WO2022184120A1 - 羟基酪醇烟酰胺共晶，其制备方法及组合物 - Google Patents

羟基酪醇烟酰胺共晶，其制备方法及组合物 Download PDF

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WO2022184120A1
WO2022184120A1 PCT/CN2022/078935 CN2022078935W WO2022184120A1 WO 2022184120 A1 WO2022184120 A1 WO 2022184120A1 CN 2022078935 W CN2022078935 W CN 2022078935W WO 2022184120 A1 WO2022184120 A1 WO 2022184120A1
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hydroxytyrosol
nicotinamide
crystal
composition
temperature
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PCT/CN2022/078935
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English (en)
French (fr)
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梅雪锋
江宇航
朱冰清
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中国科学院上海药物研究所
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Priority to EP22762582.9A priority Critical patent/EP4303212A1/en
Priority to JP2023554035A priority patent/JP2024510430A/ja
Priority to US18/548,971 priority patent/US20240166604A1/en
Publication of WO2022184120A1 publication Critical patent/WO2022184120A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/11—Alkylated hydroxy benzenes containing also acyclically bound hydroxy groups, e.g. saligenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention relates to the technical field of medicine, in particular to a co-crystal of hydroxytyrosol nicotinamide, a preparation method and a composition thereof.
  • Hydroxytyrosol is a polyphenolic compound extracted from olive oil, and the specific structural formula is as shown in I:
  • Hydroxytyrosol has strong antioxidant capacity and wide range of biological activities. At present, it has been widely used in food, health products and cosmetics.
  • the hydroxytyrosol raw material itself has a low melting point (52°C), high hygroscopicity, and presents a waxy solid form or a viscous oily state at ambient temperature and humidity, which cannot be directly used in hard capsules or tablets, and the raw material itself is not suitable for Light, heat, moisture, oxygen, etc. are extremely unstable, and are easily oxidized and discolored during use.
  • hydroxytyrosol is protected by embedding method, and the hydroxytyrosol embedded powder formed has a loading capacity of 20-30%.
  • the powder properties of the embedded powder are optimized, but due to Hydroxytyrosol is an amphiphilic compound, the encapsulation rate is not high, and the unembedded hydroxytyrosol still has problems such as instability and easy discoloration; and because the embedding powder contains a large amount of starch excipients, the hygroscopicity is further increase.
  • the primary purpose of the present invention is to provide a co-crystal of hydroxytyrosol nicotinamide.
  • the second purpose of the present invention is to provide a preparation method of the hydroxytyrosol nicotinamide co-crystal.
  • the third object of the present invention is to propose a composition containing the hydroxytyrosol nicotinamide co-crystal.
  • the present invention prepares hydroxytyrosol co-crystals by adding auxiliary compounds.
  • the auxiliary compounds interact with hydroxytyrosol by non-covalent bonds at the molecular level. Horizontally increase the melting point of hydroxytyrosol, improve its stability, and broaden its application fields.
  • the present invention proposes a hydroxytyrosol nicotinamide co-crystal compound, wherein the molar ratio of hydroxytyrosol and nicotinamide is 1:1, and the structural formula of nicotinamide is shown in formula II:
  • the hydroxytyrosol nicotinamide co-crystals prepared by the present invention have significantly higher melting points than hydroxytyrosol. It is well known that not all co-crystals have significantly higher melting points, and some lower than the melting points of the two compounds alone. In some embodiments, the hydroxytyrosol co-crystals prepared by the present invention also have significantly reduced hygroscopicity compared to hydroxytyrosol. In some embodiments, the hydroxytyrosol co-crystals prepared by the present invention have significantly improved chemical stability compared to hydroxytyrosol.
  • the hydroxytyrosol nicotinamide co-crystal of the present invention has an X-ray powder diffraction pattern in 2 ⁇ 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, 20.8 ⁇ 0.2 diffraction angles have characteristic peaks. More particularly, having an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the melting point of the hydroxytyrosolnicotinamide co-crystal of the present invention is 111°C ⁇ 2°C.
  • the melting onset temperature of the hydroxytyrosol nicotinamide co-crystal was determined by differential scanning calorimetry to be 110 ⁇ 2°C, and the maximum peak was 111 ⁇ 2°C. More particularly, there is a differential scanning calorimetry diagram substantially as shown in FIG. 2 .
  • the infrared absorption spectrum of the hydroxytyrosol nicotinamide co-crystal is 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 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 have absorption peaks. More particularly, having an infrared spectrum substantially as shown in FIG. 3 .
  • the present invention relates to a method for preparing a hydroxytyrosol co-crystal, comprising the steps of contacting hydroxytyrosol and nicotinamide in a molecular state and then crystallizing.
  • Contacting in a molecular state may include, but is not limited to, solution synthesis, solid state milling, and the like.
  • Solution synthesis method refers to the synthesis of co-crystals in solution, including slow evaporation, cooling crystallization, suspension crystallization, elution crystallization, etc.
  • Solid-state grinding methods mainly include solid dry grinding and solvent-assisted grinding. Dry grinding is a method to obtain a co-crystal product by grinding the mixture of the main drug and ligand, and solution-assisted grinding is a method to improve the grinding efficiency by adding a small amount of solvent during the grinding process.
  • Solid state milling methods include ball milling or high-speed shearing.
  • the method for preparing hydroxytyrosol co-crystal can be one of the following methods:
  • the hydroxytyrosol and nicotinamide are mixed in a pulverizing device to obtain a co-crystal of hydroxytyrosol and nicotinamide.
  • the first method includes at least the following steps:
  • the first temperature is 10-80°C, preferably 30-50°C.
  • the organic solvent is selected from methanol, ethanol, n-propanol, n-butanol, isopropanol, isobutanol, isoamyl alcohol, tert-butanol, One or more of acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, ethyl formate, ethyl acetate, isopropyl acetate, and isobutyl acetate.
  • the organic solvent is selected from a mixed solvent of ethanol and isoamyl alcohol, a mixed solvent of ethanol and isobutanol, 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, more preferably 1:1.
  • the temperature of the second temperature is -40 to 0°C, preferably -30 to -10°C.
  • seed crystals can be added to the crystallization process to accelerate the formation of crystals.
  • the crystallization also includes the steps of solid-liquid separation and drying; wherein, the solid-liquid separation can be carried out by methods such as filtration, centrifugation, and preferably filtration; drying can be carried out by means of atmospheric drying, vacuum drying, spray drying, etc., and Vacuum drying at room temperature is preferred.
  • the second method includes at least the following steps:
  • the hydroxytyrosol and nicotinamide are placed in a pulverizing device for mixing, and the molar ratio of hydroxytyrosol and nicotinamide is less than or equal to 1:1.
  • the pulverizing equipment includes a mechanical pulverizer and a ball mill.
  • the mixing temperature is 15-50°C.
  • the frequency of the ball mill is 30-50 Hz.
  • the rotational speed of the mechanical pulverizer is 5000-30000 rpm.
  • the present invention provides a composition comprising the above co-crystal of hydroxytyrosol nicotinamide.
  • the composition in addition to the hydroxytyrosol nicotinamide co-crystal of the present invention, may also contain excess nicotinamide, excess hydroxytyrosol, and other pharmaceutically acceptable excipients. That is to say, in the raw materials of the composition, the molar ratio of hydroxytyrosol and nicotinamide is not particularly limited, as long as the raw materials of the composition can prepare the above-mentioned hydroxytyrosol nicotinamide co-crystal.
  • the molar ratio of hydroxytyrosol to nicotinamide in the composition may be 10:1 to 1:10, wherein some of the components are present in the form of co-crystals of hydroxytyrosol and the other components are present in free form. And preferably, all hydroxytyrosol is formed into a co-crystal to overcome the defects of low melting point and poor stability of hydroxytyrosol.
  • the preparation method of the composition of the present invention is preferably as follows: the composition containing hydroxytyrosol and nicotinamide is obtained by placing hydroxytyrosol and nicotinamide in a pulverizing device for co-crystal preparation.
  • the molar ratio of hydroxytyrosol and nicotinamide is less than 1:1, preferably, the molar ratio of hydroxytyrosol and nicotinamide is 1:1.01-1:10, more preferably 1:1.01-1:3 . If too much nicotinamide remains, the hygroscopicity tends to increase, which is not conducive to the stability of hydroxytyrosol.
  • the raw materials of the composition are composed of hydroxytyrosol and nicotinamide in a molar ratio of 1:1.01 to 1:3, and the molar number of free nicotinamide in the composition is based on the number of moles of hydroxytyrosol, and the number of moles of free nicotinamide is hydroxytyrosol. 101% to 200% of the number of moles.
  • the compositions all have X-ray powder diffraction patterns in 2 ⁇ angles at diffraction angles of 11.4 ⁇ 0.2, 13.6 ⁇ 0.2, 14.9 ⁇ 0.2, 17.6 ⁇ 0.2, 18.8 There are characteristic peaks at ⁇ 0.2, 20.1 ⁇ 0.2, 20.3 ⁇ 0.2, and 20.8 ⁇ 0.2 degrees. It has characteristic peaks of the hydroxytyrosol nicotinamide co-crystal of the present invention, thereby confirming that the co-crystal in the composition is consistent with the crystal form of the co-crystal of the present invention.
  • the composition has a melting onset temperature of 100 ⁇ 2°C and a maximum peak value of 101°C ⁇ 2°C as determined by differential scanning calorimetry.
  • the infrared absorption spectrum of the composition is at least at 3426 cm -1 , 3371 cm -1 , 3155 cm -1 , 1692 cm -1 , 1627 cm -1 , 1601 cm -1 , 1527 cm - 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 , 635 cm -1 has an absorption peak.
  • the composition of the present invention can be directly prepared by the grinding method.
  • the preparation time can be shortened by adding an excessive amount of nicotinamide, while ensuring that all the hydroxytyrosol forms a co-crystal. crystals, and no free hydroxytyrosol exists in the composition.
  • the composition directly prepared by the grinding method contains a certain amount of nicotinamide, it has no significant adverse effect on the melting point, hygroscopicity and stability of the composition. The technical advantages can improve the yield and reduce the cost, and are suitable for large-scale promotion and application.
  • the melting point of the hydroxytyrosol nicotinamide co-crystal of the present invention is significantly increased.
  • the hygroscopicity of the hydroxytyrosol nicotinamide co-crystal of the present invention is reduced, while the chemical stability is significantly improved.
  • the hydroxytyrosol nicotinamide-containing co-crystal composition prepared by the grinding method has the technical advantages of high yield, low cost and suitable for large-scale production.
  • Fig. 1 is the X-ray powder diffraction (XRPD) pattern of the hydroxytyrosol nicotinamide co-crystal of the embodiment of the present invention
  • Fig. 2 is the differential scanning calorimetry analysis (DSC) figure of the hydroxytyrosol nicotinamide co-crystal of the embodiment of the present invention
  • Fig. 3 is the infrared spectrum (IR) figure of the hydroxytyrosol nicotinamide co-crystal of the embodiment of the present invention
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • Fig. 6 is hydroxytyrosol itself, hydroxytyrosol embedded powder, hydroxytyrosol nicotinamide co-crystal (Example 1), composition containing hydroxytyrosol nicotinamide co-crystal (Example 4), containing hydroxytyrosol nicotinamide Dynamic moisture adsorption control graph for the composition of the amide co-crystal (Example 5).
  • the X-ray powder diffraction pattern was obtained by using a Bruker D8 Advanced X-ray powder diffractometer, which was irradiated with Cu-K ⁇ .
  • the scanning range was from 3° to 40° in the 2 ⁇ interval, and the scanning speed was 2°/min.
  • Differential scanning calorimetry was performed using TA DSC Q2000 equipment with a heating rate of 10K/min.
  • Thermo Scientific Nicolet 6700 was used as a Fourier transform infrared spectrometer.
  • Hydroxytyrosol was purchased from Shaanxi Fuheng Biotechnology Co., Ltd. with a purity of ⁇ 98%;
  • Niacinamide was purchased from Aladine Reagent, with a purity of ⁇ 98.5%;
  • Hydroxytyrosol embedded powder was purchased from Shaanxi Fuheng Biotechnology Co., Ltd., containing 30% of hydroxytyrosol and 70% of polymer excipients (mainly maltodextrin), prepared by spray drying.
  • Hydroxytyrosol (4 mmol) and nicotinamide (4 mmol) were added to a mixed solvent of 20 ml of ethanol and isoamyl alcohol (1:1 by volume) in a molar ratio of 1:1, stirred at 40°C until the solution was clear, and then Cool at -20°C, recrystallize after 24 hours to obtain a white precipitate, filter the precipitate through a Buchner funnel, and dry the solid in a vacuum drying oven at room temperature for 1 day to obtain a co-crystal of hydroxytyrosol nicotinamide.
  • This co-crystal was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry, and infrared spectroscopy. The results are shown in Figures 1-3.
  • Hydroxytyrosol (4 mmol) and nicotinamide (4 mmol) were added to a mixed solvent of 20 ml of ethanol and isobutanol (1:1 by volume) in a molar ratio of 1:1, stirred at 40 °C until the solution was clear, and then Cool at -20°C, recrystallize after 24 hours to obtain a white precipitate, filter the precipitate through a Buchner funnel, and dry the solid in a vacuum drying oven at room temperature for 1 day to obtain a co-crystal of hydroxytyrosol nicotinamide.
  • This co-crystal was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry, and infrared spectroscopy. The results are consistent with Figures 1-3.
  • This co-crystal was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry, and infrared spectroscopy. The results are consistent with Figures 1-3. It is explained that the crystal form of the obtained co-crystal is the same as that of Example 1.
  • Figure 4 shows the characteristic peaks 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°, 20.8 ⁇ 0.2° and characteristic peaks of free nicotinamide crystals at 25.3 ⁇ 0.2° and 27.3 ⁇ 0.2°.
  • Figure 5 shows that the hydroxytyrosol nicotinamide co-crystal and free nicotinamide form a deep eutectic with a eutectic endotherm at about 100°C and no melting peak for free nicotinamide.
  • the mixture is a mixture of hydroxytyrosol nicotinamide co-crystal and nicotinamide, and the crystal form is consistent with the crystal form of the co-crystal prepared in Example 1, and the molar ratio of hydroxytyrosol and nicotinamide in the co-crystal is 1:1.
  • the mixture was characterized by X-ray powder diffraction (XRPD), and the positions of the characteristic peaks were basically the same as those shown in Figure 4, indicating that the crystal form of the obtained co-crystal was the same as that of Example 1, and the hydroxytyrosol in the co-crystal was the same as that of Example 1.
  • the molar ratio to nicotinamide is 1:1.
  • the position of its absorption peak is basically consistent with that in Figure 5.
  • Example 4 The hygroscopicity of the hydroxytyrosol, the hydroxytyrosol embedded powder, the hydroxytyrosol nicotinamide co-crystal obtained in Example 1, and the composition obtained in Example 4 were compared.
  • the hygroscopicity of hydroxytyrosol and the embedding powder is as high as 16.9% and 116.3%, while the hydroxytyrosol co-crystal and the composition provided by the present invention have basically no hygroscopicity.
  • the hygroscopicity of the composition (0.94% and 0.79% hygroscopic at 80% RH) was slightly higher than that of the co-crystal (0.39% hygroscopic at 80% RH).
  • the hygroscopicity of the hydroxytyrosol co-crystal and the composition of the present invention is significantly lower than that of hydroxytyrosol and the embedded powder thereof.
  • the liquid phase method is as follows:
  • Mobile phase A phase: 0.1% trifluoroacetic acid aqueous solution, B phase: acetonitrile; flow rate: 1mL/min; detection wavelength: 280nm; chromatographic column: C18 Plus 4.6 ⁇ 150mm ⁇ 5 ⁇ m;
  • the initial hydroxytyrosol content in the samples was all set as 100%. After 30 days, the content of hydroxytyrosol is 92.3% of the initial content, the content of the embedding powder is only 57.2% of the initial content, and in the hydroxytyrosol nicotinamide co-crystal provided by the present invention, the content of hydroxytyrosol still remains at More than 99%. In the composition containing hydroxytyrosol nicotinamide co-crystal, the content of hydroxytyrosol decreased slightly.
  • the hydroxytyrosol nicotinamide co-crystal and the composition of the present invention have better chemical stability.
  • Hydroxytyrosol (4mmol) and L-proline (4mmol) were added to 20 ml of mixed solvent in a molar ratio of 1:1, wherein the mixed solvent was methanol, ethanol, methanol and n-propanol in a volume ratio of 1:1 , methanol and n-butanol in a volume ratio of 1:1, methanol and isobutanol in a volume ratio of 1:1, methanol and isoamyl alcohol in a volume ratio of 1:1, ethanol and n-propanol in a volume ratio of 1:1, Ethanol and n-butanol in a volume ratio of 1:1, ethanol and isoamyl alcohol in a volume ratio of 1:1, and ethanol and isobutanol in a volume ratio of 1:1; stir at 40 °C until the solution is clear, and cool at -20 °C , 24 hours later, the white powder of L-proline was recrystallized, and the powder preparation of hydroxytyrosol could
  • Hydroxytyrosol (4mmol) and L-carnitine (4mmol) were added to 20 ml of mixed solvent in a molar ratio of 1:1, wherein the mixed solvent was methanol, ethanol, methanol and n-propanol in a volume ratio of 1:1, a volume of Methanol and n-butanol in a ratio of 1:1, methanol and isobutanol in a volume ratio of 1:1, methanol and isoamyl alcohol in a volume ratio of 1:1, ethanol and n-propanol in a volume ratio of 1:1, and a volume ratio of 1:1 1:1 ethanol and n-butanol, 1:1 volume ratio of ethanol and isoamyl alcohol, 1:1 volume ratio of ethanol and isobutanol; stir at 40 °C until the solution is clear, cool at -20 °C, 24 After one hour, L-carnitine was recrystallized as white powder, and the powder preparation of hydroxytyrosol could not be obtained.
  • Hydroxytyrosol (4mmol) and nicotinic acid (4mmol) were added to 20 milliliters of mixed solvents in a molar ratio of 1:1, wherein the mixed solvent was methanol, ethanol, methanol at a volume ratio of 1:1 and n-propanol, a volume ratio of 1:1.
  • hydroxytyrosol can only form co-crystals with specific compounds, such as nicotinamide, while other structural analogs, such as L-proline, L-carnitine, niacin, etc. Co-crystals cannot be formed.

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Abstract

本发明涉及医药技术领域，具体将，涉及一种羟基酪醇烟酰胺共晶，其制备方法及组合物。本发明的羟基酪醇烟酰胺共晶中羟基酪醇和烟酰胺的摩尔比为1：1，晶胞参数为a＝9.4999，b＝11.8285，c＝11.4439，α＝90°，β＝96.628°，δ＝90°。本发明的羟基酪醇烟酰胺共晶的熔点高、不吸湿、稳定性好，极大提升了羟基酪醇的运用便利性。通过研磨法直接制备得到的组合物，具有产率高、成本低，适合大规模推广应用。

Description

羟基酪醇烟酰胺共晶，其制备方法及组合物 技术领域
本发明涉及医药技术领域，具体将，涉及一种羟基酪醇烟酰胺共晶，其制备方法及组合物。
背景技术
羟基酪醇是从橄榄油中提取得到的一种多酚类化合物，具体结构式如是I所示：
Figure PCTCN2022078935-appb-000001
羟基酪醇具有较强的抗氧化能力及广泛的生物学活性，目前，已被广泛应用于食品、保健品和化妆品中。但是，羟基酪醇原料本身熔点低(52℃)，吸湿性大，在环境温度和湿度下呈现蜡状的固体形态或者粘稠的油状，无法直接用于硬胶囊或片剂，且原料本身对光、热、水分、氧气等极不稳定，使用过程中易氧化变色。
目前，有报道采用包埋法对羟基酪醇进行保护，所形成的羟基酪醇包埋粉载量为20-30％，相比羟基酪醇本身，包埋粉的粉末性状得到优化，但由于羟基酪醇为两亲化合物，包封率不高，未被包埋的羟基酪醇仍然存在不稳定、易变色等问题；并且，由于包埋粉含有大量的淀粉类辅料，因此，吸湿性进一步增大。
鉴于此，特提出本发明。
发明内容
本发明的首要发明目的在于提出一种羟基酪醇烟酰胺共晶。
本发明的第二发明目的在于提出该羟基酪醇烟酰胺共晶的制备方法。
本发明的第三发明目的在于提出含有该羟基酪醇烟酰胺共晶的组合物。
为了完成本发明的发明目的，采用的技术方案为：
为了提高羟基酪醇产品的稳定性，本发明通过加入辅助化合物的方法制备得到羟基酪醇共晶，该辅助化合物在分子水平上与羟基酪醇存在非共价键相互作用，因此，能够从分子水平提高羟基酪醇的熔点，并改善其稳定性，拓宽其应用领域。
第一方面，本发明提出一种羟基酪醇烟酰胺共晶化合物，其中，羟基酪醇与烟酰胺的摩尔比为1：1，烟酰胺的结构式如式II所示：
Figure PCTCN2022078935-appb-000002
本发明通过大量实验发现，其他相似化合物如：L-脯氨酸、左旋肉碱和烟酸等，均无法将羟基酪醇制备成稳定的粉末制剂。采用烟酰胺制备共晶，可解决上述技术问题，从而完成本发明。
本发明的羟基酪醇烟酰胺共晶的晶胞参数为a＝9.4999，b＝11.8285，c＝11.4439，α＝90°，β＝96.628°，δ＝90°。
在一些实施方式中，相比羟基酪醇，本发明制备得到的羟基酪醇烟酰胺共晶具有显著提高的熔点，众所周知，并非所有的共晶都可显著提高熔点，某些共晶的熔点会低于单独两个化合物的熔点。在一些实施方式中，相比羟基酪醇，本发明制备得到的羟基酪醇共晶还具有显著降低的吸湿性。在一些实施方式中，相比羟基酪醇，本发明制备得到的羟基酪醇共晶具有显著提高的化学稳定性。
特别地，本发明的羟基酪醇烟酰胺共晶的以2θ角度表示的X-射线粉末衍射图至少在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、20.8±0.2衍射角为度处具有特征峰。更特别地，具有基本如图1所示的X-射线粉末衍射图。
特别地，本发明的羟基酪醇烟酰胺共晶的熔点为111℃±2℃。通过差示扫描量热法测定，羟基酪醇烟酰胺共晶的熔化起始温度为110±2℃，最大峰值为111±2℃。更特别地，具有基本如图2所示的差示扫描量热分析图。
特别地，羟基酪醇烟酰胺共晶的红外吸收光谱至少在3426cm -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具有吸收峰。更特别地，具有基本如图3所示的红外光谱。
第二方面，本发明涉及制备羟基酪醇共晶的方法，包括将羟基酪醇与烟酰胺以分子状态接触然后析晶的步骤。
以分子状态接触可以包括，但不限于溶液合成法、固态研磨法等。溶液合成法指的是在溶液中进行共晶的合成，包括缓慢蒸发、冷却结晶、悬浮结晶、溶析结晶等。固态研磨法主要包括固体干磨和溶剂辅助研磨。干磨法是通过研磨主体药物和配体的混合物，进而得到共晶产品的一种方法，溶液辅助研磨是在研磨过程中通过添加少量的溶剂来提高研磨效率的方法。固态研磨法的方式包括球磨或者高速剪切。
特别地，制备羟基酪醇共晶的方法可以为如下方法之一：
方法一：
将羟基酪醇和烟酰胺在有机溶剂中重结晶得到羟基酪醇烟酰胺共晶；
方法二：
将羟基酪醇和烟酰胺置于粉碎设备中进行混合得到羟基酪醇烟酰胺共晶。
特别地，方法一至少包括下列步骤：
S1、将羟基酪醇和烟酰胺在第一温度下溶于有机溶剂；
S2、将S1得到的溶液于低于第一温度的第二温度下冷却，析出羟基酪 醇共晶。
具体的，在S1中，第一温度为10～80℃，优选30～50℃。
具体的，在S1中，当制备羟基酪醇烟酰胺共晶时，有机溶剂选自甲醇、乙醇、正丙醇、正丁醇、异丙醇、异丁醇、异戊醇、叔丁醇、丙酮、甲乙酮、乙腈、四氢呋喃、硝基甲烷、甲酸乙酯、乙酸乙酯、乙酸异丙酯、乙酸异丁酯中的一种或多种。优选的，有机溶剂选自乙醇和异戊醇的混合溶剂、乙醇和异丁醇的混合溶剂、乙醇和叔戊醇的混合溶剂。混合溶剂中两种溶剂的体积比为体积比可为1：0.1～10，优选1：1～5，更优选1：1。
具体的，在S2中，第二温度的温度为-40～0℃，优选-30～-10℃。
具体的，在S2中，析晶的过程可以加入晶种，加快晶体的形成。
具体的，析晶后还包括固液分离和干燥的步骤；其中，固液分离可选用过滤、离心等方法，并优选过滤；干燥可采用常压干燥、真空干燥、喷雾干燥等方式进行，并优选常温下真空干燥。
特别地，方法二至少包括下列步骤：
将羟基酪醇和烟酰胺置于粉碎设备中进行混合，羟基酪醇和烟酰胺的摩尔比小于等于1：1。
具体的，粉碎设备包括机械式粉碎机和球磨机。
具体的，混合的温度为15～50℃。
具体的，球磨机的频率为30～50Hz。
具体的，机械式粉碎机的转速为5000～30000rpm。
第三方面，本发明提供一种组合物，其包含上述羟基酪醇烟酰胺共晶。
在一些实施方式中，组合物中除本发明的羟基酪醇烟酰胺共晶外，还可以含有过量的烟酰胺，也可以含有过量的羟基酪醇，以及其他药学上可接受的辅料。也即是说，在组合物的原料中，羟基酪醇与烟酰胺的摩尔比没有特别限定，只要组合物的原料可以制备得到上述羟基酪醇烟酰胺共晶即可。例如，在组合物中羟基酪醇与烟酰胺的摩尔比可以为10：1～1：10，其中一部分组分以羟基酪醇共晶的形式存在，而另一部分组分以游离形式存在。并优选将羟基酪醇全部形成共晶，以克服羟基酪醇熔点低、稳定差的缺陷。
第四方面，本发明的组合物的制备方法优选为：通过羟基酪醇和烟酰胺置于粉碎设备中进行共晶制备后得到含有羟基酪醇和烟酰胺的组合物。在组合物的原料中，羟基酪醇和烟酰胺的摩尔比小于1：1，优选的，羟基酪醇和烟酰胺的摩尔比为1：1.01～1：10，进一步优选为1：1.01～1：3。如烟酰胺剩余过多，则吸湿性有增大的趋势，不利于羟基酪醇的稳定性。
如添加有其他药学上可接受的辅料时，则进一步包括与其他辅料混合的步骤。
在一些实施方式中，组合物的原料由摩尔比为1：1.01～1：3的羟基酪醇和烟酰胺组成，组合物中基于羟基酪醇的摩尔数，游离烟酰胺的摩尔数为羟基酪醇摩尔数的101％～200％。当组合物中游离烟酰胺在该比例范围内时，组合物均具有以2θ角度表示的X-射线粉末衍射图在衍射角为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、20.8±0.2度处具有特征峰。其具备本发明的羟基酪醇烟酰胺共晶的特征峰，从而证实该组合物中的共晶与本发明的共晶的晶型一致。特别地，通过差示扫描量热法测定，该组合物的熔化起始温度为100±2℃，最大峰值为101℃±2℃。当组合物中游离烟酰胺在该比例范围内时，该组合物的红外吸收光谱均至少在3426cm -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具有吸收峰。
进一步优选的，本发明的组合物可采用研磨法直接制备得到，在采用研磨法制备羟基酪醇烟酰胺共晶时，通过添加过量烟酰胺，可缩短制备时间，同时确保羟基酪醇全部形成共晶，组合物中无游离状态的羟基酪醇存在。通过研磨法直接制备得到的组合物，虽然含有一定量的烟酰胺，但对组合物的熔点、吸湿性和稳定性均无显著不利影响，同时相比溶剂结晶法来说，具有制备效率高的技术优势，可提高产率、降低成本，适合大规模推广应用。
本发明的有益效果至少包括：
相比羟基酪醇本身，本发明的羟基酪醇烟酰胺共晶的熔点显著提高。 相比羟基酪醇本身及其包埋粉，本发明的羟基酪醇烟酰胺共晶的吸湿性降低，同时化学稳定性显著提高。
相比羟基酪醇烟酰胺共晶，本发明通过研磨法制备得到的含有羟基酪醇烟酰胺共晶组合物，具有产率高、成本低，适于规模化生产的技术优势。
附图说明
图1是本发明实施例的羟基酪醇烟酰胺共晶的X-射线粉末衍射(XRPD)图；
图2是本发明实施例的羟基酪醇烟酰胺共晶的差示扫描量热分析(DSC)图；
图3是本发明实施例的羟基酪醇烟酰胺共晶的红外光谱(IR)图；
图4是本发明实施例的含有羟基酪醇烟酰胺共晶的混合物的X-射线粉末衍射(XRPD)图；
图5是本发明实施例的含有羟基酪醇烟酰胺共晶的混合物的差示扫描量热分析(DSC)图；
图6是羟基酪醇本身、羟基酪醇包埋粉、羟基酪醇烟酰胺共晶(实施例1)、含有羟基酪醇烟酰胺共晶的组合物(实施例4)、含有羟基酪醇烟酰胺共晶的组合物(实施例5)的动态水分吸附对照图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
试剂和仪器
本发明实施例中X-射线粉末衍射图谱是采用Bruker D8 Advanced型号的X射线粉末衍射仪得到，该仪器采用Cu-Kα照射
Figure PCTCN2022078935-appb-000003
扫描范围在2θ区间自3°至40°，扫描速度为2°/分钟。
差式扫描量热法采用TA DSC Q2000设备，加热速度为10K/min。
傅里叶变换红外光谱仪采用Thermo Scientific Nicolet 6700。
羟基酪醇购买于陕西富恒生物科技有限公司，纯度≥98％；
烟酰胺购买于阿拉订试剂，纯度≥98.5％；
羟基酪醇包埋粉购买于陕西富恒生物科技有限公司，，其中含30％的羟基酪醇以及70％的聚合物辅料(主要为麦芽糊精)，通过喷雾干燥的方法制备得到。
实施例1
将羟基酪醇(4mmol)和烟酰胺(4mmol)按摩尔比1：1加入到20毫升乙醇和异戊醇(体积比1:1)的混合溶剂中，于40℃下搅拌至溶液澄清，于-20℃下冷却，24小时后重结晶得到白色沉淀物，通过布氏漏斗过滤沉淀物，并将固体于真空干燥箱中常温干燥1天，获得羟基酪醇烟酰胺共晶，。
晶胞参数为：a＝9.4999，b＝11.8285，c＝11.4439，α＝90°，β＝96.628°，δ＝90°
上述实验数据验证了共晶中羟基酪醇与烟酰胺的摩尔比为1：1。
此共晶通过X-射线粉末衍射(XRPD)、差示扫描量热分析、红外光谱进行表征。结果如图1-图3所示。
实施例2
将羟基酪醇(4mmol)和烟酰胺(4mmol)按摩尔比1：1加入到20毫升乙醇和异丁醇(体积比1:1)的混合溶剂中，于40℃下搅拌至溶液澄清，于-20℃下冷却，24小时后重结晶得到白色沉淀物，通过布氏漏斗过滤沉淀物，并将固体于真空干燥箱中常温干燥1天，获得羟基酪醇烟酰胺共晶。
此共晶通过X-射线粉末衍射(XRPD)、差示扫描量热分析、红外光谱进行表征。结果与图1-图3一致。
实施例3
称取羟基酪醇3.1g和烟酰胺2.4g(摩尔比为1:1)，置于球磨罐中(上海净信Tissuelyser-II样品快速研磨机)，加入适量研磨球，在室温下以40Hz频率球磨2小时，获得羟基酪醇烟酰胺共晶。
此共晶通过X-射线粉末衍射(XRPD)、差示扫描量热分析、红外光谱进行表征。结果与图1-图3一致。说明所获得的共晶的晶型与实施例1为相 同的晶型。
实施例4
称取羟基酪醇3.1g和烟酰胺4.8g(摩尔比为1:2)，置于球磨罐中(上海净信Tissuelyser-II样品快速研磨机)，加入适量研磨球，在室温下以40Hz频率球磨2小时，获得含有羟基酪醇烟酰胺共晶的混合物。
此混合物通过X-射线粉末衍射(XRPD)、差示扫描量热分析进行表征。实验结果如图4和图5所示。
图4显示了羟基酪醇烟酰胺共晶的特征峰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°、20.8±0.2°以及游离烟酰胺晶体的特征峰25.3±0.2°和27.3±0.2°。
图5显示了羟基酪醇烟酰胺共晶和游离的烟酰胺形成了低共熔物，在约100℃有一个共熔吸热峰，无游离烟酰胺的熔融峰。
上述结果表明，该混合物为羟基酪醇烟酰胺共晶和烟酰胺的混合物，且晶型与实施例1制备得到的共晶的晶型一致，共晶中羟基酪醇与烟酰胺的摩尔比为1：1。
实施例5
称取羟基酪醇1.6g和烟酰胺3.8g(摩尔比为1:3)，置于球磨罐中(上海净信Tissuelyser-II样品快速研磨机)，加入适量研磨球，在室温下以40Hz频率球磨2小时，获得含有羟基酪醇烟酰胺共晶的混合物，共晶中羟基酪醇与烟酰胺的摩尔比为1：1。
此混合物通过X-射线粉末衍射(XRPD)进行表征，其特征峰的位置与图4基本一致，说明所获得的共晶的晶型与实施例1为相同的晶型，共晶中羟基酪醇与烟酰胺的摩尔比为1：1。通过差示扫描量热分析，其吸收峰的位置与图5基本一致。
实施例6
比较羟基酪醇、羟基酪醇包埋粉、实施例1得到的羟基酪醇烟酰胺共 晶、实施例4得到的组合物的吸湿性。
取约5mg粉末样品，置于动态水分吸附仪(DVS)中，设置相对湿度范围为0～95％，温度：25℃，记录样品在不同环境湿度条件下的重量变化，以此判断物料的吸湿性大小。实验结果如图6所示。
由图6可知，在80％相对湿度时，羟基酪醇及包埋粉吸湿高达16.9％和116.3％，而本发明所提供的羟基酪醇共晶及组合物基本无吸湿性。组合物的吸湿性(80％RH下吸湿0.94％和0.79％)比共晶的吸湿性(80％RH下吸湿0.39％)略有增加。
由此可见，本发明所述羟基酪醇共晶及组合物相比羟基酪醇及其包埋粉，吸湿性显著降低。
实施例7：
比较羟基酪醇、羟基酪醇包埋粉、实施例1得到的羟基酪醇烟酰胺共晶、实施例4和实施例5得到组合物在40℃/75％RH下的化学稳定性：
将适量粉末样品置于40℃/75％RH加速稳定性箱中，包装条件：双层聚乙烯袋，于0d、14d、30d取样。采用高效液相色谱测定(含量的计算方法为外标法)羟基酪醇含量。
液相方法如下：
流动相：A相：0.1％三氟乙酸水溶液，B相：乙腈；流速：1mL/min；检测波长：280nm；色谱柱：C18 Plus 4.6×150mm×5μm；
梯度方法：
0～10min——A：B(95：5)；
10.1～14min——A：B(50：50)；
14.0～17min——A：B(95：5)。
实验结果如表1所示。
表1
Figure PCTCN2022078935-appb-000004
Figure PCTCN2022078935-appb-000005
由表1可知，样品中起始羟基酪醇含量均定为100％。30天后，羟基酪醇的含量为初始含量的92.3％，包埋粉的含量仅为初始含量的57.2％，而本发明提供的羟基酪醇烟酰胺共晶中，羟基酪醇的含量仍然保持在99％以上。含有羟基酪醇烟酰胺共晶的组合物中，羟基酪醇的含量略有下降。
由此可见，相比羟基酪醇和羟基酪醇包埋粉，本发明的羟基酪醇烟酰胺共晶及组合物具有更好的化学稳定性。
对比例1
将羟基酪醇(4mmol)和L-脯氨酸(4mmol)按摩尔比1：1加入到20毫升混合溶剂中，其中，混合溶剂为甲醇、乙醇、体积比1：1的甲醇与正丙醇、体积比1：1的甲醇和正丁醇、体积比为1：1的甲醇和异丁醇、体积比为1：1的甲醇和异戊醇、体积比1：1的乙醇与正丙醇、体积比1：1的乙醇和正丁醇、体积比1：1的乙醇和异戊醇、体积比1：1的乙醇和异丁醇；于40℃下搅拌至溶液澄清，于-20℃下冷却，24小时后重结晶析出L-脯氨酸白色粉末，未能获得羟基酪醇的粉末制剂。
由对比例1可知：采用L-脯氨酸在各种溶剂中均无法制备得到共晶。
对比例2
将羟基酪醇(4mmol)和左旋肉碱(4mmol)按摩尔比1：1加入到20毫升混合溶剂中，其中，混合溶剂为甲醇、乙醇、体积比1：1的甲醇与正丙醇、体积比1：1的甲醇和正丁醇、体积比为1:1的甲醇和异丁醇、体积比为1：1的甲醇和异戊醇、体积比1：1的乙醇与正丙醇、体积比1：1的乙醇和正丁醇、体积比1：1的乙醇和异戊醇、体积比1：1的乙醇和异丁醇；于40℃下搅拌至溶液澄清，于-20℃下冷却，24小时后重结晶析出 左旋肉碱白色粉末，未能获得羟基酪醇的粉末制剂。
由对比例2可知：采用左旋肉碱在各种溶剂中均无法制备得到共晶。
对比例3
将羟基酪醇(4mmol)和烟酸(4mmol)按摩尔比1：1加入到20毫升混合溶剂中，其中，混合溶剂为甲醇、乙醇、体积比1：1的甲醇与正丙醇、体积比1：1的甲醇和正丁醇、体积比为1：1的甲醇和异丁醇、体积比为1：1的甲醇和异戊醇、体积比1：1的乙醇与正丙醇、体积比1：1的乙醇和正丁醇、体积比1：1的乙醇和异戊醇、体积比1：1的乙醇和异丁醇；于40℃下搅拌至溶液澄清，于-20℃下冷却，24小时后重结晶析出沉淀物为烟酸配体。
由对比例3可知：采用烟酸在各种溶剂中均无法制备得到共晶。
将实施例和对比例结果进行对比，可以发现羟基酪醇只能与特定化合物，例如烟酰胺形成共晶，而与其他结构类似物，如L-脯氨酸、左旋肉碱、烟酸等均无法形成共晶。
本申请虽然以较佳实施例公开如上，但并不是用来限定权利要求，任何本领域技术人员在不脱离本申请构思的前提下，都可以做出若干可能的变动和修改，因此本申请的保护范围应当以本申请权利要求所界定的范围为准。

Claims (10)

  1. 一种羟基酪醇烟酰胺共晶，其特征在于，所述羟基酪醇烟酰胺共晶中羟基酪醇和烟酰胺的摩尔比为1：1。
  2. 根据权利要求1所述的羟基酪醇烟酰胺共晶，其特征在于，所述羟基酪醇烟酰胺共晶的晶胞参数为a＝9.4999，b＝11.8285，c＝11.4439，α＝90°，β＝96.628°，δ＝90°。
  3. 根据权利要求1所述的羟基酪醇烟酰胺共晶，其特征在于，所述羟基酪醇烟酰胺共晶以2θ角度表示的X-射线粉末衍射至少在衍射角在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、20.8±0.2度处具有特征峰；
    和/或，所述羟基酪醇烟酰胺共晶具有基本如图1所示的X-射线粉末衍射图。
  4. 根据权利要求1所述的羟基酪醇烟酰胺共晶，其特征在于，所述羟基酪醇烟酰胺共晶的熔点为111℃±2℃；
    和/或，通过差示扫描量热法测定，所述羟基酪醇烟酰胺共晶的熔化起始温度为110±2℃，最大峰值为111±2℃。
  5. 根据权利要求1所述的羟基酪醇烟酰胺共晶，其特征在于，所述羟基酪醇烟酰胺共晶的红外吸收光谱至少在3426cm -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具有吸收峰；
    优选地，所述羟基酪醇烟酰胺共晶具有基本如图3所示的红外光谱。
  6. 一种如权利要求1～5任一项所述的羟基酪醇烟酰胺共晶的制备方法，其特征在于，至少包括下列步骤：
    S1、将羟基酪醇和烟酰胺溶于有机溶剂，于第一温度下搅拌至完全溶解；
    S2、将S1得到的溶液于低于所述第一温度的第二温度下进行冷却，析晶；
    S3、固体分离，干燥，即得所述羟基酪醇烟酰胺共晶；
    和/或，所述第一温度为10～80℃、优选30～50℃；
    和/或，所述第二温度为-40～0℃、优选-30～-10℃。
  7. 根据权利要求6所述的制备方法，其特征在于，所述有机溶剂选自甲醇、乙醇、正丙醇、正丁醇、异丙醇、异丁醇、异戊醇、叔丁醇、丙酮、甲乙酮、乙腈、四氢呋喃、硝基甲烷、甲酸乙酯、乙酸乙酯、乙酸异丙酯、乙酸异丁酯中的一种或多种。
  8. 一种如权利要求1～5任一项所述的羟基酪醇烟酰胺共晶的制备方法，其特征在于，至少包括下列步骤：
    将羟基酪醇和烟酰胺置于粉碎设备中进行混合研磨，羟基酪醇和烟酰胺的摩尔比为小于或等于1：1；
    和/或，所述粉碎设备包括机械式粉碎机和球磨机；
    和/或，所述混合的温度为15～50℃；
    和/或，所述球磨机的频率为30～50Hz。
  9. 一种含有如权利要求1～5任一项所述的羟基酪醇烟酰胺共晶的组合物，其特征在于，所述组合物中还含有烟酰胺和/或药学上可接受的辅料；
    优选的，当组合物的原料由摩尔比为1：1.01～1：3的羟基酪醇和烟酰胺组成时，所述组合物以2θ角度表示的X-射线粉末衍射图在衍射角在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、20.8±0.2度处具有特征峰。
  10. 一种如权利要求9所述的组合物的制备方法，其特征在于，采用固态研磨法制备；
    优选的，至少包括下列步骤：
    将羟基酪醇和烟酰胺置于粉碎设备中进行混合研磨，羟基酪醇和烟酰胺的摩尔比为小于1：1，优选1：1.01～1：5，更优选1：1.01～1：3。
PCT/CN2022/078935 2021-03-05 2022-03-03 羟基酪醇烟酰胺共晶，其制备方法及组合物 WO2022184120A1 (zh)

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US20120225840A1 (en) * 2009-04-17 2012-09-06 Ann Fowler Hydroxytyrosol combinations for enhancing mitochondrial function and energy production
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US20120225840A1 (en) * 2009-04-17 2012-09-06 Ann Fowler Hydroxytyrosol combinations for enhancing mitochondrial function and energy production
CN105669543A (zh) * 2015-12-31 2016-06-15 中国药科大学 异甘草素烟酰胺共晶及其制备方法
CN113004198A (zh) * 2021-03-05 2021-06-22 中国科学院上海药物研究所 羟基酪醇烟酰胺共晶、其制备方法及组合物

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