Benserazide hydrochloride spherocrystal and preparation method thereof

Abstract

The invention discloses a benserazide hydrochloride spherocrystal and a preparation method thereof. The spherocrystal benserazide hydrochloride prepared by the method has the characteristics of large granularity, higher yield, excellent product quality, capability of improving the powder flowability and density and reducing static electricity, simplified process operation and easiness in realization of industrialization.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly relates to a benserazide hydrochloride spherulite and a preparation method thereof. BACKGROUND

[0002] Benserazide hydrochloride is a peripheral decarboxylase inhibitor, which is often combined with levodopa to form a compound preparation, dopa-sine, and is used for treating Parkinson's disease. The chemical name of benserazide hydrochloride is 2-amino-3-hydroxy-N'(2,3,4-trihydroxybenzyl) propylhydrazine hydrochloride, and the structure is as follows:

[0003]

[0004] WO 2015197909 reports that the DMF solvate of benserazide hydrochloride is added to a mixed solvent of 90% ethanol aqueous solution and 1-propanol, stirred at room temperature overnight, and then the precipitate is washed with 1-propanol until the DMF is completely removed, and then dried at 40-50 DEG C under vacuum to obtain anhydrous hydrochloride salt, thereby obtaining crystal form I.

[0005] IN 201941031930 reports a crystal preparation method: solid is added to water, and then a mixed solvent of ethanol and isopropanol is added at 30-35 DEG C, and then cooled to 0-5 DEG C, and then the solid is obtained by filtering and washing with a mixture of ethanol and isopropanol in a ratio of 1:1, and the yield is 55%; method two: after washing with an excess amount of methyl tert-butyl ether, white or white-like crystals are obtained by recrystallization with isopropanol, and the yield is 60%.

[0006] The above crystallization methods have a low yield of benserazide hydrochloride, and the crystal habits are needle-shaped fine particles, have poor flowability, strong electrostatic effect, and have problems such as difficulty in filtering, easy running, difficulty in drying, complicated operation, process safety and the like in industrial production. At the same time, the fine powder with high surface static electricity and low flowability can also induce serious weight deviation, powder sticking and other tabletting obstacles in the preparation process. SUMMARY

[0007] The application provides a preparation method of benserazide hydrochloride spherulite, which has a high yield, high product quality, can well improve the flowability, bulk density, tap density of the powder, reduce static electricity, has advantages in subsequent production filtering, filling, tabletting and the like, simplifies the process operation, and is easy to realize industrialization.

[0008] The method comprises the following steps:

[0009] (1) cooling the alcohol solvent 1 to 5-25 DEG C, and optionally adding crystal seeds,

[0010] (2) controlling the crystallization temperature, and adding the solution containing benserazide hydrochloride dropwise, and stirring for crystallization,

[0011] (3) filtering and drying the obtained levodopa hydrochloride spherulites,

[0012] (4) optionally, crushing the levodopa hydrochloride spherulites obtained in step (3),

[0013] wherein the levodopa hydrochloride solution in step (2) is prepared by dissolving levodopa hydrochloride in a mixed solvent of water and an alcohol solvent 2.

[0014] In some embodiments, the levodopa hydrochloride spherulites in step (3) have diffraction peaks at 2Θ = 7.7°, 18.5°, 24.6° ± 0.2° in an X-ray powder diffraction (XRPD) pattern measured with Cu-Ka radiation, and the aspect ratio of the spherulites is not more than 2.

[0015] In some embodiments, the alcohol solvent 1 in step (1) is cooled to 10-15 °C.

[0016] In some embodiments, the alcohol solvent 1 and the alcohol solvent 2 are selected from one or more of methanol, ethanol or isopropanol. In some embodiments, the alcohol solvent 1 and the alcohol solvent 2 can be the same or different.

[0017] In some embodiments, the weight-to-volume ratio (g / mL) of levodopa hydrochloride to the alcohol solvent 1 in the levodopa hydrochloride solution is 1:15-30. In some embodiments, the weight-to-volume ratio (g / mL) of levodopa hydrochloride to the alcohol solvent 1 in the levodopa hydrochloride solution is 1:15-25.

[0018] In some embodiments, the weight ratio of the seed crystal to levodopa hydrochloride in the levodopa hydrochloride solution in step (1) is 0.5-5%. In some embodiments, the weight ratio of the seed crystal to levodopa hydrochloride in the levodopa hydrochloride solution in step (1) is 1-3%.

[0019] In some embodiments, the weight-to-volume ratio (g / mL) of levodopa hydrochloride to the alcohol solvent 2 in the levodopa hydrochloride solution is 1:1.5-3.5. In some embodiments, the weight-to-volume ratio (g / mL) of levodopa hydrochloride to the alcohol solvent 2 in the levodopa hydrochloride solution is 1:2.0-3.5.

[0020] In some embodiments, the weight-to-volume ratio (g / mL) of levodopa hydrochloride to water in the levodopa hydrochloride solution is 1:1.5-3.0. In some embodiments, the weight-to-volume ratio (g / mL) of levodopa hydrochloride to water in the levodopa hydrochloride solution is 1:1.5-2.5.

[0021] In some embodiments, the solubilization temperature of benserazide hydrochloride in the benserazide hydrochloride solubilization solution is 10-30°C. In some embodiments, the solubilization temperature of benserazide hydrochloride in the benserazide hydrochloride solubilization solution is 15-25°C.

[0022] In some embodiments, the crystallization temperature in step (2) is 5-25°C. In some embodiments, the crystallization temperature in step (2) is 10-15°C.

[0023] In some embodiments, the stirring crystallization time in step (2) is 6-24 hours. In some embodiments, the stirring crystallization time in step (2) is 8-18 hours. In some embodiments, the stirring crystallization time in step (2) is 8-14 hours.

[0024] In some embodiments, after the stirring crystallization in step (2) is completed, further slow cooling crystallization can be performed. In some embodiments, the slow cooling is performed at a rate of 3-8°C / hour. In some embodiments, after the slow cooling to -5-0°C, stirring can be continued for 0-12 hours. In some embodiments, after the slow cooling to -5-0°C, stirring can be continued for 1-6 hours.

[0025] In some embodiments, the drying in step (3) is a gradual temperature-increasing drying under vacuum, with a drying temperature of 35-65°C and a drying time of 4-30 hours.

[0026] In some embodiments, the benserazide hydrochloride spherulites obtained in step (3) can be further crushed by one or more of a conical crusher, a hammer crusher, a vibrating screen, wet shearing, and an air flow classifier.

[0027] In another aspect, the present application provides a benserazide hydrochloride spherulite having diffraction peaks at 2θ = 7.7°, 18.5°, 24.6°±0.2° in an X-ray powder diffraction (XRPD) pattern measured using Cu-Kα radiation, with an aspect ratio of no more than 2.

[0028] In some embodiments, the D(10) of the benserazide hydrochloride spherulites of the present invention is 5-120 μm, D(50) is 15-210 μm, and D(90) is 50-350 μm. In some embodiments, the D(10) of the benserazide hydrochloride spherulites of the present invention is 50-120 μm, D(50) is 100-210 μm, and D(90) is 200-350 μm. In some embodiments, the D(10) of the benserazide hydrochloride spherulites of the present invention is 5-10 μm, D(50) is 15-20 μm, and D(90) is 50-70 μm. In some embodiments, the benserazide hydrochloride spherulites of the present invention are prepared into the desired particle size by pulverizing according to demand.

[0029] In some embodiments, the benserazide hydrochloride spherulites of the present invention have Figure 4 or Figure 5 Essentially the same micrographs are shown.

[0030] In some embodiments, the benserazide hydrochloride spherulites of the present invention have a bulk density of 0.30-0.45 g / ml and a tap density of 0.40-0.55 g / ml.

[0031] In some embodiments, the angle of repose of the benserazide hydrochloride spherulites of the present invention is 32.0-34.5°.

[0032] In some embodiments, the charge of the benserazide hydrochloride spherulites of the present invention is 600 to 1300V.

[0033] In some embodiments, the benserazide hydrochloride spherulites of the present invention have diffraction peaks of 2θ=7.7°, 12.2°, 18.5°, 24.6°, 25.3°, and 29.7°±0.2° in the X-ray powder diffraction (XRPD) pattern measured using Cu-Kα radiation. In some embodiments, the benserazide hydrochloride spherulites of the present invention have diffraction peaks of 2θ=7.7°, 9.2°, 11.0°, 12.2°, 13.1°, 15.1°, 18.5°, 23.0°, 24.6°, 25.3°, 27.5°, and 29.7°±0.2° in the X-ray powder diffraction (XRPD) pattern measured using Cu-Kα radiation.

[0034] In some embodiments, the differential scanning calorimeter (DSC) results of the benserazide hydrochloride spherulites of the present invention have an extrapolated onset temperature (Onset) of 158.86±2°C and a peak temperature (Peak) of 163.24±2°C.

[0035] In some embodiments, the thermogravimetric analysis (TGA) of the benserazide hydrochloride spherulites of the present invention has a volatile matter weight loss of 0.30-0.87% before the sample decomposes.

[0036] In some embodiments, the crystal form of the spherulites of benserazide hydrochloride according to the present application has substantially the same XRPD pattern as shown in Figure 1. Figure 1

[0037] In some embodiments, the crystal form of the spherulites of benserazide hydrochloride according to the present application has substantially the same DSC pattern as shown in Figure 2. Figure 2

[0038] In some embodiments, the crystal form of the spherulites of benserazide hydrochloride according to the present application has substantially the same TGA pattern as shown in Figure 3. Figure 3

[0039] In another aspect, the present application provides a spherulite of benserazide hydrochloride, which is prepared by the above method.

[0040] In another aspect, the present application also provides a pharmaceutical composition comprising the above spherulite of benserazide hydrochloride,

[0041] In another aspect, the present application also provides a pharmaceutical composition comprising the above spherulite of benserazide hydrochloride and at least one pharmaceutically acceptable carrier.

[0042] In another aspect, the present application also provides a pharmaceutical composition comprising the above spherulite of benserazide hydrochloride and levodopa.

[0043] In another aspect, the present application also provides use of the above spherulite of benserazide hydrochloride in the preparation of a medicament for treating Parkinson's disease. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 XRPD pattern of the spherulites of benserazide hydrochloride prepared according to Example 1 of the present application;

[0045] Figure 2 DSC pattern of the spherulites of benserazide hydrochloride prepared according to Example 1 of the present application;

[0046] Figure 3 TGA pattern of the spherulites of benserazide hydrochloride prepared according to Example 1 of the present application;

[0047] Figure 4 Polarized light microscope photograph of the spherulites of benserazide hydrochloride prepared according to Example 1 of the present application;

[0048] Figure 5 Polarized light microscope photograph of the spherulites of benserazide hydrochloride prepared according to Example 2 of the present application;

[0049] Figure 6 Polarized light microscope photograph of the crystals of benserazide hydrochloride prepared according to Comparative Example 1 of the present application;

[0050] ​​​Figure 7 Polarizing microscope photograph of benserazide hydrochloride crystals prepared according to the present application Comparative Example 2;

[0051] Figure 8 Polarizing microscope photograph of benserazide hydrochloride crystals prepared according to the present application Comparative Example 3;

[0052] Figure 9 Polarizing microscope photograph of benserazide hydrochloride crystals prepared according to the present application Comparative Example 4. DETAILED DESCRIPTION

[0053] The following detailed description is further to the specification herein, and the examples are only for illustration and should not be considered as limiting the present application in any way.

[0054] The spherulite described in the present application is a spherical polycrystalline aggregate with a special radial symmetry structure, and the constituent units are radially arranged around a crystal nucleus due to non-crystallographic bifurcation. It can be directly observed by conventional observation methods such as polarizing microscope, scanning electron microscope (SEM) and the like.

[0055] The raw materials and reagents used in the present application can be purchased through conventional market purchase.

[0056] The seed crystal described in the present application can be obtained by crystallization of benserazide hydrochloride in a mixed solvent of water and alcohol, and if it is a large particle sample, it can be properly crushed or ground. The seed crystal is not specifically required to be spherical.

[0057] In the present application, the detection instruments and methods used are as follows:

[0058] X-ray powder diffraction instrument (XRPD) detection method:

[0059] Instrument: Netherlands, Panalytical X'Pert Pro MPD or equivalent

[0060] Light tube type: Empyrean XRD tube Cu LFF HR

[0061] Voltage current: 45kV, 40mA

[0062] Goniometer: PW3050 / 60 vertical goniometer, radius 240mm

[0063] Detector: X'Celerator super power detector

[0064] Scanning mode: continuous scanning

[0065] Scanning range (2θ): 3.0-50.0°.

[0066] Thermogravimetric Analyzer (TGA) detection method: Discovery TGA5500 of American TA company, temperature rising speed 10℃ / min, temperature range: room temperature to 500℃.

[0067] Differential Scanning Calorimeter (DSC) detection method: Discovery DSC250 of American TA company, temperature rising speed 10℃ / min, temperature range: room temperature to 180℃.

[0068] Polarizing Microscope (PLM): BX53 of Japan Olympus.

[0069] Example 1

[0070] Glass jacketed reactor 1 was added with 200ml ethanol, 240ml water, temperature control 15℃, 100g crude benserazide hydrochloride was added and stirred to dissolve. Glass jacketed reactor 2 was added with 2100ml ethanol, temperature control 10℃, 1% seed crystal was added and stirred slowly. The solution in reactor 1 was added dropwise into reactor 2, after dropwise addition, the solution was stirred for crystallization for about 10h, then the temperature was decreased to -5℃ at a rate of 5℃ / h, after 2h of incubation, the solution was filtered. The filter cake was dried in vacuum oven at 25℃ for 3h, then the temperature was increased to 45℃ for 14h to obtain dry product. The XRPD of the product is shown in Figure 1 , the DSC and TGA curves are shown in Figure 2 and Figure 3 , respectively, the yield was 80%. The microscope photo is shown in Figure 4 .

[0071] Example 2

[0072] Glass jacketed reactor 1 was added with 420ml ethanol, 460ml water, temperature control 18℃, 200g crude benserazide hydrochloride was added and stirred to dissolve. Glass jacketed reactor 2 was added with 4000ml ethanol, temperature control 10℃, 3% seed crystal was added and stirred slowly. The solution in reactor 1 was added dropwise into reactor 2, after dropwise addition, the solution was stirred for crystallization for about 13h, then the temperature was decreased to -5℃ at a rate of 3℃ / h, after 2h of incubation, the solution was filtered. The filter cake was dried in vacuum oven at 25℃ for 3h, then the temperature was increased to 45℃ for 12h to obtain dry product. The XRPD, DSC and TGA spectra of the product were consistent with those of benserazide hydrochloride in Example 1, the yield was 82%, the microscope photo is shown in Figure 5 .

[0073] Example 3

[0074] A stainless steel reactor 1 in the workshop was charged with 540 L of methanol, 280 L of water, and the temperature was controlled at 15-17 °C. 180 kg of crude benzylhydrazine hydrochloride was added and stirred to dissolve. A stainless steel reactor 2 in the workshop was charged with 3600 L of ethanol, and the temperature was controlled at 10-13 °C. 2% of seed crystal was added and stirred slowly. The solution in reactor 1 was added dropwise into reactor 2. After the addition was completed, the mixture was stirred for about 13 h, then the temperature was decreased to -2-0 °C at a rate of 5 °C / h, and the mixture was kept at this temperature for 5 h before filtration. The vacuum oven was used for cooling and drying at 25 °C for 3 h, then the temperature was increased to 35 °C for drying for about 3 h, and then the temperature was increased to 45 °C for drying for about 24 h to obtain the dry product. The XRPD, DSC and TGA spectra of the dry product were consistent with those of the benzylhydrazine hydrochloride in Example 1, and the dry product was spherulitic. The yield was 79%.

[0075] Example 4

[0076] A glass jacketed reactor 1 was charged with 35 ml of methanol, 18 ml of water, and the temperature was controlled at 15 °C. 10 g of crude benzylhydrazine hydrochloride was added and stirred to dissolve. A glass jacketed reactor 2 was charged with 200 ml of ethanol, and the temperature was controlled at 10 °C. The solution in reactor 1 was added dropwise into reactor 2. After the addition was completed, the mixture was stirred for 17 h, then the temperature was decreased to -5 °C at a rate of 5 °C / h, and the mixture was kept at this temperature for 4 h before filtration. The vacuum oven was used for cooling and drying at 25 °C for 2 h, and then the temperature was increased to 45 °C for drying for 4 h to obtain the dry product. The XRPD, DSC and TGA spectra of the dry product were consistent with those of the benzylhydrazine hydrochloride in Example 1, and the dry product was spherulitic. The yield was 75%.

[0077] Example 5

[0078] A glass jacketed reactor 1 was charged with 400 ml of ethanol, 480 ml of water, and the temperature was controlled at 20 °C. 200 g of crude benzylhydrazine hydrochloride was added and stirred to dissolve. A glass jacketed reactor 2 was charged with 4200 ml of ethanol, and the temperature was controlled at 15 °C. 2% of seed crystal was added and stirred slowly. The solution in reactor 1 was added dropwise into reactor 2. After the addition was completed, the mixture was stirred for about 10 h, then the temperature was decreased to -5 °C at a rate of 5 °C / h, and the mixture was kept at this temperature for 4 h before filtration. The vacuum oven was used for cooling and drying at 25 °C for 3 h, and then the temperature was increased to 45 °C for drying for 14 h to obtain the dry product. The XRPD, DSC and TGA spectra of the dry product were consistent with those of the benzylhydrazine hydrochloride in Example 1, and the dry product was spherulitic. The yield was 79%. The dry product was further crushed using a conical crusher to adjust the particle size distribution.

[0079] Example 6

[0080] 700ml methanol and 310ml water were added to the glass jacketed reactor 1, the temperature was controlled at 18°C, 200g of crude benserazide hydrochloride was added and stirred to dissolve. 3200ml ethanol was added to the glass jacketed reactor 2, the temperature was controlled at 15°C, 2% seed crystals were added, and the mixture was stirred slowly. The molten clear liquid in the reactor 1 was added dropwise to the reactor 2, the addition was complete, and the mixture was stirred and crystallized for about 10h, then cooled to -5°C at 5°C / hour, and kept warm for 4 hours before filtering. The mixture was cold-drawn in a vacuum oven at 25°C for 3 hours, heated to 45°C and dried for 14 hours to obtain a dry product. After testing, its XRPD, DSC and TGA spectra were consistent with those of the benserazide hydrochloride in Example 1, and were spherulites with a yield of 77%. A cone mill was further used for pulverization to adjust the particle size distribution.

[0081] Comparative Example 1

[0082] The temperature of the reaction kettle was controlled at 20°C in a glass jacket, and 967ml of methanol and 340ml of water were added. After the temperature stabilized, 200g of crude benserazide hydrochloride was added and stirred to dissolve. 500ml of ethanol was added dropwise and stirred for 2 hours. 1500ml of ethanol was added dropwise and stirred for 2 hours. The temperature was quickly cooled to -5°C, kept warm and stirred for 4 hours, and then vacuum-dried at 25°C for 3 hours. The temperature was raised to 40°C and dried for about 2 hours. The temperature was raised to 50°C and dried for about 12 hours. The yield was 64%. After testing, the XRPD, DSC and TGA spectra were consistent with those of the benserazide hydrochloride in Example 1. The crystal morphology was shown in FIG. Figure 6 .

[0083] Comparative Example 2

[0084] 40 ml of ethanol and 48 ml of water were added to a glass jacketed reactor, the temperature was controlled at 15 ° C, 20 g of crude benserazide hydrochloride was added and stirred to dissolve, the temperature was lowered to 10 ° C, 1% seed crystals were added, stirring slowly, 420 ml of ethanol was added dropwise, and after the addition was complete, the mixture was stirred and crystallized for about 10 hours, the temperature was lowered to -5 ° C at 5 ° C / hour, and the mixture was kept warm for 2 hours and then filtered. The mixture was dried in a vacuum oven at 25 ° C for 3 hours, heated to 45 ° C and dried for 10 hours to obtain a dry product with a yield of 67%. After testing, the XRPD, DSC and TGA spectra of the product were consistent with those of the benserazide hydrochloride in Example 1, and the crystal morphology was shown in FIG. Figure 7 .

[0085] Comparative Example 3

[0086] Take 20g of crude benserazide hydrochloride, put it into a glass jacketed autoclave, set the temperature to 25°C, add 70ml of water dropwise, stir and dissolve, add 210ml of a mixed solvent of 90% ethanol aqueous solution and 1-propanol in a volume ratio of 1:1 to the clear solution, stir for about 10 hours, cool to -5°C, keep warm for 5 hours, filter, rinse with 100ml of 1-propanol, continue to filter, use a vacuum oven at 25°C for 3 hours, heat to 40°C and dry for about 2h, heat to 50°C and dry for about 12 hours to obtain a dry product with a yield of 61%. After testing, its XRPD, DSC and TGA spectra are consistent with those of benserazide hydrochloride in Example 1, and the crystal morphology is shown. Figure 8 .

[0087] Comparative Example 4

[0088] Control the glass jacketed kettle at 32°C, add 310ml of water, take 100g of crude benserazide hydrochloride into the glass jacketed kettle, stir and dissolve; add 600ml of ethanol, crystals precipitate, stir for about 2 hours; continue to add 500ml of isopropanol solution, stir for about 6 hours; cool to -5°C at about 3°C / hour, stir for 4 hours, filter, rinse with 200ml of a mixed solvent of ethanol and isopropanol in a volume ratio of 1:1, continue to filter, use a vacuum oven at 25°C for 3 hours, heat to 40°C and dry for about 2h, heat to 65°C and dry for about 10 hours to obtain a dry product with a yield of 56%. After testing, its XRPD, DSC and TGA spectra are consistent with those of benserazide hydrochloride in Example 1, and the crystal morphology is shown in FIG. Figure 9 .

[0089] Test example:

[0090] The particle size, bulk density, tap density, angle of repose, charge, etc. of the benserazide hydrochloride prepared in Examples 1 to 6 and Comparative Examples 1 to 4 were characterized by the following methods or equipment. The results are shown in Table 1.

[0091] Particle size (PSD) analysis method: An appropriate amount of sample is dispersed in Isopar G and measured using a Malvern MS 3000 or equivalent laser particle size analyzer.

[0092] Content detection method: Calculate under anhydrous and solvent-free conditions, and the operation is as follows:

[0093] Reagents and test solutions:

[0094] Perchloric acid titrant: Prepare 0.1 mol / L according to the titrant instructions. Glacial acetic acid: analytical grade or chromatographic grade; anhydrous formic acid: analytical grade or chromatographic grade.

[0095] step:

[0096] Weigh 0.250g of sample and accurately weigh it in a titration cup. First, add 5ml of anhydrous formic acid to dissolve it. If it does not dissolve, sonicate for about 5s. Then add 70ml of glacial acetic acid. Mix well and immediately titrate with perchloric acid solution (0.1mol / L). Use potentiometric titration to indicate the endpoint. At the same time, make a blank control and use blank correction. Each 1ml of perchloric acid solution with a concentration of 0.1mol / L is equivalent to 29.37mg of C 10 H 16 ClN3O5.

[0097] Static charge test equipment: Japan Genesis, SK-H050 model.

[0098] Measurement of bulk density and tap density: Refer to the Pharmacopoeia 2020 edition, add the sample to be tested into the glass measuring cylinder until the volume reading is within the range of 60-100 ml, read the volume V1, weigh M, and calculate the bulk density ρ1 = M / V1 according to the formula density = weight / volume; fix the measuring cylinder on the powder density tester, set the vibration frequency, start the instrument to vibrate, and read the volume V after the vibration stops. a , continue vibrating at the same frequency and read the volume V b , when the volume difference between the two does not exceed 1mL, V b This is the endpoint volume V2. If the volume difference exceeds 1 mL, continue vibrating and calculate the tap density ρ2 = M / V2.

[0099] Angle of repose measurement: 1) Fix the lower discharge port of the glass funnel in the measuring device 100 mm above a 100 mm diameter glass base, centered. 2) Add the sample to be tested from the device funnel. When the cone formed on the lower glass base begins to flow out of the glass base, stop adding sample. Use the movable scale on the device to measure the height H of the cone. Calculate the angle of repose according to the formula θ = arctan(H / 50). 3) Repeat the measurement five times and take the average value.

[0100] Table 1 Characterization results of benserazide hydrochloride spherulites

[0101]

[0102] The embodiments of the present invention can be modified or altered in many ways without departing from the scope of this invention. Therefore, the embodiments of this invention should not be limited to the exemplary embodiments described above, but should be controlled by the limitations set forth in the claims and any equivalent forms thereof.

Claims

1. A preparation method of benserazide hydrochloride spherulites, characterized in that: The following steps are included: (1) Cooling the alcohol solvent 1 to 5-25°C, optionally adding seed crystals, (2) Control the crystallization temperature, dropwise add a clear solution containing benserazide hydrochloride, stir and crystallize, (3) Filter and dry to obtain benserazide hydrochloride spherulites. (4) Optionally, crush the benserazide hydrochloride spherulites in step (3), Wherein, the clear solution of benserazide hydrochloride in step (2) is prepared by dissolving benserazide hydrochloride in a mixed solvent of water and alcohol solvent 2.

2. The preparation method according to claim 1, characterized in that The benserazide hydrochloride spherulites in the step (3) have diffraction peaks at 2θ=7.7°, 18.5°, and 24.6°±0.2° in the X-ray powder diffraction (XRPD) pattern measured using Cu-Kα radiation, and their aspect ratio is not greater than 2.

3. The preparation method according to claim 1, characterized in that In the step (1), the alcohol solvent 1 is cooled to 10-15°C.

4. The preparation method according to claim 1, characterized in that The alcohol solvent 1 and the alcohol solvent 2 are selected from one or more of methanol, ethanol or isopropanol; the alcohol solvent 1 and the alcohol solvent 2 may be the same or different.

5. The preparation method according to claim 1, characterized in that The weight-to-volume ratio of benserazide hydrochloride to the alcohol solvent 1 in the step (1) in the benserazide hydrochloride supernatant is 1:15-30 g / mL, preferably 1:15-25 g / mL.

6. The preparation method according to claim 1, characterized in that The weight ratio of the seed crystals in step (1) to the benserazide hydrochloride in the benserazide hydrochloride clear solution is 0.5-5%, preferably 1-3%.

7. The preparation method according to claim 1, characterized in that The weight-to-volume ratio of benserazide hydrochloride to the alcohol solvent 2 in the benserazide hydrochloride supernatant is 1:1.5-3.5 g / mL, preferably 1:2.0-3.5 g / mL; the weight-to-volume ratio of benserazide hydrochloride to water in the benserazide hydrochloride supernatant is 1:1.5-3.0 g / mL; preferably 1:1.5-2.5 g / mL.

8. The preparation method according to claim 1, characterized in that The crystallization temperature in step (2) is 5-25°C, preferably 10-15°C.

9. A benserazide hydrochloride spherulite, characterized in that The spherulites have diffraction peaks at 2θ=7.7°, 18.5°, and 24.6°±0.2° in an X-ray powder diffraction (XRPD) spectrum measured using Cu-Kα radiation, and an aspect ratio of no more than 2.

10. Benserazide hydrochloride spherulites according to claim 9, characterized in that, The D(10) of the spherulites is 5-120 μm, the D(50) is 15-210 μm, and the D(90) is 50-350 μm.

11. Benserazide hydrochloride spherulites according to claim 9 or 10, characterized in that, The spherulites have a microscope photograph substantially the same as that shown in FIG. 4 or FIG. 5 .

12. Benserazide hydrochloride spherulites according to claim 9 or 10, characterized in that, The spherulites have a bulk density of 0.30-0.45 g / ml and a tap density of 0.40-0.55 g / ml.

13. Benserazide hydrochloride spherulites according to claim 9 or 10, characterized in that The repose angle of the spherulites is 32.0-34.5°.

14. The spherulite according to claim 9 or 10, characterized in that The spherulites are obtained by the preparation method according to any one of claims 1 to 8.

15. A pharmaceutical composition, characterized in that Comprising benserazide hydrochloride spherulites according to claim 9 or 10; Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier; or Preferably, the pharmaceutical composition further comprises levodopa.

16. Use of the benserazide hydrochloride spherulites according to any one of claims 9 to 14 or the pharmaceutical composition according to claim 15 in the preparation of a drug for treating Parkinson's disease.

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