CN105055323A - Anti-infective aztreonam composition - Google Patents

Abstract

The invention discloses an anti-infective aztreonam composition, belonging to the technical field of medicines. The composition comprises aztreonam and sodium chloride, wherein aztreonam is a crystal. An X-ray powder diffraction pattern obtained through measurement by using a Cu-Kalpha ray is shown in a drawing 1 in the specification. A new crystal form of aztreonam provided by the invention is different from the crystal structure of the prior art. Through experimental verification, the compound in the new crystal form has high purity, good flowability and stability and low polymer content, does not have hygroscopicity and is safe and reliable to apply clinically. Powder injections prepared by utilizing the compound in the new crystal form have good stability after undergoing compatibility with solvents, have low content of insoluble particles and are very suitable to apply clinically.

Description

A kind of anti-infectives aztreonam composition

Technical field

The invention belongs to medical art, relate to a kind of anti-infectives aztreonam composition.

Background technology

Aztreonam is a kind of white or micro-yellow polymorphic powder, and the crystal structure form having multiple crystal formation known at present has 4 kinds, i.e. α type, β type, γ type and δ type.Wherein, the aztreonam of alpha-crystal form is water-containing crystal body, usually comprises 7%-14% moisture, storage stability is poor, therefore needs the aztreonam converting it into beta crystal, and the latter is anhydrous, there is the features such as moistureproof and good mobility, be more suitable for the crude drug as pharmaceutical formulation.

In order to improve the performance of aztreonam further, this invention of special proposition, the novel crystal forms of aztreonam provided by the present invention is different from the crystalline structure of prior art, by verification experimental verification, surprisingly find that this crystal compound purity is high, good fluidity, good stability, polymer content is low, moist without drawing, clinical practice is safe and reliable, utilize the injectable powder that this crystal compound is obtained, good stability, good with solvent compatibility rear stability, particulate matter content is extremely low, is very suitable for clinical practice.

Summary of the invention

Goal of the invention of the present invention is to provide a kind of anti-infectives aztreonam composition.

In order to complete object of the present invention, the technical scheme of employing is:

A kind of anti-infectives aztreonam composition, consisting of of described compositions: aztreonam 1 weight portion, sodium chloride 0.4-0.8 weight portion; Described aztreonam is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.

Preferably, consisting of of described compositions: aztreonam 1 weight portion, sodium chloride 0.5-0.7 weight portion.

Preferably, consisting of of described compositions: aztreonam 1 weight portion, sodium chloride 0.6 weight portion.

Preferably, the dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:

(1) take aztreonam crystal and sodium chloride in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

The preparation method of the aztreonam crystal in described compositions comprises the following steps:

(1) aztreonam crude is ground, cross 90 mesh sieves, join in N-ethyl amine aqueous solution, warming while stirring to 35 DEG C; The weight ratio of aztreonam crude and N-ethyl amine aqueous solution is 1:15; Mixing speed is 260 revs/min; Add active carbon, stir aseptic filtration after 120 minutes;

(2) add chloroform while stirring, be cooled to-2 DEG C simultaneously; Mixing speed is 180 revs/min; The weight of chloroform be aztreonam, 3 times of N-ethyl acetamide mixed solution weight, adding speed is 70 ml/min; Cooling rate is 3 DEG C/h;

(3), after mixed solvent adds, after obtaining crystal, crystallize is left standstill; Filter, washing, vacuum drying 5 hours, obtains aztreonam crystalline compounds.

The polymorphism of solid chemical is the natural phenomena that a kind of general material exists, this phenomenon refers to that a kind of solid chemical can exist 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic state of material is also referred to as " allomorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physicochemical property may be different.For " allomorphism medicine " that physicochemical property is different, also can show the curative effect of different disease preventing and treating clinically, directly affect application and the clinical effectiveness of medicine.

Aztreonam is Beta-lactam medicine, the easy open loop of its monoamides ring, form impurity and easily self-polymerization occur after open loop, form high molecular polymer, thus reduction medicament contg, cause drug titers to reduce, the sterilization of aztreonam and fungistatic effect are reduced, and high polymer can cause endogenous anaphylaxis.The good stability of the aztreonam compound that the present invention prepares, not easily open loop is decomposed, its polymer content trace.

Aztreonam has and draws moist, can cause the change of the physicochemical properties such as the decline of caking, mobility, deliquescence, crystal formation change, thus affect the interior qualities such as product stability, effectiveness, safety after moisture absorption.And according to the literature, many antibiotic are stablized in the dry state, but will decompose after making moist.Therefore, hygroscopicity has very important impact for the stability of aztreonam.Therefore, if can reduce the hygroscopicity of aztreonam, then the stability for aztreonam has very important meaning.Meanwhile, bibulous medicine needs strictly to control the relative humidity between subpackage in formulation manufacturing processes, is no more than critical relative humidity, thus ensures product quality and stability.If not easily moisture absorption, then the production of convenient preparation, ensures stability simultaneously.

Aztreonam compound prepared by the present invention, the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.By to its hygroscopic research, the discovery that inventor is pleasantly surprised, its hygroscopicity of compound of the present invention is significantly less than existing crystalline compounds.Thus illustrate that aztreonam crystalline compounds of the present invention is more stable, and more adapt to the preparation of preparation.

The purity of aztreonam crystalline compounds of the present invention can reach 99.9%, and its structure is confirmed through proton nmr spectra.The preparation method of aztreonam crystalline compounds of the present invention is simple, and purity is high, and yield is high, most suitable large-scale industrial production.

The composition powder injection obtained by aztreonam crystalline compounds of the present invention, good stability, good with solvent compatibility rear stability, particulate matter content is extremely low, is very suitable for clinical practice.

Accompanying drawing explanation

Fig. 1 is the X-ray powder diffraction that the aztreonam crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.

Detailed description of the invention

Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.

embodiment 1:the preparation of aztreonam crystal

(1) aztreonam crude is ground, cross 90 mesh sieves, join in N-ethyl amine aqueous solution, warming while stirring to 35 DEG C; The weight ratio of aztreonam crude and N-ethyl amine aqueous solution is 1:15; Mixing speed is 260 revs/min; Add active carbon, stir aseptic filtration after 120 minutes;

(2) add chloroform while stirring, be cooled to-2 DEG C simultaneously; Mixing speed is 180 revs/min; The weight of chloroform be aztreonam, 3 times of N-ethyl acetamide mixed solution weight, adding speed is 70 ml/min; Cooling rate is 3 DEG C/h;

(3), after mixed solvent adds, after obtaining crystal, crystallize is left standstill; Filter, washing, vacuum drying 5 hours, obtains aztreonam crystalline compounds.

As shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.9% to the X-ray powder diffraction pattern that the aztreonam crystal prepared uses the measurement of Cu-K alpha ray to obtain.

embodiment 2:the preparation of aztreonam composition

Consist of: aztreonam crystal 1 weight portion prepared by the present invention, sodium chloride 0.4 weight portion.

Preparation method is:

(1) take aztreonam crystal and sodium chloride in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

embodiment 3:the preparation of aztreonam composition

Consist of: aztreonam crystal 1 weight portion prepared by the present invention, sodium chloride 0.5 weight portion.

Preparation method is:

(1) take aztreonam crystal and sodium chloride in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

embodiment 4:the preparation of aztreonam composition

Consist of: aztreonam crystal 1 weight portion prepared by the present invention, sodium chloride 0.6 weight portion.

Preparation method is:

(1) take aztreonam crystal and sodium chloride in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

embodiment 5:the preparation of aztreonam composition

Consist of: aztreonam crystal 1 weight portion prepared by the present invention, sodium chloride 0.7 weight portion.

Preparation method is:

(1) take aztreonam crystal and sodium chloride in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

embodiment 6:the preparation of aztreonam composition

Consist of: aztreonam crystal 1 weight portion prepared by the present invention, sodium chloride 0.8 weight portion.

Preparation method is:

(1) take aztreonam crystal and sodium chloride in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

experimental example 1influence factor tests

1, hot test

The aztreonam crystalline compounds that Example 1 prepares, simulation listing packaging, puts in sealing clean container, places 10 days at 40 ± 2 DEG C of temperature, and in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result of the test compared with 0 day.

2, high humility test

The aztreonam crystalline compounds that Example 1 prepares, simulation listing packaging, puts in sealing clean container, place 10 days under the condition of 25 ± 2 DEG C of relative humiditys 90% ± 5%, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result of the test compared with 0 day.

3, strong illumination test

The aztreonam crystalline compounds that Example 1 prepares, simulation listing packaging, puts in sealing clean container, being placed in illumination is place 10 days under the condition of 4500lx, in the 5th day and sampling in the 10th day, detect by stability high spot reviews project, result compared with 0 day.The results are shown in Table 1.

Table 1 influence factor result of the test

Result shows: the aztreonam crystalline compounds that the present invention prepares, and its stability is good, and under high temperature, high humidity, high light conditions, equal retention is stablized.Influence factor's experiment is carried out to aztreonam crystalline compounds prepared by other embodiment of the present invention, obtains identical experimental result.

experimental example 2:acceleration study

The aztreonam crystalline compounds that Example 1-3 prepares, simulation listing packaging, put in sealing clean container, in 40 DEG C ± 2 DEG C, place 6 months under relative humidity 70% ± 5% condition, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.The results are shown in Table 2.

Table 2 accelerated test result

Result shows: the aztreonam crystalline compounds that the present invention prepares, known through accelerated test result, its good stability, and polymer content is low, and total assorted content is low.

experimental example 3:wettability test

1 instrument

PL203 electronic balance, LRH-250-S constant temperature and humidity incubator, HH-400SD testing chamber for medicine stability;

2 methods

Get the glass desicator (for ensureing that saline solution is saturated, excessive salt should be had bottom exsiccator to exist) that bottom fills salt supersaturated solution, the built-in weighing botle of exsiccator, places 48h to constant humidity in calorstat.Sample thief is about 2g, puts in weighing botle, accurately weighed, bottle cap is opened, puts into exsiccator top, put in 25 DEG C of constant temperature and humidity incubators or 20 DEG C of stability test casees by different temperatures requirement and preserve, operation repetitive 3 parts, weighs respectively at different time, calculates the hydroscopicity of different time.

Computing formula: hydroscopicity=(medicated powder weight after moisture absorption-moisture absorption prodrug grain weight amount)/moisture absorption prodrug grain weight amount × 100%.Result is as table 3:

Table 3 hygroscopicity test results

According to above-mentioned experiment, the hygroscopicity of aztreonam crystalline compounds prepared by the present invention is low, good stability.

Claims (5)

1. an anti-infectives aztreonam composition, is characterized in that: described compositions consist of aztreonam 1 weight portion, sodium chloride 0.4-0.8 weight portion; Described aztreonam is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.

2. anti-infectives aztreonam composition according to claim 1, is characterized in that: described compositions consist of aztreonam 1 weight portion, sodium chloride 0.5-0.7 weight portion.

3. anti-infectives aztreonam composition according to claim 2, is characterized in that: described compositions consist of aztreonam 1 weight portion, sodium chloride 0.6 weight portion.

4., according to the arbitrary described anti-infectives aztreonam composition of claim 1-3, it is characterized in that, the dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:

(1) take aztreonam crystal and sodium chloride in proportion, fully mix;

(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.

5. anti-infectives aztreonam composition according to claim 1, is characterized in that, the preparation method of the crystal of described aztreonam comprises the following steps:

(1) aztreonam crude is ground, cross 90 mesh sieves, join in N-ethyl amine aqueous solution, warming while stirring to 35 DEG C; The weight ratio of aztreonam crude and N-ethyl amine aqueous solution is 1:15; Mixing speed is 260 revs/min; Add active carbon, stir aseptic filtration after 120 minutes;

(2) add chloroform while stirring, be cooled to-2 DEG C simultaneously; Mixing speed is 180 revs/min; The weight of chloroform be aztreonam, 3 times of N-ethyl acetamide mixed solution weight, adding speed is 70 ml/min; Cooling rate is 3 DEG C/h;

(3), after mixed solvent adds, after obtaining crystal, crystallize is left standstill; Filter, washing, vacuum drying 5 hours, obtains aztreonam crystalline compounds.