Crystal form i of aminoarteether maleate and preparation method therefor

Abstract

Disclosed in the present invention are new crystal form I of aminoarteether maleate, and a preparation method therefor and the use thereof. The preparation method therefor has the advantages of easy repeatability, process controllability, simple operation, etc., and can be used for large-scale production and application.

Description

Artemether maleate crystal form I and preparation method thereof Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and more specifically, relates to a new crystal form I of artemetheramide maleate and a preparation method thereof. Background Art

[0002] Artemisinin, the active ingredient extracted from the traditional Chinese medicine Artemisia annua, is used to treat malaria and is my country's first independently developed and exported drug. In addition to antimalarial drugs, artemisinin and its derivatives are also used to treat diseases such as schistosomiasis, viral infections, cancer, and inflammation. However, traditional artemisinin-based drugs suffer from poor water solubility, which affects their oral bioavailability. To address this issue, several novel artemisinin derivatives have been synthesized. Among them, arteetheramide maleate is a low-toxic, highly effective, and water-soluble artemisinin derivative selected for its low toxicity and excellent water solubility. It is a Category 1.1 candidate new drug for the treatment of systemic lupus erythematosus. Summary of the Invention

[0003] This invention obtains a stable crystalline form I of artemisinin derivative arteetheramide maleate through different crystallization techniques and proposes a method for preparing this crystalline form. This preparation method has the advantages of easy reproducibility, controllable process, and simple operation, and can be used for large-scale production applications.

[0004] One object of the present invention is to provide a crystalline form I of artemisinin derivative arteetheramide maleate.

[0005] Another object of the present invention is to provide a method for preparing the artemisinin derivative arteetheramide maleate crystalline form I.

[0006] To achieve the object of the present invention, according to one aspect of the present invention, the present invention provides a stable crystalline form I of artemetheramide maleate, wherein the molar ratio of artemetheramide to maleic acid is 1:1.

[0007] According to one embodiment of the present invention, the unit cell parameters of the artemether maleate crystal form I are α=90°, β=113.402°, γ=90°, belonging to the P212121 space group.

[0008] According to one embodiment of the present invention, the maleic acid artemetheramine crystalline form I has a characteristic peak in the X-ray powder diffraction expressed in 2θ angles at one or more of the following diffraction angles: 4.7°±0.2°, 9.4°±0.2°, 9.9°±0.2°, 10.7°±0.2°, 11.2°±0.2°, 13.9°±0.2°, 16.2°±0.2°, 17.3°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 21.5°±0.2°, 22.0°±0.2°, 22.9°±0.2°, 23.8°±0.2°, 26.6°±0.2°, and 27.0°±0.2°.

[0009] According to another embodiment of the present invention, the maleic acid artemetheramine crystalline form I has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at one or more of the following diffraction angles: 4.7°±0.2°, 9.4°±0.2°, 9.9°±0.2°, 10.7°±0.2°, 11.2°±0.2°, 13.9°±0.2°, 18.6°±0.2°, 22.9°±0.2°, and 26.6°±0.2°.

[0010] According to one embodiment of the present invention, the artemether maleate crystalline form I has an X-ray powder diffraction pattern substantially as shown in FIG1 .

[0011] According to one embodiment of the present invention, the artemether maleate crystalline form I has a thermogravimetric analysis spectrum substantially as shown in FIG2 .

[0012] According to one embodiment of the present invention, the artemether maleate crystalline form I begins to melt at around 138°C.

[0013] According to one embodiment of the present invention, the infrared absorption spectrum of the artemether maleate crystal form I is at least at 3475 cm -1 、3340cm -1 、2906cm -1 、1947cm -1 、1612cm -1 , 1550cm -1 、1456cm -1 、939cm -1 、661cm -1 There is an absorption peak at.

[0014] According to one embodiment of the present invention, the artemether maleate crystalline form I has an infrared absorption spectrum substantially as shown in FIG3 .

[0015] According to one embodiment of the present invention, the artemether maleate crystalline form I has a dynamic moisture adsorption spectrum substantially as shown in FIG4 .

[0016] According to another aspect of the present invention, another object of the present invention is to provide a method for preparing the artemether maleate crystalline form I, which is selected from the following methods: suspension method, solution volatilization method, cooling method and anti-solvent precipitation method.

[0017] According to one embodiment of the present invention, the suspension method comprises the following steps:

[0018] S11, adding an excess of artemether maleate raw material to a single solvent or a mixed solvent, and stirring at a certain temperature;

[0019] S12, separating and drying the solid to obtain the artemetheramide maleate crystal form I.

[0020] Preferably, the temperature is 0-50°C, preferably 25-50°C;

[0021] Preferably, the stirring time is 0.1-48 h, preferably 8-24 h.

[0022] According to one embodiment of the present invention, in step S11 of the suspension method, the single solvent is selected from isoamyl alcohol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, methyl tert-butyl ether, methyl isobutyl ketone, dichloromethane, chloroform or isopropyl acetate.

[0023] Preferably, the mixed solvent is selected from the group consisting of acetone and methyl isobutyl ether, acetone and isopropyl acetate, chloroform and methyl isobutyl ether, chloroform and isopropyl acetate, methyl ethyl ketone and water, methyl ethyl ketone and methyl tert-butyl ether, acetonitrile and water, acetonitrile and methyl tert-butyl ether, acetonitrile and methyl isobutyl ketone, tetrahydrofuran and water, tetrahydrofuran and methyl isobutyl ketone, nitromethane and water, nitromethane and methyl tert-butyl ether, and nitromethane and methyl isobutyl ketone. The volume ratio of the two solvents in the mixed solvent may be 1:0.1 to 10, preferably 1:1 to 5, and more preferably 1:1.

[0024] According to one embodiment of the present invention, the solution volatilization method comprises the following steps:

[0025] S21. Fully dissolving excess artemetheramide maleate in a single solvent or a mixed solvent, and stirring at room temperature;

[0026] S22, filtering the suspension obtained in S21 and collecting the filtrate;

[0027] S23, solid-liquid separation, and slowly volatilizing the supernatant at room temperature to obtain the maleate artemetheramide crystal form I.

[0028] According to one embodiment of the present invention, in S21, the single solvent is selected from isoamyl alcohol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, methyl tert-butyl ether, methyl isobutyl ketone, dichloromethane, chloroform or isopropyl acetate.

[0029] Preferably, the mixed solvent is selected from the group consisting of acetone and methyl isobutyl ether, acetone and isopropyl acetate, chloroform and methyl isobutyl ether, chloroform and isopropyl acetate, methyl ethyl ketone and water, methyl ethyl ketone and methyl tert-butyl ether, acetonitrile and water, acetonitrile and methyl tert-butyl ether, acetonitrile and methyl isobutyl ketone, tetrahydrofuran and water, tetrahydrofuran and methyl isobutyl ketone, nitromethane and water, nitromethane and methyl tert-butyl ether, and nitromethane and methyl isobutyl ketone. The volume ratio of the two solvents in the mixed solvent may be 1:0.1 to 10, preferably 1:1 to 5, and more preferably 1:1.

[0030] According to one embodiment of the present invention, the cooling method comprises the following steps:

[0031] S31, dissolving excess artemether maleate in a single solvent or a mixed solvent, and stirring at a first temperature until completely dissolved;

[0032] S32, cooling the solution obtained in S31 at a second temperature lower than the first temperature to crystallize;

[0033] S33, solid-liquid separation, and drying to obtain the maleate artemetheramide crystal form I.

[0034] Preferably, in S31, the first temperature is 25-80°C, preferably 50-70°C;

[0035] Preferably, in S32, the second temperature is -20-25°C, preferably -20-0°C.

[0036] According to one embodiment of the present invention, in S21, the single solvent is selected from one or more of isoamyl alcohol, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, methyl tert-butyl ether, methyl isobutyl ketone, dichloromethane, chloroform, and isopropyl acetate.

[0037] Preferably, the mixed solvent is selected from the group consisting of acetone and methyl isobutyl ether, acetone and isopropyl acetate, chloroform and methyl isobutyl ether, chloroform and isopropyl acetate, methyl ethyl ketone and water, methyl ethyl ketone and methyl tert-butyl ether, acetonitrile and water, acetonitrile and methyl tert-butyl ether, acetonitrile and methyl isobutyl ketone, tetrahydrofuran and water, tetrahydrofuran and methyl isobutyl ketone, nitromethane and water, nitromethane and methyl tert-butyl ether, and nitromethane and methyl isobutyl ketone. The volume ratio of the two solvents in the mixed solvent may be 1:0.1 to 10, preferably 1:1 to 5, and more preferably 1:1.

[0038] According to one embodiment of the present invention, the antisolvent precipitation method comprises the following steps:

[0039] S41, weighing about 25 mg of artemether maleate raw material, adding organic solvent 1 to fully dissolve;

[0040] S42, slowly adding organic solvent 2 dropwise to the solution obtained in S41;

[0041] S43, allowing the mixture to stand for a period of time until a solid precipitates, and performing solid-liquid separation to obtain the artemetheramide maleate crystalline form;

[0042] Preferably, the organic solvent 1 is selected from one or more of acetone and chloroform;

[0043] Preferably, the organic solvent 2 is selected from one or more of isoamyl alcohol, methyl ethyl ketone, acetonitrile, tetrahydrofuran, nitromethane, methyl tert-butyl ether, methyl isobutyl ketone, dichloromethane, and isopropyl acetate.

[0044] In some embodiments, the present invention provides a pharmaceutical composition comprising any of the artemether maleate crystalline form I according to the present invention and a pharmaceutically acceptable carrier or diluent. Excipients, binders, lubricants, disintegrants, colorants, flavoring and olfactory correctives, emulsifiers, surfactants, solubilizers, suspending agents, isotonicity agents, buffers, preservatives, antioxidants, stabilizers, absorption enhancers, and the like commonly used in the pharmaceutical field may also be used in appropriate combinations as needed.

[0045] In some embodiments, the artemetheramide maleate crystalline form I and / or its pharmaceutical composition described in the present invention can be used to prepare a pharmaceutical composition for treating or preventing inflammatory autoimmune diseases such as lupus, dry eye, and enteritis. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following is a brief introduction to the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0047] FIG1 is an X-ray powder diffraction (XRPD) pattern of artemetheramide maleate crystalline form I of Example 1 of the present invention;

[0048] FIG2 is a thermogravimetric analysis (TGA) spectrum of artemether maleate crystalline form I of Example 1 of the present invention;

[0049] FIG3 is an infrared (IR) absorption spectrum of artemetheramide maleate crystalline form I of Example 1 of the present invention;

[0050] FIG4 is a dynamic moisture sorption (DVS) curve of artemether maleate crystalline form I of Example 1 of the present invention;

[0051] FIG5 is a plasma drug-time curve of artemetheramide maleate crystal form I of the present invention in Beagle dogs. DETAILED DESCRIPTION

[0052] The present invention will be described in detail below. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that allows the inventor to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are merely preferred examples for illustrative purposes and are not intended to limit the scope of the present invention. It should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0053] As used herein, the terms "comprises," "includes," "has," "contains" or any other similar terms are open conjunctions that are intended to cover non-exclusive inclusions. For example, a composition or article containing multiple elements is not limited to the elements listed herein, but may also include other elements that are not explicitly listed but are generally inherent to the composition or article. In addition, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" rather than an exclusive "or." For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist). In addition, as used herein, the terms "comprises," "includes," "has," and "contains" should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as "consisting of" and "consisting essentially of."

[0054] Throughout this document, all features or conditions defined as numerical ranges or percentage ranges are for simplicity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered to encompass and specifically disclose all possible subranges and individual values ​​within those ranges, particularly integer values. For example, a description of a range "1 to 8" should be considered to specifically disclose all possible subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and so forth, particularly those defined by all integer values, and should be considered to specifically disclose individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, and 8. Unless otherwise indicated, the foregoing interpretation applies to all of the present disclosure, regardless of whether the ranges are comprehensive or not.

[0055] If a quantity or other value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that all ranges consisting of any upper limit or preferred value of the range and any lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, when a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

[0056] In this document, numerical values ​​should be understood to have the accuracy of the number of significant digits of the numerical value, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0057] The following examples are merely examples of embodiments of the present invention and do not constitute any limitation thereto. Those skilled in the art will appreciate that modifications without departing from the spirit and scope of the present invention fall within the scope of protection of the present invention. Unless otherwise specified, the reagents and instruments used in the following examples are commercially available products.

[0058] Instruments and test methods

[0059] The X-ray powder diffraction patterns in the embodiments of the present invention were obtained using a Shimadzu XRD-6000 X-ray powder diffractometer, using Cu-Kα irradiation (40 kV, 40 mW), with a scanning range of 2θ in the range of 3°-40°, a scanning rate of 4° / min, and a scanning step size of 0.02° / s.

[0060] Thermogravimetric analysis was performed using a Netzsch TG 209F3 apparatus with a temperature range of 30–400 °C, a heating rate of 10 °C / min, a purge gas of 25 mL / min, and a protective gas of 15 mL / min.

[0061] Infrared absorption spectra were measured using a Nicolet-Magna FT-IR750 infrared spectrometer from Nicolet Corporation of the United States at room temperature in the detection range of 4000-500 cm -1 The wave number.

[0062] Dynamic moisture adsorption was performed using SMSDVS Intrinsic in a test range of -95% RH and a temperature of 25°C.

[0063] The single crystal structure was determined using a Bruker Smart Apex II X-ray single crystal diffractometer from Bruker Instruments, Germany, with a graphite monochromator and Mo-Kα radiation. Temperature: 100 K, voltage: 20 kV, current: 5 mA. Data reduction and structure elucidation for all single-crystal structures were performed using the SAINT-5.0 and SHELXTL-97 programs, respectively. Absorption correction was performed using the SADABS program, and the structures were refined using the full-matrix least-squares method. The coordinates of hydrogen atoms attached to nitrogen or oxygen atoms were added from the residual electron density map.

[0064] Example 1

[0065] 200 mg of artemether maleate raw material was weighed, 5 mL of methanol solvent was added, and the mixture was stirred at 25 ° C for 24 hours, followed by centrifugation and solid-liquid separation. The solid sample was slowly evaporated and dried in air for 10 minutes, and then XRPD detection was performed to obtain artemether maleate Form I. Structural analysis showed that it was a salt with a molar ratio of artemether to maleic acid of 1:1. Figure 1 is an X-ray powder diffraction (XRPD) pattern of artemether maleate Form I prepared in this example, Figure 2 is a thermogravimetric analysis (TGA) pattern of artemether maleate Form I prepared in this example; Figure 3 is an infrared (IR) absorption spectrum of artemether maleate Form I prepared in this example; Figure 4 is a dynamic moisture adsorption (DVS) curve of artemether maleate Form I prepared in this example.

[0066] The obtained artemether maleate crystalline form I has low hygroscopicity, which is beneficial to the stability and long-term storage of the sample. As shown in Figure 4, the absorption and desorption of water by artemether maleate crystalline form I is less than 0.25% in the range of 0 to 95% relative humidity at 25°C. According to the 2020 edition of the Chinese Pharmacopoeia, a drug with a moisture gain of less than 0.2% at 25°C and 80% RH is defined as having no or almost no hygroscopicity. The moisture gain of artemether maleate crystalline form I at 25°C and 80% RH is 0.1%, showing no or almost no hygroscopicity.

[0067] Example 2

[0068] About 50 mg of artemether maleate raw material was weighed, 1 mL of methanol solvent was added, and the mixture was stirred at 50° C. for 24 hours, followed by centrifugation for solid-liquid separation. The solid sample was slowly evaporated and dried in air to obtain artemether maleate crystal form I.

[0069] Example 3

[0070] About 25 mg of artemether maleate raw material was weighed, 1 mL of a 1:1 (v / v) mixed solvent of acetone and isopropyl acetate was added, and stirred at 25°C for 24 hours, followed by centrifugation for solid-liquid separation. The solid sample was slowly evaporated and dried in air to obtain artemether maleate Form I.

[0071] Example 4

[0072] About 25 mg of artemether maleate raw material was weighed, and 1 mL of a 1:1 (v / v) mixed solvent of acetone and isopropyl acetate was added and stirred at 50°C for 24 hours. The mixture was then centrifuged to separate the solid and liquid. The solid sample was slowly evaporated and dried in air to obtain artemether maleate Form I.

[0073] Example 5

[0074] About 25 mg of artemether maleate raw material was weighed, and 1 mL of a mixed solvent of acetone and methyl isobutyl ketone (1:1 (v / v)) was added and stirred at 25°C for 24 hours. The mixture was then centrifuged to separate the solid and liquid. The solid sample was slowly evaporated and dried in air to obtain artemether maleate Form I.

[0075] Example 6

[0076] About 25 mg of artemether maleate raw material was weighed, 1 mL of a 1:1 (v / v) mixed solvent of chloroform and isopropyl acetate was added, and stirred at 25°C for 24 hours. The mixture was then centrifuged to separate the solid and liquid. The solid sample was slowly evaporated and dried in air to obtain artemether maleate Form I.

[0077] Example 7

[0078] An appropriate amount of artemether maleate raw material was weighed, and 1 mL of a mixed solvent of acetone and water in a ratio of 1:1 (v / v) was added. The mixture was ultrasonicated for 10 min to fully dissolve the mixture. The supernatant was then filtered and slowly evaporated in a fume hood to obtain artemether maleate Form I.

[0079] Example 8

[0080] An appropriate amount of artemether maleate raw material was weighed, and 1 mL of a 1:1 (v / v) mixed solvent of tetrahydrofuran and methyl tert-butyl ether was added. The mixture was ultrasonicated for 10 min to completely dissolve the mixture. The supernatant was then filtered and slowly evaporated in a fume hood to obtain artemether maleate Form I.

[0081] Example 9

[0082] An appropriate amount of artemether maleate raw material was weighed, and 1 mL of a 1:1 (v / v) mixed solvent of isopropyl acetate and methyl isobutyl ketone was added. The mixture was ultrasonicated for 10 min to completely dissolve the mixture. The supernatant was then filtered and slowly evaporated in a fume hood to obtain artemether maleate Form I.

[0083] Example 10

[0084] An appropriate amount of artemether maleate raw material was weighed, 1 mL of acetone was added, and the mixture was stirred at 60° C. to completely dissolve the mixture, and then stirred at room temperature. After a period of time, a solid was precipitated to obtain the artemether maleate crystal form I.

[0085] Example 11

[0086] An appropriate amount of artemether maleate raw material was weighed, 1 mL of tetrahydrofuran was added, and the mixture was stirred at 60° C. to completely dissolve, and then stirred at room temperature. After a period of time, solid was precipitated to obtain the artemether maleate crystal form I.

[0087] Example 12

[0088] An appropriate amount of artemether maleate raw material was weighed, 1 mL of acetonitrile was added, and the mixture was stirred at 60° C. to completely dissolve the mixture, and then stirred at room temperature. After a period of time, a solid was precipitated to obtain the artemether maleate crystal form I.

[0089] Example 13

[0090] An appropriate amount of artemether maleate raw material was weighed, 1 mL of methyl isobutyl ketone was added, and the mixture was stirred at 60°C to fully dissolve, and then cooled at 4°C for crystallization to obtain artemether maleate Form I.

[0091] Example 14

[0092] An appropriate amount of artemether maleate raw material was weighed, 1 mL of nitromethane was added, and the mixture was stirred at 60° C. to fully dissolve, and then cooled at 4° C. to crystallize to obtain artemether maleate Form I.

[0093] Example 15

[0094] About 25 mg of artemether maleate was weighed and dissolved in acetone. Subsequently, 2 mL of isopropyl acetate was slowly added along the wall. After standing for a period of time, solid precipitated to obtain the artemether maleate crystal form I.

[0095] Example 16

[0096] About 25 mg of artemether maleate was weighed and dissolved in acetone. Subsequently, 2 mL of isoamyl alcohol was slowly added along the wall. After standing for a period of time, solid precipitated to obtain the artemether maleate crystal form I.

[0097] Example 17

[0098] About 25 mg of artemether maleate was weighed and dissolved in acetone. Subsequently, 2 mL of acetonitrile was slowly added along the wall. After standing for a period of time, solid precipitated to obtain the artemether maleate crystal form I.

[0099] Test Example 1

[0100] Pharmacokinetic properties of artemether maleate form I were evaluated in Beagle dogs.

[0101] Female Beagle dogs were divided into two groups (3 dogs per group) and administered either 2.5 mg / kg intravenously or 2.5 mg / kg po of Artemether Maleate Form I. Before and after administration, approximately 0.6 mL of blood was collected from the forelimb vein under non-anesthesia into tubes pre-anticoagulated with heparin. Blood was collected at 0, 5, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, and 24 hours. Plasma was prepared by centrifugation and stored at -70°C until analysis.

[0102] HPLC-MS Analysis: A high-performance liquid chromatography-mass spectrometry (LC / MS / MS) system consisted of an Agilent 1100 series liquid chromatograph (Germany) and a Thermo Finnigan TSQ Quantum triple-stage quadrupole mass spectrometer (MS / MS). The system software was controlled by Chemstation (HPLC) and Xcalibur (USA), respectively. Chromatographic separation conditions for quantitative analysis of plasma were used. The column was an Agilent Eclipse Plus C18 column (50 mm × 2.1 mm ID, 5 μm); the mobile phase was: solvent A: CH3CN-H2O (1:99, v / v; 1 mM HCOOH); solvent B: CH3CN-H2O (99:1, v / v; 1 mM HCOOH); the flow rate was 0.35 mL / min, and the injection volume was 5 μL.

[0103] The average oral bioavailability of artemether maleate form I in Beagle dogs after oral administration was 42%.

[0104] Pharmacokinetic parameters after administration in Beagle dogs

[0105] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A crystalline form I of artemetheramide maleate, wherein the molar ratio of artemetheramide to maleic acid is 1:1, wherein the crystalline form I of artemetheramide maleate has characteristic peaks in X-ray powder diffraction expressed in 2θ degrees at one or more of the following diffraction angles: 4.7°±0.2°, 9.4°±0.2°, 9.9°±0.2°, 10.7°±0.2°, 11.2°±0.2°, 13.9°±0.2°, 18.6°±0.2°, 22.9°±0.2°, and 26.6°±0.2°.

2. The crystalline form I of artemetheramide maleate according to claim 1, characterized in that The unit cell parameters of the artemether maleate crystal form I are α=90°, β=113.402°, γ=90°, belonging to the P212121 space group.

3. The crystalline form I of artemetheramide maleate according to claim 1, characterized in that The maleate artemetheramine crystalline form I has characteristic peaks in X-ray powder diffraction expressed in 2θ angles at one or more of the following diffraction angles: 4.7°±0.2°, 9.4°±0.2°, 9.9°±0.2°, 10.7°±0.2°, 11.2°±0.2°, 13.9°±0.2°, 16.2°±0.2°, 17.3°±0.2°, 18.6°±0.2°, 19.2°±0.2°, 21.5°±0.2°, 22.0°±0.2°, 22.9°±0.2°, 23.8°±0.2°, 26.6°±0.2°, and 27.0°±0.2°.

4. The crystalline form I of artemetheramide maleate according to claim 1, characterized in that The artemetheramine maleate crystalline form I has an X-ray powder diffraction pattern substantially as shown in FIG1 ; Preferably, the artemether maleate crystalline form I has a thermogravimetric analysis spectrum substantially as shown in FIG2 ; Preferably, the artemether maleate crystalline form I begins to melt at about 138°C; Preferably, the infrared absorption spectrum of the artemetheramine maleate crystal form I is at least at 3475 cm -1 、3340cm -1 、2906cm -1 、1947cm -1 、1612cm -1 , 1550cm -1 、1456cm -1 、939cm -1 、661cm -1 There is an absorption peak at Preferably, the artemether maleate crystalline form I has an infrared absorption spectrum substantially as shown in FIG3 ; Preferably, the artemether maleate crystalline form I has a dynamic moisture adsorption pattern substantially as shown in FIG4 .

5. A pharmaceutical composition comprising the artemether maleate crystalline form I according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier, diluent, excipient, binder, lubricant, disintegrant, colorant, flavoring and olfactory corrective, emulsifier, surfactant, solubilizer, suspending agent, isotonic agent, buffer, preservative, antioxidant, stabilizer, absorption enhancer, etc., which can also be used in appropriate combination as needed.

6. Use of the artemetheramide maleate crystalline form I according to any one of claims 1 to 4 and / or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating or preventing inflammatory autoimmune diseases such as lupus, dry eye, and enteritis.

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