JPH10120408A - New production of scaly calcium hydrogen phosphate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain scaly calcium hydrogen phosphate large in an oil-absorbing capacity and in a specific surface area by hydrothermally treating calcium hydrogen phosphate dihydrate in the presence of a specific polybasic organic acid. SOLUTION: This method for producing scaly calcium hydrogen phosphate comprises dispersing calcium hydrogen phosphate dihydrate in water, adding a polybasic organic acid having a coordination ability in an aqueous medium in an amount of 0.5-10mol.% to the obtained slurry, hydrothermally treating the mixture at a temperature of >=60 deg.C for several ten min to several hr, and subsequently drying the treated product at 50-300 deg.C. The produced scaly calcium hydrogen phosphate of the formula: CaHPO4 .m H2 O [0<=(m)<=0.5] has a specific surface area of 20-60m<2> /g, a static bulk density of >=5ml/g, an oil-absorbing capacity of >=1.5liter/g, a primary particle diameter of 0.1-5μm measured with an electron microscope and an average coagulated secondary particle diameter of 2-10μm.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing flaky calcium hydrogen phosphate used for pharmaceuticals, cosmetics, foods and the like. More specifically, it has good binding properties,
The present invention relates to a simple and economical new method for producing flaky calcium hydrogen phosphate having characteristics that can be easily used as an excipient in pharmaceuticals, cosmetics, foods, and the like.

[0002] Calcium hydrogen phosphate is a calcium component,
It is used in pharmaceuticals, foods, and the like as a source of reinforcing phosphoric acid components or as an anti-caking agent. This calcium hydrogen phosphate has no hygroscopicity, is inactive, has no reactivity with the drug, and does not color the dosage form.
Attempts have been made to use it as an excipient for cosmetics, foods and the like. However, calcium hydrogen phosphate was actually in the form of plate-like crystal particles having a size of 10 μm or more, and was inadequately used as an excipient because of poor binding properties. In order to avoid this drawback, pulverize and atomize,
Moldability was imparted by adding a binder such as sodium polyacrylate.

The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that the crystal particles are small, the bulk specific volume, the surface area and the oil absorption are all large, and the scale has ideal physical properties as an excipient. Calcium hydrogen phosphate and a method for producing the same have been developed and disclosed (JP-A-7-1180).
No. 05). However, the conventional production method described above involves reacting phosphoric acid and an alkaline calcium compound or an alkali metal phosphate and a calcium compound in an aqueous medium in the presence of a polyvalent organic acid having a coordinating ability to form a columnar phosphorus compound. This was a method of producing calcium hydrogen oxyhydrate, and then subjecting the columnar material to a hydrothermal treatment at 60 ° C. or higher to produce flaky calcium hydrogen phosphate. That is, the above-mentioned production method is a production method in which scaly calcium hydrogen phosphate is produced via columnar calcium hydrogen phosphate, and is a complicated method in terms of operation. Therefore, development of a more simple and economical method for producing flaky calcium hydrogen phosphate has been desired.

[0004]

DISCLOSURE OF THE INVENTION The present invention relates to a simple and easy-to-use scaly calcium hydrogen phosphate having the property of having good binding properties and being easily used as an excipient in pharmaceuticals, cosmetics or foods. Another object of the present invention is to provide an economical new manufacturing method.

[0005]

Means for Solving the Problems The present inventors prepared calcium hydrogen phosphate dihydrate (or dihydrate) in an aqueous medium in the presence of a polyvalent organic acid capable of coordination at a temperature of 60 ° C. or higher. , Preferably 60 to 100 ° C, particularly preferably about 90 to 10 ° C.
A novel method for producing flaky calcium hydrogen phosphate characterized by hydrothermal treatment at 0 ° C. has been found, and the present invention has been completed. The present invention can be easily and economically suitably used as an excipient or the like by hydrothermally treating a columnar calcium hydrogen phosphate or a flake-like calcium hydrogen phosphate which is unsuitable as an excipient. It is a method of converting into the flaky calcium hydrogen phosphate to be obtained, and by this manufacturing method, the crystal particles are small, the bulk specific volume, the surface area, and the oil absorption are all large. It can be manufactured simply and economically.

[0006] The calcium hydrogen phosphate dihydrate used in the present invention may be a commercially available product or a product obtained by a known method in the literature. For example, alkaline calcium such as calcium carbonate or calcium hydroxide and phosphoric acid may be used. And a stoichiometric amount of a neutralization reaction product of an alkaline metal phosphate such as sodium phosphate and a water-soluble calcium compound such as calcium chloride. These neutralized reaction products can be used either as dried or undried products. Examples of commercially available products include those having a plate-like or columnar crystal structure, such as hydrogen phosphate dihydrate, and calcium hydrogen phosphate having a monoclinic crystal structure. Particularly preferred in the practice of the production method of the present invention is a case where the calcium hydrogen phosphate is a calcium hydrogen phosphate having a monoclinic crystal structure.

A polyvalent organic acid acts as a crystallization agent in the reaction with calcium hydrogen phosphate dihydrate. By the reaction in the presence of the organic acid, the existing calcium hydrogen phosphate is converted into flaky calcium phosphate and precipitated as crystals. As the polyvalent organic acid, a polyvalent organic acid having a coordinating ability is preferable. For example, citric acid, tartaric acid, ethylenediaminetetraacetic acid (EDTA), malic acid,
One or more selected from the group consisting of succinic acid can be selected. The amount of these organic acids used is determined in consideration of the size of the crystal grains to be generated. Preferably, the amount of the polyvalent organic acid having coordination ability is 0.5 to 10 m
This is a method for producing flaky calcium hydrogen phosphate, which is ol%. If the amount used is less than 0.5 mol%, the effect as a crystallization agent cannot be exerted, and large calcium hydrogen phosphate is generated. If it exceeds 10 mol%, an excessive amount is produced without affecting the crystal size. This is because the amount is used.

[0008] The addition of the above organic acid to the calcium hydrogen phosphate dihydrate slurry can be appropriately performed during the hydrothermal treatment until the crystal water of calcium hydrogen phosphate starts to be desorbed.

The hydrothermal treatment temperature after dispersing calcium hydrogen phosphate dihydrate in water and adding a polyvalent organic acid to the slurry is 60 ° C. or higher, preferably 60 to 100 ° C., particularly preferably 90 to 100 ° C. ° C. The range of the hydrothermal treatment temperature is as follows: dehydration takes time at 60 to 90 ° C, and relatively quickly dehydrates at 90 ° C or higher.
What is necessary is just to set suitably according to manufacturing equipment.

The hydrothermal treatment time varies depending on the type and amount of the calcium hydrogen phosphate dihydrate and the polyvalent organic acid used, the amount used, the reaction time and the equipment conditions, but is not particularly limited, but is preferably several tens minutes to several minutes. Time.

The above slurry is heated with stirring and heated to a predetermined temperature range.
After maintaining this temperature for 0 minutes, the reaction may be terminated.

The reaction product can be obtained by filtering, washing with water and removing water according to a conventional method.

The target substance is obtained as white scale-like calcium hydrogen phosphate by drying in a conventional manner, for example, with a shelf dryer or the like. With respect to the water content of the flaky calcium hydrogen phosphate, it can be changed from a 0.5 hydrate to an anhydride depending on drying conditions.
By heating the mixture and drying, it can be easily made an anhydride.

According to the production method of the present invention, calcium hydrogen phosphate having the following physical properties can be obtained. That is, the specific surface area is 20 to 60 m ² / g, and the static bulk specific volume is 5
The following formula wherein the primary particles measured by an electron microscope is 0.1 to 5 μm and the average particle diameter of the aggregated secondary particles is 2 to 10 μm. _The scaly calcium hydrogen phosphate represented by ₄ · mH ₂ O (where m represents a number in the range of 0 ≦ m ≦ 0.5) can be simply and economically produced.

The above-mentioned calcium hydrogen phosphate has small crystal particles, large bulk specific volume, large surface area and large oil absorption.
It is a scaly calcium hydrogen phosphate having ideal physical properties as an excipient.

The calcium hydrogen phosphate obtained by the production method of the present invention is a flaky powder having a large specific surface area, a large bulk and a large oil absorption, and has good moldability.
Moreover, since the advantage of calcium hydrogen phosphate having no reactivity with the drug originally possessed is maintained, the dosage form is not colored.

This is because the conventional commercially available calcium hydrogen phosphate is plate-like, has a surface area of 1 m ² / g or less, a static bulk specific volume of about 2 ml / g, and an oil absorption of 0.5 ml / g.
Before and after, it is shown that the flaky calcium hydrogen phosphate of the present invention is extremely advantageous as compared with the case where the primary particles are 10 μm or more as observed by an electron microscope.

Since the flaky calcium hydrogen phosphate obtained by the production method of the present invention has completely different physical properties from conventional calcium hydrogen phosphate, it is suitable for use alone or in combination with other excipients. Can be used as an agent. or,
It has a large oil absorption and a large specific surface area, so it can be used as an anti-caking agent for powdered milk, salt, seasonings, etc. It can be suitably used for cosmetics and the like.
Furthermore, because of the various physical properties described above, it is soft and does not hurt the skin. Therefore, it can be used as a slimming inhibitor by blending in toiletries such as detergents and soaps. Further, when used for these applications, the pH is neutral, so that there is no problem even if it is blended in a dosage form containing an alkaline or acidic and unstable one.

A major feature of the scaly calcium hydrogen phosphate of the present invention is that it can be easily spray-dried and granulated into a spherical product. This feature is that the conventional scale-like calcium hydrogen phosphate or columnar calcium hydrogen phosphate is spray-dried, but only dried primary particles are generated. This is in contrast to what should not be done. In addition, it is possible to some extent to use a binder or the like to make a conventional product that has been pulverized and atomized into a spray-dried granulated product, but in such a case, an absolutely distorted spherical product is obtained.

In the present invention, the fact that a binder-free single product is used as a spherical product is because various properties which are advantageous as an excipient also act on a spray-dried product. In other words, in the fine particles, the specific surface area, the bulk specific volume, the physical properties that the oil absorption amount is large, respectively, acts when spray-dried and granulated, and gives the flaky calcium hydrogen phosphate powder stickiness and cohesiveness and a spherical substance. It is presumed that it will be. This spheroid has the advantage that its formability is not inferior to that of flaky calcium hydrogen phosphate, and also has the advantage of good fluidity, which is the characteristic of the spray-dried granulated product, and has good workability and is ideal. Excipient.

Further, the spherical product which is the spray-dried granulated product is made into a more functional spherical product by adding various chemicals, binders and the like to the suspension at the time of the spray-dried granulation. It is possible. For example, a drug which is relatively easily colored, such as vitamin C, is spray-dried together with flaky calcium hydrogen phosphate to form a spherical substance, whereby a more stable drug in the preparation can be obtained. In the case of a spherical substance containing a binder or the like, it can be made stronger. On the other hand, in the case of a spherical substance having a high water content, the spherical substance strength can be set according to various uses, such as a spherical substance having good disintegration properties. As the above drug, alkaline p
H-unstable acids such as ascorbic acid and aspirin, 4
Amides such as quaternary ammonium salts and nicotinamide which is unstable to acidic pH can be used.

Examples of the binder include cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose and hydroxyethylcellulose; alkali metal alginate such as carrageenan and sodium alginate; gums such as xanthan gum, tragacanth gum, karaya gum and gum arabic; polyvinyl alcohol; Synthetic binders such as sodium polyacrylate and carboxyvinyl polymer, or inorganic binders such as magnesium aluminate metasilicate and synthetic aluminum silicate can be used.

The spraying method at the time of drying may be a known method, and is not particularly limited. Therefore, the particle size may be appropriately set according to the application such as adopting a nozzle method, a centrifugal method, or a liquid nozzle method according to the size of the particle size, and the particle size can be freely set to about 10 to 500 μm. Inlet temperature in spray drying,
The temperature conditions such as the outlet temperature vary depending on the type and amount of the solvent used. For example, when the suspension of flaky calcium hydrogen phosphate, which is the simplest spray drying, is directly spray-dried, the inlet temperature is 200 to 400. ° C, outlet temperature 100-2
About 00 ° C. is preferable. In preparing the suspension,
In addition to water, a liquid obtained by suspending or dissolving the above-mentioned various drugs and binders, or an organic solvent such as methyl alcohol, ethyl alcohol, ethylene glycol, or a mixture thereof can be suitably used.

The following examples illustrate the invention in more detail.

[0025]

【Example】

Example 1 174 g of calcium hydrogen phosphate dihydrate was dispersed in water to prepare a total amount of 1.4 L (hereinafter, slurry A).
). To this slurry A, citric acid monohydrate 2.7 was added.
2 g was added, and the mixture was heated with stirring, heated to 95 ° C., and maintained at this temperature for 30 minutes to terminate the reaction. The reaction product was filtered, washed with water, and dried to remove water, and then dried at 110 ° C. for 15 hours using a shelf dryer to obtain 128.7 g (94.6 g) of white flaky calcium hydrogen phosphate.
%).

Example 2 To the slurry A was added 6.8 g of citric acid monohydrate.
The mixture was heated with stirring, heated to 95 ° C., and maintained at this temperature for 30 minutes to terminate the reaction. Example 1 below
130.4 g (95.8%) of white scale-like calcium hydrogen phosphate was obtained by the same treatment as described above.

Example 3 13.6 g of citric acid monohydrate was added to the slurry A, and the mixture was heated to 95 ° C. while stirring and maintained at this temperature for 30 minutes to terminate the reaction. . Thereafter, the same treatment as in Example 1 was performed to obtain 130.4 g of white scale-like calcium hydrogen phosphate.

Example 4 6.8 g of DL-malic acid was added to the slurry A, and the mixture was heated to 95 ° C. while stirring and maintained at this temperature for 30 minutes to complete the reaction. Thereafter, the same treatment as in Example 1 was performed to obtain 130.2 g of white scale-like calcium hydrogen phosphate.

Example 5 1.0 mol of calcium chloride and 1.0 mol of phosphoric acid were dissolved in water to prepare 680 mL to prepare a calcium / phosphoric acid solution, and 2.0 mol of sodium hydroxide was dissolved in water. The solution was adjusted to 680 mL to prepare an alkaline solution. While stirring this calcium / phosphoric acid solution, an alkali solution was added for 20 minutes to obtain a white slurry (hereinafter referred to as slurry B). To this slurry B, 6.8 g of citric acid monohydrate was added, and the mixture was heated with stirring to increase the temperature to 95 ° C., and after maintaining this temperature for 30 minutes, the reaction was terminated. Thereafter, the same treatment as in Example 1 was performed to obtain 131.3 g of white scale-like calcium hydrogen phosphate.

Example 6 6.8 g of DL-malic acid was added to the slurry B, and the mixture was heated with stirring and heated to 95 ° C., and after maintaining this temperature for 30 minutes, the reaction was terminated. Thereafter, the same treatment as in Example 1 was performed to obtain 130.5 g of white scale-like calcium hydrogen phosphate.

REFERENCE EXAMPLE 1 Scaly calcium hydrogen phosphate was prepared according to the production method described in JP-A-7-118005, and Example 1 of the present invention was prepared.
Physical properties with the scaly calcium hydrogen phosphate obtained in Nos. 6 to 6 were compared. (Preparation method) Quick lime (CaO purity 96) while stirring 2 L of water
%) And stirred for 30 minutes to obtain lime milk, and the lime milk was sieved with 100 mesh to remove coarse particles. The concentration of this lime milk was 100 g / L in terms of CaO.
Next, 5 mol% of the yield of the generated calcium hydrogen phosphate
Is dissolved in 2 L of water, and while stirring at room temperature to 40 ° C., 294 g of a 50% strength phosphoric acid aqueous solution and 1.1 L of lime milk prepared by the above procedure are added to this solution.
And were added simultaneously for 30 minutes. Then, stirring was continued for 30 minutes to complete the reaction. Next, this reaction solution was heated to 95 ° C., stirred for 30 minutes, filtered, washed, and dried to obtain scaly calcium hydrogen phosphate. This was designated as Reference Example 1.

Comparative Example 1 A slurry (slurry A) prepared by dispersing 174 g of calcium hydrogen phosphate dihydrate in water to a total volume of 1.4 L (slurry A) was heated with stirring and heated to 95 ° C. After warming and maintaining this temperature for 30 minutes, the reaction was terminated. The reaction product was filtered, washed with water to remove water, and dried at 110 ° C. for 15 hours in a tray dryer to obtain 128.7 g of white calcium hydrogen phosphate.

Physicochemical properties Scale-like calcium hydrogen phosphate obtained in Examples 1 to 6 of the present invention, scale-like calcium hydrogen phosphate obtained in Reference Example 1, and calcium hydrogen phosphate obtained in Comparative Example 1 The physicochemical properties of were as shown in Table 1. The specific surface area is BE
According to the T method, a glass tube was inserted into a measuring cylinder with a bulk specific volume of 90 to 100 ml, and the sample was put into the glass tube with a funnel so as to have a volume of 90 to 100 ml, and the glass tube was gently pulled out to flatten the surface of the sample. This is a value obtained by determining the volume (VmL) and the weight (W) of the sample by V / W. Primary particle diameter, average secondary particle diameter Measured with a laser particle size distribution analyzer. The tablet tensile strength was determined by using a tableting tester (manufactured by Sankyo Piotech) with 600 mg of each test sample having a diameter of 11.
The tablets were placed in a 5 mm die and subjected to a molded tablet hardness test at a molding pressure of 1 t. The tablet pressure was measured, and the tablet tensile strength was calculated by the following equation. Tablet tensile strength (kg / cm ² ) T = 2F / πDL where F is tablet strength (kg), D is tablet diameter (cm), L
Indicates the tablet thickness (cm).

[0034]

[Table 1]

The oil absorption was measured in accordance with JIS K5101, and the oil absorption of each sample of Examples 6 to 6 was 1.5 mL / g or more when measured using boiled linseed oil as the oil agent. In contrast, the oil absorption of the sample of Reference Example 1 was 1.5 mL.
/ G or more, and the oil absorption of the sample of Comparative Example 1 is 0.62 m
L / g.

Examples 1 to 6 obtained by the production method of the present invention
That the calcium hydrogen phosphate is scaly can be shown by electron micrographs of these samples described later.

[0037]

According to the present invention, a novel method for producing calcium hydrogen phosphate dihydrate into scaly calcium hydrogen phosphate can be provided. According to the production method of the present invention,
It has good binding properties, can be suitably used as an excipient for pharmaceuticals, etc., and has a large oil absorption and a large specific surface area.
Scale-like calcium hydrogen phosphate that can be used for food, cosmetics, etc. can be produced easily and economically with good yield,
Very useful in industry.

[Brief description of the drawings]

FIG. 1 is an electron micrograph of the flaky calcium hydrogen phosphate obtained in Example 1. The underline in this photo is 1 μm
Is shown.

FIG. 2 is an electron micrograph of the flaky calcium hydrogen phosphate obtained in Reference Example 1. The underline in this photo is 1 μm
Is shown.

Claims (5)

[Claims] 1. A process for producing scaly calcium hydrogen phosphate comprising subjecting calcium hydrogen phosphate dihydrate to a hydrothermal treatment at 60 ° C. or higher in an aqueous medium in the presence of a polyvalent organic acid having a coordinating ability. Method. 2. A specific surface area of 20 to 60 m ² / g, a static bulk specific volume of 5 ml / g or more, an oil absorption of 1.5 l / g or more, and a primary particle measured by an electron microscope of 0.1 to 0.1 / g. 5μ
m, the average particle diameter of the aggregated secondary particles is 2 to 10 μm
The method for producing flaky calcium hydrogen phosphate according to claim 1, wherein the formula is represented by the following formula: CaHPO ₄ · mH ₂ O (where m represents a number in the range of 0 ≦ m ≦ 0.5). 3. The process for producing scaly calcium hydrogen phosphate according to claim 1, wherein the calcium hydrogen phosphate is a calcium hydrogen phosphate having a monoclinic crystal structure. 4. The method according to claim 1, wherein the polyvalent organic acid is one or more selected from the group consisting of citric acid, tartaric acid, ethylenediaminetetraacetic acid (EDTA), malic acid and succinic acid. For producing flaky calcium hydrogen phosphate. 5. The process for producing scaly calcium hydrogen phosphate according to claim 1, wherein the amount of the polyvalent organic acid used is 0.5 to 10 mol% based on the generated calcium hydrogen phosphate.