Preparation method of super-fine creatine with improved solubility and absorption efficiency

Abstract

This invention belongs to the field of sports nutrition supplements and food ingredient processing technology, and particularly relates to a method for preparing ultrafine creatine with improved solubility and absorption efficiency. Creatine monohydrate is pretreated with low water activity and then ultrafinely pulverized using a low-temperature airflow. Malic acid and citric acid are then enriched and coated onto the surface of the creatine particles under low water activity conditions. The particles are then granulated at low temperature to form porous secondary composite microparticles. These composite microparticles maintain a high crystal form retention rate of creatine monohydrate and a low creatinine production rate in their dry powder state. Upon reconstitution with water, they rapidly disintegrate and form a locally acidic interface environment, improving the wetting, dispersibility, and dissolution efficiency of creatine.

Description

Technical Field

[0001] This invention belongs to the field of sports nutrition supplements and food ingredient processing technology, and particularly relates to a method for preparing ultrafine pulverized creatine with improved solubility and absorption efficiency. Background Technology

[0002] Creatine is a commonly used sports nutrition supplement, usually in the form of creatine monohydrate in powders, solid beverages, instant drinks, or compound sports nutrition compositions. Creatine monohydrate has advantages such as stable raw material sources, low cost, and mature applications. However, its solubility and dissolution rate in room temperature water are limited, which can easily lead to problems such as floating, clumping, sedimentation at the bottom of the cup, or a rough taste during actual preparation. Especially when the single supplementation dose is high, such as taking several grams of creatine and adding it to about 200mL of water, ordinary creatine monohydrate powder often requires a long stirring time and is prone to forming insufficiently wetted clumps, affecting ease of use and uniform intake.

[0003] To improve the water solubility of creatine, existing technologies have proposed the development of organic acid salts for creatine. For example, US5973199A discloses a class of water-soluble organic acid salts for creatine, which improves the solubility of creatine in water by forming salts with organic acids. This type of technology typically uses pre-salting as a basic idea, allowing creatine to exist in the form of citrate, malate, or other organic acid salts, thereby improving water solubility. This technology can address the low solubility of ordinary creatine monohydrate to some extent, but it primarily focuses on the preparation and solubility of the creatine salt itself, without fully addressing the balance between the moisture absorption, clumping, initial wetting difficulties, and long-term stability of ordinary creatine powder in a dry state under acidic conditions. For acidic systems, if creatine is exposed to high moisture or acidic liquid environments for extended periods, the risk of creatine conversion to creatinine may increase, thus affecting the product's quality stability during storage and use.

[0004] Existing technologies have also proposed solutions to improve the processability and reconstitution properties of creatine powder through grinding or agglomeration. For example, CN119403458A discloses a water-soluble creatine agglomerate comprising ground creatine and a binder containing oligosaccharides, which improves the solubility and processability of creatine in aqueous systems by forming an agglomerated structure. This type of technology recognizes that while simply micronizing creatine can increase the specific surface area, excessively fine powder can easily lead to problems such as low bulk density, poor flowability, high dust content, poor wettability, and re-agglomeration. Therefore, binders or agglomeration processes are used to improve the performance of the powder. However, these solutions typically rely on sugars, oligosaccharides, or other binding agents to construct agglomerated particles. Their main function is physical agglomeration and improved processability, but they do not address the synergistic issues of localized salt formation, rapid deagglomeration, and low water activity stability of creatine during reconstitution from the perspective of the particle interface chemical environment.

[0005] In addition, existing instant powder technologies often employ spray drying aids, suspending stabilizers, sugar-based instant dissolving aids, or colloidal excipients to improve the dispersion and suspension of creatine in water. While these methods can improve the powder's reconstitution properties, they typically require a higher proportion of carriers or additives, leading to a decrease in creatine content per unit mass of product and potentially increasing formulation complexity, sweetness, or viscosity. Furthermore, for high-loading products with creatine monohydrate as the main active ingredient, how to achieve high content, easy wetting, rapid dissolution, low agglomeration, and stable storage of creatine powder while minimizing the amount of external loading remains a technical challenge that needs to be addressed.

[0006] As can be seen from the existing technologies described above, while pre-preparing creatine organic acid salts can improve the water solubility of creatine, it has limitations in terms of salt formation process, stability of acidic systems, and product morphology control. While ultrafine grinding or agglomeration granulation can improve the specific surface area or processability of the powder, it is difficult to simultaneously resolve the contradictions between ultrafine powder agglomeration upon contact with water, slow initial dissolution, and acidic solubilization and dry powder stability. Therefore, it is still necessary to provide a new method for preparing creatine composite microparticles that allows creatine to maintain low water activity and good storage stability in its dry powder state, while rapidly wetting and deagglomerating upon contact with water, and forming a localized acidic environment at the particle-water interface conducive to dissolution, thereby improving the dissolution efficiency and ease of use of creatine. Summary of the Invention

[0007] The purpose of this invention is to provide a low water activity interface-coated ultrafine creatine composite microparticle and its preparation method for improving the dissolution efficiency of creatine. By using low-temperature airflow ultrafine pulverization, malic acid-citric acid interface enrichment and coating, and porous secondary particle construction, creatine maintains low water activity and good stability in dry powder storage. When water is added for reconstitution, it is quickly wetted, deagglomerated, and forms a local acidic environment at the particle-water interface that is conducive to dissolution, thereby improving the reconstitution speed, dispersion uniformity, and convenience of administration of creatine.

[0008] Firstly, in order to achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0009] A method for preparing ultrafine creatine with improved solubility and absorption efficiency includes the following steps:

[0010] S1. The creatine monohydrate raw material is screened, impurities are removed and dried to obtain pretreated creatine powder.

[0011] S2. Under the protection of dry gas with a dew point not higher than -20℃, the pretreated creatine powder is subjected to air jet milling, and the material outlet temperature during the milling process is controlled not to be higher than 25℃ to obtain ultrafine creatine primary particles. The D50 of the ultrafine creatine primary particles is 3 to 8 μm and the D90 is not greater than 15 μm.

[0012] S3. Malic acid and citric acid are mixed at a mass ratio of 1:(0.5 to 1.5) to obtain a composite organic acid component. The total amount of the composite organic acid component is 6% to 14% of the mass of the ultrafine creatine particles. The composite organic acid component is then made into a low water activity coating solution with a water activity not higher than 0.45, or into an ultrafine composite organic acid powder with a D90 not greater than 20 μm.

[0013] S4. Under fluidized bed atomization deposition or dry mechanical fusion conditions with relative humidity not exceeding 25% and material temperature of 5-25℃, the composite organic acid components are deposited and enriched on the outer surface of the ultrafine creatine primary particles to form coated primary composite particles with a monohydrate creatine crystal core and a malic acid-citric acid interface layer.

[0014] S5. The coated primary composite particles are subjected to low-temperature gas-solid shear granulation and drying stabilization treatment to form porous secondary composite microparticles composed of multiple coated primary composite particles.

[0015] As a further improvement, in step S1, the creatine monohydrate raw material is creatine monohydrate powder that can pass through a 200-mesh sieve, or the D50 of the creatine monohydrate raw material is 60-80 μm; after sieving, agglomerated particles and foreign particles with a particle size greater than 90 μm are removed.

[0016] And / or, in step S1, the drying is one of vacuum drying, dehumidifying hot air drying or nitrogen circulation drying, the drying temperature is 30-45°C, the drying time is 1-4 hours, and the moisture content of the pretreated creatine powder after drying is 0.1%-0.6%.

[0017] As a further improvement, in step S2, the drying gas is one of air, nitrogen or carbon dioxide, the airflow pulverizing pressure is 0.45 to 0.90 MPa, the classifier speed is 3000 to 8000 r / min, and the temperature inside the pulverizing chamber is 5 to 20°C.

[0018] And / or, in step S2, the specific surface area of ​​the ultrafine creatine primary particles is 0.8 to 2.5 m² / g, and the particles enter step S4 within 20 minutes after pulverization, in order to reduce the hygroscopic agglomeration of the ultrafine creatine primary particles.

[0019] And / or, in step S2, the retention rate of the X-ray diffraction characteristic peaks of the monohydrate creatine crystal form in the ultrafine creatine primary particles is not less than 80%.

[0020] As a further improvement, in step S3, the mass ratio of malic acid to citric acid is 1:(0.8-1.2), and the total amount of the composite organic acid components is 8%-12% of the mass of the ultrafine creatine particles.

[0021] And / or, in step S3, the low water activity coating solution is composed of malic acid, citric acid, ethanol and water, wherein the mass ratio of ethanol to water is (60-90):(10-40), and the solid content of the low water activity coating solution is 10%-35%.

[0022] And / or, in step S3, the ultrafine composite organic acid powder is obtained by low-temperature pulverization, wherein the D50 of the ultrafine composite organic acid powder is 3-10μm, the D90 is not greater than 20μm, and the material temperature during the pulverization process is not higher than 25℃.

[0023] As a further improvement, in step S4, the total content of malic acid and citric acid in the outer surface of the coated primary composite particles within a depth range of 2μm is more than twice the total content of malic acid and citric acid in the central region of the particles, and the total amount of preformed creatine malate and creatine citrate in the dry powder state is not higher than 10% of the total amount of creatine.

[0024] And / or, in step S4, when fluidized bed atomization deposition is used, the low water activity coating liquid is sprayed into the fluidized bed containing the ultrafine creatine primary particles, the spraying rate is controlled at 1-8 g / min per kilogram of ultrafine creatine primary particles, the atomizing gas temperature is 5-20°C, and a dry gas with a dew point not higher than -20°C is simultaneously introduced; when dry mechanical fusion is used, the ultrafine creatine primary particles and the ultrafine composite organic acid powder are placed in a mechanical fusion device and subjected to shearing, compression and collision treatment at 5-25°C, so that malic acid and citric acid are embedded or adsorbed on the outer surface of the ultrafine creatine primary particles.

[0025] And / or, in step S4, the malic acid-citric acid interface layer covers more than 70% of the outer surface area of ​​the ultrafine creatine primary particles, and the malic acid and citric acid are distributed on the outer surface of the creatine monohydrate crystal core in the form of free acid, hydrogen bond complex, or locally ionized state.

[0026] As a further improvement, in step S5, the D50 of the porous secondary composite microparticles is 120-220 μm, the water content is not higher than 1.5%, and the water activity is not higher than 0.30.

[0027] And / or, in step S5, the low-temperature gas-solid shear granulation is carried out at 10-30°C, and the bulk density of the porous secondary composite microparticles obtained after granulation is 0.35-0.75 g / mL, and the angle of repose is not greater than 38°.

[0028] And / or, in step S5, the drying and stabilization treatment is one of vacuum low-temperature drying, dehumidifying airflow drying, or fluidized bed low-temperature drying, with a drying temperature of 25-45°C, until the moisture content of the porous secondary composite particles is 0.3%-1.2% and the water activity is 0.10-0.28.

[0029] As a further improvement, when the porous secondary composite microparticles are added at 5g to 200mL of water at 20-25℃ and stirred or shaken, there is no obvious clumping within 90 seconds; when 5g of creatine is added to 200mL of water at 20-25℃ and stirred at 300r / min for 120 seconds and then filtered through a 100-mesh sieve, the undissolved residue rate is no higher than 7.0% after 2 minutes.

[0030] And / or, after adding 5g of the porous secondary composite microparticles to 200mL of water at 20-25℃ and reconstitute, the pH of the resulting reconstituted solution is 3.2-4.8;

[0031] And / or, after the porous secondary composite microparticles are sealed and stored at 40°C and 75% relative humidity for 30 days, the increase in creatinine is no higher than 0.20%.

[0032] Secondly, the present invention also provides an ultrafine creatine powder with improved solubility and absorption efficiency, prepared by the aforementioned method. The low water activity interface-coated ultrafine creatine composite microparticles comprise multiple coated primary composite particles. Each coated primary composite particle comprises a creatine monohydrate crystal core and a malic acid-citric acid interface layer enriched on the outer surface of the creatine monohydrate crystal core. The low water activity interface-coated ultrafine creatine composite microparticles have a D50 of 120–220 μm, a water content not exceeding 1.5%, and a water activity not exceeding 0.30.

[0033] As a further improvement, the low water activity interface-coated ultrafine creatine composite microparticles contain 84% to 92% creatine monohydrate by mass, 6% to 14% malic acid and citric acid by mass, and the mass ratio of malic acid to citric acid is 1:(0.5 to 1.5).

[0034] And / or, in the coated primary composite particles, the retention rate of the X-ray diffraction characteristic peaks of the creatine monohydrate crystal form is not less than 80%, and the total amount of preformed creatine malate and creatine citrate in the dry powder state is not more than 10% of the total amount of creatine.

[0035] And / or, the total content of malic acid and citric acid within a 2μm depth range on the outer surface of the coated primary composite particles is more than twice the total content of malic acid and citric acid in the central region of the particles.

[0036] Thirdly, the present invention also provides a sports nutrition composition, characterized in that it comprises the aforementioned ultrafine creatine, and one or more of sweeteners, acidity modifiers, flavorings, electrolytes, amino acids, vitamins, dietary fiber, or anti-caking agents; the ultrafine creatine in the sports nutrition composition has a mass percentage content of 50% to 99%.

[0037] Compared to ordinary 200-mesh creatine monohydrate, pure ultrafine pulverized creatine, and ordinary dry mixtures of creatine and organic acids, this invention uses low-temperature airflow pulverization to form ultrafine primary particles with a high specific surface area of ​​creatine. Under low water activity conditions, malic acid and citric acid are enriched on the outer surface of the creatine particles, forming coated primary composite particles that combine the creatine monohydrate crystal core with the organic acid interface layer. Furthermore, low-temperature gas-solid shearing granulation forms porous secondary composite microparticles, so that the powder avoids floating, agglomeration, and clumping when the ultrafine powder comes into direct contact with water, and can quickly disintegrate into ultrafine particles with an organic acid interface layer on the surface during reconstitution. This structure eliminates the need for pre-forming large amounts of creatine malate or creatine citrate in the dry powder state, reducing the risk of creatine conversion to creatinine in a high-moisture, acidic environment. Upon addition of water, the organic acid interface layer is rapidly released, creating a localized acidic microenvironment at the particle-water interface. This promotes in-situ salt formation and rapid dissolution of creatine, thereby improving the wetting speed, dispersion uniformity, and dissolution efficiency of 5g of creatine added to 200mL of water. It also reduces residue at the bottom of the cup and clumping during reconstitution, while maintaining a high creatine content and good powder flowability. This structure is suitable for use in solid beverages, sports nutrition powders, and other creatine supplement compositions. Attached Figure Description

[0038] Figure 1 This is a flowchart illustrating the preparation process of the product of this invention.

[0039] Figure 2 This is a cross-sectional infrared micrograph of the coated primary composite particles in Embodiment 1 of the present invention.

[0040] Figure 3 This is a comparison chart of the undissolved residue rate after 2 minutes in a 5g / 200mL water system for both the example and the comparative examples.

[0041] Figure 4 This is a comparison diagram of the characteristic peaks of X-ray diffraction for the examples and comparative examples.

[0042] Figure 5 This is a comparison chart showing the increase in creatinine levels after the examples and comparative examples were sealed and stored for 30 days at 40°C and 75% relative humidity. Detailed Implementation

[0043] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be understood that the following embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Those skilled in the art can make adaptive adjustments to the process parameters according to the production scale, equipment model, raw material batch and testing conditions without departing from the technical concept of the present invention. As long as the low water activity pretreatment, low temperature airflow ultrafine grinding, malic acid-citric acid interface enrichment and coating, non-pre-salt state control and porous secondary particle construction are still used, they should be considered to fall within the scope of protection of the present invention.

[0044] This invention provides a method for preparing low-water-activity interface-coated ultrafine creatine composite particles to improve the dissolution efficiency of creatine during reconstitution. The core of this method involves: firstly, pretreating the creatine monohydrate raw material with low water activity, then performing airflow ultrafine pulverization under low-temperature drying gas protection to form ultrafine creatine primary particles with a D50 of 3–8 μm and a D90 not exceeding 15 μm; subsequently, under low-water-activity conditions, malic acid and citric acid are enriched on the outer surface of the ultrafine creatine primary particles through atomized deposition of a coating solution or mechanical fusion of ultrafine acid powders, forming coated primary composite particles with a creatine monohydrate crystal core and a malic acid-citric acid interface layer; finally, through low-temperature gas-solid shear granulation and drying stabilization treatment, porous secondary composite particles composed of multiple coated primary composite particles are formed. The composite microparticles maintain low water activity and high retention rate of creatine monohydrate crystal form in the dry powder state. When mixed with water, they can quickly disintegrate, wet and release the interfacial organic acid layer, thereby forming a local acidic microenvironment at the particle-water interface, promoting rapid dissolution of creatine, and reducing the risk of increased creatinine due to long-term storage of creatine in a high-moisture acidic environment.

[0045] I. Explanation of Key Terms

[0046] The "creatine monohydrate raw material" referred to in this invention refers to food-grade or sports nutrition-grade creatine monohydrate powder, the mass content of which is preferably not less than 98%. This invention preferably uses creatine monohydrate powder that can pass through a 200-mesh sieve as the starting material, but it can also use creatine monohydrate powder with a D50 of 60-80 μm as the starting material.

[0047] The term "low water activity" in this invention refers to the controlled availability of free water for reaction or migration in a material, resulting in a low water activity level. Low water activity is not simply equivalent to low moisture content; moisture content reflects the total amount of water in the material, while water activity reflects the degree of water availability. In this invention, low water activity pretreatment is used to reduce the possibility of excessive salt formation or degradation of creatine during subsequent organic acid coating and dry powder storage stages.

[0048] The "ultra-micro creatine primary particles" referred to in this invention are micron-sized particles formed by pulverizing creatine monohydrate through a low-temperature airflow, with a preferred D50 of 3-8 μm and a preferred D90 of no more than 15 μm. These primary particles have a high specific surface area, which is beneficial for rapid dissolution during reconstitution. However, if used directly, they are prone to problems such as powdering, agglomeration, difficulty in wetting, and decreased flowability.

[0049] The "malic acid-citric acid interface layer" referred to in this invention refers to a functional interface layer formed by the enrichment of malic acid and citric acid on the outer surface of ultrafine creatine primary particles. This interface layer can be formed by atomization deposition of a low water activity coating liquid, or by mechanical fusion of ultrafine composite organic acid powders. Malic acid and citric acid can exist in this interface layer as free acids, hydrogen-bonded complexes, or locally ionized states, but it is not required that creatine be completely dissolved and crystallized to form creatine malate or creatine citrate during the dry powder preparation stage.

[0050] The term "preformed creatine organic salt" as used in this invention refers to creatine malate, creatine citrate, or a complex salt thereof, which have been formed through complete dissolution, salt formation, and crystallization during the dry powder preparation or storage stage. This invention allows for the presence of localized weak interactions or small amounts of localized ionization, but preferably controls the total amount of preformed creatine malate and creatine citrate in the dry powder state to not exceed 10% of the total creatine content.

[0051] The "porous secondary composite microparticles" referred to in this invention are large-diameter composite particles formed by low-temperature gas-solid shear granulation or low-temperature fluidized bed granulation of multiple coated primary composite particles. These secondary particles exhibit good flowability and anti-dust properties in their dry powder state, and upon addition to water, they can rapidly absorb water, disintegrate, and release the coated primary composite particles through their internal pore channels.

[0052] II. Experimental Materials, Equipment, and Testing Methods

[0053] 1. Experimental materials

[0054] The creatine monohydrate raw material used in the experiment was food-grade creatine monohydrate, capable of passing through a 200-mesh sieve, with a creatine monohydrate content of not less than 98.0% and an initial water content of 9.8%–11.5%. Food-grade L-malic acid and food-grade anhydrous citric acid were used. Food-grade ethanol was used, and the conductivity of purified water was not higher than 10 μS / cm. Unless otherwise specified, all raw materials used in the examples and comparative examples were commercially available products.

[0055] 2. Experimental Equipment

[0056] The main equipment used in the experiment included: vacuum drying oven, dehumidifying nitrogen circulation drying device, low-temperature airflow pulverizer, fluidized bed coating equipment, mechanical fusion machine, low-temperature gas-solid shear granulation equipment, laser particle size analyzer, water activity meter, Karl Fischer moisture analyzer, X-ray diffractometer, Fourier transform infrared spectrometer, Raman microscopy, scanning electron microscope, high performance liquid chromatograph, pH meter, powder angle of repose measuring instrument, and constant temperature and humidity chamber.

[0057] 3. Particle size detection methods

[0058] Take approximately 0.5g of the powder to be tested and use a dry laser particle size analyzer to measure the particle size distribution, recording D10, D50, and D90. For ultrafine creatine primary particles, focus on recording D50 and D90; for porous secondary composite microparticles, focus on recording D50. Each sample is tested three times, and the average value is taken.

[0059] 4. Methods for detecting moisture content and water activity

[0060] The moisture content was determined using the Karl Fischer method, and the water activity was determined using a water activity meter at 25°C. In the examples, the moisture content of the pretreated creatine powder was preferably controlled to be no higher than 0.8%, and the water activity was preferably no higher than 0.25; the moisture content of the final porous secondary composite microparticles was preferably controlled to be no higher than 1.5%, and the water activity was preferably no higher than 0.30.

[0061] 5. XRD methods for detecting crystal form and preformed organic acid salts

[0062] X-ray diffraction was used to analyze the raw material creatine monohydrate, ultrafine creatine primary particles, coated primary composite particles, and final porous secondary composite microparticles. The testing conditions included Cu Kα radiation, a scanning range of 2θ = 5°–60°, and a scanning rate of 5° / min. The retention rate of the main characteristic peaks of creatine monohydrate in the samples was calculated using the peak area of ​​the main characteristic peaks as a reference.

[0063] Retention rate of characteristic peaks of crystal form = Area of ​​characteristic peak of creatine monohydrate in sample / Area of ​​corresponding characteristic peak of creatine monohydrate in raw material × 100%.

[0064] Meanwhile, using the characteristic peaks of pre-prepared creatine malate and creatine citrate standards as controls, the area ratio of the characteristic peaks of pre-formed creatine malate and creatine citrate in the sample was calculated. When the retention rate of the characteristic peak of the monohydrate creatine crystal form of the porous secondary composite microparticles is not less than 80%, and the sum of the characteristic peak areas of pre-formed creatine malate and creatine citrate is not higher than 10% of the characteristic peak area of ​​creatine, it is considered that the sample mainly maintains the monohydrate creatine crystal core and does not form a large amount of pre-formed creatine organic acid salt in the dry powder state.

[0065] 6. Detection method for surface enrichment of organic acids

[0066] like Figure 2 As shown, cross-sectional scanning of coated primary composite particles was performed using micro-infrared imaging. At least 20 particles were randomly selected from each sample, and the characteristic signal intensities of malic acid and citric acid within a 2 μm depth range on the outer surface of the particles, as well as the corresponding characteristic signal intensity in the central region of the particles, were measured. The ratio of these two intensities was used as the organic acid surface enrichment coefficient.

[0067] Surface enrichment coefficient = intensity of characteristic signals of malic acid and citric acid within a 2μm depth range on the outer surface of the particle / intensity of characteristic signals of malic acid and citric acid in the central region of the particle.

[0068] When the surface enrichment coefficient is not less than 2.0, it indicates that malic acid and citric acid are mainly enriched on the outer surface of creatine particles, rather than simply and uniformly mixed with creatine particles.

[0069] 7. Method for testing dissolution efficiency during reconstitution

[0070] Weigh the sample to obtain 5.00 g of creatine, add it to 200 mL of purified water at 25 °C, and stir magnetically at 300 rpm. Observe the dispersion at 30, 60, 90, and 120 seconds. At 120 seconds, filter the solution through a 100-mesh sieve, collect the undissolved residue on the sieve, and vacuum dry it at 40 °C to constant weight. Calculate the undissolved residue rate after 2 minutes.

[0071] Undissolved residue rate after 2 minutes = mass of undissolved residue after drying / equivalent mass of creatine in the added sample × 100%.

[0072] Simultaneously observe for any obvious floating clumps, clumping on the cup wall, or sedimentation at the bottom of the cup. If there are no obvious clumps within 90 seconds, and the undissolved residue rate after 2 minutes is significantly lower than that of ordinary 200-mesh creatine monohydrate and uncoated ultrafine creatine powder, then the sample is considered to have good reconstitution and dissolution efficiency.

[0073] 8. Methods for testing the flowability of powder

[0074] The flowability of the powder was tested using the angle of repose method and the bulk density method. A smaller angle of repose indicates better powder flowability. The preferred angle of repose of the porous secondary composite microparticles obtained in this invention is no greater than 38°, and the preferred bulk density is 0.35–0.75 g / mL.

[0075] 9. Accelerated Storage Stability Testing Methods

[0076] Take 50g of sample, seal it in an aluminum-plastic composite bag, and store it in a constant temperature and humidity chamber at 40℃ and 75% relative humidity for 30 days. The creatinine content was determined by HPLC before and after storage, and the increase in creatinine was calculated. A creatinine increase of no more than 0.20% indicates that the sample has good storage stability in a low water activity dry powder state.

[0077] III. Examples and Comparative Examples

[0078] Example 1

[0079] like Figure 1As shown, 10 kg of creatine monohydrate raw material that could pass through a 200-mesh sieve was weighed and sieved through a 200-mesh sieve to remove obvious agglomerated particles and foreign matter. The sieved creatine raw material was placed in a vacuum drying oven and dried for 3 hours at 38℃ and a vacuum degree of -0.085 MPa to obtain pretreated creatine powder. The water content of the pretreated creatine powder was measured to be 0.42%, and the water activity was 0.18.

[0080] Pretreated creatine powder was fed into an air jet mill for cryogenic air jet milling under nitrogen protection. The nitrogen dew point was -35℃, the milling pressure was 0.65MPa, the classifier speed was 5200 r / min, the temperature inside the milling chamber was controlled at 12–18℃, and the material outlet temperature was 21℃. After milling, ultrafine creatine primary particles were obtained, with a D50 of 5.6 μm and a D90 of 13.2 μm measured by a laser particle size analyzer. XRD analysis showed that the retention rate of the characteristic peaks of creatine monohydrate crystal form in these ultrafine creatine primary particles was 92.4%.

[0081] 0.55 kg of L-malic acid and 0.55 kg of anhydrous citric acid were weighed out at a mass ratio of 1:1, and the total amount of the composite organic acid components was 11% of the mass of the ultrafine creatine particles. The malic acid and citric acid were dissolved in an ethanol-water mixture at a mass ratio of 80:20 to prepare a low water activity coating solution with a solid content of 22%. The water activity of this coating solution was measured to be 0.36.

[0082] Ultrafine creatine primary particles were placed in a fluidized bed coating device, and dry nitrogen gas with a dew point of -35℃ was introduced to bring the material into a stable fluidized state. The fluidized bed inlet air temperature was controlled at 18℃, the material temperature at 16-22℃, and the relative humidity at 18%. A low water activity coating liquid was sprayed into the fluidized bed via atomization at a spray rate of 4 g / min per kilogram of ultrafine creatine primary particles, with the atomizing gas temperature at 15℃. Simultaneously, low-temperature dehumidification and drying were carried out during the spraying process, causing malic acid and citric acid to deposit and enrich on the outer surface of the ultrafine creatine primary particles, resulting in coated primary composite particles.

[0083] After spraying, the coated primary composite particles were transferred to a low-temperature gas-solid shear granulation device and subjected to gas-solid shear granulation at 22°C for 15 minutes, forming porous secondary composite microparticles from multiple coated primary composite particles. Subsequently, they were dried at 35°C under dehumidified nitrogen atmosphere until the water content was 0.86% and the water activity was 0.22. The resulting porous secondary composite microparticles had a D50 of 168 μm, an angle of repose of 34.6°, and a bulk density of 0.52 g / mL.

[0084] Structural testing was performed on the obtained product. Raman microscopy revealed that the total signal intensity of malic acid and citric acid within a 2 μm depth on the outer surface of the particles was 3.4 times that of the central region, indicating that the organic acids were mainly enriched on the outer surface. XRD analysis showed that the retention rate of the characteristic peaks of creatine monohydrate was 88.7%, and the sum of the characteristic peak areas of preformed creatine malate and creatine citrate was 5.8% of the characteristic peak area of ​​creatine, indicating that a large amount of preformed salts were not formed in the dry powder state.

[0085] Weigh out 5.00 g of the product containing creatine, add it to 200 mL of water at 25°C, and stir. The sample was basically wetted after 30 seconds, no obvious floating clumps after 60 seconds, the system was uniformly dispersed after 90 seconds, and the undissolved residue rate was measured to be 3.6% after filtration at 120 seconds. The pH of the reconstituted solution was 3.86. After 30 days of sealed storage at 40°C and 75% relative humidity, the increase in creatinine was 0.11%.

[0086] As can be seen from Example 1, under the conditions of combining low-temperature airflow ultrafine grinding, low water activity organic acid interface coating and low-temperature porous secondary particle construction, the obtained creatine composite microparticles can achieve a balance of high dissolution efficiency, good powder flowability and low creatinine increase.

[0087] Example 2

[0088] 10 kg of creatine monohydrate raw material that can pass through a 200-mesh sieve was weighed and pretreated using a dehumidified nitrogen circulating drying method. The drying temperature was 35℃, the drying time was 4 hours, and the dew point of the drying gas was -30℃. After drying, the moisture content of the pretreated creatine powder was measured to be 0.51%, and the water activity was 0.21.

[0089] Pretreated creatine powder was subjected to low-temperature airflow milling. The drying gas was air, the dew point was -25℃, the milling pressure was 0.58MPa, the classifier speed was 4700 r / min, and the material outlet temperature was 23℃. The resulting ultrafine creatine primary particles had a D50 of 6.8μm, a D90 of 14.6μm, and a retention rate of 90.8% for the characteristic peaks of creatine monohydrate crystal form.

[0090] Weigh out 0.60 kg of L-malic acid and 0.36 kg of anhydrous citric acid, with a mass ratio of 1:0.6. The total amount of the composite organic acid components is 9.6% of the mass of the ultrafine creatine particles. A low water activity coating solution is prepared using a mixed solvent of ethanol and water at a mass ratio of 75:25, with a solid content of 25% and a water activity of 0.40.

[0091] Ultrafine creatine primary particles were placed in a fluidized bed for atomized deposition coating. The material temperature was controlled at 18–24℃, the relative humidity at 20%, and the spraying rate at 3 g / min per kilogram of ultrafine creatine primary particles. After coating, the particles were subjected to low-temperature gas-solid shear granulation at 25℃ and then dried and stabilized in dehumidified air at 40℃ to obtain porous secondary composite microparticles. The resulting product had a water content of 1.05%, a water activity of 0.25, a D50 of 182 μm, and an angle of repose of 35.8°.

[0092] The test results showed that the total content of malic acid and citric acid within 2 μm of the outer surface of the particles was 2.9 times that of the central region. XRD showed that the retention rate of characteristic peaks of creatine monohydrate crystal form was 86.5%, and the total area of ​​characteristic peaks of preformed creatine organic acid salts was 7.2%. In the reconstitution test, 5 g of creatine was added to 200 mL of water, and no obvious clumping was observed within 90 seconds. The undissolved residue rate was 4.4% after 2 minutes, and the pH of the reconstituted solution was 4.12. After 30 days of sealed storage at 40℃ and 75% relative humidity, the increase in creatinine was 0.13%.

[0093] This embodiment shows that when the mass ratio of malic acid to citric acid is adjusted to 1:0.6 and the total amount of composite organic acid is within the range defined in the claims, it is still possible to form low water activity composite microparticles enriched on the outer surface of the organic acid, and achieve better dissolution and stability effects.

[0094] Example 3

[0095] Compared with the original experimental scheme, this embodiment controls the total amount of the composite organic acid components within the range of 6% to 14% as defined in the claims, so that the embodiment fully falls within the protection scope of the present invention.

[0096] 8 kg of creatine monohydrate raw material that could pass through a 200-mesh sieve was weighed, sieved, and then dried in a nitrogen-circulating drying oven at 42°C for 2 hours to obtain pretreated creatine powder. The moisture content was measured to be 0.38%, and the water activity was 0.16.

[0097] Pretreated creatine powder was subjected to low-temperature airflow milling under a carbon dioxide drying gas protection environment. The gas dew point was -28℃, the milling pressure was 0.72MPa, the classifier speed was 6100r / min, and the material outlet temperature was 24℃. The resulting ultrafine creatine primary particles had a D50 of 4.7μm, a D90 of 11.8μm, and a retention rate of 93.1% for the characteristic peaks of creatine monohydrate crystal form.

[0098] 0.448 kg of L-malic acid and 0.672 kg of anhydrous citric acid were weighed out at a mass ratio of 1:1.5, and the total amount of the composite organic acid components was 14% of the mass of the ultrafine creatine particles. The malic acid and citric acid were premixed and then subjected to low-temperature pulverization, with the material temperature not exceeding 20℃ during the pulverization process, to obtain ultrafine composite organic acid powder. The D50 of this ultrafine composite organic acid powder was measured to be 7.2 μm, and the D90 was 18.5 μm.

[0099] Ultrafine creatine primary particles and ultrafine composite organic acid powder are added to a mechanical fusion device. Cooling water at 15°C is circulated through the device jacket to control the material temperature between 18°C ​​and 23°C. The mechanical fusion process takes 25 minutes, with a rotor speed of 1800 r / min. During this process, the ultrafine composite organic acid powder is embedded or adsorbed onto the outer surface of the ultrafine creatine primary particles under shearing, compression, and collision, forming coated primary composite particles.

[0100] The coated primary composite particles were then transferred to a low-temperature fluidized bed granulator, where dry air with a dew point of -30°C was introduced. Granulation was carried out at 25°C for 20 minutes, followed by drying and stabilization at 38°C to obtain porous secondary composite microparticles. The resulting product had a D50 of 145 μm, a water content of 0.74%, a water activity of 0.20, an angle of repose of 36.5°, and a bulk density of 0.48 g / mL.

[0101] Test results showed that the total content of malic acid and citric acid within a 2μm range on the outer surface of the particles was 2.6 times that in the central region; XRD showed that the retention rate of characteristic peaks of creatine monohydrate crystal form was 84.2%, and the total area of ​​characteristic peaks of pre-formed creatine organic acid salts was 8.6%. In the reconstitution test, there was no obvious clumping within 90 seconds, the undissolved residue rate was 5.1% after 120 seconds, and the pH of the reconstituted solution was 3.52. After 30 days of accelerated storage, the increase in creatinine was 0.16%.

[0102] This embodiment demonstrates that the present invention is not limited to liquid coating liquid atomization deposition; malic acid and citric acid can also be enriched on the surface of creatine particles through low-temperature dry mechanical fusion. As long as the low water activity, low temperature, and non-pre-salted state are controlled, composite microparticles with good dissolution efficiency and stability can still be obtained.

[0103] Example 4

[0104] 10 kg of creatine monohydrate raw material that could pass through a 200-mesh sieve was weighed, sieved, and vacuum dried to obtain pretreated creatine powder with a moisture content of 0.47% and a water activity of 0.20. Low-temperature airflow milling was then performed at a milling pressure of 0.60 MPa, a classifier speed of 5000 r / min, and a material outlet temperature of 22℃ to obtain ultrafine creatine primary particles with a D50 of 6.1 μm and a D90 of 14.1 μm.

[0105] 0.35 kg of L-malic acid and 0.28 kg of anhydrous citric acid were weighed out at a mass ratio of 1:0.8, with the total amount of the composite organic acid component being 6.3% of the mass of the ultrafine creatine particles. Fluidized bed atomization deposition was performed using an ethanol-water low water activity coating solution with a solid content of 18% and a water activity of 0.34. The fluidized bed material temperature was controlled at 17–22℃, the relative humidity was 22%, and the spraying rate was 2 g / min per kilogram of ultrafine creatine particles.

[0106] After coating, porous secondary composite microparticles were obtained through low-temperature gas-solid shear granulation and drying stabilization. The resulting product had a D50 of 156 μm, a water content of 0.92%, a water activity of 0.23, and an angle of repose of 35.1°. Raman imaging showed a surface enrichment factor of 2.4; XRD showed that the retention rate of characteristic peaks of creatine monohydrate crystal form was 89.6%, and the total area of ​​characteristic peaks of pre-formed creatine organic acid salts was 4.9%. In the reconstitution test, the undissolved residue rate was 6.2% after 2 minutes, the pH of the reconstitution solution was 4.46, and the increase in creatinine after 30 days of accelerated storage was 0.10%.

[0107] This embodiment shows that when the total amount of the compound organic acid is near the lower limit of the claim, although the pH of the preparation solution is slightly higher and the undissolved residue rate is slightly higher than that of Example 1, it is still significantly better than ordinary creatine monohydrate and uncoated ultrafine creatine. This indicates that the present invention can achieve essentially the same technical effect in a wide range of organic acid dosages.

[0108] Comparative Example 1: Regular 200-mesh creatine monohydrate

[0109] A raw material of creatine monohydrate that could pass through a 200-mesh sieve was weighed out and used directly as Comparative Example 1 without low water activity pretreatment, low temperature airflow ultrafine grinding, organic acid interface coating, or secondary particle construction.

[0110] Tests showed that Comparative Example 1 had a D50 of 72.5 μm, a water content of 10.4%, and a water activity of 0.62. 5.00 g of creatine was weighed and added to 200 mL of water at 25°C with stirring. After 30 seconds, noticeable floating powder appeared; after 60 seconds, numerous aggregated particles appeared; after 90 seconds, significant sedimentation was observed at the bottom of the container; and after 120 seconds, filtration revealed an undissolved residue rate of 31.8%. The pH of the reconstituted solution was 6.78. Due to the absence of an organic acid interface layer, it does not exhibit in-situ salt formation induced by a localized acidic environment.

[0111] This comparative example illustrates that although ordinary 200-mesh creatine monohydrate has stable raw materials and low cost, its wetting and dissolution efficiency is poor when used in high-dose preparations, which cannot meet the needs of rapid preparation.

[0112] Comparative Example 2: Creatine was ultra-finely pulverized using only low-temperature airflow.

[0113] 10 kg of creatine monohydrate raw material that can pass through a 200-mesh sieve was weighed and processed according to the low water activity pretreatment and low temperature airflow pulverization steps in Example 1 to obtain ultrafine creatine powder, but without adding malic acid and citric acid, and without performing interface coating and secondary particle construction.

[0114] The obtained ultrafine creatine powder had a D50 of 5.4 μm, a D90 of 13.5 μm, a water content of 0.46%, and a water activity of 0.19. Reconstitution tests showed that the sample initially floated significantly after being added to water, with some ultrafine powder forming a floating layer. Even after stirring for 60 seconds, small clumps remained, and the undissolved residue rate after 120 seconds was 18.6%. The angle of repose was 47.2°, indicating poor powder flowability. After 30 days of accelerated storage, the increase in creatinine was 0.06%.

[0115] This comparative example illustrates that although the simple low-temperature airflow ultrafine pulverization increases the specific surface area of ​​creatine, the ultrafine powder is prone to floating and re-agglomeration when it comes into contact with water, and the powder fluidity decreases, which cannot fully solve the problem of wetting and dispersion in the initial stage of preparation.

[0116] Comparative Example 3: 200 mesh creatine mixed with malic acid and citric acid in a common dry mixture

[0117] Weigh out 10 kg of creatine monohydrate, 0.55 kg of L-malic acid, and 0.55 kg of anhydrous citric acid, which can pass through a 200-mesh sieve. Mix them in a conventional V-type manner according to the same organic acid ratio and dosage as in Example 1. The mixing time is 20 minutes. No low-temperature airflow ultrafine grinding, interface coating, or secondary particle construction is performed.

[0118] The obtained dry mixture still primarily contained creatine particles of 200 mesh size, with organic acid particles randomly mixed with creatine particles. Raman microscopy revealed that the total signal intensity of malic acid and citric acid within a 2 μm radius of the particle surface was not significantly different from that in the central region, with a surface enrichment coefficient of only 1.1. Reconstitution testing showed that the acidic components dissolved quickly after the sample was added to water, but creatine particles still deposited significantly, with an undissolved residue rate of 23.9% after 120 seconds. The pH of the reconstitution solution was 3.92. After 30 days of accelerated storage, due to localized hygroscopic agglomeration of the dry mixture, the increase in creatinine was 0.24%.

[0119] This comparative example shows that simply mixing ordinary 200-mesh creatine with malic acid and citric acid can lower the overall pH of the preparation solution, but it cannot form an organic acid interface layer on the surface of the creatine particles, nor can it significantly improve the wetting and dissolution efficiency of the creatine particles themselves.

[0120] Comparative Example 4: Ultrafine Creatine with Malic Acid and Citric Acid (Common Dry Mixture)

[0121] Weigh 10 kg of the ultrafine creatine granules prepared according to Example 1, weigh 0.55 kg of L-malic acid and 0.55 kg of anhydrous citric acid, and place the three in a V-type mixer and dry mix for 30 minutes without fluidized bed atomization deposition or mechanical fusion treatment, or low-temperature gas-solid shear granulation.

[0122] The obtained sample had a creatine D50 of 5.6 μm, and the organic acid particles and creatine particles were physically mixed, with a surface enrichment coefficient of 1.3. XRD showed that the creatine monohydrate crystal form retention rate was 90.5%, and the total area of ​​the characteristic peaks of the pre-formed creatine organic acid salt was 4.2%. In the reconstitution test, the sample initially floated significantly, with some acid particles dissolving first, followed by the formation of fine agglomerates from the ultrafine creatine powder. The undissolved residue rate after 120 seconds was 12.7%. The angle of repose was 45.6°, indicating poor powder flowability. After 30 days of accelerated storage, the creatinine increase was 0.21%.

[0123] This comparative example illustrates that although ultrafine grinding and dry mixing with organic acids can improve creatine dissolution to some extent, the lack of organic acid interface enrichment and coating and porous secondary particle structure still results in problems such as poor powder flowability, floating and agglomeration upon contact with water, high residual rate, and insufficient hygroscopic stability.

[0124] Comparative Example 5: Creatine organic acid salt sample dried after pre-liquid phase salt formation

[0125] Weigh out 10 kg of creatine monohydrate, 0.55 kg of L-malic acid, and 0.55 kg of anhydrous citric acid. Add an appropriate amount of purified water and stir at 45°C to ensure that the creatine and organic acids come into full contact and form creatine organic acid salts as much as possible. After concentrating the reaction solution, spray dry it to obtain pre-salt-type creatine organic acid salt powder.

[0126] The pH of the prepared solution was 3.78, and the undissolved residue rate after 120 seconds was 4.8%, indicating that pre-salting does indeed improve dissolution performance. However, XRD testing showed that the retention rate of characteristic peaks of creatine monohydrate was only 42.6%, and the total area of ​​characteristic peaks of pre-formed creatine organic acid salts was 38.5%. After 30 days of accelerated storage, the increase in creatinine was 0.38%, significantly higher than in Examples 1-4. The powder also showed slight hygroscopic agglomeration, with an angle of repose of 41.3°.

[0127] This comparative example illustrates that while pre-liquid-phase salting can increase the dissolution rate, creatine undergoes treatment in a high-moisture and acidic environment, resulting in relatively poor dry powder storage stability and a significant increase in creatinine. This invention, through low-water-activity interface coating and rehydration-triggered in-situ salting, reduces the risk of creatine being in an acidic liquid phase or high-moisture state for extended periods during the dry powder stage, while maintaining high rehydration dissolution efficiency.

[0128] IV. Summary of Test Results for Examples and Comparative Examples

[0129] Table 1 shows the structural and powder performance test results of the examples and comparative examples.

[0130]

[0131] As shown in Table 1, Examples 1-4 all formed porous secondary composite microparticles with a D50 range of 120-220 μm, and the water activity was not higher than 0.30, and the angle of repose was not higher than 38°, indicating that the powder obtained by the present invention has good low water activity and flowability. The surface enrichment coefficient of Examples 1-4 was greater than 2.0, indicating that malic acid and citric acid were not simply dry-mixed, but enriched on the outer surface of creatine particles. The crystal form retention rate of creatine monohydrate in Examples 1-4 was not less than 80%, and the proportion of characteristic peaks of pre-formed organic acid salts was not higher than 10%, indicating that the product of the present invention is different from traditional pre-salted creatine salts.

[0132] Table 2 shows the results of the dissolution and storage stability tests for the examples and comparative examples.

[0133]

[0134] From Table 2, Figure 3 and Figure 5 As can be seen, in Examples 1-4, when 5g of creatine was added to 200mL of water, no obvious clumping occurred within 90 seconds, and the undissolved residue rate after 2 minutes was 3.6%-6.2%, significantly lower than that of ordinary 200-mesh creatine monohydrate, ultrafine creatine, ordinary creatine and organic acid dry mixture, and ultrafine creatine and organic acid ordinary dry mixture. The dissolution performance of Comparative Example 5 was similar to that of the Examples, but its creatinine increase reached 0.38%, significantly higher than that of the Examples, indicating that while pre-liquid-phase salting can improve the dissolution rate, it is detrimental to the stability of the dry powder. This invention, through a non-pre-salted low-water-activity interface coating structure, enables the product to have both high reconstitution and dissolution efficiency and low creatinine increase.

[0135] Combination Figure 3 The comparison of undissolved residue rates after 2 minutes shows that the undissolved residue rate of the embodiment of the present invention is reduced by more than 80% compared to ordinary 200-mesh creatine monohydrate, and by more than 65% compared to creatine only through ultrafine grinding. Combined with... Figure 4 The comparison of X-ray diffraction characteristic peaks shows that Example 1 of the present invention maintains similar characteristic peaks to the raw material creatine monohydrate, while the characteristic peaks of the organic acid salt in Comparative Example 5 are enhanced, indicating that the product of the present invention is not a large amount of pre-formed salt in the dry powder state. Combined with... Figure 5 The comparison of creatinine increase shown in the figure indicates that the embodiment of the present invention is significantly better than the pre-liquid phase salt formation sample, which shows that the present invention does not simply pursue acid solubilization, but achieves a balance between dry powder stability and instantaneous dissolution after reconstitution.

[0136] In summary, this invention, through low water activity pretreatment, low-temperature airflow ultrafine grinding, organic acid interface enrichment and coating, and porous secondary particle construction, enables creatine to maintain a low water activity and a high crystal form retention rate in its dry powder state. During reconstitution, it rapidly wets and disintegrates, forming a localized acidic microenvironment at the particle-water interface. This improves the reconstitution and dissolution efficiency of creatine, reduces clumping and residue at the bottom of the container, and lowers the risk of creatine conversion to creatinine in acidic solubilization systems. Those skilled in the art can implement the technical solution of this invention without creative effort based on the above-mentioned raw materials, equipment, parameter ranges, and testing methods.

Claims

1. A method for preparing ultrafine pulverized creatine with improved solubility and absorption efficiency, characterized in that, Includes the following steps: S1. The creatine monohydrate raw material is screened, impurities are removed and dried to obtain pretreated creatine powder. S2. Under the protection of dry gas with a dew point not higher than -20℃, the pretreated creatine powder is subjected to air jet milling, and the material outlet temperature during the milling process is controlled not to be higher than 25℃ to obtain ultrafine creatine primary particles. The D50 of the ultrafine creatine primary particles is 3 to 8 μm and the D90 is not greater than 15 μm. S3. Malic acid and citric acid are mixed at a mass ratio of 1:(0.5 to 1.5) to obtain a composite organic acid component. The total amount of the composite organic acid component is 6% to 14% of the mass of the ultrafine creatine particles. The composite organic acid component is then made into a low water activity coating solution with a water activity not higher than 0.45, or into an ultrafine composite organic acid powder with a D90 not greater than 20 μm. S4. Under fluidized bed atomization deposition or dry mechanical fusion conditions with relative humidity not exceeding 25% and material temperature of 5-25℃, the composite organic acid components are deposited and enriched on the outer surface of the ultrafine creatine primary particles to form coated primary composite particles with a monohydrate creatine crystal core and a malic acid-citric acid interface layer. S5. The coated primary composite particles are subjected to low-temperature gas-solid shear granulation and drying stabilization treatment to form porous secondary composite microparticles composed of multiple coated primary composite particles.

2. The preparation method according to claim 1, characterized in that, In step S1, the creatine monohydrate raw material is creatine monohydrate powder that can pass through a 200-mesh sieve, or the creatine monohydrate raw material has a D50 of 60-80 μm; after sieving, agglomerated particles and foreign particles with a particle size greater than 90 μm are removed. And / or, in step S1, the drying is one of vacuum drying, dehumidifying hot air drying, or nitrogen circulation drying, the drying temperature is 30-45℃, the drying time is 1-4 hours, and the moisture content of the pretreated creatine powder after drying is 0.1%-0.6%.

3. The preparation method according to claim 1, characterized in that, In step S2, the drying gas is one of air, nitrogen or carbon dioxide, the airflow pulverizing pressure is 0.45 to 0.90 MPa, the classifier speed is 3000 to 8000 r / min, and the temperature inside the pulverizing chamber is 5 to 20°C. And / or, in step S2, the specific surface area of ​​the ultrafine creatine primary particles is 0.8 to 2.5 m² / g, and the particles enter step S4 within 20 minutes after pulverization, in order to reduce the hygroscopic agglomeration of the ultrafine creatine primary particles. And / or, in step S2, the retention rate of the X-ray diffraction characteristic peaks of the monohydrate creatine crystal form in the ultrafine creatine primary particles is not less than 80%.

4. The preparation method according to claim 1, characterized in that, In step S3, the mass ratio of malic acid to citric acid is 1:(0.8-1.2), and the total amount of the composite organic acid components is 8%-12% of the mass of the ultrafine creatine particles. And / or, in step S3, the low water activity coating solution is composed of malic acid, citric acid, ethanol and water, wherein the mass ratio of ethanol to water is (60-90):(10-40), and the solid content of the low water activity coating solution is 10%-35%. And / or, in step S3, the ultrafine composite organic acid powder is obtained by low-temperature pulverization, wherein the D50 of the ultrafine composite organic acid powder is 3-10μm, the D90 is not greater than 20μm, and the material temperature during the pulverization process is not higher than 25℃.

5. The preparation method according to claim 1, characterized in that, In step S4, the total content of malic acid and citric acid in the outer surface of the coated primary composite particles within a depth of 2μm is more than twice the total content of malic acid and citric acid in the central region of the particles, and the total amount of preformed creatine malate and creatine citrate in the dry powder state is not higher than 10% of the total amount of creatine. And / or, in step S4, when fluidized bed atomization deposition is used, the low water activity coating liquid is sprayed into the fluidized bed containing the ultrafine creatine primary particles, the spraying rate is controlled at 1 to 8 g / min per kilogram of ultrafine creatine primary particles, the atomization gas temperature is 5 to 20°C, and a dry gas with a dew point not higher than -20°C is introduced simultaneously. When dry mechanical fusion is used, the ultrafine creatine primary particles and the ultrafine composite organic acid powder are placed in a mechanical fusion device and subjected to shearing, compression and collision treatment at 5-25°C, so that malic acid and citric acid are embedded or adsorbed on the outer surface of the ultrafine creatine primary particles. And / or, in step S4, the malic acid-citric acid interface layer covers more than 70% of the outer surface area of ​​the ultrafine creatine primary particles, and the malic acid and citric acid are distributed on the outer surface of the creatine monohydrate crystal core in the form of free acid, hydrogen bond complex, or locally ionized state.

6. The preparation method according to claim 1, characterized in that, In step S5, the porous secondary composite microparticles have a D50 of 120–220 μm, a water content of no more than 1.5%, and a water activity of no more than 0.

30. And / or, in step S5, the low-temperature gas-solid shear granulation is carried out at 10-30°C, and the bulk density of the porous secondary composite microparticles obtained after granulation is 0.35-0.75 g / mL, and the angle of repose is not greater than 38°. And / or, in step S5, the drying and stabilization treatment is one of vacuum low-temperature drying, dehumidifying airflow drying, or fluidized bed low-temperature drying, with a drying temperature of 25-45°C, until the moisture content of the porous secondary composite particles is 0.3%-1.2% and the water activity is 0.10-0.

28.

7. The preparation method according to claim 1, characterized in that, When the porous secondary composite microparticles are added at 5g to 200mL of water at 20-25℃ and stirred or shaken, no obvious clumping occurs within 90 seconds; when 5g of creatine is added to 200mL of water at 20-25℃ and stirred at 300r / min for 120 seconds and then filtered through a 100-mesh sieve, the undissolved residue rate is no higher than 7.0% after 2 minutes. And / or, after adding 5g of the porous secondary composite microparticles to 200mL of water at 20-25℃ and reconstitute, the pH of the resulting reconstituted solution is 3.2-4.8; And / or, after the porous secondary composite microparticles are sealed and stored at 40°C and 75% relative humidity for 30 days, the increase in creatinine is no higher than 0.20%.

8. A micro-powdered creatine with improved solubility and absorption efficiency, characterized in that, The low water activity interface-coated ultrafine creatine composite microparticles are prepared by the preparation method according to any one of claims 1 to 7. The low water activity interface-coated ultrafine creatine composite microparticles include a plurality of coated primary composite particles. The coated primary composite particles include a creatine monohydrate crystal core and a malic acid-citric acid interface layer enriched on the outer surface of the creatine monohydrate crystal core. The low water activity interface-coated ultrafine creatine composite microparticles have a D50 of 120-220 μm, a water content of not more than 1.5%, and a water activity of not more than 0.

30.

9. The ultrafine pulverized creatine according to claim 8, characterized in that, The low water activity interface-coated ultrafine creatine composite microparticles contain 84%–92% creatine monohydrate by mass, 6%–14% malic acid and citric acid by mass, and the mass ratio of malic acid to citric acid is 1:(0.5–1.5). And / or, in the coated primary composite particles, the retention rate of the X-ray diffraction characteristic peaks of the creatine monohydrate crystal form is not less than 80%, and the total amount of preformed creatine malate and creatine citrate in the dry powder state is not more than 10% of the total amount of creatine. And / or, the total content of malic acid and citric acid within a 2μm depth range on the outer surface of the coated primary composite particles is more than twice the total content of malic acid and citric acid in the central region of the particles.

10. A sports nutrition composition, characterized in that, The composition includes the ultrafine creatine as described in any one of claims 8-9, and one or more of sweeteners, acidulants, flavorings, electrolytes, amino acids, vitamins, dietary fiber, or anti-caking agents; the ultrafine creatine in the sports nutrition composition comprises 50% to 99% by mass.

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