Crystal form i of hydroxytyrosol, preparation method therefor and use thereof

Abstract

Crystal form I of hydroxytyrosol, a preparation method therefor, and a use thereof. An X-ray powder diffraction pattern of the crystal form, expressed in 2θ angles, has diffraction peaks at diffraction angles of 10.54±0.2º, 13.76±0.2º, 15.52±0.2º, 16.70±0.2º, 17.52±0.2º, 21.16±0.2º, 21.44±0.2º, 21.62±0.2º, 21.88±0.2º, 22.44±0.2º, 24.74±0.2º, 25.78±0.2º, 26.60±0.2º, 27.06±0.2º, 29.26±0.2º, 30.54±0.2º, 33.72±0.2º, and 34.54±0.2º. The crystal form has relatively good stability, is beneficial to the improvement of physical and chemical properties of a product, and has relatively good druggability prospects.

Description

Hydroxytyrosol crystal form I and its preparation method and application Technical Field

[0001] The invention belongs to the technical field of medicinal chemistry, and particularly relates to a new crystal form of hydroxytyrosol, a preparation method and an application thereof. Background Art

[0002]

[0003] Hydroxytyrosol, whose chemical name is 3,4-dihydroxyphenylethanol, is a naturally occurring polyphenol compound that is mainly found in processed olive products such as olives and olive oil. It is its most biologically active component. The structure of hydroxytyrosol is shown in Formula I. It is well known that polyphenol compounds are easily affected by conditions such as pH, high temperature, light and metal ions and are rapidly degraded. Hydroxytyrosol is a catechol polyphenol structure that contains two phenolic hydroxyl groups and one alcoholic hydroxyl group. Studies have shown that hydroxytyrosol is extremely sensitive to light and heat, and is very easy to change color in the air. It needs to be stored in the dark and at 2-8°C. At this stage, most of the hydroxytyrosol sold on the market is a viscous oily liquid, and there is no relevant report on the preparation of the above-mentioned compound crystal form in the current public technology. Only patent CN202110244109.X studies its eutectic.

[0004] The CN202110244109.X patent specification uses grinding and solvent crystallization methods to generate eutectic products. The solvent crystallization method has the disadvantages of low yield, high cost, and is not suitable for large-scale promotion and application. Although the grinding method has the advantage of high preparation efficiency, it is easy to generate heat during the grinding process, which will affect the stability of hydroxytyrosol itself, reduce the purity of the main body, and affect its biological effectiveness. At the same time, the selection of eutectic guest molecules is very important in terms of safety and effectiveness. In addition to the guest molecules with biological activity themselves, which need to be safety evaluated, the two non-toxic molecules may also cause fatal hazards when forming eutectics.

[0005] Hydroxytyrosol is one of the most powerful antioxidants discovered to date. Its ORAC (oxygen radical absorbance capacity—its ability to absorb cell-damaging free radicals) value is close to 68,000, approximately three times higher than coenzyme Q10 and 15 times higher than green tea. Due to its potent antioxidant activity, hydroxytyrosol has anti-inflammatory, vasodilatory, and antibacterial properties. Currently, hydroxytyrosol is widely used in beauty products, health supplements, and food and beverages, boasting benefits such as whitening, anti-aging, cardiovascular protection, and cognitive improvement. Due to its high safety profile, hydroxytyrosol has been certified as "Generally Recognized as Safe" (GRAS) by the US Food and Drug Administration (FDA). The European Union has also approved hydroxytyrosol for marketing as a new food ingredient, certifying that synthetic hydroxytyrosol is as effective as its naturally derived counterpart. Hydroxytyrosol capsules, tablets, and powders have been released internationally, including Indena's Oleaselect™ tablets; Genosa's Hytolive™ granules; Seppic's Prolivols™ tablets; and HIDROX™ dry powder, a product developed jointly by CreAgri and DSM of the Netherlands. However, the raw materials used in the capsules and formulations produced by these companies are primarily plant extracts (mixtures containing 20% ​​to 50% hydroxytyrosol), not pure substances.

[0006] Due to its viscous liquid state and stability issues, hydroxytyrosol faces great challenges in storage, transportation and formulation processes. Currently, all hydroxytyrosol products sold on the market are derived from plant extracts, and their antioxidant properties are somewhat inferior to those of pure hydroxytyrosol, which ultimately limits its application as a product or additive in food, health products, cosmetics and medicines.

[0007] Summary of the Invention

[0008] One of the purposes of the present invention is to study and prepare a new crystal form I of hydroxytyrosol.

[0009] The present invention aims to provide a method for preparing a hydroxytyrosol crystal form I solid and its application. Compared with commercially available hydroxytyrosol and eutectic samples, the crystal form sample has good chemical stability, is conducive to the process processing and improvement of the physicochemical properties of the drug, improves the drug properties, and has extremely high practical value in food, health products, cosmetics and medicines. At the same time, the crystal form sample of the present invention has extremely strong antioxidant properties, and its IC 50 The value is more than 9 times that of plant-derived hydroxytyrosol solid powder. Its extremely low concentration of hydroxytyrosol (10 μg / ml) can exert a good free radical scavenging ability (DPPH scavenging rate reaches more than 95%).

[0010] The present invention provides a hydroxytyrosol crystal form I, which has characteristic peaks in an X-ray powder diffraction pattern at reflection angles 2θ of about 10.54±0.2°, about 13.76±0.2°, about 15.52±0.2°, about 16.70±0.2°, about 17.52±0.2°, about 21.16±0.2°, about 21.44±0.2°, about 21.62±0.2°, about 21.88±0.2°, about 24.74±0.2°, about 25.78±0.2°, about 26.60±0.2°, about 27.06±0.2°, about 30.54±0.2°, about 33.72±0.2° and about 34.54±0.2°.

[0011] In a preferred embodiment of the present invention, the hydroxytyrosol crystalline form I has a reflection angle 2θ of its X-ray powder diffraction pattern, and further has diffraction peaks at one or more of the following 2θ angles: about 22.44±0.2°, 23.06±2°, 24.26±0.2°, 25.1±0.2°, about 29.26±0.2°, 30.8±0.2°, 33.26±0.2°, 34.18±0.2°, and 35.44±0.2°.

[0012] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydroxytyrosol crystal form I expressed in 2θ is shown in Table 1 below:

[0013] Table 1

[0014] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the hydroxytyrosol crystal form I expressed in 2θ angles is substantially as shown in FIG1 .

[0015] In a preferred embodiment of the present invention, the hydroxytyrosol crystal form I has an endothermic peak at about 54±5° C. in differential scanning calorimetry analysis. Its DSC spectrum is shown in FIG2 . More specifically, its differential scanning calorimetry analysis shows a characteristic endothermic peak at 54.49° C.

[0016] In a preferred embodiment of the present invention, the TG spectrum of the hydroxytyrosol crystal form I is shown in FIG3 , and thermogravimetric analysis shows no obvious weight loss and no obvious solvent residue when heated to 50-150° C., proving that it is an anhydrous crystal form.

[0017] In a preferred embodiment of the present invention, the purity of the hydroxytyrosol crystal form I is ≥99.0%; preferably, the purity of the hydroxytyrosol is ≥99.5%.

[0018] In a preferred embodiment of the present invention, the infrared spectrum of the hydroxytyrosol crystal form I is shown in FIG4 , at 3276.7 cm -1、2940.3cm -1 、2888.3cm -1 、2068.5cm -1 、1864.3cm -1 、1607.2cm -1 、1528.39cm -1 、1445.1cm -1 、1373.7cm -1 、1286.4cm -1 、1256.2cm -1 、1194.6cm -1 、1151.3cm -1 、1114.3cm -1 、1048.9cm -1 、 1028.8cm -1 、1011.1cm -1 、911.1cm -1 、875.9cm -1 、848.4cm -1 、809.4cm -1 、781.9cm -1 、753.4cm -1 、718.4cm -1 、634.3cm -1 、589.8cm -1 、455.0cm -1 、418.3cm -1 There is a characteristic peak.

[0019] The hydroxytyrosol crystal form I of the present invention can be prepared using the following method:

[0020] Hydroxytyrosol oil is dissolved in an organic solvent at 30-60°C, cooled to -25--5°C, stirred and crystallized for 40-50 hours, centrifuged and filtered, and dried in vacuo at room temperature to obtain a hydroxytyrosol Form I solid.

[0021] The organic solvents described in the present invention refer to one or more combinations of alcohols, ketones, lipids, alkanes and halogenated hydrocarbons.

[0022] The alcohol solvents include but are not limited to: ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol; ketone solvents include but are not limited to: acetone, cyclohexanone, methyl isobutyl ketone; lipid solvents include but are not limited to: methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate; isobutyl acetate; alkane solvents include but are not limited to: n-hexane, n-heptane, cyclohexane; halogenated hydrocarbon solvents include but are not limited to: dichloromethane, dichloroethylene, trichloroethylene, chloroform, carbon tetrachloride.

[0023] On the other hand, the present invention provides a pharmaceutical composition comprising hydroxytyrosol as a pharmaceutically active ingredient, wherein the pharmaceutical composition comprises hydroxytyrosol crystal form I and pharmaceutically acceptable excipients.

[0024] In a preferred embodiment of the present invention, the excipients used in the pharmaceutical composition can be any excipients commonly available to those skilled in the art, such as solid excipients, liquid excipients, or semisolid excipients.

[0025] In a preferred embodiment of the present invention, since the active ingredient hydroxytyrosol crystal form I has good fluidity and compressibility, in this case, the active ingredient powder is used and mixed evenly and thoroughly with one or more carriers or excipients, and the product is directly filled into capsules or pressed into tablets, avoiding unstable factors such as moisture and heat in the granule manufacturing process.

[0026] The present invention also provides a composition using hydroxytyrosol as a cosmetic ingredient. The cosmetic composition comprises hydroxytyrosol crystal form I and cosmetically acceptable excipients.

[0027] In a preferred embodiment of the present invention, the auxiliary materials used in the cosmetic composition can be any auxiliary materials commonly available to those skilled in the art, such as nutritional additives, surfactants, moisturizers and the like.

[0028] The advantages of the present invention over the prior art are:

[0029] (1) The present invention studies and prepares a new crystal form I of hydroxytyrosol for the first time. The study found that the purity of the crystal form is greater than 99.0%, the chemical stability is good, and it can form a regular crystal form. Compared with the product form of the prior art, it has better drugability (such as fluidity, compressibility, etc.). The patented crystal form is simply mixed with excipients and tableted to obtain a dosage form that meets the requirements of the drug. It effectively overcomes the deficiency of the existing high-purity hydroxytyrosol that is difficult to make into a drug and has very good drugability, providing a variety of raw material options for subsequent drug development.

[0030] (2) The hydroxytyrosol crystal form I provided by the present invention has an antioxidant activity of IC 50 The value is more than 9 times that of the plant-derived hydroxytyrosol solid powder. The hydroxytyrosol crystal form I provided by the present invention can significantly inhibit the generation of free radicals at a relatively low concentration (10 μg / ml) (the DPPH free radical scavenging rate reaches more than 95%), and can be used as a product or additive in beauty products, health products, food, beverages and medicines to exert relevant antioxidant effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG1 is an X-ray powder diffraction pattern of hydroxytyrosol Form I prepared in Example 1.

[0032] FIG2 is a differential scanning calorimetry curve of the hydroxytyrosol crystal form I obtained in Example 1: in the marked peak, the onset temperature is 52.35° C., the peak tip temperature is 96.23° C., and the normalized flame value is 113.66 J / kg.

[0033] FIG3 is a thermogravimetric analysis curve of hydroxytyrosol Form I obtained in Example 1.

[0034] FIG4 is an infrared spectrum of the hydroxytyrosol crystal form I obtained in Example 1.

[0035] Figure 5 shows the effects of hydroxytyrosol crystal form I and plant-extracted hydroxytyrosol solid powder on DPPH scavenging rate. Specific implementation plan

[0036] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples without specifying specific conditions are all based on conventional methods and conditions.

[0037] In the following examples, the hydroxytyrosol oily substance was obtained from Nanjing Sibeiyuan Pharmaceutical Technology Co., Ltd., with a purity of ≥98%; the plant-derived hydroxytyrosol solid powder was obtained from Shaanxi Fuheng Biotechnology Co., Ltd., with a content of 20%.

[0038] Example 1

[0039] 50 g of hydroxytyrosol oil was added to 50 ml of ethanol and stirred at 40°C until clear. The mixture was slowly cooled to -25°C and stirred for 48 hours. The mixture was centrifuged and the filter cake was vacuum dried at room temperature for 16 hours. The solid was collected to obtain hydroxytyrosol Form I with an HPLC purity of 99.64%.

[0040] The X-ray powder diffraction pattern is shown in FIG1 , the differential scanning calorimetry curve is shown in FIG2 , the thermogravimetric analysis curve is shown in FIG3 , and the infrared spectrum is shown in FIG4 .

[0041] Example 2

[0042] To 50 g of the hydroxytyrosol oil, add 50 ml of propanol and stir at 40°C until clear. Slowly cool to -25°C and stir slowly for 48 hours. Centrifuge and dry the filter cake under vacuum at room temperature for 16 hours. Collect the solid to obtain hydroxytyrosol Form I with an HPLC purity of 99.88%.

[0043] Example 3

[0044] To 50 g of the hydroxytyrosol oil, add 70 ml of butanol and stir at 50°C until clear. Slowly cool to -25°C and stir slowly for 48 hours. Centrifuge and dry the filter cake in vacuo at room temperature for 16 hours. Collect the solid to obtain hydroxytyrosol Form I with an HPLC purity of 99.60%.

[0045] Example 4

[0046] To 50 g of the hydroxytyrosol oil, add 50 ml of isobutanol and stir at 60°C until clear. Slowly cool to -25°C and stir slowly for 48 hours. Centrifuge and dry the filter cake in vacuo at room temperature for 16 hours. Collect the solid to obtain hydroxytyrosol Form I with an HPLC purity of 99.69%.

[0047] Example 5

[0048] To 50 g of the hydroxytyrosol oil, add 40 ml of cyclohexanone and stir at 50°C until clear. Slowly cool to -25°C and stir slowly for 48 hours. Centrifuge and dry the filter cake in vacuo at room temperature for 16 hours. Collect the solid to obtain hydroxytyrosol Form I with an HPLC purity of 99.76%.

[0049] Example 6

[0050] To 50 g of the hydroxytyrosol oil, add 60 ml of methyl isobutyl ketone (MIBK) and stir at 50°C to dissolve. Slowly cool to -25°C and stir slowly for 48 hours. Centrifuge and dry the filter cake under vacuum at room temperature for 16 hours. Collect the solid to obtain hydroxytyrosol Form I with an HPLC purity of 99.65%.

[0051] Example 7

[0052] 50 g of hydroxytyrosol oil was added to 200 ml of chloroform and stirred at 50°C until dissolved. The mixture was slowly cooled to -25°C and stirred for 48 hours. The mixture was centrifuged and the filter cake was vacuum dried at room temperature for 16 hours. The solid was collected to obtain hydroxytyrosol Form I with an HPLC purity of 99.71%.

[0053] Example 8

[0054] Comparison of the chemical stability of hydroxytyrosol betaine eutectic, hydroxytyrosol oil, plant-derived hydroxytyrosol solid powder, and hydroxytyrosol form I in Example 1 at 40°C and RH75% in CN202110244109.X

[0055] An appropriate amount of powder sample was placed in an accelerated stabilization chamber at 40°C and RH75%, and packaged in double polyethylene bags. Samples were taken at 0 days, 14 days, 30 days, 2 months, 3 months, and 6 months, and the hydroxytyrosol content was determined using high performance liquid chromatography. The results are shown in Table 2 below:

[0056] Table 2 Test results at 40°C and RH75% Note*: Data is derived from the stability data in patent CN202110244109.X.

[0057] The test results show that the hydroxytyrosol content in the samples at day 0 is set to 100%. After 30 days, the content of the hydroxytyrosol betaine cocrystal is 99.3% of the initial content, the content of the hydroxytyrosol oil is 94.5% of the initial content, and the content of the plant-extracted hydroxytyrosol solid powder is 99.4% of the initial content. The content of the hydroxytyrosol crystal form I sample provided by the present invention is 99.9% of the initial content at 30 days, and its content is still 99.5% of the initial content after being placed for 6 months. It can be seen that compared with the hydroxytyrosol betaine cocrystal, the hydroxytyrosol oil and the plant-extracted hydroxytyrosol solid powder, the hydroxytyrosol crystal form I of the present invention has better chemical stability.

[0058] Example 9 investigates the long-term stability of the hydroxytyrosol crystal form I obtained in Example 1

[0059] An appropriate amount of pilot sample was taken and placed in a simulated commercial packaging (double polyethylene bag) at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 10% for 12 months. Samples were taken at the end of the 3rd, 6th, 9th and 12th months, and the hydroxytyrosol content was determined by high performance liquid chromatography. The results were compared with the data from month 0.

[0060] Table 3 Long-term test results

[0061] The long-term test results, as shown in Table 3, show that the purity of hydroxytyrosol at day 0 in the samples was determined to be 100%. Samples of hydroxytyrosol Form I provided by the present invention were placed in an environment simulating commercial packaging conditions, at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 10%, for 12 months. The test data for months 3, 6, 9, and 12 were compared with the data for month 0, showing no significant change in content. These test results demonstrate that the product is relatively stable under long-term test conditions.

[0062] Example 10: Fluidity test of the hydroxytyrosol crystal form I obtained in Example 1

[0063] Test method: Refer to the method under 2.9.36 Power Flow in the European Pharmacopoeia EP8.0

[0064] Table 4 Fluidity test results

[0065] The flowability test results are shown in Table 4. Generally, the angle of repose of the solid powder is less than 30° and the Carr coefficient is less than 15%, indicating that the solid powder has good flowability. The hydroxytyrosol crystal form I provided by the present invention has good flowability and meets the flowability requirements of general solid preparation production processes.

[0066] Example 11 Investigating the free radical removal performance of the plant-extracted hydroxytyrosol solid powder and the hydroxytyrosol crystal form I obtained in Example 1

[0067] DPPH (1,1-diphenyl-2-trinitrophenylhydrazine) is a stable free radical that can exist stably in organic solvents. It has a single electron and can accept an electron or hydrogen ion. It has a maximum absorption at a wavelength of 517nm. In the presence of free radical scavengers, the single electron of DPPH is captured, causing its color to lighten. The absorbance at the wavelength of maximum light absorption decreases at a linear rate. The decrease in absorbance level represents an increase in antioxidant activity, thereby evaluating the antioxidant capacity of the test sample.

[0068] IC 50 Generally refers to the half inhibition concentration, and its value can be used to indicate the antioxidant strength of different antioxidants, IC 50 The lower the value, the stronger the free radical scavenging ability of the antioxidant;

[0069] The specific experimental steps of the DPPH free radical scavenging experiment are as follows:

[0070] (1) 3 ml of the hydroxytyrosol crystal form I and the phytogenic hydroxytyrosol solid powder solution obtained in Example 1 at different concentrations were taken and mixed with 3 ml of DPPH anhydrous ethanol solution (0.04 mg / ml) (tube A1);

[0071] (2) Take 3 ml of anhydrous ethanol (solvent for the analyte) and mix it with 3 ml of DPPH anhydrous ethanol solution (0.04 mg / ml) (tube A2);

[0072] (3) Take 3 ml of the hydroxytyrosol crystal form I and the phytogenic hydroxytyrosol solid powder solution obtained in Example 1 at different concentrations, and mix them with 3 ml of the absolute ethanol solution (tube A3):

[0073] (4) After the above solutions were protected from light for 30 min, the absorbance of tubes A1, A2, and A3 was measured at 517 nm.

[0074] The formula for calculating the clearance rate is: Clearance rate % = (A2 + A3 - A1) / A2 × 100%.

[0075] The hydroxytyrosol crystal form I obtained in this Example 1 and the plant-extracted hydroxytyrosol solid powder were subjected to DPPH free radical scavenging experiments, and the results are shown in Table 5, Table 6 and Figure 5.

[0076] Table 5 DPPH clearance results of different samples

[0077] Table 6 IC of different samples 50 value

[0078] The above experimental results show that: when the solid concentration is 10 μg / ml, the DPPH scavenging rate of the plant-derived hydroxytyrosol solid powder is only 13.84%, while the DPPH scavenging rate of the hydroxytyrosol crystal form I provided by the present invention reaches more than 95%, and in the concentration range of 1 to 20 μg / ml, the free radical scavenging rate of the hydroxytyrosol crystal form I provided by the present invention is significantly better than that of the plant-derived hydroxytyrosol solid powder; at the same time, IC 50 The measurement results show that the antioxidant capacity of the hydroxytyrosol crystal form I provided by the present invention is close to more than 9 times that of the plant-derived hydroxytyrosol solid powder, indicating that the hydroxytyrosol crystal form I provided by the present invention has an extremely strong DPPH free radical scavenging rate and has better antioxidant capacity.

Claims

1. A hydroxytyrosol crystal form I, characterized in that The reflection angle 2θ of its X-ray powder diffraction pattern has characteristic peaks at 10.54±0.2°, 13.76±0.2°, 15.52±0.2°, 16.70±0.2°, 17.52±0.2°, 21.16±0.2°, 21.44±0.2°, 21.62±0.2°, 21.88±0.2°, 24.74±0.2°, 25.78±0.2°, 26.60±0.2°, 27.06±0.2°, 30.54±0.2°, 33.72±0.2° and 34.54±0.2°.

2. The hydroxytyrosol crystalline form I according to claim 1, has a reflection angle 2θ of an X-ray powder diffraction pattern, and further has diffraction peaks at one or more of the following 2θ angles: 22.44±0.2°, 23.06±2°, 24.26±0.2°, 25.1±0.2°, 29.26±0.2°, 30.8±0.2°, 33.26±0.2°, 34.18±0.2°, and 35.44±0.2°.

3. Hydroxytyrosol crystal form I according to claim 1 or 2, is characterized in that, Its X-ray powder diffraction pattern has characteristic peaks at the following reflection angles 2θ: Preferably, the X-ray powder diffraction pattern thereof expressed in 2θ degrees is substantially as shown in FIG1 .

4. The hydroxytyrosol crystal form I according to any one of claims 1 to 3, characterized in that The DSC of the hydroxytyrosol crystal form I has an endothermic peak at 54±5°C.

5. The hydroxytyrosol crystal form I according to any one of claims 1 to 3, characterized in that The TG spectrum of the hydroxytyrosol crystal form I is shown in FIG3 .

6. The hydroxytyrosol crystal form I according to any one of claims 1 to 3, characterized in that The purity of hydroxytyrosol is ≥99.0%; preferably, the purity of hydroxytyrosol is ≥99.5%.

7. The hydroxytyrosol crystal form I according to any one of claims 1 to 3, characterized in that The infrared spectrum of the hydroxytyrosol crystal form I is at 3276.7 cm -1 、2940.3cm -1 、2888.3cm -1 、2068.5cm -1 、1864.3cm -1 、1607.2cm -1 、1528.39cm -1 、1445.1cm -1 、1373.7cm -1 、1286.4cm -1 、1256.2cm -1 、1194.6cm -1 、1151.3cm -1 、1114.3cm -1 、1048.9cm -1 、1028.8cm -1 、1011.1cm -1 、911.1cm -1 、875.9cm -1 、848.4cm -1 、809.4cm -1 、781.9cm -1 、753.4cm -1 、718.4cm -1 、634.3cm -1 、589.8cm -1 、455.0cm -1 、418.3cm -1 There is a characteristic peak.

8. The method for preparing the hydroxytyrosol crystal form I according to any one of claims 1 to 7, characterized in that: Dissolving the hydroxytyrosol oil in an organic solvent at 30-60° C., cooling to -25--5° C., stirring and crystallizing for 40-50 hours; centrifuging and filtering, and vacuum drying at room temperature to obtain a hydroxytyrosol crystal form I solid; Preferably, the organic solvent is one or more of alcohols, ketones, lipids, alkanes or halogenated hydrocarbons.

9. The preparation method of hydroxytyrosol crystal form I according to claim 8, wherein The alcohol solvent is selected from: ethanol, propanol, isopropanol, n-butanol, isobutanol or tert-butanol; the ketone solvent is selected from: acetone, cyclohexanone or methyl isobutyl ketone; the lipid solvent is selected from: methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; the alkane solvent is selected from: n-hexane, n-heptane or cyclohexane; the halogenated hydrocarbon solvent is selected from: dichloromethane, dichloroethylene, trichloroethylene, chloroform or carbon tetrachloride.

10. A pharmaceutical composition, characterized in that The invention comprises a therapeutically effective amount of the hydroxytyrosol crystal form I component according to any one of claims 1 to 7, and pharmaceutically or cosmetically acceptable excipients.

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