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Crystallization process of promestriene crystal

A promestrine and crystallization technology, which is applied in the field of medicine, can solve the problems of unstable pharmaceutical properties of preparations, large static electricity in flaky crystals, and low bioavailability, and achieve the effects of good fluidity, low static electricity, and high bioavailability

Active Publication Date: 2020-02-21
BEIJING JINCHENG TAIER PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] 1. Flaky crystals have high static electricity, high viscosity, small crystal grains, poor fluidity and poor stability
[0011] 2. The pharmaceutical properties of preparations obtained from flaky crystals are unstable, the success rate of preparations is low, and the bioavailability is low, which is only suitable for a few types of preparations such as tablets or creams
[0012] 3. Because promestriene and ethanol are easy to form intermolecular hydrogen bonds, the solubility is increased, so the refining yield is only 80%, and a large amount of promestriene remains in the refined mother liquor, which causes great pollution to the environment and increases the Security risks

Method used

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  • Crystallization process of promestriene crystal
  • Crystallization process of promestriene crystal
  • Crystallization process of promestriene crystal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Under the protection of nitrogen at room temperature, add 10 g of crude promestriene and 50 g of ethylene glycol isopropyl ether into a 100 ml four-necked flask, add 1 g of 1,4-dioxane and 0.02 g of formic acid, and heat up to 65°C to dissolve. Add 0.02 g of medicinal charcoal for decolorization and filtration, stir the filtrate under the action of 20KHz and 200W ultrasonic waves within 2 hours and cool down to 41°C, then stop the ultrasonic vibration, add 0.001 g of seed crystals, keep stirring and crystallize for 2 hours, then ultrasonically oscillate for 5 minutes, then Gradient cooling, stirring to 36°C within 30 minutes, then heat preservation and stirring and ultrasonic oscillation for 1 minute, then heat preservation and stirring for 30 minutes, continued stirring within 30 minutes to 31°C, then heat preservation and stirring and ultrasonic oscillation for 1 minute, then heat preservation Stir for 30 minutes, continue to lower the temperature to 26°C, 21°C, 16°C, ...

Embodiment 2

[0072] Under the protection of nitrogen at room temperature, add 20 grams of promestriene crude product and 80 grams of ethylene glycol isopropyl ether into a 250 ml four-necked bottle, add 4 grams of 1,4-dioxane and 0.05 grams of formic acid, and heat up to 64 ° C to dissolve. Add 0.04g of medicinal charcoal for decolorization and filtration, stir the filtrate under the action of 20KHz, 200W ultrasonic wave and cool it down to 42°C, then stop the ultrasonic oscillation, add 0.002g of seed crystal, keep stirring and crystallize for 2 hours, then ultrasonically oscillate for 5 minutes, and then cool down gradually. Stir to 37°C within 30 minutes, then keep stirring and ultrasonically oscillate for 1 minute, then keep stirring for 30 minutes, continue to stir and drop to 32°C within 30 minutes, then keep stirring and ultrasonically oscillate for 1 minute, then keep stirring for 30 minutes, Continue to lower the temperature to 27°C, 22°C, 17°C, 12°C, and 7°C and repeat the above p...

Embodiment 3

[0074] Under nitrogen protection at room temperature, add 50 grams of promestriene crude product and 150 grams of ethylene glycol isopropyl ether into a 250 ml four-necked bottle, add 30 grams of methyl tert-butyl ether and 0.15 grams of formic acid, heat up to 63 ° C to dissolve, add 0.14 Decolorize and filter the filtrate under the action of 20KHz, 200W ultrasonic waves and cool down to 43°C, then stop the ultrasonic oscillation, add 0.005g of seed crystals, keep stirring and crystallize for 2 hours, then ultrasonically oscillate for 5 minutes, and then cool down gradually, within 30 minutes Stir internally to 37°C, then keep stirring and ultrasonically oscillate for 1 minute, then keep stirring for 30 minutes, continue to stir within 30 minutes and drop to 32°C, then keep stirring and ultrasonically oscillate for 1 minute, then keep stirring for 30 minutes, and continue to separate Lower the temperature to 27°C, 22°C, 17°C, 12°C, and 7°C and repeat the above process, continu...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a crystallization process of a promestriene crystal. The method comprises crystallizing a promestriene crude product by using a main solvent, a cosolvent and an organic acid to obtain the promestriene crystal. The crystallization process is safe, environment-friendly and simple and convenient to operate, the quality and yield are improved, the refining yield is 93-95%, the purity is 99.98% or above, and the method is suitable for industrial production; the prepared columnar crystal is small in static electricity, low in viscosity, good in fluidity, large in crystal grain, uniform in particle, high in wet and heat stability, high in preparation success rate and high in bioavailability, and medicine side effects are reduced.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a crystallization process of promestriene crystals. Background technique [0002] Promestriene is a local estrogen supplement developed by Dalimei Pharmaceutical Company in Monaco (acquired by Merck & Co., USA in 1999). It was approved by the US patent in 1977. Its preparations mainly include Colpotrophine, which was launched in France in 1978, and Delipoderm, which was launched in France in 1978. Promestriene, Genapofen (Promestriene Soft Capsules and Cream) and Kebaojing (Chloroquinaldol / Promestriene Vaginal Tablets) have been collected by Martindale Drug Manual, and have been clinically used in more than 40 foreign countries for 40 years For more than a decade, it is still the first-line drug for the treatment of vaginal infection and atrophic vaginitis in many countries. Clinical practice shows that it is safe and effective, and well tolerated by patients. [0...

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCC07J1/0077
Inventor 张忠政游亚新刘文杰孙滨张宾张治中张彤王琨李景坤张国斌
Owner BEIJING JINCHENG TAIER PHARMA CO LTD
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