JP2004091442A - Water-soluble magnesium citrate salt hydrate and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a magnesium citrate salt hydrate easily soluble in water and exhibiting excellent effect as a raw material for pharmaceuticals, a magnesium enriching agent, a raw material or an intermediate for industrial chemicals, etc., and provide a method for producing the salt. <P>SOLUTION: The invention provides a magnesium citrate salt hydrate expressed by C<SB>12</SB>H<SB>10</SB>Mg<SB>3</SB>O<SB>14</SB>-xH<SB>2</SB>O (x is an integer of 1-9), having a solubility of ≥20 g in 100 ml of water at 25°C and produced by reacting an aqueous solution or suspension of citric acid with metallic magnesium or a magnesium salt and pulverizing or solidifying the reaction product by spray-drying or low-temperature vacuum drying. The invention further provides a method for the production of the salt. <P>COPYRIGHT: (C)2004,JPO

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a magnesium citrate hydrate used for a raw material for medicine, a raw material for industrial chemicals, a magnesium fortifier, and the like, and a method for producing the same.
[0002]
[Prior art]
When citric acid or citrate is added to and reacted with a metallic magnesium or basic magnesium salt in an aqueous solution or suspension thereof, a transparent aqueous solution is obtained. Crystals are formed by adding steps such as heating and cooling to this aqueous solution, and the crystals vary in crystallization conditions, for example, the number of hydrates constituting one molecule, the number of citric acid, or the number of magnesium, There are various structures. In addition, except for a part of them, the solubility in water is low, and the crystals are insoluble or cloudy in water. Therefore, it is difficult to dissolve the obtained crystals again in water and use them as a transparent aqueous solution.
[0003]
On the other hand, in the Japanese Pharmacopoeia Non-Pharmaceutical Standard 1997, USP Official Monograph, etc. It is used in the form of a liquid solution (aqueous solution) of magnesium hydrogen citrate as an internal medicine for pretreatment in surgery.
Examples of the powder used for the same purpose include a salt of an amorphous substance (see, for example, JP-A-55-108814 and JP-A-5-194205) or a pentahydrate salt of a crystalline substance (for example, U.S. Pat. No. 2,226,0004 and JP-A-6-228046 are known.
[0004]
However, these magnesium salts were all related to magnesium hydrogen citrate represented by C ₆ H ₆ MgO ₇ .
[0005]
[Problems to be solved by the invention]
The present invention, conventional _C 12 has been considered insoluble or finely dissolved in water from the _{H 10 Mg 3 O 14 · nH} 2 O: represented by (n 0 to 9 integer), citrate tri hydrated magnesium A method for extracting a powder soluble in water was discovered, and it was found that it was inexpensive, high quality, and stable over time as compared with the conventional production method, and completed the present invention.
[0006]
[Means for Solving the Problems]
According to the present invention, a reaction is carried out by adding metallic magnesium or a magnesium salt to an aqueous solution or suspension of citric acid, and then immediately drying the reaction solution by spray drying, drying under reduced pressure, or the like to obtain a powder. ℃ in dissolved in 5 volumes of water, good stability, the _{formula: C 12 H 10 Mg 3 O} 14 · xH 2 O: magnesium citrate salt hydrate represented by (x 1 to 9 integer), and Related to manufacturing method.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
As described above, the magnesium citrate hydrate according to the present invention is prepared by adding metallic magnesium or a magnesium salt to an aqueous solution or suspension of citric acid at a temperature lower than room temperature to cause a reaction, and then spray-drying and depressurizing the reaction solution. It is solidified by a process such as concentration and drying. The citric acid used in the present invention also includes a lactone of citric acid hydrate, citric anhydride, isocitric acid and its dehydrated isocitrate.
[0008]
Among the metal magnesium or magnesium salts used in the present invention (hereinafter referred to as “magnesium raw material”), the magnesium salts include magnesium hydroxide, magnesium carbonate, magnesium oxide and the like. Among these, magnesium hydroxide or heavy magnesium carbonate is easy to use because of good compatibility with water and high reactivity with citric acid. Since it is necessary to react at low temperature in an aqueous solution, the form of the magnesium salt is desirably a powder having a fine particle diameter of 200 mesh pass or less. These magnesium raw materials can be used alone or in combination of two or more.
[0009]
It is preferable that the water used in the present invention does not contain salts other than magnesium as much as possible, and it is preferable to use purified water such as ion-exchanged water or distilled water.
[0010]
The citric acid solution in the present invention is used in the form of an aqueous solution or suspension. When citric acid is added to water, if the amount of water used is too small, the amount of generated magnesium citrate in water is small, so the amount of water is based on 100 parts of citric acid (parts by weight, the same applies hereinafter). And 300 parts or more, preferably 400 parts or more. On the other hand, when the amount of water used is large, the evaporation time of water becomes longer to dry the magnesium citrate solution obtained in the reaction, which increases the cost. On the other hand, the amount is preferably 500 parts or less, and more preferably 430 parts or less.
[0011]
An aqueous solution or suspension of citric acid (hereinafter referred to as an aqueous suspension (1)) may be in a state in which the entire amount of citric acid is dissolved or in a suspended state, but the reaction proceeds sufficiently. In order to obtain a homogeneous hydrate of magnesium citrate as a result, it is preferable that the reaction system becomes a homogeneous solution as the reaction proceeds. For this purpose, the temperature of the aqueous suspension (1) at the time of dissolving citric acid is desirably 15 ° C. or higher, and preferably about 25 ° C.
[0012]
Next, by adding the magnesium raw material while stirring the suspension aqueous solution (1), the reaction between the two proceeds to form an aqueous solution or suspension containing the magnesium citrate hydrate (hereinafter referred to as the aqueous suspension solution (2)). available.
[0013]
The amount of the magnesium raw material used in this reaction is desirably 1.5 mol or more, preferably 1.51 mol or more, more preferably 1.52 mol or more, based on 1 mol of citric acid. The magnesium raw material for preparing the aqueous suspension (1) may be added little by little, and after the complete dissolution, the next addition may be performed. The pH after the completion of the addition of the magnesium raw material is 5.3 to 8.0.
[0014]
In order to allow this reaction to proceed quickly, the temperature of the solution is desirably 20 ° C. or higher, preferably 25 ° C. or higher. On the other hand, if the reaction temperature is too high, crystals will precipitate. The temperature is preferably set to 40 ° C. or lower, preferably 30 ° C. or lower in order not to precipitate crystals. When the reaction is completed, the aqueous suspension (2) becomes a transparent aqueous solution. Crystals may precipitate even when reacted under the above conditions, but in this case, the crystals may be magnesium citrate hydrate or other substances. Shall be removed and not mixed with magnesium citrate. The crystals to be crystallized here have very low solubility in water, and even when dried and mixed with soluble crystals, these crystals become insoluble when dissolved in water. Therefore, they must be separated before drying.
[0015]
In the present invention, a solid that is easily soluble in water is obtained from a clear solution of an aqueous suspension of magnesium citrate (2). For this purpose, it is important to concentrate and dry the aqueous solution at a low temperature in a short time to form a solid, or to separate the amorphous solution from the aqueous solution as an amorphous solid before the crystal grows at a low temperature and a short time, and to dry it.
[0016]
In the present invention, as a result of examining these means in various fields, one of the methods of drying at a low temperature in a short time by spray drying is to obtain an individual which is easily soluble in water and stable over time. I discovered that.
[0017]
This method is a method of obtaining a solid in a short time at a low temperature, and is almost instantaneous dry powdering without spending time until the magnesium citrate forms a crystal form. It was discovered that solids were obtained as amorphous powders by this method.
[0018]
In the present invention, drying at a low temperature and in a short time was carried out by using the above-mentioned transparent aqueous suspension solution (2) (pH 5.3 to 8.0) and drying with a spray dryer. The temperature of the air for drying is preferably 150 ° C. or higher at the sample inlet, more preferably 180 ° C., and most preferably 200 ° C. The sample outlet temperature is 70 ° C. or higher, more preferably 100 ° C.
[0019]
On the other hand, the powder obtained here is both amorphous and hydrated. The number has from 1 to 9 moles of water per mole of magnesium citrate. This number of water molecules is comparable to the number of hydrates having a crystalline form having low solubility in water.
[0020]
The thus obtained magnesium citrate hydrate of the present invention has different water molecules (the number of x) depending on the drying conditions such as the drying temperature during spray drying, the drying time, and the concentration of the aqueous solution. However, C ₁₂ H ₁₀ Mg ₃ O ₁₄ · x _H 2 O: has a type (x 1 to 9 integer), in the 25 ° C. to dissolve more than 20g of water 100 ml, keeping clear and stable state. The pH of the aqueous solution was 5.9 to 7.7. The magnesium content is 11, 7 to 13, and 5% (in terms of hydrated salt).
[0021]
In the present invention, as a method for obtaining an amorphous magnesium citrate hydrate, the above-mentioned transparent solution of the aqueous suspension (2) was used, and concentrated at a temperature of 60 ° C. or lower under reduced pressure. When the solution (hereinafter referred to as “suspension aqueous solution 3”) has reached a sufficiently concentrated state, it has been found that the solution is spread on a thin plate and dried and solidified again at 60 ° C. or less under reduced pressure.
[0022]
When the clear solution of the aqueous suspension (3) is heated and stirred for a long time, crystals of magnesium citrate hydrate precipitate. To prevent this, the temperature of the solution is set to 60 ° C. or lower, preferably 55 ° C. or lower. There is no mechanical agitation to facilitate the formation of crystals. In order to concentrate in this state, the pressure is -0.0055 MPa or less. Preferably it is -0.0053 MPa or less.
[0023]
As the concentration progresses, the solution becomes viscous. This liquid is spread on a thin plate and dried by heating under reduced pressure. The reduced pressure may be the same as that for the concentration of the aqueous suspension (3), but the heating temperature needs to be lower than the decomposition temperature, and therefore may be 80 ° C. It is preferably 70 ° C. or lower, more preferably 60 ° C. or lower. The dried product obtained here is dissolved in water five times.
[0024]
【Example】
Next, the magnesium citrate hydrate and the method for producing the same of the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
[0025]
Embodiment 1 FIG.
280 g of citric acid monohydrate was dissolved in 1,200 ml of ion-exchange purified water and kept at 10 to 15 ° C. At this time, the pH of the citric acid aqueous solution was 1.5. While stirring this aqueous citric acid solution, 117 g of magnesium hydroxide was reacted and gradually added while confirming that it was dissolved.
Meanwhile, the temperature of the reaction solution was externally cooled and kept at 30 to 35 ° C. After completion of the addition of magnesium hydroxide, the reaction was completed and the stirring was continued until the reaction solution became transparent. After the completion of the reaction, the pH of the aqueous solution was 6.5.
[0026]
The obtained aqueous suspension solution (2) was spray-dried with a rotary disk type spray drier using hot air at an inlet temperature of 200 ° C and an outlet temperature of 50 to 70 ° C. The amount of the obtained white powder was 255 g.
[0027]
The Mg content of this white powder was 12.1%, the loss on drying at 180 ° C. for 2 hours was 23.5% by weight, and the pH of a 5% aqueous solution was 6.4. The loss on drying in a vacuum desiccator at room temperature was 5.2%. Powder from This _{is C 12 H 10 Mg 3 O 14} · 6H 2 O of salt hydrate. 25 g of this powder was dissolved in 100 g of water at 25 ° C.
[0028]
The infrared absorption spectrum of the obtained white powder was determined in a measurement mode (% T) by a potassium bromide tablet method using a Shimadzu Fourier transform infrared spectrophotometer FTIR-8200D manufactured by Shimadzu Corporation. The result is shown in FIG.
The X-ray analysis spectrum of the obtained crystal was measured under the following conditions. The result is shown in FIG.
・ Model: RINT1400 manufactured by Rigaku Denki Co., Ltd.
・ Target: Copper (monochromator)
・ Voltage and current: 30KV, 90mA
・ Scanning speed: 4.000 / min
[0029]
The magnesium citrate powder obtained in Example 1 is stable in a powder state. 25 g was dissolved at 25 ° C. in 100 ml of water. The solution was allowed to stand at 22 to 25 ° C., but no change was observed for 10 days.
[0030]
Embodiment 2. FIG.
Embodiment 1 FIG. The aqueous suspension (2) prepared in the same manner as in (1) was concentrated under reduced pressure to obtain an aqueous suspension (3). The concentration temperature was 60 ° C. or less. As the concentration progressed, the viscosity increased. No stirring was performed. When the charged amount (1,600 g) became 1/4 (400 g), the mixture was discharged into two 30 cm × 20 cm enamel-lined containers and flattened. This was dried at 60-70 ° C under reduced pressure. The obtained dried product was 310 g.
[0031]
The dried product was pulverized to have a Mg content of 11.3% and a loss on drying at 180 ° C. for 2 hours of 26.2% by weight. The pH of a 5% aqueous solution was 6.2. The loss on drying in a vacuum desiccator was 10.4%. Powder from This _{is C 12 H 10 Mg 3 O 14} · 4.5H 2 O of salt hydrate. Further, 25 g of this powder was dissolved in 100 g of water at 25 ° C.
[0032]
This dried product was used as a powder. The infrared absorption spectrum and the X-ray analysis spectrum were measured according to the above. The results are shown in FIGS.
[0033]
The magnesium citrate powder obtained in Example 2 is stable in a powder state. 25 g was dissolved at 25 ° C. in 100 ml of water. The solution was allowed to stand at 22 to 25 ° C., but no change was observed for 10 days.
[0034]
【The invention's effect】
As described in detail above, magnesium citrate exists in various crystal forms having various hydrates, but the one that is well soluble in water has been an anhydride and this compound is an amorphous substance.
On the other hand, in the present invention, an amorphous powder can be obtained by drying and solidifying the reaction solution of metallic magnesium or a magnesium salt with citric acid in a short time by spray drying or reduced pressure drying at a low temperature. Was. This powder contains 1 to 9 moles of water per mole of magnesium citrate. These powders are stable, and 20 to 30 g are dissolved in 100 ml of water at 25 ° C., and the solution is stable at room temperature. Since the magnesium citrate of the present invention is readily soluble in water, it is useful as a powder for pharmaceutical raw materials, industrial chemical raw materials, formulation of magnesium fortifiers and the like, for example, powders, tablets and capsules. .
[0035]
ADVANTAGE OF THE INVENTION According to this invention, it is a method which can produce magnesium citrate with high solubility which could not be achieved in a good yield and simply by powdering at a low temperature in a short time.
[Brief description of the drawings]
FIG. 1 is an infrared absorption spectrum of the powder obtained in Example 1.
FIG. 2 is an X-ray analysis diagram of the powder obtained in Example 1.
FIG. 3 is an infrared absorption spectrum of the powder obtained in Example 2.
FIG. 4 is an X-ray analysis diagram of the powder obtained in Example 2.

Claims (3)

It is obtained by spray-drying a solution obtained by adding magnesium carbonate or magnesium hydroxide to an aqueous solution of citric acid and reacting the solution with C ₁₂ H ₁₀ Mg ₃ O ₁₄ .xH ₂ O (x: an integer of 1 to 9). Magnesium citrate hydrate dissolved in water five times as represented. It is obtained by spray-drying a solution obtained by adding magnesium carbonate or magnesium hydroxide to an aqueous solution of citric acid and reacting the solution with C ₁₂ H ₁₀ Mg ₃ O ₁₄ .xH ₂ O (x: an integer of 1 to 9). A method for producing a magnesium citrate hydrate dissolved in water five times as represented. A solution obtained by adding magnesium carbonate or magnesium hydroxide to an aqueous solution of citric acid and reacting the mixture is dried at 60 ° C. or lower under reduced pressure, and obtained by C ₁₂ H ₁₀ Mg ₃ O ₁₄ xH ₂ O (x: 1 to 9). The method for producing a magnesium citrate hydrate dissolved in water five times as represented by the following formula:

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