Hydroxytyrosol nicotinamide cocrystal, method for producing the same and composition

Abstract

The present invention relates to the field of pharmaceutical technology, specifically to hydroxytyrosol nicotinamide cocrystal, its preparation method and composition. The molar ratio of hydroxytyrosol and nicotinamide in the hydroxytyrosol nicotinamide cocrystal of the present invention is 1:1, and the cell parameters are a=9.4999, b=11.8285, c=11.4439, α=90°, β=96.628°, δ=90°. The hydroxytyrosol nicotinamide cocrystal of the present invention has a high melting point, is not hygroscopic, has good stability, and improves the convenience of use of hydroxytyrosol. The composition directly prepared by grinding method has a high yield, low cost, and is suitable for large-scale wide application.

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical technology field, and in particular to hydroxytyrosol nicotinamide cocrystals, their preparation methods and compositions. [Background technology]

[0002] Hydroxytyrosol is a polyphenolic compound extracted from olive oil, and its specific structural formula is shown in Formula I.

[0003] [ka]

[0004] Hydroxytyrosol has relatively strong antioxidant properties and a wide range of biological activities, and is currently widely used in foods, supplements, and cosmetics. However, hydroxytyrosol raw material itself has a low melting point (52°C), is highly hygroscopic, and exists as a waxy solid or sticky oil at ambient temperature and humidity, making it unable to be directly applied to hard capsules or tablets. In addition, the raw material itself is extremely unstable against light, heat, moisture, oxygen, etc., and is prone to oxidation and discoloration during use.

[0005] Currently, hydroxytyrosol is protected by the embedding method, and the embedded powder formed has a loading rate of 20-30%. Compared with pure hydroxytyrosol, the powder properties of the embedded powder are more optimized. However, because hydroxytyrosol is an amphiphilic compound, the encapsulation rate is not high, and unembedded hydroxytyrosol still has issues such as instability and discoloration. Furthermore, it has been reported that the embedded powder contains a large amount of starch-based additives, which further increases its hygroscopicity.

[0006] In view of the above, the present invention is presented. Summary of the Invention

[0007] A first object of the present invention is to provide a hydroxytyrosol nicotinamide cocrystal.

[0008] A second object of the present invention is to provide a method for producing this hydroxytyrosol nicotinamide cocrystal.

[0009] A third object of the present invention is to provide a composition containing this hydroxytyrosol nicotinamide cocrystal.

[0010] In order to achieve the object of the present invention, the technical solutions adopted are as follows:

[0011] In order to improve the stability of hydroxytyrosol products, the present invention prepares hydroxytyrosol cocrystals by incorporating auxiliary compounds, which have non-covalent interactions with hydroxytyrosol at the molecular level, thereby increasing the melting point of hydroxytyrosol at the molecular level, improving its stability, and broadening its application field.

[0012] In a first aspect, the present invention provides a hydroxytyrosol nicotinamide co-crystal compound, in which the molar ratio of hydroxytyrosol to nicotinamide is 1:1, and the structural formula of nicotinamide is shown in Formula II.

[0013] [ka]

[0014] Through extensive experiments, the present inventors have found that other similar compounds, such as L-proline, L-carnitine, and nicotinic acid, cannot be used to prepare stable powder formulations of hydroxytyrosol. By using nicotinamide to prepare cocrystals, the above technical problems were solved, and the present invention was completed.

[0015] The cell parameters of the hydroxytyrosol nicotinamide cocrystal of the present invention are a=9.4999, b=11.8285, c=11.4439, α=90°, β=96.628°, δ=90°.

[0016] In some embodiments, compared to hydroxytyrosol, the hydroxytyrosol-nicotinamide cocrystals produced by the present invention have significantly improved melting points. However, as is well known, not all cocrystals have significantly improved melting points, and some cocrystals may have melting points lower than the melting points of the two compounds alone. In some embodiments, compared to hydroxytyrosol, the hydroxytyrosol cocrystals produced by the present invention also have significantly reduced hygroscopicity. In some embodiments, compared to hydroxytyrosol, the hydroxytyrosol cocrystals produced by the present invention have significantly improved chemical stability.

[0017] In particular, the hydroxytyrosol nicotinamide cocrystal of the present invention has characteristic peaks at diffraction angles of at least 11.4±0.2, 13.6±0.2, 14.9±0.2, 17.6±0.2, 18.8±0.2, 20.1±0.2, 20.3±0.2, and 20.8±0.2° in an X-ray powder diffraction pattern shown in 2θ angles. More particularly, it has an X-ray powder diffraction pattern essentially as shown in FIG.

[0018] In particular, the hydroxytyrosol nicotinamide cocrystal of the present invention has a melting point of 111° C.±2° C. According to differential scanning calorimetry (DSC) measurements, the hydroxytyrosol nicotinamide cocrystal has an onset melting temperature of 110±2° C. and a maximum peak value of 111±2° C. More particularly, it has a DSC diagram essentially as shown in FIG.

[0019] In particular, the hydroxytyrosol nicotinamide cocrystal exhibits an infrared absorption spectrum of at least 3426 cm -1 , 3371cm -1 , 3155cm -1 , 1692cm -1 , 1627cm -1, 1601cm -1 , 1527cm -1 , 1409cm -1 , 1356cm -1 , 1260cm -1 , 1200cm -1 , 1117cm -1 , 1060cm -1 , 1026cm -1 , 929cm -1 , 849cm -1 , 809cm -1 , 711cm -1 , 654cm -1 , 635cm -1 More particularly, it has an infrared spectrum essentially as shown in FIG.

[0020] In a second aspect, the present invention relates to a method for producing hydroxytyrosol co-crystals, comprising contacting hydroxytyrosol and nicotinamide in the molecular state, followed by crystallization.

[0021] Contact in a molecular state includes, but is not limited to, solution synthesis, solid-state grinding, etc. Solution synthesis refers to synthesizing cocrystals in solution, including slow evaporation, cooling crystallization, suspension crystallization, and dissolution crystallization. Solid-state grinding mainly includes dry grinding and solvent-assisted grinding of solids. Dry grinding is a method of obtaining cocrystal products by grinding a mixture of the main drug and ligand. Solution-assisted grinding is a method of improving grinding efficiency by adding a small amount of solvent during the grinding process. Methods of solid-state grinding include ball milling or high-speed shearing.

[0022] In particular, the method for producing hydroxytyrosol cocrystals may be one of the following methods:

[0023] Method one: Hydroxytyrosol and nicotinamide are recrystallized in an organic solvent to obtain a hydroxytyrosol nicotinamide cocrystal; Method two: Hydroxytyrosol and nicotinamide are placed in a grinding device and mixed to obtain hydroxytyrosol nicotinamide cocrystals.

[0024] In particular, Method 1 includes at least the following steps: S1: Dissolving hydroxytyrosol and nicotinamide in an organic solvent at a first temperature; S2: The solution obtained in S1 is cooled to a second temperature lower than the first temperature to precipitate hydroxytyrosol co-crystals.

[0025] Specifically, in S1, the first temperature is 10 to 80°C, and preferably 30 to 50°C.

[0026] Specifically, when producing a hydroxytyrosol-nicotinamide cocrystal in S1, the organic solvent is one or more selected from the group consisting of methanol, ethanol, n-propanol, n-butyl alcohol, isopropanol, isobutyl alcohol, isoamyl alcohol, tert-butyl alcohol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, ethyl formate, ethyl acetate, isopropyl acetate, and isobutyl acetate. Preferably, the organic solvent is selected from the group consisting of a mixed solvent of ethanol and isoamyl alcohol, a mixed solvent of ethanol and isobutyl alcohol, and a mixed solvent of ethanol and tert-amyl alcohol. The volume ratio of the two solvents in the mixed solvent may be 1:0.1-10, preferably 1:1-5, and more preferably 1:1.

[0027] Specifically, in S2, the second temperature is -40 to 0°C, and preferably -30 to -10°C.

[0028] Specifically, in step S2, seed crystals can be added during the crystallization process to accelerate the formation of crystals.

[0029] Specifically, after crystallization, the process further includes the steps of solid-liquid separation and drying; the solid-liquid separation can be performed by a method selected from filtration, centrifugation, etc., preferably filtration; the drying can be performed by a method such as atmospheric drying, vacuum drying, spray drying, etc., preferably vacuum drying at room temperature.

[0030] In particular, the second method includes at least the following steps: Hydroxytyrosol and nicotinamide are mixed in a grinding device, and the molar ratio of hydroxytyrosol to nicotinamide is 1:1 or less.

[0031] Specifically, the grinding device includes a mechanical grinder and a ball mill.

[0032] Specifically, the mixing temperature is 15 to 50°C.

[0033] Specifically, the frequency of the ball mill is 30 to 50 Hz.

[0034] Specifically, the rotation speed of the mechanical crusher is 5,000 to 30,000 rpm.

[0035] In a third aspect, the present invention provides a composition comprising the hydroxytyrosol nicotinamide cocrystal described above.

[0036] In some embodiments, the composition may contain, in addition to the hydroxytyrosol-nicotinamide cocrystal of the present invention, an excess of nicotinamide, an excess of hydroxytyrosol, or other pharmacologically acceptable additives. That is, the molar ratio of hydroxytyrosol to nicotinamide in the raw materials of the composition is not particularly limited, as long as the above-described hydroxytyrosol-nicotinamide cocrystal can be produced from the raw materials of the composition. For example, the molar ratio of hydroxytyrosol to nicotinamide in the composition may be 10:1 to 1:10, and some of the components may exist as hydroxytyrosol cocrystals, while the other components may exist as free substances. More preferably, all of the hydroxytyrosol is formed into cocrystals, overcoming the drawbacks of hydroxytyrosol, such as its low melting point and poor stability.

[0037] In a fourth aspect, the method for producing a composition of the present invention preferably includes producing a cocrystal by adding hydroxytyrosol and nicotinamide to a grinding device, and then obtaining a composition containing hydroxytyrosol and nicotinamide. In the raw materials for the composition, the molar ratio of hydroxytyrosol to nicotinamide is lower than 1:1, preferably 1:1.01 to 1:10, and more preferably 1:1.01 to 1:3. If too much nicotinamide remains, it tends to increase hygroscopicity, which is detrimental to the stability of hydroxytyrosol.

[0038] When other pharmacologically acceptable additives are added, the method further includes a step of mixing the other additives.

[0039] In some embodiments, the raw materials of the composition consist of hydroxytyrosol and nicotinamide in a molar ratio of 1:1.01 to 1:3, and the number of moles of free nicotinamide relative to the number of moles of hydroxytyrosol in the composition is 101% to 200% of the number of moles of hydroxytyrosol. When the free nicotinamide in the composition is in this proportional range, the composition has characteristic peaks at diffraction angles of 11.4±0.2, 13.6±0.2, 14.9±0.2, 17.6±0.2, 18.8±0.2, 20.1±0.2, 20.3±0.2, and 20.8±0.2° in its X-ray powder diffraction pattern, expressed as 2θ angles. This demonstrates that the cocrystal in this composition is identical to the crystalline form of the cocrystal of the present invention, as it has characteristic peaks of the hydroxytyrosol-nicotinamide cocrystal of the present invention. In particular, the composition has a melting onset temperature of 100±2° C. and a maximum peak value of 101±2° C. when measured by differential scanning calorimetry. When the free nicotinamide in the composition is in this proportional range, the composition has an infrared absorption spectrum with a melting onset temperature of at least 3426 cm -1 , 3371cm -1 , 3155cm -1 , 1692cm -1 , 1627cm -1 , 1601cm -1 , 1527cm -1 , 1409cm -1 , 1356cm -1 , 1260cm -1 , 1200cm -1 , 1117cm -1 , 1060cm -1 , 1026cm -1 , 929cm -1 , 849cm -1 , 809cm -1 , 711cm -1 , 654cm -1 , 635cm -1 It has an absorption peak at

[0040] More preferably, the composition of the present invention can be directly produced by grinding. When producing hydroxytyrosol nicotinamide cocrystals by grinding, adding an excess amount of nicotinamide can shorten the production time and ensure that all hydroxytyrosol forms cocrystals, ensuring that no free hydroxytyrosol is present in the composition. The composition directly produced by grinding contains a certain amount of nicotinamide, but does not significantly affect the melting point, hygroscopicity, and stability of the composition. Compared with solvent crystallization, this method has the technical advantages of high production efficiency, improved yield, and reduced costs, making it suitable for a wide range of large-scale applications.

[0041] The advantageous effects of the present invention include at least the following:

[0042] Compared to hydroxytyrosol itself, the hydroxytyrosol nicotinamide cocrystal of the present invention has a significantly improved melting point. Compared to hydroxytyrosol itself and its embedded powder, the hydroxytyrosol nicotinamide cocrystal of the present invention has reduced hygroscopicity and significantly improved chemical stability.

[0043] Compared with the cocrystal of hydroxytyrosol and nicotinamide, in the present invention, the composition containing the hydroxytyrosol nicotinamide cocrystal produced by the grinding method has the technical advantages of high yield, low cost, and suitability for large-scale production. [Brief explanation of the drawings]

[0044] [Figure 1] 1 is an X-ray powder diffraction (XRPD) pattern of a hydroxytyrosol nicotinamide cocrystal according to an example of the present invention. [Figure 2] FIG. 1 is a differential scanning calorimetry (DSC) diagram of a hydroxytyrosol nicotinamide cocrystal according to an example of the present invention. [Figure 3] FIG. 1 is an infrared spectrum (IR) diagram of a hydroxytyrosol nicotinamide cocrystal according to an example of the present invention. [Figure 4]1 is an X-ray powder diffraction (XRPD) pattern of a mixture containing a hydroxytyrosol nicotinamide cocrystal according to an example of the present invention. [Figure 5] FIG. 1 is a differential scanning calorimetry (DSC) diagram of a mixture containing a hydroxytyrosol nicotinamide cocrystal according to an example of the present invention. [Figure 6] Dynamic moisture sorption contrast diagram of hydroxytyrosol itself, hydroxytyrosol embedded powder, hydroxytyrosol nicotinamide cocrystal (Example 1), a composition containing hydroxytyrosol nicotinamide cocrystal (Example 4), and a composition containing hydroxytyrosol nicotinamide cocrystal (Example 5). DETAILED DESCRIPTION OF THE INVENTION

[0045] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the drawings and examples, in which the specific examples described herein are only used to explain the present invention and are not intended to limit the present invention.

[0046] Reagents and equipment The X-ray powder diffraction patterns in the examples were obtained using a Bruker D8 Advanced X-ray powder diffractometer, using Cu-Kα radiation (λ=1.54056 Å), scanning from 3° to 40° in the 2θ interval, and a scanning rate of 2° / min.

[0047] The differential scanning calorimetry was performed using a TA DSC Q2000 instrument with a heating rate of 10 K / min.

[0048] The Fourier transform infrared spectrometer used was a Thermo Scientific Nicolet 6700.

[0049] Hydroxytyrosol was purchased from Shaanxi Fuheng Biotechnology Co., Ltd. with a purity of ≥98%.

[0050] Nicotinamide was purchased from Aladdin reagent and had a purity of ≥98.5%; Hydroxytyrosol embedded powder was purchased from Shaanxi Fuheng Biotechnology Co., Ltd., containing 30% hydroxytyrosol and 70% polymer additives (mainly maltodextrin), and was produced by the method of spray drying. [Example]

[0051] Example 1 Hydroxytyrosol (4 mmol) and nicotinamide (4 mmol) were added in a molar ratio of 1:1 to 20 ml of a mixed solvent of ethanol and isoamyl alcohol (volume ratio 1:1), stirred at 40°C until the solution became clear, cooled to -20°C, and recrystallized after 24 hours to obtain a white precipitate. The precipitate was filtered using a Buchner funnel, and the solid was dried at room temperature in a vacuum drying box for 1 day to obtain a hydroxytyrosol nicotinamide cocrystal.

[0052] Cell parameters: a = 9.4999, b = 11.8285, c = 11.4439, α = 90°, β = 96.628°, δ = 90° The above experimental data demonstrated that the molar ratio of hydroxytyrosol to nicotinamide in the cocrystal was 1:1.

[0053] This cocrystal was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry, and infrared spectroscopy, and the results are shown in Figures 1-3.

[0054] Example 2 Hydroxytyrosol (4 mmol) and nicotinamide (4 mmol) were added in a 1:1 molar ratio to 20 ml of a mixed solvent of ethanol and isobutyl alcohol (volume ratio 1:1), stirred at 40°C until the solution became clear, cooled to -20°C, and recrystallized after 24 hours to obtain a white precipitate. The precipitate was filtered using a Buchner funnel, and the solid was dried at room temperature in a vacuum drying box for 1 day to obtain a hydroxytyrosol nicotinamide cocrystal.

[0055] This cocrystal was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry, and infrared spectroscopy. The results were consistent with those shown in Figures 1 to 3.

[0056] Example 3 3.1 g of hydroxytyrosol and 2.4 g of nicotinamide (molar ratio 1:1) were weighed and placed in a ball mill (Shanghai Jingxin Tissuelyser-II rapid sample grinding machine), and an appropriate amount of grinding balls was added. The mixture was ball milled at room temperature at a frequency of 40 Hz for 2 hours to obtain hydroxytyrosol-nicotinamide cocrystals.

[0057] This cocrystal was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry, and infrared spectroscopy. The results were consistent with those shown in Figures 1 to 3. It was demonstrated that the crystalline form of the obtained cocrystal was the same as that of Example 1.

[0058] Example 4 3.1 g of hydroxytyrosol and 4.8 g of nicotinamide (molar ratio 1:2) were weighed and placed in a ball mill (Shanghai Jingxin Tissuelyser-II rapid sample grinding machine). An appropriate amount of grinding balls was added and the mixture was ball milled at room temperature at a frequency of 40 Hz for 2 hours to obtain a mixture containing hydroxytyrosol nicotinamide cocrystals.

[0059] The mixture was characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry. The experimental results are shown in Figures 4 and 5.

[0060] Figure 4 shows the characteristic peaks of the hydroxytyrosol-nicotinamide cocrystal at 11.4 ± 0.2°, 13.6 ± 0.2°, 14.9 ± 0.2°, 17.6 ± 0.2°, 18.8 ± 0.2°, 20.1 ± 0.2°, 20.3 ± 0.2°, and 20.8 ± 0.2°, as well as the characteristic peaks of the free nicotinamide crystal at 25.3 ± 0.2° and 27.3 ± 0.2°.

[0061] FIG. 5 shows that the hydroxytyrosol nicotinamide co-crystal and free nicotinamide form a low melting point eutectic, with one eutectic endothermic peak at about 100° C. and no melting peak of free nicotinamide.

[0062] The above results prove that this mixture is a mixture of hydroxytyrosol nicotinamide cocrystal and nicotinamide, that the crystal form is consistent with that of the cocrystal produced in Example 1, and that the molar ratio of hydroxytyrosol to nicotinamide in the cocrystal is 1:1.

[0063] Example 5 1.6 g of hydroxytyrosol and 3.8 g of nicotinamide (molar ratio 1:3) were weighed and placed in a ball mill (Shanghai Jingxin Tissuelyser-II rapid sample grinding machine). An appropriate amount of grinding balls was added and ball milled at room temperature at a frequency of 40 Hz for 2 hours to obtain a mixture containing hydroxytyrosol nicotinamide cocrystals, in which the molar ratio of hydroxytyrosol to nicotinamide in the cocrystals was 1:1.

[0064] This mixture was analyzed by X-ray powder diffraction (XRPD), and the positions of its characteristic peaks were essentially consistent with those in Figure 4, proving that the crystalline form of the resulting cocrystal was the same as that in Example 1 and that the molar ratio of hydroxytyrosol to nicotinamide in the cocrystal was 1:1. Differential scanning calorimetry analysis revealed that the positions of its absorption peaks were essentially consistent with those in Figure 5.

[0065] Example 6 The hygroscopicity of hydroxytyrosol, hydroxytyrosol embedded powder, the hydroxytyrosol nicotinamide cocrystal obtained in Example 1, and the composition obtained in Example 4 was compared.

[0066] Approximately 5 mg of powder sample was placed in a dynamic moisture sorption apparatus (DVS) under a relative humidity range of 0-95% and a temperature of 25°C. The weight change of the sample under different environmental humidity conditions was recorded to determine the hygroscopicity of the sample. The experimental results are shown in Figure 6.

[0067] 6 shows that at 80% relative humidity, hydroxytyrosol and the embedded powder exhibited significant moisture absorption of 16.9% and 116.3%, whereas the hydroxytyrosol co-crystal and composition provided herein exhibited essentially no moisture absorption. The moisture absorption of the composition (0.94% and 0.79% moisture absorption at 80% RH) was slightly increased compared to that of the co-crystal (0.39% moisture absorption at 80% RH).

[0068] This results in the hydroxytyrosol cocrystals and compositions described in this invention being significantly less hygroscopic than hydroxytyrosol and its embedded powder.

[0069] Example 7: The chemical stability at 40°C / 75% RH of hydroxytyrosol, hydroxytyrosol embedded powder, the hydroxytyrosol nicotinamide cocrystal obtained in Example 1, and the compositions obtained in Examples 4 and 5 was compared.

[0070] An appropriate amount of powder sample was placed in a 40°C / 75%RH accelerated stability box, packaged in a double-layered polyethylene bag, and sampled at 0 days, 14 days, and 30 days. The hydroxytyrosol content was measured using high-performance liquid chromatography (the content calculation method was the external standard method).

[0071] The liquid phase method was as follows.

[0072] Mobile phase: Phase A: 0.1% trifluoroacetic acid aqueous solution, Phase B: acetonitrile; Flow rate: 1 mL / min; Detection wavelength: 280 nm; Chromatography column: C18 Plus 4.6 × 150 mm × 5 μm; Gradient Method: 0~10min――A:B (95:5); 10.1~14min――A:B (50:50); 14.0~17min――A:B (95:5).

[0073] The experimental results are shown in Table 1.

[0074] [Table 1]

[0075] As shown in Table 1, the initial hydroxytyrosol content in each sample was 100%. After 30 days, the hydroxytyrosol content was 92.3% of the initial content, while the content in the embedded powder was only 57.2% of the initial content. Meanwhile, in the hydroxytyrosol nicotinamide cocrystals provided by the present invention, the hydroxytyrosol content remained above 99%. In the composition containing the hydroxytyrosol nicotinamide cocrystals, the hydroxytyrosol content was slightly reduced.

[0076] Thereby, compared to hydroxytyrosol and hydroxytyrosol embedded powder, the hydroxytyrosol nicotinamide cocrystals and compositions of the present invention have greater chemical stability.

[0077] Comparative Example 1 Hydroxytyrosol (4 mmol) and L-proline (4 mmol) were added to 20 ml of a mixed solvent in a molar ratio of 1:1 (mixed solvents were methanol, ethanol, 1:1 volume ratio of methanol and n-propanol, 1:1 volume ratio of methanol and n-butyl alcohol, 1:1 volume ratio of methanol and isobutyl alcohol, 1:1 volume ratio of methanol and isoamyl alcohol, 1:1 volume ratio of ethanol and n-propanol, 1:1 volume ratio of ethanol and n-butyl alcohol, 1:1 volume ratio of ethanol and isoamyl alcohol, and 1:1 volume ratio of ethanol and isobutyl alcohol), and stirred at 40°C until the solution became clear. The solution was then cooled to -20°C, and after 24 hours, recrystallization occurred, resulting in the precipitation of a white powder of L-proline. No hydroxytyrosol powder preparation was obtained.

[0078] From Comparative Example 1, it was found that cocrystals could not be produced using L-proline in any of the various solvents.

[0079] Comparative Example 2 Hydroxytyrosol (4 mmol) and L-carnitine (4 mmol) were added to 20 ml of a mixed solvent in a molar ratio of 1:1 (mixed solvents were methanol, ethanol, 1:1 volume ratio of methanol and n-propanol, 1:1 volume ratio of methanol and n-butyl alcohol, 1:1 volume ratio of methanol and isobutyl alcohol, 1:1 volume ratio of methanol and isoamyl alcohol, 1:1 volume ratio of ethanol and n-propanol, 1:1 volume ratio of ethanol and n-butyl alcohol, 1:1 volume ratio of ethanol and isoamyl alcohol, and 1:1 volume ratio of ethanol and isobutyl alcohol), and stirred at 40°C until the solution became clear. The solution was then cooled to -20°C, and after 24 hours, recrystallization occurred, resulting in the precipitation of a white powder of L-carnitine. No hydroxytyrosol powder preparation was obtained.

[0080] From Comparative Example 2, it was found that cocrystals could not be produced using L-carnitine in any of the various solvents.

[0081] Comparative Example 3 Hydroxytyrosol (4 mmol) and nicotinic acid (4 mmol) were added to 20 ml of a mixed solvent in a 1:1 molar ratio (mixed solvents were methanol, ethanol, 1:1 volume ratio of methanol and n-propanol, 1:1 volume ratio of methanol and n-butyl alcohol, 1:1 volume ratio of methanol and isobutyl alcohol, 1:1 volume ratio of methanol and isoamyl alcohol, 1:1 volume ratio of ethanol and n-propanol, 1:1 volume ratio of ethanol and n-butyl alcohol, 1:1 volume ratio of ethanol and isoamyl alcohol, and 1:1 volume ratio of ethanol and isobutyl alcohol), and stirred at 40°C until the solution became clear. The solution was then cooled to -20°C and recrystallized after 24 hours. The precipitate was the nicotinic acid ligand.

[0082] From Comparative Example 3, it was found that nicotinic acid could not produce cocrystals in any of the various solvents.

[0083] By comparing the results of the Examples and Comparative Examples, it was found that hydroxytyrosol can form cocrystals with certain compounds, such as nicotinamide, but cannot form cocrystals with other structural analogues, such as L-proline, L-carnitine, and nicotinic acid.

[0084] The present application is disclosed as a preferred example, but is not intended to limit the scope of the claims, and those skilled in the art can make changes or modifications without departing from the concept of the present application, and therefore the scope of protection of the present application shall be as defined in the claims of the present application.

Claims

1. A hydroxytyrosol nicotinamide cocrystal having a molar ratio of hydroxytyrosol to nicotinamide of 1:1, The hydroxytyrosol nicotinamide cocrystal has characteristic peaks at diffraction angles of at least 11.4±0.2, 13.6±0.2, 14.9±0.2, 17.6±0.2, 18.8±0.2, 20.1±0.2, 20.3±0.2, and 20.8±0.2° in X-ray powder diffraction indicated by 2θ angles.

2. 2. The hydroxytyrosol nicotinamide cocrystal according to claim 1, characterized in that the cell parameters of the hydroxytyrosol nicotinamide cocrystal are a = 9.4999, b = 11.8285, c = 11.4439, α = 90°, β = 96.628°, and δ = 90°.

3. The melting point of the hydroxytyrosol nicotinamide cocrystal is 111°C ± 2°C; and, when measured by differential scanning calorimetry, the hydroxytyrosol nicotinamide cocrystal has a melting onset temperature of 110±2°C and a maximum peak value of 111±2°C. The hydroxytyrosol nicotinamide cocrystal according to claim 1.

4. The hydroxytyrosol nicotinamide cocrystal has an infrared absorption spectrum of at least 3426 cm －１ , 3371 cm －１ , 3155 cm －１ , 1692 cm －１ , 1627 cm －１ , 1601 cm －１ , 1527 cm －１ , 1409 cm －１ , 1356 cm －１ , 1260 cm －１ , 1200 cm －１ , 1117 cm －１ , 1060 cm －１ , 1026 cm －１ , 929 cm －１ , 849 cm －１ , 809 cm －１ , 711 cm －１ , 654 cm －１ , 635 cm －１ The hydroxytyrosol nicotinamide cocrystal according to claim 1, characterized in that it has an absorption peak at

5. A method for producing the hydroxytyrosol nicotinamide cocrystal according to any one of claims 1 to 4, comprising: S1: Dissolving hydroxytyrosol and nicotinamide in an organic solvent and stirring at a first temperature until complete dissolution; S2: A step of cooling the solution obtained in S1 to a second temperature lower than the first temperature to crystallize; S3: A step of separating and drying the solid to obtain the hydroxytyrosol nicotinamide cocrystal; Including, the first temperature is 10 to 80°C; and the second temperature is −40 to 0° C.; A manufacturing method characterized by:

6. the first temperature is 30 to 50°C; and the second temperature is −30 to −10° C.; The manufacturing method according to claim 5 .

7. 6. The method according to claim 5, wherein the organic solvent is one or more selected from the group consisting of methanol, ethanol, n-propanol, n-butyl alcohol, isopropanol, isobutyl alcohol, isoamyl alcohol, tert-butyl alcohol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, ethyl formate, ethyl acetate, isopropyl acetate, and isobutyl acetate.

8. A method for producing the hydroxytyrosol nicotinamide cocrystal according to any one of claims 1 to 4, comprising the steps of: hydroxytyrosol and nicotinamide are introduced into a grinding device and mixed and ground, and the molar ratio of hydroxytyrosol to nicotinamide is 1:1; The grinding device includes a mechanical grinder and a ball mill; The temperature of the mixing is 15 to 50°C; And the frequency of the ball mill is 30 to 50 Hz; A manufacturing method characterized by:

9. A composition containing the hydroxytyrosol nicotinamide cocrystal according to any one of claims 1 to 4, wherein the composition further comprises nicotinamide or a pharmacologically acceptable additive. A composition characterized by:

10. 10. A method for producing the composition of claim 9, comprising: A production method comprising at least a step of introducing hydroxytyrosol and nicotinamide into a grinding device, mixing and grinding the mixture, and providing a molar ratio of hydroxytyrosol to nicotinamide of 1:1.01 to 1:5.

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