Pharmaceutical crystal having low water solubility, preparation method therefor, and use thereof

Abstract

A pharmaceutical crystal having low water solubility, a preparation method therefor, and the use thereof. A crystal form I of pamoate of a compound Z has characteristic diffraction peaks at the diffraction angles 2θ of 9.9±0.2°, 10.7±0.2°, 12.1±0.2°, 14.9±0.2°, 17.3±0.2°, 19.4±0.2°, 20.7±0.2° and 23.1±0.2°. Compared with amorphous pamoate of the compound Z, said crystal has good stability, is free of polymorphic transformation, does not involve obvious increases of related substances, and has a low solubility. A production process therefor is simple and only uses water as a solvent in the whole process without the need of using an organic solvent. Using the crystal form I of pamoate of the compound Z for preparing a long-acting sustained-releasing pharmaceutical composition for Parkinson's disease can achieve a high drug encapsulation ratio and low burst release, and enables drug release of the composition in vivo to last for over two weeks, so that the frequency of drug administration to patients can be reduced, and the medication compliance is improved.

Description

A drug crystal with low water solubility, its preparation method and uses Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a low-water-soluble drug crystal, its preparation method, and its uses. Background Technology

[0002]

[0003] The structure of compound Z is shown in the above formula. It is a second-generation monoamine oxidase inhibitor that can block the breakdown of the neurotransmitter dopamine. In the dopaminergic motor dysfunction model, compound Z exerts its anti-Parkinson's effect by increasing dopamine levels and indirectly increasing dopaminergic activity.

[0004] Compound Z is currently marketed as an oral tablet form of mesylate. In the BCS classification of biopharmaceutics, compound Z mesylate is classified as Class III, exhibiting high solubility and low permeability. Oral tablets are prone to peak-valley phenomena, leading to adverse reactions and on / off side effects in patients during the later stages of medication. Furthermore, its high solubility poses significant challenges to formulation and manufacturing processes if compound Z mesylate is to be developed into a long-acting sustained-release formulation. Therefore, developing a salt or ester of compound Z with low water solubility, or further developing it into a long-acting sustained-release formulation, has significant clinical value and advantages. It can also effectively reduce blood drug concentration fluctuations caused by missed doses or discontinuation, thereby further reducing the likelihood of "wear-off phenomenon" and "on / off phenomenon."

[0005] Chinese patent application CN111212640A discloses a method for preparing dihydroxynaphthyl salts of some monoamine drugs (rotigotine, ropinirole, and pramipexole). For example, the method involves adding a solution of disodium dihydroxynaphthyl salt or other dihydroxynaphthyl salts in a suitable solvent, such as water, to a solution of the monoamine drug hydrochloride, and stirring the solution for approximately 3 or 12 hours until precipitation occurs. However, the inventors have only been able to obtain amorphous compound Z dihydroxynaphthyl salt using the above method, and the method described in the disclosed examples has also failed to successfully crystallize compound Z dihydroxynaphthyl salt. Summary of the Invention

[0006] The purpose of this invention is to provide compound Z dihydroxynaphthalate crystal form I, its preparation method, and its uses.

[0007] The compound Z bis(hydroxynaphthalate) crystal form I (referred to as crystal form I) has characteristic diffraction peaks at diffraction angles 2θ of 9.9±0.2°, 10.7±0.2°, 12.1±0.2°, 14.9±0.2°, 17.3±0.2°, 19.4±0.2°, 20.7±0.2°, and 23.1±0.2°.

[0008] In some embodiments, the crystal form I also has one or more characteristic diffraction peaks at diffraction angles 2θ of 5.0±0.2°, 12.6±0.2°, 13.9±0.2°, 14.5±0.2°, 15.5±0.2°, 16.9±0.2°, 21.4±0.2°, and 24.1±0.2°.

[0009] In some embodiments, crystal form I has characteristic peaks at diffraction angles 2θ of 5.0±0.2°, 9.9±0.2°, 10.7±0.2°, 12.1±0.2°, 12.6±0.2°, 13.9±0.2°, 14.5±0.2°, 14.9±0.2°, 15.5±0.2°, 16.9±0.2°, 17.3±0.2°, 19.4±0.2°, 20.7±0.2°, 21.4±0.2°, 23.1±0.2°, and 24.1±0.2°.

[0010] In some embodiments, the X-ray powder diffraction (XRD) pattern of crystal form I is shown in Figure 1.

[0011] In some embodiments, the infrared spectrum of crystal form I is at approximately 3289, 1643, 1451, 1351, 760, 1558, 1394, 1233, and 1202 cm⁻¹. -1 It has a peak value.

[0012] In some embodiments, the differential scanning calorimetry (DSC) curve of crystal form I has an endothermic peak at 157℃±2℃.

[0013] In some embodiments, the preparation method of compound Z dihydroxynaphthate crystal form I includes the following steps:

[0014] Component A and component B are dissolved in water to obtain solution A and solution B, respectively. Solution A and solution B are stirred and mixed, and stirring is continued for 0-5 hours (this is called mixing and stirring). The precipitate is collected by filtration and washed with water to remove impurities. Then the precipitate is dispersed in water and stirred for no less than 6 hours (this is called crystallization stirring). The precipitate is collected by filtration and dried to obtain the final product.

[0015] In some embodiments, component A is a dicarboxylic acid and its water-soluble salt, including but not limited to dihydroxynaphthic acid, disodium dihydroxynaphthate, and dipotassium dihydroxynaphthate, preferably disodium dihydroxynaphthate.

[0016] In some embodiments, component B is compound Z and its water-soluble salt, including but not limited to compound Z, compound Z methanesulfonate, compound Z acetate, compound Z tartrate, preferably compound Z methanesulfonate.

[0017] In some embodiments, the concentration of component A in solution A is 1.5%-4.5% (w:v).

[0018] In some embodiments, the concentration of component A in solution A is 2.25% (w:v).

[0019] In some embodiments, the ratio of component B to water in solution B is 1.7%-5.3% (w:v).

[0020] In some embodiments, the ratio of component B to water in solution B is 2.65% (w:v).

[0021] In some embodiments, the temperature of solutions A and B is 5-40°C, preferably 25±2°C.

[0022] The drying process includes, but is not limited to, vacuum drying, spray drying, fluidized bed drying, and freeze drying.

[0023] The compound Z dihydroxynaphthate crystal form I can be used to prepare drugs for treating Parkinson's disease.

[0024] A long-acting sustained-release composition comprising the compound Z dihydroxynaphthate crystal form I.

[0025] In some embodiments, the long-acting sustained-release composition further comprises a sustained-release material.

[0026] The sustained-release material is a biodegradable and biocompatible polymer material.

[0027] The biodegradable and biocompatible polymeric materials mentioned above include, but are not limited to, at least one of lactide-glycolic acid copolymer, polylactide and its derivatives.

[0028] The long-acting sustained-release composition can be administered by injection or surgical procedure. Specifically, the long-acting sustained-release composition can be an implant, microspheres or microparticles, or a suspension.

[0029] The long-acting sustained-release composition described herein can provide sustained drug release in vivo for no less than 2 weeks after administration.

[0030] The preparation methods of the long-acting sustained-release composition include, but are not limited to, the emulsification-solvent evaporation method.

[0031] In the long-acting sustained-release composition prepared by the emulsification-solvent evaporation method, the encapsulation efficiency of compound Z dihydroxynaphthalate crystal form I is not less than 80%.

[0032] In some embodiments, the encapsulation efficiency of compound Z dihydroxynaphthalate crystal form I in the long-acting sustained-release composition prepared by the emulsification-solvent evaporation method is not less than 85%.

[0033] In some embodiments, the encapsulation efficiency of compound Z dihydroxynaphthalate crystal form I in the long-acting sustained-release composition prepared by the emulsification-solvent evaporation method is not less than 90%.

[0034] This application has the following advantages and beneficial effects compared to the prior art:

[0035] 1. Compared with the amorphous compound Z bishydroxynaphthenate, its crystalline form (compound Z bishydroxynaphthenate crystal form I) has good stability, does not undergo crystal transformation, does not significantly increase related substances, and has low solubility.

[0036] 2. This invention creatively obtains the crystal form of compound Z bis(hydroxynaphthalate) by removing soluble impurities and eliminating their influence on crystal nucleation and growth.

[0037] 3. The production process of compound Z bishydroxynaphthenate crystal form I provided by the present invention is simple. The entire process uses only water as a solvent and does not require the use of organic solvents. It is environmentally friendly and pollution-free, conforms to the concept of green chemistry, and further reduces the cost of drug production.

[0038] 4. When the long-acting sustained-release anti-Parkinson's drug composition prepared by the present invention using compound Z dihydroxynaphthate crystal form I has a high drug encapsulation rate and low burst release, the composition continuously releases the drug in the body for more than 2 weeks, which can reduce the frequency of patient administration, improve medication compliance, effectively reduce blood drug concentration fluctuations caused by missed doses or discontinuation of medication, and reduce the probability of "end-of-dose phenomenon" and "on-off phenomenon". Attached Figure Description

[0039] Figure 1 shows the XRD pattern of compound Z dihydroxynaphthalate crystal form I.

[0040] Figure 2 is the XRD pattern of the precipitate after stirring for 3 hours in Example 1.

[0041] Figure 3 is the XRD pattern of the precipitate after stirring for 6 hours in Example 1.

[0042] Figure 4 is the XRD pattern of the precipitate after stirring for 12 hours in Example 1.

[0043] Figure 5 shows the 1H NMR spectrum of compound Z dihydroxynaphthalate crystal form I.

[0044] Figure 6 shows the carbon NMR spectrum of compound Z dihydroxynaphthalate crystal form I.

[0045] Figure 7 shows the differential scanning calorimetry (DSC) curve of the amorphous compound Z-bis(hydroxynaphthyl) salt.

[0046] Figure 8 shows the differential scanning calorimetry (DSC) curve of crystal form I of compound Z bis(hydroxynaphthalate).

[0047] Figure 9 shows the infrared spectrum of compound Z dihydroxynaphthalate crystal form I.

[0048] Figure 10 shows the XRD pattern of the precipitate after stirring for 3 hours in Comparative Example 1.

[0049] Figure 11 shows the XRD pattern of the precipitate after stirring for 24 hours in Comparative Example 1.

[0050] Figure 12 shows the XRD pattern of compound Z bis(hydroxynaphthalate) crystal form I on day 0.

[0051] Figure 13 shows the XRD pattern of compound Z dihydroxynaphthalate crystal form I at a high temperature of 60℃ for 10 days.

[0052] Figure 14 shows the XRD pattern of compound Z dihydroxynaphthenate crystal form I at high humidity (92.5% RH) for 10 days.

[0053] Figure 15 shows the XRD pattern of compound Z dihydroxynaphthalate crystal form I under strong light for 10 days.

[0054] Figure 16 shows the XRD pattern of compound Z dihydroxynaphthalate crystal form I after 6 months of accelerated XRD.

[0055] Figure 17 shows the XRD pattern of compound Z dihydroxynaphthalate crystal form I after a long-term period of 24 months.

[0056] Figure 18 is a blood drug concentration-time curve. Detailed Implementation

[0057] The present invention will be described in detail below with reference to the embodiments and accompanying drawings.

[0058] In this application, the X-ray powder diffraction detection method is as follows:

[0059] Panaco Empyrean X-ray powder diffractometer (PW3040 / 60, Panaco Analytical Instruments Ltd., Netherlands), Cu-Kα radiation, wavelength Equipped with Bragg-Brentano High Definition. Incident light path: divergence slit 1 / 8°, Soler slit 0.04 rad, light-shielding mask 10 mm, anti-scattering slit 1 / 2°; Diffraction light path: anti-scattering slit P7.5; X-ray sample stage: rotation mode; Scanning detector: PIXcel1D-Medipix3; X-ray tube voltage 45 kV, X-ray tube current 40 mA, scanning range 2-40° (2θ), step size 0.026°, step time: 36.465 s. Data acquisition software is Data Collector, and data viewing software is HighScore Plus.

[0060] In this application, the DSC detection method is as follows: the amorphous compound Z dihydroxynaphthate and compound Z dihydroxynaphthate crystal form I are detected using a NETZSCH DSC analyzer, the temperature range is room temperature to 200℃, the heating rate is 10℃ / min, and the atmosphere is nitrogen.

[0061] In this application, the method for detection by 1H NMR is as follows: using deuterated DMSO as solvent, compound Z dihydroxynaphthalate crystal form I is prepared into a 15-20 mg / mL solution, and detected by a 600 MHz 1H NMR spectrometer.

[0062] In this application, the carbon NMR detection method is as follows: using deuterated DMSO as solvent, compound Z dihydroxynaphthalate crystal form I is prepared into a 15-20 mg / mL solution, and detected by a 600 MHz carbon NMR spectrometer.

[0063] In this application, the method for determining the content of compound Z refers to high performance liquid chromatography (ChP General Rule 0512), specifically as follows: Accurately weigh an appropriate amount of compound Z bis(hydroxynaphthyl) salt, dissolve it in acetonitrile, dilute with water to the mark, and mix well. Accurately weigh an appropriate amount of reference standard, dissolve it in acetonitrile, dilute with water to the mark, and mix well. Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph for analysis, record the chromatograms, and calculate the content based on peak area using the external standard method.

[0064] Example 1

[0065] Weigh 4.5 g (10 mmol) of disodium dihydroxynaphthate and dissolve it in 200 mL of water; weigh 5.3 g (20 mmol) of compound Z methanesulfonate and dissolve it in 200 mL of water; under conditions of 25±2℃, slowly stir and mix the compound Z methanesulfonate solution with the disodium dihydroxynaphthate solution to form a white to off-white precipitate; after mixing, continue stirring for 1 h (this is called mixing stirring); filter and collect the precipitate, and wash with water to remove impurities; then add the precipitate to water and continue stirring at 25±2℃; prepare in parallel, filter and collect part of the precipitate after stirring for 3 h, 4 h, 5 h, 6 h, 9 h, 12 h, 18 h, and 24 h (this is called crystallization stirring), dry to obtain compound Z dihydroxynaphthate, and perform XRD, 1H NMR, 1C NMR, DSC, and infrared detection.

[0066] XRD patterns show that the precipitate obtained by mixing and stirring for 1 hour and crystallizing for less than 5 hours has no obvious crystallization. Figure 2 shows the representative XRD pattern of the precipitate after crystallization stirring for 3 hours. When stirring for more than 6 hours, the precipitate has obvious crystallization. Figure 3 shows the XRD pattern of the precipitate after crystallization stirring for 6 hours (the pattern data is shown in Table 1). Figure 4 shows the XRD pattern of the precipitate after crystallization stirring for 12 hours (the pattern data is shown in Table 2). Figure 1 shows the XRD pattern of the precipitate after crystallization stirring for 24 hours (the pattern data is shown in Table 3).

[0067] Table 1: XRD pattern analysis data of compound Z bis(hydroxynaphthyl) salt obtained by stirring for 6 h

[0068] Table 2: XRD pattern analysis data of compound Z bis(hydroxynaphthol) salt crystal form I obtained after stirring for 12 h

[0069] Table 3: XRD pattern analysis data of compound Z bis(hydroxynaphthol) salt crystal form I obtained after stirring for 24 h

[0070] For ease of description later, the crystalline compound Z-bishydroxynaphthate will be named compound Z-bishydroxynaphthate crystal form I.

[0071] The results of the 1H NMR spectrum show that the molar ratio of dihydroxynaphthenic acid and compound Z in the crystal form I of compound Z prepared by the above method is 1:2. Figure 5 shows the representative 1H NMR spectrum after crystallization stirring for 24 h.

[0072] The results of the carbon NMR spectrum show that the product obtained is indeed compound Z bis(hydroxynaphthalate). Figure 6 shows the representative carbon NMR spectrum after crystallization and stirring for 24 hours.

[0073] DSC analysis results showed that the amorphous compound Z dihydroxynaphthalate only underwent a glass transition and had no melting point. Figure 7 shows the DSC curve of the precipitate after 3 hours of crystallization stirring. In contrast, compound Z dihydroxynaphthalate crystal form I had an endothermic peak at approximately 157 °C. The endothermic peak temperatures at 6, 9, 12, 18, and 24 hours of crystallization stirring were 157.8, 157.1, 157.4, 158.0, and 158.3, respectively. Figure 8 shows the DSC curve of the sample after 24 hours of crystallization stirring.

[0074] Infrared spectroscopy results showed that the infrared spectra of the sample after crystallization stirring for 24 hours (Figure 9) were at approximately 3289, 1643, 1451, 1351, 760, 1558, 1394, 1233, and 1202 cm⁻¹. -1 The presence of a peak value confirms that the obtained product is indeed compound Z bis(hydroxynaphthyl) salt.

[0075] Table 4: Infrared spectral analysis data of compound Z dihydroxynaphthate crystal form I

[0076] Example 2

[0077] Weigh 4.5 g (10 mmol) of disodium dihydroxynaphthate and dissolve it in 200 mL of water; weigh 5.3 g (20 mmol) of compound Z methanesulfonate and dissolve it in 200 mL of water; under stirring at 25 ± 2 °C, slowly mix the compound Z methanesulfonate solution with the disodium dihydroxynaphthate solution to form a white to off-white precipitate; prepare in parallel, filter and collect the precipitate after mixing and stirring for 0 h, 0.5 h, 1.5 h, 2 h, 3 h and 5 h respectively, and wash with low temperature water; then divide each precipitate into 2 portions, add water, and crystallize and stir at 25 ± 2 °C for 3 h and 6 h respectively; filter and collect the precipitate, dry to obtain compound Z dihydroxynaphthate, and perform XRD detection.

[0078] The results showed that when crystallization stirring was performed for 3 hours, there was no significant difference in stirring time within 0-5 hours, and amorphous compound Z-bishydroxynaphthate was obtained in all cases. However, when crystallization stirring was performed for 6 hours, crystalline compound Z-bishydroxynaphthate was obtained in all cases within 0-5 hours, indicating that whether crystallization occurred was directly related to the stirring time. Furthermore, with the increase of stirring time, the particle size (D50) of the precipitate increased from 28 μm at 0 hours to 61 μm at 5 hours.

[0079] Comparative Example 1

[0080] Weigh 4.5 g (10 mmol) of disodium dihydroxynaphthate and dissolve it in 200 mL of water; weigh 5.3 g (20 mmol) of compound Z methanesulfonate and dissolve it in 200 mL of water; under conditions of 25 ± 2 °C, slowly stir the compound Z methanesulfonate solution with the disodium dihydroxynaphthate solution until a white to off-white precipitate is formed. After mixing, continue stirring and filter to collect the precipitate after stirring for 3 h, 6 h, 12 h and 24 h respectively. Dry the precipitate to obtain compound Z dihydroxynaphthate and perform XRD detection.

[0081] The XRD patterns show that the precipitate does not show obvious crystallization. Figure 10 shows the XRD pattern of the precipitate obtained by stirring for 3 hours, and Figure 11 shows the XRD pattern of the precipitate obtained by stirring for 24 hours.

[0082] Comparative Example 2

[0083] Following the method in Example 1, 50 mg of the amorphous compound Z dihydroxynaphthate was prepared by stirring for 3 hours and dissolved in 1.25 mL of acetone. At room temperature, 12.5 mL of n-hexane or petroleum ether was added to the solution while stirring. In both cases, oil precipitation occurred, resulting in a yellow oily substance. Crystals of compound Z dihydroxynaphthate could not be obtained.

[0084] Comparative Example 3

[0085] Following the method in Example 1, 400 mg of the amorphous compound Z dihydroxynaphthate was prepared by stirring for 3 hours to crystallize. It was dissolved in 5 mL of dimethyl sulfoxide. The solution was slowly added to 100 mL of water at room temperature to obtain an oily substance, forming an emulsion. Crystals of compound Z dihydroxynaphthate could not be obtained.

[0086] Comparative Example 4

[0087] Compound Z (187.4 mg) and dihydroxynaphthyl acid (212.6 mg) were added to 5 mL of dimethyl sulfoxide and stirred to form a solution. The solution was then slowly added to 100 mL of water at room temperature, forming only an emulsion; crystals of compound Z dihydroxynaphthyl acid salt were not obtained.

[0088] Example 3

[0089] Solubility determination: According to the General Rules of Part IV of the 2020 Edition of the Chinese Pharmacopoeia, compound Z bis(hydroxynaphthyl) salt crystal form I (product of the crystallization stirring method in Example 1) or rasagiline mesylate was ground into a fine powder. Approximately 10 mg was taken as the test sample and placed in a test tube. A quantitative amount of solvent at 25±2℃ was added, and the mixture was vigorously shaken for 30 seconds every five minutes. The dissolution was observed within 30 minutes. If the sample could not dissolve, more solvent was added. Complete dissolution was considered to occur when no solute particles or droplets were visible. The solubility of compound Z bis(hydroxynaphthyl) salt crystal form I in different solvents is shown in Table 5.

[0090] Table 5: Solubility of Compound Z dihydroxynaphthate crystal form I in different solvents

[0091] Rasagilan mesylate is readily soluble in water, while rasagilan dihydroxynaphthyl acid is only slightly soluble in water. Further determination was made of the specific solubility of compound Z dihydroxynaphthyl acid salt in water under different conditions.

[0092] Take 6 mL of ultrapure water and place it in a 10 mL centrifuge tube. Add approximately 10 mg each of compound Z methanesulfonate and compound Z dihydroxynaphthate prepared in Example 1. Seal the tube and investigate the solubility at 25 °C. Maintain the solution temperature and manually shake the sample periodically during the process. After shaking for 1 day, take samples. Sampling method: Incubate the test tube at a constant temperature until the supernatant is clear. Transfer 2 mL of the supernatant to a 20 mL volumetric flask, dilute to the mark with buffer, and shake well. Determine the content according to the high performance liquid chromatography method (ChP General Rule 0512). Perform three replicates. The results are shown in Table 6. The solubility of crystalline compound Z dihydroxynaphthate is lower than that of amorphous compound Z dihydroxynaphthate.

[0093] Table 6 Solubility of compound Z bis(hydroxynaphthyl)ate

[0094] Example 4

[0095] Stability assessment:

[0096] 1) Influencing Factors Experiment

[0097] Compound Z dihydroxynaphthalate crystal form I (crystallized and stirred for 24 h in Example 1) and amorphous compound Z dihydroxynaphthalate (crystallized and stirred for 3 h in Example 1) were dispensed into labeled weighing bottles and evenly spread on the bottom of the bottles. Two samples were prepared for each time condition. The samples were placed at 50℃, 60℃, 75%RH, 92.5%RH and strong light (5100 Lux) for 5 days and 10 days, respectively. Samples were taken and sent for testing of appearance, content, moisture, related substances, and XRD (only the 10-day sample was tested). The experimental results are shown in Tables 7 and 8 and Figures 12 to 15.

[0098] XRD patterns showed that the compound Z dihydroxynaphthalate crystal form I prepared in Example 1 did not undergo crystal transformation under the experimental conditions of high temperature (60℃, 10 days, Figure 13), high humidity (92.5%RH, 10 days, Figure 14), and strong light (5100Lux, 10 days, Figure 15), and the amorphous compound Z dihydroxynaphthalate remained amorphous.

[0099] Moreover, the changes in related substances of compound Z dihydroxynaphthalate crystal form I were not obvious under high temperature and high humidity conditions, but the increase of related substances was obvious under strong light conditions; while the increase of related substances of amorphous compound Z dihydroxynaphthalate crystal form I was significantly higher under high temperature, high humidity and strong light conditions than that of compound Z dihydroxynaphthalate crystal form I.

[0100] 2) Accelerated Experiment

[0101] Samples (with inner and outer packaging) were placed at 40±2℃ and 75±5%RH for testing. Samples were taken in January, February, March and June of the test period and sent for testing of appearance, content, moisture, related substances and XRD. The experimental results are shown in Tables 9 and 10.

[0102] XRD results showed that compound Z dihydroxynaphthate crystal form I did not undergo crystal transformation under accelerated testing conditions for 6 months, and amorphous compound Z dihydroxynaphthate remained amorphous. Figure 16 shows the XRD pattern of the sample after 6 months. Furthermore, there was no significant increase in related substances in compound Z dihydroxynaphthate crystal form I, while there was a significant increase in related substances in amorphous compound Z dihydroxynaphthate.

[0103] 3) Long-term experiment

[0104] Samples (with inner and outer packaging) were taken and placed at 25±2℃ and 60±5%RH for testing. Samples were taken in March, June, September, December, 18 and 24 of the test period and sent for testing of appearance, content, moisture, related substances and XRD. The experimental results are shown in Tables 11 and 12.

[0105] XRD results showed that compound Z dihydroxynaphthate crystal form I did not undergo crystal transformation under the long-term 24-month test conditions, and amorphous compound Z dihydroxynaphthate remained amorphous. Figure 17 shows the XRD pattern of the sample after 24 months. Furthermore, the related substances of compound Z dihydroxynaphthate crystal form I did not increase significantly, while the related substances of amorphous compound Z dihydroxynaphthate increased significantly.

[0106] The results of comprehensive influencing factor tests, accelerated tests, and long-term tests show that compound Z dihydroxynaphthalate crystal form I is more stable than the amorphous compound Z dihydroxynaphthalate.

[0107] Example 5

[0108] Using compound Z methanesulfonate and compound Z dihydroxynaphthate, prepared by crystallization stirring in Example 1 for 3 h, 6 h, and 24 h, as drugs, long-acting sustained-release microspheres were prepared using lactide-glycolic acid copolymer (9505, 25 kDa) as a carrier, and the drug encapsulation efficiency was investigated. Specifically, 8 parts of the carrier were dissolved in 8.5 times their volume of ethyl acetate, then 2 parts of the drug were added, stirred and mixed thoroughly, and then rapidly injected into a 1% concentration of PVA aqueous solution. The mixture was homogenized and emulsified at 2000 rpm for 5 min, and then stirred for another 6 h to evaporate the organic solvent. The solid was collected by filtration, washed with water, and freeze-dried to obtain long-acting sustained-release microspheres.

[0109] The content of salt of compound Z in the microspheres was detected, and the encapsulation efficiency of the drug was calculated (measured content / theoretical content*100%).

[0110] The burst release rate was determined as follows: 30 mg of microspheres were weighed and dispersed in 350 mL of 0.01 M PBS buffer at pH 7.4. The mixture was incubated at 37 °C with shaking for 24 h. The salt content of compound Z was measured in the supernatant, and the burst release rate of the drug was calculated as (total drug amount in supernatant / total drug amount in 30 mg microspheres * 100%).

[0111] The results, shown in Table 13, indicate that the drug encapsulation efficiency and burst release rate of microspheres prepared from different salts of compound Z vary. In particular, the differences in encapsulation efficiency and burst release rate are significant when the solubility of the salts differs considerably. The lower the solubility of the salt of compound Z, the higher the drug encapsulation efficiency, and the lower the burst release rate on the first day. Unexpectedly, the burst release rate of microspheres prepared from crystal form I of compound Z bis(hydroxynaphthyl) naphthalate was only 26.3% of that of amorphous compound Z bis(hydroxynaphthyl) naphthalate microspheres, and did not exceed 5.6%.

[0112] Table 13 Encapsulation efficiency and burst release rate of salt of compound Z in microspheres

[0113] Example 6

[0114] The microspheres from Examples 5-4 were suspended in a 0.01% sodium carboxymethyl cellulose aqueous solution and subjected to a single intramuscular injection pharmacokinetic study in New Zealand rabbits at a dose of 0.5 mg / kg. The plasma concentration-time curves over 28 days are shown in Figure 18. The results show that compound Z dihydroxynaphthyl salt crystal form I can be combined with sustained-release materials to form an anti-Parkinson's drug composition with in vivo release for more than 2 weeks, and the drug concentration fluctuation is very small. This composition is expected to improve patient medication adherence, effectively reduce plasma drug concentration fluctuations caused by missed doses or discontinuation of medication, thereby reducing the probability of end-of-dose phenomenon and on-off phenomenon.

[0115] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A compound Z-bis(hydroxynaphthol) salt crystal form I, characterized in that: Characteristic diffraction peaks are observed at diffraction angles 2θ of 9.9±0.2°, 10.7±0.2°, 12.1±0.2°, 14.9±0.2°, 17.3±0.2°, 19.4±0.2°, 20.7±0.2°, and 23.1±0.2°.

2. The compound Z bis(hydroxynaphthalate) crystal form I according to claim 1, characterized in that: The compound Z bis(hydroxynaphthalate) crystal form I also has one or more characteristic diffraction peaks at diffraction angles 2θ of 5.0±0.2°, 12.6±0.2°, 13.9±0.2°, 14.5±0.2°, 15.5±0.2°, 16.9±0.2°, 21.4±0.2°, and 24.1±0.2°.

3. The compound Z bis(hydroxynaphthol) salt crystal form I according to any one of claims 1-2, characterized in that: The peak temperature of DSC heat absorption is 157℃±2℃.

4. A method for preparing compound Z bis(hydroxynaphthyl) salt crystal form I according to any one of claims 1-3, characterized in that... Includes the following steps: Component A and component B were dissolved in water to obtain solution A and solution B, respectively. Solution A and solution B were stirred and mixed, and stirring was continued for 0-5 hours. The precipitate was collected by filtration and washed with water. The precipitate is then dispersed in water and stirred for at least 6 hours. The precipitate is then filtered, collected, and dried to obtain the final product. Component A is a dicarboxylic acid or its water-soluble salt; Component B is compound Z or its water-soluble salt.

5. The preparation method according to claim 4, characterized in that: The dicarboxylic acid or its water-soluble salt is dihydroxynaphthic acid, disodium dihydroxynaphthate, or dipotassium dihydroxynaphthate; The compound Z and its water-soluble salts are compound Z, compound Z methanesulfonate, compound Z acetate, and compound Z tartrate.

6. The use of compound Z dihydroxynaphthate crystal form I according to any one of claims 1-3 in the preparation of a drug for treating Parkinson's disease.

7. A long-acting sustained-release composition, characterized in that: The compound Z-bis(hydroxynaphthol) salt crystal form I is contained in any one of claims 1-3.

8. The long-acting sustained-release composition according to claim 7, characterized in that: It also contains sustained-release materials; The sustained-release material is a biodegradable and biocompatible polymer material.

9. The long-acting sustained-release composition according to claim 8, characterized in that: The biodegradable and biocompatible polymeric material is at least one of lactide-glycolic acid copolymer, polylactide and its derivatives.

10. The long-acting sustained-release composition according to any one of claims 7-9, characterized in that: It is an implant, microsphere, microparticle, or suspension.

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