CN104622695A - Cefoxitin sodium powder preparation for injection - Google Patents

Abstract

The invention discloses a cefoxitin sodium powder preparation for injection. The cefoxitin sodium powder preparation is prepared by the following steps: (1) controlling the temperature, and preparing a sodium-forming agent solution; (2) adding acetone and methyl alcohol to a reaction tank, cooling, stirring under nitrogen protection, adding cefoxitin acid until dissolving, adding activated carbon, decolorizing, filtering, mixing a solvent and washing; (3) controlling the temperature of a crystallization tank, the stirring speed and the nitrogen pressure by molecular assembly and shape optimization techniques for crystal products in a grain process by Hebei Huamin Pharmaceutical Co.,Ltd. in North China, dropwise adding the sodium-forming agent solution, and adding acetone according to a feeding rate form; (4) filtering and drying crystalline liquid, detecting and discharging; and (5) carrying out sub-package of preparations with different specifications, and controlling the environment temperature and humidity to obtain cefoxitin sodium for injection. The cefoxitin sodium for injection, prepared by the preparation method, has good hydrodynamics performance, and is perfect in crystalline form and uniform in particle size distribution; and the color grade, the clarity, the purity and the stability are greatly improved.

Description

A kind of cefoxitin sodium powder-needle preparation for injection

Technical field

The present invention relates to a kind of cefoxitin sodium powder-needle preparation for injection, belong to medical art.

Background technology

Cefoxitin sodium is cephamycin-type antibiotic, and its parent nucleus is similar to cephalosporin, and anti-microbial property is also similar, is put into second generation cephalosporin traditionally.Feature is have stronger antibacterial action to gram-negative bacteria, has high resistance beta-lactam enzymatic property.Antimicrobial spectrum comprises escherichia coli, pneumobacillus, indole-positive Bacillus proteus and Serratieae, klebsiella bacillus, hemophilus influenza, salmonella, shigella dysenteriae etc.Also better effect is had to staphylococcus and multiple streptococcus.Clinically be mainly used in respiratory tract infection caused by sensitive organism, endocarditis, peritonitis, pyelonephritis, urinary tract infection, the infection such as septicemia and bone, joint, skin and soft tissue.

Cefoxitin sodium is second generation cephalosporin, and molecular weight is 449.44, and structural formula is as follows:

Its chemical name is (6R, 7S)-3-[(1-carbamyl oxygen) methyl]-7-methoxyl group-8-oxo-7-[2-(2-thienyl) acetylamino]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid sodium salt.

Cefoxitin sodium can disturb the synthesis of bacteria cell wall, makes newborn cell wall produce defect and bacteriolyze occurs.This effect realizes by acting on penicillin-binding protein (PBP) on cell wall.

NCPC Hebei Huamin Pharmaceutical Co., Ltd.'s systematic study morphological feature of cefoxitin sodium product, establishes crystal habit optimization method, uses coupling crystallization new technique to achieve molecular assembly assembling with regularly arranged.And the equipment that exploitation is advanced, the configuration of optimization device and inside dimension, to reach excellent hydrodynamic performance, ensure that product crystal form is perfect, even particle size distribution.Due to influencing each other of Coupling Crystallization Alternative parameter, and the maximization of coupling crystallizer, control giving the computer of flow process to bring obvious large time delay to affect, for above controlling difficulties, utilize BACH system, and develop Adaptive Fuzzy Control algorithm software, solve the impact that large time delay effect associates with multivariate, ensure the operational stability of coupling crystallization flow process; Fully realize automatization and operation accuracy, reduce personal error.Consider that the general character of cephalo-type process of producing product is for realizing resource-sharing, the equipment that fully realizes maximizes economization and produces, and reduces product cost, and the Flexible Production Technology of exploitation advanced person is also the key of this project.From raw material to final products, each link of whole process is all optimized, and uses advanced technology, equipment and control and management system, ensures that whole production process is reached advanced world standards.

Disclosed some methods preparing cefoxitin preparation of sodium both at home and abroad at present, but the cefoxitin preparation of sodium that these methods are made has effect, and material is not high, the problems such as impurity is on the high side, and the side effect caused thus is obvious.

Address this problem and must research and develop the crucial production technology of novel coupling crystallization, to optimize the process parameters such as solvent burden ratio, temperature, time, pressure, pH value, crystallization is carried out under the suitable conditions, thus ensure the quality of product.

Summary of the invention

The object of the invention is to provide a kind of preparation method of cefoxitin sodium powder-needle preparation for injection, the cefoxitin sodium powder body obtained is made to reach excellent hydrodynamic performance by the crucial production technology of novel coupling crystallization, crystal form is perfect, even particle size distribution, the larger raising of color level, clarity, purity and stability.

For achieving the above object, the invention provides a kind of cefoxitin sodium powder-needle preparation for injection, prepared by following steps:

(1) control temperature 13 DEG C ~ 16 DEG C, becomes sodium agent solvent to dissolve and makes into sodium agent solution, for subsequent use;

(2) retort adds acetone and methanol, is cooled to 10 DEG C.Stirred under nitrogen atmosphere adds cefoxitin acid to dissolving.Add active carbon, filter after decolouring, wash filtering residue, filter flask with the mixed solvent of acetone and methanol, filtrate enters in crystallizer;

(3) crystallization control tank temperature 13 DEG C ~ 16 DEG C, mixing speed controls at 60 revs/min, controls nitrogen pressure < 0.2MPa, drips into sodium agent solution; Press surface low rate of acceleration and add acetone:

Time (min)	Rate of addition (L/min)
		0-10	1.0-1.2
10-30	0
		30-60	1.6-1.8
60-90	1.9-2.1
		90-130	2.1-2.3
130-210	5.0-5.2
		210-270	8.6-8.8
270-300	0

(4) crystal solution was cooled to 0-5 DEG C of growing the grain after 1 hour, put into the dry three-in one machine of filtration washing; After loose, proceed to VTD drying, moisture content, residual solvent are surveyed in sampling, qualified, discharging;

(5) carry out the preparation subpackage of different size, the temperature that controls environment is 20 ~ 24 DEG C, and humidity is less than 40%, obtains cefoxitin sodium for injection.

Preferably, in step (1), the agent of described one-tenth sodium is sodium acetate or Sodium isooctanoate..

Preferably, in step (1), described solvent is one or both mixing in methanol, acetone.。

Preferably, in step (1), the agent of described one-tenth sodium and described solvent mass ratio are 1:8 ~ 9.

Preferably, in step (2), the compound concentration of described cefoxitin acid is not more than 0.4g/ml.

Preferably, in step (2), the mol ratio of described acetone and methanol mixed solvent and described cefoxitin acid is 1:1.5 ~ 1.7.

Preferably, in step (3), press surface low rate of acceleration and add acetone:

Time (min)	Rate of addition (ml/min)
		0-10	1.1-1.2
10-30	0
		30-60	1.6-1.7
60-90	1.9-2.0
		90-130	2.1-2.2
130-210	5.1-5.2
		210-270	8.7-8.8
270-300	0

Preferably, in step (3), press surface low rate of acceleration and add acetone:

Time (min)	Rate of addition (ml/min)
		0-10	1.15
10-30	0
		30-60	1.65
60-90	1.95
		90-130	2.2
130-210	5.1
		210-270	8.8
270-300	0

Preferably, in step (3), the agent of described one-tenth sodium dropwised in 100 ~ 120 minutes.

Compared with the cefoxitin sodium for injection that traditional handicraft is obtained, the present invention use coupling crystallization technique and the particle process crystal product molecule assembling cefoxitin sodium for injection impurity obtained with form optimisation technique few, the few thus stability advantages of higher of residual solvent in raw material.

Detailed description of the invention

Embodiment 1

(1) in stainless steel reaction tank, add load weighted methanol 163kg, anhydrous sodium acetate 18kg, control reacting liquid temperature at 13 ~ 16 DEG C, stir and solid material is all dissolved, for subsequent use;

(2) in the stainless steel reaction tank of cleaning-drying, add acetone 576kg, the methanol 144kg of the amount of weighing up, feed liquid is cooled to 10 DEG C.Add cefoxitin acid 90kg under stirring, stirred under nitrogen atmosphere is to dissolving.In dissolving tank, add active carbon 6kg, stir decolouring 30 minutes at 10 DEG C.Dissolving destaining solution is filtered in aseptic crystallization tank; In dissolving tank, add the acetone 360kg/ methanol 58kg got ready mix washing liquid, washing liquid is filtered in crystallizer.；

(3) feed liquid 13 ~ 16 DEG C in crystallization control tank, mixing speed controls at 60 revs/min, controls nitrogen pressure < 0.2MPa, drips sodium acetate solution, added at 100 ~ 120 minutes; Press surface low rate of acceleration and add dissolved agent acetone:

Time (min)	Rate of addition (L/min)
		0-10	1.2
10-30	0
		30-60	1.8
60-90	2.0
		90-130	2.1
130-210	5.2
		210-270	8.6
270-300	0

(4) crystal solution was cooled to 0-5 DEG C of growing the grain after 1 hour, put into the dry three-in one machine of filtration washing; After loose, proceed to VTD drying, moisture content, residual solvent are surveyed in sampling, qualified, discharging.

(5) cefoxitin sodium aseptic powder 80kg sends between the subpackage of B level after cleaning de-bag, under A level laminar flow, adopt screw filling machine to be divided in sterile vial by former medicine according to 1.0g/ bottle, the humiture that controls environment is 20 ~ 24 DEG C, humidity is less than 40%, obtains cefoxitin sodium powder-needle preparation for injection.

Embodiment 2

(1) in stainless steel reaction tank, add load weighted methanol 172kg, anhydrous sodium acetate 19kg, control reacting liquid temperature at 13 ~ 16 DEG C, stir and solid material is all dissolved.

(2) in the stainless steel reaction tank of cleaning-drying, add acetone 569kg, the methanol 140kg of the amount of weighing up, feed liquid is cooled to 10 DEG C.Add cefoxitin acid 90kg under stirring, stirred under nitrogen atmosphere is to dissolving.In dissolving tank, add active carbon 6kg, stir decolouring 30 minutes at 10 DEG C.Dissolving destaining solution is filtered in aseptic crystallization tank; In dissolving tank, add the acetone 360kg/ methanol 58kg got ready mix washing liquid, washing liquid is filtered in crystallizer.

(3) feed liquid 13 ~ 16 DEG C in crystallization control tank, mixing speed controls at 60 revs/min, controls nitrogen pressure < 0.2MPa, drips sodium acetate solution, add, press surface low rate of acceleration and add dissolved agent acetone at 100 ~ 120 minutes:

Time (min)	Rate of addition (ml/min)
		0-10	1.15

10-30	0
		30-60	1.65
60-90	1.95
		90-130	2.2
130-210	5.1
		210-270	8.8
270-300	0

(4) crystal solution was cooled to 0-5 DEG C of growing the grain after 1 hour, put into the dry three-in one machine of filtration washing; After loose, proceed to VTD drying, moisture content, residual solvent are surveyed in sampling, qualified, discharging.

(5) cefoxitin sodium aseptic powder 80kg sends between the subpackage of B level after cleaning de-bag, under A level laminar flow, adopt screw filling machine to be divided in sterile vial by former medicine according to 2.0g/ bottle, the humiture that controls environment is 20 ~ 24 DEG C, humidity is less than 40%, obtains cefoxitin sodium powder-needle preparation for injection.

Embodiment 3

(1) in stainless steel reaction tank, add load weighted methanol 154kg, Sodium isooctanoate. 17kg, control reacting liquid temperature at 13 ~ 16 DEG C, stir and solid material is all dissolved.

(2) in the stainless steel reaction tank of cleaning-drying, add acetone 544kg, the methanol 136kg of the amount of weighing up, feed liquid is cooled to 10 DEG C.Add cefoxitin acid 85kg under stirring, stirred under nitrogen atmosphere is to dissolving.In dissolving tank, add active carbon 6kg, stir decolouring 30 minutes at 10 DEG C.Dissolving destaining solution is filtered in aseptic crystallization tank; In dissolving tank, add the acetone 360kg/ methanol 58kg got ready mix washing liquid, washing liquid is filtered in crystallizer.

(3) feed liquid 13 ~ 16 DEG C in crystallization control tank, mixing speed controls at 60 revs/min (8Hz), controls nitrogen pressure < 0.2MPa, drips sodium iso-octoate solution, added at 100 ~ 120 minutes, press surface low rate of acceleration and add dissolved agent acetone:

Time (min)	Rate of addition (L/min)
		0-10	1.1
10-30	0
		30-60	1.7
60-90	2.0
		90-130	2.2
130-210	5.1
		210-270	8.7
270-300	0

(4) crystal solution puts into the dry three-in one machine of filtration washing.After powder is loose, proceed to CTD drying, moisture content, residual solvent are surveyed in sampling, qualified, discharging.

(5) cefoxitin sodium aseptic powder 85kg sends between the subpackage of B level after cleaning de-bag, under A level laminar flow, adopt screw filling machine to be divided in sterile vial by former medicine according to 1.0g/ bottle, the humiture that controls environment is 20 ~ 24 DEG C, humidity is less than 40%, obtains cefoxitin sodium powder-needle preparation for injection.

By above-described embodiment and comparative example simulation listing packaging, temperature 40 DEG C, place 6 months under relative humidity 75% condition, respectively at the 1st, 2,3, sampling in June, investigate the project such as appearance character, color level, clarity, visible foreign matters, particulate matter, related substance, and with 0 day results contrast.

Result of the test sees the following form:

As can be seen from above-mentioned accelerated test result, adopt cefoxitin sodium for injection injectable powder of the present invention within 6 months, to investigate through accelerated test, there is not significant change in indices, and traditional handicraft change is relatively obvious, and stability is higher than conventional art.

More than describe preferred embodiment of the present invention in detail.Should be appreciated that those of ordinary skill in the art just design according to the present invention can make many modifications and variations without the need to creative work.Therefore, all technical staff in the art, all should by the determined protection domain of claims under this invention's idea on the basis of existing technology by the available technical scheme of logical analysis, reasoning, or a limited experiment.

Claims (9)

1. a cefoxitin sodium powder-needle preparation for injection, is characterized in that, described cefoxitin sodium powder-needle preparation for injection is prepared by following steps:

(1) control temperature 13 DEG C ~ 16 DEG C, becomes sodium agent solvent to dissolve and makes into sodium agent solution, for subsequent use;

(2) retort adds acetone and methanol, is cooled to 10 DEG C; Stirred under nitrogen atmosphere adds cefoxitin acid to dissolving; Add active carbon, filter after decolouring, wash filtering residue, filter flask with the mixed solvent of acetone and methanol, filtrate enters in crystallizer;

(3) crystallization control tank temperature 13 DEG C ~ 16 DEG C, mixing speed controls at 60 revs/min, controls nitrogen pressure < 0.2MPa, drips into sodium agent solution; Press surface low rate of acceleration and add acetone:

Time (min) Rate of addition (L/min) 0-10 1.0-1.2 10-30 0 30-60 1.6-1.8 60-90 1.9-2.1 90-130 2.1-2.3 130-210 5.0-5.2 210-270 8.6-8.8 270-300 0

(4) crystal solution was cooled to 0-5 DEG C of growing the grain after 1 hour, put into the dry three-in one machine of filtration washing; After loose, proceed to VTD drying, moisture content, residual solvent are surveyed in sampling, qualified, discharging;

(5) carry out the preparation subpackage of different size, the temperature that controls environment is 20 ~ 24 DEG C, and humidity is less than 40%, obtains cefoxitin sodium for injection.

2. according to cefoxitin sodium powder-needle preparation for injection according to claim 1, it is characterized in that, in described step (1), the agent of described one-tenth sodium is sodium acetate or Sodium isooctanoate..

3. according to cefoxitin sodium powder-needle preparation for injection according to claim 1, it is characterized in that, in described step (1), described solvent is one or both mixing in methanol, acetone.。

4. according to cefoxitin sodium powder-needle preparation for injection according to claim 1, it is characterized in that, in described step (1), the agent of described one-tenth sodium and described solvent mass ratio are 1:8 ~ 9.

5. cefoxitin sodium powder-needle preparation for injection according to claim 1, is characterized in that, in described step (2), the compound concentration of described cefoxitin acid is not more than 0.4g/ml.

6. cefoxitin sodium powder-needle preparation for injection according to claim 1, is characterized in that, in described step (2), the mol ratio of described acetone and methanol mixed solvent and described cefoxitin acid is 1:1.5 ~ 1.7.

7. cefoxitin sodium powder-needle preparation for injection according to claim 1, is characterized in that, in described step (3), presses surface low rate of acceleration and adds acetone:

Time (min) Rate of addition (ml/min) 0-10 1.1-1.2 10-30 0 30-60 1.6-1.7 60-90 1.9-2.0 90-130 2.1-2.2 130-210 5.1-5.2 210-270 8.7-8.8 270-300 0

8. cefoxitin sodium powder-needle preparation for injection according to claim 1, is characterized in that, in described step (3), presses surface low rate of acceleration and adds acetone:

Time (min) Rate of addition (ml/min) 0-10 1.15 10-30 0 30-60 1.65 60-90 1.95 90-130 2.2 130-210 5.1 210-270 8.8 270-300 0

9. cefoxitin sodium powder-needle preparation for injection according to claim 1, is characterized in that, in described step (3), described one-tenth sodium agent solution dropwised in 100 ~ 120 minutes.