A high-purity gastrodin crystal and its preparation method and application

Abstract

The present invention provides a new gastrodin crystal form, and the X-ray powder diffraction spectrum obtained by using Cu-Kα ray measurement shows that the crystal form is discovered for the first time, and the present invention enriches the crystal form research of gastrodin. The preparation process of the present invention is simple, and the obtained crystal form compound has high purity, good solubility and high bioavailability, which greatly broadens the application scenarios of gastrodin and improves the compliance of patients with medication.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemistry, and in particular to a high-purity gastrodin crystal and a preparation method and application thereof. Background Art

[0002] Gastrodia elata Bl is the dried tuber of the orchid plant Gastrodia elata, also known as red arrow, mother, ghost Duyou, magic grass, single shake Zhi, red arrow fat, Dingfeng grass, Heli grass, single shake, automatic grass, water potato. It is dug from the beginning of winter to before Qingming of the following year (winter hemp is better), and is a famous Chinese medicinal material. It has been used as medicine as early as more than 2,000 years ago, and the ones produced in Zhaotong, Yunnan are the best. It is rich in gastrodin, vanillin, protein, amino acids, and trace elements. It is pungent, warm, and non-toxic. The Chinese Pharmacopoeia records its functions and indications as: anti-epileptic, anti-palpitation, anti-rheumatic; sedative, antispasmodic, analgesic, tonic, calming the liver and calming the wind. Functions and indications: calming the liver, calming the wind and stopping spasms. It is used for headache, dizziness, numbness of limbs, epilepsy, convulsions, and tetanus. Dizziness, neurasthenia, wind-cold dampness, infantile convulsions, etc. Clinical application has proved that it has significant therapeutic effects on vascular neurosis headache, sequelae of concussion, etc. Pharmacological studies have shown that the main active ingredient of Gastrodia elata is gastrodin. The chemical name is: 4-hydroxymethylbenzene-β-D-pyranoglucoside hemihydrate, molecular formula C 13 H 19 O8, molecular weight 295.38.

[0003] The commonly used dosage forms of gastrodin in clinical use include injection, powder injection, tablets, capsules, etc. The research reports on the crystal form of gastrodin are as follows:

[0004] Patent CN 103224539 B mentions a crystal form of gastrodin: gastrodin is dissolved in ethanol / methanol or a mixed solvent of the two at room temperature, filtered through carbon, anti-solvent chloroform / ether is added dropwise, crystallized at low temperature, and dried to obtain the crystal form.

[0005] Patent CN 103788148 B mentions a gastrodin crystal form: gastrodin is dissolved in acetone / DMSO or a mixed solvent of the two at room temperature, filtered through carbon, anti-solvent chloroform is added dropwise, crystallized, and dried to obtain the crystal form.

[0006] Patent CN 104447904 A mentions a crystal form of gastrodin: gastrodin is dissolved in ethanol / methanol or a mixed solvent of the two at room temperature, filtered through carbon, anti-solvent ethyl acetate is added dropwise, crystallized at low temperature, and dried to obtain the crystal form.

[0007] The above-mentioned reports on the crystalline compounds of gastrodin are all hemihydrates, and the solubility or bioavailability of the prepared pharmaceutical preparations need to be further improved. Summary of the invention

[0008] In view of this, the technical problem to be solved by the present invention is to provide a high-purity gastrodin crystal and a preparation method and application thereof, and the prepared pharmaceutical preparation has high solubility and bioavailability.

[0009] To achieve the above object, the present invention provides a high-purity gastrodin crystal, whose X-ray powder diffraction pattern has diffraction peaks at 2θ±0.2°, and the 2θ is 6.901°, 8.618°, 12.939°, 13.820°, 18.903°, and 20.783°.

[0010] Furthermore, the 2θ is 6.901°, 8.618°, 12.939°, 13.820°, 15.962°, 17.540°, 18.903°, 20.783°, 21.384°, 24.205°, 26.024°, 31.924°, 32.248°, 34.907°, and 39.645°.

[0011] The structural formula of gastrodin is shown in Formula I:

[0012]

[0013] Specifically, the detailed parameters of the X-ray diffraction of the gastrodin crystals of the present invention are as follows: Figure 1 shown.

[0014] The X-ray powder diffraction pattern obtained by Cu-Ka ray measurement is as follows: Figure 2 shown.

[0015] In the present invention, the 2θ value of the X-ray powder diffraction pattern may vary slightly between machines or samples, and its value may differ by about 0.2 units, or by about 0.1 units, so the quoted values ​​cannot be interpreted as absolute values. It should also be understood that the size of the peak height may also differ by about 5 units, or by about 4 units, or by about 3 units, or by about 2 units, or by about 1 unit, so the XRPD trace intensity included in the present invention is illustrative and is not intended to be used for absolute comparison.

[0016] The present invention provides a method for preparing the above-mentioned gastrodin crystals, comprising the following steps:

[0017] The gastrodin Form 1 crystal form is dissolved in methanol, and then isopropyl ether or methyl tert-butyl ether is added to precipitate solids, which are centrifuged and dried to obtain gastrodin crystals;

[0018] Alternatively, the gastrodin Form 1 crystal form is placed in a mixed solvent of methanol and isopropyl ether, or methanol and methyl tert-butyl ether, stirred for crystallization, and then centrifuged and dried to obtain gastrodin crystals.

[0019] The volume ratio of methanol to isopropyl ether is preferably 1:(5-15).

[0020] The volume ratio of methanol to methyl tert-butyl ether is preferably 1:(5-15).

[0021] The gastrodin Form 1 crystal form is prepared according to the following method:

[0022] The gastrodin Form A crystal hemihydrate is dried at a temperature of 80° C.-160° C. to obtain the gastrodin Form 1 crystal.

[0023] The drying time is preferably 5 to 40 minutes.

[0024] In the present invention, the Form A crystal hemihydrate sample is prepared according to the following method:

[0025] Gastrodin is dissolved in ethanol, methanol or a mixed solvent of the two at room temperature, filtered through carbon, anti-solvent ethyl acetate is added dropwise, crystallized at low temperature, and dried to obtain gastrodin Form A crystal hemihydrate.

[0026] For details, please refer to the Chinese patent application number 201410379348.6.

[0027] The prepared gastrodin crystals are subjected to DSC and TGA detection, and the DSC spectrum shows that the melting point is 140°C.

[0028] TGA showed that the crystalline compound had a slow weight loss of about 0.1% before 120°C, was anhydrous, and had a decomposition temperature of 292°C.

[0029] The DVS / isothermal adsorption curve shows that the weight change of the crystalline compound in the range of 0% RH to 80% RH is about 3.8%, and it is easy to absorb moisture. After being placed in dry conditions at room temperature for 14 days, the crystalline form remains unchanged. After being placed in the open air at room temperature ≤ 33% RH for 7 days, the crystalline form remains basically unchanged. After being placed in the open air at room temperature 75% RH for 7 days, it turns into Form A crystalline form.

[0030] The present invention names the newly prepared gastrodin crystals as Form 4.

[0031] The present invention provides the use of the above-mentioned gastrodin crystals, or the gastrodin crystals prepared by the above-mentioned preparation method in preparing drugs for preventing, alleviating or treating vascular neurotic headaches and sequelae of concussion.

[0032] The present invention provides a pharmaceutical preparation comprising the above-mentioned gastrodin crystals, or the gastrodin crystals prepared by the above-mentioned preparation method and pharmaceutically acceptable excipients.

[0033] In the present invention, the dosage form of the pharmaceutical preparation can be tablets, hard capsules, soft capsules, dry suspensions, dropping pills or micropills.

[0034] Experimental results show that the pharmaceutical preparation prepared using the gastrodin crystals provided by the present invention has higher solubility and bioavailability.

[0035] The gastrodin crystals provided by the present invention can be used in combination with other drugs.

[0036] Based on this, the present invention provides a pharmaceutical composition comprising the above-mentioned gastrodin crystals, or the gastrodin crystals prepared by the above-mentioned preparation method and other drugs for preventing, alleviating or treating vascular neurotic headache and sequelae of concussion.

[0037] The present invention provides a new crystal form of gastrodin. The X-ray powder diffraction spectrum measured using Cu-Kα rays shows that the crystal form is discovered for the first time. The present invention enriches the crystal form research of gastrodin. The preparation process of the present invention is simple, and the obtained crystal form compound has high purity, good solubility and high bioavailability, which greatly broadens the application scenarios of gastrodin and improves the compliance of patients with medication.

[0038] It should be noted that the formation of a crystal form is affected by many factors. Even a small change in any factor such as reaction temperature, time, stirring speed, reactant concentration, crystallization condition control, etc. may produce unexpected changes. The inventors experienced many failures in the research process, but finally spent a lot of energy to study the control details and finally obtained the crystalline compound described in the present invention. Each control point in the preparation process of the compound described in the present invention is crucial to the result. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is an X-ray diffraction parameter diagram of gastrodin crystal Form 4 obtained in Example 3 of the present invention;

[0040] Figure 2 The X-ray powder diffraction pattern of the gastrodin crystal Form 4 obtained in Example 3 of the present invention, wherein the ordinate represents the diffraction intensity expressed in counts / second (cps), and the abscissa represents the diffraction angle 2θ expressed in degrees;

[0041] Figure 3 This is the DSC graph of gastrodin crystal Form 4 obtained in Example 1 of the present invention;

[0042] Figure 4This is the TGA graph of gastrodin crystal Form 4 obtained in Example 1 of the present invention;

[0043] Figure 5 This is the isothermal adsorption curve of the gastrodin crystal Form 4 obtained in Example 1 of the present invention;

[0044] Figure 6 This is the DVS spectrum of the gastrodin crystal Form 4 obtained in Example 1 of the present invention;

[0045] Figure 7 This is a PLM morphology diagram of gastrodin crystal Form 4 obtained in Example 1 of the present invention;

[0046] Figure 8 This is the XRPD diagram of the stability of the gastrodin crystal Form 4 sealed and dried at room temperature obtained in Example 1 of the present invention;

[0047] Fig. 9 This is the XRPD diagram of the stability of the gastrodin crystal Form 4 prepared in Example 1 of the present invention under different humidity conditions at room temperature;

[0048] Fig.10 is the X-ray powder diffraction pattern of gastrodin Form A crystal hemihydrate;

[0049] Fig.11 This is the X-ray powder diffraction pattern of Form 1 crystal of gastrodin. DETAILED DESCRIPTION

[0050] To further illustrate the present invention, the high-purity gastrodin crystals provided by the present invention, and the preparation method and application thereof are described in detail below in conjunction with the examples.

[0051] In the following examples, unless otherwise stated, the test methods are generally carried out according to conventional conditions or conditions recommended by the manufacturers.

[0052] The X-ray powder diffraction pattern of the present invention is collected on a Bruker D8 Advance Diffractometer X-ray powder diffractometer.

[0053] The method parameters of X-ray powder diffraction described in the present invention are as follows:

[0054] X-ray reflection parameters: Cu-Ka

[0055] Voltage: 40 kilovolts (kV)

[0056] Current: 40 milliamperes (mA)

[0057] Divergence slit: 1 / 32°

[0058] Anti-scatter slit: 1 / 16°

[0059] Scanning range: from 3.0 to 40.0 degrees

[0060] Sampling step: 0.02 degrees

[0061] Measurement time per step: 0.2 seconds / step

[0062] The differential scanning calorimetry analysis diagram of the present invention is collected on a DSC TA Instruments Q200 differential scanning calorimeter.

[0063] The method parameters of differential scanning calorimetry analysis described in the present invention are as follows:

[0064] Temperature range / ℃:0℃-250℃

[0065] Scanning rate / ℃ / min:10℃ / min

[0066] Protective gas: Nitrogen, 50 ml / min

[0067] The thermogravimetric analysis diagram of the present invention was collected on a TA Instruments Q500 TGA thermogravimetric analyzer.

[0068] The method parameters of the thermogravimetric analysis described in the present invention are as follows:

[0069] Temperature range / ℃:10-350℃

[0070] Scanning rate / ℃ / min:10℃ / min

[0071] Protective gas: Nitrogen, 40 ml / min

[0072] The dynamic moisture adsorption instrument, analytical balance, and constant temperature and humidity chamber used in the present invention are shown in Table 1 below:

[0073] Table 1 Parameters of the dynamic moisture adsorption instrument, analytical balance, and constant temperature and humidity chamber used in the present invention

[0074]

[0075]

[0076] Preparation of Gastrodin Form 1 Sample

[0077] Weigh 3.0 g of the raw material Form A crystalline gastrodin hemihydrate, place it in an oven at 115° C. for about 15 minutes, cool it to room temperature, and the obtained solid is the Form 1 crystalline compound of gastrodin.

[0078] The preparation method of Form A crystalline gastrodin hemihydrate refers to Chinese patent application number 201410379348.6.

[0079] The X-ray powder diffraction pattern of gastrodin Form A hemihydrate is as follows Fig.10 shown.

[0080] The X-ray powder diffraction pattern of gastrodin Form 1 is as follows Fig.11 shown.

[0081] Example 1 Preparation of Form 4 Crystalline Form of Gastrodin

[0082] Take about 200 mg of gastrodin Form 1 sample, add 0.8 mL of methanol to dissolve, add 6.4 mL of isopropyl ether dropwise under stirring at room temperature to precipitate solid, continue stirring for about 30 minutes, centrifuge, and vacuum dry at room temperature overnight to obtain Form 4 crystal sample, recorded as Sample 1.

[0083] Example 2 Preparation of Form 4 Crystalline Form of Gastrodin

[0084] Take about 200 mg of gastrodin Form 1 sample, add 0.8 mL of methanol to dissolve it, and add the solution dropwise into 6.4 mL of isopropyl ether under stirring at room temperature to precipitate solid. Continue stirring for about 30 minutes, centrifuge, and vacuum dry at room temperature overnight to obtain a Form 4 crystal sample, which is recorded as Sample 2.

[0085] Example 3 Preparation of Form 4 Crystalline Form of Gastrodin

[0086] Take about 30 mg of gastrodin Form 1 sample, add 2 mL of methyl tert-butyl ether and 0.2 mL of methanol in sequence, stir the slurry at 4°C for 3 days, centrifuge, and vacuum dry at room temperature overnight to obtain a Form 4 crystal sample, recorded as Sample 3.

[0087] Experiment 1: X-ray powder diffraction detection

[0088] Sample 3 was taken for XRPD detection, and its X-ray powder diffraction parameters were as follows: Figure 1 The X-ray powder diffraction pattern is shown in Figure 2 shown.

[0089] The XRPD results of samples 1 and 2 were similar to those of sample 3.

[0090] Experiment 2: Differential Scanning Calorimetry and Thermogravimetric Analysis

[0091] Sample 3 was taken for DSC and TGA testing, and the results were as follows: Figure 3 , Figure 4 As shown, the results show that sample 3 has a melting point of 141°C, a slow weight loss of about 0.1% before 120°C, is anhydrous, and has a decomposition temperature of 292°C.

[0092] DSC and TGA tests were performed on samples 1 and 2, and the results were similar to Figure 3 , Figure 4 resemblance.

[0093] Experiment 3: Dynamic moisture adsorption detection

[0094] Sample 3 was taken for isothermal adsorption test and DVS analysis experiment. The isothermal adsorption curve is shown in Figure 5 As shown, the DVS spectrum is as follows Figure 6 shown.

[0095] The results show that sample 3 has a significant change of about 3.8% in the range of 0% RH to 80% RH, and is easily hygroscopic.

[0096] Isothermal adsorption tests and DVS analysis experiments were performed on samples 1 and 2, and the results were similar.

[0097] Experiment 4: PLM

[0098] The crystal morphology was observed using a polarizing microscope. The PLM morphology is shown in the figure below. Figure 7 shown.

[0099] Experiment 5: Stability evaluation experiment

[0100] Take an appropriate amount of sample 3, place it in a sealed dry condition at room temperature for 14 days, place it open at room temperature at 75% RH for 1 day and 7 days, place it open at room temperature at 44% RH for 7 days, and place it open at room temperature at 33% RH for 7 days, and conduct accelerated stability tests. Characterize the sample with XRPD to detect its crystal form. The test results are as follows: Figure 8-9 shown.

[0101] The test results show that the crystal form of sample 3 remains unchanged after being placed in dry conditions at room temperature for 14 days.

[0102] When left exposed at room temperature ≤33% RH for 7 days, the crystal form remains basically unchanged.

[0103] When left exposed at room temperature (44% RH) for 7 days, the crystal form remained essentially unchanged.

[0104] When left exposed at room temperature (75% RH) for 1 day, the crystal form remained unchanged.

[0105] The mixture was left exposed at room temperature (75% RH) for 7 days and then transformed into Form A crystal.

[0106] Samples 1 and 2 were subjected to accelerated stability evaluation tests with similar results.

[0107] This indicates that the gastrodin crystal form Form 4 prepared by the present invention has good stability.

[0108] Example 4

[0109] The gastrodin tablets were prepared using the gastrodin Form 4 crystalline compound obtained in Example 1 as follows:

[0110] Gastrodia elata crystals 100g

[0111] 300g starch

[0112] Microcrystalline cellulose 50g

[0113] L-Hydroxypropylcellulose 30g

[0114] HPMC (20%) 5g

[0115] Sodium carboxymethyl starch 10g

[0116] Magnesium stearate 5g

[0117] The gastrodin crystals, starch, microcrystalline cellulose, L-hydroxypropyl cellulose, and sodium carboxymethyl starch are respectively passed through a 100-mesh sieve for use, the gastrodin crystals, starch, microcrystalline cellulose, and L-hydroxypropyl cellulose are weighed according to the optimal amount, and are fully mixed and uniformly prepared with an appropriate amount of 20% HPMC (15cps) to prepare a soft material, and the mixture is passed through a 20-mesh sieve for granulation, dried at 50°C, granulated, and the prescribed amount of CMS-Na is added, mixed uniformly, and the tablet weight is determined to be 0.5g, and the prescribed amount of magnesium stearate is added and tableted on a tablet press. That is, the crystalline tablet of the present invention is obtained.

[0118] Experiment 6: Oral dissolution test of Gastrodia elata tablets

[0119] (1) Test instruments: The instruments used were Waters e2695 high performance liquid chromatograph (2489 UV detector, Empower3 chemical workstation, chromatographic column LunaC18 250×4.6 mm); German PT WS1210 dissolution apparatus.

[0120] (2) Test method:

[0121] According to the dissolution determination method (Appendix XC Method 2 of Part II of the 2015 edition of the Chinese Pharmacopoeia), 900 ml of 0.05 mol / L potassium dihydrogen phosphate buffer (take 6.8 g of potassium dihydrogen phosphate, dissolve it in water and dilute it to 1000 ml, mix well, and adjust the pH value to 6.8±0.05 with 6.0 mol / L sodium hydroxide solution) is used as the dissolution medium, the speed is 75 revolutions per minute, and the operation is carried out according to the law. After 30 minutes, 10 ml of the solution is taken, filtered, the initial filtrate is discarded, and the subsequent filtrate is taken as the test solution; another amount of gastrodin reference substance is taken and added with the dissolution medium to prepare a 1 ml solution containing 25 ug of gastrodin as the reference substance solution.

[0122] (3) Detection method: The mobile phase was a mixture of acetonitrile and 0.1% phosphoric acid water (3:97), the detection wavelength was 220 nm, the chromatographic column was LunaC18 (250×4.6 mm), and the column temperature was 35°C. 10 μl of the test sample and reference sample solution were respectively injected into the liquid chromatograph, the chromatograms were recorded, and the amount of gastrodin dissolved in each tablet was calculated by the external standard method.

[0123] (4) Test samples:

[0124] Tablet 1: The gastrodin crystals prepared in Example 1 were used to prepare the gastrodin tablets in Example 4;

[0125] Tablet 2: Gastrodin tablets prepared by the crystalline compound prepared by the method described in Patent No. CN103788148 B using the same components and method as Example 4;

[0126] Tablet 3: A Gastrodin tablet prepared by using the crystalline compound prepared by the method described in Patent No. CN104447904A using the same components and method as Example 4.

[0127] (5) Test results:

[0128] Table 2 Dissolution of 3 batches of tablets:

[0129]

[0130] The test data in the above table show that the solubility of the gastrodin tablets whose raw material is gastrodin Form 4 crystals is higher than that of the gastrodin crystal tablets reported in other related crystal form patents with dissolution advantages.

[0131] Experiment 7: In vivo blood concentration test of Gastrodia elata tablets

[0132] (1) Test instruments, drugs and reagents

[0133] Instruments: The instruments used were Waters e2695 high performance liquid chromatograph (2489 UV detector, Empower3 chemical workstation, chromatographic column LunaC18 250×4.6 mm); DL-8R refrigerated centrifuge.

[0134] (2) Test samples:

[0135] Tablet 1: The gastrodin crystals prepared in Example 1 were used to prepare the gastrodin tablets in Example 4;

[0136] Tablet 2: Gastrodin tablets prepared by the crystalline compound prepared by the method described in Patent No. CN103788148 B in Example 4;

[0137] Tablet 3: Gastrodin tablets prepared by the crystalline compound prepared by the method described in Patent No. CN104447904 A according to Example 4.

[0138] Specifications: Each tablet contains 0.1g of gastrodin.

[0139] (3) Experimental design

[0140] Thirty adult rats were randomly divided into three groups.

[0141] The first group was fed with crushed rat chow accompanied with Tablet 1 at 7:00 a.m.;

[0142] The second group was fed with mouse chow accompanied by crushed tablet 2 at 7:00 a.m.;

[0143] The third group was fed with mouse chow accompanied with crushed tablet 3 at 7:00 am.

[0144] Ensure one tablet per rat.

[0145] 1 mL of venous blood was collected at 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 10.0, 14.0, and 18.0 hours after administration, anticoagulated with heparin, and centrifuged. The plasma was collected and stored in a -20°C refrigerator for testing. Care was taken to avoid light during blood collection and centrifugation. The concentration of gastrodin in plasma was measured.

[0146] (4) The test results are shown in Table 3:

[0147] Table 3 Mean blood drug concentration (mg / L)-time (h) of 3 batches are as follows:

[0148]

[0149] It can be seen from Table 3 above that the average blood drug concentration of the crystalline preparation of the present invention in mice after administration is higher than that of Tablets 2 and 3. This shows that the gastrodin compound provided by the present invention has good absorption in the body, good efficacy, and high oral bioavailability.

[0150] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A high-purity gastrodin crystal, characterized in that: The X-ray powder diffraction pattern has diffraction peaks at 2θ±0.2°, and the 2θ is 6.901°, 8.618°, 12.939°, 13.820°, 18.903°, and 20.783°; The method for preparing the gastrodin crystals comprises the following steps: The gastrodin Form 1 crystal form is dissolved in methanol, and then isopropyl ether or methyl tert-butyl ether is added to precipitate solids, which are centrifuged and dried to obtain gastrodin crystals; Alternatively, the gastrodin Form 1 crystal form is stirred and crystallized in a mixed solvent of methanol and isopropyl ether, or methanol and methyl tert-butyl ether, and then centrifuged and dried to obtain gastrodin crystals; The gastrodin Form 1 crystal form is prepared according to the following method: The gastrodin Form A crystal hemihydrate is dried at a temperature of 115° C. to 160° C. to obtain the gastrodin Form 1 crystal; The Form A crystalline hemihydrate is prepared according to the following method: Gastrodin is dissolved in ethanol, methanol or a mixed solvent of the two at room temperature, filtered through carbon, anti-solvent ethyl acetate is added dropwise, crystallized at low temperature, and dried to obtain gastrodin Form A crystal hemihydrate.

2. The high-purity gastrodin crystal according to claim 1, characterized in that: The X-ray powder diffraction pattern has a diffraction peak at 2θ±0.2°, and the 2θ is 6.901°, 8.618°, 12.939°, 13.820°, 15.962°, 17.540°, 18.903°, 20.783°, 21.384°, 24.205°, 26.024°, 31.924°, 32.248°, 34.907°, and 39.645°.

3. The high-purity gastrodin crystal according to claim 1, characterized in that: The X-ray powder diffraction pattern is shown in FIG2 .

4. The high-purity gastrodin crystal according to claim 1, characterized in that: The melting point of the gastrodin crystals is 140°C.

5. The high-purity gastrodin crystal according to claim 1, characterized in that: The decomposition temperature of the gastrodin crystals is 292°C.

6. The method for preparing high-purity gastrodin crystals according to any one of claims 1 to 5, comprising the following steps: The gastrodin Form 1 crystal form is dissolved in methanol, and then isopropyl ether or methyl tert-butyl ether is added to precipitate solids, which are centrifuged and dried to obtain gastrodin crystals; Alternatively, the gastrodin Form 1 crystal form is stirred and crystallized in a mixed solvent of methanol and isopropyl ether, or methanol and methyl tert-butyl ether, and then centrifuged and dried to obtain gastrodin crystals; The gastrodin Form 1 crystal form is prepared according to the following method: The gastrodin Form A crystal hemihydrate is dried at a temperature of 115° C. to 160° C. to obtain the gastrodin Form 1 crystal; The Form A crystalline hemihydrate is prepared according to the following method: Gastrodin is dissolved in ethanol, methanol or a mixed solvent of the two at room temperature, filtered through carbon, anti-solvent ethyl acetate is added dropwise, crystallized at low temperature, and dried to obtain gastrodin Form A crystal hemihydrate.

7. Use of the gastrodin crystals according to any one of claims 1 to 5, or the gastrodin crystals prepared by the preparation method according to claim 6, in the preparation of drugs for preventing, alleviating or treating vascular neurosis headaches and sequelae of concussion.

8. A pharmaceutical preparation, characterized in that It comprises the gastrodin crystals as described in any one of claims 1 to 5, or the gastrodin crystals prepared by the preparation method as described in claim 6, and pharmaceutically acceptable excipients.

9. The pharmaceutical preparation according to claim 8, characterized in that The dosage form of the pharmaceutical preparation is tablet, hard capsule, soft capsule, dry suspension, dropping pill or micropill.

10. A pharmaceutical composition, characterized in that The invention comprises the gastrodin crystals as described in any one of items 1 to 5, or the gastrodin crystals prepared by the preparation method as described in claim 6, and other drugs for preventing, alleviating or treating vascular neurosis headache and sequelae of concussion.

Images