JP2770470B2 - Process for producing mixed crystals of disodium 5'-guanylate and disodium 5'-inosinate - Google Patents

Description

The present invention relates to a 5'-nucleotide mixture, particularly a mixture of disodium 5'-guanylate and disodium 5'-inosinate, which is useful as a seasoning, a pharmaceutical or the like. As a mixed crystal thereof.

[Prior Art] The following two are known as typical examples of a method for producing disodium 5'-inosinate (hereinafter referred to as IN) and disodium 5'-guanylate (hereinafter referred to as GN) as mixed crystals. I have.

(1) A method of dissolving IN and GN in an aqueous solution containing an organic solvent such as methanol, and obtaining a mixed crystal of IN and GN from this (JP-B-40-12)
No. 914).

(2) A method of dissolving IN and GN in water to obtain a mixed crystal by cooling or concentrating crystallization (JP-A-50-160295 and JP-A-53-124686).

It is known that IN and GN form a mixed crystal in an aqueous solution or an aqueous solution containing an organic solvent such as methanol by incorporating GN into the crystal lattice of IN. The X-ray diffraction pattern of this mixed crystal shows almost the same pattern as the X-ray diffraction pattern of IN, and it is considered that GN having a similar chemical structure enters the lattice of IN and is stabilized by hydrogen bonding. The IN crystal has good crystal growth properties, and the GN incorporated in the crystal exists stably, and its physical properties are almost the same as those of the IN crystal.

When a mixed crystal of IN and GN is obtained, the method (1) can crystallize at a high recovery rate, but industrially requires expensive equipment such as explosion proof because an organic solvent such as methanol is used. However, there is a disadvantage that the manufacturing cost is increased. In the method (2), in order to carry out crystallization with sufficient precision as a product standard, it is necessary to control the concentration of the concentrated drain and the feed solution and to strictly control the setting conditions such as temperature and pressure. As the complexity increases, the equipment cost becomes enormous. Furthermore, in this method, it is very difficult to obtain a mixed crystal having a desired composition using a crystallization mother liquor.

[Problems to be Solved by the Invention] The present invention has been made in view of the above problems, and when the mixed crystal of IN and GN is manufactured by a crystallization method, the ratio of IN and GN is freely controlled. In addition, the crystallization mother liquor can be continuously recycled from the mother liquor by simply recycling it and adding GN without strictly controlling the composition, and creating a GN slurry solution. It is an object to provide a method that can be manufactured easily and at low cost.

[Means for Solving the Problems] As a result of intensive studies to achieve the above-mentioned problems, the present inventors measured the common solubility of IN and GN, and when cooling or concentrating crystallization, The body is divided into a mixed crystal region and a GN α or β crystal region, equilibrium on the boundary, this boundary shows common solubility, and this common solubility diagram is constant at a certain temperature It was found that the ratio of IN and GN in the mixed crystal present at that time was constant.

Thus, under a constant temperature condition, if the IN solution is introduced so as to eliminate GN in the slurry solution containing GN,
The α or β crystal of GN gradually changes to a mixed crystal with IN,
It is only necessary to stop the addition of the IN solution when the mixed crystal is completely mixed.
It was found that a mixed crystal containing IN and GN could be obtained.

More importantly, the IN of the crystallized mother liquor
Since the weight ratio of GN is always almost constant, the mother liquor can be easily reused by adding GN to this to make a slurry solution of GN.

That is, the method for producing a mixed crystal of GN and IN according to the present invention comprises:
The IN-containing aqueous solution is gradually added to the 5'-disodium guanylate-containing slurry solution in which the liquid bottom of GN exists, and GN and IN
Characterized in that a mixed crystal of

IN and GN in the present invention may be those obtained by a known method such as a fermentation method and an organic synthesis. For example, usually 5'-disodium inosinate heptahydrate can be used as IN and 5'-disodium guanylate heptahydrate can be used as GN, but there is no particular limitation. The grade of the raw material used here is usually preferably a purified product, but is not particularly limited to this.

The crystallization operation first produces a GN-containing slurry solution in which GN is mainly suspended in water.

Here, the GN-containing slurry solution may contain IN, impurity inorganic salts derived from raw materials, and the like, but their content is limited to a concentration at which IN crystals do not precipitate in the process of forming the target mixed crystal. The slurry solution is kept at a constant temperature. To this, an IN-containing solution, preferably a saturated aqueous solution thereof, is gradually added, and when the liquid bottom body of GN completely changes to a mixed crystal with IN, the crystal form is confirmed by a microscope or the like, and the crystallization is completed. I do. The IN-containing solution may contain GN, impurity inorganic salts derived from raw materials, and the like, but is limited to conditions under which a mixed crystal of GN and IN can be formed.

At the time of crystallization, in order to improve the crystallization rate of the mixed crystal, it is preferable to use an IN-containing solution having a concentration close to the saturation concentration at a high temperature.
Of course, when the IN-containing solution is at a high temperature, care must be taken so that the temperature of the crystallization solution does not rise sharply. The addition of the IN-containing solution is preferably performed as slowly as possible.
This is because the IN-containing aqueous solution is quenched and crystallized as IN,
This is in order to avoid adhesion to the vessel wall or sedimentation in the crystallization tank to generate mixed crystals in excess of IN. In order to improve the crystallization rate, NaCl, Na ₂ SO ₄ , NH ₄ Cl,
It is also effective to add a salt such as (NH ₄ ) ₂ SO _{4 for} salting out, and to crystallize in a region having low solubility.

In order to change the composition of IN and GN of the mixed crystal, the crystallization temperature may be changed to, for example, 20 ° C., 30 ° C., 40 ° C., 50 ° C., and crystallization corresponding to the common solubility at that temperature is performed. The composition in the mixed crystal can be freely set.

If the crystallization operation is performed at a temperature of, for example, 30 ° C or more, α of GN
The crystals change to mixed crystals. On the other hand, when performed at a low temperature such as 20 ° C., GN exists as β crystals, but it has been confirmed that the β crystals also change to mixed crystals in this case, and the crystallization operation may be the same.

PH of GN-containing slurry solution and IN-containing aqueous solution to be crystallized
As for, mixed crystals can be obtained without any particular limitation as long as they are in the disodium salt region, that is, GN is in the range of pH 6 to 10, and IN is in the range of pH 6 to 10.

[Action] As shown in FIG. 1, the common solubility of IN and GN is
It is represented as a coexistence line of the GN crystal. This coexistence line is used even in a region where mixed crystals and GN crystals having various composition ratios (IN / GN weight ratios) determined by the crystallization temperature and the crystallization solution composition (NaCl concentration, IN, GN concentration, etc.) is there.

Assuming that the crystallization liquid composition is constant, the coexistence line depends only on the temperature, and at a certain temperature, the crystallization mother liquor composition has a predetermined value, and the IN / GN weight ratio in the mixed crystal to be crystallized at this time is independent of any mixed crystal. Will be the same.

Therefore, according to the present invention, in various crystallization compositions, by performing crystallization by the above operation at a constant temperature, by taking the IN / GN weight ratio in the mixed crystal at each temperature, to have the desired composition Mixed crystals can be obtained only by temperature control.

By utilizing the fact that the concentration of the crystallized mother liquor becomes an invariant point by keeping the temperature constant on the coexistence line, the conventional mixed crystal crystallization method can be drastically improved.

[Examples] Hereinafter, examples in which the present invention is performed by the invariant point crystallization method using the above invariant points will be specifically described.

Example 1 1.00 kg of GNγ crystals were dispersed in 1.94 kg of water containing 0.27 kg of sodium chloride to precipitate GNα crystals, and the temperature of the slurry was set at 40 ° C. To this, 0.76 kg of IN was heated and melted at 70 ° C. 3.
A 60 kg aqueous solution of sodium chloride (0.44 kg of NaCl) was slowly added.

The GNα crystal gradually changed to a mixed crystal, and when the IN aqueous solution was added, the GNα crystal completely disappeared. This was separated by a centrifugal separator to obtain a mixed crystal having a crystallization ratio of 58%. At this time, the weight of IN and GN of the mixed crystal was 0.51 kg, and the weight ratio of IN / GN (IN was calculated as 7.5 hydrate and GN was calculated as heptahydrate) was 1.0.

This mixed crystal was subjected to powder X-ray diffraction (FIG. 2) and compared with that of the concentrated crystallization method (FIG. 3). As a result, the invariant point crystallization method according to the present invention was the same as the powder X-ray diagram of IN alone (FIG. 4), and the same result as that obtained by the concentrated crystallization method was obtained.

Example 2 In Example 1, the crystallization temperature was changed variously,
A study was made to control the IN / GN weight ratio.

As a result, as shown in FIG. 5, the crystallization temperature and the mixed crystal IN
A linear relationship was observed in the / GN weight ratio, indicating that a desired mixed crystal composition could be easily obtained by changing the temperature.

[Effects of the Invention] As described above, according to the present invention, a mixed crystal having a desired IN / GN weight ratio can be produced by relatively easy temperature control without strictly setting the composition of the crystallization mother liquor. It is easy to recover IN and GN from mother liquor. In addition, since the control of the crystallization conditions is easy and the equipment cost is not much, the mixed crystal of IN and GN can be manufactured at low cost.

[Brief description of the drawings]

FIG. 1 is a common solubility diagram of GN and IN showing the principle of the method of the present invention. 2 to 4 show a mixed crystal according to Example 1 of the present invention (FIG. 2) and a mixed crystal obtained by a conventional concentrated crystallization method (FIG. 3).
FIG. 4) and X-ray powder diffraction diagrams of IN alone (FIG. 4). FIG. 5 is a graph showing the relationship between the crystallization temperature and the IN / GN weight ratio of the mixed crystal. In the weight ratio of IN / GN, IN was calculated as 7.5 hydrate and GN was calculated as heptahydrate.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Mieko Igarashi 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-ku, Kawasaki-shi, Kanagawa Examiner at Ajinomoto Co., Inc. Central Research Laboratory Shinichi Naito (56) References Japanese Patent Publication No. 40-12914 , B1) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07H 19/20 C07H 1/06 CA (STN) REGISTRY (STN) WPIDS (STN)

Claims (3)

(57) [Claims] (1) When disodium 5'-guanylate and disodium 5'-inosinate are crystallized by a crystallization method to form a mixed crystal, a liquid bottom of disodium 5'-guanylate is present. The aqueous solution containing disodium 5'-inosinate is gradually added to the slurry solution containing disodium 5'-guanylate to give disodium 5'-guanylate and 5 '
A method for producing a mixed crystal of disodium 5'-guanylate and disodium 5'-isocyanate, which comprises forming a mixed crystal of disodium inosinate. 2. The crystallization temperature is selected based on a common solubility diagram of disodium 5'-guanylate and disodium 5'-inosinate when setting the composition of the mixed crystal. 2. The production method according to 1. 3. When producing a mixed crystal, the end point of the crystallization is determined by the α crystal or β crystal of disodium 5′-guanylate in the crystallization liquid.
3. The method according to claim 1, wherein the crystal disappears.