Cocrystal of coenzyme QH and nicotinamide, its production method and use

Abstract

The present invention relates to a cocrystal of coenzyme QH and nicotinamide, its preparation method and use. Compared with conventional coenzyme QH, the cocrystal has a higher melting point and better stability. The preparation method of the cocrystal of coenzyme QH is simple, easy to control, and has good reproducibility. The present invention greatly improves the convenience of using coenzyme QH, saves costs during storage, transportation and use, and expands the application scope of coenzyme QH.

Description

[Technical field]

[0001] The present invention relates to the technical field of coenzyme Q10, specifically to a cocrystal of coenzyme QH and nicotinamide and its preparation method. Compared with the conventional coenzyme QH, the cocrystal has a higher melting point and better stability. The preparation method of the coenzyme QH cocrystal is simple, easy to control, and has good reproducibility. The present invention greatly improves the convenience of using coenzyme QH, saves costs during storage, transportation and use, and expands the application scope of coenzyme QH. [Background technology]

[0002] Coenzyme Q10 is the only coenzyme Q substance in the human body, and is a fat-soluble compound that is widely present in the body. It is a coenzyme that does not bind tightly to proteins in the respiratory chain, and plays an important role in proton transfer and electron transfer in the respiratory chain of the human body. Coenzyme Q10 is an agonist of cell metabolism and cellular respiration, and is also an important antioxidant and non-specific immune enhancer, which can inhibit mitochondrial peroxidation, promote oxidative phosphorylation reaction, and protect the integrity of biological membrane structure. Coenzyme Q10 also has an enhancing effect on immune non-specificity, enhances the ability of antibody production, and improves T cell function. Coenzyme Q10 is essentially a metabolic agonist, which can activate cellular respiration, accelerate the production of adenosine triphosphate, and play the role of detoxification emergency. In addition, coenzyme Q10 can modify the oxygen deficiency situation of cells and tissues, and has good protective and improving effects on the liver, brain, heart and nervous system, and enhance the non-specific immune response in the body. Currently, coenzyme Q10 is widely used in the food, supplement, cosmetic and pharmaceutical industries, and has attracted the attention of many researchers and consumers.

[0003] Coenzyme Q10 is divided into two forms: oxidized and reduced. Generally, 40-90% of coenzyme Q10 in the human body exists in the reduced form. Reduced coenzyme Q10 is also commonly called coenzyme QH. Compared with oxidized coenzyme Q10, coenzyme QH has better antioxidant properties and more effective absorption. However, coenzyme QH is easily oxidized in air and has poor stability, which has limited its further application and development. To improve the stability of coenzyme QH, scientists have adopted various methods, such as adding antioxidants, preparing new crystal forms and cocrystals.

[0004] CN102381948A and CN101318889A disclose a method of stabilizing coenzyme QH by adding ascorbic acid or its derivatives. The inventors found that after grinding coenzyme QH together with 10% by mass of ascorbic acid or its derivatives and leaving it in the air at 25°C for 4 days, about 13% of coenzyme QH was oxidized.

[0005] In CN103635452A, a stable crystalline form of coenzyme QH was produced, but it still oxidized when left in air for a long period of time. The inventors found that after leaving this crystalline form in air at 25°C for 28 days, about 6% of coenzyme QH was still oxidized.

[0006] WO2019162429A discloses seven types of cocrystals of coenzyme QH, among which the cocrystals of coenzyme QH with 3,4-dihydroxybenzoic acid and 3,5-dihydroxybenzoic acid have good stability. However, these two ligands are not suitable for large-scale use in food, and the preparation method of the cocrystals is complicated, requiring stirring in a solvent for more than three days.

[0007] Therefore, there is a need to develop more stable coenzyme QH products. Summary of the Invention

[0008] In order to improve the stability of coenzyme QH products, the present invention has conducted extensive experiments to form cocrystals between multiple compounds and coenzyme QH. As a result, stable cocrystals are formed by using edible nicotinamide (a form of vitamin B3) as a ligand, which changes the intermolecular interaction and spatial arrangement of the coenzyme QH molecule at the molecular level, enhances the stability of the coenzyme QH molecule against oxygen, improves its melting point, and further improves its chemical stability, widening its application field. However, other similar compounds, such as nicotinic acid (a form of vitamin B3), riboflavin (vitamin B2), calcium pantothenate (vitamin B5), folic acid (vitamin B9) and ascorbic acid (vitamin C), cannot form cocrystals with coenzyme QH to improve the melting point of coenzyme QH and thereby improve its stability. Thus, a method of using nicotinamide to prepare cocrystals with coenzyme QH is determined, solving the above technical problems and achieving the present invention.

[0009] The more stable cocrystal of coenzyme QH can broaden the range of applications of coenzyme QH, and therefore the cocrystal of coenzyme QH and nicotinamide described in the present invention has high practical application value.

[0010] One object of the present invention is to provide a cocrystal of coenzyme QH and nicotinamide.

[0011] A second object of the present invention is to provide a method for producing the cocrystal of coenzyme QH and nicotinamide.

[0012] A third object of the present invention is to provide a product selected from the group consisting of supplements, foods, cosmetics, pharmaceuticals, medicinal additives, and feeds, which contains the above-mentioned cocrystal of coenzyme QH and nicotinamide.

[0013] A fourth object of the present invention is to provide a use of the above-mentioned cocrystal of coenzyme QH and nicotinamide in the production of a product selected from the group consisting of supplements, foods, cosmetics, medicines, medicinal additives, and feeds.

[0014] In one embodiment of the present invention, there is provided a co-crystal of coenzyme QH and nicotinamide, wherein the stoichiometric ratio of coenzyme QH to nicotinamide is 1:1.

[0015] The cocrystal of coenzyme QH and nicotinamide has characteristic peaks at 2θ angles of 4.3°±0.2°, 5.7°±0.2°, 17.1°±0.2°, 17.9°±0.2°, 18.9°±0.2°, 19.8°±0.2°, 20.8°±0.2°, and 23.1°±0.2° in an X-ray powder diffraction pattern; in particular, it has characteristic peaks at 2θ angles of about 8.4°±0.2°, 9.9°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 27.8°±0.2°, and 30.3°±0.2°. More particularly, the cocrystal of coenzyme QH and nicotinamide has an X-ray powder diffraction pattern essentially as shown in FIG. 1.

[0016] In particular, the cocrystal of coenzyme QH and nicotinamide has a characteristic endothermic peak at about 57±2°C in a differential scanning calorimetry diagram when heated at a rate of 10°C / min, as measured by differential scanning calorimetry; preferably, the differential scanning calorimetry diagram has a characteristic endothermic peak at about 57±2°C in a differential scanning calorimetry diagram essentially as shown in Figure 2.

[0017] In particular, the cocrystal of coenzyme QH and nicotinamide has a peak at about 3465 cm in the infrared spectrum. -1 , 3170cm -1 , and 1697 cm -1 In particular, it has a characteristic peak at about 2964 cm -1 , 2945cm -1 , 2907cm -1 , 2847cm -1 , 1664cm -1 , 1607cm -1 , 1445cm -1 , 1422cm -1 , 1384cm -1 , 1280cm-1 , 1261cm -1 , 1197cm -1 , 1164cm -1 , 1149cm -1 , 1109cm -1 , 1009cm -1 , 907cm -1 , 877cm -1 , 795cm -1 , 751cm -1 , 599cm -1 , 475cm -1 and preferably has an infrared spectrum essentially as shown in FIG.

[0018] In a second aspect, the present invention provides a method for producing said coenzyme QH co-crystal, which is one of the following methods:

[0019] Method 1: Coenzyme QH and nicotinamide are recrystallized in a solvent, precipitated, and dried to obtain the cocrystal of coenzyme QH and nicotinamide;

[0020] Method 2: Coenzyme QH and nicotinamide are ball-milled in a solvent for more than 10 minutes, and the resulting solid is then dried to obtain a cocrystal of coenzyme QH and nicotinamide.

[0021] Wherein, the solvent is selected from the group consisting of solvents that have a certain solubility for the raw material but do not alter the raw material.Preferably, the solvent is one or more selected from the group consisting of water, alcohols, ketones, esters, alkanes, aromatic hydrocarbons and halogenated alkanes;more preferably, the solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, methyl tert-butyl ether, n-hexane and n-heptane.

[0022] The production method of the present invention is simple in operation, the crystallization process is easily controlled, the degree of crystallization is high, and the cocrystal of coenzyme QH and nicotinamide is stably obtained with good reproducibility.

[0023] In a third aspect, the present invention provides a coenzyme QH composition comprising a co-crystal of coenzyme QH and nicotinamide as described above.

[0024] In some embodiments, the coenzyme QH composition may further contain an excess amount of nicotinamide, an excess amount of coenzyme QH, or other additives in addition to the cocrystal of coenzyme QH and nicotinamide of the present invention. That is, the molar ratio of coenzyme QH and nicotinamide in the raw material of the coenzyme QH composition is not particularly limited, and it is sufficient that the cocrystal of coenzyme QH and nicotinamide can be produced from the raw material of the coenzyme QH composition. For example, in the coenzyme QH composition, the stoichiometric ratio of coenzyme QH and nicotinamide may be 2:1 to 1:2, and some of the components exist as cocrystals of coenzyme QH and nicotinamide, and the other components exist as free forms. Preferably, all of the coenzyme QH is formed into a cocrystal to overcome the disadvantages of coenzyme QH's low melting point and poor stability. The other additives are not particularly limited and can vary depending on the purpose of application. For example, when applied to pharmaceuticals, they may be pharmacologically acceptable additives; when applied to supplements, they may be additives that are acceptable for supplements; when applied to food, they may be additives that are acceptable for food; when applied to cosmetics, they may be additives that are acceptable for cosmetics; and when applied to feed, they may be additives that are acceptable for feed.

[0025] In some embodiments, the stoichiometric ratio of coenzyme QH to nicotinamide in the coenzyme QH composition is 2:1.

[0026] The coenzyme QH composition having a stoichiometric ratio of coenzyme QH to nicotinamide of 2:1 has characteristic peaks in an X-ray powder diffraction pattern at 2θ angles of approximately 4.3°±0.2°, 5.7°±0.2°, 8.4°±0.2°, 9.9°±0.2°, 17.1°±0.2°, 17.9°±0.2°, 18.6°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 20.8°±0.2°, 27.8°±0.2°, and 30.3°±0.2°.

[0027] The Coenzyme QH composition having a 2:1 stoichiometric ratio of Coenzyme QH to nicotinamide has an X-ray powder diffraction pattern essentially as shown in FIG.

[0028] The coenzyme QH composition, having a stoichiometric ratio of coenzyme QH to nicotinamide of 2:1, has a characteristic endothermic peak at about 57±2°C in a differential scanning calorimetry diagram when heated at a rate of 10°C / min; preferably, has a differential scanning calorimetry diagram essentially as shown in Figure 5.

[0029] The coenzyme QH composition having a 2:1 stoichiometric ratio of coenzyme QH to nicotinamide has a wavelength of about 3465 cm in the infrared spectrum. -1 , 3195cm -1 , 2964cm -1 , 2945cm -1 , 2909cm -1 , 2848cm -1 , 1696cm -1 , 1664cm -1 , 1607cm -1 , 1445cm -1 , 1427cm -1 , 1384cm -1 , 1280cm -1 , 1261cm -1 , 1197cm -1 , 1164cm -1 , 1149cm -1 , 1109cm -1 , 1009cm -1 , 907cm -1 , 877cm -1 , 795cm -1 , 751cm -1 , 599cm -1 , 475cm -1 and preferably has an infrared spectrum essentially as shown in FIG.

[0030] In some further embodiments, the stoichiometric ratio of coenzyme QH to nicotinamide in the coenzyme QH composition is 1:1.5.

[0031] The coenzyme QH composition having a stoichiometric ratio of coenzyme QH to nicotinamide of 1:1.5 has characteristic peaks in an X-ray powder diffraction pattern at 2θ angles of approximately 4.3°±0.2°, 5.7°±0.2°, 8.4°±0.2°, 9.9°±0.2°, 17.1°±0.2°, 17.9°±0.2°, 18.6°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 20.8°±0.2°, 27.8°±0.2°, and 30.3°±0.2°.

[0032] The coenzyme QH composition having a stoichiometric ratio of coenzyme QH to nicotinamide of 1:1.5 has an X-ray powder diffraction pattern essentially as shown in FIG.

[0033] The coenzyme QH composition, having a stoichiometric ratio of coenzyme QH to nicotinamide of 1:1.5, has a characteristic endothermic peak at about 57±2°C in a differential scanning calorimetry diagram when heated at a rate of 10°C / min; preferably, has a differential scanning calorimetry diagram essentially as shown in Figure 8.

[0034] The coenzyme QH composition having a stoichiometric ratio of coenzyme QH to nicotinamide of 1:1.5 has a wavelength of about 3465 cm in the infrared spectrum. -1 , 3367cm -1 , 3167cm -1 , 2944cm -1 , 2909cm -1 , 2845cm -1 , 1697cm -1 , 1681cm -1 , 1619cm -1 , 1445cm -1 , 1422cm -1 , 1384cm -1 , 1280cm -1 , 1261cm -1 , 1197cm -1 , 1164cm -1 , 1149cm -1 , 1109cm -1 , 1009cm -1, 907cm -1 , 877cm -1 , 795cm -1 , 751cm -1 , 599cm -1 , 475cm -1 and preferably has an infrared spectrum essentially as shown in FIG.

[0035] In some further embodiments, the stoichiometric ratio of coenzyme QH to nicotinamide in the coenzyme QH composition is 1:2.

[0036] The coenzyme QH composition having a stoichiometric ratio of coenzyme QH to nicotinamide of 1:2 has characteristic peaks in an X-ray powder diffraction pattern at 2θ angles of about 4.3°±0.2°, 5.7°±0.2°, 8.4°±0.2°, 9.9°±0.2°, 14.8°±0.2°, 17.1°±0.2°, 17.9°±0.2°, 18.6°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 20.8°±0.2°, 25.3°±0.2°, 25.8°±0.2°, 27.3°±0.2°, 27.8°±0.2°, and 30.3°±0.2°.

[0037] The Coenzyme QH composition having a 1:2 stoichiometric ratio of Coenzyme QH to nicotinamide has an X-ray powder diffraction pattern essentially as shown in FIG.

[0038] The coenzyme QH composition, having a stoichiometric ratio of coenzyme QH to nicotinamide of 1:2, has a characteristic endothermic peak at about 57±2°C in a differential scanning calorimetry diagram when heated at a rate of 10°C / min; preferably, has a differential scanning calorimetry diagram essentially as shown in Figure 11.

[0039] The coenzyme QH composition having a stoichiometric ratio of coenzyme QH to nicotinamide of 1:2 has a wavelength of about 3465 cm in the infrared spectrum. -1 , 3367cm -1 , 3167cm -1 , 2944cm -1 , 2909cm-1 , 2845cm -1 , 1697cm -1 , 1681cm -1 , 1619cm -1 , 1445cm -1 , 1422cm -1 , 1384cm -1 , 1280cm -1 , 1261cm -1 , 1197cm -1 , 1164cm -1 , 1149cm -1 , 1109cm -1 , 1009cm -1 , 907cm -1 , 877cm -1 , 795cm -1 , 751cm -1 , 599cm -1 , 475cm -1 and preferably has an infrared spectrum essentially as shown in FIG.

[0040] In another aspect, the present invention provides a coenzyme QH product, which is selected from the group consisting of supplements, foods, cosmetics, pharmaceuticals, medicinal additives, and feeds, and which comprises a cocrystal of coenzyme QH and nicotinamide or the above-mentioned coenzyme QH composition.

[0041] In another aspect, the present invention provides a use of the cocrystal of coenzyme QH and nicotinamide or the above-mentioned coenzyme QH composition in the manufacture of a coenzyme QH product selected from the group consisting of supplements, foods, cosmetics, pharmaceuticals, medicinal additives, and feed.

[0042] The product may further include other suitable ingredients necessary for the product, for example, but not limited to, a food may include a food base and a food-based acceptable edible food additive (e.g., sweetener, flavoring, preservative, flavoring, coloring, etc.); a cosmetic may include a cosmetically acceptable cosmetic base and additive (e.g., solvent, flavoring, preservative, flavoring, coloring, etc.); a pharmaceutical may include a medicament active ingredient and a pharmacologically acceptable additive (e.g., carrier, diluent, adjuvant, coloring, etc.); a feed may include a feed base (e.g., soybean meal, hay, etc.) and a feed-based acceptable feed additive (e.g., sweetener, flavoring, preservative, flavoring, coloring, etc.), but not limited to these.

[0043] The above-mentioned product is prepared by adding the cocrystal of coenzyme QH and nicotinamide according to the present invention or the coenzyme QH composition according to the present invention. Other than adding the cocrystal of coenzyme QH and nicotinamide according to the present invention or the coenzyme QH composition according to the present invention, the preparation method of the above-mentioned product can be prepared by a general method.

[0044] The X-ray powder diffraction patterns in the present invention were obtained using a Bruker D8 Advanced model X-ray cocrystal diffractometer using Cu-Kα radiation (λ=1.54056 Å) with a scan range of 3° to 40° in the 2θ interval and a scan rate of 5° / min.

[0045] The differential scanning calorimetry was performed using a TA DSC Q2000 instrument with a heating rate of 10 K / min.

[0046] The Fourier transform infrared spectrometer used was a Thermo Scientific Nicolet 6700.

[0047] The ball mill used was the Joshin JX-2G planetary ball mill.

[0048] Liquid chromatography was performed using an Agilent 1260 Infinity HPLC.

[0049] Although the present invention has been described in detail above, the above-mentioned embodiments are merely illustrative and do not limit the present invention. Furthermore, the present specification is not limited by the above-mentioned prior art, the contents of the invention, or the theories described in the following examples.

[0050] Numerical ranges throughout this application include any subranges thereof and any value incremented by the smallest subunit of a given value therein, unless expressly stated otherwise. Numerical values ​​throughout the application represent approximate measures or limits of the range of embodiments including minor deviations from the given values, as well as approximate measures or limits of the range of embodiments having values ​​approximately equal to the stated values ​​and embodiments having the exact values ​​stated, unless expressly stated otherwise. Except for the working examples described at the end of the detailed description, all values ​​of parameters (e.g., quantities or conditions) in this application, including the appended claims, are understood to be modified in all cases by the term "about", regardless of whether "about" actually appears before the value. "About" means that the stated value is allowed to be slightly inaccurate (the precision of the value is somewhat close; roughly, or reasonably close to the value; approximate value). If the inaccuracy provided by "about" is not understood in this technical field in this ordinary sense, "about" as used herein at least indicates the variation that may occur with the ordinary methods of measuring and using these parameters. For example, "about" can include variations of up to 10%, up to 5%, up to 4%, up to 3%, up to 2%, up to 1%, or up to 0.5%, and in some embodiments up to 0.1%.

[0051] Unless expressly stated otherwise, the terms "comprising," "including," "having," "containing," or other similar terms used throughout this application are open ended terms indicating that a cocrystal or product may contain, in addition to the elements recited herein, other elements not expressly recited but normally inherent to the cocrystal or product. Also, as used herein, the terms "comprising," "including," "having," and "containing" are considered to be specifically disclosed and to include both closed and semi-closed conjunctions such as "consisting of" and "consisting essentially of." "Consisting essentially of" means that the elements recited herein constitute 95% or more, 97% or more, and in some embodiments 99% or more of the cocrystal or product.

[0052] Beneficial effects The present invention provides a stable cocrystal of coenzyme QH and nicotinamide. Compared with coenzyme QH itself, this cocrystal has a significantly improved chemical stability. The cocrystal disclosed in the present invention has the advantages of a simple preparation method, good reproducibility, low cost, environmental friendliness, and easy control. The cocrystal disclosed in the present invention has better chemical stability and can further expand the application range of coenzyme QH. Therefore, the cocrystal of coenzyme QH and nicotinamide has high practical application value. [Brief description of the drawings]

[0053] [Figure 1] 1 is an X-ray powder diffraction (XRPD) pattern of a cocrystal containing coenzyme QH and nicotinamide (both in a 1:1 stoichiometric ratio) provided by the present invention. [Diagram 2] FIG. 2 is a differential scanning calorimetry (DSC) diagram of a cocrystal containing coenzyme QH and nicotinamide (both in a 1:1 stoichiometric ratio) provided by the present invention. [Diagram 3] FIG. 2 is an infrared spectrum (IR) diagram of a cocrystal containing coenzyme QH and nicotinamide (both in a 1:1 stoichiometric ratio) provided by the present invention. [Figure 4]1 is an X-ray powder diffraction (XRPD) pattern of a Coenzyme QH composition provided by the present invention, comprising Coenzyme QH and nicotinamide (both in a stoichiometric ratio of 2:1). [Diagram 5] FIG. 2 is a differential scanning calorimetry (DSC) diagram of a coenzyme QH composition provided by the present invention, comprising coenzyme QH and nicotinamide (both in a stoichiometric ratio of 2:1). [Figure 6] FIG. 2 is an infrared spectrum (IR) diagram of a coenzyme QH composition provided by the present invention, comprising coenzyme QH and nicotinamide (both in a stoichiometric ratio of 2:1). [Figure 7] 1 is an X-ray powder diffraction (XRPD) pattern of a coenzyme QH composition provided by the present invention, comprising coenzyme QH and nicotinamide (both in a stoichiometric ratio of 1:1.5). [Figure 8] FIG. 2 is a differential scanning calorimetry (DSC) diagram of a coenzyme QH composition provided by the present invention, comprising coenzyme QH and nicotinamide (both in a stoichiometric ratio of 1:1.5). [Figure 9] FIG. 2 is an infrared spectrum (IR) diagram of a coenzyme QH composition provided by the present invention, comprising coenzyme QH and nicotinamide (both in a stoichiometric ratio of 1:1.5). [Figure 10] 1 is an X-ray powder diffraction (XRPD) pattern of a coenzyme QH composition provided by the present invention, comprising coenzyme QH and nicotinamide (both in a stoichiometric ratio of 1:2). [Figure 11] FIG. 2 is a differential scanning calorimetry (DSC) diagram of a coenzyme QH composition provided by the present invention, comprising coenzyme QH and nicotinamide (both in a stoichiometric ratio of 1:2). [Figure 12] FIG. 2 is an infrared spectrum (IR) diagram of a coenzyme QH composition provided by the present invention, comprising coenzyme QH and nicotinamide (both in a stoichiometric ratio of 1:2). [Figure 13] FIG. 2 is a differential scanning calorimetry (DSC) diagram of the coenzyme QH itself produced in Example 1 of the present invention. [Figure 14] FIG. 2 is a differential scanning calorimetry (DSC) diagram of Comparative Example 1 provided in the present invention. [Figure 15]FIG. 2 is a differential scanning calorimetry (DSC) diagram of Comparative Example 2 provided in the present invention. [Figure 16] FIG. 2 is a differential scanning calorimetry (DSC) diagram of Comparative Example 3 provided in the present invention. [Figure 17] FIG. 2 is a differential scanning calorimetry (DSC) diagram of Comparative Example 4 provided in the present invention. [Figure 18] FIG. 2 is a differential scanning calorimetry (DSC) diagram of Comparative Example 5 provided in the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be described in more detail with reference to the drawings and examples below. It should be noted that the specific examples described herein are only used to explain the present invention and do not limit the present invention. EXAMPLES

[0055] Example 1 10g of oxidized coenzyme Q10 and 6g of L-ascorbic acid were added to 100g of 95% ethanol, and the mixture was stirred at 78℃ to carry out the reduction reaction. After 20 hours, the mixture was cooled to 0℃, and stirred for 1 hour while maintaining the temperature, and then filtered under reduced pressure. The filter cake was rinsed three times with 95% ethanol and dried under reduced pressure to obtain white cocrystals. All operations except for drying under reduced pressure were carried out under nitrogen protection. The weight ratio of coenzyme QH / oxidized coenzyme Q10 in the obtained sample was 99.2 / 0.8.

[0056] This powder was detected by differential scanning calorimetry (DSC), and the results are shown in Figure 13. As can be seen from Figure 13, QH has a characteristic endothermic peak at about 49°C.

[0057] Example 2 0.4 g of nicotinamide and 1 g of coenzyme QH obtained in Example 1 were added to 10 ml of a solvent of isopropanol / isopropyl acetate = 1 / 1, stirred at 40 ° C until it became clear, and recrystallized 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 12 hours to obtain a cocrystal of coenzyme QH and nicotinamide.

[0058] The contents of coenzyme QH and nicotinamide in the obtained cocrystal of coenzyme QH and nicotinamide were measured by high performance liquid chromatography, respectively, and the content of coenzyme QH was about 86.1%, and the content of nicotinamide was about 12.6%, which indicated that the stoichiometric ratio of coenzyme QH to nicotinamide in this cocrystal was about 1:1.

[0059] The cocrystal was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy, and the results are shown in Figures 1-3, respectively.

[0060] As shown in Figure 1, the cocrystal of coenzyme QH and nicotinamide has characteristic peaks in the X-ray powder diffraction pattern at 2θ angles of approximately 4.3°, 5.7°, 8.4°, 9.9°, 17.1°, 17.9°, 18.6, 18.9°, 19.1°, 19.8°, 20.8°, 23.1°, 27.8°, 30.3°, etc.

[0061] As shown in FIG. 2, the differential scanning calorimetry diagram of the cocrystal of coenzyme QH and nicotinamide has a characteristic endothermic peak at about 57° C.

[0062] As shown in FIG. 3, the cocrystal of coenzyme QH and nicotinamide has a peak at about 3465 cm in the infrared spectrum. -1 , 3170cm -1 , 2964cm -1 , 2945cm -1 , 2907cm -1 , 2847cm -1 , 1697cm -1 , 1664cm -1, 1607cm -1 , 1445cm -1 , 1422cm -1 , 1384cm -1 , 1280cm -1 , 1261cm -1 , 1197cm -1 , 1164cm -1 , 1149cm -1 , 1109cm -1 , 1009cm -1 , 907cm -1 , 877cm -1 , 795cm -1 , 751cm -1 , 599cm -1 , 475cm -1 It has a characteristic peak at

[0063] Example 3 0.122 g of nicotinamide and 0.87 g of coenzyme QH obtained in Example 1 were added to 2 ml of ethanol, stirred at 60°C until clear, and recrystallized to obtain a white solid. The solid was dried at room temperature in a vacuum drying box for 12 hours to obtain a cocrystal of coenzyme QH and nicotinamide.

[0064] The contents of coenzyme QH and nicotinamide in the obtained cocrystal of coenzyme QH and nicotinamide were measured by high performance liquid chromatography, respectively, and the content of coenzyme QH was about 84.0%, and the content of nicotinamide was about 11.8%, which indicated that the stoichiometric ratio of coenzyme QH to nicotinamide in this cocrystal was about 1:1.

[0065] The cocrystal was characterized by solid-state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy, and the results were essentially consistent with those of the cocrystal of coenzyme QH and nicotinamide in Example 2.

[0066] Example 4 0.244 g of nicotinamide and 1.72 g of coenzyme QH obtained in Example 1 were placed in a ball mill, 1 ml of ethanol was added, and the mixture was ball milled for 2 hours. The solid was then dried at room temperature in a vacuum drying box for 12 hours to obtain a cocrystal of coenzyme QH and nicotinamide.

[0067] The cocrystal was characterized by solid-state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy, and the results were essentially consistent with those of the cocrystal of coenzyme QH and nicotinamide in Example 2.

[0068] Example 5 0.244 g of nicotinamide and 1.72 g of coenzyme QH obtained in Example 1 were placed in a ball mill, 1 ml of a 1 / 1 mixture of ethanol and ethyl acetate was added, and the mixture was ball milled for 2 hours. The solid was then dried at room temperature in a vacuum drying box for 12 hours to obtain a cocrystal of coenzyme QH and nicotinamide.

[0069] The cocrystal was characterized by solid-state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy, and the results were consistent with those of the cocrystal of coenzyme QH and nicotinamide in Example 2.

[0070] Example 6 0.122 g of nicotinamide and 1.72 g of coenzyme QH obtained in Example 1 were placed in a ball mill can, 1 ml of ethanol was added, and the mixture was ball milled for 2 hours. The solid was then dried at room temperature in a vacuum drying box for 12 hours to obtain a coenzyme QH composition in which the stoichiometric ratio of coenzyme QH to nicotinamide was 2:1.

[0071] The Coenzyme QH composition was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy, and the results are shown in Figures 4-6, respectively.

[0072] As can be seen from the X-ray powder diffraction (XRPD) pattern in Figure 4, the coenzyme QH composition has characteristic peaks of the cocrystal of the above coenzyme QH and nicotinamide at 2θ angles of approximately 4.3°, 5.7°, 17.1°, 17.9°, 18.9°, 19.8°, 20.8°, and 23.1° in the XRPD pattern, indicating that the coenzyme QH composition contains the above cocrystal of coenzyme QH and nicotinamide.

[0073] As can be seen from the differential scanning calorimetry (DSC) diagram in Figure 5, the DSC diagram of the coenzyme QH composition has characteristic endothermic peaks at about 50℃-60℃, among which the first peak essentially coincides with the melting peak of coenzyme QH, and the second peak essentially coincides with the cocrystal of coenzyme QH and nicotinamide, indicating that the composition is formed with coenzyme QH and the cocrystal of coenzyme QH and nicotinamide.

[0074] As can be seen from the infrared spectrum of FIG. 6, the coenzyme QH composition has an infrared spectrum of about 3465 cm -1 , 3170cm -1 , 1697cm -1 This indicates that the coenzyme QH composition contains the above-mentioned cocrystal of coenzyme QH and nicotinamide.

[0075] Example 7 0.366 g of nicotinamide and 1.72 g of coenzyme QH obtained in Example 1 were placed in a ball mill, 1 ml of ethanol solvent was added, and the mixture was ball milled for 2 hours. The solid was then dried at room temperature in a vacuum drying box for 12 hours to obtain a coenzyme QH composition with a stoichiometric ratio of coenzyme QH to nicotinamide of 1:1.5.

[0076] The Coenzyme QH composition was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy, and the results are shown in Figures 7-9, respectively.

[0077] As can be seen from the X-ray powder diffraction (XRPD) pattern in Figure 7, the coenzyme QH composition has characteristic peaks of the cocrystal of the above coenzyme QH and nicotinamide at 2θ angles of approximately 4.3°, 5.7°, 17.1°, 17.9°, 18.9°, 19.8°, 20.8°, and 23.1° in the XRPD pattern, indicating that the coenzyme QH composition contains the above cocrystal of coenzyme QH and nicotinamide.

[0078] As can be seen from the differential scanning calorimetry (DSC) diagram in Figure 8, the differential scanning calorimetry diagram of the coenzyme QH composition had a characteristic endothermic peak at about 56°C, which was almost identical to the cocrystal of coenzyme QH and nicotinamide described above.

[0079] As can be seen from the infrared spectrum of FIG. 9, the coenzyme QH composition has an infrared spectrum of about 3465 cm -1 , 3170cm -1 , 1697cm -1 This indicates that the coenzyme QH composition contains the cocrystal of coenzyme QH and nicotinamide. -1 This showed that the composition was formed with nicotinamide and a cocrystal of nicotinamide with coenzyme QH.

[0080] Example 8 0.488 g of nicotinamide and 1.72 g of the coenzyme QH obtained in Example 1 were placed in a ball mill can, 1 ml of ethanol solvent was added, and the mixture was ball milled for 2 hours. The solid was dried at room temperature in a vacuum drying box for 12 hours to obtain a coenzyme QH composition in which the stoichiometric ratio of coenzyme QH to nicotinamide was 1:2.

[0081] The Coenzyme QH composition was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy, and the results are shown in Figures 10-12, respectively.

[0082] As can be seen from the X-ray powder diffraction (XRPD) pattern in Figure 10, the coenzyme QH composition has characteristic peaks of the cocrystal of the above coenzyme QH and nicotinamide at 2θ angles of approximately 4.3°, 5.7°, 17.1°, 17.9°, 18.9°, 19.8°, 20.8°, and 23.1° in the XRPD pattern, indicating that the coenzyme QH composition contains the above cocrystal of coenzyme QH and nicotinamide.

[0083] As can be seen from the differential scanning calorimetry (DSC) diagram in Figure 11, the differential scanning calorimetry diagram of the coenzyme QH composition had a characteristic endothermic peak at about 56°C, which was almost identical to the cocrystal of coenzyme QH and nicotinamide described above.

[0084] As can be seen from the infrared spectrum of FIG. 12, the coenzyme QH composition has an infrared spectrum of about 3465 cm -1 , 3170cm -1 , 1697cm -1 This indicates that the coenzyme QH composition contains the cocrystal of coenzyme QH and nicotinamide. -1 This showed that the composition was formed with nicotinamide and a cocrystal of nicotinamide with coenzyme QH.

[0085] Example 9 (Comparison of the stability of coenzyme QH itself and the coenzyme QH cocrystal described in the present invention) The experiments were carried out using coenzyme QH obtained in Example 1 and the cocrystals of coenzyme QH and nicotinamide or coenzyme QH compositions obtained in Examples 4-6.

[0086] A comparison was made between the stability difference between the coenzyme QH obtained in Example 1 and the cocrystals containing coenzyme QH and nicotinamide obtained in Examples 4-6. The coenzyme QH obtained in Example 1 and the coenzyme QH cocrystals obtained in Examples 4-6 were stored open and protected from light under conditions of 25°C / 60% relative humidity. The weight ratio of coenzyme QH to oxidized coenzyme Q10 was analyzed by HPLC. The results are shown in Table 1.

[0087] [Table 1]

[0088] As shown by the above results, compared with the coenzyme QH prepared in Example 1, the coenzyme QH composition or cocrystal disclosed in the present invention has better stability, and can still maintain stability for a long period of time even under conditions where no protective measures against oxygen are adopted, thereby indicating that the coenzyme QH cocrystal described in the present invention has significantly improved stability compared with coenzyme QH itself.

[0089] Comparative Example 1 0.244 g of nicotinic acid and 1.72 g of the coenzyme QH obtained in Example 1 were placed in a ball mill, 1 ml of ethanol was added, and the mixture was ball milled for 2 hours. The solid was then dried at room temperature in a vacuum drying box for 12 hours to obtain a yellow powder.

[0090] This powder was detected by differential scanning calorimetry (DSC), and the results are shown in FIG. 14, which shows that there was no obvious difference in melting point compared to QH itself.

[0091] Comparative Example 2 0.752 g of riboflavin and 1.72 g of the coenzyme QH obtained in Example 1 were placed in a ball mill, 1 ml of ethanol was added, and the mixture was ball milled for 2 hours. The solid was then dried at room temperature in a vacuum drying box for 12 hours to obtain a yellow powder.

[0092] This powder was detected by differential scanning calorimetry (DSC), and the results are shown in FIG. 15, showing that there was no obvious difference in melting point compared to QH itself.

[0093] Comparative Example 3 0.477 g of calcium pantothenate and 1.72 g of the coenzyme QH obtained in Example 1 were placed in a ball mill can, 1 ml of ethanol was added, and the mixture was ball milled for 2 hours. The solid was then dried at room temperature in a vacuum drying box for 12 hours to obtain a near-white powder.

[0094] This powder was detected by differential scanning calorimetry (DSC), and the results are shown in FIG. 16, showing that there was no obvious difference in melting point compared to QH itself.

[0095] Comparative Example 4 0.882 g of folic acid and 1.72 g of the coenzyme QH obtained in Example 1 were placed in a ball mill, 1 ml of ethanol was added, and the mixture was ball milled for 2 hours. The solid was then dried at room temperature in a vacuum drying box for 12 hours to obtain a yellow powder.

[0096] This powder was detected by differential scanning calorimetry (DSC), and the results are shown in FIG. 17, showing that there was no obvious difference in melting point compared to QH itself.

[0097] Comparative Example 5 0.352 g of ascorbic acid and 1.72 g of the coenzyme QH obtained in Example 1 were placed in a ball mill, 1 ml of ethanol was added, and the mixture was ball milled for 2 hours. The solid was then dried at room temperature in a vacuum drying box for 12 hours to obtain a near-white powder.

[0098] This powder was detected by differential scanning calorimetry (DSC), and the results are shown in FIG. 18, showing that there was no obvious difference in melting point compared to QH itself.

[0099] From the above results, it was found that nicotinic acid, riboflavin, calcium pantothenate, folic acid and ascorbic acid were unable to form cocrystals with coenzyme QH to improve its stability.

Claims

1. A cocrystal of coenzyme QH and nicotinamide, characterized in that the stoichiometric ratio of coenzyme QH to nicotinamide in the cocrystal is 1:1, and the cocrystal has an X-ray powder diffraction pattern having characteristic peaks at 2θ angles of 4.3°±0.2°, 5.7°±0.2°, 17.1°±0.2°, 17.9°±0.2°, 18.9°±0.2°, 19.8°±0.2°, 20.8°±0.2°, and 23.1°±0.2°.

2. and further having an X-ray powder diffraction pattern having characteristic peaks at 2θ angles of 8.4°±0.2°, 9.9°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 27.8°±0.2°, and 30.3°±0.2°. A cocrystal of coenzyme QH and nicotinamide according to claim 1.

3. A cocrystal of coenzyme QH and nicotinamide as described in claim 1, wherein the cocrystal has a differential scanning calorimetry diagram having a characteristic endothermic peak at 57±2°C when heated at a rate of 10°C / min, as determined by differential scanning calorimetry measurement.

4. The cocrystal has a molecular weight of 3465 cm －１ , 3170 cm －１ , and 1697 cm －１ and further having a characteristic peak at 2964 cm －１ , 2945 cm －１ , 2907 cm －１ , 2847 cm －１ , 1664 cm －１ , 1607 cm －１ , 1445 cm －１ , 1422 cm －１ , 1384 cm －１ , 1280 cm －１ , 1261 cm －１ , 1197 cm －１ , 1164 cm －１ , 1149 cm －１ , 1109 cm －１ , 1009 cm －１ , 907 cm －１ , 877 cm －１ , 795 cm －１ , 751 cm －１ , 599 cm －１ , 475 cm －１ The cocrystal of coenzyme QH and nicotinamide described in claim 1, having an infrared spectrum with a characteristic peak at

5. A method for producing a cocrystal of coenzyme QH and nicotinamide according to any one of claims 1 to 4, which is one of the following methods: Method 1: Coenzyme QH and nicotinamide are recrystallized in a solvent, precipitated, and dried to obtain a cocrystal of coenzyme QH and nicotinamide. Method 2: Coenzyme QH and nicotinamide are ball-milled in a solvent for 10 minutes or more, and the resulting solid is then dried to obtain a cocrystal of coenzyme QH and nicotinamide.

6. 6. The method according to claim 5, wherein the solvent is one or more selected from the group consisting of water, alcohols, ketones, esters, alkanes, aromatic hydrocarbons, and halogenated alkanes.

7. The method of claim 6, characterized in that the solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, methyl tert-butyl ether, n-hexane, and n-heptane.

8. A coenzyme QH composition comprising a cocrystal of coenzyme QH and nicotinamide according to any one of claims 1 to 4.

9. The coenzyme QH composition according to claim 8, characterized in that in the composition, the stoichiometric ratio of coenzyme QH to nicotinamide is 2:1 to 1:

2.

10. A coenzyme QH product selected from the group consisting of supplements, foods, cosmetics, pharmaceuticals, medicinal additives, and feeds, comprising a cocrystal of coenzyme QH and nicotinamide described in any one of claims 1 to 4, or a coenzyme QH composition described in claim 8 or 9.

11. Use of the cocrystal of coenzyme QH and nicotinamide described in any one of claims 1 to 4, or the coenzyme QH composition described in claim 8 or 9, in the manufacture of a coenzyme QH product, which is a product selected from the group consisting of supplements, foods, cosmetics, pharmaceuticals, medicinal additives, and feed.

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