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Preparation method of doxycycline monohydrate

A technology for doxycycline and doxycycline hydrochloride, which is applied in the field of compound preparation, can solve the problems of complex process, low yield, toxic sulfosalicylic acid, etc., and achieves stable material quality, high raw material yield and high technological simple effect

Active Publication Date: 2021-08-17
ZHENJIANG GAOHAI BIOLOGICAL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] "A method for producing doxycycline monohydrate (CN106946728A)" discloses a preparation method of doxycycline monohydrate, but the method is complex (after obtaining the doxycycline monohydrate crude product In the purification process, sulfosalicylic acid is used to precipitate salt-forming substances, and sulfosalicylic acid is toxic, difficult to degrade, and difficult to recycle. If it is directly discharged or handled improperly, it will pollute the environment and cause harm to the human body) , low yield (the crude product of α-6-deoxyoxytetracycline 5-sulfosalicylate of 100g, the highest final doxycycline monohydrate finished product is only 43g)
[0005] Moreover, the existing doxycycline monohydrate preparation technology is difficult to obtain doxycycline monohydrate with stable quality, and the obtained doxycycline monohydrate has many related impurities, which is difficult to achieve Relevant European standards and American standards (methylene ≤ 2.0%, β-doxycycline ≤ 2.0%, metacycline ≤ 0.5%)

Method used

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  • Preparation method of doxycycline monohydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] The preparation method of doxycycline monohydrate is as follows:

[0035] (1) drop into 70% ethanol 1250Kg successively in the dissolution kettle of 2000L, drop into yellow doxycycline hydrochloride 500Kg under stirring, drop the temperature to 0 ℃ after throwing, start to drip ammoniacal liquor 200Kg slowly from the high position of ammoniacal liquor, keep the solution temperature over 10°C. When the material gradually changes from yellow to reddish brown, continuously measure the pH value with precision test paper (measured once every 3 minutes), control the pH ≤ 7.5, stir until completely dissolved, and continue stirring for 10 minutes.

[0036] (2) After confirming that the pH value remains unchanged, slowly add high-level pre-filtered CP hydrochloric acid under stirring, adjust the pH value to 6.00 at one time, heat the solution to 50°C while stirring, and keep it warm for half an hour to precipitate doxycycline Monohydrate crystals, turn on the cooling water to c...

Embodiment 2

[0038] The preparation method of doxycycline monohydrate is as follows:

[0039] (1) Put 1000Kg of 70% ethanol in a 2000L dissolving kettle successively, throw in 500Kg of yellow doxycycline hydrochloride under stirring, cool down to -5°C at the end of the throwing, start to slowly add 150Kg of ammonia water from the high position of ammonia water, and keep the solution temperature Not more than 10°C. When the material gradually changes from yellow to reddish brown, continuously measure the pH value with precision test paper (measured once every 4 minutes), control the pH ≤ 7.5, stir until completely dissolved, and continue stirring for 7 minutes.

[0040] (2) After confirming that the pH value remains unchanged, slowly add high-level pre-filtered CP hydrochloric acid under stirring, adjust the pH value to 6.50 at one time, heat the solution to 45°C while stirring, and keep it warm for half an hour to precipitate doxycycline Monohydrate crystals, turn on the cooling water to ...

Embodiment 3

[0042] (1) drop into 70% ethanol 1500Kg successively in the dissolving kettle of 2000L, drop into yellow doxycycline hydrochloride 500Kg under stirring, drop the temperature to 10 ℃ after throwing, start to drip ammoniacal liquor 250Kg slowly from the high position of ammoniacal liquor, keep the solution temperature over 15°C. When the material gradually changes from yellow to reddish brown, continuously measure the pH value with precision test paper (measured once every 5 minutes), control the pH ≤ 7.5, stir until it is completely dissolved, and continue stirring for 5 minutes.

[0043] (2) After confirming that the pH value remains unchanged, slowly add high-level pre-filtered CP hydrochloric acid under stirring, adjust the pH value to 5.50 at one time, heat the solution to 38°C while stirring, and keep it warm for half an hour to precipitate doxycycline Monohydrate crystals, turn on the cooling water to cool down and stir for 2 hours, then all the crystals will be precipita...

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Abstract

The invention discloses a preparation method of a doxycycline monohydrate. The method comprises the following steps: (1) adding doxycycline hydrochloride into ethanol, cooling the obtained solution, then dropwise adding ammonia water into the solution, keeping the temperature of the solution not more than 15 DEG C and the pH value of the solution not more than 7.5, and stirring until the doxycycline hydrochloride is completely dissolved; and (2) adjusting the pH value of the solution obtained in the previous step to 5.50-6.50 by using acid, then separating out doxycycline monohydrate crystals by using a crystallization method, filtering, washing and drying. The doxycycline monohydrate which is stable in quality, high in purity and low in impurity content is prepared through the method, the process is simple and environmentally friendly, the raw material yield is high, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of compound preparation, and in particular relates to a preparation method of doxycycline monohydrate. Background technique [0002] Doxycycline monohydrate is a broad-spectrum bacteriostatic agent with bactericidal effect at high concentrations. Many rickettsia, mycoplasma, chlamydia, atypical mycobacteria, and spirochetes are also sensitive to this product. This product has a better effect on Gram-positive bacteria than Gram-negative bacteria, but Enterococcus is resistant to it. Others such as Actinomycetes, Bacillus anthracis, Listeria monocytogenes, Clostridium, Nocardia, Vibrio, Brucella, Campylobacter, and Yersinia are sensitive to this product. [0003] The fat solubility of doxycycline monohydrate is 5 times larger than that of tetracycline and 50 times larger than that of oxytetracycline. Its antibacterial spectrum is the same as that of tetracycline, but its effect is 2 to 10 times stronger than...

Claims

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Application Information

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IPC IPC(8): C07C237/26C07C231/12C07C231/24
CPCC07C231/12C07C231/24C07C2603/46C07C237/26Y02A50/30
Inventor 李义高庄旭祥李小彪赵阳
Owner ZHENJIANG GAOHAI BIOLOGICAL PHARMA CO LTD
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