A kind of crystal form of azlocillin sodium and its crystallization preparation method

A technology of azlocillin sodium crystals and azlocillin sodium, which is applied in the crystal form of azlocillin sodium and its crystal preparation field, can solve the problems of products such as easy floating, poor fluidity, and difficult operation, and achieve easy commercialization Large-scale implementation, less toxic and side effects, and good safety effects

Active Publication Date: 2019-04-23
TIANJIN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The applicant's research found that the crystal forms reported in the above research are all microcrystalline powders, and the products generally have problems of low bulk density and poor fluidity, which brings a lot of inconvenience to the subsequent processing of the drug. For example, due to the low bulk density, the product It is easy to float during the drying and packaging process; due to poor fluidity, it is difficult to continuously operate the product packaging process, etc.

Method used

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  • A kind of crystal form of azlocillin sodium and its crystallization preparation method
  • A kind of crystal form of azlocillin sodium and its crystallization preparation method
  • A kind of crystal form of azlocillin sodium and its crystallization preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Add 1.00 g of azlocillin sodium solid into 20 mL of water, stir at 25°C until completely dissolved, and add 60 mL of methyl acetate to the solution at a speed of 1.20 ml / min under the action of ultrasonic waves with a frequency of 20 kHz and a power of 50 W to precipitate crystal, then cooled to 5°C at a rate of 0.6°C / min, stirred for 3 hours, filtered with suction, and dried the obtained wet product at 30°C under normal pressure for 4.5 hours to obtain a new crystal form of azlocillin sodium. The X-ray powder diffraction pattern of the new crystal product is as follows: image 3 As shown, it has characteristics at diffraction angles 2θ=4.40, 7.52, 8.67, 11.35, 12.93, 14.51, 15.04, 16.80, 17.86, 19.49, 19.92, 21.67, 22.55, 23.50, 24.11, 25.24, 26.23, 27.16, 32.84 degrees Peak; TGA of the new crystalline product such as Figure 4 As shown, the decomposition temperature of the new crystal form is 229°C, and the product has good stability; the appearance of the crystal is...

Embodiment 2

[0036]Add 2.00 g of azlocillin sodium solid into 20 mL of methanol, stir at 25 °C until completely dissolved, and add 100 mL of acetonitrile to the solution at a speed of 0.20 ml / min under the action of ultrasonic waves with a frequency of 40 kHz and a power of 80 W to precipitate crystals , then lower the temperature to 0°C at a rate of 0.6°C / min, stir for 3h, filter with suction, and dry the obtained wet product at 25°C under normal pressure for 6.0h to obtain a new crystal form of azlocillin sodium. 2θ=4.31, 7.58, 8.76, 11.23, 12.94, 14.59, 14.97, 16.85, 17.93, 19.50, 19.92, 21.55, 22.71, 23.42, 24.04, 25.36, 26.39, 27.18, 32.75 degrees have characteristic peaks; The decomposition temperature is 228°C, and the product has good stability; the crystal appearance is spherical, the particle size is 297 μm, the bulk density is 0.794 g / mL, the product purity is 99.7%, and the process yield is 98.3%.

Embodiment 3

[0038] Add 4.00g of azlocillin sodium solid into 20mL N.N-dimethylformamide, stir at 30°C until it is completely dissolved, and inject it into the solution at a speed of 0.80ml / min under the action of ultrasonic waves with a frequency of 30kHz and a power of 65W. Add 80mL of acetonitrile to precipitate crystals, then cool down to 0°C at a rate of 0.4°C / min, stir for 2h, filter with suction, and dry the obtained wet product at 30°C under normal pressure for 4.5h to obtain azlocillin sodium new Crystal form products, which have diffraction angles 2θ=4.51, 7.63, 8.70, 11.45, 12.78, 14.55, 15.09, 16.83, 17.82, 19.59, 20.07, 21.87, 22.80, 23.34, 24.21, 25.33, 26.16, 27.18, 32.65 degrees Characteristic peaks; the decomposition temperature of the new crystal form is 229.5°C, and the product has good stability; the appearance of the crystal is spherical, the particle size is 302 μm, the bulk density is 0.787 g / mL, the product purity is 99.5%, and the process yield is 97.7%.

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Abstract

The invention relates to a crystal form of azlocillin sodium and a crystallization preparing method thereof. An X-ray powder diffraction spectrum is used for carrying out representation at the diffraction angle 2<theta> degrees and the characteristic peak of TGA; under the temperature ranging from 25 DEG C to 35 DEG C, an azlocillin sodium solid is added into a good solvent, stirring is carried out to enable azlocillin sodium to be dissolved completely, and a solution with the concentration being 0.05-0.2 g / mL is prepared; under the condition of applying the ultrasonic wave effect, a poor solvent is added into the solution, and a crystal is separated out, wherein the use amount of the poor solvent is 3-5 times of the volume of the good solvent; then temperature is lowered to 0 DEG C-10 DEG C, and stirring continues to be carried out for 1-3 h; crystal slurry is filtered, washed and dried to obtain an azlocillin sodium crystal-form product. The decomposition temperature of the novel crystal form is 229+ / -1 DEG C, and it shows that the stability of the product is improved. Meanwhile, the crystal-form product is of a sphere shape, is large in grain size, has higher bulk density and better mobility, and is more beneficial for the follow-up formulation process, product storage and use.

Description

technical field [0001] The invention belongs to the technical field of separation and purification of antibiotic drugs, and in particular relates to a crystal form of azlocillin sodium and a crystallization preparation method thereof. Background technique [0002] Azlocillin sodium (Azlocillin sodium) is a broad-spectrum, high-efficiency semi-synthetic penicillin. Its CAS number is 37091-65-9, and its chemical name is (2S, 5R, 6R)-3,3-dimethyl-6-[(R)-2-(2-oxo-1-imidazolidine Acylamino)-2-phenylacetamido]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid sodium salt. Molecular formula is C 20 h 22 N 5 NaO 6 S, the molecular weight is 483.47. The structural formula is as formula (I). [0003] [0004] Azlocillin sodium was researched and developed by Bayer Company of Germany, and it was listed for the first time in May 1977 under the trade name of Securopen. Azlocillin sodium belongs to the third-generation spectrum semi-synthetic penicillin, which plays a b...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D499/68
CPCC07B2200/13C07D499/68
Inventor 侯宝红周亚男郝红勋鲍颖王静康尹秋响张美景王召徐昭
Owner TIANJIN UNIV
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