Carboxylic acid-loaded salt carrier and preparation method thereof

Abstract

The present invention provides a carboxylate carrier loaded with carboxylic acid, which is a free-flowing powder of a granular solid. The compound of the present invention is stable, biocompatible and digestible, facilitates high acid loading and controlled release of customizable acid strength in solution, and facilitates the handling of liquid carboxylic acids, such as formic acid, acetic acid, glycolic acid, propionic acid, butyric acid and lactic acid, in powder form. The compound of the present invention is soluble in polar solvents, except for the carrier component, which is thermally stable at up to 300°C. The present invention further provides a method for making the free-flowing compound of the present invention, which comprises loading the carrier carboxylic acid with at least one loaded carboxylic acid selected from preferably liquid short-chain carboxylic acids by contacting an alkaline earth metal base, a carrier carboxylic acid and a component of the loaded carboxylic acid. The powder product obtained by the method of the present invention has the characteristics of low moisture, a defined and uniform particle size, free flow and no agglomeration.

Description

Technical Field

[0001] The present invention relates to a solid compound loaded with an organic acid, and more particularly to a carboxylate carrier loaded with carboxylic acid which exhibits controlled acid release and has the characteristics of free flow, homogeneity and granulation, and discloses a preparation method thereof. Background Art

[0002] Organic acids are used in a variety of applications due to their organoleptic, physiological and chemical properties. Organic acids are carbon-containing compounds that contain + ) acceptor (such as water) to produce a balanced reaction, which can provide a molecule or ion with a functional group that can provide a proton. In the case of water as a proton acceptor, an oxonium ion H is formed. 3 O + , making the solution acidic. Acidity is a key factor in many applications, such as buffers for (bio)chemical assays, preservation, cosmetic formulations, antimicrobial formulations, excipients in pharmaceutical applications, and is therefore an important factor in many production industries. The tendency to donate a proton is measured by the acid constant (or pK) of a substance, which indicates the acid strength of the molecule. a This means that acidity increases with the pK a The components that can donate more than one proton are represented by multiple pK ax Description, where each pK ax Describe the different acid-base reactions of proton x.

[0003] Most organic acids donate protons via their carboxyl group (-COOH) and are defined as carboxylic acids in this context. As basic chemicals used in technical compounds in foods, personal care products, plastics, surfactants and detergents, complexing agents, colorants, and many other consumer and industrial products, carboxylic acids are of great economic importance for large-scale global production. In the era of globalized production, efficient economics of basic chemicals such as organic acids is a prerequisite for the global development of downstream processes, and the economic, safe and simple transportation of effective, inexpensive and easily metered organic acid compounds is essential for modern industry.

[0004] In the pharmaceutical, cosmetic, food and feed industries, carbon chain lengths less than five carbon atoms Short chain carboxylic acidsUsed as acidulants, flavouring compounds, pH buffers and agents to control microbial growth, liquid carboxylic acids such as acetic acid are used in a range of pharmaceutical applications, such as renal dialysis fluids. The short-chain liquid carboxylic acids used in these areas are typically formic, acetic, glycolic, propionic, lactic and butyric acids. As discussed by Stratford (2003), Kornhauser et al. (2010) and demonstrated by numerous scientific papers, these substances are used in low concentrations of typically 2% to 10% (by weight) or less in the final product and are generally harmless. However, in concentrated form, these substances are corrosive, flammable, volatile and are classified as hazardous. As a result, these substances are subject to the European Commission (2008) Dangerous Goods Regulation, making them costly to transport and store, (2006) further demonstrated this. Therefore, these acids are difficult to handle in a safe manner in the pharmaceutical, cosmetic, food or feed industry and may also pose a threat to the environment.

[0005] In this regard, WO 91 / 19692 discloses a solid metastable complex of calcium, citrate and malate with high bioavailability. However, the disclosed complex requires that the acidic anions citrate and malate are present in the complex in their deprotonated form (as carboxylates). Therefore, WO 91 / 19692 does not disclose substances that bind acids in protonated form. In order to stabilize the complex, it must be ensured that a calcium supernatant is present in the complex during drying, since lower proportions of salt may precipitate out of the solution. In addition, metastable complexes are also disadvantageous, since very large amounts of the complex are required to achieve the desired effect.

[0006] US 3,534,095 discloses a dihydrate fumarate of magnesium or calcium and a method for preparing the same. Here, the stoichiometric ratio of fumaric acid to magnesium or calcium is fixed at 1:1. Similarly, US 2002 / 0068113 discloses a compound salt of the formula Ca(R 1 )(R 2 ) calcium double salt, wherein R 1 and R 2 Is saturated or mono- or polyunsaturated C 1 -C 5 - Hydrocarbyl acids, which can be used, for example, in food, animal feed, pet food, cosmetics and pharmaceuticals. However, the fixed stoichiometric relationship between the salts of divalent magnesium or calcium cations and the short-chain carboxylic acids is a disadvantage, since very large amounts of (double) salts are required to achieve the desired preservative effect and a minimum pH value below the shutdown point is required, in particular the pK of the corresponding acid. a value to ensure adequate and effective antibacterial function.

[0007] In order to mitigate high transport costs or reduce hazardous characteristics, these liquid short-chain carboxylic acids are often (partially) neutralized and / or diluted. The lower concentration of active substance when diluting / neutralizing such liquid acids leads to a reduction in the efficacy of the application (e.g. in terms of its antimicrobial and acidifying properties).

[0008] A specific example of this use in the food industry is described in patent US2008 / 0317921 A1, where Listeria monocytogenes, Escherichia coli and other pathogens in meat products are controlled by using an aqueous solution of sodium lactate mixed with vinegar, acetic acid or its acid salts. Attempts to compensate for the dilution of organic acids by using a higher amount of diluent compounds have resulted in limited efficacy and high transportation costs of the material compounds, making the application of short-chain carboxylic acids in various industries impractical and uneconomical. In addition, even the acid in diluted form is subject to varying degrees of dangerous goods transportation regulations. For formic acid, acetic acid, propionic acid, lactic acid, glycolic acid and butyric acid, which are used as buffers, fragrances, moisturizers, antibacterial agents, preservatives, pH regulators and skin conditioners in cosmetics and skin applications (see the cosmetic ingredient database CosING), there are similar processing challenges, making these challenges a basic limitation in a wide range of industrial fields. Similarly, other organic acids such as salicylic acid or benzoic acid are also used in the cosmetics and pharmaceutical industries for their antifungal and antiseptic functions, where salicylic acid is used for its keratolytic properties. These substances exhibit the same general acid handling problems, resulting in a less efficient and therefore more costly manufacturing process.

[0009] A common method for improving carboxylic acid treatment is to adsorb the aforementioned acid into a high surface mineral carrier system. WO 97 / 07687 discloses particles composed of a core material of a porous carrier and an organic acid and a swellable coating material. Similar high surface mineral carrier systems include mineral silicates, such as precipitated silica, zeolite, bentonite, vermiculite or diatomaceous earth. Carboxylic acid and mineral silicates are mixed to produce a solid product having a carboxylic acid content of generally 30% by weight to 70% by weight. Such products are currently used in the feed industry as so-called "acidifiers" to promote animal growth and health, as described in EP 1761133 B1, wherein the carrier is diatomaceous earth. However, due to the high proportion of non-functional, inert and indigestible silicate carriers, this method is not optimal. Mineral silicates such as magnesium aluminum silicate are used as absorbents in the cosmetics industry, but their potential as acid carriers has not yet been developed.

[0010] US2002 / 0086090 discloses a solid preparation of a mixed acid of sorbic acid, at least one liquid organic acid and at least one other solid organic acid, both of which refer to the aggregated state at room temperature (23° C.). The complex is a pure mixture of acids, i.e., no chemical reaction occurs between the acids, no carrier is formed, and therefore, dangerous goods regulations are not conducive to the economical and efficient transportation of the acid.

[0011] Another possible industrial application of carboxylic acids is the use of acid adducts of alkali metal salts of carboxylic acids, such as sodium diacetate or potassium diacetate. These substances are solids with the structure

[0012] M + RCOO - ·RCOOH

[0013] M + Sodium + ) or potassium (K + ) ions, RCOO - is a short-chain carboxylate ion, such as acetate, and RCOOH is the corresponding short-chain carboxylic acid, such as acetic acid. As described in US 3,672,914 A, the resulting solid acid acetate can be used, for example, to impart salt and vinegar flavors to potato chips or salad dressings. However, according to the CosING database, adducts such as sodium diacetate or potassium diacetate have limited approval in cosmetic products in the EU and are not related to technical challenges in the wider industrial field. According to Grillo et al. (1970), alkali metal cations (practically limited to sodium or potassium) are associated with typical modern civilization diseases, such as obesity, coronary artery disease, type 2 diabetes or hypertension, while excess potassium acts as a laxative in the human and animal digestive tract and may cause hyperkalemia, as demonstrated by Mandal (1997). In addition, the fixed stoichiometric relationship between monovalent alkali metal cation salts and short-chain carboxylic acids is a disadvantage. In this regard, it is highly desirable to provide the benefits of organic acids, especially short-chain carboxylic acids, including alternative bioavailable metal salts, which preferably support human and animal health as important agents in biochemical pathways, such as magnesium, which is important for, for example, muscle contraction, blood coagulation or vitamin absorption, and calcium, which is an important component of bones and teeth. To date, the problems that have presented disadvantages in the handling and transportation of liquid carboxylic acids are due to their high dosage requirements and their limited feasibility due to the high cost of the compounds.

[0014] WO 99 / 12432 discloses soaking salts containing at least one salt of one or more organic carboxylic acids in liquid form, wherein 0.5 to 30% by weight of at least one liquid organic carboxylic acid has been incorporated relative to the carboxylate. However, this corresponds to salts in which the amount of acid incorporated is only less than a stoichiometric ratio of 1. Moreover, as described in WO 91 / 19692 (see above), such soaking salts comprising carboxylic acids in liquid form tend to precipitate out of solution. These soaking salts are therefore not stable over a long period of time, since there is a risk that the composition changes over time during storage.

[0015] DE 414171 discloses an acidic lactic acid calcium salt comprising (C 3 H5 O 3 ) 2 Ca+2C 3 H 6 O 3 +2H 2 O. However, the salt contains a large amount of water, at least 8.3%. This significantly increases the storage and transportation requirements and also makes it more difficult to determine the correct proportion of acid to be added in its application. Summary of the invention

[0016] Purpose of the invention / technical problem

[0017] There is an urgent need to overcome the above-mentioned shortcomings of existing organic acid compounds and to provide a safe-processing, free-flowing powdered compound that can carry and release liquid carboxylic acids in a controlled manner without the use of mineral carriers and without the need to incorporate sodium or potassium ions in the compound, while being customizable in terms of the type and amount of acid loaded.

[0018] Furthermore, the process for making the carboxylic acid-supported salt support should be simple, should provide a high loading capacity for the supported acid, should be based on inexpensive starting materials and should not require additives or catalysts, thus facilitating an economical synthesis on an industrial scale.

[0019] Technical Solution

[0020] According to the present invention, this object is achieved by supporting a short-chain carboxylic acid, most preferably C 1 -C 4 Further advantageous developments of the invention are specified in the dependent claims.

[0021] Therefore, the present invention provides a solid compound prepared as a powder, which exhibits good fluidity and comprises the following structure,

[0022] or

[0023] Preferably, it is prepared by the simple preparation method described herein, comprising the following components

[0024] Carrier Carboxylates More preferred

[0025] in

[0026] M 2+is an alkaline earth metal ion, preferably calcium (Ca), magnesium (Mg), barium (Ba), or a divalent metal ion selected from iron (Fe), copper (Cu), zinc (Zn), manganese (Mn), tin (Sn), or a mixture thereof,

[0027] R 1 is an optionally substituted C 1 -C 10 Alkyl, optionally substituted mono- or polyunsaturated C 1 -C 10 A hydrocarbon group or an optionally substituted aryl group, wherein the substituents are independently selected from a carbonyl group (═O) (preferably comprising a carbonyl group adjacent to a hydroxyl group by forming a carboxylic acid group (preferably a deprotonated carboxylic acid group), an amino group (NH 2 ), hydroxyl (OH), halogen, cyano (CN) or a mixture thereof, and

[0028] Where m is 0 to 2,

[0029] Supported carboxylic acid R 2 COOH,

[0030] Where R 2 is an optionally substituted C 1 -C 10 Alkyl or optionally substituted mono- or polyunsaturated C 1 -C 10 Hydrocarbyl, wherein the substituents are independently selected from carbonyl (═O) (preferably comprising a carbonyl group adjacent to a hydroxyl group by forming a carboxylic acid group (preferably a deprotonated carboxylic acid group), amino (NH 2 ), hydroxyl (OH), halogen or cyano (CN) or a mixture thereof,

[0031] 1 of them <n≤6;

[0032] The carrier carboxylic acid or (R 1 COO (m+1)- The pK of the corresponding carboxylic acid a1 ≤Carboxylic acid R 2 pK of COOH a1 ,

[0033] The supported carboxylic acid R 2 COOH, preferably protonated supported carboxylic acid is physically adsorbed on the support carboxylate or within the structure.

[0034] The present invention relates to carboxylic acid loaded salt carriers and their synthesis, which produce dry powder carrier salts having essential advantages in dosability and processability, such as good flowability and high acid effect through high molar concentrations without restrictions imposed by hazardous goods regulations. These acidic, solid and free-flowing compounds can be used in pharmaceutical, cosmetic, food and feed applications.

[0035] A method has been discovered for producing short chain carboxylic acids, preferably C 1 -C 4 A novel process for the preparation of carboxylic acids. The process comprises the reaction of a carrier acid and an alkaline earth metal ion source (preferably as a base) with a supported acid present in a reaction mixture and is generally conducted by mixing the starting materials under thermal control and subsequently drying a powder of a specified size from condensed byproducts. Taking advantage of the acid strength of the starting materials, a physically adsorbed acid inclusion component of a salt carrier of a supported carboxylic acid is obtained from the process in good yield, thereby providing an acidic functional powder exhibiting good flowability.

[0036] Effects of the Invention

[0037] Product advantages and description

[0038] Inclusion / physical adsorption

[0039] The compounds of the present invention relate to a series of carboxylate carriers loaded with carboxylic acids, referred to as acid-loaded carriers, which have controlled acidity and appear in powder form, containing liquid short-chain carboxylic acids. The term powder as used herein refers to a granular material that is solid or semi-solid when placed in an open container at atmospheric pressure and room temperature (rt, 23°C).

[0040] Inclusion compounds, such as the carboxylate carrier of the present invention, are compounds in which one chemical component (carrier) has the ability to capture other components. Inclusion of reactive components such as short-chain carboxylic acids has important benefits because the loaded components, preferably the loaded carboxylic acids, are physically adsorbed in the matrix / cavity of the carrier material, which is an interaction without covalent bonding, so their reactivity is mediated in the inclusion compound. The mediated reactivity of the carrier of the loaded reactant is conducive to controlling its acidity, which is crucial for the industrial development of the reaction pathway. Among others, the mediated reactivity of the inclusion compound helps to promote safety / stability during storage or transportation in technical chemistry.

[0041] The intensity of physical adsorption is the main indicator of the stability of the inclusion compound according to the present invention and can be semi-quantitatively analyzed by thermal analysis. Thermal analysis is an analysis of the property changes associated with the applied temperature changes. Thermogravimetric analysis (TGA) is the most widely used thermal analysis method, which measures the weight change as a function of temperature (or time) in the material, and is therefore suitable for evaluating the quality of the compounds of the present invention by analyzing the physicochemical transformations that are highly correlated with the stability of the inclusion compound formulation (e.g., desorption processes, decomposition and / or dehydration). The compounds of the present invention advantageously exhibit controlled desorption of the loaded acid, which can be independently caused by similar heat-induced purification of the compounds of the present invention. In addition, the thermally induced desorption of the loaded carboxylic acid from the compounds of the present invention is shown to be quantitative in different temperature ranges, while the carrier component advantageously remains stable at up to 300°C.

[0042] Differential thermal analysis (DTA), in which the temperature of a sample is compared with that of an inert reference material during a programmed change of temperature, verifies the control of endothermic processes that are highly relevant for the compounds of the invention, such as the evaporation of water as a purification and / or desorption of the compounds of the invention, which is the release of the active compound. Thus, the study of the weight change (TGA signal) and the simultaneous detection of the thermal phenomena (DTA signal) are proof of concept for the successful release of the acid by the compounds of the invention.

[0043] It has been shown that the desorption of the supported acid of the compounds of the invention requires a significant energy stimulus to release the supported acid from the acid-supporting carrier, such as through the entry of thermal energy, when compared to the acid isolated alone. The additional energy required to release the supported carboxylic acid from the support structure clearly demonstrates the stability of the compounds of the invention, which is based on the strength of the physical adsorption of the supported carboxylic acid at the support structure. Therefore, the material is an inclusion compound.

[0044] Thus, the advantageously delayed evaporation or increased heat energy required to release the supported carboxylic acid from the support structure demonstrates the stability of the compounds of the invention. If supported according to the invention, the delayed release of the liquid short-chain carboxylic acid by evaporation effectively inhibits uncontrolled release of the supported short-chain acid by evaporation, making it unnecessary to require cumbersome cooling of the formulation to below room temperature, or extensive sealing of the containers used for storing the compounds of the invention.

[0045] Organic Acids and pK a (Overview)

[0046] Organic acids are carbon-containing compounds whose acidity has wide applications and is important for a wide range of production industries. The compounds according to the present invention contain supported carboxylic acids in a dry state, thus facilitating the control of their acidic reactivity. Since the present invention is primarily concerned with the acidity in the primary equilibrium of the proton dissociation from the carboxyl group (-COOH), the pK a1 Values ​​are most relevant.

[0047] Strong acid-base reactions, such as reactions of carrier carboxylic acids, are usually exothermic. 1 COO (m+1)- or pK of the corresponding acid or metal counterion a1 Equal to or less than the loaded carboxylic acid R 2 COOH or any R 2 pK of the mixture of COOH a1 In this context, the pK of the components of the invention is technically utilized. a The difference acts as a powerful reaction force to produce inclusion complexes. In this approach, it is not necessary to support the expected reaction pathway for generating the compounds of the present invention, such as by using other additives, reactants or catalysts. Since no further additives, reactants or catalysts are needed, the required product has a higher purity and significantly simplifies purification. In addition, the characteristics of the solid product obtained will not be contaminated by the additives required for other situations of the residual.

[0048] Carrier Carboxylic Acid

[0049] The solid compound according to the present invention comprises a carrier carboxylate (R 1 COO (m+1)- or The carrier acid is called a carrier acid, which reacts with an alkaline earth metal base to form an acid salt carrier. According to the present invention, the carrier acid has a lower pK relative to the acid to be supported in the carrier. a or stronger acidity, which is conducive to the in-situ generation of its corresponding salt by neutralization of the carrier acid to form a carrier structure. Therefore, the carrier acid is inactive after the formation of the inclusion compound of the present invention and serves as a stable carrier for the supported acid. Therefore, the term "carrier carboxylic acid" herein corresponds to a partially deprotonated or completely deprotonated form (also called carboxylate) of the corresponding carboxylic acid and contains - depending on the pH value during the preparation of the solid compound - at least one deprotonated carboxylic acid group (-COO - ), more preferably all carboxylic acid groups of the carrier carboxylic acid in the carrier carboxylate are deprotonated. Preferably, the deprotonated carboxylic acid groups are bound to the divalent metal ion (M 2+ ) are combined to form a carrier carboxylate, and more preferably to form a composite structure.

[0050] According to the present invention, the carrier (R 1 COO (m+1)- or metal counter ions The pK of the corresponding acid a1 Equal to or less than the loaded carboxylic acid R 2 COOH or any R of a mixture thereof 2 pK of COOH a1According to a preferred embodiment of the present invention, the carrier carboxylic acid (R 1 COO (m+1)- or With the corresponding loaded carboxylic acid R 2 pK between COOH a1 The difference (ΔpK a1 ) is 0.1≤ΔpK a1 ≤5.0, preferably 0.2≤ΔpK a1 ≤4.0, more preferably 0.3≤ΔpK a1 ≤3.0. The carrier carboxylate (R 1 COO (m+1)- or The corresponding acid and the loaded carboxylic acid R 2 pK between COOH a1 The difference between the pK and pK of the acid-base reactive component of the present invention is beneficially increased. This increased stability is very beneficial for the transportation and storage of the compound of the present invention. In addition, the preferred pK of the acid-base reactive component of the present invention is a The differences can advantageously improve the selectivity of the intended reaction pathway and inhibit side reactions.

[0051] The carrier carboxylic acid (R 1 COO (m+1)- or Open R 1 , which is selected from optionally substituted C 1 -C 10 Alkyl, optionally substituted mono- or polyunsaturated C 1 -C 10 Hydrocarbyl or optionally substituted aryl, wherein the substituent is selected from carbonyl (=O) (preferably comprising a carbonyl adjacent to a hydroxyl group by forming a carboxylic acid group), amino (NH 2 ), hydroxyl (OH), halogen or cyano.

[0052] According to the present invention, R 1 By formula -X, -C β X 3 or -C β X 2 R 3 or or Description, where C β It's about the carrier Preferably, R 1 Selected from the formula -X, -C β X 3 or -C β X 2 R 3 According to the present invention, it is more preferred to select the formula -X or -Cβ X 2 R 3 As R 1 Therefore, R 1 The preferred groups selected advantageously constitute carrier carboxylic acids with increased acidity due to the reduced resonance stability of the deprotonated carrier carboxylic acid form. Thus, high yields and rapid acid-base reactivity of the carrier carboxylic acid are achieved, while generating the corresponding carrier carboxylate or carrier component, respectively, upon neutralization. The increased acidity kinetically mitigates side reactions and allows the stimulation of the desired reaction pathway, without, for example, having to be attributed to additional additives, reactants or catalysts.

[0053] According to the present invention, R 3 It may contain optionally substituted C 1 -C 10 Preferably, R 3 Selected from optionally substituted C 1 -C 8 Alkyl, optionally substituted mono- or polyunsaturated C 1 -C 8 More preferably, R 3 Selected from optionally substituted C 1 -C 6 Alkyl, optionally substituted mono- or polyunsaturated C 1 -C 6 The advantageous technical effect is derived from R as defined above. 3 The reduced alkyl chain length of the alkyl groups is preferred because these structures have increased solubility in polar solvents. Good solubility in polar solvents (such as water) is highly relevant to any technological reaction pathway and manufacturing process and is advantageous for the application of the supported carboxylates in industry.

[0054] According to the present invention, R 3 The substituents may include an amide group, an ester group, an ether group, a thioether group, a carbonyl group (═O) (preferably including a carbonyl group adjacent to a hydroxyl group by forming a carboxylic acid group (—COOH), an amino group (—NH 2 ), hydroxyl (-OH) or X, wherein X is selected from fluorine (-F), chlorine (-Cl), bromine (-Br). 3 The substituents are preferably selected from carbonyl (=O) (preferably including a carbonyl adjacent to a hydroxyl group by forming a carboxylic acid group), amino (-NH 2 ) or hydroxyl group (-OH). 3 The substituents are more preferably selected from carbonyl (=O) (including a carbonyl adjacent to a hydroxyl group by forming a carboxylic acid group), amino (-NH 2 ) or hydroxyl group (-OH).

[0055] Substituent X can be selected from hydrogen (H), hydroxyl (OH), fluorine (F), chlorine (Cl), bromine (Br) or another electron withdrawing functional group such as cyano (CN). Preferred substituents of X are selected from hydrogen (H), hydroxyl (OH), fluorine (F), chlorine (Cl) or another electron withdrawing functional group such as cyano (CN). More preferably, according to the present invention, hydrogen (H) or hydroxyl (OH) groups are selected as X. The substituents of X selected herein include structures that are relatively cheap to synthesize and / or naturally abundant and of the greatest technological significance.

[0056] More preferred examples of the carrier carboxylic acid component of the present invention are selected from R 1 , and choose hydrogen (H) as -X to form formic acid. If you choose -C β R 3 X 2 As R 1 and X is selected from hydrogen (H) or hydroxyl (OH) groups (constituting more preferred secondary C β Atoms) are given as further examples of more preferred carrier carboxylic acids. The general formula defined herein encompasses more preferred carrier acids of the invention (defined herein as partially deprotonated or fully deprotonated forms of the corresponding carboxylic acids) which are highly relevant to industrial products, such as acetic acid (HAc), propionic acid (HProp), lactic acid (HLac), glycolic acid (HGly), butyric acid (HBu), succinic acid (HSuc), fumaric acid (HFum) or maleic acid, adipic acid (HAd), malic acid (HMa), malonic acid (HMal), tartaric acid (HT), aspartic acid (HAsp), glutamic acid (HGlu), benzoic acid (HBen), salicylic acid (HSal), citric acid (HCit), ascorbic acid (HAsc) and formic acid (HFo).

[0057] According to a preferred embodiment, the carrier carboxylic acid is selected from acetic acid (HAc), propionic acid (HProp), lactic acid (HLac), glycolic acid (HGly), butyric acid (HBu), succinic acid (HSuc), fumaric acid (HFum) or maleic acid, adipic acid (HAd), malic acid (HMa), malonic acid (HMal), tartaric acid (HT), aspartic acid (HAsp), glutamic acid (HGlu), benzoic acid (HBen), salicylic acid (HSal), citric acid (HCit), ascorbic acid (HAsc) and formic acid (HFo) or a mixture thereof to form the corresponding carrier carboxylate.

[0058] In case the carrier carboxylate comprises a mixture of two or more carrier carboxylic acids per molecule, the carrier carboxylate forms a so-called "double salt". Thus, the solid compound according to the invention is a combination of a double salt of a carrier carboxylate and one or more supporting acids as defined herein.

[0059] The following formula shows the carrier carboxylate (R 1 COO (m+1)-4 or The general formula (the following formula, solid box), by selecting the formula -X or -C β X 2 R 3 As R 1 The most preferred carrier carboxylic acid is defined by the general formula, and the examples that follow (formula below, right side).

[0060] The coefficient m defines the carrier acid (R 1 COOH) acid R 1 Preferably, R 1 The negative charge in is 0, 1, or 2, so m is 0 to 2.

[0061]

[0062] Since the carrier carboxylic acid must have a lower pK than the supported carboxylic acid a , most preferably including formic acid, acetic acid, propionic acid, lactic acid, glycolic acid and butyric acid, thus advantageously giving a wide choice of paired carrier acids, thereby advantageously providing a universal platform for carboxylate carriers loaded with carboxylic acids.

[0063] The carrier carboxylic acid according to the present invention may comprise a carboxylic acid that is solid at room temperature and is selected from arachidic acid, stearic acid, palmitic acid, myristic acid, enanthic acid, octanoic acid, oxalic acid, aspartic acid, glutamic acid, malonic acid, tartaric acid, salicylic acid, fumaric acid or maleic acid, citric acid, malic acid, ascorbic acid, succinic acid, benzoic acid, adipic acid, formic acid, glycolic acid, lactic acid, acetic acid, butyric acid and propionic acid. Preferred carboxylic acid carrier acids according to the present invention are selected from enanthic acid, octanoic acid, oxalic acid, aspartic acid, glutamic acid, malonic acid, tartaric acid, salicylic acid, fumaric acid or maleic acid, citric acid, malic acid, ascorbic acid, succinic acid, benzoic acid, adipic acid, formic acid, glycolic acid, lactic acid, acetic acid, butyric acid and propionic acid. More preferably, according to the present invention, the carboxylic acid carrier acid is selected from aspartic acid, glutamic acid, malonic acid, tartaric acid, salicylic acid, fumaric acid or maleic acid, citric acid, malic acid, ascorbic acid, succinic acid, benzoic acid, adipic acid, formic acid, glycolic acid, lactic acid, acetic acid, butyric acid and propionic acid, wherein the latter six are liquid at room temperature. The carboxylic acid selected has a reduced hydrophobicity relative to a longer-chain straight-chain carboxylic acid. Therefore, the carboxylic acid carrier acid most preferably selected according to the present invention has solubility in polar solvents, which helps to facilitate processing and manufacturing.

[0064] For example, compounds according to the invention comprising citrate have been shown to significantly improve the growth performance of aquaculture fish (Reviews in Aquaculture, 2017).

[0065] In addition, the use of the ascorbate carrier in combination with the loaded acetic acid according to the present invention is suitable, for example, for use as a color preservative in food and feed applications. The loaded acetic acid in the compounds described herein advantageously acts as an acidifier (controls pH to mitigate myoglobin oxidation). The compounds of the present invention comprising ascorbic acid (vitamin C) derivatives advantageously provide the important role of ascorbic acid as an antioxidant, protecting cellular components from free radical damage.

[0066] The selected pK of the preferred carrier carboxylic acid according to the invention is a1 The values ​​are listed in Table 1 below, with asterisks indicating liquid at room temperature:

[0067] Table 1. Selection of preferred carrier carboxylic acids according to the present invention and their pK a1 Values, where an asterisk (*) indicates that the material is liquid at room temperature.

[0068] acid <![CDATA[pK a1 ]]> Aspartic acid 1.99 Glutamate 2.16 Malonic acid 2.83 tartaric acid 2.98 Salicylic acid 2.75 Fumaric Acid 3.00 Citric acid 3.09 Malic Acid 3.40 Formic acid* 3.77 Glycolic acid* 3.83 Lactic acid* 3.86 ascorbic acid 4.25 Succinic acid 4.19 benzoic acid 4.20 Adipic acid 4.43 Acetic acid* 4.76 Butyrate* 4.82 Propionic acid* 4.88

[0069] The pK of an organic acid can often be altered by changing the length of the alkyl chain or the functional substituents along the latter end. a Generally speaking, the pK of an organic acid is a It decreases only slightly with increasing alkyl chain length. β The appropriate substituents of the acidity of the atom can more effectively change the pK of organic acids. a , and this is also true for X.

[0070] In one embodiment of the present invention, X is selected from hydrogen (H) or an electron withdrawing group selected from fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (I) or cyano (-CN). In a preferred embodiment of the present invention, X is selected from hydrogen (H) or an electron withdrawing group selected from fluorine (-F), chlorine (-Cl), bromine (-Br) or cyano (-CN). In a more preferred embodiment of the present invention, X is selected from hydrogen (H) or an electron withdrawing group selected from fluorine (-F), chlorine (-Cl) or cyano (-CN).

[0071] In the embodiment of the present invention, the C of the carrier carboxylic acid selected β The substituent on X has an electronegativity greater than that of carbon. C Higher electronegativity (EN) and induce inductive electron withdrawal, thereby increasing the acidity of the carrier carboxylic acid. Therefore, the pK of the preferred embodiment of the present invention is a1 Depending on the carrier carboxylic acid, this is advantageously reduced relative to EN C Substituents X with higher electronegativity, in the order (F>Cl>Br>I), are even more significant and are considered in more preferred embodiments of the present invention.

[0072] The increased acid strength when selecting X according to a (more) preferred embodiment of the present invention advantageously promotes a wider selection of carrier acid pairs and supported acid pairs, while reducing the pK of the carrier carboxylic acid relative to the supported carboxylic acid according to the criteria of the present invention. a Therefore, the pK is reduced by functional β-substituents. a1 Opens up avenues for new compounds of supported / charged acids.

[0073] The following formula shows the carrier carboxylate (R 1 COO (m+1)- or (The following formula, solid line frame) is a general formula, from R 1 The structures of embodiments of the carrier carboxylic acids of the present invention are defined (the following formula, dashed box) and the examples that follow (the following formula, right side). The structures shown are similar to the examples shown in the previous more preferred options.

[0074]

[0075] Furthermore, the above advantages are enhanced by purposefully selecting the substituent X to modify the acidity of the carrier carboxylic acid, increasing the pK between the carrier acid and the supported acid. a1 Thus, increased stability of the acid-loaded carboxylate carrier for transportation and storage, increased safety, and increased selectivity and / or reaction rate of the acid-base reaction are advantageously achieved.

[0076] Another advantage is that di- or tri-carboxylic acids, especially completely or partially deprotonated di- or tri-carboxylic acids, are used as carrier carboxylic acids (R 1 COO (m+1)- Availability, where R 1 Contains at least one or two carboxylic acid groups (-COOH), preferably deprotonated carboxylic acid groups (-COO - ), so m is 1 or 2, which can be multiple carboxyl groups (multidentate ligands) and / or carrier carboxylic acids (R 1 COO (m+1)- With metal ion M 2+ Combined, where R 1 Contains at least one amino group (-NH 2 ) and / or at least one hydroxyl group (-OH), thereby forming a chelate complex. The chelate effect greatly enhances the stability of the carrier salt and reduces the ligand exchange with the loaded acid. For example, the loaded carboxylic acid is oxalic acid, citric acid, itaconic acid, malic acid, maleic acid, tartaric acid, salicylic acid, glycolic acid, succinic acid, adipic acid, ascorbic acid or a mixture thereof. Preferably, the R of the carrier carboxylic acid is 1 One or two carboxylic acid groups (-COOH), preferably deprotonated carboxylic acid groups (-COO- ), producing a significant chelated complex, wherein the carrier carboxylic acid is, for example, selected from oxalic acid, succinic acid, adipic acid, malic acid, maleic acid, citric acid, itaconic acid, tartaric acid or a mixture thereof.

[0077] Loaded acid and pKa

[0078] The term "supported carboxylic acid" herein preferably refers to the protonated form of the corresponding carboxylic acid, wherein the carboxylic acid comprises at least one protonated carboxylic acid group (-COOH), preferably all carboxylic acid groups of the (supported) carboxylic acid are in protonated form. Advantageously, the (protonated) carboxylic acid is solid in the solid compound according to the invention, preferably by physical adsorption and / or cluster formation with a support carboxylate.

[0079] The acid-reactive component of the compound according to the invention comprises one or more supported carboxylic acids R 2 COOH, preferably one or more protonated supported carboxylic acids, referred to as supported acids, wherein R 2 It may contain optionally substituted C 1 -C 10 Alkyl, optionally substituted mono- or polyunsaturated C 1 -C 10 A hydrocarbon group or an optionally substituted aryl group, preferably R 2 Selected from optionally substituted C 1 -C 8 Alkyl groups, optionally substituted mono- or polyunsaturated C 1 -C 8 A hydrocarbon group or an optionally substituted aryl group, more preferably R 2 Selected from optionally substituted C 1 -C 4 Alkyl, optionally substituted mono- or polyunsaturated C 1 -C 4 The supported acid in the present invention is preferably a short-chain carboxylic acid, most preferably a C alkyl chain length of less than 5. 1 -C 4 , which is related to their liquid aggregate state at room temperature (rt). Therefore, liquid carboxylic acids such as formic acid, acetic acid, glycolic acid, propionic acid, butyric acid and lactic acid can be handled in powder form, which is highly relevant for safety purposes and beneficially does not require dilution. These aspects are highly relevant to the application of the liquid short-chain carboxylic acids in the pharmaceutical, cosmetic, food and feed industries.

[0080] R 2 The substituents may be selected from hydrogen (-H), a carbonyl (=O) group (preferably comprising a carbonyl group adjacent to a hydroxyl group by forming a carboxylic acid group), an amino group (-NH 2) group, hydroxyl (-OH)) group, halogen (including fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I)), or cyano (-CN) group) or a mixture thereof. 2 Preferred substituents of R are selected from hydrogen (-H), carbonyl (=O) groups (preferably comprising a carbonyl group adjacent to a hydroxyl group by forming a carboxylic acid group (-COOH), preferably a protonated carboxylic acid group), a hydroxyl (-OH) group or a mixture thereof. More preferably, according to the present invention, hydrogen (-H) or a hydroxyl (-OH) group or a mixture thereof is selected as R 2 According to the present invention, R 2 The most preferred substituents include carboxylic acids, which are naturally abundant and / or relatively cheap to synthesize and are of the greatest technological significance. In addition, the supported acid advantageously does not contain a basic group such as an amino group (-NH 2 ), which would interfere with their intended acid-reactive properties according to the present invention.

[0081] An example of a preferred supported carboxylic acid according to the present invention is shown in the following formula, which comprises C 1 -C 4 Short chain carboxylic acids, such as formic acid, acetic acid, glycolic acid, propionic acid, lactic acid and / or butyric acid or mixtures thereof, as described above, are advantageously biocompatible and bioavailable. Herein, the present invention has the advantage that these short chain carboxylic acids, which are usually present in liquid form (e.g., at room temperature), are present as solids in the salt. Therefore, the loaded short chain carboxylic acids can be processed in powder form, which is highly relevant to safety purposes and advantageously does not require dilution.

[0082]

[0083] The preferred R 2 pK of the first acidity of COOH short-chain carboxylic acids a As given in Table 2 below:

[0084] Table 2. R preferably used according to the present invention 2 COOH short-chain carboxylic acids and their pK a value.

[0085] acid <![CDATA[pK a1 ]]> Formic acid 3.77 Glycolic acid 3.83 lactic acid 3.86 Acetic acid 4.76 Butyric acid 4.82 Propionic acid 4.88

[0086] The preferred supported acids of the present invention are effective acidifiers for a wide range of industrial applications since they advantageously exhibit high acidity as much as possible, while requiring controlled reactivity for storage, transportation and safety, thereby facilitating their economical handling.

[0087] Regarding the pK of the carrier acid and the supported acid according to the present invention a Difference in the pK of the standard, loaded carboxylic acid aAdvantageously enables the selection of several ligand counterions (R 1 COO) (m+1)- or Here, a wide range of carboxylate carriers loaded with carboxylic acids can be generated and customized.

[0088] The acid-loaded carriers are beneficial for a wide range of application fields. It has been shown that the compounds according to the invention are suitable as antimicrobial preservatives in cosmetic, pharmaceutical, food, and feed applications. In addition to antibacterial, preservative, and hygiene functions, carboxylic acids and their salts (e.g., formic acid and formate) have shown significant livestock efficacy in weight gain of fattening pigs together with propionic acid and propionate (Nutrition Research Reviews, 1999).

[0089] The compounds according to the invention are also suitable as nutritional product additives in human and animal nutritional supplements, for example when loaded with lactic acid. Like other nutritional products, lactic acid is a natural substance that can be extracted from biological sources, and thus when incorporated into the compounds of the invention, for example, as an additive when included in a food matrix, it can provide important health benefits.

[0090] Another advantage is the availability of dibasic or tribasic carboxylic acids as the loaded carboxylic acids, where R 2 contains one or two protonated carboxylic acid groups (-COOH), preferably protonated carboxylic acid groups, which can be multiple carboxyl groups (polydentate ligands) or the loaded carboxylic acid (R 2 COOH) associated with the metal ion M 2+ wherein R 2 contains at least one amino group (-NH 2 ) and / or at least one hydroxyl group (-OH), resulting in a higher affinity for the carrier carboxylate, especially for the metal ion M 2+ , thus increasing the ratio of physical adsorption (physisorption) of the loaded carboxylic acid above or within the solid compound. Preferably, the R 2 loaded with acid contains at least one hydroxyl group (-OH). This effect greatly enhances the stability of the solid compound, and thus preferably allows 2 < n ≤ 10, most preferably 2 < n ≤ 6. For example, the loaded carboxylic acid is oxalic acid, citric acid, itaconic acid, malic acid, maleic acid, tartaric acid, salicylic acid, glycolic acid, succinic acid, adipic acid, ascorbic acid, or a mixture thereof, preferably lactic acid, glycolic acid, salicylic acid, or a mixture thereof.

[0091] As a preferred embodiment of the invention, the compounds of the invention can be composed of the same acid or a mixture with the loaded carboxylic acid R 2 COOH. Containing several loaded carboxylic acids R 2Compounds with COOH enable the overall acidic strength of the acid-loaded carrier to be customized. The Fédération Européenne des Fabricants d'Adjuvants pour la Nutrition Animale clearly recommends such a creative combination of carboxylic acids and medium-chain fatty acids to improve growth performance.

[0092] According to the present invention, various synthetic routes using formate as a carboxylic acid carrier loaded with carboxylic acids such as lactic acid, acetic acid, and butyric acid will advantageously produce compounds that comply with EU feed additive regulations and achieve various functions from hygiene control to anti-corrosion to growth promotion.

[0093] According to a preferred embodiment, the acid to be loaded is selected from acetic acid (HAc), propionic acid (HProp), formic acid (HFo), lactic acid (HLac), salicylic acid (HSal), or a mixture thereof.

[0094] According to a preferred embodiment of the present invention, the substituent R of the carrier carboxylic acid 1 and the substituent R of the carboxylic acid to be loaded 2 of R COOH 2 are different (R 1 ≠R 2 ). For example, this can be used to provide solid compounds, such as preservatives, which contain multiple acids in the molecule to provide various combinations of acidic anions.

[0095] Advantageously herein, the molar mass of the carboxylic acid to be loaded (R 2 COOH) is lower than the molar mass of the carrier carboxylic acid (R 1 COOH).

[0096] The ratio (n) of the acid to be loaded or its salt to the carrier acid

[0097] The molar ratio n of the carboxylic acid to be loaded to the carrier carboxylate is important because it advantageously defines the ratio of the reactive component to the carrier component. Therefore, n advantageously sets the acid concentration in the compounds of the present invention and favors the customized reactivity of the final application.

[0098] Typically, the range of the molar ratio n includes 0.1 ≤ n ≤ 10. According to the present invention, n is preferably 0.5 ≤ n ≤ 8, and most preferably n according to the present invention is selected in the range of 1 < n ≤ 6. The results show that compounds with the characteristic of the molar ratio n within the preferred range according to the present invention have high acidic efficacy and are stable at the same time. Herein, it is possible to load carboxylic acids on the carboxylate carrier loaded with carboxylic acids and / or have a high molar concentration of carboxylic acids, thus providing economical transportation, storage, and use considering safety aspects.

[0099] Preferably, the molar ratio n satisfies 2 ≤ n ≤ 10, more preferably 2 < n ≤ 10, and most preferably n is selected in the range of 2 < n ≤ 6 according to the present invention. For example, n is at least 2.5 to 6, preferably n > 3.0.

[0100] In addition, the change in the ratio n can be customized in a simple manner, which is a change in the molar feed ratio of the starting materials of the method according to the present invention.

[0101] As a preferred embodiment of the present invention, the solid compound of the present invention contains less than 2 equivalents of water relative to the carrier carboxylic acid, more preferably less than 1 equivalent of water, and most preferably less than 0.5 equivalent of water, such as less than 0.4, 0.3, 0.2, 0.1. For example, excess water can be removed by a desiccant (a hygroscopic substance for removing water) or controlled heating. Preferably, the compound of the present invention contains less than 10.0 wt%, more preferably less than 8.0 wt%, especially less than 7.0 wt%, and most preferably less than 6.0 wt% of water. On the one hand, this is advantageous because the stability of the acid is increased, thus avoiding unnecessary increases in storage and transportation costs. On the other hand, the water content does not have to be included in the calculation of the required amount of acid.

[0102] The structure of the solid compound may contain a second or further loaded carboxylic acid R 4 COOH, where R 2 and R 4 are independently selected as defined above for R 2 preferably selected from optionally substituted C 1 -C 10 alkyl, optionally substituted mono- or polyunsaturated C 1 -C 10 hydrocarbyl or optionally substituted aryl, where the substituents are preferably selected from carbonyl (=O), carboxylic acid group (-COOH) (preferably protonated carboxylic acid group), amino (-NH 2 ), hydroxyl (-OH), halogen or cyano (-CN) or a mixture thereof.

[0103] As described above, R 4 (as defined above for R 2 ) preferably contains one or two carboxylic acid groups (-COOH), preferably protonated carboxylic acid groups, which can be multiple protonated carboxyl groups (polydentate ligands) or loaded carboxylic acids (R 4 COOH) (preferably protonated carboxylic acid groups) associated with the metal ion M 2+ , where R 4 contains at least one amino (-NH 2 ) and / or at least one hydroxyl (-OH), resulting in a preference for the carrier carboxylate, especially for the metal ion M 2+has a higher affinity, thus increasing the rate of physical adsorption (physisorption) of the carboxylic acid loaded on or within the solid compound. Preferably, the loaded acid R 2 contains at least one hydroxyl group (-OH). This effect greatly enhances the stability of the solid compound, so it is preferably allowed that 2 < n ≤ 10, and most preferably 2 < n ≤ 6. For example, the loaded carboxylic acid is oxalic acid, citric acid, itaconic acid, malic acid, maleic acid, tartaric acid, salicylic acid, glycolic acid, succinic acid, adipic acid, ascorbic acid or a mixture thereof, preferably lactic acid, glycolic acid, salicylic acid or a mixture thereof.

[0104] According to a preferred embodiment, the second loaded acid is selected from acetic acid (HAc), propionic acid (HProp), formic acid (HFo), lactic acid (HLac), salicylic acid (HSal) or a mixture thereof. More preferably, the second loaded carboxylic acid is selected from acetic acid (HAc), propionic acid (HProp), formic acid (HFo), lactic acid (HLac) or a mixture thereof.

[0105] Providing a solid compound, for example as a preservative, containing various acids in the molecule to provide various combinations of acid anions may be useful. Thus, according to a preferred embodiment of the present invention, the substituent R of the carrier carboxylic acid 1 , the loaded carboxylic acid R 2 COOH's substituent R 2 and the second loaded carboxylic acid R 4 COOH's substituent R 4 are different (R 1 ≠R 2 ≠R 4 ).

[0106] Advantageously herein, the molar mass of the loaded carboxylic acid R 2 and / or R 4 is greater than the molar mass of the carrier carboxylic acid R 1 .

[0107] However, it may be useful to provide an increased concentration of acid or acid anions, for example to adjust the buffering effect within the product or solution. Thus, according to a preferred embodiment of the present invention, the substituent R of the carrier carboxylic acid 1 and the substituent R of the second loaded carboxylic acid R 4 COOH 4 are (R 1 =R 4 ), and are different from the substituent R of the loaded carboxylic acid R 2 COOH 2 (R 2 ≠R 1 and R 2 ≠R 4 ).

[0108] Advantageously, the carboxylic acid R of the load 2 has a lower molar mass than the carrier carboxylic acid R 1 and the carboxylic acid R of the second load 4 .

[0109] Generally, the molar ratio o of the second load carboxylic acid to the carrier carboxylate ranges from 0.1 ≤ o ≤ 10, preferably o ranges from 0.5 ≤ o ≤ 8, and most preferably o is selected from the range 1 < o ≤ 6.

[0110] According to a preferred embodiment, n + o ≥ 1, more preferably n + o ≥ 2, and most preferably n + o > 2, where in each case the sum of n + o is not greater than 10, preferably not greater than 8, and most preferably n + o is not greater than 6. Thus, the sum of n + o is, for example, at least about 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or at least about 5.0.

[0111] Polarity / dipole characteristics / hydrophilic-lipophilic balance

[0112] The carrier and load components of the clathrate must have a certain attractive interaction or cohesion to achieve the desired physical adsorption, which may be related to the polarity of the organic acid component.

[0113] The concept of polarity refers to the charge separation that can cause a dipole moment, for example, between atoms in a covalent bond or between two ions of opposite charge. Generally, the dipole moment is generated by the difference in electronegativity EN. This means that due to the significant difference in EN between the heteroatom and carbon, the carbonyl (-C=O), carboxylic acid (-COOH), amino (-NH C ) or hydroxyl (-OH) affects the overall polarity of the substituted carboxylic acid component of the present invention. 2 )

[0114] The overall polarity or dipole moment respectively affects important parameters of the acid-loaded carrier compound of the present invention, such as solubility, aggregation state, and stability.

[0115] A suitable and easy descriptor for the net polarity of the organic acid of the present invention is through the ratio of polar groups (for example, selected from hydrophilic groups such as carbonyl (-C=O), carboxylic acid (-COOH), amino (-NH 2 ) or hydroxyl (-OH)) to lipophilic organic groups (such as -CH 1 -, -CH 2 -, -CH 3 -, and =CH1 -). For simplicity, the length of the alkyl chain relative to the number of polar / hydrophilic groups or organic acids is useful for indicating the tendency of the organic acid to have polar interactions, and thus the properties relevant to the present invention can be estimated, predicted and controlled.

[0116] The overall adjustable polarity of the components of the invention is highly beneficial for their use in emulsion formulations by selecting components with a certain lipophilicity / hydrophilicity profile. Thus, the compounds according to the invention can be used, for example, as active ingredients in cosmetic and pharmaceutical applications, in particular for acidity adjustment in pH-defined skin cleansing products, to aid the cleaning effect in shaving soaps or to support disinfection in lotions.

[0117] It has been shown that increased compound stability is obtained by combining components of the invention with high polarity (referring to derivatives containing lipophilic groups). Since the increased stability of the compounds of the invention is directly related to safety aspects, easy assessment of the polarity of the components can be beneficial in designing compounds with a certain stability or processing safety, respectively. Therefore, custom compounds can be selected based on the polarity characteristics of the individual components, taking into account the specific conditions of transportation and storage. For example, overseas transportation may require a more stable compound than a short-term transportation.

[0118] The overall polarity of the components of the present invention is inevitably related to the tendency of the components to absorb water (in short, hygroscopicity). Since water is a by-product released during the process of the present invention, an assessment of the overall polarity of the components predicts the conditions for drying the acid-loaded support, for example, whether extensive drying under reduced pressure or high heating rates is required. This assessment is highly relevant to the economic planning of the manufacturing process.

[0119] Predictions of hygroscopicity facilitate the purposeful selection of appropriate containers and, where possible, effective suppression of water molecules suspended in the component molecules. In this context, physical changes in the compounds of the invention, such as changes in volume, boiling point, viscosity or any other physical characteristic or property, are advantageously mitigated.

[0120] Flowability (based on size and cohesion or polarity or hygroscopicity)

[0121] The present invention provides a solid inclusion compound prepared as a powder, which exhibits good flowability. Flowability describes the relative flowability of a large number of particles between adjacent particles or refers to the ability of powder to flow.

[0122] The good flowability obtained by the powder carrier system of the present invention beneficially promotes good powder product quality, manufacturing efficiency, transportation safety and storage in a wide range of fields of powder processing industry. Among the general influences on flowability, such as the packing density and cohesive properties of the components in the inclusion complex discussed above, as described below, particle size and particle size distribution have a major influence on the flowability of powders (compare Baker et al., 1979).

[0123] granularity

[0124] Particle size and particle size distribution are used as suitable indicators of the fluidity of the carboxylate carrier supporting the carboxylic acid. The particle size of the powdered compound is generally determined by the average particle size d av Definition: It is the diameter of the majority of particles present in a given powder particle size distribution. Usually, the average particle size d of a free-flowing powder is av Including average particle size 10μm≤d av ≤500 μm, preferably according to the present invention 20 μm≤d av The average particle size is within the range of ≤300 μm, more preferably 50 μm ≤d av Average particle size in the range of ≤250μm.

[0125] It seems that the preferred particle size range advantageously ensures the best flowability of the compound of the present invention, provides the multiple flowability advantages as described above, and advantageously mitigates the presence of aerosol particles. The diameter of aerosol particles is usually a few nanometers in size, and tends to form a heterogeneous mixture with the surrounding gas (e.g., air), which is harmful if the suspended particles are inhaled through the lungs. It has been shown that if the compound of the present invention has a preferred size range as described above, the generation of undesirable aerosols is advantageously avoided. Therefore, as long as it is in contact with organisms during processing and handling, the compound of the present invention supports health protection.

[0126] It is further shown that the preferred diameter range of the particles of the compounds of the present invention further contributes to the optimal loading capacity. Generally, based on the increase in the relative surface of the carrier particles, the amount of components that can be loaded onto the particle carrier increases with the decrease in the particle volume diameter. Therefore, the preferred size range mainly supports flowability, followed by an optimal range between smaller particle sizes that support high loading capacity and sufficiently large particles that mitigate the appearance of aerosol characteristics.

[0127] Particle size distribution

[0128] In addition to particle size, particle size distribution is also a suitable indicator of the fluidity of the carboxylate carrier supporting the carboxylic acid. The particle size distribution of the powdered compound is usually expressed in terms of the average particle size (d X0 ), which defines whether a given diameter is less than or greater than the value X0 vol % of the particle portion.

[0129] The particle size distribution of the compound of the present invention is 50 Can include 10μm≤d 50 ≤800μm, preferably including 10μm≤d 50 ≤500μm, especially 20μm≤d 50 ≤300μm, more preferably selected from 50μm≤d 50 ≤250μm.

[0130] The particle size distribution defined therein represents a low dispersity of the particle size of the free-flowing powder of the invention. The low particle size dispersity, which is an important factor for the flowability of the powdered carrier compound of the invention, advantageously contributes to the quality of a good powder product. If the compound of the invention is, for example, used in the pharmaceutical industry, the powder flow behavior determined by the particle size distribution is advantageous, for example, for defined weight bottling of the pharmaceutical compound and for content uniformity.

[0131] According to the invention, a narrow size distribution is advantageous and at least 50%, preferably at least 90%, by weight of the powdered acid-supported salt carrier has a particle size of less than 450 μm. 90 The particle size distribution of the compound of the present invention is 90 Including 10μm≤d 90 ≤1000μm, preferably selected from 50μm≤d 90 ≤800μm, more preferably selected from 150μm≤d90≤450μm.

[0132] If with powdered C 1 -C 4 Carboxylic acid supported salt carrier 50 Parameters compared to which the particle size distribution d is defined 90 allows even higher uniformity. In addition to the defined d 50 In addition to the advantages of 90 The preferred range of values ​​supports the efficiency and safety of any powder processing manufacturing process. For example, gravity feeding and smooth and accurate powder dosing are facilitated on a commercial scale, which has been proven to be correct for the compound by diffraction granulometry. For example, the regular outflow of powder from a vertical silo or silo for the storage of a size-limited acid-loaded salt carrier advantageously avoids capacity shortages and production interruptions, which would result in the loss of expensive production time.

[0133] By appropriately designing the reaction parameters (e.g. stirring time, time and intensity of the drying process), the average particle size and / or particle size distribution of the solid compound according to the present invention can be optimally adapted to the requirements of the specific use / application of the solid compound without the need for destructive mechanical grinding processes.

[0134] Alkali

[0135] According to the present invention, the carrier carboxylic acid reacts with a base to form an acid salt carrier. In the present invention, the term "base" is applicable to a variety of bases. Generally, a hydrated inorganic base or a more useful positively charged M 1+ , two positive charges M 2+ or three positive charges M 3+ The most satisfactory results of the compounds of the present invention are obtained by comprising a divalent metal base M 2+ of base is obtained.

[0136] Divalent metal ion M 2+ Usually selected from iron (Fe), copper (Cu), zinc (Zn), manganese (Mn), tin (Sn), lead (Pb), nickel (Ni) or alkaline earth metal ions, preferably calcium (Ca), magnesium (Mg), barium (Ba), or a mixture thereof. The divalent metal ion carries two positive charges, which is advantageous for the composition and stoichiometry of the compound of the present invention.

[0137] According to a preferred embodiment of the present invention, M 2+ It is an alkaline earth metal ion, preferably calcium (Ca), magnesium (Mg), barium (Ba), or a divalent metal ion selected from iron (Fe), copper (Cu), zinc (Zn), manganese (Mn), tin (Sn) or a mixture thereof.

[0138] According to the present invention, M 2+ Preferably, it is selected from iron (Fe) or alkaline earth metal ions, preferably calcium (Ca), magnesium (Mg), barium (Ba) or mixtures thereof. The divalent metal ions of the compounds of the present invention selected are preferably selected based on their bioavailability, benefiting from the convenience of their abundance in nature.

[0139] More preferably, according to the present invention, M 2+ Selected from alkaline earth metal ions, preferably calcium (Ca), magnesium (Mg) or mixtures thereof. In addition to the benefits of using calcium or magnesium related to the beneficial stoichiometry of calcium or magnesium as seen in the use of the compounds of the present invention, calcium or magnesium also has bioavailability and biocompatibility. In addition, they are crucial in biochemical pathways because magnesium is important, for example, for neurogenic processes such as muscle contraction, blood coagulation or vitamin absorption, and calcium is an important component of bones and teeth. Therefore, incorporating calcium or magnesium in a carrier acid / salt structure can produce digestible compounds suitable as nutritional supplements to improve human and animal health. An example of a digestible compound of the present invention with health benefits is a preparation comprising calcium citrate or magnesium citrate. Therefore, the use of the compound according to the present invention is suitable as an animal technology additive in animal nutrition, such as a gastrointestinal acidifier or a non-antibiotic growth promoter.

[0140] The use of compounds according to the invention, in particular compounds comprising alkaline earth metal ions such as Ca and / or Mg, is suitable as flavoring and palatability agents in pharmaceutical, food and feed applications. For example, carriers loaded with acid acetates according to the invention can be used to impart salt and vinegar flavors to potato chips or salad dressings. Here, compounds of the invention can replace conventional formulations containing potassium diacetate or sodium diacetate, thereby providing an alternative to the limited licensing of alkaline formulations in cosmetics in Europe according to the European Commission.

[0141] Almost any calcium or magnesium base can be used to react with the carrier carboxylic acid to form the acid salt support. However, in a preferred embodiment of the present invention, the alkaline earth metal base is selected from calcium hydroxide (Ca(OH) 2 ), calcium oxide (CaO), calcium carbonate (CaCO 3 ), magnesium oxide (MgO), magnesium hydroxide (Mg(OH) 2 ) or magnesium carbonate (MgCO 3 ), which is advantageously used as a low-cost starting material for synthesizing the compounds of the present invention.

[0142] The choice of the alkaline earth metal base used determines the type and amount of condensates released as by-products when the acid-base reaction between the carrier carboxylic acid and the metal base forms the acid salt carrier according to the invention. Oxygen ions (O 2- ) or hydroxide (OH - ) determines the heat of reaction released during the exothermic acid-base reaction between the carrier carboxylic acid and the metal base to form the acid salt carrier according to the invention.

[0143] The use of alkaline earth metal carbonates as starting materials results, for example, in the instantaneous and exothermic CO 2 Significant heat release during formation, this can be used for, for example, to simplify drying process.Therefore, the selection of the alkaline earth metal alkali adopted helps to regulate the thermal condition of the inventive method.The gaseous carbon dioxide released further usefully supports mixing in the reaction vessel and is a reliable indicator for completing acid-base reaction.Using alkaline earth metal hydroxide and oxide as alkali is a preferred embodiment according to the inventive method, produces water as by product.

[0144] If water is released as a by-product, the condensed water formed creates microcompartments between the particle components comprising the carrier carboxylic acid and the metal base and improves the reaction environment of the acid-base reaction, since the condensed water acts as a solvent for the residual, still unreacted reaction parts. Subsequently, the presence of water as a by-product contributes to the creation of microcompartments which accelerate the reaction rate, thereby promoting the complete conversion of the reactants. The in-situ generation of water as a solvent is particularly important for the preferred solvent-free reaction process, since it compensates for possible poor mixing or contact of the reaction parts, respectively.

[0145] In summary, the compounds of the present invention are based on inexpensive starting materials and contain only organic components, which are carboxylic acids and / or carboxylates, and alkaline earth metal bases, have favorable biocompatibility and / or digestibility. Since no further additives or catalysts are required, the economic processing of organic acids on an industrial scale is facilitated.

[0146] Process advantages and description

[0147] General treatment of loaded acid

[0148] The supported carboxylic acid can be loaded onto the support in a variety of ways. Generally speaking, any method that provides intimate contact between the components that produce the supported carboxylate support is suitable for providing a uniform, free-flowing, non-caking compound according to the present invention. The components must have sufficient fluidity to achieve good dispersion so that when in contact with each other, the carboxylic acid to be loaded is substantially uniformly dispersed throughout the weight of the support particles.

[0149] The support salt can thus be loaded in a variety of ways. Typically, the particles are brought into contact with one another in the gas phase by passing an inert gas (capable of vapor-depositing possible liquid components during spraying) through a quantity of particles in a fluidized bed apparatus, or when the particles are located on a static or mobile screening device.

[0150] Inventive method

[0151] The present invention contemplates the loading of the supported salt particles by simultaneously generating the supported salt from the corresponding acid of the supported salt and by trapping the supported carboxylic acid in the support structure in an in-situ manner, preferably in the absence of a solvent. The compounds of the present invention are obtained by a simple manufacturing process comprising mixing the supported carboxylic acid, the supported carboxylic acid and the alkaline earth metal base, followed by drying the obtained compound under controlled temperature, humidity and particle size.

[0152] A method for preparing the carboxylate support of the present invention has been found, wherein starting materials comprising a support carboxylic acid, a supported carboxylic acid and an alkaline earth metal base are gently mixed, wherein the support carboxylic acid (R 1 COO (m11)- or premixed with a base, known as an ex-post process, or more preferably with a supported carboxylic acid R 2 COOH premixed, known as the in-situ process. For two preferred embodiments of the process of the invention, the exothermic acid-base reaction is a resalification between an alkaline earth metal base and a support carboxylate salt producing a support structure, which must be carried out after the latter is loaded with a short-chain carboxylic acid.

[0153] The post hoc method is a preferred method for preparing the compounds according to the present invention. First, a 2+ The alkaline earth metal base and the carrier carboxylic acid (R 1 COO (m+1)- or Premix. The mixture is stirred at a temperature below the boiling point of the most volatile compound present until the carrier carboxylate is produced. or The homogeneous mixture is dried, however, it may be advantageous to omit the drying and then add the supported carboxylic acid R 2 The homogeneous mixture obtained is sieved before the addition of COOH and then stirred at a temperature below the boiling point of the most volatile compound present until homogeneity of the compound is obtained. Finally, the mixture obtained is dried a second time, preferably followed by grinding and sieving of the powder obtained. The advantage of the ex post method is that the drying and sieving are carried out simultaneously, facilitating intermediate size selection and purification, thereby advantageously reducing the extent of these steps required at the end of the method of the invention. Therefore, in the case of compounds that require extensive grinding, the ex post method may be preferred.

[0154] In one embodiment of the preferred method of the present invention, the carrier carboxylate is purchased or As the supported carboxylic acid R 2 This embodiment of the preferred process of the invention is suitable if the carrier carboxylic acid is available at low cost or if the sequence of the compounds of the invention is varied.

[0155] According to another preferred embodiment of the post-process, first, an alkaline earth metal base is reacted with a carrier carboxylic acid (R 1 COO (m+1)- or Premix. The mixture is stirred at a temperature below the boiling point of the most volatile compound present until the carrier carboxylate is produced. or By utilizing the residual heat generated by the exothermic carrier salt reaction, the supported carboxylic acid R 2COOH is added to the homogeneous mixture, which is then stirred at a temperature below the boiling point of the most volatile compound present until a homogeneous compound is obtained. Finally, the mixture obtained is dried, preferably followed by grinding and sieving of the powder obtained.

[0156] A more preferred process of the invention for preparing the compounds of the invention comprises an initial acid mix wherein all compounds are added simultaneously, referred to as an in situ process. In an in situ process, a carrier carboxylic acid (R 1 COO (m+1)- or and the carboxylic acid R to be loaded 2 COOH premix until homogeneity of the mixture is obtained. After the initial acid mixing, add 2+ The alkaline earth metal base of the alkaline earth metal ion is added to the mixture of carboxylic acid compounds with stirring below the boiling point of the most volatile compound present. Finally, the mixture obtained is dried, preferably followed by grinding and sieving the powder obtained.

[0157] However, the in situ generation of the compounds of the present invention advantageously allows the synthesis of the support while grinding with the acid to be loaded, thereby promoting efficient inclusion of the latter, resulting in high carboxylic acid loadings if compared to ex post methods. Furthermore, it is advantageous that the in situ method of the present invention does not require an intermediate drying step as required in the embodiment of the ex post method.

[0158] However, all components (base, ligand acid, and supported / free acid) can technically be added to one reaction vessel in any order, as these components are expected to form the desired products of the present invention by resalting according to their chemical properties.

[0159] Starting Materials

[0160] According to the method of the present invention, the starting material is preferably used in concentrated form, thereby advantageously affecting the probability of effective reaction, reducing the reaction time and the entire manufacturing process, respectively. Therefore, the liquid acid concentration is preferably more than 70%, and more preferably the acid concentration is more than 95%. However, with reference to good laboratory practice, the appropriate concentration of the liquid starting material is known to those skilled in the art.

[0161] It is known to those skilled in the art that the solid starting material is preferably dry and has a uniform particle size. In addition, it is known to those skilled in the art that a small particle size is preferred for the mixed reaction process so that the reactants have the maximum surface area and the mixture has the maximum possible uniformity. Wherein the preferred particle size and size distribution advantageously minimize the input of mechanical energy required for mixing during the reaction in the dry state.

[0162] temperature

[0163] The mixing of short-chain carboxylic acids is generally carried out in a temperature range of 0 °C < T < 25 °C, preferably 0 °C < T < 20 °C according to the present invention, and most preferably 5 °C < T < 15 °C according to the present invention, which is lower than the boiling point of any component at atmospheric pressure. Maintaining the preferred temperature range during the process of the method of the present invention advantageously prevents the evaporation of starting materials and the undesired solidification when the reaction mixture freezes.

[0164] However, the present invention is not limited to the preferred temperature range of the method of the present invention. For example, other temperature ranges can be used to release a limited amount of the loaded acid, so that the degree of carboxylic acid loading can be customized. The amount of the residual loaded carboxylic acid can be quantified by the released carboxylic acid, for example, by thermal analysis such as thermogravimetric analysis (TGA).

[0165] Mixing conditions / time

[0166] In addition to temperature control, gently adding the starting materials for the exothermic acid-base reaction during the process of the method of the present invention advantageously avoids a high heat energy input when releasing the reaction heat. Therefore, it is beneficial to control the reaction conditions, ensure the safety of the production process, and avoid product caking.

[0167] Generally, the particulate compounds are in contact with each other for a period of time sufficient to complete the acid-base reaction and sufficient to physically load the particulate with the expected amount of loaded carboxylic acid according to the present invention. The reaction time of the method of the present invention is usually limited to the shortest time until the reaction is completed, which is usually less than 150 minutes, preferably less than 90 minutes, and more preferably less than 20 minutes. However, the optimal reaction time depends to a large extent on the starting materials, the batch size used, and the equipment used.

[0168] The reaction time of the method of the present invention as defined therein advantageously inhibits the uncontrolled release of the loaded acid, caking, moisture ingress, or an undesired post-reaction temperature increase due to the input of mechanical energy during mixing. The controlled input of mechanical energy is further supported by gentle and stable mixing, thereby respectively advantageously reducing the agglomeration or poor flow properties of the products of the present invention.

[0169] Water content and agglomeration

[0170] When the amount of water present is reduced, agglomeration (the process of many small particles aggregating into a larger macrostructure) is further effectively suppressed. However, if water is a released condensate, for example, if a hydroxyl alkaline earth metal base is used, water may be inevitably produced during the acid-base reaction process that forms the carrier salt structure. The method based on the Karl-Fischer titration method according to ISO 760:1978 is usually used to analyze the water content (see US 4 703 014). Characteristically, the granular powder formulation contains less than 15.0wt% water by weight percentage (wt%). Preferably, based on the weight of the granular acid-loaded carrier compound according to the present invention, the amount of water is less than 10.0wt%, more preferably less than 5.0wt%, to provide a flowable acid-loaded carrier compound of the present invention. The reduction of agglomeration caused by the limited amount of water in the product of the present invention is advantageously promoted to prevent the occurrence of other serious problems, including mainly poor fluidity, hindered powder filling and deteriorated particle size uniformity.

[0171] The TGA graph of the compound obtained from the process of the present invention, magnesium formate loaded with propionic acid (MgFo-HProp[2]) (see FIG. 4(A) ), confirmed the low water content, as no water was released when the sample was continuously heated in the temperature range of 1° C. to 300° C.

[0172] However, the compounds of the present invention need not be completely anhydrous. Partially hydrated acid-loaded carriers may still be suitable for many uses of the present invention as long as the amount of water does not exceed the amount of water required for particle agglomeration (which is a separate parameter with respect to component selection).

[0173] dry

[0174] After resalting, which is an acid-base reaction to form the support salt structure, a possibly partially hydrated acid-loaded support is obtained, which is further processed by drying, grinding and sieving to form a dry and size-selected free-flowing powder of the present invention to provide a commercially marketable granular, free-flowing product.

[0175] Drying provides a carrier compound according to the pure acid load of the present invention, because possible low molecular weight by-products, such as condensed water, are removed. Due to the different boiling points of by-products (especially water) and the acid of the load, the controlled thermal purification of the compounds of this invention is advantageously promoted. For example, the evidence of the successful drying of the compounds of this invention is provided by thermogravimetric analysis (TGA).

[0176] As discussed above, the drying of the process according to the invention is preferably carried out at a temperature which is 5 °C < T < 15 °C lower than the boiling point of any of the components of the compounds of the invention, in order to advantageously maintain the expected molar ratio of the compounds according to the feed ratio. Thus, it can be assumed that the feed ratio of the carrier carboxylic acid to the loaded carboxylic acid is equal to the loading capacity of the compounds of the invention. According to the invention, cooling the acid-loaded carrier to room temperature immediately after the process according to the invention reduces the slow evaporation of the loaded acid and thus advantageously maintains the expected molar ratio of the components of the compounds of the invention according to the feed ratio.

[0177] The heat of reaction released during the exothermic reaction for generating the carrier carboxylic acid (e.g., during in-situ neutralization) can be maintained, for example, by using a heat-insulated reaction vessel and is advantageously used for the work-up of the compounds obtained according to the invention, for example for drying purposes. Thus, compared to a drying procedure at room temperature (r.t.), less time is advantageously required to dry the carboxylate carrier loaded with carboxylic acid.

[0178] Drying is generally carried out by using a suitable dryer selected from fluidized bed dryers, vacuum dryers, spray dryers, paddle dryers or conventional vacuum drying systems. Since the compounds of the invention can be selected from components having low boiling points, thermal degradability and low vapor pressures, purification and / or drying under mild conditions is advantageous. Thus, the drying according to the invention is preferably carried out in such a way that the loaded acid does not escape, for example, by evaporation or desorption from the final salt carrier product of the loaded acid.

[0179] The preferred drying and grinding according to the process of the invention respectively provide materials with low water content, controlled particle size and bulk density.

[0180] Granulation

[0181] The powdered C-loaded according to the invention is produced by crushing or grinding until a flowable powdered compound is obtained 1 -C 4 carboxylic acid salt carrier. Subsequent sieving is advantageous for distinguishing sizes above the desired size limit of the carrier salt of the powdered loaded acid. Both grinding and sieving are important steps for size selection of the compounds of the invention, thus advantageously achieving good flowability.

[0182] In addition to the advantages provided by the flowable powder discussed above, grinding produces a higher relative surface area, enhancing water release and thus supporting final drying.

[0183] In this respect, dry granulation effectively reduces the continuous agglomeration, thereby being conducive to better controlling the final particle size. In addition, the agglomerates are broken into smaller particles requiring less mechanical energy, which advantageously reduces the total energy input during grinding. In a preferred embodiment of the present invention, the powdered starting material is ground and dried simultaneously. Preferably, the absolute air humidity is at least 17g water / kg dry air, preferably 17 to 30g water / kg dry air, and the crushing or grinding process is adjusted simultaneously (see EP 0838529 B1). In this way, the individual particles of many small powdered short-chain carboxylic acids are effectively prevented from agglomerating into a larger spherical macrostructure.

[0184] Package

[0185] The carboxylic acid of load is hygroscopic, therefore easily absorbs moisture.In a preferred embodiment of the present invention, release the compounds of this invention through drying and grinding in a transportable form under moisture-proof conditions, preferably by being filled into a bottle or a bag.Preferably, the compound is packaged according to the good manufacturing practice (GMP) as outlined in the 21st chapter 110th part (Title 21 Part 110 of Code of Federal Regulations) of the compilation of federal regulations.For this reason, it is suitable according to the common packaging (for example, sealing polyethylene (PE) container or bag of other materials, such as fiber polypropylene with PE inner foil or PE lining) of industry practice.

[0186] In any case, the container should be sealed to avoid an undesired increase in moisture of the product of the invention, thereby advantageously maintaining its advantageous properties until use by the consumer. By this step of the invention, even atmospheric relative humidity of about > 70% at room temperature at European latitudes can be considered. Here, the acid cannot absorb such large amounts of water that it can deliquesce, as it would in the absence of moisture protection, and the fluidity of the carrier solid compound loaded with the acid is ensured.

[0187] Uses of Compounds

[0188] The compounds according to the invention are effective in a wide range of areas of the pharmaceutical, cosmetic, food and feed industries as acidity regulators, as buffer systems, for preservative purposes or as flavoring agents, which increase the shelf life, support the safety of production in the food chain, improve the flavor and / or increase the palatability.

[0189] Therefore, the present invention also comprises the use of a solid compound as defined herein for acidity regulation and / or as a buffer in cosmetic, pharmaceutical, food and feed applications.

[0190] Furthermore, the present invention also comprises the use of the solid compounds defined herein as antimicrobial preservatives in cosmetic, pharmaceutical, food and feed applications.

[0191] The invention also relates to the use of a solid compound as defined herein as a flavouring and palatant in pharmaceutical, food and feed applications.

[0192] Furthermore, the solid compounds defined herein may be used as color retaining agents in food and / or feed applications.

[0193] Furthermore, it is applicable to use the solid compounds defined herein as zootechnical additives in animal nutrition, for example as gastrointestinal acidifiers or non-antibiotic growth promoters.

[0194] It is also provided that the solid compounds defined herein can be used as nutraceutical additives in nutritional supplements for humans and animals.

[0195] The present invention also comprises the use of the solid compound as defined herein as an active ingredient in cosmetic and pharmaceutical applications. More preferably, the present invention comprises the solid compound as defined herein for use in cosmetic and pharmaceutical compositions, more preferably as an active ingredient.

[0196] Embodiments, Examples and Implementations

[0197] The present invention is further described and illustrated below through comparisons, experiments, drawings and examples, but the scope of the present invention is not limited in any way. BRIEF DESCRIPTION OF THE DRAWINGS

[0198] Figure 1 :Carrier carboxylic acid or Supported carboxylic acid R 2 COOH, and containing M 2+ Schematic diagram of the subsequent method of preparing the carboxylate salt carrier loaded with carboxylic acid of the present invention using an alkaline earth metal base component.

[0199] Figure 2 :Carrier carboxylic acid or Supported carboxylic acid R 2 COOH, and containing M 2+ Schematic diagram of the in-situ method for preparing the carboxylate salt carrier loaded with carboxylic acid of the present invention using an alkaline earth metal base component.

[0200] Figure 3: Distribution curves of cumulative volume (cum.volume) versus particle size of the samples of magnesium glutamate MgGlu-HLac[2] loaded with lactic acid in Figure 4(A), calcium acetate CaAc-HAc[2] loaded with acetic acid in Figure 4(B), and calcium tartrate CaT-HAc-HProp[1,1] loaded with acetic acid and propionic acid in Figure 4(C).

[0201] Figure 4 (A): Thermogravimetric analysis (TGA) graph of the dried sample MgFo-HProp [2] showing weight loss as a function of increasing temperature (while exposed to a constant heating rate).

[0202] Figure 4(B): Differential thermal analysis (DTA) graph of the dried sample MgFo-HProp[2] showing the thermal phenomena as a function of increasing temperature (while exposed to a constant heating rate).

[0203] Figure 5(A): Thermogravimetric analysis (TGA) graph of the as-synthesized undried partially hydrated sample CaAc-HAc[2] showing weight loss as a function of increasing temperature (while exposed to a constant heating rate) and two second-order phase transitions of dehydration and desorption of the supported carboxylic acid.

[0204] Figure 5(B): Differential thermal analysis (DTA) plot of the partially hydrated sample CaAc-HAc[2] that was not dried after synthesis, showing thermal phenomena as a function of increasing temperature (while exposed to a constant heating rate) as well as two distinct endothermic physicochemical phenomena, consistent with the trends observed in the TGA analysis of CaAc-HAc[2].

[0205] Figure 6 : pH values ​​of several representative compounds of the present invention and their corresponding separated components (which are loaded carboxylic acid R) constituting a pair of measured values ​​along the vertical axis 2 COOH and carrier carboxylic acid 5. Each of the 73 pairs is assigned a number 1-73, with reference to the corresponding number explained in Table 5. All measurements are performed at a 0.1 molar (M) concentration (c) of the sample, i.e., 0.1 moles per liter (mol / L). The pH difference of the compounds of the invention compared to the pH of the corresponding carrier carboxylic acid and / or the loaded carboxylic acid indicates the acid efficacy of the compounds of the invention. The readings can be referenced to the values ​​listed in Table 5, which are the basis of the figure.

[0206] Figure 7 (A): Comparison of the volume of French bread (FSB) in litres demonstrating the suitability of the compounds of the invention for use as preservatives in baked goods (Example 12). Bread samples were exposed to doses of the compounds of the invention as depicted on the x-axis.

[0207] FIG. 7(B) : Comparison of the area cross-section of FIG. 7(A) and the sample associated with Example 12.

[0208] Figure 8 : Color development over time of a chuck steak blank sample (fork) and a chuck steak sample with calcium acetate loaded with acetic acid (CaAsc-Hac[2], diamonds) as described in Example 13. RGB:R color conversion to black / white.

[0209] Figure 9 (A): Total bacterial counts of the samples described in Example 14, showing the usefulness of the compounds of the invention as preservatives in meat products.

[0210] Figure 9 (B): Total yeast counts of the samples described in Example 14, showing the usefulness of the compounds of the invention as preservatives in meat products.

[0211] Figure 10 (A): Test results demonstrating the antiseptic effect by testing the total bacterial count (TBC, see Example 15).

[0212] Figure 10 (B): Test results demonstrating the preservative effect by testing the total yeast / fungus count (see Example 15).

[0213] Figure 10 (C): Test results demonstrating the preservative effect by testing the Enterobacteriaceae / β-glucuronidase positive Enterobacteriaceae (E / β) counts (see Example 15).

[0214] List of reference symbols used in the figures

[0215] (T1.2) Tank

[0216] (PM1.1) Premixer

[0217] (M1.1) Mixer

[0218] (P1.1) Packaging device

[0219] (S1.1) Sieve

[0220] (SM1.1) Screening Mill

[0221] (VS1.1) Vacuum drying system

[0222] (C1.1) Grinder / cutting machine (nibbler) DETAILED DESCRIPTION

[0223] List of abbreviations for carboxylic acids and salts

[0224] Table 3 below lists examples of starting materials of preferred embodiments of the compounds of the present invention and their pK values ​​in acidic form. a and some relevant boiling points (T b,酸), which is preferably used as supported carboxylic acid. Abbreviations are used for the compound names described in the following nomenclature.

[0225] Table 3. Component abbreviations (first column) used for the names of preferred compounds according to the invention, followed by the names of the salt and acid forms of the component and the acid strength (pK a1 ).

[0226]

[0227]

[0228] Nomenclature:

[0229] If not otherwise stated, the carrier salt The name of the functional acid (R 2 COOH) are separated by a minus sign (-), where the support is always named before the supported carboxylic acid component. The brackets […] indicate the molar equivalents of supported acid relative to the supported salt and correspond to n outlined in the claims.

[0230] List of compound names

[0231] Table 4. Exemplary names for several preferred compounds according to the invention based on the abbreviations of the compounds given in Table 3, followed by an explanation of the name and the molar ratio of supported carboxylic acid to support carboxylate, support:supported acid.

[0232]

[0233]

[0234] Example 1 - General post hoc approach

[0235] Typical methods according to the preferred post hoc approach are as follows Figure 1 shown.

[0236] In the ex post process, the alkaline earth metal base present in tank T1.1 and the carrier carboxylic acid present in tank T1.2 are added to the reactor (R1) while gently mixing. After the reaction is complete, the formed carrier carboxylic acid salt is pre-dried while mixing, for example by using a vacuum drying system (VS1.1). The product (carrier salt) in the reactor (R1) is pre-screened (SM1.1) and introduced into an intermediate tank T1.3.

[0237] The carrier salt from the sieving of tank T1.3 and the carboxylic acid to be loaded from tank T1.4 are released to mixer (M1.1), while gently mixing. Alternatively, the carrier salt obtained from the outside of tank T1.5 and the carboxylic acid to be loaded from tank T1.4 are released to mixer (M1.1), while gently mixing. The carboxylate carrier product loaded with carboxylic acid obtained by mixer (M1.1) is further dried while mixing, for example, by being connected to the same vacuum drying system (VS1.1) used in the previous step. The dried product from M1.1 is subsequently ground by grinder / cutter (C1.1), to ensure enough particle size. After passing through sieve (S1.1), the product is packaged (P1.1).

[0238] In one embodiment of the preferred method of the present invention, the carrier carboxylic acid is purchased As the supported carboxylic acid R 2 For example, commercially available anhydrous calcium citrate has been shown to be suitable for forming a salt support structure, while being mixed with acetic acid to form acetic acid-loaded calcium citrate (CaCit-HAc). However, in this embodiment, the essential features of the invention are lacking, and therefore the optimal results as with the subsequent continuous or simultaneous methods according to the invention, i.e., the ex post method or the in situ method, respectively, are not shown.

[0239] Example 2 - General in situ method

[0240] Typical methods according to the more preferred in situ method are as follows Figure 2 shown.

[0241] In the in-situ process, the alkaline earth metal base is present in tank T1.1. The ligand acid and the loaded / free acid are released from tanks T1.2 and T1.3, respectively, and premixed in a container (PM1.1) until a homogeneous premix of the components is obtained. The acid premix from PM1.1 is released into the reactor (R1). The alkaline earth metal base from tank T1.1 is then gently added to R1 while mixing.

[0242] After the reaction is finished, the obtained product is dried using, for example, a vacuum drying system (VS1.1). Drying is carried out in such a way that the loaded carboxylic acid is not released from the carboxylate support of the loaded carboxylic acid, for example, by evaporation. The obtained carboxylate support of the loaded carboxylic acid is then ground by a grinder / cutter (C1.1) to ensure a sufficient particle size. After passing through a sieve (S1.1), the product is packaged (P1.1).

[0243] Examples of compounds of the invention that have been successfully processed by the in situ method include various most preferred compounds of the invention of supported carboxylic acids and supported carboxylate salts, such as calcium citrate loaded with formic acid (CaCit-HFo[2]) at a molar ratio of n=2, calcium tartrate loaded with lactic acid (CaT-HLac[2]) at n=2, magnesium aspartate loaded with salicylic acid (MgAsp-Sal[2]) at n=2, while higher acid loadings are exemplified by calcium glutamate loaded with acetate (CaGlu-HAc[4]) at n=4 or calcium citrate loaded with acetate (CaCit-HAc[6]) at n=6.

[0244] Example 3 - In situ synthesis of MgFo-HAc

[0245] This example shows the laboratory synthesis of magnesium formate MgFo-HAc loaded with acetic acid by the most preferred in situ method according to the present invention [2].

[0246] As the starting materials for MgFo-HAc[2], magnesium oxide (MgO) with a purity of >97% and a particle size of <0.03 mm, glacial acetic acid (CH 3 COOH) and formic acid (CH 2 O 2 ).

[0247] The chemical equation describes the synthesis of MgFo-HAc[2]:

[0248] MgO+2CH 3 COOH+2CH 2 O 2 →Mg(HCO 2 ) 2 *2CH 3 COOH+↑H 2 O

[0249] 41.55 g MgO, 120.10 g CH 3 COOH and 95.90 g CH 2 O 2 The solution was stirred in a sealed 5 dl thermo-glass beaker at ambient temperature (23° C.) for 30 minutes.

[0250] A white paste was obtained and dried at 95°C for 45 minutes to obtain a white, solid, free-flowing and dust-free product.

[0251] The pH measurement was suitable for determining the acidity of the obtained carboxylic acid loaded carboxylate support MgFo-HAc[2], which is characteristic of the loaded, physically adsorbed acetic acid. The acidic efficiency of the acetic acid loaded within the magnesium formate support structure was demonstrated by comparing the pH values ​​obtained with magnesium formate alone as a reference material. The pH value of MgFo-HAc[2] (pH 5.10 at 0.1 M and room temperature) was significantly lower than the pH value of the reference material magnesium formate (pH 7.90 at 0.1 M and room temperature), so it was concluded that the process according to the invention successfully produced magnesium formate as a carboxylate support, which beneficially provided a reservoir function for excess free acetic acid.

[0252] Example 4 - In situ synthesis of CaT-HAc-HProp[1,1]

[0253] This example shows the laboratory synthesis of calcium tartrate CaT-HAc-HProp loaded with acetic and propionic acids by the most preferred in situ method according to the present invention [1,1].

[0254] Use calcium hydroxide (Ca(OH) 2 ), 99-100% pure glacial acetic acid (CH 3 COOH), tartaric acid with purity>99% (C 4 H 6 O 6 ) and propionic acid (C 2 H 5 COOH) was used to produce calcium tartrate (CaT-HAc-HProp[1,1]) with 2 molar equivalents of free-loaded acetic and propionic acids in a 1:1 ratio.

[0255] The chemical equation describes the synthesis of CaT-HAc-HProp[1,1]:

[0256] Ca(OH) 2 +CH 3 COOH+C 2 H 5 COOH+C 4 H 6 O 6 →C 4 H 4 CaO 6 *[CH 3 COOH; C 2 H 5 COOH]+↑2H 2 O

[0257] For this purpose, 23.29 g of Ca(OH) 2, 18.5 g CH 3 COOH, 46.46 g of C 4 H 6 O 6 and 22.93 g of C 2 H 5 COOH was mixed in a sealed 5 dl hot glass beaker at ambient temperature (23°C) for 30 minutes. A white hydrated paste was obtained and the by-product water was evaporated at 95°C for 5 minutes to give a grey solid, free-flowing and dust-free product.

[0258] The successful loading of propionic acid and acetic acid and the acidic efficiency of the compound of the present invention were demonstrated by comparing the acidity of CaT-HAc-HProp[1,1] with that of calcium tartrate alone. The pH value of CaT-HAc-HProp[1,1] (pH 3.63 at 0.1 M and room temperature) was significantly lower than that of the reference material calcium tartrate (pH 7.33 at 0.1 M and room temperature), and therefore, it was concluded that calcium tartrate loaded with acetic acid and propionic acid was successfully generated according to the method of the present invention, which beneficially provided a storage function for excess free acetic acid.

[0259] Example 5 - Comparison between in situ and ex post methods

[0260] This example demonstrates a comparison between the in situ and post hoc methods for the generation of acetic acid-loaded calcium tartrate (CaT-HAc[2]) as an exemplary compound of the invention using 2 molar equivalents of loaded acetic acid.

[0261] In situ method: This example demonstrates the laboratory synthesis of a carboxylic acid loaded carboxylate support CaT-HAc [2] according to the more preferred in situ method of the present invention as opposed to the preferred ex post method of the present invention.

[0262] Use calcium hydroxide (Ca(OH) 2 ), 99-100% pure glacial acetic acid (CH 3 COOH) and tartaric acid (C 4 H 6 O 6 ) is used to produce CaT-HAc[2].

[0263] The following equation describes the synthesis of CaT-HAc[2]:

[0264] Ca(OH) 2 +2CH 3 COOH+C 4 H 6 O 6 →C 4 H 4CaO 6 *2CH 3 COOH+↑2H 2 O

[0265] For in situ synthesis, 24.37 g of Ca(OH) 2 , 38.71 g of CH 3 COOH and 48.62 g of C 4 H 6 O 6 Mix at ambient temperature (23°C) for 30 minutes in a sealed 5 dl hot glass beaker to avoid evaporation of reaction water and acid. a In comparison, tartaric acid (C 4 H 6 O 6 ) has a lower pK of 2.89 a All three materials can be added simultaneously while ensuring the formation of C with inbound free acetic acid. 4 H 4 CaO 6 Carrier structure.

[0266] A white hydrated paste was obtained and the by-product water was evaporated at 95°C for 5 minutes to evaporate the by-product water while avoiding the evaporation of acetic acid. After drying, a white solid, free-flowing and dust-free product was obtained.

[0267] To demonstrate that there was excess acetic acid loaded within the calcium tartrate support structure and that the compounds of the invention had the acidic characteristics expected of compounds of the invention, the pH of calcium tartrate acetate CaT-HAc [2] was compared to the pH of calcium tartrate alone.

[0268] As a result, the pH value of CaT-HAc[2] (pH 3.56 at 0.1 M and room temperature) was significantly lower than the pH value of the reference material calcium tartrate (pH 7.33 at 0.1 M and room temperature). Therefore, it was concluded that the method according to the present invention successfully generated calcium tartrate loaded with acetic acid, which beneficially provided a storage function for excess free acetic acid.

[0269] Post-process: This example demonstrates the laboratory synthesis of a carboxylic acid loaded carboxylate support CaT-HAc [2] according to the preferred post-processing method of the present invention as opposed to the more preferred in situ method of the present invention.

[0270] Use calcium hydroxide [Ca(OH) 2 ], 99-100% pure glacial acetic acid (CH 3 COOH) and tartaric acid (C 4 H6 O 6 ) was used to synthesize CaT-HAc by a post hoc method [2].

[0271] The following chemical equation describes the synthesis of CaT-HAc via a post hoc approach as a two-step process [2]:

[0272] Ca(OH) 2 +C 4 H 6 O 6 →C 4 H 4 CaO 6 +2H 2 O

[0273] C 4 H 4 CaO 6 +2H 2 O+2CH 3 COOH→C 4 H 4 CaO 6 2CH 3 COOH+↑2H 2 O

[0274] For the subsequent synthesis of CaT-HAc[2], 24.37 g of Ca(OH) 2 and 48.62 g of C 4 H 6 O 6 The mixture was first stirred in a sealed 5 dl hot glass beaker at ambient temperature (23°C) for 30 minutes. A white hydrated powder was obtained and then 38.71 g of CH 3 COOH. The mixture of the three components was subsequently stirred in a sealed 5 dl hot glass beaker at ambient temperature (23° C.) for 10 minutes.

[0275] A white hydrated paste was obtained and the by-product water was evaporated at 95°C for 10 minutes to evaporate the by-product water while avoiding the evaporation of acetic acid. After drying, a white solid, free-flowing and dust-free product was obtained.

[0276] As a result, the pH value of CaT-HAc[2] (pH 2.89 at 0.1 M and room temperature) was significantly lower than the pH value of the reference material calcium tartrate (pH 7.33 at 0.1 M and room temperature). Therefore, it was concluded that the method according to the present invention successfully produced calcium tartrate loaded with acetic acid, which beneficially provided a storage function for excess free acetic acid.

[0277] The compound CaT-HAc[2] processed by the in situ method and the ex post method were compared. Both the in situ method and the ex post method facilitated the production of CaT-HAc[2] with a reservoir function of excess free acid. The pH value of CaT-HAc[2] by the ex post method (pH 2.89 at 0.1 M and room temperature) and the pH value of CaT-HAc[2] by the in situ method (pH 3.56 at 0.1 M and room temperature) were comparable. However, for economic considerations, it can be concluded that the in situ method is most preferred because both the reaction and drying times are greatly reduced.

[0278] Example 6 - Acid holding capacity of the compounds of the present invention

[0279] This example demonstrates the acid holding capacity of very high carboxylic acid loadings (n=4), representatively demonstrated by acetic acid loaded calcium tartrate (CaT-HAc[4]) with 4 molar equivalents of loaded acid.

[0280] It is known to those skilled in the art that when at least two starting materials are provided in the first step of the method of the present invention, the starting materials can be selected in a stoichiometric or substoichiometric ratio of one to the other. In order to illustrate the acid capacity performance of the characteristic carrier calcium tartrate loaded with 4 molar equivalents of acetic acid, CaT-HAc[4] was synthesized according to the in situ method of the present invention and the acid strength of the compound of the present invention was analyzed.

[0281] Use calcium hydroxide (Ca(OH) 2 ), 99-100% pure glacial acetic acid (CH 3 COOH), and tartaric acid (C 4 H 6 O 6 ) is used to synthesize calcium tartrate CaT-HAc[4] loaded with acetic acid. The following chemical equation describes the synthesis of CaT-HAc[4]:

[0282] Ca(OH) 2 +4CH 3 COOH+C 4 H 6 O 6 →C 4 H 4 CaO 6 *4CH 3 COOH+↑2H 2 O

[0283] For the in situ method of CaT-HAc[4], 17.57 g of Ca(OH) 2 , 55.81 g of CH 3COOH and 35.05 g of C 4 H 6 O 6 Mixing was carried out at ambient temperature (23°C) for 30 minutes in a sealed 5 dl hot glass beaker. A grey paste was obtained and drying at 95°C for 6 minutes gave a white solid, free-flowing and dust-free product.

[0284] The pH value of CaT-HAc[4] (pH 3.33 at 0.1 M and room temperature) is significantly lower than the pH value of the reference material calcium tartrate (pH 7.33 at 0.1 M and room temperature), thus demonstrating high acidic efficiency, which is directly related to the very high loading capacity of the compound CaT-HAc[4] of the present invention. It is verified that the most preferred in situ method of the present invention successfully generates a compound with very high loading of carboxylic acid, which beneficially provides a high-dose storage depot function of excess liquid acid.

[0285] Example 7 - Acidity of Compounds of the Invention

[0286] This example demonstrates the acidic strength of several representative compounds of the invention, which was quantified by measuring pH.

[0287] For pH measurements, an InLab UltraMicro-ISM electrode (measuring range: pH-1 to pH 11; low-temperature membrane glass type; ceramic diaphragm; Argenthal with Ag) from Mettler-Toledo (Analytical, Switzerland) was used. + Ion trap reference system); and laboratory conventional pH electrodes (measuring range: pH 0 to pH 14; ceramic diaphragm; Argenthal with Ag + Seven2Go portable pH meter S2 (pH measurement range: -2 to 20; resolution: 0.01) with ion trap reference system).

[0288] For all samples, the compounds of the present invention were reacted with unsupported carboxylic acid R under comparable conditions of solvent, concentration, temperature, etc. 2 COOH and / or carboxylate with carrier The acidity of several representative compounds of the present invention is demonstrated by comparison of pH values.

[0289] For ease of comparison, compounds with the same loading ratio n = 2 were selected for this analysis, i.e., the loaded carboxylic acid was 2:1 relative to the carrier carboxylic acid. More examples with other loading ratios are given in Table 5. The components used for this pH characterization were dry, solid, free-flowing and exhibited complete solubility as shown by the reference salt itself. The analyte was dissolved in millipore water, stirred in a sealed vial for 5 minutes and then pH measurements were carried out at room temperature. All measurements were carried out at a sample concentration of 0.1 molar (M), i.e., 0.1 moles per liter (mol / L).

[0290] For reliability, each result is the average of at least three single measurements. Table 5 below summarizes the pH analysis results of the compounds of the present invention (third column), the corresponding carrier carboxylic acids (fourth column) and the loaded carboxylic acids (fifth column), together with the corresponding abbreviations (second column) and numbers (first column). The numbers 1 - 73 (nr., first column) are used as the assignment of 73 pairs as used in Figure 6 and include the compounds of the present invention (third column), the corresponding carrier carboxylic acids (fourth column) and the loaded carboxylic acids (fifth column).

[0291] Table 5 summarizes the experimental pH values of the exemplary compounds named in the present invention (third column), alongside their corresponding carrier carboxylic acids (fourth column) and loaded carboxylic acids (fifth column) row by row. The number (nr.) of the corresponding pair is consistent with Figure 6 that.

[0292]

[0293]

[0294]

[0295] The results given in Table 5 are shown in Figure 6 where the pH values of the compounds of the present invention are compared with those of the paired components along the vertical axis.

[0296] Compared with the pH of the corresponding carrier carboxylate and / or the corresponding unloaded carboxylic acid R 2 COOH, the significant differences in the pH values between the compounds of the present invention indicate the acidic efficiency of the compounds of the present invention and the stability of the carrier components.

[0297] First, the stability of the carrier carboxylate was verified for all samples as they exhibited pH values in the range of 7.2 < pH < 8.6 ( Figure 6, fork). This lack of acidic activity further demonstrates the integrity of the re-salification reaction, which is the latter synthesis according to the method of the present invention. Thus, the carrier advantageously acts as the intended non-reactive carrier compound and contributes to the regulation of acidity only through the loaded carboxylic acid R 2 COOH.

[0298] In contrast to the carrier carboxylate, the compounds of the present invention exhibit a significant acidity (3.3 < pH < 6.5, rectangle), comparable to that of the corresponding carboxylic acid R 2 COOH ( Figure 6 , circle). This observation shows the acidic efficiency of the physically adsorbed carboxylic acid R 2 COOH. The acidic strength after solvation of the compounds of the present invention demonstrates controlled acid release in solution, and the compounds of the present invention are proven to be beneficially stable for alternative release, such as by thermal desorption of the loaded acid (the reader is referred to Examples 8 and 9).

[0299] As a representative example of the high-loaded compounds of the present invention, calcium tartrate loaded with lactic acid, CaT-HLac[2], shows a pH of 3.27 (c = 0.1 M), which is significantly lower than the pH value of calcium tartrate, i.e., pH 7.33 (c = 0.1 M). Therefore, even for the compound with a molar excess of the loaded free acetic acid (n = 2), the depot function is clearly shown, further verifying the technical qualification of the method of the present invention.

[0300] However, compared with the neutral to weakly basic characteristics of the unloaded corresponding carrier carboxylates, all aqueous solutions containing the compounds of the present invention are characterized by a significant acidic pH.

[0301] Example 8 - Thermal Analysis of the Dried Compound

[0302] This example demonstrates the thermal analysis of a representative compound of the present invention, MgFo-HProp[2], in the dry state, including thermogravimetric analysis (TGA) and differential thermal analysis (DTA), giving information about the release of the loaded acid and the stability of the carrier structure.

[0303] Thermal analysis was performed using a Linseis STA 1600 synchronous thermal analyzer to determine the simultaneous changes in weight (TGA signal) and heat measurable conversion (DTA signal) in the temperature range between room temperature and 300 °C. The compound of the present invention (100 mg) was placed on the sample holder of the measuring device and heated to 300 °C at a heating rate of 2 Kelvin per minute in a nitrogen gas flow of 50 ml / min.

[0304] Figure 4 shows the results of the thermal characteristics of the sample MgFo-HProp[2] in the dry state.

[0305] Figure 4(A) shows the curve obtained from thermogravimetric analysis (TGA) of a dried sample of MgFo-HProp[2], showing the weight change as a function of increasing temperature while exposed to a constant heating rate. x The sample MgFo-HProp[2] shows a total weight loss of 24.4% when heated in the range of 125°C to 200°C. The weight loss is associated with the desorption of physically adsorbed supported carboxylic acids, as T x The temperature of weight loss near 100 °C is consistent with the boiling point of the propionic acid loaded (boiling point T b =141).

[0306] On the one hand, the anhydrous nature of the sample was confirmed by the fact that no other weight changes were observed, especially in the range of the boiling point of water (100°C), thus verifying the efficiency of the drying step during the manufacturing process of the present invention. On the other hand, the thermal stability of the support carboxylate MgFo-HProp[2] was clearly verified in the temperature range from room temperature to 300°C, since no further weight loss was observed in the accelerated temperature range of 200°C>T>300°C.

[0307] Turning Point x The position of gives evidence of the physical adsorption strength of the inclusion complex of the present invention, because the evaporation of the supported propionic acid requires more energy if compared with the evaporation of propionic acid (Ts=141°C), thereby verifying the stability of the compound of the present invention.

[0308] In addition, in the range of 125℃ to 200℃, T x The flat shape of the weight loss curve near the loading indicates a gentle release of the carboxylic acid compound, indicating the desired control of the acid release. This controlled release advantageously prevents the undesirable "burst release" of the loaded carboxylic acid. When the weight loss is attributed only to the desorption of the loaded acid, the weight loss can be advantageously used to obtain quantitative information about the loading capacity of the compounds of the present invention.

[0309] Figure 4(B) shows the DTA signal obtained by differential thermal analysis (DTA) of the dried sample MgFo-HProp[2], showing the thermal phenomena as a function of increasing temperature (while exposed to a constant heating rate). A single significant thermal change was detected for the sample MgFo-HProp[2] between 125°C and 200°C. Consistent with the temperature range of the major weight loss recorded by the TGA signal, the DTA signal shows an endothermic reaction occurring in this temperature range, indicating the desorption of the physically adsorbed supported carboxylic acid from the carboxylic acid carrier inclusion complex. The absolute minimum T xThe position of gives evidence of the physical adsorption strength of the inclusion complex of the present invention, because the evaporation of the supported propionic acid requires more energy compared to the evaporation of propionic acid (Ts=141°C), thereby verifying the stability of the compound of the present invention.

[0310] The consistency of the TGA and DTA curves in Figure 4 semi-quantitatively demonstrates the release of propionic acid and the purity of the product of the present invention, as well as the thermal stability of the support carboxylate MgFo-HProp[2] up to 300°C.

[0311] Example 9 - Thermal Analysis Before Drying

[0312] This example shows the thermal analysis of CaAc-HAc[2] before the drying step of the process according to the invention, including thermogravimetric analysis (TGA) and differential thermal analysis (DTA), giving information on the water content before drying, the efficiency of thermal purification during drying, the release of supported acid and the stability of the support structure.

[0313] Thermal analysis was performed according to Example 8.

[0314] FIG5(A) shows a thermogravimetric analysis (TGA) graph of a partially hydrated sample CaAc-HAc[2] before drying during the process of the present invention and represents the weight loss as a function of increasing temperature while exposed to a constant heating rate. The resulting graph shows two distinct weight loss stages. The first significant weight loss (-7.0 wt% of the total weight) occurs between 25-135°C and the second stage of weight loss (11.7 wt% of the total weight) can be observed in the range of 135-300°C. The total weight loss of the partially hydrated sample CaAc-HAc[2] at a constant heating rate between room temperature and 300°C is 18.74%.

[0315] The two distinct second-order phase transitions indicate the expected physical phenomena of evaporation of byproduct water and desorption of supported carboxylic acid during drying. The evaporation of water is indicated by the first turning point T of the TGA curve. 1 indicates that it coincides with the boiling point of water (100 °C), while the desorption of the supported carboxylic acid coincides with the second turning point T of the TGA curve. x Related, because T x Can be related to the boiling point of the supported acetic acid (118°C).

[0316] The evaporation of water occurs at T 1 and in the temperature range (T x Thus, these exemplary results for a representative sample of the compound of the invention, CaAc-HAc [2], for TGA analysis demonstrate successful drying of the compound of the invention.

[0317] Even though TGA analysis cannot provide absolute qualitative information, information about the released material can be obtained when referring to the thermal information of the DTA curve as shown in FIG5(B).

[0318] FIG5(B) shows a differential thermal analysis (DTA) graph of a partially hydrated sample CaAc-HAc[2] before drying during the process of the present invention and demonstrates the thermal phenomena as a function of increasing temperature while exposed to a constant heating rate. The DTA signal shows two different endothermic physicochemical phenomena through two minima of the DTA signal, verifying that the sample is dried to remove water (T 1 ) and the desorption of physically adsorbed carboxylic acid from the carboxylic acid carrier inclusion complex (T x ).

[0319] However, the absolute minimum T x The position of gives evidence of the physical adsorption strength of the inclusion complex of the present invention, because with the evaporation of acetic acid (boiling point T b =118°C), the evaporation of the supported acetic acid requires more energy, thus verifying the stability of the compounds of the present invention. The relatively increased thermal energy required to release the supported carboxylic acid from the support structure indicates the superposition of the energy required for evaporation (usually required for the individual carboxylic acids) and the energy required to overcome the attractive forces of physical adsorption of the supported carboxylic acid on the inclusion complex according to the present invention.

[0320] Since no further changes in TGA and DTA signals were observed, the purity of the compounds of the present invention relative to low molecular weight impurities was verified. In addition, the thermal stability of the supported carboxylate sample CaAc-HAc[2] in the temperature range between room temperature and 300°C was also verified.

[0321] Drying according to the process of the present invention advantageously facilitates thermal purification of the carboxylate support loaded with carboxylic acid to remove the main by-product water, since the boiling point of the loaded acid is different from that of the by-product.

[0322] Example 10 - Particle Size and Particle Size Distribution

[0323] This example demonstrates the powder qualities, such as flowability and non-aerosol properties, of representative compounds of the invention, as demonstrated, for example, by diffraction granulometry.

[0324] Powder particle size and particle size distribution were determined by a Cilas 920 laser diffraction particle size analyzer manufactured by Quantachrome (wavelength of incident laser beam: 830 nm), which measures the particle size distribution of wet dispersions or dry powders in the size range of 0.2 to 500 μm. All optical components are permanently mounted on a cast iron base plate, which means that the analyzer always remains aligned, and sample recirculation is achieved by two peristaltic pumps. Data analysis of the obtained diffraction patterns was performed based on the Fraunhofer Mie diffraction theory.

[0325] The results of representative samples are given by Figure 3 The distribution curves are given in Figure 4, showing the cumulative volume (cum. volume) plotted against the particle diameter. The distribution curves for the magnesium glutamate sample MgGlu-HLac[2] loaded with lactic acid are shown in Figure 4(A), the results for calcium acetate CaAc-HAc[2] loaded with acetic acid are shown in Figure 4(B), and the results for calcium tartrate CaT-HAc-HProp[1,1] loaded with acetic and propionic acids are shown in Figure 4(C).

[0326] Analysis of the shape of the distribution curve helps to estimate the average particle size (d av d 50 d 90 ). Characteristic average particle size of particle size distribution (d av d 50 d 90 ) are given in Table 6 below.

[0327] Table 6. Characteristic average particle diameter (d av d 50 d 90 ).

[0328]

[0329] The particle size distribution of samples CaAc-HAc[2] and CaT-HAc-HProp[1,1] showed a comparable average particle size d of about 220 μm. av , which is within the preferred particle size range according to the present invention, favorably supports flowability. In addition, the distribution curves of samples CaAc-HAc[2] and CaT-HAc-HProp[1,1] are similar in shape (see Figures 4(B) and 4(C)), indicating that the method of the present invention is suitable for use with a variety of samples with potentially different particle properties. Average particle size (d 50 d 90) demonstrates the uniform and / or homogeneous characteristics of the particle size of CaAc-HAc[2] and CaT-HAc-HProp[1,1]. In this context, the size distribution curves of these representative samples demonstrate the suitability of the compounds of the present invention for any powder processing manufacturing method, such as precise weight bottling, gravity feeding, and smooth and accurate powder metering for commercial scale.

[0330] In contrast, the sample MgGlu-HLac[2] shown in FIG4(A) contains smaller particles with an average particle size d av The average particle size is about 99 μm (see Table 6). The flat shape of the distribution curve in Figure 4(A) and the average particle size d av and d 50 The difference in the particle size distribution of the MgGlu-HLac[2] sample can be seen as a wider distribution. Even though the uniformity of the particle size distribution and the particle size of the MgGlu-HLac[2] sample are smaller than those obtained with the CaAc-HAc[2] and CaT-HAc-HProp[1,1] samples, advantageously no aerosol characteristics are exhibited. By the preferred size range of the compounds of the present invention, it is not expected to cause inhalation of particles through the lungs or any harmful respiratory problems. Therefore, contact with organisms does not have to be strictly avoided during processing and handling, which is advantageous for the purpose of saving processing costs.

[0331] Example 11 - Use as a preservative in baked goods

[0332] This example demonstrates the suitability of compounds of the invention for use as preservatives in baked goods.

[0333] Various compounds of the present invention were used as preservatives in the baked goods (French bread (FSB) and Mexican-style tortillas (MST)) that were the test subjects. The compounds used in this test were selected because they have been approved as GRAS food additives by the FDA and EFSA (Food Additives Database and Substances Added to Food Database, 2021) and are therefore suitable for baked food applications.

[0334] The preparation of French bread was carried out according to the ingredients in Table 7. The baking process was carried out using Princess Bread Machine 152006 (setting: P1; 1.5 lb bread size; medium color), and the total baking time was 2:53 hours. Subsequently, the bread was cooled to 21° C. and cut into 20 mm thick slices.

[0335] All ingredients were mixed into a dough and formed into flat tortilla shaped samples. All samples were baked on a stove top pan at a temperature of about 300°C for a total of 3 minutes per side. The tortilla samples were then cooled to 21°C.

[0336] Table 7. French bread (FSB) and Mexican-style tortilla (MST) recipes.

[0337]

[0338] In addition to the blank group that was not exposed to the compound of the present invention, the samples were exposed to the compound of the present invention according to the dosage of the corresponding flour weight as shown in Table 7. Then, the individual samples were hermetically sealed in polyethylene ziplock bags and stored for 30 days under comparable conditions (room temperature, in the dark). It is recognized that defining the shelf life of food is a difficult task and an area of ​​intensive research by food development scientists (including food technologists, microbiologists, packaging experts (such as Gabric, etc.)), so the preservative efficacy was determined by visual and olfactory detection of initial mold infection. The results of the preservative tests are summarized in Table 8.

[0339] Table 8. Results of the preservative capacity of additives in baked goods.

[0340]

[0341]

[0342] The chemical kinetics of the compounds of the present invention significantly increases the preservation of all samples by at least 7 days without losing the quality of the food. The compound of the present invention can effectively extend the preservation time to 30 days by increasing from 0.2wt%. Even if exposed to a small dose of the compound of the present invention, the increase in shelf life also opens up a new way for food packaging. Among them, the antiseptic ability of the compounds of the present invention is superior to conventional preservatives in similar industries due to its low cost and health benefits. Especially for products that are eaten immediately, such as fresh baked goods, whose packaging requirements are usually the lowest, the compounds according to the present invention effectively prevent the quality loss of food.

[0343] Example 12 - Volume Increase and Dough Conditioning in Baked Goods

[0344] The following tests demonstrate the bread-improving and dough-conditioning effects of several exemplary compounds according to the present invention. French bread (FSB) was used as the test subject.

[0345] All additives were dosed in such a way that each sample contained 200 ppm of ascorbic acid, which is commonly used as an active ingredient in industry standard bread improvers. One sample was not exposed to any additive (blank), one reference was exposed to ascorbic acid (200 ppm), another reference was exposed to calcium ascorbate (220 ppm), and two samples were exposed to compounds according to the invention, including calcium ascorbate loaded with acetic acid (CaAsc-HAc[2], 280 ppm) and calcium ascorbate loaded with acetic acid (CaAsc-HProp[2], 300 ppm).

[0346] The volume improvement effect was determined by volume measurement. The results of the tests performed are shown in FIG7(A), indicating that the additives cause a volume expansion of the bread relative to the blank sample. At the same dose of the active ingredient ascorbic acid and / or ascorbate, the volume enhancement effect of the compounds of the present invention is superior to that of the industry standard bread improver additive, which demonstrates that the compounds of the present invention are suitable as a volume enhancement additive for baked food dough. FIG7(B) shows cross-sections of different samples, advantageously showing a uniform volume expansion, in accordance with the visual requirements of the baking industry.

[0347] Example 13 - Used for color preservation of meat products

[0348] The following test outlines the color preservation function of an exemplary sample of the compound according to the present invention, calcium ascorbate loaded with acetic acid (CaAsc-HAc[2]). Grass-fed, grass-finished beef shoulder steak samples were used as test subjects. All tests were conducted under the same conditions of 20°C. The compound of the present invention, CaAsc-HAc[2], meets the requirements of a GRAS food additive in FDA and EFSA regulations. The additive was dosed at 0.2 wt% and applied topically to the sample.

[0349] The color retention was determined by k-means clustering method and post hoc analysis of mean RGB:R shift. The color indicates the state of myoglobin in the meat, whether it is deoxygenated, oxidized, methionylated, or present in the carboxymyoglobin state. Figure 8 It shows a clear change in color of the blank sample (dashed line) compared to the sample treated with CaAsc-HAc[2] (solid line).

[0350] The k-means clustering method and post hoc analysis of the average RGB:R shifts revealed a more quantitative view of the above color shifts. Figure 8 (B) The time trace of the color change shows a significant difference in the blank sample compared to the sample treated with CaAsc-HAc[2] after 24 h.

[0351] It shows that within the 72-hour time frame, the blank sample loses its characteristic red color earlier than the treated samples (see Figure 8 (B)). It can be concluded that CaAsc-HAc[2] contributes to the effective color preservation of meat products.

[0352] Example 14 - Use as a preservative in meat products

[0353] The following test series outlines the preservative function of acetic acid-loaded calcium ascorbate (CaAsc-HAc[2]) as a representative sample of the compounds of the present invention. Grass-fed, grass-finished beef shoulder steak samples were used as test subjects. All tests were carried out under the same conditions. The compound of the present invention, CaAsc-HAc[2], meets the requirements of a GRAS food additive in FDA and EFSA regulations. The additive was dosed at 0.2 wt% and applied topically to the samples. The tests were carried out at 4°C and 20°C. The preservative effect was determined by testing the total bacterial count and yeast / fungus count. The total bacterial count test (see Figure 9(A)) showed that the samples treated at 4°C and 20°C showed less bacterial infection compared to the blank count test. The yeast count test (see Figure 9(B)) showed that the treated samples were slightly better than the blank count test.

[0354] The use of the compound of the present invention helps to effectively reduce the total bacterial count and yeast formation within the first 164 hours after incubation. Therefore, the compound of the present invention, CaAsc-HAc[2], is beneficially suitable for use as a preservative in meat products.

[0355] Example 15 - Application as a preservative in silage

[0356] The following test series outlines the silage preservative function of calcium formate loaded with formic acid (CaFo-HFo[2]) and calcium formate loaded with propionic acid (CaFo-HProp[2]) as representative compounds according to the present invention. Feed samples containing about 90% grass and 10% green rye with a DM content of 30.75% were used as test subjects. All tests were carried out under the same conditions. The compounds of the present invention, CaFo-HProp[2] and CaFo-HFo[2], meet the requirements of GRAS food additives based on FDA and EFSA regulations. The dosage of the additive was 0.5 wt% and was applied topically to the sample. The test was carried out at room temperature for 31 days. The preservative effectiveness was determined by testing the total bacterial count (TBC), yeast / fungus count and enterobacteriaceae / β-glucuronidase positive enterobacteriaceae (E / β). The test results show that both CaFo-HProp[2] and CaFo-HFo[2] at a dosage of 0.5wt% can significantly reduce TBC (see Figure 10(A)), yeast count (see Figure 10(B)) and E / β count (see Figure 10(C)). In particular, CaFo-HProp[2] can completely inhibit the growth of yeast and β-glucuronidase-positive enterobacteriaceae (especially Escherichia coli), which are particularly undesirable in silage fermentation (Figure 10).

[0357] It can be concluded that the compounds of the present invention are able to reduce total bacterial counts, yeast formation and enterobacteria formation better than the blank test within the first 744 hours after incubation.

[0358] Example 16 - For cosmetic applications

[0359] This example demonstrates the use of the compounds of the invention in cosmetic applications, here shown by suitability as additives to shaving soaps.

[0360] The following liquid shaving soaps were made: no additives (blank), with the addition of 1 wt% malic acid, 1 wt% calcium citrate, 2 wt% lactic acid loaded calcium salicylate (CaSal-HLac[2]) and 1% acetic acid loaded calcium citrate (CaCit-HAc[2]). Table 9 gives an overview of the samples.

[0361] Table 9. Application samples and results in shaving soap.

[0362]

[0363]

[0364] Each Aleppo-style Arabic soap sample, consisting of 16% sodium hydroxide, 71.4% olive oil and 12.6% laurel oil, was cut into 22g sample sizes, placed in a bowl, and 22g of water was added. The mixture was stirred, and the hard soap pieces remained undissolved, and were placed in a microwave oven at 600W for 50 seconds. Then, the respective additives were added to 44g of water according to the aforementioned dosage, causing the remaining hard soap pieces to dissolve. In addition, changes in color and consistency can be observed as the mixture becomes a white and creamy substance. The mixture was placed in a microwave oven at 600W for 80 seconds. The resulting mixture was then mixed by hand and packed into jars for testing and storage. Table 9 summarizes the thickening and stability results.

[0365] In summary, mixing the acid loaded carrier material with Aleppo type Arabic hard soap and water produces a thick foam, but the soap solution is stable. This makes the product suitable for use in shaving soaps as its flowing nature exhibits a gliding effect while shaving, giving a smoother and closer shave, while the use of acids has the potential to cleanse the skin of impurities while disinfecting razor burns.

Claims

1. A solid compound prepared as a powder exhibiting good fluidity and comprising the following structure, Carrier Carboxylates in M 2+ is an alkaline earth metal ion, or a divalent metal ion selected from iron (Fe), copper (Cu), zinc (Zn), manganese (Mn), tin (Sn), lead (Pb), nickel (Ni), or a mixture thereof, R 1 is an optionally substituted C1-C 10 alkyl or optionally substituted aryl, wherein the substituent is selected from a carbonyl group (=O), a carboxylic acid group (-COOH), an amino group (-NH2), a hydroxyl group (-OH), a halogen, a cyano group (-CN) or a mixture thereof, or (R 1 COO (m+1)- ascorbate, and Where m is 0 to 2, Supported carboxylic acid R 2 COOH, Where R 2 is an optionally substituted C1-C 10 Alkyl or optionally substituted mono- or polyunsaturated C1-C 10 a hydrocarbon group wherein the substituent is selected from a carbonyl group (=O), a carboxylic acid group (-COOH), an amino group (-NH2), a hydroxyl group (-OH), a halogen group or a cyano group (-CN) or a mixture thereof, and Where 2≤n≤10; Features Carrier carboxylic acid (R 1 COO (m+1)- The pK of the corresponding carboxylic acid a1 ≤Carboxylic acid R 2 pK of COOH a1 , The supported carboxylic acid R 2 COOH is physically adsorbed on the support carboxylate In the structure of wherein the water content of the solid compound is less than 2 equivalents of water relative to the carrier carboxylic acid, Where R 2 COOH is a short chain carboxylic acid of formic acid, acetic acid, glycolic acid, propionic acid, lactic acid and / or butyric acid, or a mixture thereof.

2. The solid compound according to claim 1, wherein The alkaline earth metal ion is calcium (Ca), magnesium (Mg) or barium (Ba).

3. The solid compound according to claim 1, wherein the structure of the solid compound further comprises: The second supported carboxylic acid R 4 o R of COOH 4 COOH, where R 4 Selected from optionally substituted C1-C 10 Alkyl or optionally substituted mono- or polyunsaturated C1-C 10 A hydrocarbon group, wherein the substituent is selected from a carbonyl group (=O), a carboxylic acid group (-COOH), an amino group (-NH2), a hydroxyl group (-OH), a halogen group or a cyano group (-CN) or a mixture thereof, and wherein 0.1 <o≤10。 4. The solid compound according to claim 3, wherein R 4 COOH is a short chain carboxylic acid of formic acid, acetic acid, glycolic acid, propionic acid, lactic acid and / or butyric acid, or a mixture thereof.

5. The solid compound according to any one of claims 1 to 3, wherein M 2+ It is calcium (Ca) or magnesium (Mg).

6. The solid compound according to any one of claims 1 to 3, wherein (R 1 COO (m+1)- Including formate, acetate, glycolate, propionate, lactate, butyrate, succinate, adipate, malate, malonate, citrate, tartrate, aspartate, glutamate, benzoate, and salicylate.

7. The solid compound according to any one of claims 1 to 3, wherein The average particle size is in the range of 10 to 500 μm.

8. The solid compound according to any one of claims 1 to 3, wherein The compound contains less than 10.0 wt % water.

9. A method for preparing a compound according to any one of claims 1 to 8, which comprises providing a carrier structure by: (a) 1 COO (m+1)- and R 2 COOH carboxylic acid premix, wherein the liquid acid concentration is higher than 70%, (b) will include M 2+ A cationic alkaline earth metal base is added to step (a), (c) stirring the mixture of step (b) at a temperature below the boiling point of the most volatile acid present, (d) drying the mixture obtained in step (c).

10. A method for preparing a compound according to any one of claims 1 to 8, which comprises providing a carrier structure by: (a) will include M 2+ The alkaline earth metal base of the cation and (R 1 COO (m+1)- Acid premixes, where the liquid acid concentration is above 70%, (b) stirring the mixture of step (a) at a temperature below the boiling point of the acid present, (c) R 2 COOH acid is added to the In salt, (d) stirring the mixture of step (c) at a temperature below the boiling point of the most volatile acid present, (e) drying the mixture obtained in step (d).

11. A method of preparing a compound according to claim 9 or claim 10, wherein the compound is stirred at a temperature below the boiling point of any component for less than 50 minutes.

12. A method of preparing a compound according to claim 9 or claim 10, wherein the reaction mixture is cooled to a temperature below 60°C to package the final product without further purification.

13. Use of a compound according to any one of claims 1 to 8 for acidity regulation and / or as a buffer in cosmetic, pharmaceutical, food and feed applications.

14. Use of a compound according to any one of claims 1 to 8 as an antimicrobial preservative in cosmetic, pharmaceutical, food and feed applications.

15. Use of a compound according to any one of claims 1 to 8 as a flavoring and palatant in pharmaceutical, food and feed applications.

16. Use of a compound according to any one of claims 1 to 8 as a color retention agent in food and feed applications.

17. Use of a compound according to any one of claims 1 to 8 as an zootechnical additive in animal nutrition, such as a gastrointestinal acidifier or non-antibiotic growth promoter.

18. Use of a compound according to any one of claims 1 to 8 as a nutraceutical additive in nutritional supplements for humans and animals.

19. The solid compound according to any one of claims 1 to 8 for use in a pharmaceutical composition.

20. Use of a compound according to any one of claims 1 to 8 as an active ingredient in cosmetics.

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