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 low water-soluble drug crystal and preparation method and use thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a low water-soluble drug crystal and preparation method and use thereof. BACKGROUND

[0002]

[0003] Compound Z, the structure of which is shown in the formula above, is a second-generation monoamine oxidase inhibitor, and can block the decomposition of neurotransmitter dopamine, and plays an anti-Parkinson role in a dopaminergic motor function disorder model by increasing dopamine levels and indirectly increasing dopaminergic activity.

[0004] Compound Z is in the form of an oral tablet of a mesylate salt in the currently marketed drug preparation. Compound Z mesylate is classified as type III in the BCS classification of biological drugs, has high solubility and low permeability, and an oral tablet is prone to peak-valley phenomenon, which causes adverse reactions, and on-off side effects in patients in the later stage after administration; if the compound Z mesylate is made into a long-acting sustained-release preparation, its high solubility poses a great challenge to the prescription and process. Therefore, developing a low water-soluble salt or ester of compound Z, or further making it into a long-acting sustained-release preparation, has significant clinical value and advantages, and can effectively reduce the blood drug concentration fluctuation caused by missed medication or drug withdrawal, thereby further reducing the probability of “end-of-dose phenomenon” and “on-off phenomenon”.

[0005] Chinese patent application CN111212640A discloses a preparation method of a pamoate salt of a part of monoamine drugs (rotigotine, ropinirole and pramipexole), such as a pamoate salt of a monoamine drug can be prepared by adding a solution of disodium pamoate or other pamoate salt in a suitable solvent such as water into a solution of a monoamine drug hydrochloride, and stirring the solution for about 3 or 12 hours until precipitation occurs. However, the inventors can only obtain an amorphous compound Z pamoate salt by using the above method, and the method disclosed in the reference embodiment cannot successfully obtain a crystal of the compound Z pamoate salt. SUMMARY

[0006] The present application aims to provide a compound Z pamoate salt crystal form I and a preparation method and use thereof.

[0007] The compound Z pamoate salt crystal form I (referred to as crystal form I) has characteristic diffraction peaks at diffraction angles 2theta 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 Form I has one or more characteristic peaks at diffraction angles 2-theta 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°, 24.1±0.2°.

[0009] In some embodiments, the Form I has characteristic peaks at diffraction angles 2-theta 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°, 24.1±0.2°.

[0010] In some embodiments, the Form I has an X-ray powder diffraction (XRD) pattern as shown in Figure 1.

[0011] In some embodiments, the Form I has an infrared spectrum as shown in Figure 2. -1 with peaks.

[0012] In some embodiments, the Form I has a differential scanning calorimetry (DSC) curve with an endothermic peak at 157°C±2°C.

[0013] In some embodiments, the method for preparing the compound Z pamoate Form I comprises the following steps:

[0014] Component A and Component B are dissolved in water respectively to obtain A solution and B solution respectively; the A solution and the B solution are stirred and mixed uniformly, and continue to be stirred for 0-5 hours (hereinafter referred to as mixing stirring), the precipitate is collected by filtration and washed with water to remove impurities; then the precipitate is dispersed in water, and stirred for not less than 6 hours (hereinafter referred to as crystallization stirring), the precipitate is collected by filtration and dried to obtain the compound Z pamoate Form I.

[0015] In some embodiments, the Component A is a dibasic acid and water-soluble salts thereof, including but not limited to pamoic acid, disodium pamoate, dipotassium pamoate, and preferably disodium pamoate.

[0016] In some embodiments, the Component B is compound Z and water-soluble salts thereof, including but not limited to compound Z, compound Z mesylate, compound Z acetate, compound Z tartrate, and preferably compound Z mesylate.

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

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

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

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

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

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

[0023] The compound Z pamoate Form I can be used in the preparation of a medicament for treating Parkinson's disease.

[0024] A long-acting sustained-release composition containing the compound Z pamoate Form I.

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

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

[0027] The biodegradable biocompatible polymer material includes but is not limited to at least one of poly(lactide-co-glycolide), polylactide and its derivatives.

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

[0029] The long-acting sustained-release composition can provide sustained release of the drug in the body for not less than 2 weeks after administration.

[0030] The preparation method of the long-acting sustained-release composition includes but is not limited to emulsion-solvent evaporation method.

[0031] The long-acting sustained-release composition prepared by the emulsion-solvent evaporation method has an encapsulation efficiency of compound Z pamoate Form I of not less than 80%.

[0032] In some embodiments, the long-acting sustained-release composition prepared by the emulsion-solvent evaporation method has an encapsulation efficiency of compound Z pamoate Form I of not less than 85%.

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

[0034] The present application has the following advantages and beneficial effects over the prior art:

[0035] 1. The crystalline form of compound Z pamoate salt (compound Z pamoate salt crystalline form I) has good stability, does not undergo crystal transformation, has no significant increase in related substances, and has low solubility, as compared to amorphous compound Z pamoate salt.

[0036] 2. The present application eliminates the influence of impurities on crystal nucleation and crystal growth by removing soluble impurities, and creatively obtains a crystalline form of compound Z pamoate salt.

[0037] 3. The production process of the compound Z pamoate salt crystalline form I provided by the present application is simple, and only water is used as a solvent throughout the process, without the need to use organic solvents, which is environmentally friendly, non-polluting, and in line with 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 is prepared from the compound Z pamoate salt crystalline form I, the drug has a high encapsulation rate, low burst release, and the composition continuously releases the drug in the body for more than 2 weeks, which can reduce the frequency of drug administration by patients, improve drug compliance, effectively reduce the blood concentration fluctuation caused by missed drug administration or drug withdrawal, and reduce the probability of occurrence of "end-of-dose phenomenon" and "on-off phenomenon". BRIEF DESCRIPTION OF DRAWINGS

[0039] FIG. 1 is an XRD pattern of compound Z pamoate salt crystalline form I.

[0040] FIG. 2 is an XRD pattern of the precipitate stirred for 3 h in Example 1.

[0041] FIG. 3 is an XRD pattern of the precipitate stirred for 6 h in Example 1.

[0042] FIG. 4 is an XRD pattern of the precipitate stirred for 12 h in Example 1.

[0043] FIG. 5 is a nuclear magnetic hydrogen spectrum of compound Z pamoate salt crystalline form I.

[0044] FIG. 6 is a nuclear magnetic carbon spectrum of compound Z pamoate salt crystalline form I.

[0045] FIG. 7 is a differential scanning calorimetry curve (DSC) of amorphous compound Z pamoate salt.

[0046] FIG. 8 is a differential scanning calorimetry curve (DSC) of compound Z pamoate salt crystalline form I.

[0047] FIG. 9 is an infrared spectrum of compound Z pamoate salt crystalline form I.

[0048] Figure 10 is the XRD pattern of the precipitate of Comparative Example 1 stirred for 3h.

[0049] Figure 11 is the XRD pattern of the precipitate of Comparative Example 1 stirred for 24h.

[0050] Figure 12 is the XRD pattern of Compound Z pamoate Form I zero day.

[0051] Figure 13 is the XRD pattern of Compound Z pamoate Form I at high temperature 60°C, 10 days.

[0052] Figure 14 is the XRD pattern of Compound Z pamoate Form I at high humidity 92.5% RH, 10 days.

[0053] Figure 15 is the XRD pattern of Compound Z pamoate Form I at strong light 10 days.

[0054] Figure 16 is the XRD pattern of Compound Z pamoate Form I at accelerated 6 months.

[0055] Figure 17 is the XRD pattern of Compound Z pamoate Form I at long term 24 months.

[0056] Figure 18 is a blood concentration-time curve. DETAILED DESCRIPTION

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

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

[0059] PANalytical Empyrean sharp shadow X-ray powder diffractometer (PW3040 / 60, PANalytical Analytical Instruments Co., Ltd., Netherlands), Cu-Ka radiation, wavelength equipped with Bragg-Brentano High Definition. Incident light path: divergence slit 1 / 8°, Soller slit 0.04 rad, light shield 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 the present application, the DSC detection method is as follows: using the DSC tester of NETZSCH to detect the amorphous compound Z pamoate and the compound Z pamoate Form I, the temperature range is from room temperature to 200℃, the heating rate is 10℃ / min, and the nitrogen atmosphere.

[0061] In the present application, the hydrogen nuclear magnetic resonance spectrum detection method is as follows: using deuterated DMSO as the solvent, the compound Z pamoate Form I is prepared into a 15-20mg / mL solution, and then detected by a 600MHz hydrogen nuclear magnetic resonance spectrometer.

[0062] In the present application, the carbon nuclear magnetic resonance spectrum detection method is as follows: using deuterated DMSO as the solvent, the compound Z pamoate Form I is prepared into a 15-20mg / mL solution, and then detected by a 600MHz carbon nuclear magnetic resonance spectrometer.

[0063] In the present application, the content determination method of the compound Z refers to the high performance liquid chromatography (ChP General Rule 0512), specifically as follows: accurately weighing a proper amount of the compound Z pamoate, dissolving in acetonitrile, diluting with water to the scale, and then shaking to make uniform. Accurately weighing a proper amount of the reference substance, dissolving in acetonitrile, diluting with water to the scale, and then shaking to make uniform. Accurately taking the test sample solution and the reference substance solution, respectively injecting into the liquid chromatograph for analysis, recording the chromatogram, and calculating the content by the external standard method according to the peak area.

[0064] Example 1

[0065] Accurately weighing 4.5g (10mmol) of disodium pamoate, dissolving in 200mL of water; accurately weighing 5.3g (20mmol) of compound Z mesylate, dissolving in 200mL of water; under the condition of 25±2℃, slowly stirring and mixing the compound Z mesylate solution with the disodium pamoate solution to generate white to white-like precipitate; after the mixing is completed, continue to stir for 1h (hereinafter referred to as mixing stirring); collecting the precipitate by filtration and washing with water to remove impurities; then adding the precipitate into water, and continuing to stir under the condition of 25±2℃; in parallel, collecting part of the precipitate by filtration after stirring for 3h, 4h, 5h, 6h, 9h, 12h, 18h, 24h (hereinafter referred to as crystallization stirring) respectively, and drying to obtain the compound Z pamoate, and then detecting by XRD, hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, DSC, infrared spectrum and the like.

[0066] The XRD spectrum shows that the precipitate obtained by mixing stirring for 1h and crystallization stirring for 5h has no obvious crystallization, the XRD representative spectrum of the precipitate obtained by crystallization stirring for 3h is shown in FIG. 2; the precipitate obtained by stirring for more than 6h has obvious crystallization, the XRD spectrum of the precipitate obtained by crystallization stirring for 6h is shown in FIG. 3 (the spectrum data is shown in Table 1), the XRD spectrum of the precipitate obtained by crystallization stirring for 12h is shown in FIG. 4 (the spectrum data is shown in Table 2), and the XRD spectrum of the precipitate obtained by crystallization stirring for 24h is shown in FIG. 1 (the spectrum data is shown in Table 3).

[0067] Table 1: XRD pattern analysis data of compound Z pamoate obtained by stirring for 6h

[0068] Table 2: XRD pattern analysis data of compound Z pamoate Form I obtained by stirring for 12h

[0069] Table 3: XRD pattern analysis data of compound Z pamoate Form I obtained by stirring for 24h

[0070] For convenience of the following description, the crystallized compound Z pamoate is named as compound Z pamoate Form I.

[0071] The results of the nuclear magnetic hydrogen spectrum show that the molar ratio of pamoic acid and compound Z in the compound Z pamoate Form I prepared by the above method is 1:2, and Figure 5 is a representative nuclear magnetic hydrogen spectrum of the crystallization stirring for 24h.

[0072] The results of the nuclear magnetic carbon spectrum show that the obtained product is indeed compound Z pamoate, and Figure 6 is a representative nuclear magnetic carbon spectrum of the crystallization stirring for 24h.

[0073] The results of the DSC detection show that the amorphous compound Z pamoate only has a glass transition without a melting point, and Figure 7 is a DSC curve of the precipitate of the crystallization stirring for 3h; while the compound Z pamoate Form I has an endothermic peak at about 157°C, and the endothermic peak temperatures of the crystallization stirring for 6h, 9h, 12h, 18h and 24h are 157.8, 157.1, 157.4, 158.0 and 158.3 respectively, and Figure 8 is a DSC curve of the sample of the crystallization stirring for 24h.

[0074] The results of the infrared spectrum detection show that the infrared spectrum (Figure 9) of the sample of the crystallization stirring for 24h has peaks at about 3289, 1643, 1451, 1351, 760, 1558, 1394, 1233, 1202 cm -1 with peaks, proving that the obtained product is indeed compound Z pamoate.

[0075] Table 4: Infrared spectrum analysis data of compound Z pamoate Form I

[0076] Example 2

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

[0078] The results show that when the crystallization stirring time is 3 h, there is no obvious difference in the mixing and stirring time of 0-5 h, and amorphous compound Z pamoate salt is obtained; when the crystallization stirring time is 6 h, crystalline compound Z pamoate salt can be obtained in the mixing and stirring time of 0-5 h, indicating that whether the crystal is formed is directly related to the crystallization stirring time. Moreover, with the increase of the mixing and stirring time, the particle size (D50) of the precipitate increases from 28 μm at 0 h to 61 μm at 5 h.

[0079] Comparative Example 1

[0080] Take 4.5 g (10 mmol) of disodium pamoate and dissolve it in 200 mL of water; take 5.3 g (20 mmol) of compound Z methanesulfonate and dissolve it in 200 mL of water; slowly mix the compound Z methanesulfonate solution with the disodium pamoate solution under stirring at 25 ± 2°C to generate white to white-like precipitate, continue stirring after the mixing is completed, and collect the precipitate by filtration at 3 h, 6 h, 12 h, and 24 h of continued stirring, and dry to obtain compound Z pamoate salt, and perform XRD detection.

[0081] The XRD spectrum shows that the precipitate has no obvious crystal, and FIG. 10 is the XRD spectrum of the precipitate obtained by stirring for 3 h, and FIG. 11 is the XRD spectrum of the precipitate obtained by stirring for 24 h.

[0082] Comparative Example 2

[0083] According to the method of Example 1, amorphous compound Z pamoate salt 50 mg with 3 h of crystallization stirring is prepared and dissolved in 1.25 mL of acetone, 12.5 mL of n-hexane or petroleum ether is added to the solution under stirring at room temperature, and oiling-out of the solution occurs to obtain yellow oil, and no crystal of compound Z pamoate salt can be obtained.

[0084] Comparative Example 3

[0085] According to the method of Example 1, amorphous compound Z pamoate 400 mg stirred for 3 h was dissolved in 5 mL of dimethyl sulfoxide, the solution was slowly added to 100 mL of water at room temperature to obtain an oil, an emulsion was formed, and no crystals of compound Z pamoate were obtained.

[0086] Comparative Example 4

[0087] Compound Z (187.4 mg) and pamoic acid (212.6 mg) were added to 5 mL of dimethyl sulfoxide, and a solution was formed by stirring. The solution was slowly added to 100 mL of water at room temperature, only an emulsion was formed, and no crystals of compound Z pamoate were obtained.

[0088] Example 3

[0089] Solubility test: According to the Chinese Pharmacopoeia 2020 edition four part of the general rules, compound Z pamoate form I (product of the method of crystallization stirring for 24 h in Example 1) or rasagiline mesylate was ground into fine powder, about 10 mg was taken as the test sample in a test tube, 25±2 ℃ solvent was added, and it was shaken vigorously for 30 s every five minutes, and the dissolution was observed within 30 min. If the sample cannot be dissolved, continue to add solvent, and when no solute particles or droplets are visible, it is considered completely dissolved. The solubility of compound Z pamoate form I in different solvents is shown in Table 5.

[0090] Table 5: Solubility of compound Z pamoate form I in different solvents

[0091] The solubility of rasagiline mesylate in water is easily soluble, while the solubility of rasagiline pamoate in water is extremely slightly soluble, and the specific solubility of compound Z pamoate prepared under different conditions in water was further determined.

[0092] Take 6 mL of ultrapure water and place it in a 10 mL centrifuge tube, add about 10 mg of compound Z mesylate and each compound Z pamoate prepared in Example 1, seal, and investigate the solubility at 25 ℃, keep the solution temperature, and shake the sample manually during the period. After shaking for 1 day, take the sample, the sampling method is to place the test tube in a constant temperature environment, and when the supernatant is clear, take 2 mL of the supernatant to a 20 mL volumetric flask with a pipette, dilute to the mark with buffer, shake well, and determine the content by high performance liquid chromatography (ChP General Rule 0512), in triplicate. The results are shown in Table 6, the solubility of the crystalline compound Z pamoate is lower than that of the amorphous compound Z pamoate.

[0093] Table 6 Solubility of compound Z pamoate

[0094] Example 4

[0095] Stability Investigation:

[0096] 1) Influencing Factor Experiment

[0097] Take compound Z pamoate Form I (crystallization stirring for 24 h in Example 1) and amorphous compound Z pamoate (crystallization stirring for 3 h in Example 1), and evenly spread on the bottom of the weighing bottle. Each time condition has two parallel samples. The samples are placed at 50℃, 60℃, 75% RH, 92.5% RH and strong light (5100 Lux) for 5 days and 10 days, and the samples are taken for inspection of properties, content, moisture, related substances, XRD (only for 10-day samples), and the experimental results are shown in Tables 7, 8, Figs. 12-15.

[0098] The XRD spectrum shows that the compound Z pamoate Form I prepared in Example 1 does not change into another crystal form under the test conditions of high temperature (60℃, 10 days, Fig. 13), high humidity (92.5% RH, 10 days, Fig. 14), and strong light (5100 Lux, 10 days, Fig. 15), and the amorphous compound Z pamoate remains amorphous.

[0099] Moreover, the related substances of compound Z pamoate Form I do not change significantly under the conditions of high temperature and high humidity, and only increase significantly under the condition of strong light; and the related substances of amorphous compound Z pamoate increase significantly higher than those of compound Z pamoate Form I under the conditions of high temperature, high humidity and strong light.

[0100] 2) Accelerated Experiment

[0101] Take the samples (with inner packaging + outer packaging), and place them under the conditions of 40±2℃ and 75±5% RH for testing, and take samples at 1, 2, 3 and 6 months during the test period, and send them for inspection of properties, content, moisture, related substances and XRD, and the experimental results are shown in Tables 9 and 10.

[0102] The XRD detection results show that compound Z pamoate Form I does not change into another crystal form under the test conditions of acceleration for 6 months, and the amorphous compound Z pamoate remains amorphous, and Fig. 16 is the XRD spectrum of the sample at 6 months. Moreover, the related substances of compound Z pamoate Form I do not increase significantly, and the related substances of amorphous compound Z pamoate increase significantly.

[0103] 3) Long-term Experiment

[0104] Take the samples (with inner packaging + outer packaging), and place them under the conditions of 25±2℃ and 60±5% RH for testing, and take samples at 3, 6, 9, 12, 18 and 24 months during the test period, and send them for inspection of properties, content, moisture, related substances and XRD, and the experimental results are shown in Tables 11 and 12.

[0105] The XRD detection results show that the compound Z pamoate Form I does not change into another crystal form, and the amorphous compound Z pamoate remains amorphous under the long-term 24-month test conditions. The XRD pattern of the sample at the 24th month is shown in Figure 17. Moreover, the related substances of the compound Z pamoate Form I do not increase significantly, while the related substances of the amorphous compound Z pamoate increase significantly.

[0106] According to the results of the comprehensive influence factor test, the accelerated test and the long-term test, the compound Z pamoate Form I is more stable than the amorphous compound Z pamoate.

[0107] Example 5

[0108] The compound Z mesylate and the compound Z pamoate prepared by stirring for 3 h, 6 h and 24 h in Example 1 were used as drugs, and poly(lactide-co-glycolide) (9505, 25 KDa) was used as a carrier to prepare long-acting sustained-release microspheres, and the drug encapsulation rates were investigated. The specific method was as follows: 8 parts of the carrier were dissolved in 8.5 times of ethyl acetate, then 2 parts of the drug were added and stirred uniformly, then 1% PVA aqueous solution was quickly injected, homogenized at 2000 rpm for 5 min, and then the organic solvent was volatilized by stirring for 6 h. The solid was collected by filtration, washed with water, and freeze-dried to obtain long-acting sustained-release microspheres.

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

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

[0111] The results shown in Table 13 show that the drug encapsulation rates and burst release rates of the microspheres prepared from different salts of compound Z are different. In particular, when the solubilities of the salts of compound Z are quite different, the differences in the encapsulation rates and burst release rates are also quite large. The smaller the solubility of the salt of compound Z, the higher the drug encapsulation rate, and the lower the burst release rate on the first day. Unexpectedly, the burst release rate of the microspheres prepared from the compound Z pamoate Form I is only 26.3% of that of the microspheres prepared from the amorphous compound Z pamoate, and does not exceed 5.6%.

[0112] Table 13 Encapsulation rates and burst release rates of the salts of compound Z in the microspheres

[0113] Example 6

[0114] The microspheres of Example 5-4 were suspended in 0.01% aqueous sodium carboxymethylcellulose and administered to New Zealand rabbits by single intramuscular injection at a dose of 0.5 mg / kg. The blood concentration-time curve over 28 days is shown in Figure 18. The results show that the use of Compound Z pamoate Form I in combination with a sustained release material can produce an anti-Parkinson's drug composition that is released in vivo over a period of more than 2 weeks, and that the drug concentration fluctuation is very small. This composition is expected to improve patient compliance, effectively reduce the blood concentration fluctuation caused by missed doses or drug withdrawal, and thus reduce the probability of the occurrence of end-of-dose and on-off phenomena.

[0115] The above examples are the preferred embodiments of the present application, but the embodiments of the present application are not limited to the above examples, and any changes, modifications, substitutions, combinations, simplifications, etc. made without departing from the spirit and principles of the present application are equivalent replacement methods and are included in the scope of the present application.

Claims

1. A crystalline form I of compound Z pamoate, characterized in that: There are 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°.

2. The pamoate salt form I of compound Z according to claim 1, characterized in that: The compound Z pamoate salt form I also has characteristic diffraction peaks at one or more positions with 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 pamoate salt form I of compound Z according to any one of claims 1 to 2, characterized in that: The DSC endothermic peak temperature was 157°C ± 2°C.

4. A method for preparing the crystalline form I of compound Z pamoate according to any one of claims 1 to 3, characterized in that The following steps are involved: Dissolve component A and component B in water to obtain solution A and solution B, respectively; stir solution A and solution B to mix thoroughly, continue stirring for 0-5 hours, collect the precipitate by filtration and wash with water; Then disperse the precipitate in water, stir for not less than 6 hours, collect the precipitate by filtration, and dry it; The component A is a dibasic acid or a water-soluble salt thereof; The component B is compound Z or a water-soluble salt thereof.

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

6. Use of the pamoate salt form I of compound Z according to any one of claims 1 to 3 in the preparation of an anti-Parkinson's disease medicament.

7. A long-acting sustained-release composition, characterized in that: Contains the pamoate salt form I of compound Z according to any one of claims 1 to 3.

8. The long-acting sustained-release composition according to claim 7, characterized in that: It also contains sustained-release material; 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 polymer material is at least one of lactide-glycolide copolymer, polylactide and derivatives thereof.

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

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