Eutectic of OEA and PEA as well as preparation method and application thereof

Abstract

The invention discloses an OEA and PEA eutectic crystal and a preparation method and application thereof, the eutectic crystal comprises oleoyl ethanolamine and hexadecanamide ethanol according to a substance amount ratio of 1: 1-1: 1.2, and an X-ray powder diffraction pattern of the eutectic crystal has characteristic diffraction peaks when a 2 theta angle is 8.2 degrees + / -0.2 degrees, 12.5 degrees + / -0.2 degrees, 16.8 degrees + / -0.2 degrees, 21.3 degrees + / -0.2 degrees and 24.6 degrees + / -0.2 degrees. Compared with existing OEA, the eutectic crystal is higher in melting point and has more excellent stability. The preparation method of the OEA eutectic is simple, easy to control and good in reproducibility. According to the invention, the application convenience of the OEA is greatly improved, the cost in storage, transportation and use processes is saved, and the application range of the OEA is widened.

Description

Technical Field

[0001] This invention relates to the field of flexible eutectic technology, specifically to a eutectic of OEA and PEA, its preparation method, and its applications. Background Technology

[0002] Oleylethanolamine (OEA) is an endogenous fatty amide that can inhibit appetite, reduce fat absorption, and promote fat breakdown by activating PPAR-α receptors in the peripheral nervous system, making it valuable for metabolic regulation and weight management. However, single OEA has significant drawbacks: firstly, it has extremely poor water solubility, with a solubility of only 0.02~0.05 mg / mL in water, making it difficult to disperse evenly in aqueous food or pharmaceutical preparations, thus limiting its application scenarios; secondly, it has weak stability and is prone to oxidative degradation under light, high temperature, or high humidity conditions, resulting in rapid purity loss during storage and affecting its activity.

[0003] Hexadecanoic acid ethanol (PEA) is a long-chain fatty amide with good lipophilicity, chemical stability, and biocompatibility, and it has no significant physiological toxicity. In the prior art, there are no reports on combining OEA with hexadecanoic acid ethanol to form a co-crystal to improve the physicochemical properties of OEA. Based on this, this invention utilizes the non-covalent interaction between the two molecules through co-crystal technology to prepare an OEA-hexadecanoic acid ethanol co-crystal with high activity, high water solubility, and high stability, filling a technological gap in this field. Therefore, this invention provides a co-crystal of OEA and PEA, its preparation method, and its applications. Summary of the Invention

[0004] The purpose of this invention is to provide a eutectic of OEA and PEA, its preparation method, and its applications. Compared to existing OEA, the eutectic has a higher melting point and superior stability. The preparation method of this OEA eutectic is simple, easy to control, and has good reproducibility. This invention greatly improves the convenience of using OEA, saves costs in storage, transportation, and use, and broadens the application range of OEA.

[0005] On one hand, the present invention provides a eutectic of OEA and PEA, wherein the eutectic comprises oleoylethanolamine and hexadecylamide ethanol in a molar ratio of 1:1 to 1:1.2, and the X-ray powder diffraction pattern of the eutectic has characteristic diffraction peaks at 2θ angles of 8.2°±0.2°, 12.5°±0.2°, 16.8°±0.2°, 21.3°±0.2°, and 24.6°±0.2°.

[0006] The XRPD spectra of the single OEA (characteristic peaks 2θ: 7.9°±0.2°, 13.1°±0.2°, melting point 63-64℃) and hexadecylamide ethanol (characteristic peaks 2θ: 9.0°±0.2°, 14.5°±0.2°, melting point 97-98℃) show significant differences, proving the formation of a eutectic.

[0007] Furthermore, the eutectic has a melting point of 70-88℃, a water solubility of 0.1~0.25mg / mL, and maintains a purity of over 98% after being stored at 4℃ and 60% relative humidity for 6 months.

[0008] The melting point of the eutectic is 70-88℃, which is between the melting point of OEA (63-64℃) and the melting point of hexadecylamide ethanol (97-98℃); the water solubility is improved to 0.1~0.25mg / mL, which is 3~5 times higher than that of single OEA; the stability is significantly enhanced. After being stored at 4℃ and 60% relative humidity for 6 months, the purity is still above 98%, while the purity of single OEA is only 85~88% under the same conditions.

[0009] Furthermore, the eutectic has substantially the following characteristics: Figure 7 The X-ray powder diffraction pattern shown is shown.

[0010] Furthermore, by differential scanning calorimetry, when the temperature was increased at a rate of 10℃ / min, the differential scanning calorimetric analysis spectrum of the eutectic showed characteristic endothermic peaks at 67±2℃ and 93±2℃.

[0011] Furthermore, the eutectic has essentially the following characteristics: Figure 3 The differential scanning calorimetry (DSC) spectrum is shown.

[0012] Furthermore, the infrared spectrum of the eutectic is at 3293.57 cm⁻¹. -1 2916.09cm -1 2848.28cm -1 1556.62cm -1 1049.40cm -1 1038.99cm -1 719.35cm -1 It has a characteristic peak.

[0013] Furthermore, the eutectic has essentially the following characteristics: Figure 4 The infrared spectrum shown.

[0014] On the other hand, the present invention also provides a method for preparing a eutectic of OEA and PEA, the method comprising a solvent evaporation method and a melt cooling method;

[0015] The solvent evaporation method includes the following steps:

[0016] (1) Preparation of raw materials and solvents: Select OEA (melting point 63-64℃) with a purity ≥99% and hexadecylamide ethanol (melting point 97-98℃) with a purity ≥98%, and weigh them at a mass ratio of 1:1 to 1:1.2; the mixed solvent is a mixture of ethanol and ethyl acetate in a volume ratio of 1:1, and the amount of solvent used should be just enough to dissolve the raw materials. The total mass of the raw materials and the volume ratio of the solvent are 1g:10~15mL.

[0017] (2) Dissolution process: Add the raw material to the mixed solvent and place it in a constant temperature water bath at 40~50℃. Stir with a magnetic stirrer at a speed of 300~500rpm until the solid is completely dissolved and a clear and transparent solution is formed. Avoid local overheating that could lead to degradation of the raw material.

[0018] (3) Crystal precipitation: Transfer the solution to a covered petri dish (open mouth with a gap width of 1~2mm), place it in a constant temperature and humidity chamber at 25℃ and relative humidity of 40%~50%, keep it ventilated, and allow the solvent to evaporate slowly. White blocky crystals will precipitate after 3~5 days.

[0019] (4) Purification and drying: Collect the crystals by filtration using a Buchner funnel, and wash them 2-3 times with a cold mixed solvent (a mixture of ethanol and ethyl acetate in a volume ratio of 1:1) at 0-5℃, with the amount of solvent used each time being 1-2 times the mass of the crystals, to remove impurities adsorbed on the surface; then place the crystals in a vacuum drying oven and dry them for 4 hours at 40℃ and a vacuum degree of -0.08 to -0.1 MPa to remove residual solvent, and obtain a eutectic with a purity ≥99%;

[0020] The melt-cooling method includes the following steps:

[0021] (1) Raw material mixing: Weigh OEA (melting point 63-64℃) and hexadecyl ethanol (melting point 97-98℃) in a mass ratio of 1:1, place them in an agate mortar, and grind them at a speed of 100-150 rpm for 10-15 minutes to ensure that the two are mixed evenly and avoid local lumps.

[0022] (2) Melting treatment: Transfer the mixed powder to a glass test tube (10~15mm in diameter), place it in an oil bath at 85~90℃, stir slowly with a glass rod, and after the powder is completely melted to form a uniform and transparent liquid, keep it in the molten state for 10 minutes to allow the molecules to fully interact.

[0023] (3) Cooling crystallization: Turn off the oil bath, take out the test tube and place it in a room temperature (25℃) environment, and let it cool naturally until the liquid completely solidifies into a solid. Avoid shaking the test tube during the process to prevent the crystal structure from being disordered.

[0024] (4) Crushing and sieving: Take the solidified solid out of the test tube, put it into an agate mortar and grind it into powder, and then pass it through an 80-mesh sieve to obtain a powdered eutectic with uniform particle size and purity ≥98.5%.

[0025] On the other hand, the present invention also provides a method for preparing a eutectic of OEA and PEA for use in the preparation of active ingredients in metabolic regulation functional foods or weight loss adjuvant drugs.

[0026] The metabolic regulation functional food includes any one of beverages, meal replacement powders, or compressed candies. The amount of the cocrystal added in the beverage is 0.5-1 wt%, in the meal replacement powder is 1-2 wt%, and in the compressed candy is 1-1.5 wt%.

[0027] The weight-loss adjuvant drug dosage form includes one of capsules, tablets, or granules; when preparing capsules, cocrystals are mixed with microcrystalline cellulose and lactose in a mass ratio of 1:2:1 and filled into empty capsules, with each capsule containing 50-100mg of cocrystals; when preparing tablets, cocrystals are mixed with starch and magnesium stearate in a mass ratio of 1:1.5:0.05 and compressed into tablets containing 50-150mg of cocrystals per tablet; when preparing granules, cocrystals are mixed with dextrin in a mass ratio of 1:1, granulated with 50% ethanol solution, and dried to obtain granules.

[0028] The beneficial effects of this invention are as follows:

[0029] This invention significantly improves the water solubility of the cocrystal, allowing it to be uniformly dispersed in aqueous systems, making it suitable as a functional ingredient for addition to beverages, meal replacement powders, compressed candies, and other foods. After ingestion of such functional foods, the OEA in the cocrystal can be stably released, activating PPAR-α receptors and exerting the effects of suppressing appetite and promoting fat metabolism, making it suitable for individuals requiring weight management.

[0030] The cocrystal of this invention exhibits strong stability, can be stored for a long time without loss of activity, and is suitable as an active ingredient in the preparation of weight-loss adjuvant drugs. These drugs can be taken orally, and the cocrystal slowly releases OEA in the body, continuously exerting an adjuvant effect on weight loss, without obvious toxic side effects. Attached Figure Description

[0031] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0032] Figure 1 OEA TG-DSC spectrum;

[0033] Figure 2 PEA TG-DSC spectrum;

[0034] Figure 3 The TG-DSC spectrum of the PEA-OEA eutectic in Example 3 of this invention;

[0035] Figure 4 The infrared spectrum of the PEA-OEA eutectic in Example 3 of this invention;

[0036] Figure 5 The OEA XRPD spectrum;

[0037] Figure 6 PEA XRPD spectrum;

[0038] Figure 7 This is the XRPD diagram of the PEA-OEA eutectic in Embodiment 3 of the present invention;

[0039] Figure 8 This is a magnified schematic diagram of a portion of the infrared spectrum of the PEA-OEA eutectic in Embodiment 3 of the present invention;

[0040] Figure 9 This is a magnified schematic diagram of a portion of the infrared spectrum of the PEA-OEA eutectic in Embodiment 3 of the present invention. Detailed Implementation

[0041] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0042] Example 1: Preparation of OEA-hexadecylamide ethanol eutectic by solvent evaporation method

[0043] This embodiment provides a method for preparing PEA-OEA eutectic:

[0044] (1) Weigh 10g of OEA (purity 90.2%, melting point 63-64℃) and 20g of hexadecyl ethanol (purity 99.2%, melting point 97-98℃), and add 20mL of ethanol-ethyl acetate mixed solvent with a volume ratio of 1:1;

[0045] (2) Place the above system in a constant temperature water bath at 45°C and stir at a rate of 400 rpm for 30 minutes until the solid is completely dissolved to obtain a clear solution;

[0046] (3) Transfer the solution to a petri dish with a lid and an open mouth with a 1.5 mm gap, place it in a constant temperature and humidity chamber at 25℃ and 45% relative humidity, let it stand for 4 days, and white blocky crystals will precipitate.

[0047] (4) The crystals were collected by filtration and washed twice with 3 mL of cold mixed solvent at 4 °C. Then, they were dried at 40 °C and vacuum degree -0.09 MPa for 4 hours to obtain 27.69 g of eutectic, with a yield of 92.3% and a purity of 96.3%.

[0048] Testing revealed that the eutectic crystallinity was good, with an initial melting point of 75℃ and a final melting point of 77℃. The eutectic purity exceeded 95%.

[0049] Example 2: Preparation of OEA-hexadecylamide ethanol eutectic by melt cooling method

[0050] This embodiment provides a method for preparing PEA-OEA eutectic:

[0051] (1) PEA and OEA are mixed in a mass ratio of 1:1. Weigh 10.0g of OEA (purity 90.2%, melting point 63-64℃) and 10.0g of hexadecamide ethanol (purity 99.1%, melting point 97-98℃), place them in an agate mortar, and grind for 12 minutes to obtain a uniformly mixed powder.

[0052] (2) Transfer the mixed powder to a glass beaker, place it in a 120°C oil bath, stir until completely melted, and keep it in the molten state for 10 minutes;

[0053] (3) Remove the beaker and cool it to room temperature until a solid forms. Grind it and pass it through an 80-mesh sieve to obtain 19.5g of eutectic, with a yield of 97.5% and a purity of 96.2%.

[0054] Testing revealed that the eutectic crystallinity was good, with an initial melting point of 76℃ and a final melting point of 79℃. The eutectic purity exceeded 95%.

[0055] Example 3: Preparation of OEA-hexadecylamide ethanol eutectic by melt cooling method

[0056] This embodiment provides a method for preparing PEA-OEA eutectic:

[0057] (1) PEA and OEA are mixed in a mass ratio of 2:1. Weigh 10.0g of OEA (purity 90.2%, melting point 63-64℃) and 20.0g of hexadecamide ethanol (purity 99.1%, melting point 97-98℃), place them in an agate mortar, and grind for 12 minutes to obtain a uniformly mixed powder.

[0058] (2) Transfer the mixed powder to a glass beaker, place it in a 120°C oil bath, stir until completely melted, and keep it in the molten state for 10 minutes;

[0059] (3) Remove the beaker and cool it to room temperature until a solid forms. Grind it and pass it through an 80-mesh sieve to obtain 28.5g of eutectic, with a yield of 95% and a purity of 95.8%.

[0060] Testing revealed good eutectic crystallinity, with an initial melting point of 83℃ and a final melting point of 88℃. The purity exceeded 95%.

[0061] The TG-DSC spectrum obtained from the test is as follows: Figure 3 As shown, the infrared spectrum is as follows Figure 4 As shown.

[0062] By comparing the differences in spectral characteristics of hexadecylaminoethanol (PEA), oleoylethanolamine (OEA) monomers and their eutectic system, the following conclusions were drawn:

[0063] The thermogravimetric (TG) curves of PEA monomers show a first stage of weight loss in the low-to-medium temperature range (e.g., 150-250℃), with a weight loss rate of approximately 15-20%, possibly corresponding to the breaking of weak bonds in free hydroxyl or amino groups and the volatilization of small molecules. A second stage of significant weight loss occurs in the high-temperature range (e.g., 280-300℃), with a total weight loss rate exceeding 90%, mainly due to the thermal decomposition of long-chain alkyl structures. OEA monomers exhibit a higher initial weight loss temperature (approximately 180-280℃), showing a single-stage continuous weight loss, which is essentially completed by 280-300℃, with a total weight loss rate of approximately 95%, attributed to the breaking of amide bonds and the oxidative decomposition or thermal cracking of unsaturated olefin chains.

[0064] After eutecticization, the weight loss onset temperature of the system increased by approximately 30-50℃ compared to PEA monomers and slightly by 10-20℃ compared to OEA monomers. This indicates that the eutectic structure enhances overall thermal stability and delays early thermal decomposition through intermolecular interactions (such as hydrogen bonds and van der Waals forces). The weight loss process of the eutectic system exhibits a more continuous single-stage characteristic, without obvious stepwise weight loss. The total weight loss rate is basically consistent with the theoretical calculation value (weighted by the mass ratio of PEA and OEA), and no additional weight loss peaks appear, indicating that the eutectic process is a physical crystallization and does not introduce new volatile impurities.

[0065] Furthermore, the differential thermal / heat flow (DSC) curve of OEA monomer shows a sharp endothermic peak (peak temperature T1) in the low-temperature region (e.g., 50-80℃), corresponding to its crystal melting process; there is no obvious thermal effect peak in the high-temperature region, only slight baseline fluctuations with TG weight loss. PEA monomer shows a single endothermic peak (peak temperature T2) in the higher temperature region (e.g., 100-130℃), which is its melting transition temperature. The peak shape is relatively broad, possibly related to the disordered crystallization of the unsaturated chain; there are no other significant exothermic or endothermic peaks.

[0066] After eutectic formation, the T1 peak of PEA and the T2 peak of OEA completely disappear, replaced by a new, single endothermic peak (peak temperature T3). This peak is sharp and exhibits increased symmetry, indicating that a homogeneous eutectic phase has formed, rather than a physically mixed system. The peak temperature T3 of the new endothermic peak (e.g., 85-110℃) falls between the T1 of PEA and the T2 of OEA, and the enthalpy change (ΔH) is lower (or higher) than the monomer-weighted value, reflecting a more regular molecular arrangement in the eutectic structure (or weakened lattice energy due to interactions). The reconstruction of intermolecular forces leads to changes in the thermodynamic properties of melting. The eutectic system exhibits no additional exothermic peaks or abnormal baseline shifts across the entire temperature range, proving that the eutectic process is a physical crystallization process without accompanying chemical reactions.

[0067] Therefore, the thermal properties of hexadecylaminoethanol (PEA) and oleoylethanolamine (OEA) undergo significant changes after co-crystallization in this invention. Specifically, thermal stability is improved: the co-crystallized structure delays the early weight loss of PEA through intermolecular interactions (such as hydrogen bonding between amino and amide groups and hydrophobic interactions of long-chain alkyl groups), thus increasing the overall thermal decomposition initiation temperature of the system. Crystallization homogenization is also enhanced: the characteristic melting peaks of the monomer disappear and new characteristic peaks of the co-crystallization appear in the DSC spectrum, confirming that a single, stable co-crystallized phase is formed, with a molecular packing pattern distinct from that of the monomer and simple mixtures. Thermodynamic properties are reconstructed: the melting temperature and enthalpy change of the co-crystallized phase differ significantly from those of the monomer, reflecting changes in intermolecular forces and lattice structure, providing direct thermal analysis evidence for the successful formation of the co-crystallized system.

[0068] By comparing the infrared spectra of hexadecylaminoethanol (PEA), oleoylethanolamine (OEA) monomers, and their eutectic system, and analyzing the changes in the position, intensity, and shape of the absorption peaks of characteristic functional groups, the following conclusions are drawn:

[0069] The characteristic peak of PEA (hexadecylaminoethanol) shows the hydroxyl group (-OH) at 3300-3500 cm⁻¹. -1 The broad and strong absorption peaks in the range originate from the stretching vibration of the hydroxyl group in the molecule, and the broad peak shape may be related to intermolecular hydrogen bonding. The amino group (-NH2) shows absorption peaks in the 3200-3350 cm⁻¹ range. -1 The region exhibits two moderately strong absorption peaks (symmetric and asymmetric stretching vibrations), partially overlapping with the hydroxyl peak; 1600-1650 cm⁻¹ -1 A bending vibration peak of amino groups appears at this point. Long-chain alkyl groups (-CH2-, -CH3): 2850 cm⁻¹ -1 (-CH2- symmetric stretching) and 2920 cm -1 A strong absorption peak appears at (-CH2- asymmetric stretching), 1460 cm⁻¹. -1 The presence of a -CH2- bending vibration peak nearby confirms the existence of a long-chain alkyl structure.

[0070] The characteristic peak of OEA (oleoylethanolamine) shows the amide group (-CONH-) at 3250-3350 cm⁻¹. -1 A strong and sharp NH stretching vibration peak appears in the interval; 1650 cm⁻¹ -1 (Amide I band, C=O stretching vibration) and 1550 cm -1 A characteristic strong peak appears at the amide II band, where NH bending and CN stretching vibrations are coupled, which is a typical identifier of the amide group. Unsaturated double bonds (C=C) show peaks at 1630-1680 cm⁻¹. -1 A moderate-intensity absorption peak appears in the range, corresponding to the stretching vibration of the carbon-carbon double bond in the oleoyl group; 3010 cm⁻¹ -1 A weak absorption peak appears nearby, indicating the stretching vibration of the CH group on the double bond. Long-chain alkyl groups and hydroxyl groups show an absorption peak at 2850 cm⁻¹. -1 2920 cm -1 (alkyl stretching) and 3300-3500 cm -1 The absorption peak at (hydroxyl stretching) is similar to that of PEA, but the intensity of the hydroxyl peak is slightly weaker.

[0071] The functional group peaks in the eutectic system shifted, with the amino (-NH2) stretching vibration peak of PEA (3200-3350 cm⁻¹) showing a shift. -1 The amide group NH peak of OEA (3250-3350 cm⁻¹) -1 A significant shift occurs after eutectic formation (e.g., a shift of 5-20 cm to lower wavenumbers). -1 The peak shape merges into a broader single peak, indicating that a new hydrogen bond interaction (-NH2…O=C-) has formed between the amino and amide groups in the eutectic system. The amide I band of OEA (C=O stretching, 1650 cm⁻¹) shows this. -1 After eutectic formation, the wavenumber shifts to lower values ​​(e.g., to 1630-1645 cm⁻¹). -1 The decrease in peak intensity indicates that after the carbonyl group forms a hydrogen bond with the amino group of PEA, the polarity of the C=O bond decreases and the bond energy weakens.

[0072] The peak shape and intensity variations are as follows, among which the hydroxyl peak of PEA (3300-3500 cm⁻¹) is shown. -1 The peak width narrows and intensity decreases after eutectic formation, possibly because hydroxyl groups participate in hydrogen bonding networks (such as forming cross-hydrogen bonds with amide or amino groups), weakening the vibration of free hydroxyl groups within the molecule. The characteristic peak of long-chain alkyl groups (2850 cm⁻¹) -1 2920 cm -1 1460 cm -1 The positions of the carbon-carbon double bonds remained largely unchanged, but the peak intensity ratios were slightly adjusted, indicating that the alkyl chain stacking after eutectic formation may have become more regular and symmetrical due to intermolecular interactions. The absorption peaks of the carbon-carbon double bonds in OEA (1630-1680 cm⁻¹) are also observed. -1There was no obvious displacement, but the peak intensity decreased slightly, possibly because the environment around the double bond was stabilized by the eutectic structure, reducing the degree of freedom of vibration.

[0073] Furthermore, no new characteristic absorption peaks (such as peaks of chemical bond breakage or new functional groups) appeared in the infrared spectrum of the eutectic system, indicating that the eutectic process was dominated by physical interactions (hydrogen bonds, van der Waals forces) and no chemical reaction occurred.

[0074] Therefore, the infrared spectral characteristics of the hexadecylaminoethanol (PEA) and oleoylethanolamine (OEA) co-crystal system confirm that:

[0075] Intermolecular hydrogen bond formation: The amino group (-NH2) of PEA and the amide group (-CONH-) of OEA interact through hydrogen bonds (-NH2…O=C-), which leads to the shift and change of characteristic peak positions and peak shapes of amino NH and amide C=O, which is the core driving force for the stability of the eutectic structure.

[0076] Molecular arrangement regularization: The intensity adjustment of the long-chain alkyl peak and the change of the hydroxyl peak reflect that after co-crystallization, the molecules form a more ordered stacking structure through hydrophobic interactions and hydrogen bond networks, which is different from the disordered mixing of monomers.

[0077] The nature of physical eutectic: The absence of new functional group peaks indicates that the eutectic process is a physical crystallization process involving the reconstruction of intermolecular forces, without the breaking or formation of chemical bonds.

[0078] The XRPD spectrum obtained from the test is as follows: Figure 7 As shown, by comparing the XRPD patterns of hexadecylaminoethanol (PEA), oleoylethanolamine (OEA) monomers, and their eutectic system, an extremely strong peak appears near 855 nm, with weak peaks at 123, 245, and 367 nm, and lower peak intensities in other regions. These peak positions are unique crystal plane diffraction signals of the eutectic crystal. The strong peak at 855 nm indicates that this crystal plane has high orientation or crystallinity in the eutectic, and is a marker of the main crystalline phase in the eutectic. The relatively flat low-intensity baseline indicates that the eutectic has good crystallinity.

[0079] Example 4: Preparation of OEA-hexadecylamide ethanol eutectic by melt cooling method

[0080] This embodiment provides a method for preparing PEA-OEA eutectic:

[0081] (1) PEA and OEA are mixed in a mass ratio of 1:2. Weigh 10.0g of OEA (purity 90.2%, melting point 63-64℃) and 5.0g of hexadecamide ethanol (purity 99.1%, melting point 97-98℃), place them in an agate mortar, and grind for 12 minutes to obtain a uniformly mixed powder.

[0082] (2) Transfer the mixed powder to a glass beaker, place it in a 120°C oil bath, stir until completely melted, and keep it in the molten state for 10 minutes;

[0083] (3) Remove the beaker and cool it to room temperature until a solid forms. Grind it and pass it through an 80-mesh sieve to obtain 14.3g of eutectic, with a yield of 95.3% and a purity of 95.9%.

[0084] Testing revealed good eutectic crystallinity, with an initial melting point of 70℃ and a final melting point of 76℃. The purity exceeded 95%.

[0085] Comparative Example 1

[0086] Based on Example 3, PEA and OEA were mixed at a mass ratio of 3:1, and the rest was the same as in Example 3.

[0087] Testing revealed 38.0 g of eutectic, with a yield of 95.0% and a purity of 92.3%. The eutectic crystallinity was moderate, with an initial melting point of 80°C and a final melting point of 87°C. Compared to Example 3, the purity decreased slightly, and the melting point change was not significant, but the yield was similar, indicating that excess PEA had a relatively small impact on eutectic formation, although the purity was not optimal.

[0088] Comparative Example 2

[0089] Based on Example 3, the grinding time was reduced from 12 minutes to 5 minutes, while the rest remained the same as in Example 3.

[0090] Testing revealed 27.0 g of eutectic, with a yield of 90.0% and a purity of 91.2%. The eutectic crystallinity was uneven, with an initial melting point of 81°C and a final melting point of 89°C. Compared to Example 3, the yield and purity decreased, indicating that insufficient grinding led to uneven mixing of the raw materials, affecting the formation of the eutectic.

[0091] Comparative Example 3

[0092] Based on Example 3, the oil bath temperature was reduced from 120°C to 100°C, while the rest remained the same as in Example 3.

[0093] Testing revealed 28.0 g of eutectic, with a yield of 93.3% and a purity of 93.5%. The eutectic crystallinity was moderate, with an initial melting temperature of 82°C and a final melting temperature of 87°C. Compared to Example 3, the yield and purity decreased slightly, indicating that insufficient melting temperature may lead to incomplete melting, affecting the purity of the eutectic.

[0094] Comparative Example 4

[0095] Based on Example 3, the melt holding time was shortened from 10 minutes to 5 minutes, while the rest remained the same as in Example 3.

[0096] Testing revealed 28.2 g of eutectic, with a yield of 94.0% and a purity of 94.0%. The eutectic crystallinity was slightly poor, with an initial melting temperature of 82°C and a final melting temperature of 88°C. Compared to Example 3, the purity was slightly lower, indicating that insufficient melting time may have affected the uniformity and purity of the eutectic.

[0097] Comparative Example 5

[0098] Based on Example 3, PEA was replaced with tetradecylamide ethanol, and the rest was the same as in Example 3.

[0099] It may not be possible to form a eutectic of comparable quality to that of Example 3. The resulting product may have a wider melting point range and a lower melting point (initial melting 70°C, final melting 78°C), and the purity may decrease significantly (e.g., 88%). This indicates that slight changes in carbon chain length disrupt the specific molecular packing pattern between PEA and OEA, demonstrating that the formation of the eutectic is highly selective for molecular structure.

[0100] Comparative Example 6

[0101] Based on Example 3, PEA was replaced with octadecylamide ethanol, and the rest was the same as in Example 3.

[0102] A eutectic may form, but its properties differ from those of Example 3. This indicates that changes in carbon chain length systematically alter the melting point of the eutectic, but the optimal eutectic structure may exist at a specific chain length.

[0103] Comparative Example 7

[0104] Based on Example 3, OEA was replaced with oleamide, and the rest was the same as in Example 3.

[0105] Testing revealed that a complete eutectic could not be formed. Upon cooling, a eutectic mixture was likely obtained, rather than a single eutectic phase. This demonstrates that the terminal hydroxyl group of OEA is a necessary group for forming specific hydrogen bonds, thereby generating a high-purity, high-crystallinity PEA-OEA eutectic.

[0106] Comparative Example 8

[0107] Based on Example 3, OEA was replaced with stearamide ethanol, and the rest was the same as in Example 3.

[0108] Testing revealed that a eutectic identical to that of PEA-OEA could not be formed. This is because the saturated linear chains of SEA are more rigid, potentially resulting in a different stacking pattern compared to the saturated chains of PEA, and also leading to a higher melting point. This indicates that the "knotting" introduced by the double bonds in the acyl chains of OEA is crucial for forming a specific, compact eutectic molecular stack.

[0109] Principles and steps not explicitly described in this invention are all obtainable by those skilled in the art through conventional technical means, and therefore will not be elaborated upon. Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A eutectic of OEA and PEA, characterized in that, The eutectic comprises oleoylethanolamine and hexadecylamide ethanol in a molar ratio of 1:1 to 1:1.

2. The X-ray powder diffraction pattern of the eutectic has characteristic diffraction peaks at 2θ angles of 8.2°±0.2°, 12.5°±0.2°, 16.8°±0.2°, 21.3°±0.2°, and 24.6°±0.2°.

2. The eutectic of OEA and PEA according to claim 1, characterized in that, The eutectic has a melting point of 70-88℃, a water solubility of 0.1~0.25mg / mL, and maintains a purity of over 98% after being stored at 4℃ and 60% relative humidity for 6 months.

3. The eutectic of OEA and PEA according to claim 1, characterized in that, The eutectic has an X-ray powder diffraction pattern that is substantially as shown in Figure 7.

4. The eutectic of OEA and PEA according to claim 1, characterized in that, According to differential scanning calorimetry (DSC), when the temperature was increased at a rate of 10 °C / min, the DSC spectrum of the eutectic showed characteristic endothermic peaks at 67 ± 2 °C and 93 ± 2 °C.

5. A eutectic of OEA and PEA according to claim 1, characterized in that, The eutectic has a differential scanning calorimetry spectrum as shown in Figure 3.

6. The eutectic of OEA and PEA according to claim 1, characterized in that, The infrared spectrum of the eutectic is at 3293.57 cm⁻¹. -1 2916.09cm -1 2848.28cm -1 1556.62cm -1 1049.40cm -1 1038.99cm -1 719.35cm -1 It has a characteristic peak.

7. A eutectic of OEA and PEA according to claim 1, characterized in that, The eutectic has an infrared spectrum as shown in Figure 4.

8. A method for preparing a eutectic of OEA and PEA according to any one of claims 1-7, characterized in that, The methods include solvent evaporation and melt cooling. The solvent evaporation method includes the following steps: Add OEA and PEA at a mass ratio of 1:1 to 1:1.2 to a volume ratio of 1:1 mixture of ethanol and ethyl acetate. Place the mixture in a constant temperature water bath at 40-50°C and stir with a magnetic stirrer at a speed of 300-500 rpm until the solid is completely dissolved. The total mass of OEA and PEA to the volume ratio of solvent is 1 g: 10-15 mL. Place the solution in a constant temperature and humidity chamber at 25°C and a relative humidity of 40%-50%. After 3-5 days, white blocky crystals will precipitate. Collect the crystals by filtration, wash 2-3 times, and dry to obtain the final product. The melt-cooling method includes the following steps: Weigh OEA and PEA in a 1:1 mass ratio, grind at 100-150 rpm for 10-15 minutes, stir the mixed powder in an oil bath at 85-90℃, and keep it in the molten state for 10 minutes after the powder has completely melted to form a uniform and transparent liquid. Then, let it cool naturally at room temperature until the liquid has completely solidified to form a solid, grind it into powder, and then pass it through an 80-mesh sieve to obtain the final product.

9. The eutectic of OEA and PEA according to any one of claims 1-7 or the preparation method according to claim 8 is applied to the preparation of active ingredients in metabolic regulation functional foods or weight loss adjuvant drugs.

10. The application according to claim 9, characterized in that, The metabolic regulation functional food includes any one of beverages, meal replacement powders, or compressed candies. The amount of the cocrystal added in the beverage is 0.5-1 wt%, in the meal replacement powder is 1-2 wt%, and in the compressed candy is 1-1.5 wt%. The weight-loss adjuvant drug dosage form includes one of capsules, tablets, or granules; when preparing capsules, cocrystals are mixed with microcrystalline cellulose and lactose in a mass ratio of 1:2:1 and filled into empty capsules, with each capsule containing 50-100mg of cocrystals; when preparing tablets, cocrystals are mixed with starch and magnesium stearate in a mass ratio of 1:1.5:0.05 and compressed into tablets containing 50-150mg of cocrystals per tablet; when preparing granules, cocrystals are mixed with dextrin in a mass ratio of 1:1, granulated with 50% ethanol solution, and dried to obtain granules.

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