Doriipenem hydrate crystal and preparation method thereof

A hydrate and crystallization technology, which is applied in the direction of pharmaceutical formulations, medical preparations containing active ingredients, antibacterial drugs, etc., can solve the problems of poor crystal stability of doripenem, complicated preparation methods, time-consuming and energy-consuming, etc., and achieve excellent The effects of stability, simple preparation method, and excellent solubility properties

Active Publication Date: 2008-01-09
CHIA TAI TIANQING PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is to solve the problems of poor crystal stability of doripenem in the prior art, complicated preparation method, time-consuming and energy-consuming, etc., and provide new doripenem with excellent stability and solubility, and suitable for industrial production Crystallization, especially of the new doripenem hydrate

Method used

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  • Doriipenem hydrate crystal and preparation method thereof
  • Doriipenem hydrate crystal and preparation method thereof
  • Doriipenem hydrate crystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The crude product of doripenem (10 g) was dissolved in distilled water (200 mL) at 50-55°C, added with activated carbon (0.6 g) for decolorization, and suction filtered. Add isopropanol (90 mL) to the filtrate while it was hot, cool to 15-20°C and stir for 1 hour, then cool to 0-5°C and stir for 2 hours. Isopropanol (90 mL) was added dropwise to the resulting suspension, then stirred at 0-5°C for 2 hours, and finally cooled to -10°C and stirred overnight. The precipitated crystals were collected by filtration, and the filter cake was washed with isopropanol:water (volume ratio 4:1). The resulting filter cake was dried at 50° C. under reduced pressure (0-10 mmHg) for about 4 hours until the water content was about 6%, and the doripenem type V crystallized.

[0044] The powder X-ray diffraction spectrum of the obtained crystal is shown in Fig. 1, wherein at diffraction angles 2θ=6.45, 13.05, 14.99, 15.31, 15.89, 16.64, 17.50, 18.07, 19.67, 20.65, 21.07, 22.17, 23.44, 23....

Embodiment 2

[0050] The crude product of doripenem (10 g) was dissolved in distilled water (100 mL) at 60-65°C, added with activated carbon (0.3 g) for decolorization, and suction filtered. The filtrate was cooled to room temperature, stirred for 1 hour, then cooled to 0-5°C and stirred for 3 hours; isopropanol (100 mL) was added dropwise to the obtained suspension, and then stirred at 0-5°C for 2 hours. Finally, it was cooled to -15°C and stirred overnight, the precipitated crystals were collected by filtration, and the filter cake was washed with isopropanol:water (volume ratio 4:1). The resulting filter cake was dried at 50° C. under reduced pressure (10-20 mmHg) for about 5.5 hours until the water content was about 6%, and doripenem type VI crystallized.

[0051] The powder X-ray diffraction spectrum of the resulting crystal is shown in Figure 2, wherein there are main peaks at diffraction angles 2θ=12.91, 14.87, 15.75, 16.52, 20.52, 20.97, 22.05, 23.31, 23.79, 24.37, 25.98, 27.43, 28....

Embodiment 3

[0058] The crude product of doripenem (10 g) was dissolved in distilled water (200 mL) at 50-55°C, added with activated carbon (0.6 g) for decolorization, and suction filtered. Add isopropanol (90 mL) to the filtrate while it is hot, put doripenem type V crystal seed crystals into the resulting solution, cool to 15-20°C and stir for 1 hour, then cool to 0-5°C and stir for 2 hours. Isopropanol (90 mL) was added dropwise to the resulting suspension, then stirred at 0-5°C for 2 hours, and finally cooled to -10°C and stirred overnight. The precipitated crystals were collected by filtration, and the filter cake was washed with isopropanol:water (volume ratio 4:1). The resulting filter cake was dried at 50°C under reduced pressure (0-10mmHg) for about 4 hours to a water content of about 6%, and doripenem type V crystals (8.4g, purification rate 84%).

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Abstract

Two torilpenan 1.5 hydrate crystals are simple and reliable. It has excellent stability and dissolubility. In powdery X-ray diffraction diagram, a torilpenan crystal has main peak at diffraction angle 2 theta=6.45, 13.05, 14.99, 15.31, 15.89, 16.64, 17.50, 18.07, 19.67, 20.65, 21.07, 22.17, 23.44, 23.90, 24.49, 26.08, 27.57, 28.22, 29.00, 31.69, 34.97, 38.08 and 39.87; another torilpenan crystal has main peak at diffraction angle 2 theta=12.91, 14.87, 15.75, 16.52, 20.52, 20.97, 22.05, 23.31, 23.79, 24.37, 25.98, 27.43, 28.12, 28.85 and 34.08.

Description

technical field [0001] The invention relates to doripenem hydrate crystals and a preparation method thereof, in particular to doripenem 1.5 hydrate crystals and a preparation method thereof. Background technique [0002] Doripenem is a β-methylcarbapenem (carbapenem) antibiotic that has broad-spectrum and balanced potent antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, and anaerobic bacteria. Other names of doripenem include: S-4661, doripenem, etc. The chemical name is (4R, 5S, 6S)-3-[[(3S, 5S)-5-[(sulfamoylamino)methyl]pyrrolidin-3-yl]thio]-4-methyl-6 -[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, the structural formula is as follows: [0003] [0004] Japanese patent application JP5294970 discloses amorphous doripenem, but this amorphous doripenem is unstable, easily changes color and decreases in purity under normal storage conditions. In order to overcome the defect of poor stability of amorphous doripen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20A61K31/4025A61P31/04
Inventor 张庆文唐志军时惠麟
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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