CN120698868A - D-3-hydroxybutyric acid preparation method and ketogenic effervescent tablet - Google Patents

D-3-hydroxybutyric acid preparation method and ketogenic effervescent tablet

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Publication number
CN120698868A
CN120698868A CN202510837380.2A CN202510837380A CN120698868A CN 120698868 A CN120698868 A CN 120698868A CN 202510837380 A CN202510837380 A CN 202510837380A CN 120698868 A CN120698868 A CN 120698868A
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CN
China
Prior art keywords
acid
hydroxybutyric acid
anhydrous ethanol
particles
ketogenic
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Pending
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CN202510837380.2A
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Chinese (zh)
Inventor
陈舒明
刘剑宏
陈筱骏
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Shanghai Kangxin Chemical Co ltd
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Shanghai Kangxin Chemical Co ltd
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Priority to CN202510837380.2A priority Critical patent/CN120698868A/en
Publication of CN120698868A publication Critical patent/CN120698868A/en
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/40—Effervescence-generating compositions
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/52—Adding ingredients
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Mycology (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses a method for preparing D-3-hydroxybutyric acid, which comprises the steps of adding D-3-hydroxybutyric acid ester into food-grade sodium hydroxide aqueous solution with concentration not higher than 1.2M, stirring at the temperature not higher than 45 ℃ for hydrolysis reaction until the hydrolysis is completed to obtain D-3-hydroxybutyric acid sodium aqueous solution, controlling the temperature not higher than 45 ℃ in the D-3-hydroxybutyric acid sodium aqueous solution, adding food-grade hydrochloric acid equivalent to sodium hydroxide for neutralization reaction to obtain D-3-hydroxybutyric acid aqueous solution, carrying out reduced pressure distillation on the reaction solution until crystallization is carried out, cooling to 5 ℃, growing crystals, separating and drying to obtain D-3-hydroxybutyric acid crystals. The invention also discloses a ketogenic effervescent tablet containing D-3-hydroxybutyric acid as an active ingredient and a preparation method thereof.

Description

Preparation method of D-3-hydroxybutyric acid and ketogenic effervescent tablet
Technical Field
The invention belongs to the technical field of fine chemical engineering, and particularly relates to a method for preparing D-3-hydroxybutyric acid and a ketogenic effervescent tablet.
Background
Beta-hydroxybutyric acid (beta-Hydroxybutyrate) is called BHB for short, which is classified into D-3-hydroxybutyric acid, L-3-hydroxybutyric acid and their racemates DL-3-hydroxybutyric acid according to the configuration, and BHB is a ketone substance which is produced in liver mainly through fatty acid oxidation and is metabolized by extrahepatic tissues. The ketone body comprises three components of acetoacetic acid, beta-hydroxybutyric acid and acetone, wherein the beta-hydroxybutyric acid accounts for the highest total amount of the ketone body and is commonly called ketogenesis. Wherein D-3-hydroxybutyric acid is a compound produced in mammals by long chain fatty acid metabolism in the liver, exists as a main ketone body in plasma and peripheral tissues, and can be used as an energy source in most tissues of the body.
BHB plays an important role in human body, can provide energy for brain development and body growth as an energy metabolite, and can activate G protein coupled receptors, posttranslational modification proteins or inhibit nuclear histone deacetylase as a signal molecule, regulate cell functions, nerve functions and the like. BHB levels may rise in cases of hunger, intermittent fasting, ketogenic diet, and diabetic ketoacidosis. Clinically, BHB detection can be used for diagnosis and disease assessment of gestational diabetes and Diabetic Ketoacidosis (DKA), monitoring of insulin treatment, prognosis assessment of arrhythmia cardiomyopathy and the like, and BHB can also be used as a therapeutic agent for diseases such as brain trauma, metabolic syndrome, muscle dysfunction, inflammation and the like. Meanwhile, the BHB is used as a dietary supplement component, can supplement the BHB of a human body, replace part of BHB generated by glucose metabolism, reduce the intake of carbon water, reduce and reduce the accumulation of fat in viscera, supplement energy and strengthen physique. A large number of researches show that BHB has the functions of providing energy, promoting cell division, preventing cell aging, protecting cerebral neurons, improving neurodegenerative diseases and the like as an energy metabolite and a signal molecule, and plays an important role in preventing and treating various diseases.
There are many reports on the production of BHB, and the patent document with publication number of CN02100014.X discloses a method for producing D- (-) -3-hydroxybutyric acid, which is obtained by fermenting a microorganism and obtaining a solution of D-BHB acid after a series of treatments. Patent document CN114349625A discloses a method for preparing 3-hydroxybutyric acid, which comprises acidic hydrolysis of esters such as methyl BHB, and then concentrating under reduced pressure to prepare BHB acid solution. The patent document with publication number CN110862316A discloses a crystal form of (R) -3-hydroxybutyric acid and application thereof, and D-BHB-Na is converted into D-BHB acid crystal. Patent document CN116940352a discloses a composition and method of beta-hydroxybutyric acid for oral delivery of ketone bodies, referring to the usual dosage forms of beta-hydroxybutyric acid compositions, which are then used to formulate beverages of different flavors as ketogenic compositions. The patent document with publication number CN119019245A discloses a method for preparing medical grade 3-hydroxy sodium butyrate, which takes 3-hydroxy methyl butyrate or ethyl butyrate as a raw material, firstly uses sodium hydroxide to catalyze hydrolysis reaction in 95% alcohol solution to generate a crude product of 3-hydroxy sodium butyrate, then uses methanol and water to dissolve, then adds an addition product to carry out addition reaction, and then uses acetone to carry out crystallization to refine to obtain a finished product. However, none of the presently disclosed references to dietary supplements containing ketogenic (BHB) are directed to a process for producing solid crystals of BHB from BHB esters, nor to solid dosage formulations for use with BHB crystals.
Disclosure of Invention
Currently, the 3-hydroxybutyric acid product sold on the market is DL-configuration racemate, and the racemic 3-hydroxybutyric acid and its salt without optical activity, especially sodium salt, are accepted by consumers. In view of the fact that D-3-hydroxybutyric acid is a currently accepted ketogenic active ingredient, with the development of single chiral trend of pharmaceutical active ingredient (API), market research has shown that D-3-hydroxybutyric acid and salts thereof may gradually become the mainstream of BHB consumer market. We have attempted to prepare from commercially available chiral compounds D-3-hydroxybutyrate such as methyl or ethyl ester as disclosed in CN119019245A, but found that the optical purity of the resulting product was far less than expected and that the intermediate was racemized during the reaction.
Thus, the reaction process is changed, and a novel method for preparing the D-3-hydroxybutyric acid crystal with high optical purity and the sodium salt crystal thereof by chemical reaction is explored. Furthermore, we also develop a new solid beverage type effervescent tablet containing BHB crystal, namely ketogenic effervescent tablet or BHB effervescent tablet. Specifically, the invention comprises the following technical scheme.
In a first aspect, the present invention provides a process for preparing D-3-hydroxybutyric acid, comprising the steps of:
A. Hydrolysis by adding methyl or ethyl D-3-hydroxybutyrate to an aqueous solution of food-grade sodium hydroxide or potassium hydroxide at a concentration of not higher than 1.2M, preferably not higher than 1.0M, for example not higher than 0.9M or 0.8M, and stirring at a temperature of not higher than 45 ℃, preferably not higher than 40 ℃, more preferably not higher than 35 ℃, for example not higher than 30 ℃ until hydrolysis is completed to obtain an aqueous solution of sodium D-3-hydroxybutyrate;
B. a neutralization reaction, namely adding food-grade hydrochloric acid equivalent to sodium hydroxide or potassium hydroxide into the aqueous solution of the D-3-hydroxybutyric acid obtained in the step A, wherein the temperature is controlled to be not higher than 45 ℃, preferably not higher than 40 ℃, more preferably not higher than 35 ℃, for example not higher than 30 ℃, and carrying out the neutralization reaction to obtain an aqueous solution of the D-3-hydroxybutyric acid;
C. and B, crystallizing, namely performing reduced pressure distillation on the reaction solution in the step B until crystallization. Cooling to below 10deg.C, such as about 5deg.C, standing for crystallizing, centrifuging or filtering, and drying to obtain D-3-hydroxybutyric acid crystal.
In one embodiment, the molar ratio of sodium hydroxide or potassium hydroxide to methyl/ethyl D-3-hydroxybutyrate in step A is 0.5 to 1.0:1.0, preferably substantially equivalent.
Preferably, the hydrolysis reaction temperature in step a is controlled between 10-35 ℃, preferably between 15-30 ℃, in order to avoid racemisation of the chiral compound.
Optionally, ethanol may be added in step a at a final concentration of not higher than 20%, preferably not higher than 15%, for example not higher than 12% or 10%, in order to facilitate impurity separation, facilitating separation of the by-product crotonic acid.
Preferably, the HPLC purity of crotonic acid in the product D-3-hydroxybutyric acid in step C is 0.30% or less, and the content is 0.015% or less as measured by an external standard method, and more preferably, crotonic acid is not detected.
In a second aspect the present invention provides the use of a D-3-hydroxybutyric acid crystal as described above in the manufacture of a solid dietary supplement, wherein said solid dietary supplement is a solid formulation selected from effervescent tablets, granules, capsules, granules, powders/powders, tablets, pills, etc.
In a third aspect, the present invention provides a ketogenic effervescent tablet, i.e. a BHB effervescent tablet, comprising as an active ingredient the D-3-hydroxybutyric acid crystals, or racemic DL-3-hydroxybutyric acid or L-3-hydroxybutyric acid as described above.
In one embodiment, the formulation of the ketogenic effervescent tablet comprises the following components:
An acid source comprising BHB, i.e., D-3-hydroxybutyric acid, DL-3-hydroxybutyric acid or L-3-hydroxybutyric acid;
an acid (source) particulate binder comprising maltodextrin;
The carbon dioxide source is selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, magnesium carbonate, and calcium carbonate, and their mixture;
Alkali (source) particle fillers including lactose;
a lubricant selected from the group consisting of polyethylene glycols such as polyethylene glycol 6000, sorbitol, and mixtures thereof;
A humectant comprising ethanol;
flavoring agent: is selected from the group consisting of stevioside, psicose, sucralose, mogrosides, and mixtures of two or more thereof;
the fruit flavoring agent is selected from fruit powder, fruit flavoring essence such as strawberry essence, lemon essence or sweet orange essence, etc.
Optionally, the formulation of the ketogenic effervescent tablet is selected from one of the following groups:
The materials of the formula I comprise acid particles containing D-3-hydroxybutyric acid, maltodextrin, sorbitol and absolute ethyl alcohol, alkali particles containing sodium bicarbonate, lactose, mannose, stevioside and absolute ethyl alcohol, lubricant polyethylene glycol 6000, essence such as strawberry essence;
the materials of the formula II comprise acid particles containing D-3-hydroxybutyric acid, maltodextrin, sorbitol and absolute ethyl alcohol, alkali particles containing sodium bicarbonate, magnesium carbonate, lactose, mannose, psicose and absolute ethyl alcohol, lubricant polyethylene glycol 6000, essence such as mango essence;
the materials of the formula III comprise acid particles containing D-3-hydroxybutyric acid, maltodextrin, sorbitol and absolute ethyl alcohol, alkali particles containing sodium bicarbonate, calcium carbonate, lactose, mannose, sucralose and absolute ethyl alcohol, lubricant polyethylene glycol 6000, essence such as lemon essence;
The fourth material of the formula comprises acid particles containing D-3-hydroxybutyric acid, maltodextrin, sorbitol and absolute ethyl alcohol, alkali particles containing sodium bicarbonate, potassium carbonate, lactose, mannose, mogroside and absolute ethyl alcohol, lubricant polyethylene glycol 6000, essence such as pineapple essence;
the materials of the formula five comprise acid particles containing D-3-hydroxybutyric acid, maltodextrin, sorbitol and absolute ethyl alcohol, alkali particles containing sodium bicarbonate, magnesium carbonate, calcium carbonate, lactose, mannose, mogroside, stevioside and absolute ethyl alcohol, lubricant polyethylene glycol 6000, essence such as peppermint essence;
The materials of the formula six comprise acid particles containing DL-3-hydroxybutyric acid, maltodextrin, sorbitol and absolute ethyl alcohol, alkali particles containing sodium bicarbonate, lactose, mannose, stevioside and absolute ethyl alcohol, lubricant polyethylene glycol 6000, essence such as strawberry essence;
The seventh material comprises acid particles containing L-3-hydroxybutyric acid, maltodextrin, sorbitol and absolute ethanol, alkali particles containing sodium bicarbonate, lactose, mannose, stevioside and absolute ethanol, lubricant polyethylene glycol 6000, and essence such as strawberry essence.
In a fourth aspect, the present invention provides a method for preparing a ketogenic effervescent tablet as described above, comprising the steps of:
1) Acid particle preparation:
Placing the solid raw materials of acid particles into a wet granulator, stirring, uniformly mixing, spraying absolute ethyl alcohol, stirring to form uniform particles passing through 10 meshes, starting a boiling dryer, setting the temperature to be not higher than 35 ℃, setting the vacuum degree to be not lower than-0.08 MPa, drying until the drying weight loss is not higher than 0.5%, starting the granulator, and passing through a 10-mesh sieve to obtain acid particles A;
2) Alkali particle preparation:
Placing solid materials of alkali particles in a wet granulator, stirring, uniformly mixing, spraying absolute ethyl alcohol, stirring to form uniform particles, starting a boiling dryer, setting the temperature to be not higher than 65 ℃, setting the vacuum degree to be not lower than-0.08 MPa, drying until the weight loss on drying is not higher than 0.5%, starting the granulator, and sieving through a 10-mesh sieve to obtain alkali particles B;
3) Total mixing:
placing acid particles A, alkali particles B, polyethylene glycol, fruit powder or essence into a mixer, and uniformly mixing until the weight loss on drying is not higher than 0.5% and the water content is not higher than 0.25% to obtain a mixture C;
4) Tabletting:
Adding the mixture C into a tablet press, and regulating the tablet press according to the standard of 4.5g of tablet weight to obtain the ketogenic effervescent tablet with tablet weight, hardness and appearance finish meeting the preset requirements.
Preferably, the temperature of the boiling dryer in the step 1) is set to about 30 ℃, the vacuum degree is not lower than-0.085 MPa, and the temperature of the boiling dryer in the step 2) is set to about 50 ℃, the vacuum degree is not lower than-0.085 MPa.
It is to be understood that the term "about" or "about" when used herein in describing a numerical feature means that the number represented may have an error range or float range of + -10%, + -9%, + -8%, + -7%, + -6% or + -5%.
Further, the method also comprises the steps of sub-packaging tablets and the like.
The invention develops a method for preparing D-3-hydroxybutyric acid crystals, which takes chiral D-3-hydroxybutyric acid methyl (ethyl) ester as a raw material, uses dilute alkali to hydrolyze under the condition of temperature control, and obtains the D-3-hydroxybutyric acid crystals with optical activity after hydrochloric acid neutralization and acidification, wherein the chiral is maintained to be more than 95%, namely the reaction racemization rate is lower than 5%, and the method is suitable for industrial production. The D-3-hydroxybutyric acid crystal can be further used for preparing BHB effervescent tablets as a dietary supplement.
Drawings
FIG. 1 is a photograph of a crystal of D-3-hydroxybutyric acid produced according to the present invention.
Fig. 2 is a process flow diagram of the preparation of ketogenic effervescent tablets of the present invention.
Fig. 3 is a photograph of strawberry-flavored ketogenic effervescent tablets prepared in example 2.
Detailed Description
The aqueous solution of BHB is easy to absorb alkaline components in air to deteriorate, even if the aqueous solution is low in pH, the aqueous solution is poor in taste, difficult to sell and popularize and difficult to transport, after being prepared into crystals, the aqueous solution of BHB greatly improves the stability of BHB, is easy to store and transport, and is also easy to prepare solid preparations such as granules, medicinal granules, powder, tablets, effervescent agents and the like.
Since D-3-hydroxybutyric acid has a clear biological activity, we used commercially available D-3-hydroxybutyrate (optical purity ee value 92%) as a raw material, and tried to refer to the method in CN119019245A, which was prepared by a simple sodium hydroxide catalytic hydrolysis reaction and a subsequent hydrochloric acid neutralization reaction. The hydrolysis product D-3-hydroxybutyric acid was initially found to have very low, if not no, optical activity, indicating that severe racemization occurred during the reaction. Therefore, the reaction conditions are changed, the proposal of assisting dissolution of an alcohol solvent such as methanol, ethanol or isopropanol is basically abandoned, the process conditions such as reaction temperature and the like are strictly controlled, the optical purity of the D-3-hydroxybutyric acid crystal of the product is obviously improved, and the retention rate of the optical activity is more than 95 percent. The purity of the prepared D-3-hydroxybutyric acid crystal reaches 98.5%, and the water content is less than 5%.
As used herein, the terms "(increase in optical activity retention)," increase "or" increase "may mean an increase of at least 10% compared to a reference level (such as a prior art process product), for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to and including 100% compared to the reference level.
In addition, no crotonic acid or crotonate can be detected in the D-3-hydroxybutyric acid crystal, and the D-3-hydroxybutyric acid crystal can be completely used for preparing dietary supplements which are safe to eat.
After the D-3-hydroxybutyric acid crystals are prepared, based on the natural acidity, the effervescent agent which is not applicable to the D-3-hydroxybutyric acid sodium salt is preferentially selected when the dietary supplement solid dosage form is prepared. The effervescent tablet finished product can meet the requirements of easy disintegration, good taste and storage resistance by multiple adjustments in the design of the effervescent formulation and the test process.
Since 3-hydroxybutyric acid and sodium salt thereof without optical activity are accepted by consumers in marketing market, and no side effect is found in L-3-hydroxybutyric acid or salt thereof, the effervescent tablet can be prepared by adopting DL-configuration or L-configuration BHB. In particular, DL-3-hydroxybutyric acid, which is inactive, is more economical because it is relatively inexpensive.
In the test, it was found that BHB can be directly used as an acid source without adding other acid sources such as citric acid, malic acid and the like. When the BHB is used as an acid source independently, other edible acid sources (such as citric acid, malic acid and the like) are not added, so that the irritation of the other edible acid sources to oral mucosa and the inadaptation of taste are avoided, the formula materials are reduced, the production cost is reduced, and the effective concentration of the unit tablet is improved.
The single use of the ketogenic BHB as an acid source component can play the double roles of bioactivity and acidity, and the formula complexity and the production and processing cost of the ketogenic effervescent tablet are reduced.
The balanced electrolyte supports ketogenic applications and provides balanced sodium, potassium, calcium and magnesium after disintegration in water to support ketogenic applications and reduce electrolyte imbalance while improving BHB solubility. The reaction in water is as follows:
nBHB+Mn+(HCO3)n -→Mn+(BHB)n -+n CO2↑+nH2O
n is 1-2.
M n+ represents Na +、K+、Ca2+、Mg2+
In the formula of the ketogenic effervescent tablet, polyethylene glycol 6000 is preferably used as a lubricant, wherein the mass ratio of the polyethylene glycol 6000 in the formula is 0.5-2% of the total weight, and the preferred mass ratio is about 1.0%, and the following table is adopted.
Mass ratio Disintegration conditions Sticking and punching condition Appearance of
0.5 Good quality Slightly sticking and punching Slightly speckled
1.0 Good quality Non-sticking punch Smooth and glossy
1.5 Good quality Non-sticking punch Smooth and glossy
2.0 Poor quality Non-sticking punch Smooth and glossy
The preparation process of the ketogenic effervescent tablet can be seen in fig. 2, and generally comprises the following steps:
According to the proportion, the BHB, the acid granule adhesive and the sorbitol are uniformly mixed to obtain a mixture, the mixture is wetted by a wetting agent to prepare an acidic soft material, the acidic soft material is granulated to obtain acidic wet granules, and the acidic wet granules are dried and granulated to obtain acid granules A;
Uniformly mixing a carbon dioxide source, a flavoring agent and an alkali granule filler according to a proportion, wetting to prepare an alkali soft material, sequentially granulating the alkali soft material, and drying and granulating to obtain alkali granules B;
And uniformly mixing the acid particles A, the alkali particles B and the auxiliary materials according to the proportion, preparing a mixture C, and tabletting to obtain the BHB effervescent tablet.
In the step of preparing the acid particles A, the size of the acid wet particles is preferably 10 meshes, a high-efficiency wet granulation machine is adopted, the drying is finished by adopting a high-efficiency boiling dryer, the drying temperature is about 30 ℃, and the particles pass through a 10-mesh sieve by adopting a high-efficiency particle finishing machine.
In the step of preparing the alkali particles B, the size of the alkali wet particles is 10 meshes, a high-efficiency wet granulator is adopted, the drying is finished by adopting a high-efficiency boiling dryer, the drying temperature is about 60 ℃, and the granules are finished by adopting a high-efficiency granule finishing machine and pass through a 10-mesh sieve.
In the step of uniformly mixing and tabletting the acid particles A, the alkali particles B and the auxiliary materials to obtain the mixture C, the uniform mixing operation is finished by a two-dimensional motion mixer, and the tabletting operation is finished by a tablet press.
The invention is further illustrated by the following examples. It is to be understood that these examples are for illustrative purposes only and are not limiting of the invention. Various changes and modifications may be made by one skilled in the art in light of the teachings of this invention, and are intended to fall within the scope of this invention.
Examples
The amounts, amounts and concentrations of various substances are referred to herein, wherein the percentages refer to percentages by mass unless otherwise specified.
In the examples herein, if no specific description is made regarding the operating temperature, this temperature is generally referred to as room temperature (15-35 ℃).
Methyl D-3-hydroxybutyrate and ethyl D-3-hydroxybutyrate were obtained from Ningbo enzyme Sai Biotechnology Co., ltd. The ee values of methyl D-3-hydroxybutyrate and ethyl D-3-hydroxybutyrate were 92%.
HPLC detection method of 3-hydroxybutyric acid in examples:
instrument liquid chromatograph Agilent1260
Agilent ZORBAX SB-Aq 4.6 mm. Times.250 mm. Times.5 μm.
Mobile phase: 0.1% aqueous perchloric acid solution: acetonitrile=95:5 (v/v);
Flow rate 1.0ml/min
Column temperature of 30 DEG C
Detector differential refraction detector
Detection wavelength of 214nm
Sample volume 10. Mu.l
And calculating the component content by an external standard method.
And the model number of the polarimeter is Rudolph Autopol V.
High-efficiency wet granulator, HLSG-100 of Jituo mechanical Co., suzhou, city.
An efficient boiling dryer, namely GFG-120, which is manufactured by Haomai drying engineering Co., ltd.
High-efficiency granulator, jiangsu Pengduo mechanical science and technology Co., ltd., KZL-100.
Two-dimensional motion mixer, jie Crypton drying equipment Co., ltd., EYH-150.
Tablet press, ZP19, shanghai Tianhe pharmaceutical machinery Co., ltd.
EXAMPLE 1 preparation of D-3-hydroxybutyric acid crystals
250Kg of methyl D-3-hydroxybutyrate and 800kg of water were added to a 3000L reactor and stirred. Slowly dripping 16.90 kg of 5% sodium hydroxide solution at 15-20 ℃, controlling the pH of the system to 10, hydrolyzing, and tracking the high-efficiency liquid phase. After completion of the reaction, about 258kg of 30% concentrated hydrochloric acid was slowly added dropwise to pH3. Concentrating under reduced pressure until crystallization. 28kg of absolute ethyl alcohol is added, cooled to 5 ℃, and the mixture is left to stand for crystal growth. Centrifuging and spin-drying to obtain 198kg. The weight yield is 90%, the content is 97.3%, the moisture is 2.7%, and the ee value is 90.1%. No crotonic acid was detected by HPLC.
Example 2 preparation of strawberry-flavored ketogenic (D-BHB) effervescent tablets
1. D-BHB effervescent tablet ingredients
2. Preparation process of effervescent tablet
The effervescent tablet preparation process is shown in figure 2.
Preparation of acid particles A
Placing 15kg of D-3-hydroxybutyric acid, 6.8kg of maltodextrin and 2.3kg of sorbitol in a high-efficiency wet granulator, stirring, mixing for 8 minutes, adding a proper amount of absolute ethyl alcohol, spraying liquid for 6 minutes, stirring to form uniform particles passing through 10 meshes, starting a high-efficiency boiling dryer, setting the temperature to 30 ℃, setting the vacuum degree to be more than-0.085 MPa, drying until the weight loss on drying is less than 0.5%, and starting the high-efficiency granulator to pass through a 10-mesh sieve.
Preparation of alkali particles B
Placing 12.00kg of sodium bicarbonate, 6.97kg of lactose, 0.77kg of mannose and 0.50kg of stevioside in a high-efficiency wet granulator, stirring, mixing for 10 minutes, adding a proper amount of absolute ethyl alcohol, spraying liquid for 6 minutes, stirring to form uniform particles, starting an efficient boiling dryer, setting the temperature to 50 ℃, setting the vacuum degree to be more than-0.085 MPa, drying until the drying weight loss is less than 0.5%, and starting the efficient granulator to pass through a 10-mesh sieve.
General mixing
The acid particles A, the alkali particles B, 0.50kg of polyethylene glycol 6000 and 0.21kg of strawberry essence are placed in a mixer for 45 minutes, and the total mixing time is less than 0.5% of drying loss and less than 0.25% of water are detected by sampling.
Tabletting
The tablet press is regulated according to the standard of 4.5g of the weight of the photo, so as to ensure the compounding requirement of the weight and the hardness of the tablet. The average sheet weight, hardness, and appearance finish were checked every 30 minutes for compliance.
The obtained ketogenic effervescent tablet is shown in figure 3.
Example 3 preparation of mango-flavored ketogenic (D-BHB) effervescent tablets
1. Proportioning materials
2. The preparation method is the same as in example 2.
Example 4 preparation of lemon flavored ketogenic (D-BHB) effervescent tablets one, formulation
2. The preparation method is the same as in example 2.
Example 5 preparation of pineapple flavor ketogenic (D-BHB) effervescent tablet A, formulation
2. The preparation method is the same as in example 2.
Example 6 preparation of mint flavored ketogenic (D-BHB) effervescent tablets one, formulation
2. The preparation method is the same as in example 2.
Example 7 preparation of strawberry-flavored ketogenic (L-BHB) effervescent tablets one, formulation
2. The preparation method is the same as in example 2.
Example 8 preparation of strawberry-flavored ketogenic (DL-BHB) effervescent tablets one, formulation
2. The preparation method is the same as in example 2.
The above embodiments are only for illustrating the technical solution of the present invention, but not for limiting the same, and various modifications and variations of the present invention will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1.一种制备D-3-羟基丁酸的方法，其特征在于，包括如下步骤：1. A method for preparing D-3-hydroxybutyric acid, comprising the steps of: A.水解反应：在浓度不高于1.2M、优选不高于1.0M、例如不高于0.9M或0.8M的食品级氢氧化钠或氢氧化钾水溶液中，加入D-3-羟基丁酸甲酯或乙酯，在不高于45℃、优选不高于40℃、更优选不高于35℃、例如不高于30℃的温度下，搅拌进行水解反应，直至水解完毕，得D-3-羟基丁酸钠水溶液；A. Hydrolysis reaction: Add D-3-hydroxybutyric acid methyl ester or ethyl ester to a food-grade sodium hydroxide or potassium hydroxide aqueous solution having a concentration of not more than 1.2 M, preferably not more than 1.0 M, for example, not more than 0.9 M or 0.8 M, and stir at a temperature not more than 45° C., preferably not more than 40° C., more preferably not more than 35° C., for example, not more than 30° C., to carry out a hydrolysis reaction until the hydrolysis is complete to obtain an aqueous solution of sodium D-3-hydroxybutyrate; B.中和反应：在步骤A所得D-3-羟基丁酸钠/钾水溶液中，控制温度不高于45℃、优选不高于40℃、更优选不高于35℃、例如不高于30℃，加入与氢氧化钠或氢氧化钾等当量的食品级盐酸进行中和反应，得到D-3-羟基丁酸水溶液；B. Neutralization reaction: To the sodium/potassium D-3-hydroxybutyrate aqueous solution obtained in step A, food-grade hydrochloric acid in an amount equivalent to sodium hydroxide or potassium hydroxide is added at a temperature not exceeding 45° C., preferably not exceeding 40° C., more preferably not exceeding 35° C., for example, not exceeding 30° C., to carry out a neutralization reaction to obtain an aqueous solution of D-3-hydroxybutyric acid; C.析晶：对步骤B的反应液进行减压蒸馏，至析晶。冷却至10℃以下，养晶，离心分离或过滤，干燥，得D-3-羟基丁酸晶体。C. Crystallization: The reaction solution of step B is subjected to reduced pressure distillation to crystallize. Cool to below 10°C, grow the crystals, centrifuge or filter, and dry to obtain D-3-hydroxybutyric acid crystals. 2.如权利要求1所述的方法，其特征在于，步骤A中氢氧化钠或氢氧化钾与D-3-羟基丁酸甲酯或乙酯的加入量摩尔比为0.5-1.0：1.0。2. The method according to claim 1, wherein the molar ratio of sodium hydroxide or potassium hydroxide to methyl or ethyl D-3-hydroxybutyrate in step A is 0.5-1.0:1.0. 3.如权利要求1所述的方法，其特征在于，步骤A中的水解反应温度为10-35℃、优选15℃-30℃。3. The method according to claim 1, wherein the hydrolysis reaction temperature in step A is 10-35°C, preferably 15-30°C. 4.如权利要求1所述的方法，其特征在于，步骤A中可以加入终浓度不高于20％、优选不高于15％例如不高于12％或10％的乙醇。4. The method according to claim 1, wherein ethanol is added in step A to a final concentration of no more than 20%, preferably no more than 15%, for example no more than 12% or 10%. 5.如权利要求1-4中所述的D-3-羟基丁酸晶体在制备固体膳食补充剂中的用途，其中所述固体膳食补充剂是固体制剂，选自泡腾片、颗粒剂、胶囊剂、冲剂、粉剂/散剂、片剂、丸剂。5. Use of the D-3-hydroxybutyric acid crystals as described in claims 1 to 4 in the preparation of a solid dietary supplement, wherein the solid dietary supplement is a solid preparation selected from effervescent tablets, granules, capsules, granules, powders/powders, tablets, and pills. 6.一种生酮泡腾片即BHB泡腾片，其特征在于，包含如权利要求1-4中所述的D-3-羟基丁酸晶体、或者外消旋DL-3-羟基丁酸或者L-3-羟基丁酸作为有效成分。6. A ketogenic effervescent tablet, namely a BHB effervescent tablet, characterized in that it contains the D-3-hydroxybutyric acid crystals, or racemic DL-3-hydroxybutyric acid or L-3-hydroxybutyric acid as described in claims 1-4 as an active ingredient. 7.如权利要求6所述的生酮泡腾片，其特征在于，配方包括下述组分：7. The ketogenic effervescent tablet according to claim 6, wherein the formula comprises the following components: 酸源：包含BHB即D-3-羟基丁酸，DL-3-羟基丁酸或L-3-羟基丁酸；Acid source: Contains BHB, namely D-3-hydroxybutyrate, DL-3-hydroxybutyrate or L-3-hydroxybutyrate; 酸颗粒粘合剂：包含麦芽糊精；Acid Granule Binder: Contains maltodextrin; 二氧化碳源：选自下组：碳酸氢钠，碳酸钠，碳酸钾，碳酸氢钾，碳酸镁，碳酸钙，它们两种以上的混合物；Carbon dioxide source: selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, and mixtures of two or more thereof; 碱颗粒填充剂：包括乳糖；Alkaline granular fillers: including lactose; 润滑剂：选自下组：聚乙二醇例如聚乙二醇6000，山梨醇，它们的混合物；Lubricant: selected from the group consisting of polyethylene glycol such as polyethylene glycol 6000, sorbitol, and mixtures thereof; 湿润剂：包括乙醇；Wetting agents: including ethanol; 矫味剂：选自下组：甜菊糖苷，阿洛酮糖，三氯蔗糖，罗汉果甜苷，它们两种以上的混合物；Flavoring agent: selected from the group consisting of steviol glycosides, psicose, sucralose, mogrosides, and mixtures of two or more thereof; 果味剂：选自果粉、果味香精。Fruit flavor: selected from fruit powder and fruit flavor. 8.如权利要求7所述的生酮泡腾片，其特征在于，所述生酮泡腾片的配方选自下组之一：8. The ketogenic effervescent tablet according to claim 7, wherein the formula of the ketogenic effervescent tablet is selected from one of the following groups: 配方一的物料包括：酸颗粒，包含D-3-羟基丁酸、麦芽糊精、山梨醇和无水乙醇；碱颗粒，包含碳酸氢钠、乳糖、甘露糖、甜菊糖苷和无水乙醇；润滑剂聚乙二醇6000；香精例如草莓香精；The materials of Formula 1 include: acid granules containing D-3-hydroxybutyric acid, maltodextrin, sorbitol and anhydrous ethanol; base granules containing sodium bicarbonate, lactose, mannose, steviol glycosides and anhydrous ethanol; lubricant polyethylene glycol 6000; flavoring such as strawberry flavor; 配方二的物料包括：酸颗粒，包含D-3-羟基丁酸、麦芽糊精、山梨醇和无水乙醇；碱颗粒，包含碳酸氢钠、碳酸镁、乳糖、甘露糖、阿洛酮糖和无水乙醇；润滑剂聚乙二醇6000；香精例如芒果香精；The materials of formula 2 include: acid granules containing D-3-hydroxybutyric acid, maltodextrin, sorbitol and anhydrous ethanol; base granules containing sodium bicarbonate, magnesium carbonate, lactose, mannose, allulose and anhydrous ethanol; lubricant polyethylene glycol 6000; flavoring such as mango flavor; 配方三的物料包括：酸颗粒，包含D-3-羟基丁酸、麦芽糊精、山梨醇和无水乙醇；碱颗粒，包含碳酸氢钠、碳酸钙、乳糖、甘露糖、三氯蔗糖和无水乙醇；润滑剂聚乙二醇6000；香精例如柠檬香精；The materials of formula 3 include: acid granules containing D-3-hydroxybutyric acid, maltodextrin, sorbitol and anhydrous ethanol; base granules containing sodium bicarbonate, calcium carbonate, lactose, mannose, sucralose and anhydrous ethanol; lubricant polyethylene glycol 6000; flavoring such as lemon flavor; 配方四是的物料包括：酸颗粒，包含D-3-羟基丁酸、麦芽糊精、山梨醇和无水乙醇；碱颗粒，包含碳酸氢钠、碳酸钾、乳糖、甘露糖、罗汉果甜苷和无水乙醇；润滑剂聚乙二醇6000；香精例如菠萝香精；The materials of formula 4 include: acid granules containing D-3-hydroxybutyric acid, maltodextrin, sorbitol and anhydrous ethanol; base granules containing sodium bicarbonate, potassium carbonate, lactose, mannose, mogroside and anhydrous ethanol; lubricant polyethylene glycol 6000; flavoring such as pineapple flavor; 配方五的物料包括：酸颗粒，包含D-3-羟基丁酸、麦芽糊精、山梨醇和无水乙醇；碱颗粒，包含碳酸氢钠、碳酸镁、碳酸钙、乳糖、甘露糖、罗汉果甜苷、甜菊糖苷和无水乙醇；润滑剂聚乙二醇6000；香精例如薄荷香精；The materials of formula 5 include: acid particles containing D-3-hydroxybutyric acid, maltodextrin, sorbitol and anhydrous ethanol; base particles containing sodium bicarbonate, magnesium carbonate, calcium carbonate, lactose, mannose, mogroside, steviol glycoside and anhydrous ethanol; lubricant polyethylene glycol 6000; flavoring such as mint flavoring; 配方六的物料包括：酸颗粒，包含DL-3-羟基丁酸、麦芽糊精、山梨醇和无水乙醇；碱颗粒，包含碳酸氢钠、乳糖、甘露糖、甜菊糖苷和无水乙醇；润滑剂聚乙二醇6000；香精例如草莓香精；The materials of formula six include: acid granules containing DL-3-hydroxybutyric acid, maltodextrin, sorbitol and anhydrous ethanol; base granules containing sodium bicarbonate, lactose, mannose, steviol glycosides and anhydrous ethanol; lubricant polyethylene glycol 6000; flavoring such as strawberry flavor; 配方七的物料包括：酸颗粒，包含L-3-羟基丁酸、麦芽糊精、山梨醇和无水乙醇；碱颗粒，包含碳酸氢钠、乳糖、甘露糖、甜菊糖苷和无水乙醇；润滑剂聚乙二醇6000；香精例如草莓香精。The materials of formula seven include: acid granules containing L-3-hydroxybutyric acid, maltodextrin, sorbitol and anhydrous ethanol; base granules containing sodium bicarbonate, lactose, mannose, steviol glycoside and anhydrous ethanol; lubricant polyethylene glycol 6000; flavoring such as strawberry flavor. 9.一种制备如权利要求7所述生酮泡腾片的方法，其特征在于，包括下述步骤：9. A method for preparing the ketogenic effervescent tablet according to claim 7, characterized in that it comprises the following steps: 1)酸颗粒制备：1) Preparation of acid particles: 将酸颗粒固体原料置于湿法制粒机中，搅拌，混合均匀，再喷入无水乙醇，搅拌，形成通过10目的均匀颗粒；启动沸腾干燥机，温度设定不高于35℃，真空度不低于-0.08MPa，烘料至干燥失重不高于0.5％；启动整粒机，通过10目筛，得酸颗粒A；The solid raw material of acid particles is placed in a wet granulator, stirred and mixed evenly, and then anhydrous ethanol is sprayed into it and stirred to form uniform particles passing through a 10-mesh sieve; a boiling dryer is started, the temperature is set to no higher than 35° C., the vacuum degree is set to no lower than -0.08 MPa, and the material is dried until the loss on drying is no higher than 0.5%; a granulator is started, and the particles are passed through a 10-mesh sieve to obtain acid particles A; 2)碱颗粒制备：2) Preparation of alkali particles: 将碱颗粒固体原料置于湿法制粒机中，搅拌，混合均匀，再喷入无水乙醇，搅拌，形成均匀的颗粒；启动沸腾干燥机，温度设定不高于65℃，真空度不低于-0.08MPa，烘料至干燥失重不高于0.5％；启动整粒机，通过10目筛，得碱颗粒B；The solid raw material of alkali particles is placed in a wet granulator, stirred and mixed evenly, and then anhydrous ethanol is sprayed into it and stirred to form uniform granules; a boiling dryer is started, the temperature is set to no higher than 65°C, the vacuum degree is set to no lower than -0.08MPa, and the material is dried until the loss on drying is no higher than 0.5%; a granulator is started, and the granules are passed through a 10-mesh sieve to obtain alkali particles B; 3)总混：3) Total mixing: 将酸颗粒A、碱颗粒B、聚乙二醇、果粉或香精置于混合机中，混合均匀，至干燥失重不高于0.5％、水份不高于0.25％，得混合物C；Place acid particles A, base particles B, polyethylene glycol, fruit powder or essence in a mixer and mix uniformly until the loss on drying is no more than 0.5% and the moisture content is no more than 0.25% to obtain mixture C; 4)压片：4) Tablet pressing: 在压片机中加入混合物C，按照片重4.5g的标准调试压片机，得到片重、硬度、外观光洁度符合预定要求的生酮泡腾片。Mixture C was added to the tablet press, and the tablet press was adjusted according to the standard of tablet weight of 4.5 g to obtain ketogenic effervescent tablets whose tablet weight, hardness and appearance smoothness met the predetermined requirements. 10.如权利要求9所述的方法，其特征在于，步骤1)中沸腾干燥机的温度设定为30℃左右，真空度不低于-0.085MPa；步骤2)中沸腾干燥机的温度设定为50℃左右，真空度不低于-0.085Mpa。10. The method according to claim 9, characterized in that the temperature of the boiling dryer in step 1) is set to about 30°C and the vacuum degree is not less than -0.085 MPa; the temperature of the boiling dryer in step 2) is set to about 50°C and the vacuum degree is not less than -0.085 MPa.
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