Compound of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate and preparation method thereof

Abstract

The invention relates to a compound which comprises 3-hydroxybutyric acid and sodium 3-hydroxybutyrate. The ratio of the 3-hydroxybutyric acid to the sodium 3-hydroxybutyrate is (1: 10) to (10: 1). The preparation method comprises the following steps: (1) obtaining a substance A through one of the following methods: mixing 3-hydroxybutyric acid and sodium 3-hydroxybutyrate; or adding 3-hydroxybutyric acid into the alkaline Na compound aqueous solution, stirring, removing water, and steaming to be nearly dry; or carrying out heating reaction on 3-hydroxybutyric acid alkyl ester and water in the presence of a catalyst, cooling, filtering, adding an alkaline Na compound aqueous solution into the filtrate, carrying out reduced pressure distillation to remove water, and steaming to be nearly dry; (2) adding one or more solvents selected from the group consisting of water, THF, DMF, DMSO, DMAC, alcohols, halogenated hydrocarbons, ketones and esters into the substance A obtained in the step (1), stirring and cooling to precipitate a solid; and (3) filtering out the solid, and drying to obtain the compound. The compound is applied to preparation of ketogenic substances for increasing or maintaining the blood ketone level of a subject.

Description

Complex of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate and preparation method thereof Technical Field

[0001] The present invention belongs to the technical field of dietary or nutritional supplements, and particularly relates to a complex of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate and a preparation method thereof. Background Art

[0002] Currently, there is a growing demand for dietary or nutritional supplements aimed at improving individual health and reducing disease risk; athletes also use dietary or nutritional supplements to improve strength and performance.

[0003] Normally the human body relies on glucose for energy, but when the supply of glucose is insufficient to meet the body's energy needs, such as during prolonged exercise, hunger, or a lack of dietary carbohydrates, the body turns to consuming fat as fuel. Because the brain and central nervous system cannot directly use fat for energy, the liver produces ketone bodies from fatty acids as an alternative fuel, which are then released into the blood / plasma. Ketone bodies not only provide fuel for the brain, but are also used by skeletal and cardiac muscles. The metabolism of ketone bodies is associated with several beneficial effects, including anticonvulsant effects, enhanced brain metabolism, neuroprotection, muscle protection, and improved cognitive and physical performance. Based on the science-based improvement in the efficiency of cellular metabolism, managed through ketone supplementation, it can have beneficial effects on physical, cognitive and mental health, and have long-term effects on health against common avoidable diseases such as obesity, cardiovascular disease, neurodegenerative diseases, diabetes and cancer.

[0004] Despite the many health advantages of pursuing a ketogenic diet or lifestyle and maintaining a state of nutritional ketosis, significant barriers exist to achieving and maintaining ketosis. One of these barriers is the difficulty of transitioning to ketosis. The fastest endogenous pathway to ketosis, through depletion of the body's glucose reserves, is through fasting and exercise. This is physically and emotionally demanding, making it challenging for even the most motivated and disciplined individuals.

[0005] Numerous studies on exogenous ketones have shown that the ingestion of compounds that increase blood ketone body levels can provide various clinical benefits, including enhanced physical and cognitive performance and the treatment of cardiovascular disease, diabetes, neurodegenerative diseases, and epilepsy. Therefore, it is desirable to directly provide ketone bodies to humans or animals as an energy source. Dietary or nutritional supplements may contain carboxylic acids, such as β-hydroxybutyrate (also known as 3-hydroxybutyrate or BHB), which is one of the three major ketone bodies (i.e., acetoacetate, acetone, and BHB).

[0006] However, existing known ingestible exogenous ketone bodies have disadvantages that limit their use. β-Hydroxybutyrate, a source of exogenous ketones, is well known for its extremely acidic nature. Due to this acidity, the amount and concentration of β-Hydroxybutyrate that can be used in an ingestible form are limited. The acidity issue of D-BHB acid has been addressed in some applications by forming β-Hydroxybutyrate into sodium, magnesium, calcium, and potassium salts. However, while salts can address the acidity issue, the use of ketone salts is limited to very small amounts due to the accompanying salt overload that can lead to electrolyte imbalances. Besides small doses, the taste is also unpleasant. The aforementioned issues persist when simply physically mixing BHB acid and salts, and achieving a uniform mix is ​​difficult.

[0007] Therefore, in order to solve the problems of strong acidity and high hygroscopicity of existing BHB acid and high salt load, gastrointestinal side effects, and unpleasant taste of existing BHB salts, it is necessary to further find substances that can effectively avoid or balance the above problems so that they can be better used as ketogenic substances in diets or nutritional supplements, which is particularly beneficial for the process preparation of solid particles and the application of granules.

[0008] Summary of the Invention

[0009] In one aspect, the present invention provides a complex comprising 3-hydroxybutyric acid and sodium 3-hydroxybutyrate.

[0010] In some embodiments, the complex comprises a 3-hydroxybutyrate anion, a sodium ion, and a hydrogen ion. In some embodiments, the anion in the structure of the complex comprises a 3-hydroxybutyrate anion, and the cation comprises a sodium ion and a hydrogen ion.

[0011] In some embodiments, the 3-hydroxybutyrate anion content in the complex is greater than the 3-hydroxybutyrate anion content in sodium 3-hydroxybutyrate.

[0012] In some embodiments, the ratio of 3-hydroxybutyric acid to sodium 3-hydroxybutyrate is 1:10 to 10: 1. In some embodiments, the ratio of 3-hydroxybutyric acid to sodium 3-hydroxybutyrate can be 1:10 to 10:1, 1:8 to 8:1, 1:5 to 5:1, 1:3 to 3:1, 1:2 to 2:1, 1:1.

[0013] In some embodiments, the complex comprises no less than 50% of the R configuration and no more than 50% of the S configuration; or more than 50% of the S configuration and less than 50% of the R configuration.

[0014] In some embodiments, the complex is 3-hydroxybutyric acid·sodium 3-hydroxybutyrate.

[0015] In some embodiments, the complex has the following structure:

[0016] In some embodiments, the complex is R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate and / or S-3-hydroxybutyric acid·sodium S-3-hydroxybutyrate.

[0017] In some embodiments, the compound comprises not less than 50% of R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate and not more than 50% of S-3-hydroxybutyric acid·sodium S-3-hydroxybutyrate; or more than 50% of S-3-hydroxybutyric acid·sodium S-3-hydroxybutyrate and less than 50% of R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate. In some embodiments, the compound may comprise 51-100%, 51-99%, 55-95%, 60-90%, 70-80% of R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate; 0-49%, 1-49%, 5-45%, 10-40%, 20-30% of S-3-hydroxybutyric acid·sodium S-3-hydroxybutyrate. In some embodiments, the complex may contain 51-100%, 51-99%, 55-95%, 60-90%, 70-80% S-3-hydroxybutyric acid·S-3-hydroxybutyrate sodium; 0-49%, 1-49%, 5-45%, 10-40%, 20-30% R-3-hydroxybutyric acid·R-3-hydroxybutyrate sodium.

[0018] In some embodiments, the complex has the following structure:

[0019] and / or

[0020] In some embodiments, the complex is in crystalline form.

[0021] In some embodiments, the complex has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 9.8°±0.2°, 10.8°±0.2°, 18.9±0.2°, and 31.1°±0.2°.

[0022] In some embodiments, the X-ray powder diffraction pattern of the composite further comprises one or more peaks at diffraction angles (2θ) of 13.4°±0.2°, 21.6°±0.2°, 32.7°±0.2°.

[0023] In some embodiments, the X-ray powder diffraction pattern of the composite further comprises one or more peaks at diffraction angles (2θ) of 15.1°±0.2°, 23.0°±0.2°, 31.9°±0.2°.

[0024] In some embodiments, the composite has an X-ray powder diffraction pattern as shown in FIG1A , FIG1B , or FIG1C .

[0025] In some embodiments, the infrared spectrum of the composite has the following absorption bands, expressed as the inverse of the wavelength (cm -1 )(±2cm -1 ): 1715, 1452, 1414, 1368, 1306, 1217, 1148, 1094, 1057, 980, 853, 710, 573, 467.

[0026] In some embodiments, the complex has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 6.9°±0.2°, 10.7°±0.2°, 18.1°±0.2°, 22.3°±0.2°, 23.0±0.2°, 26.8°±0.2°, and 31.2°±0.2°.

[0027] In some embodiments, the X-ray powder diffraction pattern of the composite further comprises one or more peaks at diffraction angles (2θ) of 17.2°±0.2°, 21.6°±0.2°, 25.8°±0.2°.

[0028] In some embodiments, the complex has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.7°±0.2°, 10.7°±0.2°, 13.2°±0.2°, 18.7±0.2°, 21.4°±0.2°, 31.4°±0.2°, and 32.6°±0.2°.

[0029] In some embodiments, the X-ray powder diffraction pattern of the composite further comprises one or more peaks at diffraction angles (2θ) of 15.0°±0.2°, 23.9°±0.2°, 34.3°±0.2°.

[0030] In some embodiments, the complex is prepared as a food, beverage, supplement, or pharmaceutical formulation.

[0031] In another aspect, the present invention provides a 3-hydroxybutyric acid·sodium 3-hydroxybutyrate complex, which is obtained by the following method:

[0032] (1) obtaining substance A by one of the following methods: mixing 3-hydroxybutyric acid and sodium 3-hydroxybutyrate; or adding 3-hydroxybutyric acid to an aqueous solution of an alkaline sodium compound, stirring and removing water, and evaporating to near dryness; or allowing an alkyl 3-hydroxybutyrate to react with water by heating in the presence of a catalyst, cooling and filtering, adding an aqueous solution of an alkaline sodium compound to the filtrate, removing water by distillation under reduced pressure, and evaporating to near dryness;

[0033] (2) adding one or more solvents selected from the group consisting of water, THF, DMF, DMSO, DMAC, alcohols, halogenated hydrocarbons, ketones, and esters to the substance A obtained in step (1), stirring and cooling, preferably cooling to 0-20° C. or 0-10° C., to precipitate a solid;

[0034] (3) filtering out the solid and drying it, preferably at 35-65° C., to obtain a composite.

[0035] In some embodiments, the alcohol in step (2) is methanol, ethanol, isopropanol, n-butanol, preferably ethanol, isopropanol, the halogenated hydrocarbons are chlorobenzene, dichlorobenzene, dichloromethane, preferably dichloromethane, the ketones are acetone, methyl butyl ketone, methyl isobutyl ketone, preferably acetone, and the esters are ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, preferably ethyl acetate.

[0036] In some embodiments, the alkaline Na compound in step (1) can be NaOH, Na2CO3, NaHCO3, NaOMe, NaOAc or NaOCHO, preferably NaOH; the alkyl 3-hydroxybutyrate can be methyl 3-hydroxybutyrate, ethyl 3-hydroxybutyrate, propyl 3-hydroxybutyrate, butyl 3-hydroxybutyrate, preferably methyl 3-hydroxybutyrate.

[0037] In some embodiments, the complex is R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate and / or S-3-hydroxybutyric acid·sodium S-3-hydroxybutyrate.

[0038] In some embodiments, the complex is in crystalline form.

[0039] In another aspect, the present invention provides a method for preparing the above-mentioned composite, comprising the following steps:

[0040] (1) obtaining substance A by one of the following methods: mixing 3-hydroxybutyric acid and sodium 3-hydroxybutyrate; or adding 3-hydroxybutyric acid to an aqueous solution of an alkaline sodium compound, stirring and removing water, and evaporating to near dryness; or allowing an alkyl 3-hydroxybutyrate to react with water by heating in the presence of a catalyst, cooling and filtering, adding an aqueous solution of an alkaline sodium compound to the filtrate, removing water by distillation under reduced pressure, and evaporating to near dryness;

[0041] (2) adding one or more solvents selected from the group consisting of water, THF, DMF, DMSO, DMAC, alcohols, halogenated hydrocarbons, ketones, and esters to the substance A obtained in step (1), stirring and cooling, preferably cooling to 0-20° C. or 0-10° C., to precipitate a solid;

[0042] (3) filtering out the solid and drying it, preferably at 35-65° C., to obtain a composite.

[0043] In some embodiments, in step (2), the alcohol is methanol, ethanol, isopropanol, or n-butanol, preferably ethanol or isopropanol; the halogenated hydrocarbon is chlorobenzene, dichlorobenzene, or dichloromethane, preferably dichloromethane; the ketone is acetone, methyl butyl ketone, or methyl isobutyl ketone, preferably acetone; and the ester is ethyl acetate, isopropyl acetate, n-butyl acetate, or isobutyl acetate, preferably ethyl acetate.

[0044] In some embodiments, the alkaline Na compound in step (1) can be NaOH, Na2CO3, NaHCO3, NaOMe, NaOAc or NaOCHO, preferably NaOH; the alkyl 3-hydroxybutyrate can be methyl 3-hydroxybutyrate, ethyl 3-hydroxybutyrate, propyl 3-hydroxybutyrate, butyl 3-hydroxybutyrate, preferably methyl 3-hydroxybutyrate.

[0045] In another aspect, the present invention provides a composition comprising an effective amount of the above-mentioned complex and a pharmaceutically acceptable carrier.

[0046] In some embodiments, the composition is used as a ketogenic substance.

[0047] In some embodiments, the composition is prepared as a food, beverage, supplement, or pharmaceutical formulation.

[0048] In another aspect, the present invention provides use of the complex in preparing a ketogenic substance for increasing or maintaining blood ketone levels in a subject.

[0049] In some embodiments, ketogenic substances can be used as a nutritional supplement, energy therapy, medical treatment, or strength and / or endurance sports supplement.

[0050] In another aspect, the present invention provides use of a composition for preparing a ketogenic substance for increasing or maintaining blood ketone levels in a subject, wherein the composition comprises the complex of the present invention and a pharmaceutically acceptable carrier.

[0051] In some embodiments, the ketogenic substance is a nutritional supplement, an energy treatment, a medical treatment, or a strength and / or endurance sports supplement.

[0052] Compared to existing technologies, the complex of the present invention offers the following advantages: it is odorless and effectively avoids issues such as acidity, hygroscopicity, salt loading, intestinal side effects, and electrolyte imbalance. Compared to other exogenous ketones, the complex exhibits superior adaptability. When administered to a subject, the complex exhibits a superior overall effect compared to either the acid or salt alone, or simply physically mixed components. On one hand, the complex of the present invention addresses the strong acidity, intestinal side effects, and high hygroscopicity of BHB acid, while simultaneously addressing the electrolyte imbalance caused by the high salt loading of BHB salt. It also avoids the uneven mixing associated with physical mixing, thus offering broad application prospects as a ketogenic substance in dietary supplements and food products. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] FIG1A is an XRPD pattern of the R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate complex of the present invention.

[0054] FIG1B is an XRPD pattern of the 3-hydroxybutyric acid·sodium 3-hydroxybutyrate complex of the present invention.

[0055] FIG1C is an XRPD pattern of the S-3-hydroxybutyric acid·S-3-hydroxybutyrate sodium complex of the present invention.

[0056] FIG2 is an infrared spectrum (IR) of the 3-hydroxybutyric acid·sodium 3-hydroxybutyrate complex of the present invention.

[0057] FIG3A is a Raman spectrum of the R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate complex of the present invention.

[0058] FIG3B is a Raman spectrum of the 3-hydroxybutyric acid·sodium 3-hydroxybutyrate complex of the present invention.

[0059] FIG3C is a Raman spectrum of the S-3-hydroxybutyric acid·S-3-hydroxybutyrate sodium complex of the present invention.

[0060] FIG4A is a TGA chart of the R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate complex of the present invention.

[0061] FIG4B is a TGA chart of the 3-hydroxybutyric acid·sodium 3-hydroxybutyrate complex of the present invention.

[0062] FIG4C is a TGA chart of the S-3-hydroxybutyric acid·S-3-hydroxybutyrate sodium complex of the present invention.

[0063] FIG5A is a DSC spectrum of the R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate complex of the present invention.

[0064] FIG5B is a DSC spectrum of the 3-hydroxybutyric acid·sodium 3-hydroxybutyrate complex of the present invention.

[0065] FIG5C is a DSC spectrum of the S-3-hydroxybutyric acid·sodium S-3-hydroxybutyrate complex of the present invention. DETAILED DESCRIPTION

[0066] The preferred embodiments of the present invention will now be described in detail with reference to the embodiments thereof. Although the present invention will be described in conjunction with the preferred embodiments, it should be understood that they are not intended to limit the present invention to these embodiments. On the contrary, the present invention is intended to cover substitutions, modifications and equivalents, which may be included within the spirit and scope of the present invention as defined in the claims. In addition, in the detailed description of the present invention, many specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that the present invention can be practiced without these specific details. In other cases, well-known methods, procedures, components and other features are not described in detail to avoid unnecessarily obscuring various aspects of the present invention.

[0067] The 3-hydroxybutyric acid and sodium 3-hydroxybutyrate complex of the present invention comprises 3-hydroxybutyric acid and sodium 3-hydroxybutyrate in any appropriate ratio, and the complex can be a hydrate, anhydrous form, or a corresponding crystalline form with a fixed water content ratio.

[0068] As used herein, the term "or" is intended to include "and" and "or." In other words, the term "or" can also be replaced with "and / or."

[0069] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0070] As used herein, the term "comprises" or "includes" or variations thereof refers to instances where the term is used in its non-limiting sense, meaning that items following the term are included, but items not specifically mentioned are not excluded. It also includes the more restrictive verbs 'consisting essentially of' and 'consisting of.'

[0071] As used herein, the terms "about" and "approximately" provide flexibility in numerical values ​​by providing that a given value may be "slightly higher" or "less than" an endpoint. The flexibility of this term can be determined by the specific variables and is within the knowledge of those skilled in the art to determine based on experience and the relevant description herein.

[0072] "β-Hydroxybutyrate," also known as 3-hydroxybutyric acid, βHB, or BHB, refers to a compound with the general formula: CH3CH2OHCH2COOH. "β-Hydroxybutyrate derivatives" refer to compounds with the following chemical structure: wherein X is hydrogen, a metal ion, an amino cation (e.g., an amino acid), or the like.

[0073] When X is hydrogen, the compound is β-hydroxybutyric acid. When X is a metal ion or an amino cation, the compound is β-hydroxybutyrate. The aforementioned compound can be in any desired physical form, such as crystals, powders, solids, liquids, solutions, suspensions, or gels.

[0074] As used herein, the term "administer" refers to the process of delivering a disclosed complex or active ingredient to a subject. The complexes of the present invention can be administered by various suitable means to achieve the desired effect, including oral, intragastric, and parenteral (referring to intravenous and intraarterial and other suitable parenteral routes), etc. The complexes of the present invention can be administered to a subject at a therapeutically effective dose and / or at a frequency to induce or maintain ketosis. In some embodiments, a single dose will include an amount of about 1-50 grams, or about 2-40 grams, or about 5-30 grams, or about 10-20 grams, about 0.5-25 grams, or about 0.75-20 grams, or about 1-15 grams, or about 1.5-12 grams. In some embodiments, multiple doses of the complex are administered over a period of time. The frequency of administration of the complex can vary depending on any of a variety of factors, such as the time since the previous treatment, the purpose of the treatment, etc. The duration of complex administration (e.g., the time period over which the agent is administered) can vary depending on any of a variety of factors, including the subject's response, the desired therapeutic effect, etc.

[0075] As used herein, the term "effective amount" refers to the amount required to achieve the effects taught herein. The amount to be administered can vary depending on factors such as individual sensitivity, individual age, sex, and weight, individual idiosyncrasies, and the like. In accordance with the present disclosure, a suitable single dose size is a dose that, when administered one or more times over an appropriate time period, achieves the effects described above.

[0076] As used herein, the term "pharmaceutically acceptable" refers to pharmaceutically, physiologically, dietary and / or nutritionally acceptable, and refers to those compositions or agents, materials or combinations of compositions and / or dosage forms thereof that are within the scope of sound medical judgment, suitable for contact with the tissues of humans and animals, compatible with the other ingredients of the composition, without excessive toxicity, irritation, allergic response or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0077] In some embodiments, the β-hydroxybutyrate can be R-β-hydroxybutyrate, which is endogenously produced by mammals during ketosis, so that administering R-β-hydroxybutyrate to a subject provides additional amounts and / or increased plasma levels that can be immediately used by the body, e.g., for energy production (e.g., as an alternative energy source to glucose).

[0078] The complexes and / or compositions of the present invention can be used to prepare ketogenic substances for increasing or maintaining blood ketone levels in a subject, increasing ketone body levels in a subject, including inducing and / or maintaining elevated ketone body levels (e.g., ketosis) at a desired level in a subject to which it is administered. "Ketosis" refers to a subject's blood ketone level in the range of about 0.5 mmol / L to about 16 mmol / L. Ketosis can improve mitochondrial function, reduce the production of reactive oxygen species, reduce inflammation, and increase the activity of neurotrophic factors. "Keto adaptation" refers to long-term nutritional ketosis (>1 week) to achieve sustained, non-pathological "mild ketosis" or "therapeutic ketosis." In some cases, "elevated ketone body levels" may not mean that the subject is in a state of "clinical ketosis," but still has an elevated ketone supply for producing energy and / or achieving other beneficial effects of ketone bodies.

[0079] Administration of the complexes and / or compositions of the present invention can increase or maintain blood ketone levels in a subject, acting as a ketogenic substance, and produce one or more desired effects, including but not limited to appetite suppression, weight loss, fat loss, lowered blood sugar levels, improved mental alertness, increased physical energy, improved cognitive function, reduced traumatic brain injury, reduced effects of diabetes, improved neurological disorders, reduced cancer, reduced inflammation, anti-aging, anti-glycation, reduced seizures, improved mood, increased strength, increased muscle mass, or improved body composition.

[0080] In some embodiments, the complex of the present invention can be prepared as a composition together with a dietary or pharmaceutically acceptable carrier. In the present invention, the administration form of the composition involves a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the composition and is harmless to the subject, i.e., suitable for consumption or nutritionally acceptable. The above-mentioned carriers include those non-toxic compatible substances commonly used in health foods and dietary supplements and pharmaceutical preparations, such as sugars, starches, cellulose and its derivatives, powdered tragacanth gum, malt, gelatin, talc, oils, glycols, polyols, esters, agar, alginic acid, pyrogen-free water, isotonic saline, etc.

[0081] In some embodiments, the complexes of the present invention can be administered with other supplements, such as vitamins, minerals, nootropics, and other supplements known in the art. Examples of vitamins, minerals, and herbal supplements that can be added to the ketogenic composition include one or more of vitamin A, vitamin C, vitamin D3, vitamin E, niacin, vitamin B6, folic acid, 5-MTHF, vitamin B12, iodine, zinc, copper, manganese, chromium, caffeine, theobromine, theophylline, methyltaxine, huperzine A, epicatechin, and enzymes.

[0082] In some embodiments, the complexes of the present invention can be provided in solid or powder form. Such solid form compositions can be formulated to have sufficient ease of handling and manufacturability. The complexes can be provided in liquid form, such as an injection or oral spray for rapid delivery and absorption. The liquid form can include one or more liquid carriers, such as water, ethanol, glycerol, propylene glycol, 1,3-propanediol, and the like.

[0083] In some embodiments, the complexes of the present invention can be administered as suppositories, tablets, pills, granules, powders, films, capsules, beverages, aerosols, alcohol, tinctures, tonics, liquid suspensions, or syrups.

[0084] The complexes and / or compositions of the present invention can be prepared into food and beverage products for human consumption, as well as nutritional supplements, energy treatments, medical treatments, or strength and / or endurance sports supplements, as ketogenic substances, thereby providing a dietary source of exogenous ketones to increase or maintain blood ketone levels in a subject. The resulting products can exhibit reduced acidity, lower hygroscopicity, improved taste, better palatability, a uniform appearance, and a well-balanced ketogenic effect, without intestinal side effects, electrolyte imbalance, or high salt load.

[0085] The following examples are illustrative of selected embodiments of the present invention and are not intended to limit the scope of the invention.

[0086] Preparation of the complex of the present invention

[0087] Example 1. Preparation of R-3-hydroxybutyric acid and sodium R-3-hydroxybutyrate complex

[0088] Add 110 g of R-3-hydroxybutyric acid, 110 g of sodium R-3-hydroxybutyrate, and 440 mL of dichloromethane into a 1 L reaction flask, heat to 40°C, stir to dissolve, cool to 0-10°C, precipitate solid, filter, and dry at 40°C to obtain 150 g of R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate complex.

[0089] Example 2. Preparation of R-3-hydroxybutyric acid and sodium R-3-hydroxybutyrate complex

[0090] In a 1 L reaction flask, 104 g of R-3-hydroxybutyric acid, 116 g of sodium R-3-hydroxybutyrate, and 440 mL of acetone were added, heated to 60°C, stirred to dissolve, cooled to 0-10°C, the solid precipitated, filtered, and dried at 55°C to obtain 140 g of R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate complex.

[0091] Example 3. Preparation of R-3-hydroxybutyric acid and sodium R-3-hydroxybutyrate complex

[0092] Add 200 mL of water and 20 g of sodium hydroxide to a 1 L reaction flask, stir and dissolve, cool to below 25°C, add 104 g of R-3-hydroxybutyric acid, stir for half an hour, remove water by distillation under reduced pressure, evaporate to near dryness, add 200 mL of dichloromethane, stir, cool to 0-10°C, precipitate solid, filter, and dry at 40°C to obtain 75 g of R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate complex.

[0093] Example 4. Preparation of R-3-hydroxybutyric acid and sodium R-3-hydroxybutyrate complex

[0094] Add 200 mL of water and 20 g of sodium hydroxide to a 1 L reaction flask, stir and dissolve, cool to below 25°C, add 104 g of R-3-hydroxybutyric acid, stir for half an hour, remove water by distillation under reduced pressure, evaporate to near dryness, add 200 mL of acetone, stir, cool to 0-10°C, precipitate solid, filter, and dry at 55°C to obtain 98 g of R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate complex.

[0095] Example 5. Preparation of R-3-hydroxybutyric acid and sodium R-3-hydroxybutyrate complex

[0096] 60 g of methyl R-3-hydroxybutyrate, 360 mL of water, and 24 g of catalyst were added to a 1 L reaction flask. The reaction was heated at 90-95° C. for 24 hours until the reaction was complete. The filtrate was cooled to room temperature, and the catalyst was filtered off. 9 g of sodium hydroxide in 50 mL of aqueous solution was added to the filtrate. The water was removed by distillation under reduced pressure. After evaporation to near dryness, 100 mL of dichloromethane was added, stirred, and cooled to 0-10° C. The solid precipitated, filtered, and dried at 40° C. to obtain 40 g of R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate complex.

[0097] Example 6. Preparation of R-3-hydroxybutyric acid and sodium R-3-hydroxybutyrate complex

[0098] 60 g of methyl R-3-hydroxybutyrate, 360 mL of water, and 24 g of a catalyst were added to a 1 L reaction flask. The reaction was heated at 90-95° C. for 24 hours until the reaction was complete. The filtrate was cooled to room temperature, and the catalyst was filtered off. A 50 mL aqueous solution of 9 g of sodium hydroxide was added to the filtrate. The water was removed by distillation under reduced pressure. After evaporation to near dryness, 100 mL of acetone was added, stirred, and cooled to 0-10° C. The solid precipitated, filtered, and dried at 55° C. to obtain 50 g of an R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate complex.

[0099] Example 7. Preparation of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate complex

[0100] Add 110 g of 3-hydroxybutyric acid, 110 g of sodium 3-hydroxybutyrate, and 440 mL of dichloromethane into a 1 L reaction flask, heat to 40°C, stir to dissolve, cool to 0-10°C, precipitate solid, filter, and dry at 40°C to obtain 155 g of 3-hydroxybutyric acid·sodium 3-hydroxybutyrate complex.

[0101] Example 8. Preparation of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate complex

[0102] Add 200 mL of water and 20 g of sodium hydroxide to a 1 L reaction flask, stir and dissolve, cool to below 25°C, add 104 g of 3-hydroxybutyric acid, stir for half an hour, remove water by distillation under reduced pressure, evaporate to near dryness, add 200 mL of acetone, stir, cool to 0-10°C, precipitate solid, filter, and dry at 60°C to obtain 102 g of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate complex.

[0103] Example 9. Preparation of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate complex

[0104] In a 1L reaction flask, 60 g of methyl 3-hydroxybutyrate, 360 mL of water, and 24 g of a catalyst were added. The reaction was heated at 90-100°C for 24 hours until the reaction was complete. The reaction was cooled to room temperature, and the catalyst was filtered off. The filtrate was added with 9 g of sodium hydroxide in 50 mL of an aqueous solution. The water was removed by distillation under reduced pressure. After evaporation to near dryness, 100 mL of acetone was added, stirred, and cooled to 0-10°C. The solid precipitated, filtered, and dried at 60°C to obtain 42 g of a 3-hydroxybutyric acid and sodium 3-hydroxybutyrate complex.

[0105] Example 10. Preparation of S-3-hydroxybutyric acid and sodium S-3-hydroxybutyrate complex

[0106] Add 100 g of S-3-hydroxybutyric acid, 100 g of sodium S-3-hydroxybutyrate, and 400 mL of dichloromethane to a 1 L reaction flask, heat to 40°C, stir to dissolve, cool to 0-10°C, precipitate solid, filter, and dry at 40°C to obtain 130 g of S-3-hydroxybutyric acid·sodium S-3-hydroxybutyrate complex.

[0107] Example 11. Preparation of S-3-hydroxybutyric acid and sodium S-3-hydroxybutyrate complex

[0108] In a 1 L reaction flask, 104 g of S-3-hydroxybutyric acid, 116 g of sodium S-3-hydroxybutyrate, and 440 mL of acetone were added, heated to 60°C, stirred to dissolve, cooled to 0-10°C, the solid precipitated, filtered, and dried at 55°C to obtain 138 g of S-3-hydroxybutyric acid·sodium S-3-hydroxybutyrate complex.

[0109] Example 12. Preparation of S-3-hydroxybutyric acid and sodium S-3-hydroxybutyrate complex

[0110] Add 200 mL of water and 20 g of sodium hydroxide to a 1 L reaction flask, stir and dissolve, cool to below 25°C, add 104 g of S-3-hydroxybutyric acid, stir for half an hour, remove water by distillation under reduced pressure, evaporate to near dryness, add 200 mL of dichloromethane, stir, cool to 0-10°C, precipitate solid, filter, and dry at 40°C to obtain 73 g of S-3-hydroxybutyric acid·S-3-hydroxybutyrate sodium complex.

[0111] Example 13. Preparation of S-3-hydroxybutyric acid and sodium S-3-hydroxybutyrate complex

[0112] Add 200 mL of water and 20 g of sodium hydroxide to a 1 L reaction flask, stir and dissolve, cool to below 25°C, add 104 g of S-3-hydroxybutyric acid, stir for half an hour, remove water by distillation under reduced pressure, evaporate to near dryness, add 200 mL of acetone, stir, cool to 0-10°C, precipitate solid, filter, and dry at 55°C to obtain 98 g of S-3-hydroxybutyric acid·S-3-hydroxybutyrate sodium complex.

[0113] Example 14. Preparation of S-3-hydroxybutyric acid and sodium S-3-hydroxybutyrate complex

[0114] In a 1 L reaction flask, 60 g of methyl S-3-hydroxybutyrate, 360 mL of water, and 24 g of a catalyst were added. The reaction was heated at 90-95° C. for 24 hours until the reaction was complete. The reaction was cooled to room temperature, and the catalyst was filtered off. The filtrate was added with a 50 mL aqueous solution of 9 g of sodium hydroxide. The water was removed by distillation under reduced pressure. After evaporation to near dryness, 100 mL of dichloromethane was added, stirred, and cooled to 0-10° C. The solid precipitated, filtered, and dried at 40° C. to obtain 42 g of a complex of S-3-hydroxybutyric acid and sodium S-3-hydroxybutyrate.

[0115] Example 15. Preparation of S-3-hydroxybutyric acid and sodium S-3-hydroxybutyrate complex

[0116] In a 1 L reaction flask, 60 g of methyl S-3-hydroxybutyrate, 360 mL of water, and 24 g of a catalyst were added. The reaction was heated at 90-95° C. for 24 hours until the reaction was complete. The reaction was cooled to room temperature, and the catalyst was filtered off. The filtrate was added with a 50 mL aqueous solution of 9 g of sodium hydroxide. The water was removed by distillation under reduced pressure. After evaporation to near dryness, 100 mL of acetone was added, stirred, and cooled to 0-10° C. The solid precipitated, filtered, and dried at 55° C. to obtain 48 g of a complex of S-3-hydroxybutyric acid and sodium S-3-hydroxybutyrate.

[0117] Characterization of the complex of the present invention

[0118] The composites prepared in Examples 1-15 were subjected to X-ray powder diffraction (XRPD), elemental analysis, Raman spectroscopy (Raman), infrared spectroscopy (IR), TGA, DSC, DVS and other tests.

[0119] Example 16. X-ray powder diffraction

[0120] X-ray powder diffraction patterns were obtained using a SmartLab 3KW X-ray powder diffractometer under the following conditions: diffraction line: Cu_K-beta (40 kV, 40 mA), scan rate: 20.00 deg / min, scan range: 3° to 60°. The XRPD pattern of the complex obtained in Example 1 is shown in Figure 1A, and the XRPD data obtained in Example 1 are shown in Table 1A. The XRPD results of the complexes prepared in Examples 2-6 were essentially consistent with those in Example 1.

[0121] Table 1A

[0122] The XRPD pattern of the complex obtained in Example 7 is shown in FIG1B , and the XRPD data obtained in Example 7 are shown in Table 1B . The XRPD results of the complexes prepared in Examples 8-9 were substantially consistent with those in Example 7.

[0123] Table 1B

[0124] The XRPD pattern of the complex obtained in Example 10 is shown in FIG1C , and the XRPD data obtained in Example 10 are shown in Table 1C . The XRPD results of the complexes prepared in Examples 11-15 were substantially consistent with those in Example 10.

[0125] Table 1C

[0126] Example 17. Infrared spectroscopy

[0127] The composite of Example 1 was analyzed by infrared spectroscopy using a Shimadzu Fourier transform attenuated total reflection infrared spectrometer. FIG2 is an infrared spectrum (IR) diagram of the composite of Example 1. As can be seen from FIG2 , the composite has a peak at 1715 cm -1 、1452cm -1 、1414cm -1 、1368cm -1 、1306cm -1 、1217cm -1 、1148cm -1 、1094cm -1 、1057cm -1 , 980cm -1 、853cm -1 , 710cm -1 、573cm -1 、467cm -1The IR results of the composites prepared in Examples 2-15 are basically consistent with those in Example 1.

[0128] Example 18. Sodium content and BHB content determination

[0129] The sodium content of the complex prepared in Example 1 was measured using ICP-MS according to the second method of GB 5009.268-2016 and the third method of GB 5009.91-2017. The 3-hydroxybutyric acid content of the complex was also determined using HPLC. The test results were consistent with the structure of the complex. The sodium and 3-hydroxybutyric acid content of the complexes prepared in Examples 2-15 were consistent with those in Example 1.

[0130] Example 19. NMR ( 1 H / 13 C) Determination

[0131] The complex of Example 1 was recorded in an AVIII-HD-400 spectrometer. 1 H NMR and 13 C NMR spectrum: 1 H NMR (400MHz, DMSO-d6) δ7.61 (s, 1H), 3.92 (h, J = 6.2Hz, 1H), 2.17 (d, J = 6.5Hz, 2H), 1.04 (d, J = 6.3Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 176.43, 64.21, 45.62, 23.64. The complex prepared in Example 2-15 has a C NMR of 101 MHz, DMSO-d6, δ 176.43, 64.21, 45.62, 23.64. 1 H / 13 C) The results are basically consistent with those in Example 1.

[0132] Example 20. Elemental Analysis

[0133] Elemental analysis of the complex of Example 10 showed: C 41.7%, H 6.5%. The elemental analysis results of other examples were also consistent with those of Example 10, and the results were consistent with the structure of the 3-hydroxybutyric acid·sodium 3-hydroxybutyrate complex.

[0134] Example 21. Raman spectroscopy

[0135] The characteristic Raman spectrum of the composite can be obtained by Raman spectroscopy analysis. FIG3A is the Raman spectrum of the composite of Example 1. The composite of Example 1 has a Raman spectrum at 2966.80 cm -1 、2929.23cm -1 、2912.39cm -1 、2872.19cm -1 、2668.47cm -1、1619.34cm -1 、1445.99cm -1 、1347.96cm -1 、1213.01cm -1 、1050.15cm -1 、962.24cm -1 、918.94cm -1 、845.50cm -1 、65.80cm -1 There is a characteristic absorption peak at ±2cm -1 The error tolerance is 0.001, and the Raman spectra of the composites prepared in Examples 2-6 are basically consistent with those in Example 1. FIG3B is the Raman spectrum of the composite of Example 7. The composite of Example 7 has a Raman spectrum at 435.61 cm -1 、860.27cm -1 、929.06cm -1 、972.40cm -1 、1058.42cm -1 、1086.36cm -1 、1224.66cm -1 、1360.71cm -1 、1408.20cm -1 、1453.85cm -1 、1629.35cm -1 、2885.95cm -1 、2910.89cm -1 、2942.27cm -1 、2980.01cm -1 There are characteristic absorption peaks at ±2cm -1 The error tolerance is , and the Raman spectra of the composites prepared in Examples 8-9 are basically consistent with those in Example 7. FIG3C is the Raman spectrum of the composite of Example 10. The composite of Example 10 has a Raman spectrum at 472.68 cm - 1 、858.58cm -1 、912.63cm -1 、929.06cm -1 、972.40cm -1 、1060.07cm -1 、1089.64cm - 1 、1151.72cm -1 、1223.05cm -1 、1359.12cm -1 、1456.99cm -1、1629.35cm -1 、2882.01cm -1 、2925.81cm -1 、2939.66cm -1 、2978.71cm -1 There are characteristic absorption peaks at ±2cm -1 The Raman spectra of the composites prepared in Examples 11-15 were basically consistent with those in Example 10.

[0136] Example 22. Thermogravimetric analysis (TGA)

[0137] Figure 4A is a TGA chart of the composite of Example 1. The composite exhibited a weight loss of 46.23% when heated from 25°C to 260°C and a weight loss of 11.09% when heated from 260°C to 300°C, corresponding to endothermic peaks at 225.6°C and 276.9°C, respectively. The TGA results of the composites prepared in Examples 2-6 were substantially consistent with those of Example 1. Figure 4B is a TGA chart of the composite of Example 7. The composite exhibited a weight loss of 2.02% when heated from 23.9°C to 50.0°C. The TGA results of the composites prepared in Examples 8-9 were substantially consistent with those of Example 7. Figure 4C is a TGA chart of the composite of Example 10. The composite exhibited a weight loss of 0.19% when heated from 23.8°C to 90.0°C. The TGA results of the composites prepared in Examples 11-15 were substantially consistent with those of Example 10.

[0138] Example 23. Differential Scanning Calorimetry (DSC)

[0139] Figure 5A is a DSC spectrum of the complex of Example 1, which includes an endothermic peak at 120.01°C ± 3°C. The DSC spectrum results of the complexes prepared in Examples 2-6 are basically consistent with those in Example 1. Figure 5B is a DSC spectrum of the complex of Example 7, which includes an endothermic peak at 117.20°C ± 3°C. The DSC spectrum results of the complexes prepared in Examples 8-9 are basically consistent with those in Example 7. Figure 5C is a DSC spectrum of the complex of Example 10, which includes an endothermic peak at 120.23°C ± 3°C. The DSC spectrum results of the complexes prepared in Examples 11-15 are basically consistent with those in Example 10.

[0140] Determination of properties of the complex of the present invention

[0141] Example 24. Determination of moisture content of the composite of the present invention

[0142] R-3-hydroxybutyric acid, sodium R-3-hydroxybutyrate, a mixture of R-3-hydroxybutyric acid and sodium R-3-hydroxybutyrate, and the R-3-hydroxybutyric acid / sodium R-3-hydroxybutyrate complexes of Examples 1-6 were tested for moisture content at different times using a KF moisture meter under certain sample placement conditions. The experimental results are shown in Table 2A.

[0143] Table 2A

[0144] 3-hydroxybutyric acid, sodium 3-hydroxybutyrate, a mixture of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate, and the 3-hydroxybutyric acid / sodium 3-hydroxybutyrate complexes of Examples 7-9 were tested for moisture content at different times using a KF moisture meter under certain sample placement conditions. The experimental results are shown in Table 2B.

[0145] Table 2B

[0146] S-3-hydroxybutyric acid, sodium S-3-hydroxybutyrate, a mixture of S-3-hydroxybutyric acid and sodium S-3-hydroxybutyrate, and the S-3-hydroxybutyric acid / sodium S-3-hydroxybutyrate complexes of Examples 10-12 were tested for moisture content at different times using a KF moisture meter under certain sample placement conditions. The experimental results are shown in Table 2C.

[0147] Table 2C

[0148] The above results show that the moisture content of the R-3-hydroxybutyric acid·Sodium R-3-hydroxybutyrate complex is significantly lower than that of R-3-hydroxybutyric acid, sodium R-3-hydroxybutyrate, and a mixture of R-3-hydroxybutyric acid and sodium R-3-hydroxybutyrate; the moisture content of the 3-hydroxybutyric acid·Sodium 3-hydroxybutyrate complex is significantly lower than that of 3-hydroxybutyric acid, sodium 3-hydroxybutyrate, and a mixture of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate; the moisture content of the S-3-hydroxybutyric acid·Sodium S-3-hydroxybutyrate complex is significantly lower than that of S-3-hydroxybutyric acid, sodium S-3-hydroxybutyrate, S-3-hydroxybutyric acid and a mixture of sodium S-3-hydroxybutyrate, which can increase the application scenarios of the complex products. Since R-3-hydroxybutyric acid, 3-hydroxybutyric acid, and S-3-hydroxybutyric acid solids have strong hygroscopicity and are easily deliquescent, they cannot be well applied in the field of solid preparations, which greatly limits their application in the fields of solid nutritional products and dietary supplements. However, the R-3-hydroxybutyric acid·R-3-hydroxybutyrate sodium complex of the present invention has significantly better water absorption performance than R-3-hydroxybutyric acid, sodium R-3-hydroxybutyric acid, and a mixture of R-3-hydroxybutyric acid and sodium R-3-hydroxybutyric acid. The 3-hydroxybutyric acid·3-hydroxybutyrate sodium complex has significantly better water absorption performance than 3-hydroxybutyric acid, sodium 3-hydroxybutyric acid, and a mixture of 3-hydroxybutyric acid and sodium 3-hydroxybutyric acid. The S-3-hydroxybutyric acid·S-3-hydroxybutyrate sodium complex has significantly better water absorption performance than S-3-hydroxybutyric acid, sodium S-3-hydroxybutyric acid, S-3-hydroxybutyric acid, and a mixture of sodium S-3-hydroxybutyric acid. In addition, simple mixtures of acids and sodium salts are prone to uneven mixing. Therefore, the complex has a wider range of applications and is particularly suitable for the preparation and application of solid preparations.

[0149] Example 25. Stability of the complex of the present invention

[0150] The stability of R-3-hydroxybutyric acid, sodium R-3-hydroxybutyrate, a mixture of R-3-hydroxybutyric acid and sodium R-3-hydroxybutyrate, and the R-3-hydroxybutyric acid·sodium R-3-hydroxybutyrate complex of Examples 1-6 were measured at temperatures of 60°C, 70°C, and 80°C. The experimental results are shown in Table 3A.

[0151] Table 3A

[0152] The stability of 3-hydroxybutyric acid, sodium 3-hydroxybutyrate, a mixture of 3-hydroxybutyric acid and sodium 3-hydroxybutyrate, and the 3-hydroxybutyric acid·sodium 3-hydroxybutyrate complex of Examples 7-9 at temperatures of 60°C, 70°C, and 80°C was tested. The experimental results are shown in Table 3B.

[0153] Table 3B

[0154] The stability of S-3-hydroxybutyric acid, sodium S-3-hydroxybutyrate, a mixture of S-3-hydroxybutyric acid and sodium S-3-hydroxybutyrate, and the S-3-hydroxybutyric acid·sodium S-3-hydroxybutyrate complex of Examples 10-12 was measured at temperatures of 60°C, 70°C, and 80°C. The experimental results are shown in Table 3C.

[0155] Table 3C

[0156] The above results show that the stability of the R-3-hydroxybutyric acid·R-3-hydroxybutyrate sodium complex is very high, significantly better than R-3-hydroxybutyric acid and the mixture of R-3-hydroxybutyric acid and R-3-hydroxybutyric acid sodium; the stability of the 3-hydroxybutyric acid·3-hydroxybutyrate sodium complex is very high, significantly better than 3-hydroxybutyric acid and the mixture of 3-hydroxybutyric acid and 3-hydroxybutyric acid sodium; the stability of the S-3-hydroxybutyric acid·S-3-hydroxybutyric acid sodium complex is very high, significantly better than S-3-hydroxybutyric acid and the mixture of S-3-hydroxybutyric acid and S-3-hydroxybutyric acid sodium.

[0157] This invention addresses the issues of BHB acid's strong acidity, intestinal side effects, high hygroscopicity, and poor stability, while also addressing the electrolyte imbalance caused by the high salt load of BHB salt. The complex exhibits a superior overall effect compared to either the acid or salt alone, or simply physically mixed components, and possesses suitable hygroscopicity and stability, making it particularly suitable for the preparation of solid dosage forms. Furthermore, at appropriate dosages, the complex exhibits a ketogenic effect comparable to that of BHB acid and BHB salt, and at moderate doses, exhibits a ketogenic effect superior to that of BHB salt. Furthermore, the complex produced by this invention exhibits high purity, uniform particle size distribution, good fluidity, low agglomeration, and good bioavailability. Furthermore, the preparation process is controllable, cost-effective, and environmentally friendly.

[0158] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any person skilled in the art may make various changes, modifications, substitutions and variations to these embodiments without departing from the principles and purpose of the present invention. The scope of the present invention is defined by the claims and their equivalents.

Claims

1. A composite, characterized in that The complex includes 3-hydroxybutyric acid and sodium 3-hydroxybutyrate.

2. The composite according to claim 1, characterized in that The anions in the structure of the complex include 3-hydroxybutyrate anions, and the cations include sodium ions and hydrogen ions.

3. The composite according to claim 1 or 2, characterized in that The ratio of 3-hydroxybutyric acid to sodium 3-hydroxybutyrate is 1:10 to 10:

1.

4. The composite according to any one of claims 1 to 3, characterized in that The complex contains not less than 50% of the R configuration and not more than 50% of the S configuration; or more than 50% of the S configuration and less than 50% of the R configuration.

5. The composite according to any one of claims 1 to 4, characterized in that The complex is 3-hydroxybutyric acid and sodium 3-hydroxybutyrate.

6. The composite according to any one of claims 1 to 5, characterized in that The complex has the following structure:

7. The composite according to any one of claims 1 to 6, characterized in that The complex is R-3-hydroxybutyric acid·R-3-hydroxybutyrate sodium and / or S-3-hydroxybutyric acid·S-3-hydroxybutyrate sodium.

8. The composite according to any one of claims 1 to 6, characterized in that The complex contains not less than 50% of R-3-hydroxybutyric acid·R-3-hydroxybutyrate sodium and not more than 50% of S-3-hydroxybutyric acid·S-3-hydroxybutyrate sodium; or more than 50% of S-3-hydroxybutyric acid·S-3-hydroxybutyrate sodium and less than 50% of R-3-hydroxybutyric acid·R-3-hydroxybutyrate sodium.

9. The composite according to claim 7 or 8, characterized in that The complex has the following structure: and / or 10. The composite according to any one of claims 1 to 9, characterized in that The complex is in crystalline form.

11. The composite according to any one of claims 1 to 10, characterized in that The X-ray powder diffraction pattern of the composite includes peaks at diffraction angles (2θ) of 9.8°±0.2°, 10.8°±0.2°, 18.9±0.2°, and 31.1°±0.2°.

12. The composite according to claim 11, characterized in that The X-ray powder diffraction pattern of the composite further includes one or more peaks located at diffraction angles (2θ) of 13.4°±0.2°, 21.6°±0.2°, and 32.7°±0.2°.

13. The composite according to claim 11 or 12, characterized in that The X-ray powder diffraction pattern of the composite further includes one or more peaks located at diffraction angles (2θ) of 15.1°±0.2°, 23.0°±0.2°, and 31.9°±0.2°.

14. The composite according to any one of claims 1 to 10, characterized in that The X-ray powder diffraction pattern of the composite is shown in FIG1A , FIG1B or FIG1C .

15. The composite according to any one of claims 1 to 10, characterized in that The infrared spectrum of the composite has the following absorption bands, expressed as the reciprocal of the wavelength (cm -1 )(±2cm -1 ): 1715, 1452, 1414, 1368, 1306, 1217, 1148, 1094, 1057, 980, 853, 710, 573, 467.

16. The composite according to any one of claims 1 to 10, characterized in that The X-ray powder diffraction pattern of the composite includes peaks at diffraction angles (2θ) of 6.9°±0.2°, 10.7°±0.2°, 18.1°±0.2°, 22.3°±0.2°, 23.0±0.2°, 26.8°±0.2°, and 31.2°±0.2°.

17. The composite according to claim 16, characterized in that The X-ray powder diffraction pattern of the composite further includes one or more peaks located at diffraction angles (2θ) of 17.2°±0.2°, 21.6°±0.2°, and 25.8°±0.2°.

18. The composite according to any one of claims 1 to 10, characterized in that The X-ray powder diffraction pattern of the composite includes peaks at diffraction angles (2θ) of 7.7°±0.2°, 10.7°±0.2°, 13.2°±0.2°, 18.7±0.2°, 21.4°±0.2°, 31.4°±0.2°, and 32.6°±0.2°.

19. The composite according to claim 18, characterized in that The X-ray powder diffraction pattern of the composite further includes one or more peaks located at diffraction angles (2θ) of 15.0°±0.2°, 23.9°±0.2°, and 34.3°±0.2°.

20. The composite according to any one of claims 1 to 19, characterized in that The complex is prepared as a food, a beverage, a supplement or a pharmaceutical preparation.

21. A 3-hydroxybutyric acid and sodium 3-hydroxybutyrate complex, characterized in that: The complex is obtained by the following method: (1) obtaining substance A by one of the following methods: mixing 3-hydroxybutyric acid and sodium 3-hydroxybutyrate; or adding 3-hydroxybutyric acid to an aqueous solution of an alkaline sodium compound, stirring and removing water, and evaporating to near dryness; or allowing an alkyl 3-hydroxybutyrate to react with water by heating in the presence of a catalyst, cooling and filtering, adding an aqueous solution of an alkaline sodium compound to the filtrate, removing water by distillation under reduced pressure, and evaporating to near dryness; (2) adding one or more solvents selected from the group consisting of water, THF, DMF, DMSO, DMAC, alcohols, halogenated hydrocarbons, ketones, and esters to the substance A obtained in step (1), stirring and cooling to precipitate a solid; (3) filtering out the solid and drying it to obtain the composite.

22. The composite according to claim 21, characterized in that The complex is R-3-hydroxybutyric acid·R-3-hydroxybutyrate sodium and / or S-3-hydroxybutyric acid·S-3-hydroxybutyrate sodium.

23. The composite according to claim 21 or 22, characterized in that The complex is in crystalline form.

24. A method for preparing the composite according to any one of claims 1 to 10, characterized in that: The method comprises the following steps: (1) obtaining substance A by one of the following methods: mixing 3-hydroxybutyric acid and sodium 3-hydroxybutyrate; or adding 3-hydroxybutyric acid to an aqueous solution of an alkaline sodium compound, stirring and removing water, and evaporating to near dryness; or allowing an alkyl 3-hydroxybutyrate to react with water by heating in the presence of a catalyst, cooling and filtering, adding an aqueous solution of an alkaline sodium compound to the filtrate, removing water by distillation under reduced pressure, and evaporating to near dryness; (2) adding one or more solvents selected from the group consisting of water, THF, DMF, DMSO, DMAC, alcohols, halogenated hydrocarbons, ketones, and esters to the substance A obtained in step (1), stirring and cooling to precipitate a solid; (3) filtering out the solid and drying it to obtain the composite.

25. The method according to claim 24, characterized in that In step (2), the alcohols are methanol, ethanol, isopropanol, and n-butanol; the halogenated hydrocarbons are chlorobenzene, dichlorobenzene, and dichloromethane; the ketones are acetone, methyl butyl ketone, and methyl isobutyl ketone; and the esters are ethyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate.

26. The method according to claim 24 or 25, characterized in that The alkaline Na compound in step (1) is NaOH, Na2CO3, NaHCO3, NaOMe, NaOAc or NaOCHO; the alkyl 3-hydroxybutyrate is methyl 3-hydroxybutyrate, ethyl 3-hydroxybutyrate, propyl 3-hydroxybutyrate or butyl 3-hydroxybutyrate.

27. A composition, characterized in that The composition comprises an effective amount of the complex according to any one of claims 1 to 23, and a pharmaceutically acceptable carrier.

28. The composition according to claim 27, characterized in that The composition is used as a ketogenic substance.

29. The composition according to claim 27 or 28, characterized in that The composition is prepared as food, beverage, supplement or pharmaceutical preparation.

30. Use of the complex according to any one of claims 1 to 23, characterized in that Use of the complex in preparing a ketogenic substance for increasing or maintaining the blood ketone level of a subject.

31. The use according to claim 30, characterized in that The ketogenic substance is a nutritional supplement, an energy treatment, a medical treatment, or a strength and / or endurance sports supplement.

32. Use of a composition in preparing a ketogenic substance for increasing or maintaining blood ketone levels in a subject, characterized in that: The composition comprises the complex according to any one of claims 1 to 23, and a pharmaceutically acceptable carrier.

33. The use according to claim 32, characterized in that The ketogenic substance is a nutritional supplement, an energy treatment, a medical treatment, or a strength and / or endurance sports supplement.

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