HK1209095B - Method for producing stabilized amorphous calcium carbonate - Google Patents

Abstract

Provided is a method for preparing a stable amorphous calcium carbonate (ACC), which can be obtained either in suspension or as a powder. The method comprises stepwise combination of a soluble calcium salt, a soluble carbonate, a first and second stabilizer, and a water miscible organic solvent as described herein. The present invention further relates to stable ACC suspensions and dry powders produced by the method of the present invention.

Description

Process for producing stabilized amorphous calcium carbonate

Technical Field

The present invention relates to a novel process for the preparation of Amorphous Calcium Carbonate (ACC) based on stepwise addition of a stabilizing solution and an organic solvent. The ACC produced by the process of the present invention features increased stability both in solution/suspension and as a dry powder and can be used in e.g. paper, dyes, plastics, inks, adhesives, marble repair, medical devices and pharmaceutical industry.

Background

Calcium carbonate (CaCO)₃) Is the calcium salt of carbonic acid, which is widely used today in various industries. It is most known as a calcium supplement to be taken to increase daily calcium intake. Calcium carbonate has six known polymorphs, three of which are anhydrous crystals, calcite, aragonite and vaterite; the two are crystal hydrates, namely mono-calcite and hexahydrate calcite; and one is hydrated amorphous, i.e. Amorphous Calcium Carbonate (ACC). ACC is a transitional polymorph that precipitates from supersaturated solutions following the Ostwald' sstep rule. If not stabilized by any means, ACC will rapidly and completely crystallize into one of the five more stable polymorphs within seconds. Amorphous polymorphs as crystalline amorphous polymorphs having no major XRD peaks but having a broad low intensity between 20-302 thetaDegree peak and 1082cm in Raman spectroscopy^-1The distinctive 40-120nm globules with a broad low intensity peak nearby are characterized in contrast to the 1-10 μm crystals that are characteristic of other polymorphs, which also have a distinct major XRD peak and a distinct raman peak.

Synthetic ACC has been synthesized for over 100 years, and there are several methods for synthesizing ACC today using a variety of molecules for stabilizing the transitional unstable amorphous phase. Three widely used methods all use supersaturated solutions of calcium ions from soluble sources, such as calcium chloride, or from the dissolution of insoluble calcium salts, such as calcium hydroxide, using hydrogen-binding molecules, such as sucrose. Such supersaturated solutions of calcium ions are then reacted with a source of carbonate from carbon dioxide gas, alkali metal carbonates (such as sodium carbonate), from organic carbonates, from ammonium carbonate, or from the hydrolysis of dialkyl carbonates (such as dimethyl carbonate) under hydroxide ions (see, e.g., US 4,237,147).

Commercial production is not practical since the ACC has a stability time in aqueous solution of no more than two minutes. Today, large scale production involving mixing and separating hundreds or even thousands of liters in less than two minutes using liquid-solid phase separation techniques such as filtration or centrifugation is not applicable. Commercial production can become practical if the stabilization time in solution can be extended to several hours, thus allowing the use of standard liquid-solid phase separation techniques (such as filtration or centrifugation).

No mention was made in the previous reports mentioned above of the period of time in which the ACC remains stable in solution, except that Hyun et al [ Materials Chemistry and Physics,93(2005) 376-. However, Hyun et al can only produce stable ACC in the presence of toxic ammonia (as described by Hyun, which is critical for stability). Furthermore, the calcium carbonate concentrations used in the publications are relatively low, which makes them impractical for industrial use.

When trying to reproduce the other published procedures, the applicant of the present invention produced ACC that is stable only in solution for several minutes and crystallizes thereafter. In some cases, although ACC is produced, it cannot be isolated from solution. For example, producing ACC using the procedure described in example 2 of US 4,237,147 only produces a slurry from which filtration is not possible and from which ACC cannot be isolated. Furthermore, from the slurry should be obtained a powder using spray drying as suggested in this patent, which would contain only ACC of-2/15 with the remaining 13/15 parts being sucrose.

In general, any attempt to replicate the procedure described in US 4,237,147 using calcium chloride or some other soluble calcium salt did not produce 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, there is no previous publication describing the production of ACC that remains stable in aqueous solutions or suspensions for long periods of time, using only up to 10% by weight of stabilizer. Furthermore, in all these processes, the carbonation step is the final synthesis step, usually followed by a liquid-solid separation step.

There is a need in the art for a novel process for producing ACC with increased stability (either as a suspension in an aqueous phase or as a dry powder) that can be adapted for producing ACC on a commercial production scale.

Disclosure of Invention

The present invention relates to a manufacturing process for producing Amorphous Calcium Carbonate (ACC) exhibiting specific XRD and raman spectra characteristic of amorphous forms. The novel process of the present invention utilizes hydrogen bonding molecules and organic solvents as stabilizers and results in ACC with increased stability when suspended in an aqueous phase or in the solid state as a dry powder. The method of the 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 solvent and a second stabilizer to form a suspension of stabilized ACC from which stabilized ACC can be isolated. In certain embodiments, the first stabilizer and the second stabilizer may be the same or different.

Accordingly, in one embodiment, the present invention provides a process for preparing Amorphous Calcium Carbonate (ACC), said process comprising the steps of: combining a solution comprising a soluble calcium salt and a first stabilizer with a solution comprising a soluble carbonate salt to form an ACC suspension; and adding simultaneously or sequentially in any order a water-miscible organic solvent and a solution comprising a second stabilizer, provided that the second stabilizer and organic solvent contact the ACC suspension within about 2 minutes of forming the ACC suspension, thereby obtaining a stabilized ACC suspension, wherein the total amount of stabilizers constitutes at most about 12% by weight of the stabilized ACC suspension and the water-miscible organic solvent constitutes at least about 5% by weight of the stabilized ACC suspension. The first stabilizer and the second stabilizer may be the same or different, and each possibility represents a separate embodiment of the present invention.

In another embodiment, the present invention provides a method of preparing ACC comprising the steps of: i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizing agent; ii) preparing an aqueous solution comprising soluble carbonate; iii) preparing an aqueous solution comprising a 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 simultaneous or sequential addition of the solutions prepared in steps iii) and iv) in any order, provided that the solutions contact the ACC suspension within about 2 minutes of forming the ACC suspension, thereby obtaining a stabilized ACC suspension, wherein the total amount of stabilizer constitutes at most about 12 wt% of the stabilized ACC suspension and the water-miscible organic solvent constitutes at least about 5 wt% of the stabilized ACC suspension. The first stabilizer and the second stabilizer are the same or different, and each possibility represents a separate embodiment of the present invention.

In another embodiment, the present invention provides a method of preparing ACC comprising the steps of: i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizing agent; ii) preparing an aqueous solution comprising soluble carbonate; iii) preparing 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 adding the solution prepared in step iii) to the ACC suspension within about 2 minutes of forming the ACC suspension to form a stabilized ACC suspension, wherein the total amount of stabilizer constitutes at most about 12% by weight of the stabilized ACC suspension and the water-miscible organic solvent constitutes at least about 5% by weight of the stabilized ACC suspension. The first stabilizer and the second stabilizer are the same or different, and each possibility represents a separate embodiment of the present invention.

In a presently preferred embodiment, the present invention provides a method for preparing stable ACC, said method comprising the steps of: i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizing agent; ii) preparing an aqueous solution comprising soluble carbonate and combining it with the calcium salt of step i) to obtain an ACC suspension; iii) preparing an aqueous solution of a second stabilizer, thereby obtaining a stabilized 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 the ACC suspension so as to form a stabilized ACC suspension, wherein the total amount of stabilizing agent constitutes at most about 12 wt% of the stabilized ACC suspension, and the water-miscible organic solvent constitutes at least about 5 wt% of the stabilized ACC suspension. The first stabilizer and the second stabilizer are the same or different, and each possibility represents a separate embodiment of the present invention.

In certain embodiments, the method according to the present invention may further comprise the step of isolating ACC from the stable ACC suspension. The method may further comprise the step of drying the isolated ACC, thereby obtaining a stabilized ACC powder. The separation may comprise filtration or centrifugation and the drying step may comprise vacuum heating or freeze-drying, and each possibility represents a separate embodiment of the invention. Thus, in certain embodiments, the methods of the present invention provide a stabilized ACC powder comprising less than about 15%, preferably less than 8% (e.g., between about 1% and about 7%) by weight water, and typically between about 30% and about 33% by weight calcium. Each possibility represents a separate embodiment of the invention.

It is understood that for each of the foregoing embodiments, each of the terms "first stabilizer" and "second stabilizer" encompasses a single stabilizing compound or a combination of more than one stabilizing compound. Thus, in certain embodiments, the aqueous calcium solution may comprise one stabilizing compound or a combination of two or more stabilizing compounds (collectively, "first stabilizing agents"). In other embodiments, the solution comprising the second stabilizing agent may comprise one stabilizing compound or a combination of two or more stabilizing compounds (collectively "second stabilizing agents"). Regardless of the number of stabilizers used, the total amount of stabilizers constitutes up to about 12% by weight of the stabilized 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, sodium or potassium carbonate), or ammonium carbonate. Each possibility represents a separate embodiment of the invention. In certain embodiments, the calcium salt and the carbonate salt 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 lower alcohols and ketones (e.g., methanol, ethanol, propanol, isopropanol, acetone, diethyl ketone, and cyclohexanone). A presently preferred water miscible organic solvent is ethanol. Each possibility represents a separate embodiment of the invention.

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

The first stabilizer and the second stabilizer used in the process of the present invention may be the same or different. In certain embodiments, the first stabilizer and the second stabilizer are each independently selected from the group consisting of: organic acids, phosphorylated organic acids, phosphate esters of hydroxycarboxylic acids, sulfate esters of hydroxycarboxylic acids, phosphorylated amino acids and derivatives thereof, amino acid sulfate esters, and hydroxyl-containing organic compounds in combination with bases such as alkali metal hydroxides. The hydroxyl-containing compound in combination with the hydroxide preferably also has other functional groups such as carboxyl groups and the like, but the hydroxyl group is not esterified. The organic acid may include, for example, ascorbic acid or acetic acid, and preferably it includes a carboxylic acid having at least two carboxyl groups and a molecular weight of not more than 250g/mol, such as citric acid, tartaric acid, malic acid, and the like. The ester may include, for example, phosphoenolpyruvate. In another embodiment, the phosphate or sulfate ester of a hydroxycarboxylic acid includes amino acids, examples of which include phosphoserine, phosphothreonine, sulfoserine, and sulfothreonine. In another embodiment, the stabilizing molecule is a phosphate derivative of an amino acid, such as creatine phosphate. The hydroxyl-containing compound in combination with the hydroxide may include, for example, monosaccharides, disaccharides, trisaccharides, oligosaccharides, and polysaccharides (e.g., sucrose) or other polyols (e.g., glycerol). The hydroxyl-containing compound may also include hydroxy acids (such as citric acid, tartaric acid, malic acid, etc.) or hydroxyl-containing amino acids (such as serine or threonine). Each possibility represents a separate embodiment of the invention.

In certain embodiments, at least one of the first stabilizer and the second stabilizer is a polyol in combination with an alkali metal hydroxide, or the stabilizer is a phosphorylated amino acid, wherein the total amount of polyol or phosphorylated amino acid in the suspension of stabilized ACC is from about 1mM to about 1000mM, for example from about 10mM to about 100 mM. The polyol preferably comprises a saccharide. In a preferred embodiment, the stabilizing agent is a phosphorylated amino acid, wherein the total concentration of phosphorylated amino acids in the suspension of stabilized ACC is from about 2mM to about 200mM, e.g., from up to about 20 mM. In another preferred embodiment, the stabilizing agent is a di-or tri-carboxylic acid (e.g., citric acid), wherein the total concentration of di-or tri-carboxylic acid in the stabilized ACC suspension is from about 2mM to about 200mM, e.g., from up to about 20 mM. In another preferred embodiment, the stabilizing agent is a non-phosphorylated hydroxyl-containing amino acid (e.g., serine or threonine) in combination with an alkali metal hydroxide, wherein the total concentration of amino acids in the suspension of stable ACC is from about 2mM to about 200mM, e.g., from up to about 20mM, and the total concentration of hydroxide in the suspension of stable ACC is between about 1mM and about 2000mM, e.g., about 0.1M. In another preferred embodiment, the stabilizing agent is a polyol in combination with an alkali metal hydroxide, wherein the total concentration of polyol in the suspension of stabilized ACC is from about 10mM to about 1000mM, such as up to about 100mM, and the total concentration of hydroxide in the suspension of stabilized ACC is between about 1mM and about 2000mM, such as about 0.1M. Each possibility represents a separate embodiment of the invention.

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

The step of combining the ACC suspension with the second stabilizer solution and the organic solvent is preferably performed at a temperature between about-10 ℃ and about 60 ℃, preferably between about-3 ℃ and ambient temperature (room temperature), and more preferably between about 0 ℃ and about 15 ℃. Each possibility represents a separate embodiment of the invention.

In a presently preferred embodiment, the present invention provides a process for the preparation of Amorphous Calcium Carbonate (ACC), said process comprising the steps of: i) preparing an aqueous solution of calcium chloride at a concentration of up to about 1M and a stabilizing agent in an amount between about 1mmol per 1mol of calcium chloride and about 150mmol per 1mol of calcium chloride (e.g., from about 4mmol per 1mol of calcium chloride to about 80mmol per 1mol of calcium chloride); ii) preparing an aqueous solution of sodium carbonate in the same molar concentration as the calcium chloride in step i) and combining it with the calcium salt solution of step i) to obtain an ACC suspension; iii) preparing a stabilizing solution comprising about 350g of ethanol per 1mol of calcium chloride in step i) and the same stabilizer as in step i) but in double amount; and iv) combining the stabilizing solution with the calcium carbonate suspension to obtain a stabilized ACC suspension. In one embodiment, the stabilizing agent in steps i) and iii) is phosphoserine in an amount from about 3mmol per 1mol of calcium to about 9mmol per 1mol of calcium and phosphoserine in an amount from about 8mmol per 1mol of calcium to 16mmol per 1mol of calcium, respectively, e.g. phosphoserine in an amount of about 6mmol per 1mol of calcium and phosphoserine in an amount of about 12mmol per 1mol of calcium, or phosphoserine in an amount of about 4mmol per 1mol of calcium and phosphoserine in an amount of about 8mmol per 1mol of calcium, respectively. In certain embodiments, the method further comprises the step of filtering the stable ACC suspension and optionally the step of additional vacuum drying at a temperature between 40 ℃ and about 50 ℃. In another embodiment, the stabilizer is sucrose and sodium hydroxide in amounts of about 20-100mmol sucrose per 1mol calcium and about 50-200mmol NaOH per 1mol calcium, e.g. about 25-70mmol sucrose per 1mol calcium and about 100mmol NaOH per 1mol calcium, such as about 25mmol sucrose per 1mol calcium and about 100mmol NaOH per 1mol calcium, and in step iii) about 40-200mmol sucrose per 1mol calcium and about 100-400mmol NaOH per 1mol calcium, such as about 50-200mmol sucrose per 1mol calcium and about 200mmol NaOH per 1mol calcium, such as about 140mmol sucrose per 1mol calcium and about 200mmol NaOH per 1mol calcium. In certain embodiments, the method further comprises the step of centrifuging and freeze drying the sediment. Each possibility represents a separate embodiment of the invention.

In one presently preferred embodiment, the method according to the present invention includes combining calcium chloride, an alkali metal carbonate, a phosphorylated organic acid, and an alcohol in an aqueous mixture to yield a stable ACC suspension comprising between about 2.5 and 5 weight percent ACC, between about 0.001 and about 0.3 weight percent (e.g., between about 0.05 and about 0.2 weight percent) phosphorylated organic acid, and between about 8 and about 32 weight percent ethanol (e.g., between about 10 and about 15 weight percent).

Another preferred method according to the present invention comprises combining calcium chloride, alkali metal carbonate, saccharide and sodium hydroxide, and alcohol in an aqueous mixture to obtain a stable ACC suspension comprising between about 2.5% and about 5% by weight ACC, between about 1% and about 4% by weight saccharide, about 0.5% by weight hydroxide, and 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 dicarboxylic acid, a tricarboxylic acid (e.g., citric acid), and an alcohol in an aqueous mixture to yield a stable ACC suspension comprising between about 2.5% and about 5% by weight ACC, between about 0.001% and about 0.2% by weight dicarboxylic or tricarboxylic acid, and between about 8% and about 32% by weight ethanol. Another preferred method according to the present invention comprises combining calcium chloride, an alkali metal carbonate, a di-or tri-carboxylic acid, a phosphorylated organic acid, and an alcohol in an aqueous mixture to obtain a stable ACC suspension comprising between about 2.5% and about 5% by weight ACC, a total of between about 0.001% and about 0.2% by weight di-or tri-carboxylic acid and phosphorylated organic acid, and between about 8% and about 32% by weight ethanol.

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

Another preferred method according to the present invention comprises combining calcium chloride, sodium carbonate, a non-phosphorylated hydroxyl-containing amino acid (e.g., serine), a saccharide and sodium hydroxide, and an alcohol in an aqueous mixture to yield a stable ACC suspension comprising between about 2.5% and about 5% by weight ACC, a total of between about 1% and about 4% by weight non-phosphorylated hydroxyl-containing amino acid and saccharide, about 0.5% by weight hydroxide, and between about 10% and about 15% by weight ethanol.

In another embodiment, the method of the invention further comprises isolating the ACC from the suspension and drying to obtain CaCO comprising between about 75% and about 88% by weight₃And less than about 10% by weight water.

In further embodiments, the present invention provides stabilized ACC suspensions and stabilized ACC powders produced from the methods as described herein. Thus, in one embodiment, the present invention provides a stable ACC suspension produced by the method of the present invention. In one embodiment, the stable ACC suspension comprises between about 2.5% and about 5% ACC by weight, between about 0.05% and about 0.2% phosphorylated organic acid by weight, and between about 10% and about 15% ethanol by weight. In another embodiment, the stable ACC suspension comprises between about 2.5% and about 5% ACC by weight, between about 1% and about 4% saccharides by weight, about 0.5% hydroxide by weight, and between about 10% and about 15% ethanol by weight. In another embodiment, the stable ACC suspension comprises between about 2.5% and about 5% by weight ACC, between about 0.05% and about 0.2% by weight organic acid (e.g., di-or tri-carboxylic acids such as citric acid), and between about 10% and about 15% by weight ethanol. In another embodiment, the stable ACC suspension comprises between about 2.5% and about 5% ACC by weight, between about 0.05% and about 0.2% organic acid (e.g., a non-phosphorylated hydroxyl-containing amino acid), about 0.5% hydroxide by weight, and between about 10% and about 15% ethanol by weight. Suspensions containing combinations of stabilizers are also contemplated. Each possibility represents a separate embodiment of the invention.

In other embodiments, the present invention provides stabilized ACC powders produced by the methods of the present invention. In one embodiment, the powder comprises between about 75% and about 88% by weight CaCO₃Less than about 10 wt% water, and an organic acid (e.g., a phosphorylated organic acid, a non-phosphorylated organic acid, a di-or tri-carboxylic acid, a hydroxyl-containing amino acid, or any other organic acid described herein). In other embodiments, the stabilized ACC powder comprises between about 75% and about 88% CaCO by weight₃Less than about 10 wt% water, and between about 1 wt% and about 5 wt% saccharide. Each possibility represents a separate embodiment of the invention.

In other aspects, the invention also relates to the use of the above-described suspensions and powders in dyes, paper products, plastics, inks, adhesives, marble repair products, medical devices, pharmaceuticals, food supplements, and/or food additives, and each possibility represents a separate embodiment of the invention.

In certain preferred embodiments, stabilized ACC is produced by mixing a supersaturated solution of calcium ions from a soluble calcium salt (such as calcium chloride), which also contains a first stabilizing molecule such as phosphoserine, with a supersaturated solution of carbonate from a soluble carbonate salt (such as sodium carbonate). Without additional stabilization, the precipitated ACC rapidly crystallizes in solution to a mixture of calcite and vaterite in less than about 2 minutes. However, in the method of the present invention, after allowing the precipitated ACC suspension in step 1 to mix for-10 seconds, a stabilizing solution containing a second stabilizing molecule (such as phosphoserine) is added. After allowing the precipitated ACC suspension and the stabilizing solution in step 2 to mix for-10 seconds, an organic solvent (such as ethanol) is added. After the addition of the organic solvent, ACC is stabilized and can be maintained in suspension for several days, depending on the concentrations of the first and second stabilizers and the ratio of the organic solvent. It has also been found that lowering the reaction temperature improves the stabilization time in solution. The order of addition of the second stabilizer and the alcohol may be reversed, or they may be added together in one solution of the second stabilizer contained in the alcohol.

The procedure may be carried out batchwise, in which the solutions are added to one another in a single addition, or as a continuous process in which the solutions are mixed, for example, in a continuous flow using continuous flow technology equipment.

Further embodiments of the invention and the full scope of applicability will become apparent from the detailed description given hereinafter. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Drawings

FIG. 1: raman spectra of several calcium carbonate samples taken using a micro-Raman method (micro-Raman). The spectra belong 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 CO of vaterite₂Raman shift of the main peak of the vibration.

FIG. 2: XRD spectrum of ACC produced by the process of the invention. The XRD spectrum of ACC is characterized by a broad low intensity peak from-20-302 theta.

FIG. 3: XRD spectrum of vaterite. The vaterite XRD spectrum is characterized by three major peaks at 24, 27 and 332 θ.

FIG. 4: XRD spectrum of calcite. The calcite XRD spectrum is characterized by multiple peaks and the most prominent peak at-292 theta.

Detailed Description

The present invention provides synthetic procedures for producing highly stable ACC in a stepwise process using hydrogen-bonding molecules and water-miscible organic solvents as stabilizers. The stepwise procedure of the present invention has been found to be far superior in safety, yield and stability to the previously described methods for producing stable ACC. It has been found that performing this procedure in separate steps according to the embodiments described herein is beneficial for producing highly stable ACC.

The surprising stability of ACC prepared according to 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 stabilizing molecules after the production of ACC allows for certain external coatings that increase the stability of ACC, and that the addition of organic solvents both reduces the activity of water and reduces the solubility of the stabilizing molecules in solution, which ensures that the rest remains on the surface or inside of the ACC particles, thus promoting the stabilization of ACC. Loste et al [ Journal of crystalline growth,254(2003) 206-: mg increases the stability of ACC by inclusion into the amorphous lattice, and since Mg radius is smaller than Ca radius, it has stronger binding to water molecules present in the ACC structure, thus inhibiting crystallization. Water binding molecules can function by the same mechanism. By binding to both calcium ions and water molecules, it can act to inhibit diffusion of water out of the amorphous lattice, thus inhibiting crystallization.

It has also been found that when certain organic acids or phosphorylated amino acids are used, there is no need to increase the solution pH with sodium hydroxide or another base. However, when sucrose or other sugars and non-phosphorylated hydroxyl-containing amino acids are used, it is necessary to raise the solution pH using, for example, an alkali metal hydroxide (such as sodium hydroxide, potassium hydroxide, and the like) in order to obtain a stabilizing effect. Koga et al [ Thermochimica Acta,318(1998) 239-. When sucrose was introduced with sodium hydroxide, it allowed to increase pH further to >14 without precipitating calcium hydroxide. Without wishing to be bound by any particular mechanism or theory, the combination of sucrose with a very high pH appears to have an improved stabilizing effect.

US 4,237,147 describes a method for producing ACC using calcium hydroxide and sucrose; however, sucrose is used in order to increase the solubility of calcium hydroxide, which requires a very large amount of sucrose relative to the amount described in the present invention. The high sucrose content described by US 4,237,147 makes the production of ACC impractical for two reasons: 1. the sucrose content is so high that ACC is only partially precipitated, which makes it almost impossible to isolate; 2. the high sucrose content is so high that it forms a viscous gel that cannot be filtered. In the present invention, because sucrose is used in small amounts as a stabilizer, not as a dissolving agent, much lower concentrations are required, which easily solves both of the problems described above.

As used herein, the term "soluble calcium salt" means a calcium salt that is soluble in water, i.e., the calcium salt is capable of being completely dissolved in water to give a clear solution. In general, a compound is considered "soluble" in water if it dissolves to the extent of at least about 1g/100mL of water (such as, for example, at least about 5g/100mL or at least about 10g/100mL) at a temperature of from about 0 ℃ to about ambient temperature (which is defined herein as from about 20 ℃ to 30 ℃). In a presently preferred embodiment, the soluble calcium salt is calcium chloride. In other embodiments, the soluble calcium salt may be calcium bromide, calcium iodide, calcium lactate, calcium gluconate, and the like. Each possibility represents a separate embodiment of the invention.

As used herein, the term "soluble carbonate" means a Carbonate (CO) that is soluble in water₃ ^2-) That is, the carbonate can be completely dissolved 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 embodimentIn one embodiment, the soluble carbonate is ammonium carbonate. Each possibility represents a separate embodiment of the invention.

As used herein, the term "stabilized ACC suspension" or "stabilized ACC" means ACC that can be maintained in suspension or as a dry solid (e.g., powder) for a period of time ranging from hours to days, weeks, or months without substantial conversion to a crystalline form. The term "substantial conversion" generally means that about 5% or more of the amorphous form is converted to the crystalline form. Thus, the method of the present invention produces ACC that typically maintains at least 95% or more (preferably at least about 97% or even more preferably at least about 99%) in amorphous form when left in suspension or as a solid powder at temperatures up to room temperature (about 20-30 ℃) or even at higher temperatures.

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

According to one aspect, the stabilizing molecules of the present invention are divided between a solution containing calcium ions and a second stabilizing solution, referred to as a "stabilizing solution". In one embodiment, the stabilizing solution is an aqueous solution comprising a second stabilizing agent and optionally a water-miscible organic solvent. In another embodiment, the stabilizing molecule may be dissolved directly in the water-miscible organic solvent.

In certain embodiments, each of the first and second stabilizers is independently selected from the group consisting of: organic acids, phosphorylated organic acids, phosphate esters of hydroxycarboxylic acids, sulfate esters of hydroxycarboxylic acids, phosphorylated amino acids and derivatives thereof, amino acid sulfate esters, and hydroxyl-containing organic compounds in combination with alkali metal hydroxides. According to one aspect, the stabilizing molecule is selected from, but not limited to, an organic acid, a phosphorylated amino acid, a phosphate group-containing molecule (such as, but not limited to, phosphoenolpyruvate or phosphocreatine), or a sulfate group-containing molecule (such as, but not limited to, an amino acid sulfate, such as sulfoserine or sulfothreonine), or any combination of the foregoing. According to another aspect, the stabilizing molecules include 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 polysaccharides, e.g., sucrose, mannose, glucose, etc.; or (ii) a non-phosphorylated amino acid containing a hydroxyl group.

In general, stabilizing molecules can be divided into two groups: 1) stabilizers which themselves have a strong stabilizing effect, the stabilizing molecules in this group including organic acids such as phosphoric or sulfuric esters of carboxylic acids (e.g., citric acid, tartaric acid, malic acid, etc.) and hydroxycarboxylic acids having at least two carboxyl groups and a molecular weight of no greater than about 250g/mol (e.g., phosphoenolpyruvate, phosphoserine, phosphothreonine, sulfoserine, or sulfothreonine); 2) there is a need for stabilizing molecules that add hydroxide in order to deprotonate the hydroxyl groups of the stabilizing molecule and improve its stabilizing effect. Stabilizing molecules in this group include monosaccharides, disaccharides, trisaccharides, oligo-or polysaccharides (glucose, mannose, fructose, sucrose, etc.), non-phosphorylated hydroxyl-containing molecules (including polyols and amino acids (e.g., glycerol, serine, threonine, etc.)). The term "non-phosphorylated hydroxyl-containing amino acid" refers to an amino acid, which may be natural or non-natural, that contains at least one hydroxyl group (OH) in its side chain.

According to one aspect of the invention, the stabilizing molecule in the calcium solution and the stabilizing molecule in the stabilizing solution are the same molecule. According to another aspect of the invention, it is two different molecules. In a preferred embodiment of the invention, the first and second stabilizer are the same and the amount of stabilizer used in e.g. step i) and step iii) of the process is in a ratio of from about 1:1 to about 10:1, e.g. about 1:2, about 1:3, about 1:5, about 2:1, about 3:1 or about 5:1 (ratio of first stabilizer to second stabilizer). Each possibility represents a separate embodiment of the invention.

According to one aspect of the invention, the organic solvent is derived 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, cyclohexanone, etc.), or other water-miscible organic solvent. Other examples of water-miscible organic solvents include, but are not limited to, ethers such as tetrahydrofuran or dioxane, acetonitrile, dimethoxyethane, diethoxyethane, Dimethylformamide (DMF), and Dimethylsulfoxide (DMSO). As used herein, the term "water-miscible organic solvent" refers to an organic solvent that is capable of being mixed with water in all proportions to form a homogeneous solution.

The total amount of stabilizer used in the process of the present invention means the combined amount of stabilizers used, e.g., the total amount of the first and second stabilizers as described herein. Typically, the total amount of stabilizer constitutes at most about 12% by weight of the stabilized ACC suspension, preferably at most about 10% by weight of the stabilized ACC suspension, and more preferably at most about 8% or at most about 5% or at most about 3% by weight of the stabilized ACC suspension. Each possibility represents a separate embodiment of the invention.

The water-miscible organic solvent constitutes at least about 5% by weight of the stable ACC suspension. Ethanol is the presently preferred organic solvent.

In certain embodiments, the calcium concentration in the calcium ion solution may vary from about 4mM to about 2M. For practical reasons, the calcium concentration should be maintained between about 0.5M-1M, for example between 0.5M and 0.75M, or between 0.75M and 1M. Each possibility represents a separate embodiment of the invention.

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

In further embodiments, the calcium to carbonate molar ratio may vary from about 2:1 to about 1:1.5, respectively. For practical reasons, it is preferred to use an equimolar ratio of 1:1, however, as one skilled in the art would expect, a variety of ratios may be utilized.

In further embodiments, the concentration of the stabilizing molecule in the calcium ion solution is between about 0.0001% by weight 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 one skilled in the art.

In further embodiments, the concentration of the stabilizing molecule in the stabilizing solution is between about 0.0002% by weight and about 20% by weight of the calcium ion solution. More preferably, the concentration is between about 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 one skilled in the art.

According to one aspect of the invention, when a hydroxyl-, phosphate-, or sulfate-containing molecule is combined with a hydroxide as the stabilizing molecule, the molar ratio of the hydroxyl-, phosphate-, or sulfate-containing molecule to the hydroxide is between about 4:1 and about 0.5:1, such as about 3:1, 2:1, 1:1, or 0.75:1, and each possibility represents a separate embodiment of the invention.

In further embodiments, the ratio between the amount of stabilizing molecule in the stabilizing solution and the amount of stabilizing molecule 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, and each possibility represents a separate embodiment of the invention. It has been found that for each pair of stabilizing molecules there is a different optimum ratio which can be readily determined by one skilled in the art.

In further embodiments, the organic solvent is used in a weight ratio of about 15:1 to about 1:3 (water: solvent) of the total aqueous solution. Different organic solvents perform better at different ratios, for example, ethanol has been found to perform well at a weight ratio of 7:1, whereas acetone performs well at a ratio of 5: 1. The optimal ratio of water to organic solvent can be readily determined by one skilled in the art.

In further embodiments, the temperature at which the reaction can be carried out is in the range of from about-10 ℃ to about 60 ℃. The temperature range of the reaction is preferably maintained between about-3 ℃ and ambient temperature (room temperature (RT)), more preferably between about 0 ℃ and about 15 ℃.

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 product as a dry powder. According to another aspect of the invention, the moisture should preferably be maintained below 10%, even more preferably below 8%.

According to one aspect of the invention, the dried stable product can be maintained at ambient conditions. According to another aspect of the invention, the dried stabilized product should be maintained in a humidity controlled environment preferably less than 20% relative humidity.

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

The produced ACC may be filtered using standard liquid/solid separation methods such as, but not limited to, vacuum or pressure filtration, centrifugation or decantation, and then dried using standard drying equipment such as, but not limited to, an air dryer, a vacuum oven or turbo oven, a spray dryer, a flash dryer, a freeze dryer or a paddle dryer.

The following examples are provided to more fully illustrate certain embodiments of the invention. In no way should it be construed, however, as limiting the broad scope of the invention. Many variations and modifications of the principles disclosed herein will be readily apparent to those skilled in the art without departing from the scope of the invention.

Example 1

In a typical procedure, the calcium solution contained 1 liter of water, 88.8g of calcium chloride and 888mg of phosphoserine. The carbonate solution contained 1 liter of water and 84.8g of sodium carbonate. The stabilizing solution contained 200ml of water and 1.776g of phosphoserine and used 350ml of ethanol as organic solvent. The calcium solution and carbonate solution were mixed together to precipitate unstable ACC, and after 20 seconds the stabilizer solution was added to the ACC suspension followed by ethanol, which produced a stable ACC suspension. The resulting stabilized ACC suspension stabilizes ACC in solution for at least 3 hours at-20 ℃ and at least 9 hours at 0 ℃. Then, during the time the ACC was still stable in suspension, it was filtered using a Buchner funnel and the filter cake was dried using a conventional oven at 40-50 ℃.

Example 2

The calcium solution contained 1 liter of water, 88.8g of calcium chloride and 700mg of citric acid. The carbonate solution contained 1 liter of water and 84.8g of sodium carbonate. The stabilizing solution contained 200ml of water and 1.4g of citric acid and 350ml of ethanol was used as organic solvent. The calcium solution and carbonate solution were mixed together to precipitate unstable ACC, and after 20 seconds the stabilizer solution was added to the ACC suspension followed by ethanol, which produced a stable ACC suspension. The resulting stabilized ACC suspension stabilizes ACC in solution for at least 3 hours at-20 ℃ and at least 9 hours at 0 ℃. Then, the ACC was filtered using a buchner funnel during the time it was still stable in suspension and the filter cake was dried using a vacuum oven at 40-50 ℃ under nitrogen atmosphere at 400 mb.

Example 3

The calcium solution contained 1 liter of water, 88.8g of calcium chloride and 888mg of threonine phosphate. The carbonate solution contained 1 liter of water and 84.8g of sodium carbonate. 1.776g of citric acid were dissolved in 350ml of ethanol. The calcium solution and carbonate solution were mixed together to precipitate out unstable ACC and after 20 seconds the ethanol-stabilizer solution was added to the ACC suspension, which resulted in a stable ACC suspension. The resulting stabilized ACC suspension stabilizes ACC in solution for at least 5 hours at-20 ℃ and at least 9 hours at 0 ℃. Then, the ACC was filtered using a buchner funnel during the time it was still stable in suspension and the filter cake was dried using a conventional oven at 40-50 ℃.

Example 4

The calcium solution contained 1 liter of water, 88.8g of calcium chloride, 20g of sucrose and 3.35g of sodium hydroxide. The carbonate solution contained 1 liter of water and 84.8g of sodium carbonate. The stabilizing solution contained 200ml of water, 40g of sucrose and 6.67g of sodium hydroxide and used 350ml of ethanol as organic solvent. The calcium solution and carbonate solution were mixed together to precipitate unstable ACC, and after 20 seconds the stabilizer solution was added to the ACC suspension followed by ethanol, which produced a stable ACC suspension. The resulting stabilized ACC suspension comprises ACC stable for at least 10 hours at-20 ℃ and at least 24 hours at 0 ℃. The ACC was then centrifuged using a bench top (bench top) centrifuge at 4000rpm for 5 minutes, the supernatant was discarded, and the concentrated product was freeze-dried overnight at-80 ℃ under high vacuum using a freeze-dryer.

Example 5

The calcium solution contained 1 liter of water, 88.8g of calcium chloride, 10g of serine and 3.8g of sodium hydroxide. The carbonate solution contained 1 liter of water and 84.8g of sodium carbonate. The stabilizing solution contained 200ml of water, 20g of serine and 7.62g of sodium hydroxide and used 350ml of ethanol as organic solvent. The calcium solution and carbonate solution were mixed together to precipitate unstable ACC, and after 20 seconds the stabilizer solution was added to the ACC suspension followed by ethanol, which produced a stable ACC suspension. The resulting stabilized ACC suspension comprises ACC stable for at least 2 hours at-20 ℃ and at least 8 hours at 0 ℃. The ACC was then centrifuged at 4000rpm using a bench top centrifuge for 5 minutes, the supernatant was discarded, and the concentrated product was freeze-dried overnight at-80 ℃ under high vacuum using a freeze-dryer.

Example 6

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

Fig. 1 and 2 show representative ACC raman and XRD spectra of dried samples prepared according to examples 1 and 2 described above. Figures 3 and 4 show the XRD spectra of vaterite and calcite for comparison.

While the present invention has been particularly described, it will be understood by those skilled in the art that various changes and modifications may be made. Accordingly, the invention should not be construed as limited to the specifically described embodiments, and the scope and concept of the invention will be more readily understood by reference to the claims that follow.

Claims (45)

1. A method of preparing a stable Amorphous Calcium Carbonate (ACC) suspension, the method 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 salt to form an ACC suspension; and

ii) adding simultaneously or sequentially in any order a water-miscible organic solvent and a solution comprising a second stabilizer, provided that said second stabilizer and said water-miscible organic solvent contact said ACC suspension within 2 minutes of forming said ACC suspension, thereby obtaining a stabilized ACC suspension;

wherein the first stabilizer and the second stabilizer are the same or different; and wherein the total amount of stabilizer constitutes at most 12 wt% of the stabilized ACC suspension and the water-miscible organic solvent constitutes at least 5 wt% of the stabilized ACC suspension.

2. The method of claim 1, comprising the steps of:

i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizing agent;

ii) preparing an aqueous solution comprising soluble carbonate;

iii) preparing a solution comprising a second stabilizer;

iv) preparing a solution comprising a water miscible organic solvent; and

v) combining the aqueous solution prepared in step ii) with the aqueous solution prepared in step i) so as to form an ACC suspension, followed by simultaneous or sequential addition of the solutions prepared in steps iii) and iv) in any order, provided that the solutions contact the ACC suspension within 2 minutes of forming the ACC suspension, thereby obtaining the stable ACC suspension.

3. The method of claim 1, comprising the steps of:

i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizing agent;

ii) preparing an aqueous solution comprising soluble carbonate;

iii) preparing a solution of a second stabilizer in a water-miscible organic solvent; and

iv) combining the aqueous solutions prepared in steps i) and ii) so as to obtain an ACC suspension, followed by adding the solution prepared in step iii) to the ACC suspension within 2 minutes of forming the ACC suspension so as to form a stable ACC suspension.

4. The method of claim 1, comprising the steps of:

i) preparing an aqueous solution comprising a soluble calcium salt and a first stabilizing agent;

ii) preparing an aqueous solution comprising soluble carbonate and combining it with the soluble calcium salt of step i) to obtain an ACC suspension;

iii) preparing an aqueous solution of a second stabilizer, thereby obtaining a stabilized solution;

iv) combining the stabilizing solution with the ACC suspension; and

v) adding a water-miscible organic solvent, wherein said stabilizing solution and said water-miscible organic solvent are added to said ACC suspension within 2 minutes of forming said ACC suspension, so as to form a stabilized ACC suspension.

5. The method of claim 1, wherein the soluble calcium salt is calcium chloride.

6. The method of claim 1, wherein the soluble carbonate is an alkali metal carbonate or ammonium carbonate.

7. The process of claim 6, wherein the alkali metal carbonate is lithium carbonate, sodium carbonate or potassium carbonate.

8. The method of claim 1, wherein the soluble calcium salt and the soluble carbonate salt are present in a molar ratio of from 0.5 to 2.0.

9. The method of claim 1, wherein the water-miscible organic solvent is selected from the group consisting of lower alcohols and ketones.

10. The process 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.

11. The method of claim 10, wherein the water-miscible organic solvent is ethanol.

12. The method of claim 1, wherein the concentration of the soluble calcium salt solution is from 4mM to 2M, and wherein the concentration of the soluble carbonate solution is from 4mM to 2M.

13. The method of claim 1, wherein the first stabilizer and the second stabilizer are each independently selected from the group consisting of: organic acids, phosphorylated organic acids, phosphate or sulfate esters of hydroxycarboxylic acids, phosphorylated amino acids and derivatives thereof, and hydroxyl-containing organic compounds in combination with alkali metal hydroxides.

14. The method of claim 13, wherein at least one of the first stabilizer and the second stabilizer 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 a molecular weight of not more than 250 g/mol.

15. The method of claim 14, wherein at least one of the first stabilizer and the second stabilizer is selected from the group consisting of citric acid, tartaric acid, and malic acid.

16. The method of claim 13, wherein at least one of the first and second stabilizers is a phosphate or sulfate ester of a hydroxycarboxylic acid, a phosphorylated amino acid derivative, or an amino acid sulfate ester.

17. The method of claim 16, wherein at least one of the first stabilizer and the second stabilizer is selected from phosphoenolpyruvate, phosphocreatine, phosphoserine, phosphothreonine, sulfoserine, and sulfothreonine.

18. The method of claim 13, wherein at least one of the first stabilizer and the second stabilizer is a hydroxyl-containing organic compound in combination with an alkali metal hydroxide, wherein the hydroxyl-containing organic compound is selected from the group consisting of: monosaccharides, disaccharides, trisaccharides, oligosaccharides and polysaccharides; and non-phosphorylated hydroxyl-containing compounds.

19. The method of claim 18, wherein at least one of the first stabilizer and the second stabilizer is a hydroxyl-containing organic compound in combination with an alkali metal hydroxide, wherein the hydroxyl-containing organic compound is selected from non-phosphorylated amino acids.

20. The method of claim 18, wherein at least one of the first stabilizer and the second stabilizer is selected from the group consisting of: glucose, mannose, fructose, sucrose, glycerol, serine, and threonine, and wherein the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide.

21. The method of claim 13, wherein at least one of the first stabilizer and the second stabilizer is selected from the group consisting of: a polyol in combination with an alkali metal hydroxide, a phosphorylated amino acid, an amino acid sulfate, a dicarboxylic acid, a tricarboxylic acid, a non-phosphorylated hydroxyl-containing amino acid in combination with an alkali metal hydroxide, and any combination thereof, wherein the total amount of stabilizer in the suspension of stable ACC is 1mM to 1000 mM.

22. The method according to claim 13, wherein at least one of the first and second stabilizers is a phosphorylated amino acid, wherein the total concentration of the phosphorylated amino acid in the suspension of stable ACC is from 2mM to 200 mM.

23. The method according to claim 13, wherein at least one of the first and second stabilizers is citric acid, wherein the total concentration of the citric acid in the suspension of stabilized ACC is from 1mM to 200 mM.

24. The method according to claim 13, wherein at least one of the first and second stabilizers is a polyol in combination with an alkali metal hydroxide or a non-phosphorylated hydroxyl-containing amino acid in combination with an alkali metal hydroxide, wherein the total concentration of the polyol or the non-phosphorylated hydroxyl-containing amino acid in the stable ACC suspension is from 10mM to 1000mM, and the total concentration of the alkali metal hydroxide in the stable ACC suspension is between 1mM and 2000 mM.

25. The method of claim 1, wherein the first stabilizer and the second stabilizer are different.

26. The method of claim 1, wherein the first stabilizer and the second stabilizer are the same, and wherein the first stabilizer and the second stabilizer are used in a ratio from 1 to 10.

27. The method of claim 1, wherein the step of adding the second stabilizer and the water-miscible organic solvent is performed at a temperature between-10 ℃ and 60 ℃.

28. The method of claim 27, wherein the step of adding the second stabilizer and the water-miscible organic solvent is performed at a temperature between-3 ℃ and ambient temperature.

29. The method of claim 27, wherein the step of adding the second stabilizer and the water-miscible organic solvent is performed at a temperature between 0 ℃ and 15 ℃.

30. The method according to claim 1, further comprising a step of separating the ACC from the suspension of stabilized ACC and a drying step, thereby obtaining a powder of stabilized ACC.

31. The method of claim 30, wherein the separating step comprises filtration or centrifugation and the drying step comprises heating or freeze drying.

32. The method of claim 30, wherein the stable ACC powder comprises less than 15% by weight water and between 30% and 35% by weight calcium.

33. The method according to claim 32, wherein the stable ACC powder comprises less than 8 wt% water, and between 30 and 35 wt% calcium.

34. The method of claim 1, comprising the steps of:

i) preparing an aqueous solution of calcium chloride in a concentration of at most 1M and a first stabilizer in an amount between 1mmol per 1mol of calcium chloride and 80mmol per 1mol of calcium chloride;

ii) preparing an aqueous solution of sodium carbonate at the same molar concentration as the calcium chloride in step i) and combining it with the aqueous solution of step i) to obtain an ACC suspension;

iii) preparing a stabilizing solution comprising 350g of ethanol per 1mol of calcium chloride in step i) and the same but double amount of a second stabilizer as the first stabilizer used in step i); and

iv) combining the stabilizing solution with the ACC suspension within 2 minutes of forming the ACC suspension, thereby obtaining a stabilized ACC suspension.

35. The method according to claim 34, wherein the first and second stabilizing agents in steps i) and iii) are phosphoserine in an amount of 6mmol per 1mol of calcium and phosphoserine in an amount of 12mmol per 1mol of calcium, respectively, the method further comprising filtering the stabilized ACC suspension and drying in vacuo at a temperature between 40 ℃ and 50 ℃.

36. The method of claim 34, wherein the first and second stabilizers are sucrose and sodium hydroxide in an amount of 70mmol sucrose and 100mmol NaOH per 1mol calcium in step i) and sucrose and sodium hydroxide in an amount of 140mmol sucrose and 200mmol NaOH per 1mol calcium in step iii), the method further comprising isolating the ACC by centrifugation or freeze-drying.

37. The method according to claim 1, comprising combining calcium chloride, alkali metal carbonate, phosphorylated organic acid, and alcohol in an aqueous mixture to obtain a stable ACC suspension comprising between 2.5 and 5 wt% ACC, between 0.001 and 0.2 wt% phosphorylated organic acid, and between 8 and 32 wt% ethanol.

38. The method according to claim 1, comprising combining calcium chloride, alkali metal carbonate, di-or tri-carboxylic acid, and alcohol in an aqueous mixture, thereby obtaining a stable ACC suspension comprising between 2.5 and 5 wt% ACC, between 0.001 and 0.2 wt% di-or tri-carboxylic acid, and between 8 and 32 wt% ethanol.

39. The method according to claim 1, comprising combining calcium chloride, alkali metal carbonate, di-or tri-carboxylic acid, phosphorylated organic acid, and alcohol in an aqueous mixture to obtain a stable ACC suspension comprising between 2.5 and 5 wt% ACC, di-or tri-carboxylic acid and phosphorylated organic acid in total between 0.001 and 0.2 wt%, and ethanol between 8 and 32 wt%.

40. The method according to claim 1, comprising combining calcium chloride, alkali metal carbonate, saccharide and sodium hydroxide, and alcohol in an aqueous mixture, thereby obtaining a stable ACC suspension comprising between 2.5 and 5 wt% ACC, between 1 and 4 wt% saccharide, 0.5 wt% hydroxide, and between 10 and 15 wt% ethanol.

41. The method according to claim 1, comprising combining calcium chloride, alkali metal carbonate, non-phosphorylated hydroxyl-containing amino acid and sodium hydroxide, and alcohol in an aqueous mixture to obtain a stable ACC suspension comprising between 2.5 and 5 wt% ACC, between 1 and 4 wt% non-phosphorylated hydroxyl-containing amino acid, 0.5 wt% hydroxide, and between 10 and 15 wt% ethanol.

42. The method according to claim 1, comprising combining calcium chloride, sodium carbonate, non-phosphorylated hydroxyl-containing amino acids, sugars and sodium hydroxide, and alcohol in an aqueous mixture to yield a stable ACC suspension comprising between 2.5 and 5 wt% ACC, between 1 and 4 wt% in total of non-phosphorylated hydroxyl-containing amino acids and sugars, 0.5 wt% hydroxide, and between 10 and 15 wt% ethanol.

43. The method according to any of claims 37 to 42, further comprising a step of separating the ACC from the stabilized ACC suspension and a drying step, resulting in CaCO comprised between 75 and 88 wt. -%₃And less than 10% by weight water.

44. The method of claim 1, wherein the first stabilizing agent comprises a combination of two or more stabilizing compounds.

45. The method of claim 1, wherein the second stabilizing agent comprises a combination of two or more stabilizing compounds.