TWI598297B - Method for producing stabilized amorphous calcium carbonate - Google Patents

Description

Method for producing stabilized amorphous calcium carbonate

The present invention relates to a novel process for the preparation of amorphous calcium carbonate (ACC) based on the stepwise addition of a stabilizing solution and an organic solvent. The ACC produced by the method of the present invention is characterized in that the stability of the solution/suspension and the dry powder is improved, and it can be used for, for example, paper, dyes, plastics, inks, adhesives, marble repair, medical devices, and the pharmaceutical industry. in.

Calcium carbonate (CaCO ₃ ) is a calcium carbonate carbonate which is widely used in many industries today. The best known calcium supplement to take daily calcium intake. Calcium carbonate has six known polymorphs, three of which are anhydrous crystals, that is, calcite, vermiculite and vaterite; two are crystalline hydrates, that is, monohydrate calcite and hexahydrate; and one is hydrated non-hydrated Crystal form, that is, amorphous calcium carbonate (ACC). ACC is a transitional polymorph that precipitates from a supersaturated solution following the Ostwald's step rule. Without being stabilized in any way, ACC will rapidly and completely crystallize into one of five more stable polymorphs in a matter of seconds. The amorphous polymorph is characterized by a unique 40-120 nm small sphere, does not have a main peak of XRD, and has a broad low-intensity peak between 20-30 2θ, and is broad in the vicinity of 1082 cm ^-1 in Raman spectroscopy. Low-intensity peaks, compared to other polymorphs, are typically 1-10 μm crystals, and also have unique XRD main peaks and clearly distinguishable Raman peaks.

Synthetic ACC has been in existence for more than 100 years, and there are many methods for synthesizing ACC using various molecules to stabilize the transitional unstable amorphous phase. Three widely used methods all use supersaturated calcium ion solutions from soluble sources such as calcium chloride or from the insoluble calcium salts (such as calcium hydroxide) using hydrogen binding molecules (sucrose). The supersaturated calcium ion solution is then reacted with a carbonate source derived from carbon dioxide gas, an alkali metal carbonate such as sodium carbonate, an organic carbonate, ammonium carbonate or a dialkyl carbonate having a hydroxide ion. Hydrolysis reaction (such as dimethyl carbonate) (see, for example, US 4,237,147).

Commercial production systems are impractical because the ACC is stable for less than two minutes in aqueous solution. Large-scale production involving the separation of hundreds or even thousands of liters in less than two minutes and separation using liquid-solid phase separation techniques such as filtration or centrifugation is not feasible today. Commercial production can be a reality if the stabilization time in solution can be extended to hours, allowing the use of standard liquid-solid phase separation techniques such as filtration or centrifugation.

Except for Hyun et al. [ Materials Chemistry and Physics , 93 (2005) 376-382] which describes the stabilization of ACC in an ethanol medium for more than 24 hours, none of the previous reports mentioned the time when ACC remains stable in solution. segment. However, Hyun et al. can only produce stable ACC in the presence of toxic ammonia (as described by Hyun, which is critical for stability). In addition, the calcium carbonate used in this publication has a relatively low concentration, which makes its industrial use impractical.

When attempting to reproduce other disclosed steps, the ACC made by the applicant of the present invention is only stable in solution for several minutes and crystallizes thereafter. In some cases, although ACC was produced, it could not be separated from the solution. For example, the manufacture of ACC using the procedure described in Example 2 of US 4,237,147 yielded only a slurry that could not be filtered and could not separate the ACC. Further, as proposed in the patent, even if a powder is obtained from the slurry by spray drying, it will contain only ~2/15 of ACC, and the remaining 13/15 parts are sucrose.

In general, any use of calcium chloride or some other soluble calcium salt to replicate US Attempts at the steps described in 4,237,147 failed to obtain ACC or any form of precipitated calcium carbonate.

It is well known that ACC will crystallize in the presence of water, however, to the best of the applicant's knowledge, it has not previously been disclosed that only up to 10% by weight of stabilizer can be used to produce a long-term stable ACC in an aqueous solution or suspension. Additionally, in all of these methods, the carbonation step is the final synthesis step followed by a liquid solids separation step.

There is still a need in the art for a novel process for the manufacture of ACC with high stability (either as a suspension in the aqueous phase or as a dry powder) which is suitable for the manufacture of ACC on a commercial scale.

The present invention relates to a method of producing amorphous calcium carbonate (ACC) which produces a special XRD spectrum and a Raman spectrum which are usually present in an amorphous form. The novel method of the present invention uses a hydrogen bonding molecule as a stabilizer and an organic solvent, and obtains an ACC having improved stability when suspended in an aqueous phase or in a solid state of a dry powder. The method of the present invention generally comprises combining a solution comprising a soluble calcium salt and a first stabilizer with a solution comprising a soluble carbonate (e.g., a soluble alkali metal carbonate) to form an ACC suspension, and adding a water miscible organic The solvent and the second stabilizer form a stable ACC suspension from which a stable ACC can be separated. In some embodiments, the first and second stabilizers may be the same or different.

Accordingly, in one embodiment, the present invention provides a method of making amorphous calcium carbonate (ACC) comprising the steps of combining a solution comprising a soluble calcium salt and a first stabilizer with a solution comprising a soluble carbonate To form an ACC suspension; and simultaneously or in any order sequentially add a water-miscible organic solvent and a solution comprising the second stabilizer, as long as the second stabilizer and the organic solvent are within about 2 minutes of forming the ACC suspension Contacting, thereby obtaining a stable ACC suspension, wherein the total amount of the stabilizer is up to about 12% by weight of the stable ACC suspension, and the water-miscible organic solvent accounts for the stable ACC. At least about 5% by weight of the suspension. The first stabilizer and the second stabilizer may be the same or different, with each possibility representing a different embodiment of the invention.

In another embodiment, the invention provides a method of making an ACC comprising the steps of: i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizer; ii) preparing an aqueous solution comprising a soluble carbonate; iii) preparing comprising An aqueous solution of the second stabilizer; iv) preparing a solution comprising a water-miscible organic solvent; and v) combining the solution prepared in the step ii) with the solution prepared in the step i) to form an ACC suspension And then sequentially or in any order, sequentially adding the solutions prepared in the steps iii) and iv) as long as the solutions are in contact with the ACC suspension within about 2 minutes of forming the ACC suspension, thereby obtaining a stable ACC suspension. The liquid, wherein the total amount of stabilizer is at most about 12% by weight of the stabilized ACC suspension, and the water-miscible organic solvent is at least about 5% by weight of the stabilized ACC suspension. The first stabilizer and the second stabilizer are the same or different, wherein each possibility represents a different embodiment of the invention.

In another embodiment, the invention provides a method of making an ACC comprising the steps of: i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizer; ii) preparing an aqueous solution comprising a soluble carbonate; a solution of a second stabilizer in a water-miscible organic solvent; and iv) combining the solutions prepared in steps i) and ii) to obtain an ACC suspension, followed by formation of an ACC suspension for about 2 minutes. The solution prepared in step iii) is added to the ACC suspension to form a stable ACC suspension, wherein the total amount of stabilizer is up to about 12% by weight of the stable ACC suspension, the water-miscible organic The solvent is at least about 5% by weight of the stabilized ACC suspension. The first stabilizer and the second stabilizer are the same or different, wherein each possibility represents a different embodiment of the invention.

In a presently preferred embodiment, the present invention provides a method of making a stable ACC comprising the steps of: i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizer; ii) preparing an aqueous solution comprising a soluble carbonate, and Combining it with the calcium salt of step i), thereby obtaining an ACC suspension; iii) preparing an aqueous solution of the second stabilizer, thereby obtaining Stabilizing the solution; iv) combining the stabilizing solution with the ACC suspension; and v) adding a water miscible organic solvent, wherein the stabilizing solution and the organic solvent are added to the ACC suspension within about 2 minutes of forming ACC suspension to form a stable ACC suspension wherein the total amount of stabilizer is up to about 12% by weight of the stabilized ACC suspension, the water-miscible organic solvent comprising at least about 5 weight of the stabilized ACC suspension %. The first stabilizer and the second stabilizer are the same or different, wherein each possibility represents a different embodiment of the invention.

In some embodiments, the method of the invention may additionally comprise the step of separating the ACC from the stabilized ACC suspension. The method may additionally comprise the step of drying the separated ACC, thereby obtaining a stable ACC powder. The separation may comprise filtration or centrifugation, and the drying step may comprise vacuum heating or freeze drying, wherein each possibility represents a different embodiment of the invention. Accordingly, in some embodiments, the method of the present invention provides a stabilized ACC powder comprising less than about 15% by weight, preferably less than 8% (eg, between about 1 and about 7% by weight) water, and usually calcium The system is between about 30 and about 33% by weight. Each possibility represents a different embodiment of the invention.

It should be understood that for the above embodiments, the terms "first stabilizer" and "second stabilizer" each comprise a single stabilizing compound or a combination of more than one stabilizing compound. Thus, in some embodiments, the aqueous calcium solution may comprise a stabilizing compound or a combination of two or more stabilizing compounds (collectively referred to as "first stabilizers"). In other embodiments, the solution comprising the second stabilizer may comprise a stabilizing compound or a combination of two or more stabilizing compounds (collectively referred to as "second stabilizers"). Regardless of the amount of stabilizer used, the total amount of stabilizer is up to about 12% by weight of the stable ACC suspension. In a presently preferred embodiment, the calcium salt is calcium chloride or calcium nitrate. In other preferred embodiments, the soluble carbonate is an alkali metal carbonate (e.g., lithium carbonate, sodium carbonate or potassium carbonate) or ammonium carbonate. Each possibility represents a different embodiment of the invention. In some embodiments, the calcium salt and the carbonate are present in a molar ratio of from about 0.5 to about 2.0.

In another embodiment, the water-miscible organic solvent is preferably selected from the group consisting of lower alcohols and ketones (eg, methanol, ethanol, propanol, isopropanol, acetone, diethyl ketone, and cyclohexanone). One currently preferred water miscible organic solvent is ethanol. Each possibility represents a different embodiment of the invention.

In another embodiment, the soluble calcium salt solution comprises from about 4 mM to about 2 M soluble calcium salt, and the carbonate solution comprises from about 4 mM to about 2 M carbonate. Each possibility represents a different embodiment of the invention.

The first and second stabilizers used in the method of the invention may be the same or different. In some embodiments, the first and second stabilizers are each independently selected from the group consisting of organic acids, phosphorylated organic acids, phosphates of hydroxycarboxylic acids, sulfates of hydroxycarboxylic acids, phosphorylation An amino acid and a derivative thereof, an amino acid sulfate, and a hydroxyl group-containing organic compound in combination with a base such as an alkali metal hydroxide. The hydroxyl group-containing compound in combination with the hydroxide preferably further has other functional groups (e.g., a carboxyl group, etc.), but the hydroxyl group is not esterified. The organic acids may include, for example, ascorbic acid or acetic acid, and preferably, etc., include carboxylic acids having at least two carboxyl groups and having a molecular weight of not more than 250 g/mol, such as citric acid, tartaric acid, malic acid, and the like. Such esters can include, for example, phosphoenolpyruvate. In another embodiment, the phosphate or sulfate of the hydroxycarboxylic acid comprises an amino acid, examples of which include phosphonamic acid, threonine phosphate, sulfosilicic acid, and sulfosylurea. In another embodiment, the stabilizing molecule is a phosphate derivative of an amino acid, such as creatine phosphate. The hydroxyl-containing compounds combined with the hydroxides may include, for example, monosaccharides, disaccharides, trisaccharides, oligosaccharides and polysaccharides such as sucrose or other polyols such as glycerol. The hydroxyl-containing compounds may additionally include a hydroxy acid (such as citric acid, tartaric acid, malic acid, etc.) or a hydroxyl-containing amino acid (such as a serine or threonine). Each possibility represents a different embodiment of the invention.

In some embodiments, at least one of the first and second stabilizers is a polyol in combination with an alkali metal hydroxide, or the stabilizer is a phosphorylated amino acid, wherein the polyol or phosphorylated amine The total amount of base acid in the stabilized ACC suspension is from about 1 to about 1000 mM, For example, from about 10 to about 100 mM. These polyols preferably include sugars. In a preferred embodiment, the stabilizer is a phosphorylated amino acid wherein the total concentration in the stabilized ACC suspension is from about 2 to about 200 mM, such as from up to about 20 mM. In another preferred embodiment, the stabilizer is a dicarboxylic acid or a tricarboxylic acid (e.g., citric acid) wherein the total concentration in the stabilized ACC suspension is from about 2 to about 200 mM, for example, up to about 20 mM. Start. In another preferred embodiment, the stabilizer is a combination of a non-phosphorylated hydroxyl-containing amino acid (eg, serine or threonine) and an alkali metal hydroxide, wherein the amino acid is in a stable ACC suspension. The total concentration in the system is from about 2 to about 200 mM, such as from up to about 20 mM, and the total concentration of the hydroxide in the stabilized ACC suspension is between about 1 mM and about 2000 mM, such as about 0.1 M. In another preferred embodiment, the stabilizer is a polyol in combination with an alkali metal hydroxide, wherein the total concentration of the polyol in the stabilized ACC suspension is from about 10 to about 1000 mM, such as up to about 100 mM, and The total concentration of the hydroxide in the stabilized ACC suspension is between about 1 mM and about 2000 mM, such as about 0.1 M. Each possibility represents a different embodiment of the invention.

In one embodiment of the invention, the first and second stabilizers are different stabilizers. However, in a preferred embodiment of the present invention, the first stabilizer and the second stabilizer are the same, and the stabilizer is used in an amount of from about 1:1 to about 10:1 (the first stabilizer pair) The second stabilizer) preferably has a ratio of the first stabilizer to the second stabilizer of about 1:2. Each possibility represents a different embodiment of the invention.

Preferably, the step of combining the ACC suspension with the second stabilizer solution and the organic solvent is between about -10 ° C and about 60 ° C, preferably between about -3 ° C and ambient temperature (room temperature). More preferably, and more preferably between about 0 ° C and about 15 ° C. Each possibility represents a different embodiment of the invention.

In a presently preferred embodiment, the present invention provides a method of preparing amorphous calcium carbonate (ACC) comprising the steps of: i) preparing calcium chloride at a concentration of up to about 1 M and having a content of between about 1 and 150 mmol ( For example between about 4 and about 80 mmol) / 1 mole of calcium chloride An aqueous solution of a stabilizer; ii) preparing an aqueous solution of sodium carbonate having the same molar concentration as the calcium chloride in step i), and combining it with the calcium salt solution of step i), thereby obtaining an ACC suspension; Iii) preparing a stable solution comprising about 350 g of ethanol per 1 mol of calcium chloride in step i) and a stabilizer which is the same as the stabilizer in step i) but doubled in content; and iv) the stabilizing solution and the calcium carbonate The suspensions are combined to provide a stable ACC suspension. In one embodiment, the stabilizer in steps i) and iii) is phosphoric acid, in an amount of from about 3 to about 9 mmol per 1 molar calcium and from about 8 to 16 mmol per 1 molar calcium, for example about 6 mmol and about 12 mmol/1 molar calcium, or about 4 mmol and about 8 mmol/1 molar calcium. In some embodiments, the method additionally comprises the step of filtering the stabilized ACC suspension and optionally vacuum drying at a temperature between 40 ° C and about 50 ° C. In another embodiment, the stabilizer is sucrose and sodium hydroxide, and in step i), the amount is about 20-100 mmol sucrose and about 50-200 mmol NaOH / 1 mol calcium, for example about 25-70 mmol sucrose and about 100 mmol NaOH, such as about 25 mmol sucrose and about 100 mmol NaOH / 1 molar calcium, and in step iii), about 40-200 mmol sucrose and about 100-400 mmol NaOH / 1 molar calcium, for example about 50-200 mmol sucrose. About 200 mmol NaOH, such as about 140 mmol sucrose with about 200 mmol NaOH / 1 molar calcium. In some embodiments, the method additionally includes the steps of centrifuging and freeze drying the precipitate. Each possibility represents a different embodiment of the invention.

In a presently preferred embodiment, the process of the invention comprises combining calcium chloride, an alkali metal carbonate, a phosphorylated organic acid and an alcohol in an aqueous mixture, thereby providing a content comprising between about 2.5 and 5% by weight. Between ACC, between about 0.001 and about 0.3% by weight (eg, between about 0.05 and about 0.2% by weight) of phosphorylated organic acid and between about 8 and about 32% by weight (eg, A stabilized ACC suspension of between about 10 and about 15% by weight ethanol.

Another preferred method according to the present invention comprises combining calcium chloride, an alkali metal carbonate, a saccharide, and sodium hydroxide and an alcohol in an aqueous mixture, thereby obtaining a composition comprising between about 2.5 and about 5% by weight. ACC between, between about 1 and about 4% by weight of sugar, about 0.5 A weight percent hydroxide and a stabilized ACC suspension of between about 10 and about 15 weight percent ethanol.

Another preferred method according to the present invention comprises combining calcium chloride, an alkali metal carbonate, a dicarboxylic acid, a tricarboxylic acid (e.g., citric acid), and an alcohol in an aqueous mixture, thereby obtaining inclusions in between A stabilized ACC suspension of between 2.5 and about 5% by weight of ACC, between about 0.001 and about 0.2% by weight of dicarboxylic or tricarboxylic acid, and between about 8 and about 32% by weight of ethanol. Another preferred method according to the present invention comprises combining calcium chloride, an alkali metal carbonate, a dicarboxylic acid or a tricarboxylic acid, a phosphorylated organic acid and an alcohol in an aqueous mixture, thereby obtaining an inclusion of about 2.5. And between about 5% by weight of ACC, between about 0.001 and about 0.2% by weight of dicarboxylic or tricarboxylic acid and phosphoric acid organic acid, and between about 8 and about 32% by weight of ethanol Stabilize the ACC suspension.

Another preferred method according to the present invention comprises combining calcium chloride, an alkali metal carbonate, a non-phosphorylated hydroxyl-containing amino acid (for example, serine), and sodium hydroxide and an alcohol in an aqueous mixture. This results in an ACC between about 2.5 and about 5% by weight, between about 1 and about 4% by weight of the non-phosphorylated hydroxyl-containing amino acid, about 0.5% by weight of the hydroxide, and at about A stable ACC suspension of 10 to about 15% by weight of ethanol.

Another preferred method according to the present invention comprises combining calcium chloride, sodium carbonate, a non-phosphorylated hydroxyl-containing amino acid (for example, serine), a saccharide, and sodium hydroxide and an alcohol in an aqueous mixture. Thus, a non-phosphorylated hydroxyl-containing amino acid and a saccharide comprising between about 2.5 and about 5% by weight of ACC, a total amount of between about 1 and about 4% by weight, and about 0.5% by weight of hydrogen are obtained. An oxide and a stabilized ACC suspension of between about 10 and about 15% by weight ethanol.

In another embodiment, the present invention further comprises a method of separating from the ACC and the suspension was dried, thereby to obtain a stable water between about 75 and about 88 wt% of CaCO ₃ and less than about 10% by weight comprising between ACC powder.

In other embodiments, the invention provides a stable ACC obtained by the method as described herein Suspension and stable ACC powder. Thus, in one embodiment, the invention provides a stabilized ACC suspension made by the process of the invention. In one embodiment, the stabilized ACC suspension comprises between about 2.5 and about 5 weight percent ACC, between about 0.05 and about 0.2 weight percent phosphorylated organic acid, and between about 10 and about 15 weight percent. Between the ethanol. In another embodiment, the stabilized ACC suspension comprises between about 2.5 and about 5 wt% ACC, between about 1 and about 4 wt% sugar, and about 0.5 wt% hydroxide. And between about 10 and about 15% by weight ethanol. In another embodiment, the stabilized ACC suspension comprises between about 2.5 and about 5% by weight of ACC, between about 0.05 and about 0.2% by weight of an organic acid (eg, a dicarboxylic acid or a tricarboxylic acid) An acid such as citric acid and between about 10 and about 15% by weight ethanol. In another embodiment, the stabilized ACC suspension comprises between about 2.5 and about 5% by weight of ACC, between about 0.05 and about 0.2% by weight of an organic acid (eg, a non-phosphorylated hydroxyl-containing amine) Base acid), about 0.5% by weight hydroxide and between about 10 and about 15% by weight ethanol. Suspending agents comprising a combination of stabilizers are also contemplated. Each possibility represents a different embodiment of the invention.

In other embodiments, the invention provides a stabilized ACC powder made by the method of the invention. In one embodiment, the powder comprises between about 75 and about 88% by weight CaCO ₃ , less than about 10% by weight water, and an organic acid (eg, phosphorylated organic acid, non-phosphorylated organic acid, dicarboxylic acid) Acid or tricarboxylic acid, hydroxyl containing amino acid or any other organic acid described herein). In other embodiments, the stabilizer CaCO between about 75 and about 88 wt% of the powder comprises between ACC _3, less than about 10% by weight of water, and a saccharide interposed between about 1 and about 5% by weight. Each possibility represents a different embodiment of the invention.

In other aspects, the invention further relates to the use of the above suspensions and powders in dyes, paper products, plastics, inks, adhesives, marble repair products, medical devices, pharmaceuticals, food supplements, and/or food additives, Each of these possibilities represents a different embodiment of the invention.

In some preferred embodiments, the stabilized ACC is derived from a soluble calcium salt (such as Calcium chloride) a supersaturated calcium ion solution (which also contains a first stabilizing molecule such as phosphoric acid) is mixed with a supersaturated carbonate solution from a soluble carbonate such as sodium carbonate. If not further stabilized, the precipitated ACC rapidly crystallizes into a mixture of calcite and vaterite in less than about 2 minutes. However, in the process of the present invention, after allowing the precipitated ACC suspension in step 1 to be mixed for ~10 seconds, a stable solution containing a second stabilizing molecule such as phosphosamine is added. After allowing the precipitated ACC suspension and the stabilizing solution to be mixed in step 2 for ~10 seconds, an organic solvent such as ethanol is added. After the addition of the organic solvent, the ACC system is stable and can be maintained in the suspension for several days, depending on the concentration of the first and second stabilizers and the ratio of the organic solvent. It has also been found that lowering the reaction temperature increases the settling time in solution. The order of addition of the second stabilizer and the alcohol may be reversed, or they may be added together in the form of a solution containing the second stabilizer contained in the alcohol.

This step can be carried out in a batch mode (wherein the solutions are added to each other in a single addition) or in a continuous process wherein the solutions are mixed, for example, in a continuous stream using a continuous flow technique.

Other embodiments of the invention and the full scope of applicability will be apparent from the Detailed Description and the Detailed Description. It should be understood, however, that the description of the preferred embodiments of the present invention Various changes and modifications.

Figure 1: Raman spectra of several calcium carbonate samples taken using micro-Raman. The spectra correspond to the following samples: A) ACC produced by the method of the invention; B) ACC after crystallization; C) vaterite; and D) calcite. The vertical line represents the Raman shift of the main peak of the CO ₂ vibration of the vaterite.

Figure 2: XRD spectrum of ACC produced by the method of the invention. The XRD spectrum of the ACC is characterized by a broad low intensity peak of ~20-30 2θ.

Figure 3: XRD spectrum of vaterite. The meteorite XRD spectrum is characterized by 24, 27 and ~33 Two main peaks at 2θ.

Figure 4: XRD spectrum of calcite. The calcite XRD spectrum is characterized by multiple peaks and the most prominent peak at ~29 2θ.

The present invention provides a synthetic process for producing a highly stable ACC in a stepwise process using a hydrogen bonding molecule as a stabilizer and a water miscible organic solvent. It has been found that the step-by-step process of the present invention is far superior in terms of safety, yield, and stability to the methods previously described for making stable ACC. It has been found that performing the process in different steps in accordance with the embodiments described herein is beneficial for the manufacture of highly stable ACC.

The unexpected stability of ACC made in accordance with the process of the present invention is not fully understood. Without wishing to be bound by any particular mechanism or theory, it is expected that the addition of a stabilizing molecule after the preparation of ACC will result in some external coatings that enhance ACC stability, while the addition of organic solvents reduces water activity and reduces the solubility of stable molecules in solution. Thus, it is ensured that it remains on or in the surface of the ACC particles, thereby promoting stabilization of the ACC. Loste et al. [ Journal of Crystal Growth , 254 (2003) 206-218] propose that Mg can enhance the stability of ACC by being incorporated into an amorphous lattice, and because the Mg radius is smaller than the Ca radius, it exists for The binding of water molecules in the ACC structure is strong, thereby inhibiting crystallization. Water-binding molecules can function through the same mechanism. By combining calcium ions and water molecules, they can inhibit the diffusion of water out of the amorphous crystal lattice, thereby suppressing crystallization.

It has also been found that when certain organic acids or phosphorylated amino acids are used, it is not necessary to use sodium hydroxide or another base to increase the pH of the solution. However, when sucrose or other sugars and non-phosphorylated hydroxyl-containing amino acids are used, it is necessary to raise the pH of the solution with, for example, an alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide, etc.) to achieve stability. effect. Koga et al. [ Thermochimica Acta , 318 (1998) 239-244] previously proposed that high pH promotes ACC stabilization, however, Koga only uses sodium hydroxide in the experiment, which only allows Koga to precipitate before the calcium hydroxide precipitates the solution. The pH was increased to 13.5. When sucrose is introduced along with the sodium hydroxide, it can further increase the pH to > 14 without precipitating the calcium hydroxide. Without wishing to be bound by any particular mechanism or theory, the combination of sucrose and very high pH appears to have improved stabilizing effects.

No. 4,237,147 describes a process for the manufacture of ACC using calcium hydroxide and sucrose; however, the use of sucrose in order to increase the solubility of calcium hydroxide requires a very large amount of sucrose relative to the amounts described in the present invention. The high sucrose dosage described in US 4,237,147 makes the manufacture of ACC impractical for the following reasons: 1. The sucrose content is too high, so that only ACC precipitates partially, so that it can hardly be separated; 2. High sucrose content is too high, It forms a viscous gel that cannot be filtered. In the present invention, since a small amount of sucrose is used as a stabilizer rather than as a solubilizing agent, the required concentration is much lower, which easily solves the above two problems.

As used herein, the term "soluble calcium salt" means a calcium salt that is soluble in water, that is, the calcium salt is completely soluble in water to give a clear solution. Generally, a compound will have a solubility of at least about 1 g per 100 mL of water (e.g., at least about 5 g per 100 mL or at least) at a temperature of from about 0 ° C to about ambient (defined herein as about 20 ° C to 30 ° C). About 10g/100mL), it is considered "soluble" in water. In a presently preferred embodiment, the soluble calcium salt is calcium chloride. In other embodiments, the soluble calcium salt can be calcium bromide, calcium iodide, calcium lactate, calcium gluconate, and the like. Each possibility represents a different embodiment of the invention.

As used herein, the term "soluble carbonate" means a carbonate (CO ₃ ^2- ) that is soluble in water, that is, the carbonate is completely soluble in water to give a clear solution. In a presently preferred embodiment, the soluble carbonate is an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate. In another preferred embodiment, the soluble carbonate is ammonium carbonate. Each possibility represents a different embodiment of the invention.

As used herein, the term "stabilized ACC suspension" or "stable ACC" means that it can be maintained as a suspension or as a dry solid (eg, a powder) for hours to days, weeks, or months without substantial Conversion to crystalline form of ACC. The term "mass conversion" It is often meant that about 5% or more of the amorphous form is converted to a crystalline form. Thus, the process of the invention can be produced to remain amorphous at least at room temperature (about 20-30 ° C) or even at higher temperatures in the suspension or as a solid powder, typically at least 95% or more. ACC in the form (preferably at least about 97% or even better at least about 99%).

As contemplated herein, the present invention relates to the use of a stabilizer as described herein and a water miscible organic solvent to form a stable ACC suspension. The stabilizers used in the present invention are referred to herein as "first stabilizers" and "second stabilizers", respectively. Other stabilizers can also be used if desired. Preferably, the method of the invention involves the use of first and second stabilizers, which may be the same or different from each other, wherein each possibility represents a different embodiment of the invention. Additionally, the term "first stabilizer" is intended to encompass a single stable compound or a combination of more than one stable compound. Furthermore, the term "second stabilizer" is intended to encompass a single stable compound or a combination of more than one stable compound. Thus, in some embodiments, the aqueous calcium solution can comprise a stabilizer or a combination of stabilizers (collectively referred to as "first stabilizers"). In other embodiments, the solution comprising the second stabilizer may comprise a stabilizer or a combination of stabilizers (collectively referred to as "second stabilizers"). According to the invention, the total amount of stabilizer used in the process of the invention is up to about 12% by weight of the stabilized ACC suspension.

According to one aspect, the stable molecular system of the present invention is partitioned between a calcium-containing solution and a second stable solution, referred to as a "stabilized solution." In one embodiment, the stabilizing solution comprises a second stabilizer and, optionally, an aqueous solution comprising a water miscible organic solvent. In another embodiment, the stabilizing molecule can be dissolved directly in a water miscible organic solvent.

In some embodiments, the first and second stabilizers are each selected from the group consisting of organic acids, phosphorylated organic acids, phosphates of hydroxycarboxylic acids, sulfates of hydroxycarboxylic acids, phosphorylated amino acids, and A derivative thereof, an amino acid sulfate, and a hydroxyl group-containing organic compound in combination with an alkali metal hydroxide. According to one aspect, the stable molecules are selected from, but not limited to, organic acids, phosphorylated amino acids, phosphate-containing molecules such as, but not limited to, phosphoenolpyruvate or creatine phosphate, or Sulfate molecules (such as, but not limited to, amino acid sulfate An ester such as sulfosilic acid or sulfosathionine or any combination of the foregoing. According to another aspect, the stabilizing molecules comprise hydroxyl-containing molecules in combination with an alkali metal hydroxide such as, but not limited to, sodium hydroxide or potassium hydroxide, such as (i) monosaccharides, disaccharides, trisaccharides Or a polysaccharide, for example, sucrose, mannose, glucose, etc.; or (ii) a hydroxyl-containing, non-phosphorylated amino acid.

In general, these stable molecules can be divided into two categories: 1) stabilizers which themselves have a strong stabilizing effect. Such stabilizing molecules include organic acids such as carboxylic acids having at least two carboxyl groups and having a molecular weight of no more than about 250 g/mol (eg, citric acid, tartaric acid, malic acid, etc.) and phosphates or sulfates of hydroxycarboxylic acids (eg, Phosphoenolpyruvate, phosphoserine, phosphoric acid, sulfosyl or sulfosyl); 2) hydroxides need to be added to deprotonate and stabilize the hydroxyl groups of the stable molecules A stable molecule of action. Such stable molecules include monosaccharides, disaccharides, trisaccharides, oligosaccharides or polysaccharides (glucose, mannose, fructose, sucrose, etc.), non-phosphorylated hydroxyl-containing molecules (including polyols and amino acids (eg, glycerol) , serine, threonine, etc.)). The term "non-phosphorylated hydroxyl-containing amino acid" refers to a natural or non-natural amino acid having at least one hydroxyl group (OH) in its side chain.

According to one aspect of the invention, the stabilizing molecules in the calcium solution and the stabilizing molecules in the stabilizing solution are the same molecule. According to another aspect of the invention, it is of two different molecules. In a preferred embodiment of the present invention, the first stabilizer and the second stabilizer are the same, and the ratio of the stabilizer in, for example, step i) and step iii) of the method is about 1: 1 to about 10:1, such as about 1:2, about 1:3, about 1:5, about 2:1, about 3:1, or about 5:1 (first stabilizer to second stabilizer ratio). Each possibility represents a different embodiment of the invention.

According to one aspect of the invention, the organic solvent is selected from, but not limited to, an alcohol (such as methanol, ethanol, propanol or isopropanol), a ketone (such as, but not limited to, acetone, diethyl ketone, ring) Hexanone, etc.) or other water-miscible organic solvents. Examples of other water-miscible organic solvents include, but are not limited to, ethers such as tetrahydrofuran or dioxane, acetonitrile, dimethoxyethane, diethoxyethane, dimethylformamide (DMF), and dimethyl Chia 碸 (DMSO). As made in this article The term "water-miscible organic solvent" means an organic solvent which can be mixed with water in all proportions, thereby forming a homogeneous solution.

The total amount of stabilizer in the process of the invention means the combined amount of stabilizer used, for example, the total amount of the first and second stabilizers as described herein. Generally, the total amount of stabilizer is up to about 12% by weight of the stabilized ACC suspension, preferably up to about 10% by weight of the stabilized ACC suspension, and more preferably up to about 8% by weight of the stabilized ACC suspension or Up to about 5% by weight or up to about 3% by weight. Each possibility represents a different embodiment of the invention.

The water miscible organic solvent comprises at least about 5% by weight of the stabilized ACC suspension. Ethanol is a currently preferred organic solvent.

In some embodiments, the calcium concentration in the calcium ion solution can vary from about 4 mM to about 2M. For practical reasons, the calcium concentration should be maintained between about 0.5 M and 1 M, such as between 0.5 M and 0.75 M, or between 0.75 and 1 M. Each possibility represents a different embodiment of the invention.

In other embodiments, the carbonate concentration in the carbonate solution can vary from about 4 mM to about 2M. For practical reasons, the carbonate concentration should be maintained between about 0.5 M and 1 M, such as between 0.5 M and 0.75 M or between 0.75 and 1 M. Each possibility represents a different embodiment of the invention.

In other embodiments, the calcium:carbonate molar ratio can correspondingly vary from about 2:1 to about 1:1.5. For practical reasons, it is preferred to use a molar ratio of 1:1, however, various ratios can be used as would be expected by those skilled in the art.

In other embodiments, the concentration of the stabilizing molecule in the calcium ion solution is between about 0.0001% and about 10% by weight of the calcium ion solution. More preferably, the concentration is between about 0.01% and about 3%; however, it has been found that each stabilizing molecule has its own optimal concentration, which can be readily determined by those skilled in the art.

In other embodiments, the stabilizing molecular concentration in the stabilizing solution is between about 0.0002% and about 20% by weight of the calcium ion solution. More preferably, the concentration is between about Between 0.02% and about 6%; however, it has been found that each stabilizing molecule has its own optimal concentration, which can be readily determined by those skilled in the art.

According to one aspect of the present invention, when a molecule containing a hydroxyl group, a phosphate or a sulfate is combined with a hydroxide as a stabilizing molecule, the hydroxyl group, phosphate or sulfate molecule has a molar ratio to the hydroxide. Between about 4:1 and about 0.5:1, such as about 3:1, 2:1, 1:1, or 0.75:1, each of which represents a different embodiment of the invention.

In other embodiments, the ratio of the amount of stabilizing molecules in the stabilizing solution to the amount of stabilizing molecules in the calcium solution is between about 1:1 and about 20:1, such as about 2:1, 5:1, 10 : 1 or 15: 1, wherein each possibility represents a different embodiment of the invention. It has been found that there are different optimum ratios for each pair of stable molecules, which can be readily determined by those skilled in the art.

In other embodiments, the total ratio of organic solvent to total aqueous solution used is from about 15:1 to about 1:3 (water: solvent). Different organic solvents perform better at different ratios. For example, it has been found that ethanol performs well at a weight ratio of ~7:1, while acetone performs well at a weight ratio of ~5:1. Those skilled in the art can readily determine the optimal ratio of water to organic solvents.

In other embodiments, the reaction temperature that can be employed is in the range of from about -10 °C to about 60 °C. The reaction temperature range is preferably maintained between about -3 ° C and ambient temperature (room temperature (RT)), more preferably between about 0 ° C and about 15 ° C.

According to one aspect of the invention, the moisture in the powder ACC should be maintained below 15% in order to maintain the stability of the dry powder product. According to another aspect of the invention, the moisture should preferably be maintained below 10%, and even more preferably below 8%.

According to one aspect of the invention, the dry stable product can be maintained under ambient conditions. According to another aspect of the invention, the dry stabilizing product should be maintained in a controlled humidity environment where the relative humidity is preferably less than 20%.

According to one aspect of the invention, the calcium content of the ACC produced is between about 30% and about 33%. Preferably, the calcium content in the ACC is between about 31.5% and about 32.5%. between.

The ACC produced can be filtered using standard liquid/solid separation methods such as, but not limited to, vacuum filtration or pressure filtration, centrifugation or decantation, and then using standard drying equipment such as, but not limited to, air drying. Drying is carried out by a machine, vacuum oven or turbine oven, spray dryer, air flow dryer, freeze dryer or paddle dryer.

The following examples are provided to more fully illustrate certain embodiments of the invention. However, the examples are not to be considered as limiting the broad scope of the invention in any way. Many variations and modifications of the principles disclosed herein will be apparent to those skilled in the art without departing from the scope of the invention.

Example 1

In a typical procedure, the calcium solution contains 1 liter of water, 88.8 grams of calcium chloride, and 888 mg of phosphoric acid. The carbonate solution contained 1 liter of water and 84.8 grams of sodium carbonate. The stable solution contained 200 ml of water and 1.776 g of phosphoric acid, and 350 ml of ethanol was used as the organic solvent. The calcium solution and the carbonate solution were mixed together to precipitate an unstable ACC. After 20 seconds, the stabilizer solution and ethanol were successively added to the ACC suspension, thereby obtaining a stable ACC suspension. The resulting stabilized ACC suspension stabilizes the ACC in the ~20 °C solution for at least 3 hours and at 0 °C for at least 9 hours. The ACC was then filtered using a Buchner funnel while the ACC was still stable in the suspension, and the filter cake was dried at 40-50 °C using a conventional oven.

Example 2

The calcium solution contained 1 liter of water, 88.8 grams of calcium chloride, and 700 mg of citric acid. The carbonate solution contained 1 liter of water and 84.8 grams of sodium carbonate. The stable solution contained 200 ml of water and 1.4 g of citric acid, and 350 ml of ethanol was used as an organic solvent. The calcium solution and the carbonate solution were mixed together to precipitate an unstable ACC. After 20 seconds, the stabilizer solution and ethanol were successively added to the ACC suspension, thereby obtaining a stable ACC suspension. The resulting stabilized ACC suspension stabilizes the ACC in the ~20 ° C solution for at least 3 hours and is stable at 0 ° C until Less than 9 hours. The ACC was then filtered using a Buchner funnel while the ACC was still stable in the suspension, and the filter cake was dried using a vacuum oven at 40-50 ° C under a 400 mbar nitrogen atmosphere.

Example 3

The calcium solution contained 1 liter of water, 88.8 grams of calcium chloride, and 888 mg of phosphoric acid. The carbonate solution contained 1 liter of water and 84.8 grams of sodium carbonate. 1.776 g of citric acid was dissolved in 350 ml of ethanol. The calcium solution and the carbonate solution were mixed together to precipitate an unstable ACC, and after 20 seconds, an ethanol-stabilizer solution was added to the ACC suspension, thereby obtaining a stable ACC suspension. The resulting stabilized ACC suspension stabilizes the ACC in the ~20 °C solution for at least 5 hours and is stable at 0 °C for at least 9 hours. The ACC was then filtered using a Buchner funnel while the ACC was still stable in the suspension, and the filter cake was dried at 40-50 °C using a conventional oven.

Example 4

The calcium solution contained 1 liter of water, 88.8 grams of calcium chloride, 20 grams of sucrose, and 3.35 grams of sodium hydroxide. The carbonate solution contained 1 liter of water and 84.8 grams of sodium carbonate. The stable solution contained 200 ml of water, 40 g of sucrose, and 6.67 g of sodium hydroxide. And 350 ml of ethanol was used as an organic solvent. The calcium solution and the carbonate solution were mixed together to precipitate an unstable ACC. After 20 seconds, the stabilizer solution and ethanol were successively added to the ACC suspension, thereby obtaining a stable ACC suspension. The resulting stabilized ACC suspension comprises an ACC that is stable for at least 10 hours at ~20 °C and stable for at least 24 hours at 0 °C. The ACC was then centrifuged at 4000 rpm for 5 minutes using a bench-top centrifuge, the supernatant was discarded, and the concentrated product was freeze-dried overnight using a freeze dryer at -80 ° C under high vacuum.

Example 5

The calcium solution contained 1 liter of water, 88.8 grams of calcium chloride, 10 grams of serine and 3.8 grams of sodium hydroxide. The carbonate solution contained 1 liter of water and 84.8 grams of sodium carbonate. The stable solution contained 200 ml of water, 20 g of serine and 7.62 g of sodium hydroxide, and used 350 ml of ethanol as an organic solvent. Mixing the calcium solution and the carbonate solution together to precipitate precipitation instability After 20 seconds, the stabilizer solution and ethanol were successively added to the ACC suspension, thereby obtaining a stable ACC suspension. The resulting stabilized ACC suspension contained an ACC that was stable for at least 2 hours at ~20 °C and stable for at least 8 hours at 0 °C. The ACC was then centrifuged at 4000 rpm for 5 minutes using a bench-top centrifuge, the supernatant was discarded, and the concentrated product was freeze-dried overnight using a freeze dryer at -80 ° C under high vacuum.

Example 6

The calcium solution contained 1 liter of water, 88.8 grams of calcium chloride, 10 grams of serine and 3.8 grams of sodium hydroxide. The carbonate solution contained 1 liter of water and 84.8 grams of sodium carbonate. The stable solution contained 200 ml of water, 20 g of sucrose, and 7.62 g of sodium hydroxide, and used 350 ml of ethanol as an organic solvent. The calcium solution and the carbonate solution were mixed together to precipitate an unstable ACC. After 20 seconds, the stabilizer solution and ethanol were successively added to the ACC suspension, thereby obtaining a stable ACC suspension. The resulting stabilized ACC suspension comprises an ACC that is stable for at least 6 hours at ~20 °C and stable for at least 24 hours at 0 °C. The ACC was then centrifuged at 4000 rpm for 5 minutes using a bench-top centrifuge, the supernatant was discarded, and the concentrated product was freeze-dried overnight using a freeze dryer at -80 ° C under high vacuum.

Figures 1 and 2 show typical ACC Raman and XRD spectra of dried samples prepared according to Examples 1 and 2 above. Figures 3 and 4 show the XRD spectra of vaterite and calcite for comparison.

Although the invention has been described in detail, it will be understood by those skilled in the art Therefore, the present invention is not to be construed as limited to the details of the embodiments of the invention.

Claims (54)

A method of producing amorphous calcium carbonate (ACC) comprising the steps of: i) combining an aqueous solution comprising a soluble calcium salt and a first stabilizer with an aqueous solution comprising a soluble carbonate to form an ACC suspension; Adding a water-miscible organic solvent and a solution containing the second stabilizer simultaneously or in any order, as long as the second stabilizer and the organic solvent are in contact with the ACC suspension within about 2 minutes of forming the ACC suspension. Thus, a stable ACC suspension is obtained; wherein the first stabilizer and the second stabilizer are the same or different; and wherein the total amount of the stabilizer is up to about 12% by weight of the stable ACC suspension, and The water miscible organic solvent comprises at least about 5% by weight of the stabilized ACC suspension. The method of claim 1, comprising the steps of: i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizer; ii) preparing an aqueous solution comprising a soluble carbonate; iii) preparing an aqueous solution comprising the second stabilizer; iv) Preparing a solution comprising a water-miscible organic solvent; and v) combining the solution prepared in step ii) with the solution prepared in step i) to form an ACC suspension, followed by simultaneously or in any order The solutions prepared in the steps iii) and iv) are added as long as the solutions are contacted with the ACC suspension within about 2 minutes of forming the ACC suspension, thereby obtaining the stabilized ACC suspension. The method of claim 1, comprising the steps of: i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizer; ii) preparing an aqueous solution comprising a soluble carbonate; iii) preparing a water-soluble organic solvent. a solution of two stabilizers; Iv) combining the solutions prepared in steps i) and ii) to obtain an ACC suspension, and then adding the solution prepared in step iii) to the ACC suspension within about 2 minutes of forming the ACC suspension. In solution to form a stable ACC suspension. The method of claim 1, comprising the steps of: i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizer; ii) preparing an aqueous solution comprising a soluble carbonate, and combining it with the calcium salt of step i) Together, thereby obtaining an ACC suspension; iii) preparing an aqueous solution of the second stabilizer, thereby obtaining a stable solution; iv) combining the stable solution with the ACC suspension; and v) adding a water-miscible organic solvent, Wherein the stabilizing solution and the organic solvent are added to the ACC suspension within about 2 minutes of forming the ACC suspension to form a stable ACC suspension. The method of claim 1, wherein the calcium salt is calcium chloride. The method of claim 1, wherein the soluble carbonate is an alkali metal carbonate or ammonium carbonate. The method of claim 6, wherein the alkali metal carbonate is lithium carbonate, sodium carbonate or potassium carbonate. The method of claim 1, wherein the calcium salt and the carbonate are present in a molar ratio of from about 0.5 to about 2.0. The method of claim 1, wherein the water-miscible organic solvent is selected from the group consisting of lower alcohols and ketones. The method of claim 9, wherein the water-miscible organic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, acetone, diethyl ketone, and cyclohexanone. The method of claim 10, wherein the water-miscible organic solvent is ethanol. The method of claim 1, wherein the concentration of the soluble calcium salt solution is from about 4 mM to about 2 M, and wherein the concentration of the soluble carbonate solution is from about 4 mM to about 2 M. The method of claim 1, wherein the first and second stabilizers are each independently selected from the group consisting of organic acids, phosphorylated organic acids, phosphates or sulfates of hydroxycarboxylic acids, and phosphorylated amine groups. An acid and a derivative thereof, and a hydroxyl group-containing organic compound in combination with an alkali metal hydroxide. The method of claim 13, wherein at least one of the first and second stabilizers is an organic acid selected from the group consisting of ascorbic acid, acetic acid, and an organic acid having at least two carboxyl groups and having a molecular weight of not more than 250 g/mol. The method of claim 14, wherein at least one of the first and second stabilizers is selected from the group consisting of citric acid, tartaric acid, and malic acid. The method of claim 13, wherein at least one of the first and second stabilizers is a phosphate or sulfate of a hydroxycarboxylic acid, a phosphorylated amino acid derivative or an amino acid sulfate. The method of claim 16, wherein at least one of the first and second stabilizers is selected from the group consisting of phosphoenolpyruvate, creatine phosphate, phosphoserine, threonine phosphate, sulfosylamine Acid and sulfosylurea. The method of claim 13, wherein at least one of the first and second stabilizers is a hydroxyl group-containing organic compound combined with an alkali metal hydroxide, wherein the hydroxyl group-containing organic compound is selected from the group consisting of monosaccharides and disaccharides. , trisaccharides, oligosaccharides and polysaccharides; and non-phosphorylated hydroxyl-containing compounds. The method of claim 18, wherein the non-phosphorylated hydroxyl-containing compound is a non-phosphorylated amino acid. The method of claim 18, wherein at least one of the first and second stabilizers is selected from the group consisting of glucose, mannose, fructose, sucrose, glycerol, serine, and sulphite And wherein the alkali metal hydroxide is selected from the group consisting of sodium hydroxide and potassium hydroxide. The method of claim 13, wherein at least one of the first and second stabilizers Is selected from the group consisting of: a polyol combined with an alkali metal hydroxide, a phosphorylated amino acid, an amino acid sulfate, a dicarboxylic acid, a tricarboxylic acid, and a non-phosphorylated combination with an alkali metal hydroxide. The hydroxyl-containing amino acid and any combination thereof, wherein the total amount of the stabilizer in the stabilized ACC suspension is from about 1 to about 1000 mM. The method of claim 13, wherein at least one of the first and second stabilizers is a phosphorylated amino acid, wherein the total concentration in the stabilized ACC suspension is from about 2 to about 200 mM. The method of claim 13, wherein at least one of the first and second stabilizers is citric acid, wherein the total concentration in the stabilized ACC suspension is from about 1 to about 200 mM. The method of claim 13, wherein at least one of the first and second stabilizers is a polyol combined with an alkali metal hydroxide or a non-phosphorylated hydroxyl group-containing amino acid combined with an alkali metal hydroxide. Wherein the total concentration of the polyol or amino acid in the stabilized ACC suspension is from about 10 mM to about 1000 mM, and the total concentration of the hydroxide in the stabilized ACC suspension is between about 1 mM and about 2000 mM. between. The method of claim 1, wherein the first and second stabilizers are different. The method of claim 1, wherein the first stabilizer is the same as the second stabilizer, and wherein the first and second stabilizers are used in a ratio of from about 1 to about 10. The method of claim 1, wherein the step of adding the second stabilizer and the water-miscible organic solvent is carried out at a temperature between about -10 ° C and about 60 ° C. The method of claim 27, wherein the step of adding the second stabilizer and the water-miscible organic solvent is carried out at a temperature between about -3 ° C and ambient temperature. The method of claim 27, wherein the step of adding the second stabilizer and the water-miscible organic solvent is carried out at a temperature between about 0 ° C and about 15 ° C. The method of claim 1, further comprising the step of separating the ACC from the stabilized ACC suspension and drying, thereby obtaining a stabilized ACC powder. The method of claim 30, wherein the separating step comprises filtering or centrifuging, and the drying step comprises heating or freeze drying. The method of claim 30, wherein the stabilized ACC powder comprises less than about 15% by weight water, and between about 30 and about 35% by weight calcium. The method of claim 32, wherein the stabilized ACC powder comprises less than about 8% by weight water. The method of claim 1, comprising the steps of: i) preparing an aqueous solution of a calcium chloride having a concentration of up to about 1 M and a first stabilizer having a concentration of between about 1 and 80 mmol/1 mol of calcium chloride; Preparing an aqueous solution of sodium carbonate having a molar concentration approximately the same as that of calcium chloride in step i), and combining it with the calcium salt solution of step i), thereby obtaining an ACC suspension; iii) preparing for inclusion 350 g of ethanol per 1 mol of calcium chloride in step i) and a stable solution of the second stabilizer which is the same as the first stabilizer in step i) but doubled in content; and iv) in the formation of the ACC suspension The stabilizing solution was combined with the ACC suspension in about 2 minutes, thereby obtaining a stable ACC suspension. The method of claim 34, wherein the first and second stabilizers in steps i) and iii) are phosphoric acid, each of which is used in an amount of about 6 mmol and about 12 mmol/1 mol of calcium, respectively. The stabilized ACC suspension is vacuum dried at a temperature between about 40 ° C and about 50 ° C. The method of claim 34, wherein the first and second stabilizers are sucrose and sodium hydroxide, the amount of which is used in step i) is about 70 mmol sucrose and about 100 mmol NaOH / 1 mol calcium, and in step iii) The amount used is about 140 mmol sucrose and about 200 mmol NaOH / 1 molar calcium, and the method additionally comprises separating ACC by centrifugation or freeze drying. The method of claim 1, which comprises combining calcium chloride, an alkali metal carbonate, a phosphorylated organic acid and an alcohol in an aqueous mixture, thereby obtaining an ACC comprising between about 2.5 and about 5% by weight. A stabilized ACC suspension of between about 0.001 and about 0.2% by weight phosphorylated organic acid and between about 8 and about 32% by weight ethanol. The method of claim 1, which comprises combining calcium chloride, an alkali metal carbonate, a dicarboxylic acid or a tricarboxylic acid and an alcohol in an aqueous mixture, thereby obtaining a content of between about 2.5 and about 5% by weight. A cross-linked ACC suspension of between about 0.001 and about 0.2% by weight of dicarboxylic or tricarboxylic acid and between about 8 and about 32% by weight of ethanol. The method of claim 1, which comprises combining calcium chloride, an alkali metal carbonate, a dicarboxylic acid or a tricarboxylic acid, a phosphorylated organic acid and an alcohol in an aqueous mixture, thereby obtaining a composition comprising between about 2.5 and Between about 5% by weight of ACC, a total amount of between about 0.001 and about 0.2% by weight of dicarboxylic or tricarboxylic acid and phosphoric acid organic acid, and between about 8 and about 32% by weight of ethanol Stabilize the ACC suspension. The method of claim 1, which comprises combining calcium chloride, an alkali metal carbonate, a saccharide, and sodium hydroxide and an alcohol in an aqueous mixture, thereby obtaining between about 2.5 and about 5% by weight. ACC, a stabilized ACC suspension of between about 1 and about 4 weight percent sugar, about 0.5 weight percent hydroxide, and between about 10 and about 15 weight percent ethanol. The method of claim 1, which comprises combining calcium chloride, an alkali metal carbonate, a non-phosphorylated hydroxyl-containing amino acid, and sodium hydroxide and an alcohol in an aqueous mixture, thereby obtaining a composition comprising between about 2.5 and Between about 5% by weight of ACC, between about 1 and about 4% by weight of non-phosphorylated hydroxyl-containing amino acid, about 0.5% by weight of hydroxide, and between about 10 and about 15% by weight Stabilized ACC suspension of ethanol. The method of claim 1, which comprises, in an aqueous mixture, calcium chloride, sodium carbonate, The non-phosphorylated hydroxyl-containing amino acid, the saccharide and the sodium hydroxide, and the alcohol are combined to provide an ACC comprising between about 2.5 and about 5% by weight, and the total amount is between about 1 and about 4 weights. Between the non-phosphorylated hydroxyl-containing amino acids and saccharides, about 0.5% by weight of hydroxide and between about 10 and about 15% by weight of a stable ACC suspension of ethanol. The method of any one of claims 37 to 42, further comprising the step of separating the ACC from the suspension and drying, thereby obtaining a CaCO ₃ comprising between about 75 and about 88% by weight and less than about 10 A weight of water stabilized ACC powder. The method of claim 1, wherein the first stabilizer comprises a combination of two or more stabilizing compounds. The method of claim 1, wherein the second stabilizer comprises a combination of two or more stabilizing compounds. A stabilized ACC suspension produced according to the method of claim 1 comprising between about 2.5 and 5% by weight of ACC, between about 0.05 and about 0.2% by weight of phosphorylated organic acid, and between 10 to about 15% by weight of ethanol. A stabilized ACC suspension produced according to the method of claim 1 which comprises between about 2.5 and 5% by weight of ACC, between about 0.05 and about 0.2% by weight of an organic acid, and between about 10 and About 15% by weight of ethanol. A stabilized ACC suspension produced according to the method of claim 1 which comprises between about 2.5 and about 5 wt% ACC, between about 1 and about 4 wt% sugar, about 0.5 wt% The hydroxide and between about 10 and about 15% by weight ethanol. A stabilized ACC suspension produced according to the method of claim 1 which comprises between about 2.5 and about 5% by weight of ACC, between about 1 and about 4% by weight of non-phosphorylated hydroxyl-containing amine groups. Acid, about 0.5% by weight hydroxide and between about 10 and about 15% by weight ethanol. A process according stable ACC as a powder of a manufacturing method of item request comprising CaCO ranging between about 75% and about 88 wt. _3, less than about 10% water by weight of an organic acid and phosphoric acid. A process according stable ACC as a powder of a manufacturing method of item request comprising CaCO ranging between about 75% and about 88 wt. _3, less than about 10% by weight of water and organic acids. A process according stable ACC as the powder of a request entry method of manufacturing, comprising CaCO ranging between about 75% and about 88 wt. _3, less than about 10% by weight water and between about 1 and about 5 wt% Sugar. A process according stable ACC as the powder of a request entry method of manufacturing, comprising CaCO ranging between about 75% and about 88 wt. _3, less than about 10% by weight water and between about 1 and about 5 wt% Non-phosphorylated hydroxyl-containing amino acids. A use of a suspension or powder according to any one of claims 46 to 53 in dyes, paper products, plastics, inks, adhesives, marble repair products, medical devices, pharmaceuticals, food supplements and/or food additives.