JPS6024080B2 - Crystal manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing crystals with good thermal stability and solubility.

Many of the chemical substances that can be the main components of pharmaceuticals are unstable in solution, and therefore it is preferable to preserve them as crystals in order to keep them stable for long periods of time.

As a method for crystallizing these compounds, for example, if the substance is easily soluble in water, there is a method in which a poor solvent is added to the aqueous solution to precipitate crystals. However, the crystals obtained by this method are undesirable for use as medicines because they are contaminated with organic solvents, which are poor solvents. On the other hand, freeze-drying of aqueous solutions of crystalline substances has also been carried out.
In this method, drying is carried out at a temperature below the eutectic temperature, so the freeze-dried product obtained is amorphous and the material does not have sufficient thermal stability. As a result of various studies in view of these shortcomings of conventional methods, the present inventors have improved the conventional freeze-drying method to: By using a low concentration and drying under reduced pressure at a temperature higher than the eutectic temperature of the solution, we succeeded in obtaining crystals with good thermal stability and excellent solubility similar to ordinary freeze-dried products. did.

That is, in the present invention, a compound that can exist as a crystal (crystalline substance) is dissolved in water to a concentration equal to or less than the content of the compound in a eutectic composition of the compound and water, and the solution is removed from the solution on ice. This is a method for producing crystals of the compound, which is characterized by drying under reduced pressure at a temperature between 0 degrees Celsius, at which the compound precipitates, and the eutectic temperature of the solution.

The compound (crystalline substance) used in the present invention may be any compound as long as it can exist as a crystal, but it is particularly effective when the amorphous substance is unstable. It is true.

Such compounds include, for example, cephaloridine,
Bufcillin sodium, 78-[2-(2-imino-4
-thiazolin-4-yl)acetami-0-3-[1-{N,N-dimethylamino)ethyl}-IH-tetrazol-5-yl]thiomethyl-3-cephemu-4-carboxylic acid dihydrochloride (hereinafter abbreviated as TTC) and other cephalosporins Examples include antibiotics, carbochromene, co-carboxylase, vitamins such as vitamin B hydrochloride, and sugars such as inositol. The content ratio of the crystalline substance in the eutectic composition of the crystalline substance and water has different values depending on the type of the crystalline substance. An example of this is as follows. Cephaloridine (about 15%), TTC (about 20%), carbochromene (about 15%), co-carboxylase (about 15%), inositol (about 10%).

The aqueous solution of the crystalline substance used in the present invention is prepared to have a concentration equal to or lower than the content of the crystalline substance in the above-mentioned eutectic composition. The lower the concentration of the aqueous solution, the better the solubility of the obtained crystals in water, but the longer the time required for crystallization; Solubility tends to be poor. For these reasons, the aqueous solution of the crystalline compound is prepared so that the content of the crystalline substance in the eutectic composition is preferably 30 to 90%, more preferably 50 to 80%. The temperature at which ice precipitates from an aqueous solution of a crystalline substance refers to the temperature at which ice precipitates when the solution is gradually cooled, and it varies depending on the type and concentration of the crystalline substance.

The temperature at which ice precipitates from the solution will be exemplified below. 10% Cephaloridine aqueous solution (10.23oo), 15% TTC (
-1.390C), 5% carbochromene aqueous solution (10.
47q0), 5% co-carboxylase aqueous solution (10.
3900), 5% inositol aqueous solution (10.5100
) The eutectic temperature of an aqueous solution of a crystalline substance is the temperature at which a eutectic between the substance to be crystallized and water begins to form when the solution is gradually cooled, and it is unique to each type of crystalline substance.

This is illustrated below. Cephaloridine (approximately -12℃)
, TTC (approximately -12°C), carbochromene (approximately -15°C)
○), co-carboxylase (approximately 1200), inositol (approximately 11000) In the present invention, the temperature range is lower than the temperature at which ice precipitates from an aqueous solution of the crystalline substance and higher than the eutectic temperature. Drying is performed under reduced pressure.

The stronger the degree of decompression, the shorter the drying time, which is preferable, but if it is too strong from the beginning, a large amount of the heat of vaporization of water and the heat of sublimation of ice will be suddenly taken away, and the temperature will drop below the eutectic temperature. As a result, a eutectic is produced. In this state, after the substance dries,
It becomes amorphous, which is not preferable. The degree of decompression is usually preferably between 5 degrees Hg and 0.5 degrees Hg at the beginning, and once the ice has sublimated to a certain extent and no longer absorbs much heat of sublimation, it should be reduced to 0.1 degrees Hg.
It is best to keep it below g. Alternatively, the degree of vacuum may be increased while heating the solution from the outside to maintain it above the eutectic temperature. The vacuum drying time varies depending on the concentration and amount of the aqueous solution of the crystalline substance used initially, the effective surface area for sublimation, the degree of vacuum, etc., but for example, 0.5 to 5 ml of the aqueous solution is filled into an ampule for injection, When the reaction is carried out at a reduced pressure of 10 to 2 hours, it is usually sufficient.

In carrying out the present invention, an aqueous solution of a crystalline substance is first lowered to below the eutectic point and completely frozen, and then the temperature is raised between the temperature at which ice precipitates and the eutectic temperature. Finer crystals can be obtained by melting the substance and some of the ice and drying it under reduced pressure at this temperature range to crystallize it. According to the method of the present invention, the crystallization rate is extremely high, and the crystals obtained show a clear crystal pattern by X-ray diffraction, and even after long-term storage, the crystals obtained by ordinary crystallization methods are different from each other. It is also stable, does not contain any impurities such as organic solvents, has a large crystal specific surface area, and has the advantage of having a shorter dissolution time in water than ordinary crystals.

The method of the present invention is preferably applied to dosage forms that can be dissolved before use, such as injections. When producing an injection of such a compound, for example, an aqueous solution containing the active ingredient at a predetermined concentration is passed through a bacterial furnace, a predetermined amount of this is filled into an ampoule or a vial, crystallized according to the method of the present invention, and the container is left as is. Seal.

By using such a method, the amount of the active ingredient can be accurately divided into individual containers, and it is possible to provide injections as stable crystals that are excellent in sterility and dust-free properties and do not contain any residual solvent. The injection prepared in this manner is used by dissolving it in a dissolving solution such as physiological saline or distilled water for injection.

EXAMPLES The present invention will be described in more detail with reference to Examples below.

Example 1 Cephaloridine was dissolved in distilled water to make a 10% aqueous solution, and after filtering out the bacterial source, it was filled into a vial at 2.5 cm.

After freezing at -40q C for 1 hour,
The temperature was raised to 0, and the pressure was reduced to 0.8 Hg for 24 hours.

Subsequently, the pressure is reduced to 0.1 Hg or less and drying is performed for an initial hour. The powder thus obtained is a stable crystalline powder. The X-ray diffraction diagram is shown in FIG. Example 2 Co-carboxylase was dissolved in distilled water to make a 5% aqueous solution, and after bacterial filtration, it was filled into ampules.

After freezing by keeping at -40qo for 1 hour, the temperature is raised to -20°C.

After drying for 4 hours at a vacuum level of 0.5 Hg, the vacuum level was reduced to 0.1.
Dry for 1 hour at a temperature below the rib Hg. The thermostability of the co-carboxylase crystals thus obtained is shown.
Example 3 Survival rate of cocarboxylase when stored at 50°C and 60°C: Dissolve carbochromene in distilled water to prepare a 5% aqueous solution, and apply it to a bacterial furnace.

Fill a vial with 1' of this, freeze by keeping at -40 qo for 1 hour, and then raise the temperature to -1.0. After drying for 4 hours while keeping the degree of vacuum at 1 Yanagi Hg, drying is completed in 1 calm hour while keeping the degree of vacuum at 0.1 Hg or less. The carbochromene thus obtained is a crystalline powder.
The powder X-ray diffraction pattern is shown in FIG. Example 4TTC
was dissolved in distilled water to make a 15% solution and filtered through a bacterial sieve.

Two doses of this were filled into a vial, kept at -40°C for 1 hour to freeze, and then the temperature was raised to -1 and 0. After drying for 3 hours while maintaining the degree of vacuum at 0.8 Hg, the degree of vacuum was reduced to 0.1 Hg.
Drying is carried out for 15 hours as follows. The thermal stability of the TTC crystal thus obtained is shown. Example 5 Remaining rate of TTO when stored at 60°C and 50°C Dissolve inositol in distilled water to make a 5% aqueous solution and filter through a bacterial oven.

This was filled into a tray to make the layer thickness 5, and heated to -40°C for 1 hour.
Store and lyophilize. Raise the temperature to -800,
After drying for 4 hours while maintaining a reduced pressure of 2 g, drying is carried out for 10 hours at a pressure of 0.1 Hg or less. Inositol thus obtained is a crystalline powder. The X-ray diffraction diagram is shown in FIG.

[Brief explanation of the drawing]

Figures 1, 2 and 3 show powder X-ray diffraction patterns of cephaloridine crystals, carbochromene crystals and inositol crystals, respectively. Figure 2 Figure 3

Claims (1)

[Claims] 1. Dissolve a compound that can exist as a crystal in water to a concentration equal to or lower than the content of the compound in the eutectic composition of the compound and water, and then dissolve the compound at a temperature at which water precipitates from the solution and at the temperature of the solution. A method for producing crystals of the compound, which comprises drying under reduced pressure at a temperature between the eutectic temperature.