Crystal of compound, and preparation method therefor and use thereof

Abstract

The present invention relates to a crystal of a compound, and a preparation method therefor and the use thereof, specifically relates to a crystal of a compound of formula (I) and a preparation method therefor, and further relates to the use of the crystal of the compound of formula (I) in the preparation of a drug for treating Parkinson's disease and restless leg syndrome.

Description

Compound crystals, preparation method and use thereof Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to multiple crystals of a compound and uses thereof. Specifically, the present invention relates to crystal form I, crystal form II and crystal form III of pramipexole pamoate and uses thereof. Background Art

[0002] Parkinson's disease (PD) is a disorder of the motor system of the nervous system. It is characterized by a progressive disease that affects movement and leads to the loss of dopamine-producing brain cells, causing tremors in the hands, arms, legs, jaw, and face and / or stiffness or rigidity in the limbs and trunk. Key symptoms include muscle rigidity, slow movements, resting tremor, and postural instability.

[0003] (S)-2-Amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (pramipexole) is a non-ergot dopamine receptor agonist developed by Boehringer Ingelheim in Germany. Currently marketed domestically and internationally, the main products are hydrochloride immediate-release and hydrochloride extended-release tablets, used to treat Parkinson's disease and restless legs syndrome.

[0004] Surveys have found that Parkinson's disease patients are mostly middle-aged and elderly, with a high prevalence of dysphagia of 70-90%, which increases the risk of aspiration pneumonia by 15-50%. Dysphagia develops early in the disease and persists throughout the course, easily triggering coughing and increasing the risk of aspiration pneumonia, a leading cause of death in Parkinson's patients. Current clinical medications are primarily oral. Pramipexole hydrochloride tablets require three doses per day, and even extended-release pramipexole hydrochloride tablets require a single daily dose. This high single-dose dosage necessitates urgent improvement in compliance. Furthermore, the pulsatile stimulation secondary to fluctuations in dopamine blood concentrations can further exacerbate abnormalities in dopamine receptor levels and function. Only continuous, steady dopamine stimulation can control or minimize the occurrence of motor complications and adverse reactions. Furthermore, a long-term release regimen exceeding 24 hours would also improve patient compliance, as patients with advanced Parkinson's disease are often noncompliant, making it difficult to assess whether they are receiving the appropriate medication dose.

[0005] In summary, the clinical practice advocates the use of long-acting sustained-release preparations, such as oral sustained-release, long-acting patches, and long-acting injections to maintain stable blood drug concentrations and improve patient compliance; therefore, there is an urgent need to seek salt forms and crystals that can be used for long-acting sustained-release preparations.

[0006] Patent CN201880067148.3 discloses four crystalline forms of pramipexole pamoate, Forms 1-4. Forms 1 and 2 each have a molar ratio of pramipexole to pamoic acid of approximately 1:1, resulting in low drug loading and a shortened long-acting drug release period for sustained-release dosage forms. Although Forms 3 and 4 each have a molar ratio of pramipexole to pamoic acid of approximately 2:1, increasing the pramipexole content, Form 3 converts to an amorphous form at room temperature, resulting in an unstable crystal form and hindering drug development and process development. Form 4 is relatively stable relative to Form 3, but its proton nuclear magnetic resonance (HNMR) and differential scanning calorimetry (DSC) spectra suggest that it is a solvate, hindering drug development. The disclosed preparation method utilizes amorphous suspension crystallization, which is also not conducive to scale-up production. Patent CN202011304450.1 discloses 19 crystal forms of pramipexole pamoate crystals A to crystals S, but some of the disclosed crystal forms are solvates or the solvents are difficult to remove, which is not conducive to drug development. Summary of the Invention

[0007] The first aspect of the present invention provides a crystal I of a compound of formula (I), wherein

[0008] The compound of formula (I) has the following structure:

[0009] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2° and 14.7±0.2°.

[0010] The second aspect of the present invention provides a crystal II of a compound of formula (I), wherein

[0011] The compound of formula (I) has the following structure:

[0012] The X-ray powder diffraction pattern of the crystal II of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.9±0.2°, 10.7±0.2°, 11.0±0.2°, 13.4±0.2°, 14.8±0.2° and 18.4±0.2°.

[0013] The third aspect of the present invention provides a crystal III of a compound of formula (I), wherein

[0014] The compound of formula (I) has the following structure:

[0015] The X-ray powder diffraction pattern of the crystal III of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.9±0.2°, 13.4±0.2°, 14.8±0.2°, 18.4±0.2°, 22.4±0.2° and 24.1±0.2°.

[0016] The fourth aspect of the present invention provides a pharmaceutical composition comprising i) any one or more of the following substances of the present invention: Crystal I, Crystal II and Crystal III of the compound of formula (I); and ii) one or more pharmaceutically acceptable carriers.

[0017] The fifth aspect of the present invention provides a pharmaceutical preparation comprising i) any one or more of the following substances of the present invention: Crystal I, Crystal II and Crystal III of the compound of formula (I); and ii) one or more pharmaceutically acceptable carriers.

[0018] The sixth aspect of the present invention provides the use of any one or more of Crystal I, Crystal II, Crystal III of the compound of formula (I), the pharmaceutical composition or the pharmaceutical preparation of the present invention in the preparation of drugs, in particular in the preparation of drugs for treating Parkinson's disease and restless legs syndrome.

[0019] The seventh aspect of the present invention provides a method for preparing the crystal of the present invention.

[0020] In some embodiments, the method for preparing Crystal III of the present invention comprises the following steps:

[0021] Dissolving any solid form of the compound of formula (I) in an organic solvent I, or dissolving any solid form of the compound of formula (II) and an organic acid in an organic solvent I;

[0022] Add anti-solvent to precipitate the solid and obtain crystal III.

[0023] In some embodiments, the method for preparing Crystal II of the present invention comprises the following steps:

[0024] suspending the crystal III of the present invention in an organic solvent II to obtain crystal II; or

[0025] Crystal III of the present invention is washed with an organic solvent III to obtain Crystal II.

[0026] In some embodiments, the method for preparing Crystal I of the present invention comprises the following steps:

[0027] The crystal II of the present invention is dried to obtain a crystal I. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG1 is an XRPD pattern of crystal I of compound of formula (I).

[0029] FIG2 is an XRPD pattern of crystal II of compound of formula (I).

[0030] FIG3 is an XRPD pattern of crystal III of compound of formula (I).

[0031] FIG4 is a Raman spectrum of crystal I of compound of formula (I).

[0032] FIG5 is a Raman spectrum of crystal II of compound of formula (I).

[0033] FIG6 is a Raman spectrum of crystal III of compound of formula (I).

[0034] FIG7 is a three-dimensional ellipsoid diagram of the minimum asymmetric unit of the crystal I of the compound of formula (I), wherein the arrows indicate the intermolecular hydrogen bonds formed after the transfer of hydrogen atoms.

[0035] FIG8 is a comparison chart of the pharmacokinetic data of crystal I of compound of formula (I) and known crystal P.

[0036] FIG9 is a scanning electron microscope image of microspheres prepared from known crystal P. DETAILED DESCRIPTION

[0037] definition

[0038] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0039] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0040] As used herein, the term "one or more" or "at least one" refers to one, two, three, four, five, six, seven, eight, nine or more.

[0041] If the number of parts or components of the present invention is not indicated before, it means that there is no limit to the number of occurrences (or existence) of the parts or components. Therefore, it should be interpreted as including one or at least one, and the singular form of the parts or components also includes the plural form, unless the value obviously represents the singular.

[0042] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring.

[0043] As used herein, the term "about" means that one of ordinary skill in the art would consider the range to be within an acceptable standard error of the stated value, such as a 95% confidence interval for the mean or within ±10% of a specified value, or a wider range, such as a range of ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3 of a specified value, etc. As used herein, it should be understood that when multiple values ​​or ranges are listed, each of the listed values ​​or ranges may be qualified as "about," even if only the first value or endpoint is given an "about" designation.

[0044] In this article, "compound (I)" and "compound of formula (I)" refer to the compound of formula (I)

[0045] The term "pharmaceutical composition" refers to an active ingredient, which may be optionally combined with one or more pharmaceutically acceptable chemical components (such as, but not limited to, carriers and / or excipients). The active ingredient is, for example, one or more of Crystal I, Crystal II, Crystal III of the compound of formula (I), or the compositions of the present invention.

[0046] The term "administration" or "administering" refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral, parenteral (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc.

[0047] With respect to a drug or pharmacologically active agent, the term "effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of one active substance in the composition may be the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0048] The term "active ingredient," "therapeutic agent," "active substance," or "active agent" refers to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition. As used herein, the term may refer to, for example, one or more of Crystal I, Crystal II, Crystal III of the compound of formula (I), a composition of the present invention, or a formulation of the present invention.

[0049] As used herein, the term "pharmaceutically acceptable carrier" refers to any carrier that has no significant irritating effect on an organism and does not impair the biological activity and performance of the active compound, including but not limited to any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier acceptable for use in humans or animals (e.g., livestock). Non-limiting examples of such carriers include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol. For additional information on carriers, reference may be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0050] As used herein, the term "amorphous" refers to any solid material that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As described below, amorphous solids produce diffuse XRPD patterns that typically include one or two broad peaks (i.e., peaks with a base width of about 5° 2θ or greater).

[0051] As used herein, the terms "crystalline form," "crystal," and "crystalline form" have the same meaning and are used interchangeably herein to refer to any solid material that exhibits a three-dimensional ordering, as opposed to an amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.

[0052] As used herein, the term "solvate" refers to a solvent compound formed when a substance dissolves in a solvent and solvent molecules combine with solute molecules or ions, causing the solute to change its original state.

[0053] As used herein, the term "hydrate" refers to a salt of a compound provided herein that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. In general, a hydrate generally refers to a compound containing water. In pharmaceuticals, a hydrate generally refers to a solid substance having a specific stoichiometric ratio formed by the hydration reaction of a drug molecule with water of crystallization.

[0054] The term "non-covalent bond form" used herein refers to weak intermolecular interactions other than covalent bonds, including but not limited to hydrogen bonds, van der Waals forces, salt bonds, hydrophobic forces, aromatic ring stacking, π-π stacking, halogen bonds, etc.

[0055] As used herein, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or parameters derived therefrom. An XRPD pattern is typically characterized by peak positions (abscissa) and / or peak intensities (ordinate).

[0056] In X-ray powder diffraction (XRPD or XRD) spectra, the diffraction pattern obtained from a crystalline compound is often characteristic for a specific crystal form, wherein the relative intensity of the bands (especially at low angles) may vary due to the preferred orientation effect caused by differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensity of the diffraction peaks is not characteristic for the crystal form being measured. When determining whether it is the same as a known crystal form, it is more important to pay attention to the relative position of the peaks rather than their relative intensities. In addition, for any given crystal form, the position of the peaks may have slight errors, which is also well known in the art of crystallography. For example, due to temperature changes, sample movement, or instrument calibration during sample analysis, the position of the peaks can move, and the measurement error of the 2θ value is sometimes about ±0.2°, ±0.1°, or ±0.05°. In some embodiments, the measurement error of the 2θ value is about ±0.2°. In other embodiments, the measurement error of the 2θ value is about ±0.1°. In yet other embodiments, the measurement error of the 2θ value is about ±0.05°. Therefore, this error should be taken into account when determining the structure of each crystal form.If a crystal form of the present invention is described as being substantially as shown in a specified figure, the term "substantially" is also intended to cover such differences in the positions of diffraction peaks.

[0057] In XRPD patterns, peak positions are typically expressed in terms of 2θ or the interplanar distance d. A simple conversion relationship exists between the two: d = λ / 2sinθ, where d represents the interplanar distance, λ represents the wavelength of the incident X-ray, and θ is the diffraction angle. While XRPD peak positions for the same compound and the same crystalline form are generally similar, the relative intensity errors may be significant. It should also be noted that in the identification of mixtures, some diffraction lines may be missing due to factors such as a decrease in content. In this case, it is not necessary to rely on all bands observed in a high-purity sample; even a single band may be characteristic for a given crystal.

[0058] As used herein, the term "2θ" refers to the peak position expressed in degrees based on the experimental setup of an X-ray diffraction experiment, and is typically the abscissa unit in a diffraction pattern. If reflection is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup needs to record the reflected beam at 2θ angles. It should be understood that the specific 2θ values ​​of the specific crystals mentioned in this article are intended to represent the 2θ values ​​(expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. X-ray powder diffraction patterns can be obtained by detecting under Cu palladium irradiation conditions using an X-ray powder diffractometer (e.g., X'Pert3 Powder diffractometer), for example, Absolute scan can be used at room temperature to detect and obtain X-ray powder diffraction patterns.

[0059] As used herein, the term "Raman spectrum" refers to the signal peaks recorded by a Raman spectrometer. Raman spectra can be recorded by a Raman spectrometer (e.g., Thermo Fisher Nicolet iS50 FT-Raman) at a specific laser wavelength (e.g., a laser wavelength of 1063 nm), a specific resolution (e.g., 8 cm -1 ) and specific sampling gain (e.g., 1.0), moving mirror speed (e.g., 0.3165), and aperture (e.g., 50.00) parameters are used to focus and scan the sample. For any given crystal form, there may be slight errors in the position of the peak, which is also well known in the field of crystallography. The measurement error of the Raman shift in the Raman spectrum is sometimes about ±2 cm -1 ±1cm -1 In some embodiments, the Raman shift is measured with an error of about ±2 cm -1 In other embodiments, the Raman shift is measured with an error of about ±1 cm -1 .

[0060] As used herein, the term "substantially the same" with respect to X-ray diffraction peak positions means that variations in representative peak positions and intensities are taken into account. For example, one skilled in the art will understand that peak positions (2θ) will exhibit some variation, typically as much as 0.1-0.2 degrees, and that the instrument used to measure diffraction will also exhibit some variation. In addition, one skilled in the art will understand that relative peak intensities will exhibit variations between instruments and due to variations in the degree of crystallinity, preferred orientation, the surface of the sample being prepared, and other factors known to one skilled in the art, and should be considered merely qualitative measurements.

[0061] The term "room temperature" as used herein refers to 20°C ± 5°C.

[0062] When describing a method, component, or step, letters or numbers are used for differentiation purposes only and do not limit the order or sequence of these methods, components, or steps. Those skilled in the art may make reasonable adjustments. For example, "organic solvent I," "organic solvent II," and "organic solvent III" are used only for differentiation purposes and do not indicate a sequence or order relationship. The objects referred to by different numbers may be the same or different.

[0063] As used herein, the term "minimum asymmetric unit" refers to the smallest independent part in a unit cell that can be composed of all atoms, ions or molecules in the unit cell after all space group symmetry operations are performed.

[0064] All technical features disclosed in this specification, or all steps in the methods or processes disclosed, except for mutually exclusive technical features and / or steps, can be combined in any manner.

[0065] Crystals of the compound of formula (I)

[0066] The present invention relates to a crystal of a compound of formula (I), wherein the compound of formula (I) has the following structure:

[0067] Crystal I

[0068] In some embodiments, the present invention provides a crystal I of a compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2° and 14.7±0.2°.

[0069] In some embodiments, the present invention provides a crystal I of a compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1° and 14.7±0.1°.

[0070] In some embodiments, the present invention provides a crystal I of a compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2° and 14.72±0.2°.

[0071] In other embodiments, the present invention provides crystal I of the compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1° and 14.72±0.1°.

[0072] In some embodiments, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) further includes one or more diffraction peaks at 2θ angles of approximately 11.9±0.2° and 21.0±0.2°; and / or the X-ray powder diffraction pattern of crystal I of the compound of formula (I) further includes one or more diffraction peaks at 2θ angles of approximately 15.3±0.2°, 18.3±0.2° and 19.8±0.2°.

[0073] In some embodiments, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) further includes one or more diffraction peaks at 2θ angles of approximately 11.9±0.1° and 21.0±0.1°; and / or the X-ray powder diffraction pattern of crystal I of the compound of formula (I) further includes one or more diffraction peaks at 2θ angles of approximately 15.3±0.1°, 18.3±0.1° and 19.8±0.1°.

[0074] In some embodiments, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) further includes one or more diffraction peaks at 2θ angles of approximately 11.89±0.2° and 21.04±0.2°; and / or the X-ray powder diffraction pattern of crystal I of the compound of formula (I) further includes one or more diffraction peaks at 2θ angles of approximately 15.32±0.2°, 18.36±0.2° and 19.86±0.2°.

[0075] In some embodiments, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) further includes one or more diffraction peaks at 2θ angles of approximately 11.89±0.1° and 21.04±0.1°; and / or the X-ray powder diffraction pattern of crystal I of the compound of formula (I) further includes one or more diffraction peaks at 2θ angles of approximately 15.32±0.1°, 18.36±0.1° and 19.86±0.1°.

[0076] In some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) further comprises diffraction peaks at one or more of the 2θ angles of about 11.9±0.2° and 21.0±0.2°. For example, in some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) comprises diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, and 14.7±0.2°; or

[0077] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2° and 21.0±0.2°; or

[0078] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2° and 21.0±0.2°. In some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) also includes diffraction peaks at one or more of 2θ angles of about 11.9±0.1° and 21.0±0.1°. For example, in some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1° and 14.7±0.1°; or

[0079] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1° and 21.0±0.1°; or

[0080] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1° and 21.0±0.1°.

[0081] In some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) further comprises diffraction peaks at one or more of the 2θ angles of about 11.89±0.2° and 21.04±0.2°. For example, in some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) comprises diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, and 14.72±0.2°; or

[0082] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2° and 21.04±0.2°; or

[0083] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2° and 21.04±0.2°.

[0084] In some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) further comprises diffraction peaks at one or more of the 2θ angles of about 11.89±0.1° and 21.04±0.1°. For example, in some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) comprises diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, and 14.72±0.1°; or

[0085] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1° and 21.04±0.1°; or

[0086] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1° and 21.04±0.1°.

[0087] In some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of about 15.3±0.2°, 18.3±0.2°, and 19.8±0.2°. For example, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, and 15.3±0.2°; or

[0088] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2° and 18.3±0.2°; or

[0089] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2° and 19.8±0.2°; or

[0090] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2° and 18.3±0.2°; or

[0091] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2° and 19.8±0.2°; or

[0092] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 18.3±0.2° and 19.8±0.2°; or

[0093] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2°, 18.3±0.2° and 19.8±0.2°; or

[0094] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2° and 15.3±0.2°; or

[0095] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2° and 18.3±0.2°; or

[0096] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2° and 19.8±0.2°; or

[0097] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2° and 18.3±0.2°; or

[0098] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2° and 19.8±0.2°; or

[0099] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 18.3±0.2° and 19.8±0.2°; or

[0100] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2°, 18.3±0.2° and 19.8±0.2°; or

[0101] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2° and 21.0±0.2°; or

[0102] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 18.3±0.2° and 21.0±0.2°; or

[0103] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 19.8±0.2° and 21.0±0.2°; or

[0104] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2°, 18.3±0.2° and 21.0±0.2°; or

[0105] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2°, 19.8±0.2° and 21.0±0.2°; or

[0106] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 18.3±0.2°, 19.8±0.2° and 21.0±0.2°; or

[0107] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2°, 18.3±0.2°, 19.8±0.2 and 21.0±0.2°; or

[0108] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2° and 21.0±0.2°; or

[0109] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 18.3±0.2° and 21.0±0.2°; or

[0110] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 19.8±0.2° and 21.0±0.2°; or

[0111] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2°, 18.3±0.2° and 21.0±0.2°; or

[0112] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2°, 19.8±0.2° and 21.0±0.2°; or

[0113] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 18.3±0.2°, 19.8±0.2° and 21.0±0.2°; or

[0114] The X-ray powder diffraction pattern of crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2°, 18.3±0.2°, 19.8±0.2° and 21.0±0.2°.

[0115] In some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of about 15.3±0.1°, 18.3±0.1°, and 19.8±0.1°. For example, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, and 15.3±0.1°; or

[0116] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1° and 18.3±0.1°; or

[0117] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1° and 19.8±0.1°; or

[0118] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1° and 18.3±0.1°; or

[0119] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1° and 19.8±0.1°; or

[0120] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 18.3±0.1° and 19.8±0.1°; or

[0121] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1°, 18.3±0.1° and 19.8±0.1°; or

[0122] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1° and 15.3±0.1°; or

[0123] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1° and 18.3±0.1°; or

[0124] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1° and 19.8±0.1°; or

[0125] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1° and 18.3±0.1°; or

[0126] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1° and 19.8±0.1°; or

[0127] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 18.3±0.1° and 19.8±0.1°; or

[0128] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1°, 18.3±0.1° and 19.8±0.1°; or

[0129] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1° and 21.0±0.1°; or

[0130] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 18.3±0.1° and 21.0±0.1°; or

[0131] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 19.8±0.1° and 21.0±0.1°; or

[0132] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1°, 18.3±0.1° and 21.0±0.1°; or

[0133] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1°, 19.8±0.1° and 21.0±0.1°; or

[0134] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 18.3±0.1°, 19.8±0.1° and 21.0±0.1°; or

[0135] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1°, 18.3±0.1°, 19.8±0.1 and 21.0±0.1°; or

[0136] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1° and 21.0±0.1°; or

[0137] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 18.3±0.1° and 21.0±0.1°; or

[0138] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 19.8±0.1° and 21.0±0.1°; or

[0139] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1°, 18.3±0.1° and 21.0±0.1°; or

[0140] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1°, 19.8±0.1° and 21.0±0.1°; or

[0141] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 18.3±0.1°, 19.8±0.1° and 21.0±0.1°; or

[0142] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1°, 18.3±0.1°, 19.8±0.1° and 21.0±0.1°.

[0143] In some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of about 15.32±0.2°, 18.36±0.2°, and 19.86±0.2°. For example, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, and 15.32±0.2°; or

[0144] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2° and 18.36±0.2°; or

[0145] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2° and 19.86±0.2°; or

[0146] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2° and 18.36±0.2°; or

[0147] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2° and 19.86±0.2°; or

[0148] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 18.36±0.2° and 19.86±0.2°; or

[0149] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2°, 18.36±0.2° and 19.86±0.2°; or

[0150] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2° and 15.32±0.2°; or

[0151] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2° and 18.36±0.2°; or

[0152] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2° and 19.86±0.2°; or

[0153] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2° and 18.36±0.2°; or

[0154] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2° and 19.86±0.2°; or

[0155] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 18.36±0.2° and 19.86±0.2°; or

[0156] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2°, 18.36±0.2° and 19.86±0.2°; or

[0157] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2° and 21.04±0.2°; or

[0158] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 18.36±0.2° and 21.04±0.2°; or

[0159] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 19.86±0.2° and 21.04±0.2°; or

[0160] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2°, 18.36±0.2° and 21.04±0.2°; or

[0161] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2°, 19.86±0.2° and 21.04±0.2°; or

[0162] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 18.36±0.2°, 19.86±0.2° and 21.04±0.2°; or

[0163] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2°, 18.36±0.2°, 19.86±0.2 and 21.04±0.2°; or

[0164] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2° and 21.04±0.2°; or

[0165] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 18.36±0.2° and 21.04±0.2°; or

[0166] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 19.86±0.2° and 21.04±0.2°; or

[0167] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2°, 18.36±0.2° and 21.04±0.2°; or

[0168] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2°, 19.86±0.2° and 21.04±0.2°; or

[0169] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 18.36±0.2°, 19.86±0.2° and 21.04±0.2°; or

[0170] The X-ray powder diffraction pattern of crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2°, 18.36±0.2°, 19.86±0.2° and 21.04±0.2°.

[0171] In some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of about 15.32±0.1°, 18.36±0.1°, and 19.86±0.1°. For example, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, and 15.32±0.1°; or

[0172] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1° and 18.36±0.1°; or

[0173] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1° and 19.86±0.1°; or

[0174] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1° and 18.36±0.1°; or

[0175] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1° and 19.86±0.1°; or

[0176] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 18.36±0.1° and 19.86±0.1°; or

[0177] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1°, 18.36±0.1° and 19.86±0.1°; or

[0178] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1° and 15.32±0.1°; or

[0179] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1° and 18.36±0.1°; or

[0180] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1° and 19.86±0.1°; or

[0181] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1° and 18.36±0.1°; or

[0182] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1° and 19.86±0.1°; or

[0183] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 18.36±0.1° and 19.86±0.1°; or

[0184] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1°, 18.36±0.1° and 19.86±0.1°; or

[0185] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1° and 21.04±0.1°; or

[0186] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 18.36±0.1° and 21.04±0.1°; or

[0187] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 19.86±0.1° and 21.04±0.1°; or

[0188] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1°, 18.36±0.1° and 21.04±0.1°; or

[0189] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1°, 19.86±0.1° and 21.04±0.1°; or

[0190] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 18.36±0.1°, 19.86±0.1° and 21.04±0.1°; or

[0191] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1°, 18.36±0.1°, 19.86±0.1 and 21.04±0.1°; or

[0192] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1° and 21.04±0.1°; or

[0193] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 18.36±0.1° and 21.04±0.1°; or

[0194] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 19.86±0.1° and 21.04±0.1°; or

[0195] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1°, 18.36±0.1° and 21.04±0.1°; or

[0196] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1°, 19.86±0.1° and 21.04±0.1°; or

[0197] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 18.36±0.1°, 19.86±0.1° and 21.04±0.1°; or

[0198] The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1°, 18.36±0.1°, 19.86±0.1° and 21.04±0.1°.

[0199] In some preferred embodiments, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2°, 18.3±0.2°, 19.8±0.2° and 21.0±0.2°.

[0200] In some preferred embodiments, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 6.0±0.1°, 10.5±0.1°, 11.9±0.1°, 12.7±0.1°, 13.7±0.1°, 14.7±0.1°, 15.3±0.1°, 18.3±0.1°, 19.8±0.1° and 21.0±0.1°.

[0201] In some preferred embodiments, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.95±0.2°, 10.50±0.2°, 11.89±0.2°, 12.66±0.2°, 13.70±0.2°, 14.72±0.2°, 15.32±0.2°, 18.36±0.2°, 19.86±0.2° and 21.04±0.2°.

[0202] In some preferred embodiments, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.95±0.1°, 10.50±0.1°, 11.89±0.1°, 12.66±0.1°, 13.70±0.1°, 14.72±0.1°, 15.32±0.1°, 18.36±0.1°, 19.86±0.1° and 21.04±0.1°.

[0203] In other preferred embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes peaks at 2θ angles substantially the same as those shown in FIG1 .

[0204] In some embodiments, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes the following diffraction peaks at 2θ angles:

[0205] In some embodiments, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) is substantially as shown in FIG1 .

[0206] In some more preferred embodiments, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) is shown in FIG1 .

[0207] In some embodiments, the Raman spectrum of the crystal I of the compound of formula (I) comprises a peak at about 3060 ± 2 cm -1 、2934±2cm -1 、1617±2cm -1 、1523±2cm -1 、1367±2cm -1 、1271±2cm -1 、722±2cm -1 and 695±2cm -1 One or more Raman shift characteristic peaks in the .

[0208] In some embodiments, the Raman spectrum of the crystal I of the compound of formula (I) comprises a peak at about 3060 ± 1 cm -1 、2934±1cm -1 、1617±1cm -1 、1523±1cm -1 、1367±1cm -1 、1271±1cm -1 、722±1cm -1 and 695±1cm -1 One or more Raman shift characteristic peaks in the .

[0209] In some embodiments, the Raman spectrum of the crystal I of the compound of formula (I) includes a peak at about 3060.31±2 cm -1 、2934.83±2cm -1 、1617.10±2cm -1 、1523.51±2cm -1 、1367.94±2cm -1 、1271.38±2cm -1 、722.52±2cm -1 and 695.25±2cm -1 One or more Raman shift characteristic peaks in the .

[0210] In some embodiments, the Raman spectrum of the crystal I of the compound of formula (I) includes a peak at about 3060.31±1 cm - 1、2934.83±1cm - 1 、1617.10±1cm - 1 、1523.51±1cm - 1 、1367.94±1cm -1 、1271.38±1cm -1 、722.52±1cm -1 and 695.25±1cm -1 One or more Raman shift characteristic peaks in the .

[0211] In some embodiments, the Raman spectrum of the crystal I of the compound of formula (I) further includes a peak at about 1578±2 cm -1 、1444±2cm -1 、1029±2cm -1 and 425±2cm -1 One or more Raman shift characteristic peaks in the .

[0212] In some embodiments, the Raman spectrum of the crystal I of the compound of formula (I) further includes a peak at about 1578±1 cm -1 、1444±1cm -1 、1029±1cm -1 and 425±1cm -1 One or more Raman shift characteristic peaks in the .

[0213] In some embodiments, the Raman spectrum of the crystal I of the compound of formula (I) further includes a peak at about 1578.11±2 cm -1 、1444.27±2cm -1 、1029.81±2cm -1 and 425.96±2cm -1 One or more Raman shift characteristic peaks in the .

[0214] In some embodiments, the Raman spectrum of the crystal I of the compound of formula (I) further includes a peak at about 1578.11±1 cm -1 、1444.27±1cm -1 、1029.81±1cm -1 and 425.96±1cm -1 One or more Raman shift characteristic peaks in the .

[0215] In some further preferred embodiments, the Raman spectrum of the crystal I of the compound of formula (I) includes a peak at about 3060±2 cm -1 、2934±2cm -1、1617±2cm -1 、1578±2cm -1 、1523±2cm - 1 、1444±2cm -1 、1367±2cm -1 、1271±2cm -1 、1029±2cm -1 、722±2cm -1 、695±2cm -1 and 425±2cm -1 One or more Raman shift characteristic peaks in the .

[0216] In some further preferred embodiments, the Raman spectrum of the crystal I of the compound of formula (I) includes a peak at about 3060±1 cm -1 、2934±1cm -1 、1617±1cm -1 、1578±1cm -1 、1523±1cm - 1 、1444±1cm -1 、1367±1cm -1 、1271±1cm -1 、1029±1cm -1 、722±1cm -1 、695±1cm -1 and 425±1cm -1 One or more Raman shift characteristic peaks in the .

[0217] In some further preferred embodiments, the Raman spectrum of the crystal I of the compound of formula (I) includes a peak at about 3060.31±2 cm -1 、2934.83±2cm -1 、1617.10±2cm -1 、1578.11±2cm - 1 、1523.51±2cm -1 、1444.27±2cm -1 、1367.94±2cm -1 、1271.38±2cm -1 、1029.81±2cm -1 、722.52±2cm -1 、695.25±2cm -1 and 425.96±2cm -1 One or more Raman shift characteristic peaks in the .

[0218] In some further preferred embodiments, the Raman spectrum of the crystal I of the compound of formula (I) includes a peak at about 3060.31±1 cm -1 、2934.83±1cm -1 、1617.10±1cm -1 、1578.11±1cm - 1 、1523.51±1cm -1 、1444.27±1cm -1 、1367.94±1cm -1 、1271.38±1cm -1 、1029.81±1cm -1 、722.52±1cm -1 、695.25±1cm -1 and 425.96±1cm -1 One or more Raman shift characteristic peaks in the .

[0219] In some embodiments, the Raman spectrum of crystal I of the compound of formula (I) includes Raman shift characteristic peaks substantially the same as those shown in FIG. 4 .

[0220] In some preferred embodiments, the Raman spectrum of the crystal I of the compound of formula (I) is substantially as shown in Figure 4. In some more preferred embodiments, the Raman spectrum of the crystal I of the compound of formula (I) is as shown in Figure 4.

[0221] In some embodiments, the crystal I of the compound of formula (I) is a non-solvate crystal. In some embodiments, the crystal I of the compound of formula (I) is an anhydrous crystal.

[0222] In some embodiments, the crystal I of the compound of formula (I) is monoclinic and has a space group of P21 (n°.4). In some embodiments, the unit cell parameters of the crystal I of the compound of formula (I) are α=90°,β=109.52(17)°,γ=90°, unit cell volume In some embodiments, the minimum asymmetric unit of the crystal I of the compound of formula (I) is shown in Figure 7. In some embodiments, the structure of the crystal I of the compound of formula (I) is refined by the SHELXL program (least squares method), and the statistical parameters after convergence of the structure refinement are R1=0.1270, wR2=0.2926, and S=1.1077.

[0223] Crystal II

[0224] In some embodiments, the present invention provides a crystal II of a compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 5.9±0.2°, 10.7±0.2°, 11.0±0.2°, 13.4±0.2°, 14.8±0.2° and 18.4±0.2°.

[0225] In some embodiments, the present invention provides a crystal II of a compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 5.9±0.1°, 10.7±0.1°, 11.0±0.1°, 13.4±0.1°, 14.8±0.1° and 18.4±0.1°.

[0226] In some embodiments, the present invention provides a crystal II of a compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 5.85±0.2°, 10.67±0.2°, 11.01±0.2°, 13.42±0.2°, 14.77±0.2° and 18.44±0.2°.

[0227] In some embodiments, the present invention provides a crystal II of a compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 5.85±0.1°, 10.67±0.1°, 11.01±0.1°, 13.42±0.1°, 14.77±0.1° and 18.44±0.1°.

[0228] In some embodiments, the X-ray powder diffraction pattern of crystal II of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of approximately 6.5±0.2°, 10.2±0.2°, 12.5±0.2°, 14.5±0.2°, 17.7±0.2°, and 22.2±0.2°. Specific examples thereof include the X-ray powder diffraction pattern of the crystal II of the compound of formula (I) at diffraction peaks at 2θ angles of about 5.9±0.2°, 10.7±0.2°, 11.0±0.2°, 13.4±0.2°, 14.8±0.2° and 18.4±0.2° and a combination of one or more diffraction peaks at 2θ angles of about 6.5±0.2°, 10.2±0.2°, 12.5±0.2°, 14.5±0.2°, 17.7±0.2° and 22.2±0.2°. Those skilled in the art can refer to the enumeration of the corresponding specific examples in Form I for illustrative purposes.

[0229] In some embodiments, the X-ray powder diffraction pattern of crystal II of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of approximately 6.5±0.1°, 10.2±0.1°, 12.5±0.1°, 14.5±0.1°, 17.7±0.1°, and 22.2±0.1°. Specific examples thereof include the X-ray powder diffraction pattern of the crystal II of the compound of formula (I) at diffraction peaks at 2θ angles of about 5.9±0.1°, 10.7±0.1°, 11.0±0.1°, 13.4±0.1°, 14.8±0.1° and 18.4±0.1° and a combination of one or more diffraction peaks at 2θ angles of about 6.5±0.1°, 10.2±0.1°, 12.5±0.1°, 14.5±0.1°, 17.7±0.1° and 22.2±0.1°. Those skilled in the art can refer to the enumeration of the corresponding specific examples in Form I for illustrative purposes.

[0230] In some embodiments, the X-ray powder diffraction pattern of crystal II of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of approximately 6.45±0.2°, 10.22±0.2°, 12.54±0.2°, 14.50±0.2°, 17.67±0.2°, and 22.24±0.2°. Specific examples thereof include the X-ray powder diffraction pattern of the crystal II of the compound of formula (I) at diffraction peaks at 2θ angles of about 5.85±0.2°, 10.67±0.2°, 11.01±0.2°, 13.42±0.2°, 14.77±0.2° and 18.44±0.2° and a combination of one or more diffraction peaks at 2θ angles of about 6.45±0.2°, 10.22±0.2°, 12.54±0.2°, 14.50±0.2°, 17.67±0.2° and 22.24±0.2°. Those skilled in the art can refer to the enumeration of the corresponding specific examples in Form I for illustrative purposes.

[0231] In some embodiments, the X-ray powder diffraction pattern of crystal II of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of approximately 6.45±0.1°, 10.22±0.1°, 12.54±0.1°, 14.50±0.1°, 17.67±0.1°, and 22.24±0.1°. Specific examples thereof include the X-ray powder diffraction pattern of the crystal II of the compound of formula (I) at diffraction peaks at 2θ angles of about 5.85±0.1°, 10.67±0.1°, 11.01±0.1°, 13.42±0.1°, 14.77±0.1° and 18.44±0.1° and a combination of one or more diffraction peaks at 2θ angles of about 6.45±0.1°, 10.22±0.1°, 12.54±0.1°, 14.50±0.1°, 17.67±0.1° and 22.24±0.1°. Those skilled in the art can refer to the enumeration of the corresponding specific examples in Form I for illustrative purposes.

[0232] In some preferred embodiments, the X-ray powder diffraction pattern of crystal II of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.9±0.2°, 6.5±0.2°, 10.2±0.2°, 10.7±0.2°, 11.0±0.2°, 12.5±0.2°, 13.4±0.2°, 14.5±0.2°, 14.8±0.2°, 17.7±0.2°, 18.4±0.2° and 22.2±0.2°.

[0233] In some preferred embodiments, the X-ray powder diffraction pattern of crystal II of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.9±0.1°, 6.5±0.1°, 10.2±0.1°, 10.7±0.1°, 11.0±0.1°, 12.5±0.1°, 13.4±0.1°, 14.5±0.1°, 14.8±0.1°, 17.7±0.1°, 18.4±0.1° and 22.2±0.1°.

[0234] In some preferred embodiments, the X-ray powder diffraction pattern of crystal II of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.85±0.2°, 6.45±0.2°, 10.22±0.2°, 10.67±0.2°, 11.01±0.2°, 12.54±0.2°, 13.42±0.2°, 14.50±0.2°, 14.77±0.2°, 17.67±0.2°, 18.44±0.2° and 22.24±0.2°.

[0235] In some preferred embodiments, the X-ray powder diffraction pattern of crystal II of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.85±0.1°, 6.45±0.1°, 10.22±0.1°, 10.67±0.1°, 11.01±0.1°, 12.54±0.1°, 13.42±0.1°, 14.50±0.1°, 14.77±0.1°, 17.67±0.1°, 18.44±0.1° and 22.24±0.1°.

[0236] In other preferred embodiments, the X-ray powder diffraction pattern of the crystal II of the compound of formula (I) includes peaks at 2θ angles substantially the same as those shown in FIG. 2 .

[0237] In some embodiments, the X-ray powder diffraction pattern of the crystal II of the compound of formula (I) includes the following diffraction peaks at 2θ angles:

[0238] In some embodiments, the X-ray powder diffraction pattern of crystal II of the compound of formula (I) is substantially as shown in FIG2 .

[0239] In some more preferred embodiments, the X-ray powder diffraction pattern of crystal II of the compound of formula (I) is shown in FIG2 .

[0240] In some embodiments, the Raman spectrum of the crystal II of the compound of formula (I) includes a peak at about 3054±2 cm -1 、2935±2cm -1 、2254±2cm -1 、1621±2cm -1 、1590±2cm -1 、1515±2cm -1 、1441±2cm -1 、1400±2cm -1 、1369±2cm -1 、1270±2cm -1 、1168±2cm -1 、1028±2cm -1 、723±2cm -1 、696±2cm -1 、424±2cm -1 and 393±2cm -1 One or more Raman shift characteristic peaks in the .

[0241] In some embodiments, the Raman spectrum of the crystal II of the compound of formula (I) includes a peak at about 3054±1 cm -1 、2935±1cm -1、2254±1cm -1 、1621±1cm -1 、1590±1cm -1 、1515±1cm -1 、1441±1cm -1 、1400±1cm -1 、1369±1cm -1 、1270±1cm -1 、1168±1cm -1 、1028±1cm -1 、723±1cm -1 、696±1cm -1 、424±1cm -1 and 393±1cm -1 One or more Raman shift characteristic peaks in the .

[0242] In some embodiments, the Raman spectrum of the crystal II of the compound of formula (I) includes a peak at about 3054.58±2 cm -1 、2935.80±2cm -1 、2254.43±2cm -1 、1621.64±2cm -1 、1590.26±2cm -1 、1515.27±2cm -1 、1441.63±2cm -1 、1400.39±2cm -1 、1369.24±2cm -1 、1270.44±2cm -1 、1168.06±2cm -1 、1028.89±2cm -1 、723.90±2cm -1 、696.11±2cm -1 、424.90±2cm -1 and 393.50±2cm -1 One or more Raman shift characteristic peaks in the .

[0243] In some embodiments, the Raman spectrum of the crystal II of the compound of formula (I) includes a peak at about 3054.58±1 cm -1 、2935.80±1cm -1 、2254.43±1cm -1 、1621.64±1cm -1 、1590.26±1cm -1 、1515.27±1cm -1、1441.63±1cm -1 、1400.39±1cm -1 、1369.24±1cm -1 、1270.44±1cm -1 、1168.06±1cm -1 、1028.89±1cm -1 、723.90±1cm -1 、696.11±1cm -1 、424.90±1cm -1 and 393.50±1cm -1 One or more Raman shift characteristic peaks in the .

[0244] In some embodiments, the Raman spectrum of crystal II of the compound of formula (I) includes Raman shift characteristic peaks substantially the same as those shown in FIG. 5 .

[0245] In some preferred embodiments, the Raman spectrum of crystal II of the compound of formula (I) is substantially as shown in FIG5 ; in some more preferred embodiments, the Raman spectrum of crystal II of the compound of formula (I) is as shown in FIG5 .

[0246] Crystal III

[0247] In some embodiments, the present invention provides a crystal III of the compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 5.9±0.2°, 13.4±0.2°, 14.8±0.2°, 18.4±0.2°, 22.4±0.2° and 24.1±0.2°.

[0248] In some embodiments, the present invention provides a crystal III of the compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 5.9±0.1°, 13.4±0.1°, 14.8±0.1°, 18.4±0.1°, 22.4±0.1° and 24.1±0.1°.

[0249] In some embodiments, the present invention provides a crystal III of the compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 5.88±0.2°, 13.42±0.2°, 14.80±0.2°, 18.40±0.2°, 22.42±0.2° and 24.14±0.2°.

[0250] In some embodiments, the present invention provides a crystal III of the compound of formula (I), whose X-ray powder diffraction pattern includes diffraction peaks at 2θ angles of approximately 5.88±0.1°, 13.42±0.1°, 14.80±0.1°, 18.40±0.1°, 22.42±0.1° and 24.14±0.1°.

[0251] In some embodiments, the X-ray powder diffraction pattern of crystal III of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of approximately 6.4±0.2°, 10.0±0.2°, 10.2±0.2°, 10.6±0.2°, 10.9±0.2°, 11.2±0.2°, 12.7±0.2° and 16.2±0.2°. Specific examples thereof include the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) at diffraction peaks at 2θ angles of about 5.9±0.2°, 13.4±0.2°, 14.8±0.2°, 18.4±0.2°, 22.4±0.2° and 24.1±0.2° and a combination of one or more diffraction peaks at 2θ angles of about 6.4±0.2°, 10.0±0.2°, 10.2±0.2°, 10.6±0.2°, 10.9±0.2°, 11.2±0.2°, 12.7±0.2° and 16.2±0.2°. Those skilled in the art can refer to the enumeration of the corresponding specific examples in Form I for illustrative purposes.

[0252] In some embodiments, the X-ray powder diffraction pattern of crystal III of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of approximately 6.4±0.1°, 10.0±0.1°, 10.2±0.1°, 10.6±0.1°, 10.9±0.1°, 11.2±0.1°, 12.7±0.1°, and 16.2±0.1°. Specific examples thereof include the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) at diffraction peaks at 2θ angles of about 5.9±0.1°, 13.4±0.1°, 14.8±0.1°, 18.4±0.1°, 22.4±0.1° and 24.1±0.1° and a combination of one or more diffraction peaks at 2θ angles of about 6.4±0.1°, 10.0±0.1°, 10.2±0.1°, 10.6±0.1°, 10.9±0.1°, 11.2±0.1°, 12.7±0.1° and 16.2±0.1°. Those skilled in the art can refer to the enumeration of the corresponding specific examples in Form I for illustrative purposes.

[0253] In some embodiments, the X-ray powder diffraction pattern of crystal III of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of approximately 6.40±0.2°, 10.06±0.2°, 10.26±0.2°, 10.64±0.2°, 10.94±0.2°, 11.21±0.2°, 12.68±0.2° and 16.21±0.2°. Specific examples thereof include the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) at diffraction peaks at 2θ angles of about 5.88±0.2°, 13.42±0.2°, 14.80±0.2°, 18.40±0.2°, 22.42±0.2° and 24.14±0.2° and at about 6.40±0.2°, 10.06±0.2°, 10.26±0.2°, 10.64±0.2°, 10.94±0.2°, 11.21±0.2°, 12.68±0.2° and 16.21±0.2°. A combination of one or more diffraction peaks at 2θ angles. Those skilled in the art can refer to the enumeration of the corresponding specific examples in Form I for illustrative purposes.

[0254] In some embodiments, the X-ray powder diffraction pattern of crystal III of the compound of formula (I) further includes diffraction peaks at one or more of 2θ angles of approximately 6.40±0.1°, 10.06±0.1°, 10.26±0.1°, 10.64±0.1°, 10.94±0.1°, 11.21±0.1°, 12.68±0.1° and 16.21±0.1°. Specific examples thereof include the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) at diffraction peaks at 2θ angles of about 5.88±0.1°, 13.42±0.1°, 14.80±0.1°, 18.40±0.1°, 22.42±0.1° and 24.14±0.1° and a combination of one or more diffraction peaks at 2θ angles of about 6.40±0.1°, 10.06±0.1°, 10.26±0.1°, 10.64±0.1°, 10.94±0.1°, 11.21±0.1°, 12.68±0.1° and 16.21±0.1°. Those skilled in the art can refer to the enumeration method of the corresponding specific examples in Form I for illustrative purposes.

[0255] In some preferred embodiments, the X-ray powder diffraction pattern of crystal III of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.9±0.2°, 6.4±0.2°, 10.0±0.2°, 10.2±0.2°, 10.6±0.2°, 10.9±0.2°, 11.2±0.2°, 12.7±0.2°, 13.4±0.2°, 14.8±0.2°, 16.2±0.2°, 18.4±0.2°, 22.4±0.2° and 24.1±0.2°.

[0256] In some preferred embodiments, the X-ray powder diffraction pattern of crystal III of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.9±0.1°, 6.4±0.1°, 10.0±0.1°, 10.2±0.1°, 10.6±0.1°, 10.9±0.1°, 11.2±0.1°, 12.7±0.1°, 13.4±0.1°, 14.8±0.1°, 16.2±0.1°, 18.4±0.1°, 22.4±0.1° and 24.1±0.1°.

[0257] In some preferred embodiments, the X-ray powder diffraction pattern of crystal III of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.88±0.2°, 6.40±0.2°, 10.06±0.2°, 10.26±0.2°, 10.64±0.2°, 10.94±0.2°, 11.21±0.2°, 12.68±0.2°, 13.42±0.2°, 14.80±0.2°, 16.21±0.2°, 18.40±0.2°, 22.42±0.2° and 24.14±0.2°.

[0258] In some preferred embodiments, the X-ray powder diffraction pattern of crystal III of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.88±0.1°, 6.40±0.1°, 10.06±0.1°, 10.26±0.1°, 10.64±0.1°, 10.94±0.1°, 11.21±0.1°, 12.68±0.1°, 13.42±0.1°, 14.80±0.1°, 16.21±0.1°, 18.40±0.1°, 22.42±0.1° and 24.14±0.1°.

[0259] In other preferred embodiments, the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) includes peaks at 2θ angles substantially the same as those shown in FIG. 3 .

[0260] In some embodiments, the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) includes the following diffraction peaks at 2θ angles:

[0261] In some embodiments, the X-ray powder diffraction pattern of crystal III of the compound of formula (I) is substantially as shown in FIG3 .

[0262] In some more preferred embodiments, the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) is shown in FIG3 .

[0263] In some embodiments, the Raman spectrum of the crystal III of the compound of formula (I) includes a peak at about 3051±2 cm -1 、2999±2cm -1 、2915±2cm -1 、1620±2cm -1 、1583±2cm -1 、1441±2cm -1 、1399±2cm -1 、1368±2cm -1 、1312±2cm -1 、1270±2cm -1 、1168±2cm -1 、1028±2cm -1 、722±2cm -1 、695±2cm -1 、672±2cm -1 、424±2cm -1 and 335±2cm -1 One or more Raman shift characteristic peaks in the .

[0264] In some embodiments, the Raman spectrum of the crystal III of the compound of formula (I) includes a peak at about 3051±1 cm -1 、2999±1cm -1 、2915±1cm -1 、1620±1cm -1 、1583±1cm -1 、1441±1cm -1 、1399±1cm -1 、1368±1cm -1 、1312±1cm -1 、1270±1cm -1 、1168±1cm -1 、1028±1cm -1 、722±1cm -1 、695±1cm -1、672±1cm -1 、424±1cm -1 and 335±1cm -1 One or more Raman shift characteristic peaks in the .

[0265] In some embodiments, the Raman spectrum of the crystal III of the compound of formula (I) includes a peak at about 3051.20±2 cm -1 、2999.29±2cm -1 、2915.06±2cm -1 、1620.79±2cm -1 、1583.44±2cm -1 、1441.40±2cm -1 、1399.26±2cm -1 、1368.93±2cm -1 、1312.37±2cm -1 、1270.71±2cm -1 、1168.50±2cm -1 、1028.75±2cm -1 、722.19±2cm -1 、695.71±2cm -1 、672.55±2cm -1 、424.80±2cm -1 and 335.61±2cm -1 One or more Raman shift characteristic peaks in the .

[0266] In some embodiments, the Raman spectrum of the crystal III of the compound of formula (I) includes a peak at about 3051.20±1 cm -1 、2999.29±1cm -1 、2915.06±1cm -1 、1620.79±1cm -1 、1583.44±1cm -1 、1441.40±1cm -1 、1399.26±1cm -1 、1368.93±1cm -1 、1312.37±1cm -1 、1270.71±1cm -1 、1168.50±1cm -1 、1028.75±1cm -1 、722.19±1cm -1 、695.71±1cm -1 、672.55±1cm -1、424.80±1cm -1 and 335.61±1cm -1 One or more Raman shift characteristic peaks in the .

[0267] In some embodiments, the Raman spectrum of crystal III of the compound of formula (I) includes Raman shift characteristic peaks substantially the same as those shown in FIG. 6 .

[0268] In some preferred embodiments, the Raman spectrum of the crystal III of the compound of formula (I) is substantially as shown in Figure 6. In some more preferred embodiments, the Raman spectrum of the crystal III of the compound of formula (I) is as shown in Figure 6.

[0269] Preparation method of the crystal of the present invention

[0270] Another object of the present invention is to provide a method for preparing the crystal of the present invention.

[0271] In some embodiments, the method for preparing Crystal III of the present invention comprises:

[0272] Dissolving any solid form of the compound of formula (I) in an organic solvent I, or dissolving any solid form of the compound of formula (II) and an organic acid in an organic solvent I;

[0273] Add anti-solvent to precipitate the solid and obtain crystal III.

[0274] In some embodiments, the organic acid is pamoic acid.

[0275] In some embodiments, the molar ratio of the compound of formula (II) to the organic acid is about 1: 1 to 5: 1. In some preferred embodiments, the molar ratio of the compound of formula (II) to the organic acid is about 2:1.

[0276] In some embodiments, the organic solvent I is dimethyl sulfoxide.

[0277] In some embodiments, the mass volume ratio (g:ml) of the compound of formula (II) to the organic solvent I is about 1:1-1:10; preferably about 1:5-1:8; more preferably about 1:6.25.

[0278] In some embodiments, the anti-solvent is one or more of acetonitrile, acetone, butanone, ethyl acetate, isopropyl acetate, isopropyl ether, and methyl tert-butyl ether; preferably, acetonitrile or ethyl acetate.

[0279] In some embodiments, the method for preparing Crystal II of the present invention comprises the following steps:

[0280] Crystal III of the present invention is suspended in an organic solvent II to obtain Crystal II.

[0281] In some embodiments, the Crystalline III of the present invention is suspended at room temperature.

[0282] In some embodiments, the Crystalline III of the present invention is suspended for 0.5-6 hours; preferably for 1-2 hours.

[0283] In some embodiments, the organic solvent II is one or more of acetonitrile, acetone, ethyl acetate, and methyl tert-butyl ether; preferably acetonitrile.

[0284] In other embodiments, the method for preparing Crystal II of the present invention comprises the following steps:

[0285] Crystal III of the present invention is washed with an organic solvent III to obtain Crystal II.

[0286] In some embodiments, the crystal III of the present invention is washed with an organic solvent III 1-10 times; preferably 3-5 times, for example 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times.

[0287] In some embodiments, the organic solvent III is one or more of acetonitrile, acetone, ethyl acetate, and methyl tert-butyl ether; preferably acetonitrile.

[0288] In some embodiments, the method for preparing Crystal I of the present invention comprises the following steps:

[0289] The crystal II of the present invention is dried to obtain a crystal I.

[0290] In some embodiments, Crystal II of the present invention is dried under vacuum conditions.

[0291] In some embodiments, the crystal II of the present invention is dried at 20°C-100°C; preferably, it is dried at 50°C-90°C; for example, the crystal II of the present invention is dried at 50°C, 60°C, 70°C, 80°C or 90°C.

[0292] Pharmaceutical compositions and uses

[0293] Another object of the present invention is to provide a pharmaceutical composition comprising crystals of a compound of formula (I), in particular any one or more of Crystals I, Crystals II and Crystals III of the compound of formula (I), and one or more pharmaceutically acceptable carriers.

[0294] Another object of the present invention is to provide a pharmaceutical preparation comprising crystals of a compound of formula (I), in particular any one or more of Crystals I, Crystals II and Crystals III of the compound of formula (I), and one or more pharmaceutically acceptable carriers.

[0295] In some embodiments, the pharmaceutical formulations provided herein are microspheres.

[0296] In some embodiments, the pharmaceutical composition or pharmaceutical preparation comprises 0.01 to 1000 mg of a crystal of a compound of formula (I), particularly any one or more of Crystals I, Crystals II, and Crystals III of the compound of formula (I), and one or more pharmaceutically acceptable carriers.

[0297] Another object of the present invention is to provide crystals of the compound of formula (I) of the present invention (e.g., crystal I, crystal II, crystal III or any combination thereof), pharmaceutical compositions or pharmaceutical preparations, and their use in preparing drugs, particularly in preparing drugs for treating Parkinson's disease and restless legs syndrome.

[0298] Another object of the present invention is to provide a crystal of the compound of formula (I) of the present invention (e.g., crystal I, crystal II, crystal III or any combination thereof), a pharmaceutical composition or a pharmaceutical preparation for the treatment of Parkinson's disease and restless legs syndrome.

[0299] Another object of the present invention is to provide a method for treating Parkinson's disease and restless legs syndrome, which comprises administering to an individual in need thereof a therapeutically effective amount of a crystal of the compound of formula (I) of the present invention (e.g., Crystal I, Crystal II, Crystal III or any combination thereof of the compound of formula (I)), a pharmaceutical composition or a pharmaceutical preparation.

[0300] Administration of the compounds of the present invention in pure form or in the form of a suitable pharmaceutical composition can be carried out by any accepted mode of administration that provides agents with similar utilities. The pharmaceutical composition of the present invention can be prepared by combining the compounds of the present invention or their salts with a suitable pharmaceutically acceptable carrier.

[0301] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods and the like.

[0302] Typical routes of administration of the compounds of the present invention or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0303] In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable carriers, excipients, and / or media well known in the art. These carriers, excipients, and media enable the compounds of the present invention to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0304] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules to obtain tablets or dragee cores. Beneficial effects

[0305] The crystals of the present invention have high drug loading capacity and stable physicochemical properties, which facilitate drug development. For example, the crystals of the present invention can effectively avoid pore formation during the development of microsphere formulations, thereby preventing the sudden release of drugs in the body and the adverse effects of increased blood drug concentrations.

[0306] Example

[0307] The present invention is further described below through examples. The examples of the present invention are only used to illustrate the technical solutions of the present invention and are not used to limit the scope of the present invention. Those skilled in the art may make some non-essential improvements and adjustments, which still fall within the scope of protection of the present invention.

[0308] Test instrument information and methods used in the experiment:

[0309] The test conditions of X-ray powder diffraction (XRPD) are:

[0310] An X`Pert3 Powder diffractometer was used, which employed Cu-palladium irradiation and absolute scan detection at room temperature. The detection range was 3.5° to 40°, with a step size of 0.013, a dwell time of 50 s, and one scan.

[0311] The Raman spectroscopy test conditions are as follows: Thermo Fisher Nicolet iS50 FT-Raman was used. The instrument uses a laser wavelength of 1063nm to directly focus and scan the sample with a resolution of 8cm -1 , scan times 128 times, sampling gain 1.0, moving mirror speed 0.3165, aperture 50.00.

[0312] Liquid chromatography detection instrument: Agilent 1260 HPLC

[0313] HPLC experimental conditions are as follows:

[0314] All solvents used in this disclosure were commercially available and used without further purification.

[0315] Example 1. Preparation of Crystal III of Compound of Formula (I)

[0316] Weigh 20g (0.095mol) of pramipexole and 18.3g (0.047mol) of pamoic acid, add them to a round-bottomed flask, add 125ml of dimethyl sulfoxide, dissolve and add 125ml of acetonitrile, and stir for 60 minutes. Add 375ml of acetonitrile dropwise, finish dripping, stir at room temperature for 2h, filter, and collect the solid. XRPD detection is carried out on the solid, and the obtained XRPD pattern is shown in Figure 3. That is, Crystal III of compound of formula (I) of the present invention. Raman spectroscopy detection is carried out on the solid, and the obtained Raman spectrum is shown in Figure 6.

[0317] Example 2. Preparation of Crystal II of Compound of Formula (I)

[0318] Weigh 20g (0.095mol) of pramipexole and 18.3g (0.047mol) of pamoic acid, add them to a round-bottom flask, add 125ml of dimethyl sulfoxide, dissolve and add 125ml of acetonitrile, and stir for 60 minutes. Add 375ml of acetonitrile dropwise, finish dripping, stir at room temperature for 2h, filter, collect the filter cake, beat with 400ml of acetonitrile at room temperature for 2h, filter, and collect the solid. XRPD detection is performed on the solid, and the obtained XRPD pattern is shown in Figure 2. This is Crystal II of Formula (I) compound of the present invention. Raman spectroscopy detection is performed on the solid, and the obtained Raman spectrum is shown in Figure 5.

[0319] Example 3. Another preparation of crystal II of compound of formula (I)

[0320] Weigh 20g (0.095mol) of pramipexole and 18.3g (0.047mol) of pamoic acid, add them to a round-bottomed flask, add 125ml of dimethyl sulfoxide, add 125ml of ethyl acetate after the solution is clear, and stir for 60 minutes. Add 375ml of ethyl acetate dropwise, finish dripping, stir at room temperature for 2h, filter, collect the filter cake, use 400ml of acetonitrile to beat pulp at room temperature for 2h, filter, and collect the solid. XRPD detection is carried out on the solid, and the obtained XRPD pattern is shown in Figure 2. That is, Crystal II of Formula (I) compound of the present invention. Raman spectroscopy detection is carried out on the solid, and the obtained Raman spectrum is shown in Figure 5.

[0321] Example 4. Preparation of Crystal I of Compound of Formula (I)

[0322] Weigh 20g (0.095mol) of pramipexole and 18.3g (0.047mol) of pamoic acid, add them to a round-bottom flask, add 125ml of dimethyl sulfoxide, add 125ml of acetonitrile after dissolving, and stir for 60 minutes. Add 375ml of acetonitrile dropwise, stir at room temperature for 2h, filter, collect the filter cake, slurry with 400ml of acetonitrile at room temperature for 2h, filter, and collect the solid. Dry the solid under vacuum at 80°C to obtain the final solid. The final solid is subjected to XRPD detection, and the obtained XRPD spectrum is shown in Figure 1. This is crystal I of the compound of formula (I) of the present invention. Raman spectroscopy is performed on the solid, and the obtained Raman spectrum is shown in Figure 4. By gas chromatography (GC) detection, acetonitrile is <0.04% and DMSO is <0.5%.

[0323] Example 5. Microcrystalline electron diffraction (MicroED) test of crystal I of compound of formula (I)

[0324] The crystal I of the compound of formula (I) was subjected to microcrystalline electron diffraction (MicroED) test, and the data were obtained using Talos F200C (operating voltage 200kV, corresponding electron wavelength ) Cryo-electron microscopy was used in conjunction with a Ceta-D camera (Thermo Fisher Scientific), and the data collection software used was EPU-D (Version 1.4.0.125REL).

[0325] After the quality of the microcrystals was inspected using a polarizing microscope Axio Scope 5 POL (Ziess), microcrystals with high diffraction resolution were selected for MicroED data collection. During the test, the microcrystals were irradiated with a parallel electron beam (NanoProbe mode), and the Ceta-D camera collected MicroED data of the microcrystals in continuous exposure mode. XDS software was used to complete the diffraction point indexing, unit cell parameter determination, and diffraction intensity integration, and the XSCALE program was used to complete the data merging to obtain the final diffraction data file. During the crystal structure analysis process, the atomic scattering factor of electrons (waves) was used for theoretical structure factor calculation, and the SHELXD (Dual space recycling algorithm) software was used to complete the structure analysis and obtain the initial structure model. The SHELXL program (least squares method) was used to complete the structure refinement, and the results are shown in Figure 7.

[0326] The results of structural refinement show that the structure belongs to the monoclinic system, the space group is P21 (no.4), and the unit cell parameters are α=90°, β=109.52(17)°, γ=90°, The minimum asymmetric unit (see Figure 7 for the ellipsoidal representation of the target molecule in the minimum asymmetric unit) contains one pamoic acid molecule and two pramipexole molecules, with each unit cell containing two minimum asymmetric units. The statistical parameters after convergence of the structural refinement were R1 = 0.1270, wR2 = 0.2926, and S = 1.1077.

[0327] Example 6. Preparation of known crystals of the compound of formula (I)

[0328] Referring to the method for preparing Crystal P in Example 16 of PCT / CN2021129537, 5.0 g of pramipexole and 4.6 g of pamoic acid were weighed and placed in 200 mL of acetonitrile. The temperature was raised and lowered in a cycle of 40°C-10°C, magnetically stirred for 24 hours, and filtered. XRPD analysis of the solid confirmed that it was Crystal P. This is a known crystalline form of the compound of formula (I) of the present invention. Gas chromatography (GC) analysis revealed an acetonitrile content of approximately 13%.

[0329] Example 7. Stability test of crystal I of compound of formula (I)

[0330] Crystal I prepared in Example 4 and the known crystal P prepared in Example 6 were tested for stability under conditions of high temperature, high humidity, light, and shade. The results showed that Crystal I was relatively stable under these conditions. The results are shown in the following table:

[0331] Crystals I prepared in Example 4 were tested for stability at 40°C and 25°C with packaging materials. The results showed that Crystals I were relatively stable at both 40°C and 25°C. Pharmaceutical low-density polyethylene bags were used as the inner packaging for contact with the drug powder, and polyester / aluminum / polyethylene composite film bags were used as the outer packaging. The results are shown in the following table:

[0332] Example 8. Pharmacokinetic Study of Microspheres of Crystal I and Known Crystal P of Formula (I) in Rats

[0333] Crystal I prepared in Example 4 and known crystal P prepared in Example 6 were prepared into microspheres using the single emulsification method according to the same steps, and the pharmacokinetic parameters of the microspheres prepared from the two crystal forms in rats were compared.

[0334] Experimental Methods: Sixteen male rats were randomly divided into two groups according to body weight and administered intramuscularly 4 mg / kg of microspheres containing crystals of compound I and microspheres containing known crystals of compound P. The day of administration was designated as day 0, and 0.25 ml of blood (EDTA-K2) was collected from the jugular vein before administration and at 5 minutes, 15 minutes, 30 minutes, 2 hours, 4 hours, 6 hours, 8 hours, 1 day, 3 days, 5 days, 7 days, 9 days, 11 days, 13 days, 15 days, 21 days, 28 days, 35 days, and 42 days after administration.

[0335] The collected whole blood was centrifuged at 1500 g for 10 min within 1 h to separate the plasma (4° C.). The blood drug concentration of the plasma samples after administration was measured and the drug-time curve was fitted, as shown in FIG8 .

[0336] Microspheres prepared from known crystal P release the drug rapidly in vivo, resulting in excessively high blood drug concentrations. Further electron microscopic scanning of the microspheres prepared from known crystal P is shown in Figure 9 . As shown in Figure 9 , the microspheres prepared from known crystal P have surface pores, leading to rapid drug release and high blood drug concentrations. In contrast, microspheres prepared from crystal I of the present invention exhibit a slower release rate in vivo and possess better drugability.

[0337] The above specific embodiments further describe the present invention in detail, but this should not be understood as limiting the scope of the present invention to the listed embodiments. All technical solutions implemented based on the content of the present invention fall within the scope of the present invention.

Claims

1. Crystal I of a compound of formula (I), wherein The compound of formula (I) has the following structure: The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 12.7±0.2°, 13.7±0.2° and 14.7±0.2°; Preferably, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) further comprises one or more diffraction peaks at 2θ angles of about 11.9±0.2° and 21.0±0.2°; and / or The X-ray powder diffraction pattern of the crystal I of the compound of formula (I) further includes one or more diffraction peaks at 2θ angles of about 15.3±0.2°, 18.3±0.2°, and 19.8±0.2°; Even more preferably, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) includes diffraction peaks at 2θ angles of about 6.0±0.2°, 10.5±0.2°, 11.9±0.2°, 12.7±0.2°, 13.7±0.2°, 14.7±0.2°, 15.3±0.2°, 18.3±0.2°, 19.8±0.2° and 21.0±0.2°; Even more preferably, the X-ray powder diffraction pattern of the crystal I of the compound of formula (I) comprises a peak at an angle of 2θ substantially the same as that shown in FIG1 ; Even more preferably, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) is substantially as shown in Figure 1; Most preferably, the X-ray powder diffraction pattern of crystal I of the compound of formula (I) is as shown in FIG1 .

2. The crystal I of the compound of formula (I) according to claim 1, wherein The Raman spectrum of the crystal I of the compound of formula (I) includes Raman shift characteristic peaks at one or more of approximately 3060±2 cm-1, 2934±2 cm-1, 1617±2 cm-1, 1523±2 cm-1, 1367±2 cm-1, 1271±2 cm-1, 722±2 cm-1 and 695±2 cm-1; Preferably, the Raman spectrum of the crystal I of the compound of formula (I) further includes Raman shift characteristic peaks at one or more of about 1578±2cm-1, 1444±2cm-1, 1029±2cm-1 and 425±2cm-1; Preferably, the Raman spectrum of the crystal I of the compound of formula (I) comprises Raman shift characteristic peaks substantially the same as those shown in FIG4 ; Preferably, the Raman spectrum of the crystal I of the compound of formula (I) is substantially as shown in FIG4 ; More preferably, the Raman spectrum of the crystal I of the compound of formula (I) is shown in FIG4 .

3. Crystal I of the compound of formula (I) according to claim 1 or 2, wherein The crystal I is a non-solvate crystal; Preferably, the crystal I is an anhydrous crystal.

4. The crystal I of the compound of formula (I) according to any one of claims 1 to 3, wherein The crystal I is a monoclinic system with a space group of P21 (n°.4) and a unit cell parameter of α=90°, β=109.52(17)°, γ=90°, 5. Crystal II of the compound of formula (I), wherein The compound of formula (I) has the following structure: The X-ray powder diffraction pattern of the crystal II of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.9±0.2°, 10.7±0.2°, 11.0±0.2°, 13.4±0.2°, 14.8±0.2° and 18.4±0.2°; Preferably, the X-ray powder diffraction pattern of the crystal II of the compound of formula (I) further includes one or more diffraction peaks at 2θ angles of about 6.5±0.2°, 10.2±0.2°, 12.5±0.2°, 14.5±0.2°, 17.7±0.2° and 22.2±0.2°; More preferably, the X-ray powder diffraction pattern of the crystal II of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.9±0.2°, 6.5±0.2°, 10.2±0.2°, 10.7±0.2°, 11.0±0.2°, 12.5±0.2°, 13.4±0.2°, 14.5±0.2°, 14.8±0.2°, 17.7±0.2°, 18.4±0.2° and 22.2±0.2°; Even more preferably, the X-ray powder diffraction pattern of the crystal II of the compound of formula (I) comprises a peak at an angle of 2θ substantially the same as that shown in FIG2 ; Even more preferably, the X-ray powder diffraction pattern of the crystal II of the compound of formula (I) is substantially as shown in Figure 2; Most preferably, the X-ray powder diffraction pattern of crystal II of the compound of formula (I) is as shown in FIG2 .

6. Crystal II of the compound of formula (I) according to claim 5, wherein The Raman spectrum of the crystal II of the compound of formula (I) includes Raman shift characteristic peaks at one or more of approximately 3054±2cm-1, 2935±2cm-1, 2254±2cm-1, 1621±2cm-1, 1590±2cm-1, 1515±2cm-1, 1441±2cm-1, 1400±2cm-1, 1369±2cm-1, 1270±2cm-1, 1168±2cm-1, 1028±2cm-1, 723±2cm-1, 696±2cm-1, 424±2cm-1 and 393±2cm-1; Preferably, the Raman spectrum of the crystal II of the compound of formula (I) comprises Raman shift characteristic peaks substantially the same as those shown in FIG5 ; Preferably, the Raman spectrum of the crystal II of the compound of formula (I) is substantially as shown in FIG5 ; More preferably, the Raman spectrum of the crystal II of the compound of formula (I) is as shown in FIG5 .

7. Crystal III of the compound of formula (I), wherein The compound of formula (I) has the following structure: The X-ray powder diffraction pattern of the crystal III of the compound of formula (I) includes diffraction peaks at 2θ angles of approximately 5.9±0.2°, 13.4±0.2°, 14.8±0.2°, 18.4±0.2°, 22.4±0.2° and 24.1±0.2°; Preferably, the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) further includes one or more diffraction peaks at 2θ angles of about 6.4±0.2°, 10.0±0.2°, 10.2±0.2°, 10.6±0.2°, 10.9±0.2°, 11.2±0.2°, 12.7±0.2° and 16.2±0.2°; More preferably, the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) includes diffraction peaks at 2θ angles of about 5.9±0.2°, 6.4±0.2°, 10.0±0.2°, 10.2±0.2°, 10.6±0.2°, 10.9±0.2°, 11.2±0.2°, 12.7±0.2°, 13.4±0.2°, 14.8±0.2°, 16.2±0.2°, 18.4±0.2°, 22.4±0.2° and 24.1±0.2°; Even more preferably, the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) comprises a peak at an angle of 2θ substantially the same as that shown in FIG3 ; Even more preferably, the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) is substantially as shown in Figure 3; Most preferably, the X-ray powder diffraction pattern of the crystal III of the compound of formula (I) is as shown in FIG3 .

8. The crystal III of the compound of formula (I) according to claim 7, wherein The Raman spectrum of the crystal III of the compound of formula (I) includes Raman shift characteristic peaks at one or more of about 3051±2 cm-1, 2999±2 cm-1, 2915±2 cm-1, 1620±2 cm-1, 1583±2 cm-1, 1441±2 cm-1, 1399±2 cm-1, 1368±2 cm-1, 1312±2 cm-1, 1270±2 cm-1, 1168±2 cm-1, 1028±2 cm-1, 722±2 cm-1, 695±2 cm-1, 672±2 cm-1, 424±2 cm-1 and 335±2 cm-1; Preferably, the Raman spectrum of the crystal III of the compound of formula (I) comprises Raman shift characteristic peaks substantially the same as those shown in FIG6 ; Preferably, the Raman spectrum of the crystal III of the compound of formula (I) is substantially as shown in FIG6 ; More preferably, the Raman spectrum of the crystal III of the compound of formula (I) is as shown in FIG6 .

9. A pharmaceutical composition comprising: i) Any one or more of the following substances: Crystal I of the compound of formula (I) according to any one of claims 1 to 4; Crystal II of the compound of formula (I) according to claim 5 or 6; Crystal III of the compound of formula (I) according to claim 7 or 8; ii) one or more pharmaceutically acceptable carriers.

10. A pharmaceutical preparation comprising: i) Any one or more of the following substances: Crystal I of the compound of formula (I) according to any one of claims 1 to 4; Crystal II of the compound of formula (I) according to claim 5 or 6; Crystal III of the compound of formula (I) according to claim 7 or 8; ii) one or more pharmaceutically acceptable carriers; Preferably, the pharmaceutical preparation is microspheres.

11. Use of any one or more of the following substances in the preparation of a medicament, in particular for the preparation of a medicament for the treatment of Parkinson's disease and restless legs syndrome: Crystal I of the compound of formula (I) according to any one of claims 1 to 4; Crystal II of the compound of formula (I) according to claim 5 or 6; Crystal III of the compound of formula (I) according to claim 7 or 8; The pharmaceutical composition according to claim 9; or The pharmaceutical preparation according to claim 10.

12. A method for preparing the crystal III according to claim 7 or 8, comprising the following steps: Dissolving any solid form of the compound of formula (I) in an organic solvent I, or dissolving any solid form of the compound of formula (II) and an organic acid in an organic solvent I; Add anti-solvent to precipitate the solid and obtain crystal III. in, The organic acid is pamoic acid; Preferably, The organic solvent I is dimethyl sulfoxide.

13. The method of claim 12, wherein: The molar ratio of the compound of formula (II) to the organic acid is 1:1-5:1; preferably 2:1; and / or The mass volume ratio (g:ml) of the compound of formula (II) to the organic solvent I is 1:1-1:10; preferably 1:5-1:8; and / or The anti-solvent is one or more of acetonitrile, acetone, butanone, ethyl acetate, isopropyl acetate, isopropyl ether, and methyl tert-butyl ether; preferably acetonitrile or ethyl acetate.

14. A method for preparing Crystal II according to claim 5 or 6, comprising the following steps: suspending the crystal III as claimed in claim 7 or 8 in an organic solvent II to obtain crystal II; or Washing the crystal III according to claim 7 or 8 with an organic solvent III to obtain a crystal II; Preferably, The organic solvent II is one or more of acetonitrile, acetone, ethyl acetate, and methyl tert-butyl ether; preferably acetonitrile; and / or The organic solvent III is one or more of acetonitrile, acetone, ethyl acetate, and methyl tert-butyl ether; preferably acetonitrile.

15. The method of claim 14, wherein: The suspending of the crystal III according to claim 7 or 8 in the organic solvent II is carried out for 0.5-6 hours; preferably for 1-2 hours; and / or The washing of the crystal III as claimed in claim 7 or 8 with the organic solvent III is performed 1-10 times, preferably 3-5 times.

16. A method for preparing the Crystal 1 according to any one of claims 1 to 4, comprising the following steps: Drying the crystal II according to claim 5 or 6 to obtain crystal I; Preferably, The drying of the crystal II according to claim 5 or 6 is carried out under vacuum conditions; and / or The crystal II as claimed in claim 5 or 6 is dried at 20°C-100°C, preferably at 50°C-90°C.

Images