Method for producing 5'-disodium guanylate / 5'-disodium inosinate mixed crystals

Abstract

The present invention provides a method for producing mixed crystals of 5'-disodium guanylate (G) and 5'-disodium inosinate (I), the method including a first crystallization step for forming mixed crystals including G and I in an I / G ratio of approximately 1, in terms of anhydrates, through semi-batch crystallization or continuous crystallization using an aqueous solution that contains G and I and an NaCl aqueous solution, the concentration of the NaCl aqueous solution being no less than 5 mass% and no greater than the saturation concentration, the aqueous solution that contains G and I containing 5-25 mass% of G and 5-20 mass% of I, and the G concentration being 1-1.8 times the I concentration.

Description

Method for producing mixed crystal of disodium 5'-guanylate and disodium 5'-inosinate

[0001] The present invention relates to a method for producing a mixed crystal containing disodium 5'-guanylate and disodium 5'-inosinate in an approximately 1:1 ratio when calculated as anhydrous, which is useful as a seasoning, a pharmaceutical, etc. ("disodium 5'-guanylate / disodium 5'-inosinate mixed crystal" or "I+G crystal").

[0002] The following methods have been reported so far as methods for producing mixed crystals of disodium 5'-guanylate ("5'-GMP2Na" or "GMP") and disodium 5'-inosinate ("5'-IMP2Na" or "IMP"). As methods for producing mixed crystals of 5'-GMP2Na and 5'-IMP2Na, the following methods have been reported so far, not limited to mixed crystals in a 1:1 ratio. (1) A method in which 5'-GMP2Na and 5'-IMP2Na are dissolved in water, and then cooled, concentrated, and alcohol is added to precipitate 5'-GMP2Na and 5'-IMP2Na as mixed crystals (Patent Document 1). (2) A method in which 5'-GMP2Na and 5'-IMP2Na are dissolved in an aqueous solution containing a hydrophilic organic solvent such as methanol, and then a mixed crystal of 5'-GMP2Na and 5'-IMP2Na (i.e., an I+G mixed crystal) is obtained, or a crystallization method in which an organic solvent is added to a mixed aqueous solution of 5'-IMP2Na and 5'-GMP2Na (Patent Document 2). (3) A method in which an aqueous solution containing 5'-IMP2Na is gradually added to a slurry solution in which 5'-GMP2Na exists as a bottom liquid, thereby producing an I+G mixed crystal (Patent Document 3). (4) A method characterized by gradually adding a 5'-IMP2Na-containing aqueous solution to a slurry solution containing 5'-GMP2Na as a bottom solid, and then adding mixed crystals or IMP crystals as seed crystals to generate I+G mixed crystals (Patent Document 4). In the cooling or concentration crystallization method (1), GMP that does not form mixed crystals is likely to precipitate as GMP amorphous, which further reduces the crystal size and impairs separability. Furthermore, both methods (1) and (2) use organic solvents, which increase the number of facilities required. From the perspective of environmental protection, the use of or switching to aqueous systems is recommended. Methods (3) and (4) involve aqueous crystallization, but the number of facilities required to prepare GMP and IMP separately increases. Furthermore, methods (3) and (4), in which an IMP solution is added to a GMP slurry, make it difficult to increase the recovery rate and purity of the crystals due to the presence of GMP amorphous.

[0003] Japanese Patent Publication No. 54-16582 Publication No. 40-12914 Japanese Patent Publication No. 3-215494 Publication No. 3-223299

[0004] The Joint FAO / WHO Expert Committee on Food Additives (JECFA) has stipulated that the ratio of anhydrous 5'-guanylate disodium ("5'-GMP2Na," "GMP," or "G") and disodium 5'-inosinate ("5'-IMP2Na," "IMP," or "I") mixtures should be 47 to 53% of the total anhydrate (i.e., I:G = approximately 1:1). A product that maintains a similar ratio for mixed crystals of GMP and IMP is also desired. An objective of the present invention is to obtain, from an aqueous solution in which GMP and IMP are premixed, a highly separable mixed crystal in a ratio of approximately 1:1 (I / G ratio = approximately 1) calculated as anhydrous, by crystallization in an aqueous system without using a poor solvent such as alcohol.

[0005] As a result of extensive research, the present inventors have found that the above-mentioned problems can be solved by carrying out semi-batch crystallization or continuous crystallization in an aqueous system using an aqueous solution containing G and I at predetermined concentrations and NaCl at a predetermined concentration. [1] A method for producing a mixed crystal, comprising a first crystallization step of forming a mixed crystal containing disodium 5'-guanylate and disodium 5'-inosinate by semi-batch crystallization or continuous crystallization using an aqueous solution containing said disodium 5'-guanylate and disodium 5'-inosinate and an aqueous NaCl solution, wherein the mixed crystal contains disodium 5'-guanylate and disodium 5'-inosinate at a disodium 5'-inosinate / disodium 5'-guanylate ratio of approximately 1 when calculated as anhydrous, wherein the concentration of the aqueous NaCl solution is 5% by mass or more but not more than a saturation concentration, and the aqueous solution containing disodium 5'-guanylate and disodium 5'-inosinate contains 5 to 25% by mass of disodium 5'-guanylate and 5 to 20% by mass of disodium 5'-inosinate, and the concentration of disodium 5'-guanylate is 1 to 1.8 times that of disodium 5'-inosinate. [2] The production method according to 1 above, wherein the crystallization temperature is maintained within a range of 40 to 5°C in the first crystallization step. [3] The production method according to 1 or 2 above, wherein the obtained mixed crystals are substantially free of GMP amorphous. [4] The production method according to any of 1 to 3 above, wherein no seed crystals are used. [5] The production method according to any of 1 to 4 above, further comprising a second crystallization step in which crystallization is carried out at a temperature lower than the crystallization temperature in the first crystallization step. [6] The production method according to 5 above, wherein the second crystallization is carried out at 40 to 5°C. [7] The production method according to any of 1 to 6 above, wherein the concentration of the NaCl aqueous solution is 15 to 27% by mass. [8] The production method according to any of 1 to 7 above, wherein the obtained crystals have a major axis of 30 μm or more and a minor axis of 20 μm or more as measured by image analysis. [9] The production method according to any of 1 to 8 above, wherein the crystallization operation is carried out at a pH of 6 to 10.

[10] A method for producing a mixed crystal, comprising a first crystallization step of forming a mixed crystal of disodium 5'-guanylate and disodium 5'-inosinate by semi-batch crystallization or continuous crystallization using an aqueous solution containing disodium 5'-guanylate and disodium 5'-inosinate and an aqueous NaCl solution, wherein the concentration of the aqueous NaCl solution is 13 to 17% by mass, the aqueous solution containing disodium 5'-guanylate and disodium 5'-inosinate contains 15 to 25% by mass of disodium 5'-guanylate and 15 to 20% by mass of disodium 5'-inosinate, and the GMP concentration is 1.1 times the IMP concentration, the crystallization temperature is maintained at 15°C in the first crystallization step, the method does not include any further crystallization step such as cooling crystallization, and does not use seed crystals.

[0006] According to the present invention, the ratio of GMP crystals incorporated into IMP crystals can be controlled. Therefore, according to the present invention, a large amount of GMP crystals can be incorporated, and an I+G mixed crystal with an I / G ratio of approximately 1 can be obtained. In this invention, an I / G ratio of approximately 1 means that the ratio of each anhydrate is 47 to 53 mass% relative to the total anhydrate, in other words, an I / G ratio of 47 / 53 to 53 / 47. According to the present invention, mixed crystals can be obtained without using seed crystals, eliminating the need for complicated operations and the need for equipment for seed crystal addition. According to the present invention, the separability of the I+G mixed crystals can also be controlled by controlling the crystal size. According to the present invention, the desired mixed crystals can be obtained without substantially forming amorphous GMP. Because the mixed crystals obtained according to the present invention are substantially free of amorphous GMP, separability equivalent to that of mixed crystals obtained by conventional techniques can be ensured.

[0007] FIG. 1 shows the relationship between the IMP concentration and the GMP concentration in a mixed aqueous solution of IMP and GMP. FIG. 2 shows the relationship between the NaCl concentration of the initially charged NaCl aqueous solution and the effective partition coefficient. FIG. 3 shows the crystalline form of the mixed crystal obtained by crystallization in Example 1. FIG. 4 shows the crystalline form of the mixed crystal obtained by crystallization in Example 2. FIG. 5A shows the crystalline form of the mixed crystal obtained in Example 3. The upper row shows the crystal before cooling crystallization, and the lower row shows the crystal after cooling crystallization. FIG. 5B shows the crystalline form of the mixed crystal obtained by batch crystallization in Reference Example 1. FIG. 5C shows the crystalline form of the mixed crystal obtained by methanol crystallization in Reference Example 2.

[0008] The method of the present invention includes a first crystallization step in which an I+G mixed crystal is formed by semi-batch or continuous crystallization using an aqueous solution containing GMP and IMP and an aqueous NaCl solution. The mixed aqueous solution of IMP and GMP used in the present invention can be prepared not only from the product crystals of each of the two, but also from, for example, an I+G mixed crystal having an I / G ratio outside the specified range, or from crude crystals obtained during the production process of each of the two by fermentation, organic synthesis, etc. However, it goes without saying that the content of impurities is limited to a level that does not affect the solubility or crystal growth rate of the I+G mixed crystal.

[0009] In the present invention, semi- or fed-batch crystallization refers to crystallization in which an aqueous solution containing at least GMP and IMP, and optionally an aqueous NaCl solution, is continuously or sequentially added to a crystallizer. In the present invention, continuous crystallization refers to crystallization in which an aqueous solution containing at least GMP and IMP, and optionally an aqueous NaCl solution, is continuously or sequentially added to a crystallizer, and I+G mixed crystals are continuously recovered.

[0010] In the first crystallization step, the mixed aqueous solution of IMP and GMP may be poured into a crystallization tank charged with an aqueous NaCl solution, or the aqueous NaCl solution and the mixed aqueous solution of IMP and GMP may be poured simultaneously into an empty crystallization tank or into a crystallization tank charged with water. In this case, if the pouring is performed at a space velocity (SV, a dimensionless rate expressed as the amount added per hour relative to the total amount added) of 0.05 to 1.0, for example, a mixed crystal in which GMP is incorporated into the IMP crystal lattice is precipitated. The amount of aqueous NaCl solution or water pre-charged is preferably such that the contents of the crystallization tank can be stirred even after the entire amount has been added. Good stirring conditions must be maintained to ensure rapid and uniform diffusion of the aqueous NaCl solution and the mixed aqueous solution of IMP and GMP. Furthermore, to maintain a good crystal shape of the I+G mixed crystal, stirring is preferably performed as slowly as possible, preferably at a space velocity of 0.05 to 1.0. A space velocity of 0.1 to 0.5 is more preferable, and a space velocity of 0.1 to 0.3 is even more preferable. Experiments conducted by the present inventors have shown that the higher the concentration of the NaCl aqueous solution charged into the crystallizer or added to the crystallizer together with the mixed aqueous solution of IMP and GMP, the greater the uptake of GMP. Therefore, this ratio (effective partition coefficient) was defined by Equation 1.

[0011]

[0012] Experiments conducted by the present inventors also revealed that the concentration of the NaCl aqueous solution affects the size of the GMP crystals and I+G mixed crystals incorporated into the IMP crystals. The higher the NaCl concentration, the greater the amount of GMP crystals incorporated into the IMP crystals. On the other hand, if the difference between the concentration of IMP added and the concentration of IMP in the mother liquor is taken as the degree of supersaturation, it was found that the greater the degree of supersaturation, the finer the I+G crystals. Therefore, the concentration of the NaCl aqueous solution should be 5% by mass or more but not more than the saturated concentration, preferably 15 to 27% by mass.

[0013] If the GMP concentration in the feed is high, the GMP that is not incorporated will become amorphous, reducing separability. If the GMP concentration is low, the amount of GMP incorporated into the IMP crystals will be so low that the desired I / G ratio of approximately 1 cannot be achieved. Therefore, an appropriate feed concentration must be set taking into account the effective partition coefficient. The feed concentration can be determined by calculation by experimentally determining the effective partition coefficient and the saturated solubility of IMP at a given temperature according to the NaCl concentration. While the calculation method is not limited, it can be determined by repeatedly changing the concentrations of IMP and GMP in the mixed aqueous feed solution until the desired I / G ratio is obtained. For example, the mass balance equation (12.1) in "Crystalization Engineering" by Tokuaki Kubota (Tokyo Denki University Press, 2016, pp. 189-191) can be used as a reference, and the mass balance equation and the effective partition coefficient equation (Equation 1) can be used as a simultaneous equation for calculation. Specifically, the calculation is as follows.

[0014] CS: solute concentration at the start of crystallization expressed as the amount of unsolvated substance per unit mass of solvent [kg-unsolvated solute / kg-solvent] W: solvent mass [kg-solvent] Y: solvate crystal mass [kg-solvate] R: formula weight ratio of solvate to unsolvate CM: concentration per unit mass of solvent at the end of crystallization [kg-unsolvated solute / kg-solvent] EDC: effective partition coefficient IMP : Subscript, indicates that the solute is IMP GMP : Subscript, indicates that the solute is GMP P: Desired I / G ratio

[0015] The amounts of unsolvated substances of IMP and GMP at the start of crystallization are W × CS, respectively. IMP WxCS GMP At the end of crystallization, the solvent mass is expressed as

[0016]

[0017] If we take the mass balance equation for the solute at the start and end, we get

[0018]

[0019] The ratio of IMP to GMP in the mixed crystal is

[0020]

[0021] The effective partition coefficient defined above is expressed as

[0022]

[0023] The objective variable to be designed is CS IMP and C.S. GMP Other variables that are determined by calculation are Y IMP , Y GMP , CM GMP and the formula ratio R IMP , R GMP is a constant, and W is a design item. IMP If we experimentally determine P = 1, we can add CS to equations (1) to (4). IMP By successively substituting, CS GMP As described above, the I / G ratio of approximately 1 may be in the range of 47 / 53 to 53 / 47, so by substituting the lower and upper limits of the I / G ratio into P in formula (3) and performing calculations, the lower and upper limits of the feed concentration can be set.

[0024] From the determination and calculation of the effective partition coefficients and saturated solubilities, the concentrations of IMP and GMP in the mixed aqueous solution to be charged are determined to be higher than those of IMP, with the ratio of the GMP concentration to the IMP concentration being 1 to 1.8, preferably 1.04 to 1.76, more preferably 1.04 to 1.52, and even more preferably 1.04 to 1.15. Regarding the concentrations of IMP and GMP in the mixed aqueous solution to be charged, for example, when the NaCl concentration is 15% by mass, the IMP concentration in the mixed aqueous solution can be set within a range of 5 to 20% by mass in accordance with the I / G ratio (mass ratio) of the desired I+G mixed crystal. However, to obtain an I+G mixed crystal with an I / G ratio of 1, the GMP concentration of the mixed solution must be within the range enclosed by the two straight lines in Figure 1. These correspond to a GMP / IMP ratio range of 0.92 to 1.08. 1, -●- is a line showing the charge concentrations of GMP and IMP when I / G = 0.92, and -○- is a line showing the charge concentrations of GMP and IMP when I / G = 1.08. In this specification, unless otherwise specified, the unit "%" is % by mass. In this specification, the concentrations of IMP and GMP are expressed in terms of IMP2Na7.5H2O or GMP2Na7H2O, unless otherwise specified.

[0025] Experiments conducted by the present inventors have revealed that the crystallization temperature affects the size of the crystals. Since increasing the crystallization temperature results in larger crystals, the first crystallization step, preferably performed within a range of 5 to 40°C, allows for control of the crystal size and therefore the separability of the I+G mixed crystals. The crystallization temperature in the first crystallization step can be controlled by controlling the temperature of the crystallizer. The crystallization temperature can be set to 5 to 40°C. In the system of the present invention, crystal growth is so rapid that aging time at the same temperature to wait for crystal growth is almost unnecessary. Therefore, the first crystallization step may be completed when the predetermined amounts of the aqueous NaCl solution and the mixed aqueous solution of IMP and GMP have been added to the crystallizer. While the crystallization temperature may be changed to a higher or lower temperature before the completion of the first crystallization step, maintaining the temperature at 10 to 25°C, more preferably 12 to 17°C, is preferred, as this results in I+G mixed crystals with good separability. The maintenance (aging) time varies depending on the crystallization temperature and the equipment, but from the viewpoint of equipment productivity, it is preferably, for example, 1 to 24 hours, more preferably 3 to 12 hours. In particular, aging for 3 to 12 hours at a temperature of 10 to 25° C. is preferred. Here, highly separable crystals refer to crystals that are substantially free of amorphous matter and have a major axis of 30 μm or more and a minor axis of 20 μm or more when the crystals are photographed and the lengths of the crystals in the photograph are measured by image analysis.

[0026] After the addition is complete, solid-liquid separation can be performed immediately, or a cooling operation can be performed to improve the yield. That is, the present invention may further include a second crystallization step in which crystallization is performed at a temperature lower than the crystallization temperature in the first crystallization step. The second crystallization temperature can be set, for example, to 5 to 40°C, but is preferably performed at a temperature approximately 10 to 35°C lower than the first crystallization temperature, for example, within a range of 5 to 15°C. In this case, cooling at a rate of 1 to 5°C / hour yields crystals with good separability. 1 to 3°C / hour is more preferred. The second crystallization temperature can also be maintained constant or can be changed to a higher or lower temperature within the above temperature range. The maintenance (aging) time in the second crystallization step also varies depending on the crystallization temperature and equipment, but from the viewpoint of equipment productivity, it is preferably, for example, 1 to 24 hours, more preferably 3 to 12 hours. In particular, aging at a temperature of 10 to 25°C for 3 to 12 hours is preferred. Crystals with good separability are obtained by the second crystallization step. However, from the viewpoint of avoiding amorphous precipitation, it is preferable not to include an additional crystallization step such as cooling crystallization. The pH at which the crystallization is carried out is within the range in which the disodium salt of 5'-guanylic acid and the disodium salt of 5'-inosinic acid exist, i.e., within the range of pH 6 to 10, so that I+G mixed crystals can be obtained, but a pH of approximately 7 to 8 is preferable. Note that the pH in this specification is the value at 25°C.

[0027] According to the method of the present invention, the desired mixed crystal can be obtained without seed crystals, thereby reducing the number of facilities required. According to the present invention, the desired mixed crystal can be obtained without substantial formation of GMP amorphous. In other words, if GMP amorphous is formed during the production process, separation performance is significantly impaired, making separation virtually impossible. Even if a high-moisture amorphous is forcibly separated, drying the remaining water leaves impurities in the mother liquor in the solid phase, resulting in a deterioration in quality. However, according to the present invention, the formation of GMP amorphous is substantially avoided, eliminating the need to remove GMP amorphous from the product. Therefore, according to the present invention, the desired mixed crystal can be obtained with a high yield and fewer steps. As used herein, the phrase "substantially free of GMP amorphous" means that the presence of GMP amorphous is acceptable as long as it does not interfere with stirring, e.g., does not increase the power load during stirring or cause the crystals to sink and not float up.

[0028] The present invention provides a method for producing a mixed crystal, which comprises a first crystallization step of forming a mixed crystal of disodium 5'-guanylate and disodium 5'-inosinate by semi-batch crystallization or continuous crystallization using an aqueous solution containing disodium 5'-guanylate and disodium 5'-inosinate and an aqueous NaCl solution, wherein the concentration of the aqueous NaCl solution is 13 to 17% by mass, the aqueous solution containing disodium 5'-guanylate and disodium 5'-inosinate contains 15 to 25% by mass of disodium 5'-guanylate and 15 to 20% by mass of disodium 5'-inosinate, and the GMP concentration is 1.1 times the IMP concentration, the crystallization temperature is maintained at 15°C in the first crystallization step, no further crystallization step such as cooling crystallization is included, and no seed crystals are used, which is the most preferred embodiment.

[0029] Example 1: 140 g of aqueous NaCl solution was charged into a beaker maintained at 5°C. The NaCl concentration was adjusted to a range from 0% to saturated sodium chloride concentration, as shown in Table 1. While stirring each aqueous NaCl solution, 350 g of aqueous solutions containing IMP and GMP adjusted to 17.5% and 18.5%, respectively, were added dropwise. The dropwise addition rate was set at a space velocity of 0.2. The aqueous solution containing IMP and GMP was added dropwise while stirring the NaCl solution, yielding I+G mixed crystals. To control the pH at 7.5 during crystallization, the pH of the crystallization slurry was monitored, and 1N NaOH aqueous solution was added as needed. After the entire aqueous solution containing IMP and GMP was added dropwise, the temperature was maintained at 5°C and the mixture was aged for 12 hours. It was found that increasing the NaCl concentration of the initially charged aqueous NaCl solution increased the effective partition coefficient (EDC) of GMP (Figure 2). Here, the effective partition coefficient is the ratio of the GMP concentration to the IMP concentration in the crystals and the GMP concentration to the IMP concentration in the mother liquor, and is defined by Equation 1. It was found that the higher the salt concentration, the larger the effective partition coefficient, and that a larger amount of GMP crystals was incorporated into the IMP crystals.

[0030]

[0031] The crystal shape of the mixed crystal obtained by crystallization was as shown in Figure 3. The supersaturation under each condition is as shown in Table 1, and it was found that the greater the degree of supersaturation, the finer the I+G crystals.

[0032]

[0033] Example 2: 140 g of a 15% NaCl aqueous solution and 350 g of an aqueous solution containing IMP and GMP adjusted to 17.5% and 18.5%, respectively, were simultaneously added dropwise to a beaker controlled at 5°C, 15°C, or 25°C. The addition was carried out while stirring the contents of the beaker. The total addition rate of the two solutions was 0.2 in terms of space velocity. I+G mixed crystals were obtained in the beaker. To control the pH at 7.5 during crystallization, the pH of the crystallization slurry was monitored, and 1N NaOH aqueous solution was added as needed. After the 15% NaCl aqueous solution and the aqueous solution containing IMP and GMP were all added dropwise, the temperature was maintained and the mixture was aged for 12 hours. Crystallization was carried out at the same temperature. As shown in Figure 4, increasing the crystallization temperature resulted in larger crystal shapes.

[0034] Reference Example 1 (Batch Crystallization) An aqueous solution containing IMP and GMP at 17.7% and 18.9%, respectively, was prepared by adding a 50% NaOH solution to the aqueous solution and adjusting the pH to 7.5. NaCl was added to the aqueous solution to a concentration of 27.6%. The solution was then heated to 45°C to dissolve the IMP and GMP, and then cooled to 20°C at a rate of 5°C / hour.

[0035] Reference Example 2 (Methanol Crystallization) 175 mL of a 45 vol% methanol aqueous solution was placed in a beaker and kept at 45°C, and 6.3 g of I+G mixed crystals were added as seed crystals. 763.0 g of an aqueous solution containing 78.3 g of IMP and 79.2 g of GMP and a 95 vol% methanol aqueous solution were simultaneously added to the resulting slurry over 3 hours. During the simultaneous addition, the methanol concentration in the liquid phase in the beaker was controlled to 45 vol%. The mixture was then cooled to 20°C at a rate of 5°C / hour.

[0036] Example 3: A feed solution was prepared by adding 50% NaOH solution to an aqueous solution containing 17.3% IMP and 18.5% GMP, respectively, and adjusting the pH to 7.5. Subsequently, 31 g of water was poured into a beaker, and while stirring, 426 g of the feed solution prepared above and 167 g of a 27.6% NaCl aqueous solution were simultaneously added at space velocities of 0.14 and 0.06, respectively, to crystallize the I+G mixed crystals. The total space velocity was 0.2, and the feed was completed in 5 hours. The temperature was maintained constant throughout the crystallization, and the crystallization was carried out at two levels: 25°C (Condition 1) and 40°C (Condition 2). The difference between the concentration of inosinic acid in the feed solution and its saturated solubility at the set temperature (supersaturation ΔC) was 14.6% (Condition 1) and 12.0% (Condition 2), respectively. After the feed was completed, stirring was continued for 10 hours at the set temperature, and then the crystallization slurry was cooled and crystallized to 5°C at a rate of 3°C / hr under both conditions while stirring in a beaker. The difference in saturated solubility between the start and end of cooling was 1.7% (Condition 1) and 4.4% (Condition 2), respectively. When the crystals were observed under a microscope before and after cooling crystallization, they did not become fine I + G mixed crystals like those obtained by batch crystallization (Reference Example 1, Figure 5B), but rather crystals similar to the I + G mixed crystals obtained by batch MeOH crystallization (Reference Example 2, Figure 5C) were obtained (Figure 5A). Table 2 shows a summary of the test conditions and results for the Examples and Reference Examples.

[0037]

Claims

1. a first crystallization step of forming a mixed crystal containing disodium 5'-guanylate and disodium 5'-inosinate in a ratio of disodium 5'-inosinate / disodium 5'-guanylate of approximately 1 when calculated as anhydrous, by semi-batch crystallization or continuous crystallization using an aqueous solution containing disodium 5'-guanylate and disodium 5'-inosinate and an aqueous NaCl solution, The concentration of the NaCl aqueous solution is 5% by mass or more and not more than a saturated concentration, The above-mentioned production method, wherein the aqueous solution containing disodium 5'-guanylate and disodium 5'-inosinate contains 5 to 25% by mass of disodium 5'-guanylate and 5 to 20% by mass of disodium 5'-inosinate, and the concentration of disodium 5'-guanylate is 1 to 1.8 times the concentration of disodium 5'-inosinate.

2. The method according to claim 1, wherein the crystallization temperature in the first crystallization step is maintained within a range of 5 to 40°C.

3. The method according to claim 1, wherein the resulting mixed crystal is substantially free of amorphous disodium 5'-guanylate.

4. The method of claim 1, wherein no seed crystals are used.

5. The method according to claim 1, further comprising a second crystallization step in which crystallization is carried out at a temperature lower than the crystallization temperature in the first crystallization step.

6. The method according to claim 5, wherein the second crystallization is carried out at 40 to 5°C.

7. The method according to claim 1, wherein the concentration of the aqueous NaCl solution is 15 to 27% by mass.

8. 2. The method according to claim 1, wherein the obtained crystals have a major axis of 30 μm or more and a minor axis of 20 μm or more as measured by image analysis.

9. The method according to claim 1, wherein the crystallization is carried out at a pH of 6 to 10.

10. A method for producing the mixed crystal, comprising a first crystallization step of forming a mixed crystal of disodium 5'-guanylate and disodium 5'-inosinate by semi-batch crystallization or continuous crystallization using an aqueous solution containing disodium 5'-guanylate and disodium 5'-inosinate and an aqueous NaCl solution, The concentration of the NaCl aqueous solution is 13 to 17% by mass, the aqueous solution containing disodium 5'-guanylate and disodium 5'-inosinate contains 15 to 25% by mass of disodium 5'-guanylate and 15 to 20% by mass of disodium 5'-inosinate, and the concentration of disodium 5'-guanylate is 1.1 times the concentration of disodium 5'-inosinate; In the first crystallization step, the crystallization temperature is maintained at 15°C; It does not include further crystallization processes such as cooling crystallization, The above production method does not use seed crystals.