement, the X-diffraction pattern of bromhexine hydrochloride crystal 110101-b and image 3 Consistent with the infrared absorption spectrum and Figure 4 Consistent, thus judging that the crystal form prepared by this method is consistent with crystal form I.

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Abstract

The invention provides a bromhexine hydrochloride crystal as well as a preparation method and application of the bromhexine hydrochloride crystal. According to the crystal, an X-ray powder diffraction picture under the radiation of Cu KAlpha1 has diffraction peaks in a part with reflection angles 2 Theta of 7.29, 14.33 and 24.439. The crystal can obviously improve the water solubility of bromhexine hydrochloride, and is beneficial for the preparation of an injection; and relative materials can be further reduced, so that the safety of the preparation can be improved.

Description

technical field [0001] The invention relates to a bromhexine hydrochloride crystal, a preparation method and application thereof. Background technique [0002] Bromhexine Hydrochloride is a white or off-white crystalline powder, odorless, tasteless, slightly soluble in ethanol and chloroform, very slightly soluble in water, and its chemical name is N-methyl-N-ring Hexyl-2-amino-3,5-dibromobenzylamine hydrochloride, the chemical structure is as follows: [0003] [0004] Bromhexine hydrochloride is the preferred expectorant commonly used at home and abroad. It can decompose and break acidic mucopolysaccharide fibers in sputum, and can inhibit the synthesis of acidic mucopolysaccharides in glandular goblet cells, thereby reducing the viscosity of sputum and making it easier to cough up. No nausea expectorant effect. It is mainly used for chronic bronchitis, asthma, bronchiectasis, silicosis and other patients with white sticky sputum that is difficult to cough up, especia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/52C07C209/86A61K31/137A61P11/00A61P11/08A61P11/10
Inventor 张凯程诚杜玉民薛娜韩丰年马旭伟
Owner SHIJIAZHUANG DONGFANG PHARMA
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