CO-CRYSTAL OF COENZYME QH AND NICOTINAMIDE, PREPARATION METHOD THEREFOR AND USE THEREOF
20240140897 ยท 2024-05-02
Inventors
Cpc classification
C07C46/10
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention relates to a co-crystal of coenzyme QH and nicotinamide, a preparation method therefor and the use thereof. Compared with the existing coenzyme QH, the co-crystal has a higher melting point and superior stability. The preparation method for the co-crystal of coenzyme QH is simple, easy to control and good in terms of reproducibility. The present invention greatly improves the use convenience of coenzyme QH, saves costs during storage, transportation and use, and broadens the application range of coenzyme QH.
Claims
1. A co-crystal of coenzyme QH and nicotinamide, wherein the stoichiometric ratio of coenzyme QH to nicotinamide is 1:1 in the co-crystal.
2. The co-crystal of coenzyme QH and nicotinamide according to claim 1, wherein the co-crystal has an X-ray powder diffraction pattern having characteristic peaks at 2? 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?.
3. The co-crystal of coenzyme QH and nicotinamide according to claim 1, wherein the co-crystal has a differential scanning calorimetry pattern having a characteristic endothermic peak at 57?2? C. when the temperature is increased at a rate of 10? C./min, as determined by differential scanning calorimetry.
4. The co-crystal of coenzyme QH and nicotinamide according to claim 1, wherein the co-crystal has an infrared spectrum having characteristic peaks at 3465 cm.sup.?1, 3170 cm.sup.?1 and 1697 cm.sup.?1.
5. A method for preparing the co-crystal of coenzyme QH and nicotinamide according to claim 1, subjecting coenzyme QH and nicotinamide to ball milling in a solvent for 10 minutes or more; and drying a solid obtained from the subjecting to obtain the co-crystal of coenzyme QH and nicotinamide.
6. The method according to claim 5, wherein the solvent is one or more selected from the group consisting of water, an alcohol, a ketone, an ester, an alkane, an aromatic hydrocarbon and a halogenated alkane.
7. A coenzyme QH composition, comprising the co-crystal of coenzyme QH and nicotinamide according to claim 1.
8. The coenzyme QH composition according to claim 7, wherein in the composition, the stoichiometric ratio of coenzyme QH to nicotinamide is 2:1 to 1:2.
9. A coenzyme QH product, comprising the co-crystal of coenzyme QH and nicotinamide according to claim 1, wherein the product is selected from the group consisting of a health product, a food, a cosmetic, a medicine, a pharmaceutical excipient and a feed.
10. A coenzyme QH product, comprising the coenzyme QH composition according to claim 7, wherein the product is selected from the group consisting of a health product, a food, a cosmetic, a medicine, a pharmaceutical excipient and a feed.
11. The co-crystal of coenzyme QH and nicotinamide according to claim 1, wherein the co-crystal has an X-ray powder diffraction pattern having characteristic peaks at 2? 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?.
12. The co-crystal of coenzyme QH and nicotinamide according to claim 1, wherein the co-crystal has an infrared spectrum having characteristic peaks at 2964 cm.sup.?1, 2945 cm.sup.?1, 2907 cm.sup.?1, 2847 cm.sup.?1, 1664 cm.sup.?1, 1607 cm.sup.?1, 1445 cm.sup.?1, 1422 cm.sup.?1, 1384 cm.sup.?1, 1280 cm.sup.?1, 1261 cm.sup.?1, 1197 cm.sup.?1, 1164 cm.sup.?1, 1149 cm.sup.?1, 1109 cm.sup.?1, 1009 cm.sup.?1, 907 cm.sup.?1, 877 cm.sup.?1, 795 cm.sup.?1, 751 cm.sup.?1, 599 cm.sup.?1 and 475 cm.sup.?1.
13. The method according to claim 5, wherein 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.
14. A method for preparing the co-crystal of coenzyme QH and nicotinamide according to claim 1, comprising: recrystallizing coenzyme QH and nicotinamide in a solvent to obtain a precipitate; and drying the precipitate to obtain the co-crystal of coenzyme QH and nicotinamide.
15. The method according to claim 14, wherein the solvent is one or more selected from the group consisting of water, an alcohol, a ketone, an ester, an alkane, an aromatic hydrocarbon and a halogenated alkane.
16. The method according to claim 14, wherein 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.
Description
DESCRIPTION OF THE DRAWINGS
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MODE OF THE INVENTION
[0072] In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention will be further described in detail below in conjunction with the accompanying drawings and examples. It should be understood that the specific examples described here are only used to explain the present invention, not to limit the present invention.
Example 1
[0073] To 100 g of 95% ethanol, 10 g of oxidized coenzyme Q10 and 6 g of L-ascorbic acid were added. The mixture was stirred at 78? C. for reduction for 20 hours, cooled to 0? C. and kept stirring at this temperature for 1 hour. The mixture was filtered under reduced pressure. The filter cake was washed three times with 95% ethanol, and dried under reduced pressure to obtain a white powder. All operations were performed under nitrogen protection except for drying under reduced pressure. The weight ratio of coenzyme QH/oxidized coenzyme Q10 in the obtained sample was 99.2/0.8.
[0074] The powder was detected by differential scanning calorimetry (DSC), and the result is shown in
Example 2
[0075] 0.4 g of nicotinamide and 1 g of the coenzyme QH obtained in Example 1 were added to 10 ml of a solvent of isopropanol/isopropyl acetate=1/1, stirred at 40? C. to be dissolved, and recrystallized to obtain a white precipitate, which was filtered through a Buchner funnel. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain a co-crystal of coenzyme QH and nicotinamide.
[0076] The contents of coenzyme QH and nicotinamide in the co-crystal of coenzyme QH and nicotinamide obtained were measured respectively by high performance liquid chromatography, and it was found that the content of coenzyme QH was about 86.1%, and the content of nicotinamide was about 12.6%, indicating that in this co-crystal, the stoichiometric ratio of coenzyme QH to nicotinamide was about 1:1.
[0077] This co-crystal was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are shown in
[0078] As shown in
[0079] As shown in
[0080] As shown in
Example 3
[0081] 0.122 g of nicotinamide and 0.87 g of the coenzyme QH obtained in Example 1 were added to 2 ml of ethanol, stirred at 60? C. to be dissolved, and recrystallized to obtain a white solid. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain a co-crystal of coenzyme QH and nicotinamide.
[0082] The contents of coenzyme QH and nicotinamide in the co-crystal of coenzyme QH and nicotinamide obtained were measured respectively by high performance liquid chromatography, and it was found that the content of coenzyme QH was about 84.0%, and the content of nicotinamide was about 11.8%, indicating that in this co-crystal, the stoichiometric ratio of coenzyme QH to nicotinamide was about 1:1.
[0083] This co-crystal was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results were basically consistent with the detection results of the co-crystal of coenzyme QH and nicotinamide in Example 2 respectively.
Example 4
[0084] 0.244 g of nicotinamide and 1.72 g of the coenzyme QH obtained in Example 1 were added to a ball mill jar, and 1 ml of ethanol was added thereto. The ball milling was performed for 2 hours. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain a co-crystal of coenzyme QH and nicotinamide.
[0085] This co-crystal was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results were basically consistent with the detection results of the co-crystal of coenzyme QH and nicotinamide in Example 2 respectively.
Example 5
[0086] 0.244 g of nicotinamide and 1.72 g of the coenzyme QH obtained in Example 1 were added to a ball mill jar, and 1 ml of a solvent of isopropanol/isopropyl acetate=1/1 was added thereto. The ball milling was performed for 2 hours. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain a co-crystal of coenzyme QH and nicotinamide.
[0087] This co-crystal was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results were basically consistent with the detection results of the co-crystal of coenzyme QH and nicotinamide in Example 2 respectively.
Example 6
[0088] 0.122 g of nicotinamide and 1.72 g of the coenzyme QH obtained in Example 1 were added to a ball mill jar, and 1 ml of ethanol was added thereto. The ball milling was performed for 2 hours. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain a coenzyme QH composition, wherein the stoichiometric ratio of coenzyme QH to nicotinamide is 2:1.
[0089] This coenzyme QH composition was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are shown in
[0090] It can be seen from the X-ray powder diffraction (XRPD) pattern in
[0091] It can be seen from the differential scanning calorimetry (DSC) pattern in
[0092] It can be seen from the infrared spectrum in
Example 7
[0093] 0.366 g of nicotinamide and 1.72 g of the coenzyme QH obtained in Example 1 were added to a ball mill jar, and 1 ml of ethanol was added thereto. The ball milling was performed for 2 hours. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain a coenzyme QH composition, wherein the stoichiometric ratio of coenzyme QH to nicotinamide was 1:1.5.
[0094] This coenzyme QH composition was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are shown in
[0095] It can be seen from the X-ray powder diffraction (XRPD) pattern in
[0096] It can be seen from the differential scanning calorimetry (DSC) pattern in
[0097] It can be seen from the infrared spectrum in
Example 8
[0098] 0.488 g of nicotinamide and 1.72 g of the coenzyme QH obtained in Example 1 were added to a ball mill jar, and 1 ml of ethanol was added thereto. The ball milling was performed for 2 hours. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain a coenzyme QH composition, wherein the stoichiometric ratio of coenzyme QH to nicotinamide was 1:2.
[0099] This coenzyme QH composition was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are shown in
[0100] It can be seen from the X-ray powder diffraction (XRPD) pattern in
[0101] It can be seen from the differential scanning calorimetry (DSC) pattern in
[0102] It can be seen from the infrared spectrum in
Example 9 (Comparison of the Stabilities of Coenzyme QH Itself and the Coenzyme QH Co-Crystal of the Present Invention)
[0103] The coenzyme QH obtained in Example 1 and the co-crystal of coenzyme QH and nicotinamide or the coenzyme QH compositions obtained in Examples 4-6 were used.
[0104] The coenzyme QH obtained in Example 1 and the co-crystals comprising coenzyme QH and nicotinamide obtained in Examples 4-6 were compared in terms of stability. The coenzyme QH obtained in Example 1 and the coenzyme QH co-crystals obtained in Examples 4-6 were open stored away from light under the conditions of 25? C./60% relative humidity. The weight ratio of coenzyme QH and oxidized coenzyme Q10 was analyzed by HPLC. The results are shown in Table 1.
TABLE-US-00001 TABLE 1 Weight ratio of coenzyme QH and oxidized coenzyme Q10 Coenzyme QH Coenzyme QH Number Coenzyme QH composition Co-crystal composition of obtained in obtained in obtained in obtained in days Example 1 Example 4 Example 5 Example 6 Day 0 99.2.0/0.8 97.9/2.1 98.3/1.7 98.4/1.6 Day 3 91.4/8.6 97.5/2.5 98.5/1.5 98.4/1.6 Day 7 85.9/14.1 96.3/3.7 98.3/1.7 97.9/2.1 Day 14 71.2/28.8 90.8/9.2 98.1/1.9 94.3/5.7
[0105] As shown in the above results, compared with the coenzyme QH prepared in Example 1, the coenzyme QH composition or co-crystal disclosed in the present invention has more excellent stability, and can still remain stable for a long time without deliberately taking protective measures against oxygen, indicating that the coenzyme QH co-crystal of the present invention had significantly improved stability compared with the coenzyme QH itself.
Comparative Example 1
[0106] 0.244 g of nicotinic acid and 1.72 g of the coenzyme QH obtained in Example 1 were added to a ball mill jar, and 1 ml of ethanol was added thereto. The ball milling was performed for 2 hours. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain a yellow powder.
[0107] This powder was detected by differential scanning calorimetry (DSC), and the results are shown in
Comparative Example 2
[0108] 0.752 g of riboflavin and 1.72 g of the coenzyme QH obtained in Example 1 were added to a ball mill jar, and 1 ml of ethanol was added thereto. The ball milling was performed for 2 hours. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain a yellow powder.
[0109] This powder was detected by differential scanning calorimetry (DSC), and the results are shown in
Comparative Example 3
[0110] 0.477 g of calcium pantothenate and 1.72 g of the coenzyme QH obtained in Example 1 were added to a ball mill jar, and 1 ml of ethanol was added thereto. The ball milling was performed for 2 hours. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain an off-white powder.
[0111] This powder was detected by differential scanning calorimetry (DSC), and the results are shown in
Comparative Example 4
[0112] 0.882 g of folic acid and 1.72 g of the coenzyme QH obtained in Example 1 were added to a ball mill jar, and 1 ml of ethanol was added thereto. The ball milling was performed for 2 hours. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain a yellow powder.
[0113] This powder was detected by differential scanning calorimetry (DSC), and the results are shown in
Comparative Example 5
[0114] 0.352 g of ascorbic acid and 1.72 g of the coenzyme QH obtained in Example 1 were added to a ball mill jar, and 1 ml of ethanol was added thereto. The ball milling was performed for 2 hours. The solid was dried in a vacuum oven at room temperature for 12 hours to obtain an off-white powder.
[0115] This powder was detected by differential scanning calorimetry (DSC), and the results are shown in
[0116] The above results indicate that none of niacin, riboflavin, calcium pantothenate, folic acid, and ascorbic acid could form a co-crystal with coenzyme QH to improve the stability of coenzyme QH.