JPS5817728B2 - Ampicillin Sodium - Google Patents

Description

Detailed Description of the Invention The present invention provides a method for producing ampicillin sodium salt, which is characterized by reacting a lower alkylene chloride solution of ampicillin diisopropylamine salt having a water content of 0.2 to 1.0% with sodium 2-ethylhexanoate. Regarding.

Ampicillin sodium salt obtained by the present invention has high purity and high water solubility, so it is suitable for use as a powder injection.

Ampicillin is a commonly used antibiotic worldwide, and because it is sparingly soluble in water in its free form, its sodium salt is usually used.

Moreover, since ampicillin sodium salt is unstable when made into an aqueous solution, it has to be prepared at the time of use.A so-called powder injection form is adopted in which crystals or powder of ampicillin sodium salt and a solution are prepared separately. .

The properties that powder injections must have include being able to be stored stably until just before use, but also being able to dissolve quickly in a solution such as physiological saline or distilled water for injection before use, and to avoid the presence of residual insoluble matter. There is a strong demand for such preparations from the viewpoint of speeding up medical treatment and simplifying operations.

However, in the case of the well-known ampicillin sodium salt powder injection currently in general use, even if a solution is added, dissolution is extremely slow if left as is, and even if you shake it one by one, it takes more than 15 seconds to dissolve. There are many things that require

A method of freeze-drying may be considered in an attempt to solve this problem, but in the case of freeze-dried preparations, although they dissolve quickly, they may produce trace amounts of insoluble matter, which is not preferable.

Another possible method is to obtain a product that is easily soluble by making the powder or crystal grains finer, but in the case of ampicillin sodium salt, the dissolution rate decreases due to finer particles.

This is considered to be because some of the dissolved ampicillin sodium salt forms a film and covers the surface.

The present inventors have conducted various studies to eliminate these drawbacks and obtain ampicillin sodium salt that dissolves quickly in water.
In No. 42, the temperature was 15 to 25 °C; in British Patent No. 1,212,798, it was 0 to 5 °C), and the sodium salt was generated via ampicillin triethylamine salt in 0.2% or more aqueous methylene chloride. Although it was said that in some cases, it was not possible to obtain a substance showing sufficiently high efficacy (see Japanese Patent Publication No. 46-9342), diisopropylamine salt in lower alkylene chloride containing 0.2% or more of water at 28 to 40°C. It has been found that ampicillin sodium salt can be obtained which unexpectedly maintains its efficacy, has high solubility in water, and is highly purified and easily isolated by purification, centrifugation, etc.

According to the present invention, when a powder injection drug is prepared, it is completely dissolved within 10 seconds without stirring, especially when a dissolving solution is added before administration, which is extremely advantageous in medical treatment.

In carrying out the present invention, ampicillin anhydride or mono- to trihydrate may be used in combination with a lower alkylene chloride, such as methylene chloride,
The diisopropylamine salt of ampicillin is produced by dispersing and suspending it in ethylene chloride, chloroform, etc. and adding equimolar to slightly excess diisopropylamine.

At this time, when anhydrous ampicillin is used, the water content of the ampicillin isopropylamine salt solution is 0.2 to 1. ,
Add water to dissolve in OW/W%.

Further, when a hydrate of ampicillin is used, the water content may be adjusted to 0.2 to 1.0 W/W% using a dehydrating agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, or molecular sieve.

In order to convert the ampicillin diisopropylamine salt solution obtained here into the sodium salt, the solution may be slightly heated, preferably at 28 to 40°C, and sodium 2-ethylhexanoate may be added thereto.

It is not preferable to set the reaction temperature to 26° C. or lower because the crystal particles become fine.

Sodium 2-ethylhexanoate is usually used as a solution in an organic solvent such as n-butyl acetate, n-butanol, or methylene chloride.

These solvents may be used singly or in combination, and in the case of methylene chloride, a mixed solvent is particularly suitable.

The ampicillin sodium salt produced here can be isolated immediately or after being left for a while and then filtered or centrifuged.

The isolated product is washed with an insoluble solvent such as methylene chloride and then dried.

Adding a small amount of diisopropylamine or the like to the washing liquid during washing is suitable for removing by-product 2-ethylhexanoic acid.

The obtained ampicillin sodium salt is, for example,
In the case of method No. 9342, the size is 2μ, whereas
The particle size is rod-shaped with a size of 2 to 5 microns x 25 to 125 microns, and isolation is easy.

Even though the particles are large, when made into a powder injection, it dissolves quickly and leaves no insoluble matter.

The following is an experiment comparing the dissolution rate of ampicillin sodium salt obtained according to the present invention and a product obtained by the method of Japanese Patent Publication No. 46-9342, and the results thereof.

Experiment 1 A 400 m9 crystal of ampicillin sodium salt was grown at a height of 4.
5CfrL Weighed into a cylindrical glass bottle with an inner diameter of 2.5cIrL, and after lightly tapping the bottom of the bottle three times to smooth the surface, gently added 1.2ml of distilled water along the wall of the vessel and shook for 5 seconds (shaking number 17 times, Observe with an amplitude of 10 CrrL).

If it is not dissolved, prepare a new sample and shake it for 10 seconds in the same way.

In the same manner, the shaking time is extended at 5 second intervals and observed.

Method of application 5 seconds Melting Special Publication 1977
-9342 method 15 seconds Insoluble 20 seconds Dissolution experiment 2 A crystal of ampicillin sodium salt of 400 m9 was placed at a height of 5.
5 (inner diameter), weighed into a 5 cm cylindrical glass bottle, lightly tapped the bottom 10 times to smooth the surface, and then poured 1.
Gently add 2 ml along the vessel wall and observe the time from when the crystals come into contact with the water until they are completely dissolved.

Method of application: 5 to 20 seconds
Method No. 9342 Examples of the present invention will be shown below for 4 to 5 seconds. The purity of ampicillin sodium salt in the examples is determined by the iodine method using Preventive Health Research Shin's "commonly used standard ampicillin" as the standard, and assuming that the purity is 100%. It was found by

Example 1 3.22 S' of ampicillin trihydrate and 3 g of anhydrous sodium sulfate were suspended in 32 TL of methylene chloride, and 1.21:1 of diisopropylamine was added thereto for 30 min at 25°C.
Stir for a minute and then strain.

The sodium sulfate is washed with 27 ml of methylene chloride, and the lachrymal fluid and washing solution are combined.

The obtained methylene chloride solution (water content 0.3%) was heated at 30°C.
A slurry of 35 W/W % sodium 2-ethylhexanoate in butyl acetate (3.99 S') and 7 ml of butyl acetate was stirred and added dropwise over 30 minutes.

After the dropwise addition, the crystals were left to stand for 1 hour, and the crystals were collected, washed successively with a 5% diisopropylamine methylene chloride solution and methylene chloride, and dried with ventilation at 45° C. in a nitrogen stream to obtain ampicillin sodium salt.

Yield 88% Purity 101.8% Example 2 Ampicillin trihydrate 3.22P and anhydrous sodium sulfate 31 were suspended in 22ml of methylene chloride, diisopropylamine 1.212P was added, and the mixture was stirred at 25°C for 20 minutes. Gosawa passes.

The sodium sulfate is washed with 5 TL of methylene chloride, and the F solution and the washing solution are combined.

The obtained methylene chloride solution (water content 0.5%) was heated to 36°C and mixed with 3.99 f? of 35 W/W% sodium 2-ethylhexanoate butyl acetate solution and 7 ml of butyl acetate for 20 minutes while stirring. Drip.

After dropping, the precipitated crystals were collected, washed successively with a 5% diisopropylamine methylene chloride solution and methylene chloride, and dried under reduced pressure at room temperature to obtain ampicillin sodium salt.

Yield 87.8% Purity 101.9% Example 3 Ampicillin trihydrate 644 g and anhydrous sodium sulfate 6
? was suspended in 30 ml of methylene chloride, 2.424 P of diisopropylamine was added, stirred at 25°C for 30 minutes, and then filtered.

The sodium sulfate was washed with 10 ml of methylene chloride, and the mud and washing liquid were combined.

The obtained methylene chloride solution was heated to 32°C and 35W/
W% Sodium 2-ethylhexanoate butyl acetate solution 7
．． A slurry of 98P and 7 ml of methylene chloride is added dropwise over 20 minutes while stirring.

After the dropwise addition, the precipitated crystals were left in water cooling (approximately 20°C) for 2 hours, washed sequentially with a 5% diisopropylamine methylene chloride solution and methylene chloride, and dried in a nitrogen stream at 45°C to obtain ampicillin sodium salt. get.

Yield 87.5% Purity 98.8% Example 4 13.955' of anhydrous ampicillin was dissolved in methylene chloride 160
ml, add 6.06P of diisopropylamine, stir at 25°C for 20 minutes, and then filter.

The instruments used were washed with 135 ml of methylene chloride, and the f solution and washing solution were combined.

Add 0.88 ml of water to the obtained methylene chloride solution to dissolve it (water content 0.2%).

Then, it was heated to 35°C and 35W/W% sodium 2-ethylhexanoate butyl acetate solution 207 was mixed with 40ml of butyl acetate.
A mixture of 1 and 1 was added dropwise over 40 minutes.

After dropping, the precipitated crystals were collected and washed sequentially with 5% diisopropylamine methylene chloride solution and methylene chloride at 45°C.
Drying in a nitrogen stream yields ampicillin sodium salt.

Yield 8.7% Purity 101.9% Example 5 Anhydrous ampicillin 13.95P was dissolved in methylene chloride 160m
1, add 6.06 P of diisopropylamine, stir at 25°C for 20 minutes, and then filter.

The instruments were washed with 50 ml of methylene chloride, and the mud and washing liquid were combined.

Add 18 ml of water to the obtained methylene chloride solution and dissolve it (water content 0.6%, then warm to 38 ° C and 35 W
/W% 2-ethylhexanoate) IJum butyl acetate solution 20'? and 40 TILl of butyl acetate.
Drip in minutes.

After dropping, the precipitated crystals were collected and washed sequentially with 5% diisopropylamine methylene chloride solution and methylene chloride at 45°C.
Drying in a nitrogen stream yields ampicillin sodium salt.

Yield 87% Purity 101.8%

Claims (1)

[Claims] 1. A method for producing ampicillin sodium salt, which comprises reacting a lower alkylene chloride solution of ampicillin diisopropylamine salt having a water content of 0.2 to 1.0% with 2-ethylhexanoic acid at 28 to 40°C.