JPS5811928B2 - Diyosamycin treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing solvent-free crystals of josamycin, which comprises treating solvated crystals of josamycin with a water-containing organic solvent.

Josamycin (hereinafter abbreviated as JM) is widely used today as it has low toxicity and is effective in treating staphylococci, diplococcus pneumoniae, etc.

Conventionally, JM has been industrially dissolved in benzene, the crystallized crystals are collected by filtration, and the crystals are dried to produce a product.

However, the crystals thus crystallized were solvated crystals, and it took a long time for drying to remove the solvent from the crystals.

Furthermore, depending on the drying conditions, the dried bulk powder turned into amorphous JM (see Figure 1).

Moreover, when this amorphous form of JM is made into tablets, it has the disadvantage that when the molding pressure during tablet manufacturing exceeds a certain value, the disintegration time of the tablets is significantly delayed, as shown in Halo 1. (See Table 1 in ``Time Relationships'').

As a result of various studies, the present inventors have discovered that by employing the production method described above, it is possible to produce a solvent-free crystal JM having extremely excellent properties that can eliminate these drawbacks.

That is, in the case of the present invention, the solvent can be completely removed in a very short time, the hygroscopicity is low, and even if the hardness of the tablet is increased, there is no delay in disintegration time, etc., and it is also excellent in formulation. A crystal with these properties was obtained.

In carrying out the present invention, solvated crystal JM and preferably about 2 to 10 times the amount of an organic solvent and 0.000.
Add 1 to 5% of water by weight, and keep the temperature at 80°C above room temperature.
Although there are no particular limitations on the temperature, the suspension can be carried out preferably by heating and suspending at about 40 to 70°C, collecting the crystals by filtration, and drying the obtained crystals under reduced pressure.

The solvated crystal JM used in the present invention refers to JM containing, for example, benzene or the like in the crystal, and exhibits an X-ray diffraction spectrum as shown in FIG.

In addition, examples of the organic solvent used in the present invention include n
- Solvents that hardly dissolve JM and have good mutual solubility with benzene can be used, such as hexane, petroleum ether, cyclohexane, n-hebutane, isooctane, and n-octane.

The crystalline form JM (hereinafter referred to as (A)) which is the object of the present invention and the amorphous form JM (hereinafter referred to as (B)) obtained through conventional industrial production are shown below.
(abbreviated)) is described below.

Experimental method ■ For (A) and (B), the following manufacturing conditions ((A)
, (B) are both the same) to prepare tablets with various hardnesses.

The hardness of these tablets was measured using a HEBERLEIN hardness tester, and the hardness was determined by the tablet disintegration test method of the Japanese Bureau, 8th edition.
The disintegration time was measured using the liquid.

The results are shown in Table 1.

Tablet manufacturing conditions Experimental method ■ Weighed 100 mg each of dried (A) and (B) and heated them at room temperature with a relative humidity of 63.5% (saturated ammonium nitrate solution).
It was stored in a 5% (sodium chloride saturated solution) and 85% (potassium chloride saturated solution) desiccator, and its weight was measured over time to determine the moisture absorption rate.

The results are shown in the table below.

Experimental method ■ Solvated crystal JM21 containing 20% benzene was suspended in a three-loaf flask with 75 ml of n-hexane and 0.3 ml of water, then placed in a constant temperature bath at 60°C and stirred for 2.5 hours, then collected by filtration. The crystals (hereinafter abbreviated as (C)) were placed in a Petri dish with a diameter of 9 cm and a depth of 1.9 cm and dried under reduced pressure at 90°C.

Solvated crystal JM2 containing 20% benzene as a control
0 g (hereinafter abbreviated as (D)) was placed in a petri dish of the same volume and dried under the same conditions, and after a certain period of time, a part of the sample was taken and the nuclear magnetic resonance spectrum was measured to calculate the residual amount of benzene.

The results are shown in the table below. 60 with n-hexane and a small amount of water
℃ for 25 hours and filtered, the benzene content was as low as 0.05%, and the remaining benzene was quickly removed by drying under reduced pressure.

Example 1 30 g of benzene-containing solvated crystal JM was mixed with 10 g of n-hexane.
The mixture was added to a mixture of 0 ml and 0.5 ml of water, stirred in a constant temperature bath at 60° C. for 2.5 hours, and the crystals were collected by filtration and dried under reduced pressure to obtain 21 g of crystal JM.

When this crystal was analyzed by X-ray diffraction, it showed the pattern shown in FIG.

This is clearly different from the solvated crystal JM (see Figure 2).

Based on the elemental analysis values (as C42, H69, N015) and the fact that no weight loss was observed upon further drying, this crystal does not contain a solvent.

Furthermore, this crystal is divided into n-hexane:benzene:acetone:
As a result of thin layer chromatography using a developing solvent of ethyl acetate:methanol (3:3:1:1:1), R
It showed an ultraviolet absorption spot with an f value of 0.53.

This matches the Rf value of JM.

Example 2 30 g of benzene-containing solvated crystal JM was mixed with 10 g of n-heptane.
After stirring the mixture in a thermostat at 60° C. for 2.0 hours, the crystals are filtered and dried under reduced pressure to obtain 20 g of crystal JM.

Example 3 60 gg of benzene-containing solvated crystal JM was mixed with 1 part of n-heptane.
After adding the mixture to a mixture of 50 ml and 1 ml of water and stirring in a constant temperature bath at 70° C. for 1.0 hour, the crystals were filtered and dried under reduced pressure to obtain 43 g of crystal JM.

Example 4 30 g of benzene-containing solvated crystal JM was mixed with 10 g of n-octane.
After stirring the mixture in a thermostat at 60° C. for 2.5 hours, the crystals are collected by filtration and dried under reduced pressure to obtain 21 g of crystal JM.

[Brief explanation of drawings]

Figure 1 shows the X-ray diffraction spectrum of amorphous JM, Figure 2 shows the X-ray diffraction spectrum of solvated crystal JM, and Figure 3 shows the X-ray diffraction spectrum of crystal JM obtained according to the present invention (Example 1). Figure 4 is a photomicrograph of the sample in Figure 3, Figure 5 is a photomicrograph of the sample in Figure 1, and Figure 6 is a photomicrograph of the sample in Figure 2.

Claims (1)

[Claims] 1. A method for producing solvent-free crystals of josamycin, which comprises treating solvated crystals of josamycin with a water-containing organic solvent.