Crystal form of donepezil 1-hydroxy-2-naphthoate and preparation method and application thereof

Abstract

The invention relates to a crystal form of donepezil 1-hydroxy-2-naphthoate ((+ / -)-2-[(1-benzyl-4-piperidyl) methyl]-5, 6-dimethoxy-1-indanone 1-hydroxy-2-naphthoate), a preparation method of the crystal form and application of the donepezil 1-hydroxy-2-naphthoate. The crystal form of donepezil 1-hydroxy-2-naphthoate provided by the invention has the advantages of better stability, lower hygroscopicity, lower solubility, lower pH dependence on solubility, better preparation processability and the like, and has important value for the development of long-acting injection of the drug in the future.

Description

[0001] Cross - reference to related applications

[0002] This application is based on an application with a CN application number of 202311819796.9 and a filing date of December 27, 2023, and claims its priority. The content of this CN application is hereby incorporated into this application as a whole. Technical field

[0003] The present invention relates to the fields of medicinal chemistry and crystallization technology. Specifically, this application relates to the crystal forms of donepezil 1 - hydroxy - 2 - naphthoate ((±)-2 - [(1 - benzyl - 4 - piperidyl)methyl]-5,6 - dimethoxy - 1 - indanone 1 - hydroxy - 2 - naphthoate), and its preparation methods and uses. Background art

[0004] Donepezil is widely used in the treatment of Alzheimer's disease with the effect of inhibiting acetylcholinesterase, and its structural formula is as follows:

[0005]

[0006] The first donepezil drug is Aricept - donepezil hydrochloride tablets, developed by Eisai of Japan and approved by the FDA for marketing in 1996. Currently, there are multiple dosage forms of donepezil hydrochloride on the global market, almost all of which are oral preparations. Although donepezil hydrochloride has good bioavailability, its oral treatments (tablets or capsules, etc.) generally have the following problems: (1) Severe gastrointestinal side effects; (2) Dysphagia is a common complication in AD patients, increasing the difficulty of oral medication and resulting in poor patient compliance; (3) Most AD patients have memory deficits and it is difficult to take the medicine on time and in the correct dosage every day.

[0007] The long - term maintenance of a stable therapeutic effect is an important goal in the clinical treatment of AD. The research and development of long - acting sustained - release preparations is of great value for maintaining the long - term therapeutic effect in the clinical treatment of AD. To ensure consistent and appropriate drug dosages and maximize the clinical benefits by improving patient compliance, formulating donepezil into a depot preparation or as an intramuscular preparation may be highly desirable.

[0008] Donepezil is an organic weak base. In solution, it exists in the free base form at high pH (alkaline conditions). The water solubility of donepezil increases as the pH of the solution decreases, showing strong pH - dependence. It is known that the pH of muscle tissue can change with exercise, stress, and injury, which can affect drug solubility and thus the absorption rate of injectable drugs. Therefore, it is desirable to develop a long - acting injectable sustained - release preparation in which the solubility and release rate of the active ingredient minimally depend on pH.

[0009] Patents CN1312129C, CN106397306B, CN101039910A, CN101397270B, and CN1874998A describe various salt forms of donepezil. These salt forms either improve the stability of oral administration or enhance drug solubility and dissolution rate, etc., and they possess the characteristics required for immediate-release dosage forms. However, when sustained-release delivery of these salts is needed to prolong the effect, their relatively high solubility makes it difficult to meet the requirements of long-acting injectables. CN104039765B discloses a poorly soluble salt form of donepezil - pamorate. Among them, the crystal forms of two mono-pamorates will convert to the crystal form of semi-pamorate A in the aqueous slurry. The crystal forms of semi-pamorate A and semi-pamorate B are prone to polymorphic transformation (crystal form A converts to crystal form B at high temperature, and crystal form B converts to crystal form A when exposed to air at room temperature), and crystal form A is a hydrate, and the water content of the hydrate is easily affected by temperature and humidity. Therefore, the pamorate crystal forms disclosed in CN104039765B all have stability problems. US20140243278A1 discloses the crystal forms T1, T2, and T3 of pamorate. Among them, crystal form T2 will convert to crystal form T3 at 40% RH - 80% RH, and crystal form T3 is also a hydrate, and its water content is easily affected by temperature and humidity. Therefore, the pamorate crystal forms disclosed in US20140243278A1 also have stability problems.

[0010] The prior art has the following disadvantages:

[0011] 1. The solubility of donepezil free base has a strong pH dependence. It is known that the pH of muscle tissue can change with exercise, stress, and injury. Long-acting injectables generally use intramuscular injection. After intramuscular injection, an acute inflammatory reaction will occur at the injection site, causing the local pH to decrease from about 7.0 to about 5.0. The single-dose of long-acting injectables is large. If the solubility of the drug is relatively high under this pH condition and it dissolves into the blood in a short time, it will lead to serious toxic and side effects.

[0012] 2. Most of the disclosed salt forms of donepezil possess the characteristics required for immediate-release dosage forms and have relatively high solubility, which cannot meet the requirements of long-acting injectables.

[0013] 3. The solubility of the pamorate crystal form A disclosed in CN104039765B meets the requirements of long-acting injectables, but it can be inferred from the patent disclosure data that its stability is poor. Changes in temperature and humidity may cause polymorphic changes, resulting in instability of some physical and chemical properties. Summary of the Invention

[0014] In view of the deficiencies of the prior art, the object of the present invention is to provide crystal forms of donepezil salts, their preparation methods, pharmaceutical compositions containing the crystal forms of the salts, and uses. The crystal forms of the donepezil salts of the present invention should have one or more improved properties to be more suitable for the development of long-acting injectable sustained-release formulations, especially manifested in better stability, lower hygroscopicity, lower solubility, lower pH-dependence of solubility, and better formulation processability. Thus, the following inventions are provided:

[0015] In a first aspect, the present application provides crystal form A of donepezil 1-hydroxy-2-naphthoate. The structural formula of donepezil 1-hydroxy-2-naphthoate is shown below, wherein the molar ratio of donepezil to 1-hydroxy-2-naphthoic acid is 1:1;

[0016]

[0017] Using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles has the following characteristic peaks: 10.2° ± 0.2°, 11.1° ± 0.2°, 12.6° ± 0.2°, 15.0° ± 0.2°, and 25.7° ± 0.2°.

[0018] In some embodiments, the relative intensities of the characteristic peaks are as follows:

[0019] 2θ Relative intensity (I%) 10.2±0.2° 73.1±5％ 11.1±0.2° 56.9±5％ 12.6±0.2° 68.8±5％ 15.0±0.2° 24.2±5％ 25.7±0.2° 100.0±5％ .

[0020] In some embodiments, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles also has characteristic peaks at one or more of the following: 11.5° ± 0.2°, 13.2° ± 0.2°, 18.0° ± 0.2°, 20.4° ± 0.2°, and 23.8° ± 0.2°.

[0021] In some embodiments, the relative intensities of the characteristic peaks are as follows:

[0022]

[0023]

[0024] In some embodiments, using Cu-Kα radiation, the X-ray powder diffraction pattern expressed in 2θ angles also has characteristic peaks at one or more of the following: 5.4° ± 0.2°, 16.4° ± 0.2°, 16.9° ± 0.2°, 19.3° ± 0.2°, and 24.8° ± 0.2°.

[0025] In some embodiments, the relative intensities of the characteristic peaks are as follows:

[0026] 2θ Relative intensity (I%) 5.4 2.2±5％ 16.4 37.0±5％ 16.9 61.2±5％ 19.3 51.4±5％ 24.8 34.5±5％ 。

[0027] In a specific embodiment of the present invention, without limitation, the crystal form A of 1-hydroxy-2-naphthoate has characteristic peaks and their relative intensities at the following diffraction angles 2θ in its X-ray powder diffraction pattern:

[0028] Exemplary list of peaks in the X-ray powder diffraction pattern

[0029]

[0030]

[0031] In some embodiments, the crystal form A of donepezil 1-hydroxy-2-naphthoate has substantially the same Figure 1 、 Figure 5 or Figure 9 shown X-ray powder diffraction pattern.

[0032] In some embodiments, in the Fourier transform infrared spectrum of the crystal form A of donepezil 1-hydroxy-2-naphthoate, there are characteristic peaks at least at one of the wavenumbers selected from 1686 cm -1 ±4 cm -1 、1591 cm -1 ±4 cm -1 、1499 cm -1 ±4 cm -1 、1315 cm -1 ±4 cm -1 、1259 cm -1 ±4 cm -1 、1039 cm -1 ±4 cm -1 、1403 cm-1 ± 4 cm -1 、1218 cm -1 ±4 cm -1 、1019 cm-1 ± 4 cm -1 、958 cm -1 ±4 cm -1 and 923 cm -1 ±4 cm -1 。

[0033] In some embodiments, the crystal form A of donepezil 1-hydroxy-2-naphthoate has substantially the same Figure 2 、 Figure 6 or Figure 10 shown Fourier transform infrared spectrum.

[0034] In some embodiments, for polymorph A of donepezil 1-hydroxy-2-naphthoate, in its thermogravimetric analysis (TGA) pattern, there is a weight loss of 0.03% to 0.2% (such as 0.03% to 0.05%, 0.05% to 0.1%, 0.1% to 0.15%, or 0.15% to 0.2%, for example 0.03%, 0.208%, or 0.193%) before 100 °C.

[0035] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has a TGA pattern substantially as Figure 3 , Figure 7 or Figure 11 shown.

[0036] In some embodiments, for polymorph A of donepezil 1-hydroxy-2-naphthoate, the melting point measured by differential scanning calorimetry (DSC) is 170 °C to 177 °C (such as 171 °C, 172 °C, 173 °C, 174 °C, 175 °C, 176 °C, or 177 °C).

[0037] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has a DSC pattern substantially as Figure 4 or Figure 8 shown.

[0038] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has an X-ray powder diffraction pattern substantially as Figure 1 shown.

[0039] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has a Fourier transform infrared spectrum substantially as Figure 2 shown.

[0040] In some embodiments, for polymorph A of donepezil 1-hydroxy-2-naphthoate, in its TGA pattern, there is a weight loss of 0.03% before 100 °C.

[0041] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has a TGA pattern substantially as Figure 3 shown.

[0042] In some embodiments, for polymorph A of donepezil 1-hydroxy-2-naphthoate, the melting point measured by DSC is 177 °C.

[0043] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has a DSC pattern substantially as Figure 4 shown.

[0044] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has substantially an Figure 5 X-ray powder diffraction pattern as shown.

[0045] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has substantially an Figure 6 Fourier transform infrared spectrum as shown.

[0046] In some embodiments, for polymorph A of donepezil 1-hydroxy-2-naphthoate, in its thermogravimetric analysis pattern, there is a weight loss of 0.208% before 100 °C.

[0047] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has substantially an Figure 7 thermogravimetric analysis pattern as shown.

[0048] In some embodiments, for polymorph A of donepezil 1-hydroxy-2-naphthoate, the melting point measured by a differential scanning calorimeter is 177 °C.

[0049] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has substantially an Figure 8 differential scanning calorimetry pattern as shown.

[0050] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has substantially an Figure 9 X-ray powder diffraction pattern as shown.

[0051] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has substantially an Figure 10 Fourier transform infrared spectrum as shown.

[0052] In some embodiments, for polymorph A of donepezil 1-hydroxy-2-naphthoate, in its thermogravimetric analysis pattern, there is a weight loss of 0.193% before 100 °C.

[0053] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has substantially an Figure 11 thermogravimetric analysis pattern as shown.

[0054] In some embodiments, for polymorph A of donepezil 1-hydroxy-2-naphthoate, the melting point measured by a differential scanning calorimeter is 170 °C.

[0055] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate is an anhydrate.

[0056] Polymorph A of donepezil 1-hydroxy-2-naphthoate of the present invention has no or almost no hygroscopicity. In some embodiments, the weight gain of polymorph A of donepezil 1-hydroxy-2-naphthoate is less than 0.2% in an environment of 0% RH to 80% RH, such as 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, preferably 0.18%.

[0057] In some embodiments, polymorph A of donepezil 1-hydroxy-2-naphthoate has a dynamic vapor sorption profile substantially as Figure 12 shown.

[0058] In a second aspect, the present application provides a method for preparing polymorph A of donepezil 1-hydroxy-2-naphthoate of the present invention, comprising the following steps: separately forming a suspension or solution of donepezil and 1-hydroxy-2-naphthoic acid in a good solvent at a certain temperature, after mixing, crystallizing the slurry (i.e., stirring the suspension for a certain time), separating and drying the precipitated crystals to obtain polymorph A of donepezil 1-hydroxy-2-naphthoate. Optional stirring methods include but are not limited to magnetic stirring.

[0059] In some embodiments, the temperature for forming the suspension or solution is 30 to 60 °C, more preferably 40 to 50 °C.

[0060] In some embodiments, donepezil and 1-hydroxy-2-naphthoic acid are selected to form a solution in the same good solvent.

[0061] In some embodiments, the good solvent is alcohols (such as methanol, ethanol, n-propanol, sec-butanol), esters (such as n-butyl acetate, isopropyl acetate, ethyl acetate) or toluene. Preferably, the good solvent is methanol, ethanol, n-propanol or sec-butanol, more preferably ethanol.

[0062] In some embodiments, the molar ratio of donepezil to 1-hydroxy-2-naphthoic acid in the feed is 1:0.7 to 1:1.5, more preferably 1:0.7 to 1:1.2, such as 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5.

[0063] In some embodiments, the mass-to-volume ratio (mg / mL) of donepezil to the total good solvent is 30 to 150, more preferably 50 to 80, such as 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 or 150, such as 68.4, 69.7.

[0064] In some embodiments, the mass-to-volume ratio (mg / mL) of 1-hydroxy-2-naphthoic acid to the total good solvent is 20 to 200, more preferably 40 to 80, such as 20 to 40, 40 to 60, 60 to 80, 80 to 100, 100 to 120, 120 to 140, 140 to 160, 160 to 180, or 180 to 200, such as 41.6, 42.4.

[0065] When the ratios of donepezil and 1-hydroxy-2-naphthoic acid to the total solvent are determined, the amount of the good solvent used to form the donepezil or 1-hydroxy-2-naphthoic acid suspension (or solution) can be adjusted.

[0066] The amount of the good solvent used to form the donepezil suspension (or solution) is not limited. In some embodiments, the mass-to-volume ratio (mg / mL) of donepezil to the good solvent is 80 to 440, such as 80 to 100, 100 to 150, 150 to 200, 200 to 250, 250 to 300, 300 to 350, 350 to 400, or 400 to 440, such as 80, 433.

[0067] In some embodiments, the mass-to-volume ratio (mg / mL) of 1-hydroxy-2-naphthoic acid to the good solvent used to form the 1-hydroxy-2-naphthoic acid suspension or solution is 50 to 500, more preferably 80 to 400, such as 50 to 80, 80 to 100, 100 to 200, 200 to 300, or 300 to 400, such as 98.8, 365.

[0068] In some embodiments, the mixing includes adding the suspension or solution of 1-hydroxy-2-naphthoic acid to the suspension or solution of donepezil; preferably, the slurry time is 1 to 7 days; more preferably 2 to 4 days.

[0069] In some embodiments, the good solvent can be supplemented during the slurry process.

[0070] In some embodiments, the temperature can be reduced during the slurry process, for example, the temperature can be reduced to 0 to 20 °C, more preferably 5 to 10 °C. In some embodiments, the drying temperature is 10 to 50 °C (such as 10 to 20 °C, 20 to 30 °C, 30 to 40 °C, or 40 to 50 °C), and the drying time is 1 to 5 days (such as 4 days).

[0071] In some embodiments, the slurry process includes: slurrying for a certain time (such as less than 1 hour) at a heating temperature (such as 30 to 60 °C, more preferably 40 to 50 °C), cooling to room temperature, precipitating solids, supplementing the good solvent, and continuing to slurry for a certain time (such as 2 to 4 days).

[0072] In a third aspect, the present application provides another method for preparing crystalline form A of donepezil 1-hydroxy-2-naphthoate of the present invention, comprising the following steps: forming a solution of a mixture of donepezil and 1-hydroxy-2-naphthoic acid in a good solvent, adding an anti-solvent, stirring for crystallization, and then separating the crystals and drying to obtain crystalline form A of the donepezil 1-hydroxy-2-naphthoate.

[0073] In some embodiments, the good solvent is dichloromethane, chloroform, dimethyl sulfoxide or a ketone (such as acetone or methyl ethyl ketone), more preferably dichloromethane.

[0074] In some embodiments, the mass-volume ratio (mg / mL) of donepezil to the good solvent is 10-120, more preferably 50-120, such as 10-20, 20-40, 40-60, 60-80, 80-100 or 100-120.

[0075] In some embodiments, the molar ratio of donepezil to 1-hydroxy-2-naphthoic acid in the feed is 1:0.8 to 1:1.5, more preferably 1:0.8 to 1:1.2, such as 1:0.81, such as 1:0.9, 1:1.0, 1:1.1 or 1:1.2.

[0076] In some embodiments, the anti-solvent is an alkane or water, preferably n-hexane, cyclohexane, methylcyclohexane, n-heptane or water, more preferably n-heptane.

[0077] In some embodiments, the volume ratio of the good solvent to the anti-solvent is 0.5-10, more preferably 1-5, such as 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9 or 9-10.

[0078] In some embodiments, the good solvent and the anti-solvent are selected from the following combinations:

[0079] Number Good solvent Anti-solvent 1 Dichloromethane Water 2 Chloroform n-Hexane 3 Dichloromethane Cyclohexane 4 Acetone Methylcyclohexane 5 Butanone n-Heptane 6 Dimethyl sulfoxide Water .

[0080] In some embodiments, the stirring time is 1-5 days (such as 3 days).

[0081] In some embodiments, the operating temperature for forming the solution, stirring for crystallization and separating the crystals is 10-40 °C, more preferably room temperature.

[0082] In some embodiments, the drying temperature is 10-50 °C (such as 10-20 °C, 20-30 °C, 30-40 °C or 40-50 °C), and the drying time is 1-5 days.

[0083] In a fourth aspect, the present application provides other methods for preparing crystalline form A of donepezil 1-hydroxy-2-naphthoate of the present invention, including using donepezil 1-hydroxy-2-naphthoate as a starting material and preparing crystalline form A of donepezil 1-hydroxy-2-naphthoate by any of the methods of room temperature crystal slurry, 50 °C crystal slurry, cyclic heating and cooling suspension stirring, anti-solvent addition, gas-liquid diffusion, polymer template, gas-solid diffusion, and cooling crystallization.

[0084] In some embodiments, the room temperature crystal slurry method includes placing a suspension of donepezil 1-hydroxy-2-naphthoate at room temperature and magnetically stirring for a certain period of time (such as 5 days), separating the solid (such as by centrifugation), and drying; preferably, the suspension uses methanol, acetone, acetonitrile, ethyl acetate, or methyl tert-butyl ether as a solvent.

[0085] In some embodiments, the 50 °C crystal slurry method includes placing a suspension of donepezil 1-hydroxy-2-naphthoate at 50 °C and stirring (such as magnetically stirring) for a certain period of time (such as 3 days), separating the solid (such as by centrifugation), and drying; preferably, the suspension uses sec-butyl alcohol, toluene, water, isobutyl acetate, or n-heptane as a solvent.

[0086] In some embodiments, the cyclic heating and cooling suspension stirring method includes placing a suspension of donepezil 1-hydroxy-2-naphthoate in a temperature range of 50 °C to 5 °C and performing cyclic heating and cooling magnetic stirring for a period of time (such as 5 days), separating the solid (such as by centrifugation), and drying; preferably, the suspension uses 1,4-dioxane, butanone, n-propanol, acetonitrile, dimethyl sulfoxide, or cyclohexane as a solvent.

[0087] In some embodiments, the anti-solvent addition method includes dissolving donepezil 1-hydroxy-2-naphthoate with a good solvent (such as tetrahydrofuran, dichloromethane, dimethyl sulfoxide), adding a certain amount of anti-solvent (such as isopropyl ether, n-propanol, methylcyclohexane, isopropyl acetate, water, acetonitrile, methyl tert-butyl ether), after precipitating the solid, placing the suspension at room temperature and stirring for a period of time (such as 3 days), separating the solid (such as by centrifugation), and drying; preferably, the good solvent / anti-solvent is selected from:

[0088] tetrahydrofuran / isopropyl ether

[0089] tetrahydrofuran / n-propanol

[0090] dichloromethane / methylcyclohexane

[0091] dichloromethane / isopropyl acetate

[0092] dimethyl sulfoxide / water

[0093] dimethyl sulfoxide / acetonitrile

[0094] Dimethyl sulfoxide / methyl tert-butyl ether.

[0095] In some embodiments, the gas-liquid diffusion method comprises placing a clear solution of donepezil 1-hydroxy-2-naphthoate in an atmosphere of another solvent and allowing it to stand at room temperature (e.g., for 14 days), and collecting the solid; preferably, the solvent used to form the clear solution is selected from N,N-dimethylformamide, chloroform, tetrahydrofuran, dimethyl sulfoxide, and the solvent used to form the atmosphere is selected from diethyl ether, n-hexane, ethyl acetate, methyl tert-butyl ether. Preferably, the solvent used to form the clear solution / solvent used to form the atmosphere is selected from:

[0096] N,N-dimethylformamide / diethyl ether

[0097] Chloroform / n-hexane

[0098] Tetrahydrofuran / ethyl acetate

[0099] Dimethyl sulfoxide / methyl tert-butyl ether.

[0100] In some embodiments, the polymer template method comprises adding a clear solution of donepezil 1-hydroxy-2-naphthoate to a small amount of polymer solid, allowing it to volatilize through small holes at room temperature (e.g., for 6 days), and collecting the solid; preferably, the solvent / polymer used to form the clear solution is selected from: dichloromethane / polyvinyl alcohol, methyl ethyl ketone / polyvinylpyrrolidone, acetonitrile / polyvinyl alcohol, tetrahydrofuran / polymethyl methacrylate.

[0101] In some embodiments, the gas-solid diffusion method comprises placing a solid of donepezil 1-hydroxy-2-naphthoate in an atmosphere of an organic solvent and allowing it to stand at room temperature for a period of time (e.g., for 6 days), and collecting the solid; preferably, the organic solvent is selected from acetone, methyl tert-butyl ether, chloroform, methyl acetate.

[0102] In some embodiments, the cooling crystallization method comprises dissolving donepezil 1-hydroxy-2-naphthoate in a single or mixed solvent at a high temperature (e.g., 40-60 °C, e.g., 50 °C), transferring it to a low temperature (e.g., 5-10 °C) and stirring, separating the solid after precipitation, and drying; preferably, the solvent is selected from:

[0103] Dimethyl sulfoxide / n-butyl acetate mixed solvent

[0104] N,N-dimethylacetamide / methylcyclohexane mixed solvent

[0105] Isopropanol / methylcyclohexane mixed solvent

[0106] Acetonitrile / water mixed solvent

[0107] 1,4-dioxane / ethyl acetate mixed solvent.

[0108] In some embodiments, the donepezil 1-hydroxy-2-naphthoate as the starting material exists in the form of crystalline form A.

[0109] In some embodiments, the donepezil 1-hydroxy-2-naphthoate as the starting material exists in an amorphous form.

[0110] In a fifth aspect, the present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of crystalline form A of the donepezil 1-hydroxy-2-naphthoate of the present invention; optionally further comprising at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is an injection. In some embodiments, the pharmaceutical composition is a long-acting injection. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0111] In the present invention, a long-acting injection is an injection in which a sufficient dose of a drug is dissolved in a certain carrier and enters the body through an injection route to form a small drug "depot", and the drug is slowly released in the patient's body to play a stable therapeutic role.

[0112] In a sixth aspect, the present application provides the use of crystalline form A of the donepezil 1-hydroxy-2-naphthoate of the present invention in the preparation of a drug for preventing or treating diseases or physiological dysfunctions caused by low acetylcholine levels, such as Alzheimer's disease, attention deficit disorder in children, memory loss, Parkinson's disease, brain injury, multiple sclerosis, Down syndrome, delirium, emotional disorder, Huntington's disease, sleep disorder.

[0113] In some embodiments, the crystalline form A of the donepezil 1-hydroxy-2-naphthoate is used in combination with other pharmaceutically active ingredients.

[0114] Definition of key terms

[0115] In the present invention, "crystal form" refers to a unique ordered molecular arrangement or configuration within the crystal lattice, which can be confirmed by X-ray powder diffraction pattern characterization. It is well-known to those skilled in the art that the experimental error therein depends on instrument conditions, sample preparation, and sample purity. In particular, it is well-known to those skilled in the art that X-ray diffraction patterns usually vary with instrument conditions. Additionally, the experimental error of peak angles is generally 5% or less, and the errors of these angles should also be taken into account, usually allowing an error of ±0.2°. For some hydrates and solvates, the allowed error is often greater than ±0.2°. Therefore, the difference in peak angles cannot be used as the sole criterion. Moreover, the relative intensity of peaks may vary with the sample, sample preparation, and other experimental conditions. Thus, the order of peak intensities cannot be used as the sole or decisive factor. In fact, the relative intensity of diffraction peaks in an X-ray diffraction pattern is related to the preferred orientation of the crystal. The peak intensities shown herein are illustrative rather than for absolute comparison. Additionally, due to the influence of experimental factors such as sample thickness, there will be an overall shift in peak angles, and a certain shift is usually allowed. The shape of the peaks will also vary depending on the specific circumstances. Some peaks in the same crystal form appear as single peaks in some cases and in the form of splitting, double peaks, triple peaks, or single peaks with shoulders in other cases. Therefore, those skilled in the art can understand that the X-ray diffraction pattern of a crystal form in the present invention does not have to be exactly the same as the X-ray diffraction pattern in the examples referred to herein. The "same X-ray diffraction pattern" described herein does not mean absolutely the same. The same peak positions can differ by ±0.2° and the peak intensities allow a certain variability. Any crystal form having a pattern with the same or similar characteristic peaks as those in these spectra falls within the scope of the present invention.

[0116] In some embodiments, the crystal form of the donepezil salt of the present invention is substantially pure and single, with substantially no admixture of any other crystal form or amorphous state. As used herein, "substantially pure" when referring to a new crystal form means that this new crystal form accounts for at least 80% (by weight), more preferably at least 90% (by weight), particularly at least 95% (by weight), and especially at least 99% (by weight) of the compound present.

[0117] In any preparation method of the donepezil salt and its crystal form of the present invention:

[0118] The "room temperature" refers to 10 - 30°C, preferably 25°C.

[0119] The "stirring" can be carried out by conventional methods in the art. For example, the stirring methods include magnetic stirring and mechanical stirring, and the stirring speed is 50 - 1800 revolutions per minute, preferably 300 - 900 revolutions per minute.

[0120] The "separation" can be carried out by conventional methods in the art, such as vacuum concentration, centrifugation, or filtration. Vacuum filtration or centrifugation is preferred.

[0121] The "drying" can be accomplished by using conventional techniques in the art, such as drying at room temperature, forced-air drying, or vacuum drying. The drying apparatus and method are not limited and can be a fume hood, forced-air oven, spray dryer, fluidized-bed dryer, or vacuum oven; it can be carried out under reduced pressure or without reduced pressure, preferably at a pressure less than 0.09 MPa.

[0122] Advantages of the Invention

[0123] The present invention has obtained the following beneficial effects in one or more aspects:

[0124] 1. The hygroscopicity of 1-hydroxy-2-naphthoate crystal form A is extremely low. Strong hygroscopicity of a drug will cause a decrease in the fluidity of the drug powder, caking, wetting, liquefaction, and even discoloration and decomposition, reducing the stability of the drug. At the same time, an increase in the moisture content may affect its crystallinity and the permeability, density, and melting point of the drug product. 1-hydroxy-2-naphthoate crystal form A has a weight gain of 0.18% between 0% - 80% relative humidity, with no or almost no hygroscopicity. This indicates that it does not require strict humidity control and is more suitable for industrial production.

[0125] 2. 1-hydroxy-2-naphthoate crystal form A has good physicochemical stability. The chemical stability of a drug is directly related to its purity and impurities. The purity of the drug crystal form is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions. 1-hydroxy-2-naphthoate crystal form A shows no obvious changes in its crystal form and purity after being placed for 10 days under conditions of high temperature, high humidity, and strong light irradiation, as well as after being placed for 6 months under long-term and accelerated conditions, indicating its good physicochemical stability.

[0126] 3. 1-hydroxy-2-naphthoate crystal form A has good mechanical stability and formulation processability. During the formulation process, it is often necessary to grind and pulverize the active pharmaceutical ingredient. Good mechanical stability and formulation processability can reduce the risk of changes in the crystallinity of the active pharmaceutical ingredient crystal form and crystal transformation during the formulation process.

[0127] 4. 1-hydroxy-2-naphthoate crystal form A has significantly lower solubility compared to the free base, donepezil amorphous form, and other salt forms, and its solubility is not pH-dependent, indicating that it is suitable for the development of long-acting injectables and will not dissolve into the bloodstream in a short time due to changes in the pH at the intramuscular injection site; in addition, its crystal form remains unchanged before and after the solubility test, indicating that its crystal form has excellent stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0128] Figure 1 It is the X-ray powder diffraction pattern of donepezil 1-hydroxy-2-naphthoate crystal form A prepared according to Example 1.

[0129] Figure 2It is the Fourier transform infrared spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A prepared according to Example 1.

[0130] Figure 3 It is the thermogravimetric analysis spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A prepared according to Example 1.

[0131] Figure 4 It is the differential scanning calorimetry spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A prepared according to Example 1.

[0132] Figure 5 It is the X-ray powder diffraction spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A prepared according to Example 2.

[0133] Figure 6 It is the Fourier transform infrared spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A prepared according to Example 2.

[0134] Figure 7 It is the thermogravimetric analysis spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A prepared according to Example 2.

[0135] Figure 8 It is the differential scanning calorimetry spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A prepared according to Example 2.

[0136] Figure 9 It is the X-ray powder diffraction spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A prepared according to Example 3.

[0137] Figure 10 It is the Fourier transform infrared spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A prepared according to Example 3.

[0138] Figure 11 It is the thermogravimetric analysis spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A prepared according to Example 3.

[0139] Figure 12 It is the dynamic vapor sorption spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A prepared according to Example 1.

[0140] Figure 13 It is the X-ray powder diffraction spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A before and after being placed under the conditions of high temperature, high humidity and strong light irradiation.

[0141] Figure 14 It is the X-ray powder diffraction spectrum of donepezil 1-hydroxy-2-naphthoate polymorph A before and after pharmaceutical processing.

[0142] Figure 15 X-ray powder diffraction patterns of donepezil 1-hydroxy-2-naphthoate polymorph A before and after grinding.

[0143] Figure 16 X-ray powder diffraction patterns of donepezil pamoate polymorph A before and after grinding.

[0144] Figure 17 X-ray powder diffraction patterns of amorphous donepezil 1-hydroxy-2-naphthoate before and after standing under long-term conditions.

[0145] Figure 18 X-ray powder diffraction patterns of amorphous donepezil 1-hydroxy-2-naphthoate before and after standing under accelerated conditions.

[0146] Figure 19 X-ray powder diffraction patterns of donepezil 1-hydroxy-2-naphthoate polymorph A before and after standing under long-term conditions.

[0147] Figure 20 X-ray powder diffraction patterns of donepezil 1-hydroxy-2-naphthoate polymorph A before and after standing under accelerated conditions.

[0148] Figure 21 X-ray powder diffraction pattern of donepezil 1,5-naphthalenedisulfonate polymorph B prepared according to Preparation Example 2.

[0149] Figure 22 Thermogravimetric analysis spectrum of donepezil 1,5-naphthalenedisulfonate polymorph B prepared according to Preparation Example 2.

[0150] Figure 23 X-ray powder diffraction pattern of donepezil sebacate polymorph A prepared according to Preparation Example 3.

[0151] Figure 24 Thermogravimetric analysis spectrum of donepezil sebacate polymorph A prepared according to Preparation Example 3.

[0152] Figure 25 X-ray powder diffraction pattern of donepezil glutarate polymorph A prepared according to Preparation Example 4.

[0153] Figure 26 Thermogravimetric analysis spectrum of donepezil glutarate polymorph A prepared according to Preparation Example 4.

[0154] Figure 27 X-ray powder diffraction pattern of donepezil adipate polymorph A prepared according to Preparation Example 5.

[0155] Figure 28 It is the thermogravimetric analysis spectrum of donepezil adipate crystal form A prepared according to Preparation Example 5.

[0156] Figure 29 It is the X-ray powder diffraction spectrum of amorphous donepezil 1-hydroxy-2-naphthoate prepared according to Preparation Example 6.

[0157] Figure 30 It is the thermogravimetric analysis spectrum of amorphous donepezil 1-hydroxy-2-naphthoate prepared according to Preparation Example 6. Detailed implementation manners

[0158] The present invention will be further illustrated by specific examples below, but it is not used to limit the protection scope of the present invention.

[0159] In the following examples, the experimental methods are generally carried out under conventional conditions or the conditions recommended by the manufacturer; the donepezil is obtained by the method of purchasing commercially. All kinds of reagents used in the examples are purchased commercially unless otherwise specified. Unless otherwise specified, the examples are all operated at room temperature.

[0160] Instruments and methods for collecting data

[0161] 1. X-ray powder diffraction data are collected from a Bruker D8 Advance Diffractometer. The method parameters are as follows:

[0162] X-ray reflection parameter: Cu-Kα Scanning angle range: 3~40° 2θ; step size: 0.02° 2θ; scanning time: 0.2~0.5 s / step. The peak intensity I% is automatically calculated by the software according to the peak height.

[0163] 2. Thermogravimetric analysis data are collected from a PerkinElmer thermogravimetric analyzer 8000 or a TA Instruments 550. The method parameters are as follows:

[0164] Heating rate: 10 °C / min; protective gas: N2; temperature range: room temperature~400 °C.

[0165] 3. Differential scanning calorimetry data are collected from a PerkinElmer thermogravimetric analyzer 6000. The method parameters are as follows: heating rate: 10 °C / min; protective gas: N2; temperature range: 0 °C~200 °C.

[0166] 4. The dynamic vapor sorption data was collected from SMS Intrinsic PLUS. The instrument control software is Dynamic Vapor Sorption - Intrinsic control software, and the analysis software is Dynamic Vapor Sorption - Intrinsic Analysis software. The method parameters are as follows:

[0167] Temperature: 25 °C; Relative humidity range: 0% RH - 90% RH; Relative humidity gradient: 10% RH.

[0168] 5. The Fourier transform infrared spectroscopy data was collected from Thermo Fisher Nicolet iS50. The method parameters are as follows:

[0169] Detection method: ATR method; Collection range: 400 cm -1 ~4000 cm -1 .

[0170] 6. The purity data was collected from high performance liquid chromatography (HPLC) Agilent 1260 Infinity II. The method parameters are as follows:

[0171] (1) Chromatographic column: ShimNex, 4.6 mm * 150 mm, 5 μm

[0172] (2) Mobile phase A: Triethylamine solution with pH 6.8

[0173] (3) Mobile phase B: Acetonitrile

[0174] (4) Elution gradient:

[0175] Time (min) A(％) B(％) 0 80 20 5 80 20 10 60 40 35 60 40 45 80 20

[0176] (5) Column temperature: 30 °C

[0177] (6) Detection wavelength: 270 nm

[0178] (7) Flow rate: 1.0 mL / min

[0179] 7. The particle size data of the microcrystalline sample was collected from Malvern Mastersizer 3000 laser particle size analyzer. The pump speed was 2000 rpm, the particle refractive index was 1.58, the particle absorption rate was 0.01, and the measurement was performed in parallel 3 times.

[0180] Example 1

[0181] At 40 °C, take about 12.0 g of donepezil and add it to 150 mL of ethanol to form a suspension. Take about 7.3 g of 1-hydroxy-2-naphthoic acid and add it to 20 mL of ethanol to form a solution. Add the acid solution to the donepezil suspension, stir to crystallize, after about 20 minutes of slurry at 40 °C, cool to room temperature, a large amount of solid precipitates. Add 2 mL of ethanol, continue slurry for 2 days, then filter by suction, and vacuum dry at room temperature for 4 days to obtain crystalline form A of donepezil 1-hydroxy-2-naphthoate, with a yield of 92%.

[0182] Take the sample of Example 1 for characterization, as follows:

[0183] 1. The X-ray powder diffraction pattern is as shown in Figure 1 and the X-ray powder diffraction data are shown in Table 1. The result shows a crystalline state.

[0184] Table 1 X-ray powder diffraction data

[0185] 2θ Relative intensity (I%) 5.4 2.2 10.2 73.1 11.1 56.9 11.5 50.7 12.6 68.8 13.2 47.7 14.4 6.0 15.0 24.2 16.4 37.0 16.9 61.2 18.0 69.7 19.3 51.4 20.4 99.6 21.8 17.9 22.1 21.1 23.8 99.5 24.2 5.2 24.8 34.5 25.7 100.0 26.4 24.9 27.1 3.7 27.7 4.0 28.3 2.1 28.7 3.5 29.9 4.9 31.7 6.3 32.3 6.4 34.1 2.4 34.9 7.9

[0186] 2. The Fourier transform infrared spectroscopy result is as shown in Figure 2 and is as follows.

[0187] 3. The thermogravimetric analysis result Figure 3 is as shown. The result shows an anhydrous substance.

[0188] 4. The differential scanning calorimetry result Figure 4 is as shown. The result shows a melting point of 177 °C (peak temperature).

[0189] Example 2

[0190] At 40 °C, take about 65.0 g of donepezil and add it to 150 mL of ethanol to form a suspension. Take about 39.5 g of 1-hydroxy-2-naphthoic acid and add it to 400 mL of ethanol to form a solution. Add the acid solution to the donepezil suspension, stir to crystallize, after about 20 minutes of slurry at 40 °C, cool to room temperature, a large amount of solid precipitates. Add 400 mL of ethanol and continue slurry for 2 days, then filter by suction, and vacuum dry at room temperature for 4 days to obtain crystalline form A of donepezil 1-hydroxy-2-naphthoate, with a yield of 93%.

[0191] Take the sample of Example 2 for characterization, as follows:

[0192] 1. The X-ray powder diffraction pattern is as shown in Figure 5 and the X-ray powder diffraction data are shown in Table 2. The result shows a crystalline state.

[0193] 2. The Fourier transform infrared spectroscopy result is as shown in Figure 6 and is as follows.

[0194] 3. The thermogravimetric analysis result is as shown inFigure 7 As shown, the result shows an anhydrous form.

[0195] 4. The results of differential scanning calorimetry are as Figure 8 shown. The result shows that the melting point is 177 °C (peak temperature).

[0196] Table 2 X-ray powder diffraction data

[0197]

[0198]

[0199] Example 3

[0200] 50.2 mg of donepezil and 30.4 mg of 1-hydroxy-2-naphthoic acid were taken, and after adding 0.5 mL of dichloromethane to form a solution, 0.8 mL of n-heptane was added, and the mixture was stirred for crystallization. After 3 days, it was centrifuged and dried in a blast dryer at 40 °C for 24 hours to obtain crystalline form A of donepezil 1-hydroxy-2-naphthoate.

[0201] The sample of Example 3 was characterized as follows:

[0202] 1. The X-ray powder diffraction pattern is as Figure 9 shown, and the X-ray powder diffraction data are shown in Table 3. The result shows a crystalline state.

[0203] 2. The results of Fourier transform infrared spectroscopy are as Figure 10 Figure 10 shown.

[0204] 3. The results of thermogravimetric analysis are as Figure 11 shown. The result shows an anhydrous form.

[0205] 4. The results of differential scanning calorimetry show that the melting point is 170 °C.

[0206] Table 3 X-ray powder diffraction data

[0207]

[0208]

[0209] There are certain differences in the relative peak intensities of the XRPD patterns measured in Example 3 compared with those measured in Example 1 and Example 2 (individual ones > 20%), which is due to the preferred orientation of the crystals caused by different crystallization methods. It is a common phenomenon that there are large differences in the relative peak intensities of the samples directly tested without grinding.

[0210] Example 4

[0211] Hygroscopicity Experiment of Crystal Form A of Donepezil 1-Hydroxy-2-naphthoate

[0212] Take about 18 mg of crystal form A of donepezil 1-hydroxy-2-naphthoate prepared in Example 1 and test its hygroscopicity using a dynamic vapor sorption instrument. The spectrum is as shown in Figure 12 shown, and the data are shown in Table 4.

[0213] Table 4 Results of Hygroscopicity Experiment

[0214] Crystal form Weight gain at 0% - 80% relative humidity 1-Hydroxy-2-naphthoate crystal form A 0.18％

[0215] Regarding the description of hygroscopicity characteristics and the definition of hygroscopic weight gain (refer to the General Principles of Drug Hygroscopicity Test, General Chapter 9103 of the Chinese Pharmacopoeia (2020 Edition)):

[0216] Deliquescence: Absorbing sufficient moisture to form a liquid;

[0217] Highly hygroscopic: The hygroscopic weight gain is not less than 15%;

[0218] Hygroscopic: The hygroscopic weight gain is less than 15% but not less than 2%;

[0219] Slightly hygroscopic: The hygroscopic weight gain is less than 2% but not less than 0.2%;

[0220] Non-hygroscopic or almost non-hygroscopic: The hygroscopic weight gain is less than 0.2%.

[0221] The results show that crystal form A of donepezil 1-hydroxy-2-naphthoate has a weight gain of 0.18% after equilibration at 80% relative humidity. According to the hygroscopicity definition standard, it shows non-hygroscopic or almost non-hygroscopic. This indicates that during the production and storage of drugs, it can maintain stability without strict humidity control, has low requirements for the preparation process and storage conditions, and has strong application value.

[0222] Example 5

[0223] Stress Testing of Crystal Form A of Donepezil 1-Hydroxy-2-naphthoate

[0224] Take the sample of crystal form A of donepezil 1-hydroxy-2-naphthoate prepared in Example 1 and place it under the conditions of high temperature (60°C ± 2°C / closed), high humidity (25°C ± 2°C / 97% RH ± 2% RH / open), and strong light irradiation (25°C ± 2°C / sunlight illuminance of 4500 Lux ± 500 Lux / ultraviolet irradiance of 0.8 W / m 2 , closed). After setting the time, take samples to measure X-ray powder diffraction and purity. The results are shown in Figure 13 and Table 5 respectively.

[0225] Table 5 Results of Stress Testing

[0226]

[0227] The results showed that: under all the above experimental conditions, the crystal form of the crystalline form A sample of donepezil 1-hydroxy-2-naphthoate remained unchanged, and the purity characterized by HPLC did not show an obvious decrease, indicating its excellent stability.

[0228] Example 6

[0229] Processability of the crystalline form A preparation of donepezil 1-hydroxy-2-naphthoate

[0230] Take the crystalline form A sample of donepezil 1-hydroxy-2-naphthoate prepared in Example 1, add it to a pH 7.0 citric acid buffer solution containing Tween 20 and PEG4000, stir to obtain a crude suspension, after dispersing evenly, homogenize at a high shear of 15000 rpm for 4 min, then pass through a 60-mesh sieve, and perform microfluidic homogenization. A micron suspension can be obtained by homogenizing at 1000 bar for 5 times, 1500 bar for 2 times, and 2000 bar for 2 times. Take 1 mL of the micron suspension for centrifugation, discard the supernatant, and perform X-ray powder diffraction on the precipitate ( Figure 14 ). The results showed that: the crystal form of 1-hydroxy-2-naphthoate crystalline form A remained unchanged after preparation processes such as high shear homogenization and microfluidic homogenization, indicating its good processability for preparation.

[0231] Comparative example 1

[0232] Comparative study on mechanical stability

[0233] Respectively place the crystalline form A of donepezil pamoate (the preparation method is shown in Preparation Example 1 below) and the crystalline form A of donepezil 1-hydroxy-2-naphthoate prepared in Example 1 of the present invention in a mortar and manually grind for 10 min. X-ray powder diffraction tests are carried out before and after grinding. The X-ray powder diffraction patterns of the crystalline form A of pamoate and the crystalline form A of 1-hydroxy-2-naphthoate before and after grinding are shown in Figure 15 and Figure 16 ,

[0234] The results showed that: the crystallinity of the crystalline form A of donepezil pamoate decreased significantly after grinding, while the crystal form and crystallinity of the crystalline form A of 1-hydroxy-2-naphthoate remained unchanged before and after grinding, indicating that the crystalline form A of 1-hydroxy-2-naphthoate has good mechanical stability.

[0235] Comparative example 2

[0236] Comparative study on stability

[0237] The crystalline form A of donepezil 1-hydroxy-2-naphthoate prepared in Example 1 of the present invention and the amorphous 1-hydroxy-2-naphthoate prepared in Preparation Example 6 were separately placed open in long-term (25°C / 60% RH) and accelerated (40°C / 75% RH) conditions. Samples were taken at 5 days, 1 month, and 6 months respectively for HPLC purity detection and X-ray powder diffraction detection. Among them, the amorphous 1-hydroxy-2-naphthoate underwent a crystalline form transformation after being placed for 5 days under accelerated conditions. Therefore, sampling and detection were only carried out at 5 days. The experimental results are as Figure 17 , Figure 18 , Figure 19 , Figure 20 and shown in Table 6.

[0238] Table 6 Stability data

[0239]

[0240]

[0241] Note: N / A indicates that no sampling was carried out for relevant detection

[0242] The results show that: for the crystalline form A of 1-hydroxy-2-naphthoate, there were no obvious changes in HPLC purity and crystalline form after being placed open for 6 months under long-term and accelerated conditions. The amorphous 1-hydroxy-2-naphthoate underwent a crystalline form transformation after being placed for 6 months under long-term conditions and 5 days under accelerated conditions, indicating that 1-hydroxy-2-naphthoate has good crystalline form stability.

[0243] Comparative example 3

[0244] Comparative study on equilibrium solubility

[0245] At 37°C, samples of commercially available donepezil free base, crystalline form A of donepezil pamoate (the preparation method is shown in Preparation Example 1 below), crystalline form A of donepezil 1-hydroxy-2-naphthoate prepared in Example 1 of the present invention, amorphous 1-hydroxy-2-naphthoate, and other salt forms obtained by the present inventor (the preparation methods are shown in Preparation Examples 2-5 below) were separately added to pH 7.0 phosphate buffer (simulating the pH value of normal muscle tissue) and pH 5.0 phosphate buffer (simulating the pH value of local muscle tissue at the injection site after intramuscular injection). After 24 hours, the content of donepezil in the solution was determined by HPLC. The experimental results are shown in Table 7.

[0246] Table 7 Solubility data

[0247]

[0248]

[0249] Note: N / A indicates that X-ray powder diffraction was not performed after the solubility test to investigate whether the crystal form changed.

[0250] The results showed that crystalline form A of donepezil pamolate had significantly lower solubility compared to amorphous donepezil pamolate, free base, and other salt forms, and the solubility was pH-independent, indicating its suitability for the development of long-acting injectable sustained-release formulations and that it would not dissolve into the bloodstream in a short time due to pH changes at the intramuscular injection site; furthermore, its crystal form remained unchanged before and after the solubility test, indicating excellent stability of its crystal form.

[0251] Comparative example 4

[0252] Comparative study on the stability of formulations

[0253] Crystalline samples with substantially the same D[4,3] (formulations 1 and 2) were prepared from crystalline form A of donepezil pamolate (the preparation method is shown in Preparation Example 1 below) and crystalline form A of donepezil 1-hydroxy-2-naphthoate of the present invention (the preparation method is shown in Example 1), respectively. The preparation method is as follows.

[0254] Formulation 1: Prepare 50 mL of pH 7.0 citrate-sodium dihydrogen phosphate buffer containing Tween 20 (0.2% Tween 20, 2% PEG4000, 0.75% citric acid monohydrate, 0.678% sodium dihydrogen phosphate dihydrate, 0.54% sodium hydroxide, w / v). Take 2 g of crystalline form A of donepezil pamolate and add it to the above solution. After magnetic stirring at 800 rpm for 15 min, use a high-shear homogenizer to homogenize at 15000 rpm for 4 min to obtain a coarse suspension. After passing through a 60-mesh sieve, use a microfluidic homogenizer to homogenize at 1000, 1500, and 2000 bar for 5, 2, and 2 cycles respectively to obtain Formulation 1;

[0255] Formulation 2: Prepare 50 mL of pH 7.0 citrate-sodium dihydrogen phosphate buffer containing Tween 20 (0.2% Tween 20, 2% PEG4000, 0.75% citric acid monohydrate, 0.678% sodium dihydrogen phosphate dihydrate, 0.54% sodium hydroxide, w / v). Take 2 g of crystalline form A of 1-hydroxy-2-naphthoate and add it to the above solution. After magnetic stirring at 800 rpm for 15 min, use a high-shear homogenizer to homogenize at 15000 rpm for 4 min to obtain a coarse suspension. After passing through a 60-mesh sieve, use a microfluidic homogenizer to homogenize at 1000 bar for 5 cycles to obtain Formulation 2;

[0256] The prepared crystalline samples (Formulations 1 and 2) were placed at 40 °C / 75% RH for 2 months to investigate the change in the particle size distribution of each sample.

[0257] The experimental results are shown in Table 8. It should be noted that D[4,3] refers to the "mass moment volume average particle size", and the calculation formula of D[4,3] is ∑(n i ×d i 4 ) / ∑(n i ×d i 3 ), where n i is the number of particles in a certain particle size range, and d i is the average particle size of this range.

[0258] Table 8 Formulation Stability Data

[0259]

[0260] The results show that: under the conditions of 40 °C / 75% RH for 2 months, the D[4,3] of the microcrystalline sample of pamorate polymorph A has increased significantly, while the microcrystalline sample of 1-hydroxy-2-naphthoate polymorph A of the present invention has no obvious change compared with day 0.

[0261] Example 6

[0262] Other Preparation Methods of 1-Hydroxy-2-naphthoate Polymorph A

[0263] Starting from 1-hydroxy-2-naphthoate polymorph A or 1-hydroxy-2-naphthoate amorphous, crystals are prepared by 8 methods including room temperature crystal slurry, anti-solvent addition, 50 °C crystal slurry, cyclic heating and cooling suspension stirring, gas-liquid diffusion, polymer template, gas-solid diffusion, and cooling crystallization. The obtained crystals are detected by X-ray powder diffraction, and it is proved that all the above methods obtain 1-hydroxy-2-naphthoate polymorph A.

[0264] The preparation process is as follows:

[0265] 1. Room temperature crystal slurry: Take 49.3 mg of donepezil 1-hydroxy-2-naphthoate amorphous, add 0.5 mL of methanol to form a suspension, perform room temperature crystal slurry (magnetic stirring) for 5 days, centrifuge, and vacuum dry at room temperature for 1 day to obtain donepezil 1-hydroxy-2-naphthoate polymorph A.

[0266] 2. 50 °C crystal slurry: Take 50.1 mg of donepezil 1-hydroxy-2-naphthoate polymorph A, add 1 mL of toluene to form a suspension, perform crystal slurry at 50 °C (magnetic stirring) for 5 days, centrifuge, and vacuum dry at room temperature for 4 days to obtain donepezil 1-hydroxy-2-naphthoate polymorph A.

[0267] 3. Cyclic heating and cooling with suspension stirring: Take 50.2 mg of donepezil 1-hydroxy-2-naphthoate crystal form A, add 1 mL of 1,4-dioxane to form a suspension, place it in a temperature range of 50 °C to 5 °C, and perform cyclic heating and cooling with magnetic stirring for 3 days. Then centrifuge and vacuum dry at room temperature for 1 day to obtain donepezil 1-hydroxy-2-naphthoate crystal form A.

[0268] 4. Anti-solvent addition: Take 49.61 mg of amorphous donepezil 1-hydroxy-2-naphthoate, add 0.5 mL of tetradimethyl sulfoxide to form a clear solution, add 3.0 mL of methyl tert-butyl ether, stir for crystallization. After 5 days, centrifuge and vacuum dry at room temperature for 1 day to obtain donepezil 1-hydroxy-2-naphthoate crystal form A.

[0269] 5. Gas-liquid diffusion: Take 30.0 mg of donepezil 1-hydroxy-2-naphthoate crystal form A, add 1.0 mL of tetrahydrofuran to form a clear solution, and place it in an atmosphere of ethyl acetate and let it stand for 14 days to obtain donepezil 1-hydroxy-2-naphthoate crystal form A.

[0270] 6. Polymer template: Take 20.0 mg of donepezil 1-hydroxy-2-naphthoate crystal form A and 2 mg of polyvinyl alcohol, add 1.0 mL of dichloromethane, and let it volatilize through small holes at room temperature for 6 days. Then collect the solid to obtain donepezil 1-hydroxy-2-naphthoate crystal form A.

[0271] 7. Gas-solid diffusion: Take 20.4 mg of donepezil 1-hydroxy-2-naphthoate crystal form A and place it in an atmosphere of acetone and let it stand for 6 days to obtain donepezil 1-hydroxy-2-naphthoate crystal form A.

[0272] 8. Cooling crystallization: Take 30.2 mg of donepezil 1-hydroxy-2-naphthoate crystal form A, dissolve it in a mixed solvent of dimethyl sulfoxide / n-butyl acetate at 50 °C, transfer it to 5 °C and stir. After precipitating solids, centrifuge to separate the solids and dry to obtain donepezil 1-hydroxy-2-naphthoate crystal form A.

[0273] By the above methods, donepezil 1-hydroxy-2-naphthoate crystal form A can also be obtained using the solvents shown in Table 9.

[0274] Table 9 Summary of conditions for preparing 1-hydroxy-2-naphthoate

[0275]

[0276] Note: Solvent 1 is the solvent used in the above preparation process.

[0277] Preparation example 1

[0278] Preparation of pamorate crystal form A

[0279] The pamorate polymorph A sample was prepared by referring to the method of Example 4 of CN104039765B.

[0280] Preparation example 2

[0281] Preparation of 1,5-naphthalenedisulfonate polymorph B

[0282] After adding 50.1 mg of donepezil to 0.5 mL of dichloromethane to form a solution, 23.2 mg of 1,5-naphthalenedisulfonic acid was added to the donepezil solution. A large amount of solid precipitated. Then, 2 mL of dichloromethane was added, and the mixture was stirred suspension at room temperature for 5 days, centrifuged, and dried in a blast dryer at 40 °C for 24 hours to obtain 1,5-naphthalenedisulfonate polymorph B.

[0283] 1. The X-ray diffraction pattern is as Figure 21 shown.

[0284] 2. The thermogravimetric analysis results are as Figure 22 shown.

[0285] Preparation example 3

[0286] Preparation of sebacate polymorph A

[0287] At 50 °C, 500.3 mg of donepezil was taken and added to 0.5 mL of ethanol to form a suspension. 266.7 mg of sebacic acid was taken and added to 2.0 mL of ethanol to form a solution. The acid solution was added to the donepezil suspension to obtain a clear solution. After cooling to room temperature, 7.8 mL of ultrapure water was added, and the mixture was stirred for crystallization. After continuing the crystal slurry for 1 day, it was centrifuged and dried in a vacuum at room temperature for 1 day to obtain sebacate polymorph A.

[0288] 1. The X-ray diffraction pattern is as Figure 23 shown.

[0289] 2. The thermogravimetric analysis results are as Figure 24 shown.

[0290] Preparation example 4

[0291] Preparation of glutarate polymorph A

[0292] At 50 °C, 500.3 mg of donepezil was taken and added to 0.5 mL of dimethyl sulfoxide to form a suspension. 276.8 mg of glutaric acid was taken and added to 2.0 mL of dimethyl sulfoxide to form a solution. The acid solution was added to the donepezil suspension to obtain a clear solution. After cooling to room temperature, glutarate polymorph A seeds were added, and the mixture was stirred for crystallization. After continuing the crystal slurry for 1 day, it was centrifuged and dried in a vacuum at 60 °C for 1 day to obtain glutarate polymorph A.

[0293] 1. The X-ray diffraction pattern is as Figure 25 shown.

[0294] 2. The thermogravimetric analysis results are as follows Figure 26 shown

[0295] Preparation example 5

[0296] Preparation of Adipate Crystal Form A

[0297] Take 100.0 mg of donepezil, add 1.0 mL of ethyl acetate to form a suspension. Take 46.2 mg of adipic acid, add 3.0 mL of ethyl acetate to form a solution. Add the acid solution to the donepezil suspension. After 2 days of the crystal slurry, centrifuge and vacuum dry at room temperature for 3 days to obtain adipate crystal form A

[0298] 1. The X-ray diffraction pattern is as follows Figure 27 shown

[0299] 2. The thermogravimetric analysis results are as follows Figure 28 shown

[0300] Preparation example 6

[0301] Preparation of 1-Hydroxy-2-naphthoate Amorphous

[0302] Take 2000.9 mg of the donepezil 1-hydroxy-2-naphthoate crystal form A sample prepared in Example 1, add 360 mL of a mixed solvent of acetonitrile and water to dissolve it clearly, filter, and place it in a freeze dryer to freeze-dry for 4 days. Obtain a donepezil 1-hydroxy-2-naphthoate amorphous sample

[0303] 1. The X-ray diffraction pattern is as follows Figure 29 shown

[0304] 2. The thermogravimetric analysis results are as follows Figure 30 shown

Claims

1. Form A of donepezil 1-hydroxy-2-naphthoate, the structural formula of donepezil 1-hydroxy-2-naphthoate is as follows, wherein: The molar ratio of donepezil to 1-hydroxy-2-naphthoic acid is 1:1; Using Cu-Кα radiation, the X-ray powder diffraction pattern expressed in 2θ angle has the following characteristic peaks: 10.2°±0.2°, 11.1°±0.2°, 12.6°±0.2°, 15.0°±0.2° and 25.7°±0.2°.

2. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to claim 1, wherein the relative intensities of the characteristic peaks are as follows: 。 3. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to claim 1 or 2, which has characteristic peaks at one or more of the following positions in an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Кα radiation: 11.5°±0.2°, 13.2°±0.2°, 18.0°±0.2°, 20.4°±0.2° and 23.8°±0.2°.

4. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to claim 3, wherein the relative intensities of the characteristic peaks are as follows:

5. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to claim 3 or 4, which has characteristic peaks at one or more of the following positions in an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Кα radiation: 5.4°±0.2°, 16.4°±0.2°, 16.9°±0.2°, 19.3°±0.2° and 24.8°±0.2°.

6. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to claim 5, wherein the relative intensities of the characteristic peaks are as follows: 。 7. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 6, having an X-ray powder diffraction pattern substantially as shown in Figure 1, Figure 5 or Figure 9.

8. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 7, wherein in its Fourier transform infrared spectrum, at a wavelength selected from 1686 cm -1 ±4cm -1 、1591cm -1 ±4cm -1 、1499cm -1 ±4cm -1 、1315cm -1 ±4cm -1 、1259cm -1 ±4cm -1 、1039cm -1 ±4cm -1 、1403cm-1±4cm -1 、1218cm -1 ±4cm -1 、1019cm-1±4cm -1 、958cm -1 ±4cm -1 and 923cm -1 ±4cm -1 At least one of them has a characteristic peak.

9. The crystalline form A of donepezil 1-hydroxy-2-naphthoate of claims 1-8, having a Fourier transform infrared spectrum substantially as shown in Figure 2, Figure 6 or Figure 10.

10. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 9, which has a weight loss of 0.03% to 0.2% before 100°C in a thermogravimetric analysis spectrum.

11. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 10, having a thermogravimetric analysis spectrum substantially as shown in FIG. 3, FIG. 7 or FIG.

11.

12. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 11, having a melting point of 170°C to 177°C as measured by differential scanning calorimetry.

13. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to claim 12, having a differential scanning calorimetry analysis spectrum substantially as shown in FIG. 4 or FIG.

8. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 13, which is an anhydrate.

15. The crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 15, which has a weight gain of less than 0.2% under 0% RH to 80% RH, for example, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, preferably 0.18%.

16. The crystalline Form A of donepezil 1-hydroxy-2-naphthoate of claim 15, having a dynamic vapor sorption spectrum substantially as shown in Figure 12.

17. A method for preparing the crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 16, comprising the following steps: Donepezil and 1-hydroxy-2-naphthoic acid are respectively placed in a good solvent at a certain temperature to form a suspension or solution, mixed, slurried, and the precipitated crystals are separated and dried to obtain the crystalline form A of donepezil 1-hydroxy-2-naphthoic acid salt; Preferably, the temperature for forming the suspension or solution is 30 to 60°C, more preferably 40 to 50°C; Preferably, the donepezil and 1-hydroxy-2-naphthoic acid are prepared by using the same good solvent to form a solution; Preferably, the good solvent is an alcohol (e.g., methanol, ethanol, n-propanol, sec-butanol), an ester (e.g., n-butyl acetate, isopropyl acetate, ethyl acetate) or toluene; Preferably, the good solvent is methanol, ethanol, n-propanol or sec-butanol, more preferably ethanol; Preferably, the molar ratio of donepezil to 1-hydroxy-2-naphthoic acid is 1:0.7 to 1:1.5, more preferably 1:0.7 to 1:1.2; Preferably, the mass volume ratio (mg / mL) of donepezil to the total good solvent is 30 to 150, more preferably 50 to 80; Preferably, the mixing comprises adding a suspension or solution of 1-hydroxy-2-naphthoic acid to a suspension or solution of donepezil; Preferably, the slurry time is 1 to 7 days; more preferably 2 to 4 days; Preferably, the good solvent can be added during the slurry process; Preferably, the temperature can be lowered during the slurry process; Preferably, the drying temperature is room temperature, and the drying time is 1 to 5 days (e.g., 4 days); Preferably, the slurry process includes: slurrying under heating conditions (for example, 30-60°C, more preferably 40-50°C) for a certain period of time (for example, less than 1 hour) to cool to room temperature, precipitating solid, adding good solvent, and continuing slurrying for a certain period of time (for example, 2-4 days).

18. A method for preparing the crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 16, comprising the following steps: The mixture of donepezil and 1-hydroxy-2-naphthoic acid is dissolved in a good solvent, an antisolvent is added, and the mixture is stirred for crystallization, and the crystals are separated and dried to obtain the crystalline form A of donepezil 1-hydroxy-2-naphthoic acid salt; Preferably, the good solvent is dichloromethane, chloroform, dimethyl sulfoxide or ketones (such as acetone or butanone), more preferably dichloromethane; Preferably, the mass volume ratio (mg / mL) of donepezil to good solvent is 10 to 120, more preferably 50 to 120; Preferably, the molar ratio of donepezil to 1-hydroxy-2-naphthoic acid is 1:0.8 to 1:1.5, more preferably 1:0.8 to 1:1.2; Preferably, the antisolvent is an alkane or water, preferably n-hexane, cyclohexane, methylcyclohexane, n-heptane or water, more preferably n-heptane; Preferably, the volume ratio of the good solvent to the antisolvent is 0.5 to 10, more preferably 1 to 5; Preferably, the good solvent and antisolvent are selected from the following combinations: Preferably, the stirring time is 1 to 5 days; Preferably, the operating temperature of forming the solution, stirring the crystallization and separating the crystals is 10 to 40° C., more preferably room temperature; Preferably, the drying temperature is 10-50° C., and the drying time is 1-5 days.

19. A method for preparing the crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 16, comprising using donepezil 1-hydroxy-2-naphthoate as a starting material and adopting any method selected from room temperature slurry, 50° C. slurry, cyclic heating and cooling suspension stirring, antisolvent addition, gas-liquid diffusion, polymer template, gas-solid diffusion and cooling crystallization to prepare the crystalline form A of donepezil 1-hydroxy-2-naphthoate.

20. A pharmaceutical composition comprising a preventively or therapeutically effective amount of the crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 16; optionally further comprising at least one pharmaceutically acceptable carrier.

21. The pharmaceutical composition of claim 20, which is an injection, such as a long-acting injection; the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

22. Use of the crystalline form A of donepezil 1-hydroxy-2-naphthoate according to any one of claims 1 to 16 in the preparation of a medicament for preventing or treating diseases or physiological dysfunction caused by low acetylcholine levels, such as Alzheimer's disease, attention deficit disorder in children, memory loss, parkinsonism, brain injury, multiple sclerosis, Down syndrome, delirium, mood disorders, Huntington's disease, and sleep disorders; Preferably, the crystalline form A of donepezil 1-hydroxy-2-naphthoate is used in combination with other active pharmaceutical ingredients.

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